Recommendations from Centers for Disease Control and Prevention,

Guidelines for Prevention and Treatment of Opportunistic Infections among HIV-Infected Children
Recommendations from Centers for Disease Control and Prevention, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics

About This Presentation
These slides were developed using the April 2008 Guidelines. The intended audience is clinicians involved in the care of patients with HIV. Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. Expert opinion should be sought for complex treatment regimens. – AETC NRC July 2009

Contents Introduction (slide 7) Bacterial infections (slide 13)
Serious and recurrent bacterial infections, bartonellosis, syphilis Mycobacterial infections (slide 45) TB, MAC Fungal infections (slide 76) Aspergillosis, candidiasis, coccidiomycosis, cryptococcosis, histoplasmosis, PCP Parasitic infections (slide 138) Cryptosporidiosis/microsporidiosis, malaria, toxoplasmosis Viral infections (slide 167) CMV, HBV, HCV, HHV-6/7, HHV-8, HSV, HPV, PML, VZV July 2009

Diagnosis of HIV in HIV-Exposed Infants
HIV infected: HIV positive by HIV DNA or RNA PCR on 2 separate samples or If >18 months and not breast-fed, positive by either antibody or PCR Presumptive exclusion of HIV infection: a child who has not been breast-fed is presumptively uninfected if they have no clinical or laboratory evidence of HIV infection and have two negative virologic tests, both of which are obtained at greater than two weeks of age and one of which is obtained at greater than four weeks of age. A definitive lack of infection is confirmed by having two negative viral tests both of which are obtained at greater than one month of age and one of which is attained greater than four months of age. July 2009

ART and Management of OIs
Highly active antiretroviral therapy (ART) reduces the incidence of OIs and improves survival independent of antimicrobial prophylaxis ART does not replace the need for OI prophylaxis in children with severe immunosuppression ART in the setting of acute or latent OIs can lead to immune reconstitution inflammatory syndrome (IRIS) July 2009

Immune Reconstitution Inflammatory Syndrome (IRIS)
Definition: temporarily worsening of symptoms of inflammation or infection related to starting ART Occurs after initiation of ART as immunity is restored Results from an exaggerated immune response (eg, activation of latent or occult TB) Treatment consists of nonsteroidal antiinflammatory drugs for moderate cases and corticosteroids for severe cases In adults, IRIS has been most frequently observed following initiation of treatment of individuals with mycobacterial infections, PCP, cryptococcal infection, CMV, Herpes zoster or other herpes virus infections, and hepatitis B and C, toxoplasmosis and progressive multifocal leukoencephalopathy. It is also been described in children following BCG administration. The ideal time to initiate HAART in the setting of IRIS is not known. Delaying HAART to avoid IRIS may increase the risk of rapid and fatal progression of HIV disease. July 2009

Introduction Mother-to-child transmission of OI is an important mode of acquisition HIV-infected women coinfected with OI are more likely to transmit (eg, CMV, HCV) HIV-infected women or HIV-infected family members are sources of horizontal transmission (eg, TB) An important mode of acquisition of opportunistic infections and HIV infection among children is from an infected mother to her child. HIV-infected women co-infected with opportunistic pathogens might be more likely to transmit these infections to their infants than women without HIV infection. For example, greater rates of perinatal transmission of hepatitis C and cytomegalovirus have been reported from HIV-infected than uninfected women. In addition, HIV-infected women or HIV-infected family members co-infected with certain opportunistic pathogens might be more likely to transmit these infections horizontally to their children, resulting in an increased likelihood of primary acquisition of such infections in the young child. For example, Mycobacterium tuberculosis infection among children primarily reflects acquisition from family members with active tuberculosis (TB) disease. An increase in the incidence and prevalence of tuberculosis among HIV infected persons is well documented. July 2009

Differences between Adults and Children
OI in children often reflects primary infection rather than reactivation OI occurs at a time when infant’s immune system is immature Different disease manifestations (eg, children more likely to have nonpulmonic and disseminated TB) Classical features of infection may not be present July 2009

Difficulty of Diagnosing OI in Children
Inability to describe symptoms Antibody-based tests confounded by maternal transfer of antibody Sputum difficult to obtain without invasive procedures July 2009

Frequency of OI among HIV-Infected Children
Pre-HAART era, most common OIs occurring at >1 events/100 child years Serious bacterial infections (bacteremia and pneumonia), herpes zoster, Pneumocystis jiroveci (carinii) pneumonia, candidiasis, Mycobacterium avium complex Pre-HAART era, most common OIs occurring at <1 events/100 child years Cytomegalovirus, toxoplasmosis, cryptosporidiosis, TB, systemic fungal infections The frequency of different opportunistic pathogens among HIV-infected children in the pre-HAART era varied by age, pathogen, previous opportunistic infection, and immunologic status. In the pre-HAART era, the most common opportunistic infections among children in the United States (event rates >1.0/100 child-years) were serious bacterial infections (with pneumonia, often presumptively diagnosed, and bacteremia being most common), herpes zoster, disseminated Mycobacterium avium complex (MAC), Pneumocystis jiroveci (formerly carinii) pneumonia (PCP), and candidiasis (esophageal and tracheobronchial disease). Less commonly observed opportunistic infections (event rate <1.0/100 child-years) included cytomegalovirus disease, cryptosporidiosis, tuberculosis, systemic fungal infections, and toxoplasmosis. July 2009

Changes in Frequency of OI among HIV-Infected Children
Infection Pre-HAART Rate per 100 Child Years Post-HAART Rate per 100 Child Years Bacterial pneumonia 11.1 2.2 Herpes zoster 2.9 1.1 Disseminated Mycobacterium avium 1.8 0.14 Pneumocystis jiroveci 1.3 0.09 July 2009

Treating OI among HIV-Infected Children
Rating of treatment recommendations is based on opinion of working group Letter indicating strength of recommendation (eg, A, B, C) Roman numeral indicating nature of evidence (eg, I, II, III) Each treatment recommendation is accompanied by a rating that includes a letter and a Roman number and is similar to the rating systems used in other USPHS/IDSA guidelines. The letter indicates the strength of the recommendation, which is based on the opinion of the Working Group, and the Roman numeral reflects the nature of the evidence supporting the recommendation. Multiple drug interactions between drugs to treat OI and HIV have increased toxicity and may limit the choice of ARVs for treatment. OIs continue to occur in children with drug resistance and/or treatment failure. Immune reconstitution inflammatory syndrome (IRIS) may be seen in children following treatment of HIV with HAART. July 2009

Serious Recurrent Bacterial Infections: Epidemiology
Most common infection in pre-HAART era (15/100 child years) Because of difficulties in obtaining appropriate diagnostic specimens, bacterial pneumonia is often a presumptive diagnosis in a child with fever, pulmonary symptoms, and an abnormal chest radiogram Bacteremia more common in HIV-infected children with pneumonia In an evaluation of opportunistic infections diagnosed in approximately 3,000 HIV-infected children participating in Pediatric AIDS Clinical Trials Group protocols in the pre-HAART era, serious bacterial infections were the most commonly diagnosed infection, with an event rate of 15/ 100 child-years. Pneumonia was the most common bacterial infection (11 per 100 child-years), followed by bacteremia (three/100 child-years), and urinary tract infection (two/100 child-years). Other serious bacterial infections, including osteomyelitis, meningitis, abscess, and septic arthritis, occurred at rates <0.2/100-child years. July 2009

Serious Recurrent Bacterial Infections: Epidemiology (2)
Bacteria isolated include Streptococcus pneumoniae, Haemophilus influenzae type B, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, nontyphoid Salmonella S pneumoniae accounts for >50% of bacteremia Incidence of S pneumoniae and H influenzae may be lower in regions where vaccines are administered In studies from Malawi and South Africa of approximately 600 children (36% HIV-infected) with acute bacterial meningitis, HIV-infected children were substantially more likely than those without HIV infection to have S. pneumoniae as the cause of their meningitis (58% and 74% of HIV-infected children in Malawi and South African studies, respectively, compared with 32% and 29% in children without HIV infection). The high incidence of invasive pneumococcal infections among HIV-infected children does not appear to be caused by increased rates of asymptomatic colonization with S. pneumoniae. July 2009

Serious Recurrent Bacterial Infections: Epidemiology (3)
Increased risk of Haemophilus influenzae B, invasive meningococcal disease Gram-negative bacteremia more common in children with advanced disease Case mortality with gram-negative bacteremia >40% Central venous catheter increases risk of bacterial infections July 2009

Serious Recurrent Bacterial Infections: Clinical Manifestations
Clinical presentation dependent on type of bacterial infection (eg, bacteremia, sepsis, vasculitis, septic arthritis, pneumonia, meningitis, sinusitis) Presentation similar to that of HIV-uninfected children Classical signs, symptoms, and laboratory tests may be missing in many HIV-infected children The classical signs, symptoms, and laboratory test abnormalities that usually indicate invasive bacterial infection (e.g., fever and elevated white blood cell count) are usually present but might be lacking among HIV-infected children having reduced immune competence. One third of HIV-infected children who experience acute pneumonia have recurrent episodes. July 2009

Serious Recurrent Bacterial Infections: Diagnosis
Isolation of pathogenic organism from normally sterile sites: blood, bone marrow, CSF Diagnosis of pneumonia by radiograph and physical findings Culture of catheter tips Sputum cultures may be difficult to obtain Additional studies such as ultrasound should be considered Assays for detection of bacterial antigens when available may be helpful July 2009

Serious Recurrent Bacterial Infections: Prevention
Routine use of conjugated pneumococcal and Haemophilus influenzae B vaccine (not routinely available in resource-poor countries) Avoid raw and undercooked foods, unsterilized water, unpasteurized milk products Hand washing and other precautions Avoid pets Caution with all foods when traveling July 2009

Serious Recurrent Bacterial Infections: Prevention – H influenza B
Children <5 years of age should be given H influenza B (Hib) conjugate vaccine Consider use in children >5 years Incompletely immunized children should receive 2 doses >8 weeks apart Pneumococcal conjugate vaccines (A II) >5 years: consider Hib conjugate vaccine 2 doses 1-2 months apart Children 2-59 months should receive the heptavalent pneumococcal vaccine (PCV) at 2, 4, 6, and months HIV-infected children aged <5 years should receive Hib and heptavalent pneumococcal conjugate vaccines (AII). In a placebo-controlled trial of a 9-valent pneumococcal conjugate vaccine among South African children, although vaccine efficacy was somewhat lower among children with HIV infection than those without (65% versus 85%, respectively), the incidence of invasive pneumococcal disease was substantially decreased among HIV-infected vaccine recipients. HIV-infected children aged >2 years also should receive the 23-valent pneumococcal polysaccharide vaccine (>2 months after their last conjugate vaccine dose), with a single revaccination with the pneumococcal polysaccharide vaccine 3–5 years later if the child is aged <10 years or after 5 years if the child is aged >10 years (AIII). July 2009

Serious Recurrent Bacterial Infections: Prevention – S pneumoniae
Previously unimmunized children aged 7-23 months should receive 2-3 doses of PCV Incompletely immunized children should receive 2 doses of PCV >8 weeks apart Children >2 years of age should receive 23 valent PCV (>2 months after last conjugate vaccine) Reimmunize with PCV in 3-5 years in children aged <10 years or after 5 years in children aged >10 years HIV infected children are likely to be at increased risk for meningococcal disease. Although the efficacy of conjugated meningococcal vaccine (MCV Four) and meningococcal polysaccharide vaccine (MPSV4) among HIV-infected individuals is unknown. July 2009

Serious Recurrent Bacterial Infections: Prevention
Trimethoprim sulfamethoxazole (TMP-SMX) prophylaxis reduces bacterial infection and new and recurrent episodes of malaria Atovaquone plus azithromycin provides prophylaxis for MAC as well as PCP Discontinue prophylaxis in children on ART with CD4 percentage >15% with caution IVIG was effective in preventing bacterial infection in HIV infected children with IgG levels less than 400 mg/dL but is no longer recommended if TMP-SMX prophylaxis is used. A single study showed that discontinuing antibiotic prophylaxis in children on HAART with CD4% >15 did not result in increase bacterial infections. July 2009

Serious Recurrent Bacterial Infections: Treatment
Patients with suspected serious bacterial infections should be treated empirically and promptly without waiting for laboratory results Consider local prevalence of resistance of common infectious agents Response of mildly immunodeficient children is similar to that of HIV-uninfected children July 2009

Serious Recurrent Bacterial Infections: Treatment (2)
Treat HIV-infected children outside the neonatal period with empiric therapy until cultures are available (A III) Use extended spectrum cephalosporin such as ceftriaxone or cefotaxime Consider addition of azithromycin for hospitalized patients with pneumonia Add clindamycin or vancomycin if MRSA is suspected Neutropenic children should also be treated an anti-pseudomonal drug such as ceftazidime or imipenem. Initial empiric therapy of HIV-infected children with suspected catheter sepsis should include coverage for both gram-positive and enteric gram-negative organisms such as using ceftazidime. July 2009

Serious Recurrent Bacterial Infections: Treatment Failure
Consider bacterial resistance if treatment failure occurs Consider nonbacterial cause such as TB, PCP, meningitis (Cryptococcus or TB) Look for catheter-related infections Occult abscess July 2009

Bartonellosis: Epidemiology
Bartonella henselae and Bartonella quintana are primary species causing bacillary angiomatosis and peliosis Bartonella bacteremia also occurs in HIV-infected individuals but is relatively uncommon in HIV-infected children Bartonella henselae is associated with cat scratch disease in the general population July 2009

Bartonellosis: Epidemiology (2)
Household cat is the primary vector Eradication of flea infestation may be important in preventing infection, as contamination of cat claws is a possible mechanism of human infection 90% of patients with cat scratch disease have a history of recent contact with cats The vector for Bartonella quintana is the human body louse July 2009

Bartonellosis: Clinical Manifestations
Clinical manifestations determined by host response Localized disease consisting of suppurative regional lymphadenopathy is most common in patients with an intact immune system Systemic infection is more common among immunocompromised individuals July 2009

Bartonellosis: Clinical Manifestations – Bacillary angiomatosis
Rare disorder occurring in severely immunocompromised individuals Characterized by cutaneous and subcutaneous angiomatous papules Can be confused with Kaposi sarcoma Nodules may be observed in the subcutaneous tissue and can erode to the skin July 2009

Bartonellosis: Clinical Manifestations – Bacillary peliosis
Characterized by angiomatous masses in the visceral organs The liver is most frequently infected Individuals with bacillary peliosis and bacillary angiomatosis may have relapsing fevers Dissemination can result in osteomyelitis, endocarditis, encephalopathy, seizures, neuroretinitis, and transverse myelitis Nonspecific symptoms include fever, chills, night sweats, anorexia, weight loss, abdominal pain, vomiting, and diarrhea July 2009

Bartonellosis: Diagnosis
Diagnosis usually made by means of a biopsy with demonstration of small gram-negative bacilli Isolated with difficulty from blood and tissue culture Indirect fluorescent antibody and enzyme immunoassay tests are available at some laboratories Cross-reactivity among Bartonella species and other bacteria is common PCR is the most sensitive means of diagnosis July 2009

Bartonellosis: Prevention
Reduce exposure to cats and cat fleas Treat infestations of body lice Consider risk of ownership of cats, especially for individuals who are severely immunocompromised July 2009

Bartonellosis: Treatment
Treatment of cat scratch disease in immunocompetent individuals is mainly supportive In vitro and in vivo antibiotic susceptibilities do not correlate well with efficacy Drug of choice is erythromycin or doxycycline Clarithromycin and azithromycin treatment has been associated with clinical responses July 2009

Bartonellosis: Treatment (2)
Severe disease requires IV administration Treatment should be given for 3 months for bacillary angiomatosis and 4 months for bacillary peliosis central nervous system disease, osteomyelitis and other severe systemic infections Add rifampin to either erythromycin or doxycycline for severely infected immunocompromised individuals Doxycycline has better central nervous system penetration. Endocarditis is most commonly caused by B quintana followed by B hensalae. For suspected culture negative endocarditis, 14 days of aminoglycoside treatment accompanied by ceftriaxone (to adequately treat other potential causes of culture negative endocarditis) with or without doxycycline for six weeks is recommended. (BII) four documented culture positive endocarditis doxycycline for six weeks plus gentamicin intravenously for the first 14 days is recommended. (BII) July 2009

Bartonellosis: Treatment Failure
Immunocompromised individuals who experience treatment failure should be re-treated for 4-6 months Immunocompromised HIV-infected adults who experience relapse have been treated with long-term suppression with doxycycline or a macrolide when CD4 counts are <200 cells/µL There are no data for children July 2009

Syphilis: Epidemiology
Perinatal transmission of Treponema pallidum at any stage of pregnancy or during delivery Illicit drug use during pregnancy increases risk of maternal and congenital syphilis Rate of congenital syphilis 50 times greater among infants born to HIV-infected mothers Half of new infections are in women years of age Half of all new HIV infections in the United States occur among persons aged 15–24 years, with most infections transmitted sexually. In addition, approximately two thirds of the sexually transmitted diseases diagnosed annually in the United States occur among persons aged <24 years. As a result, the prevalence and incidence of syphilis among HIV-infected youth and of HIV infection among youth with syphilis is expected to be higher than the general population. In a study of 320 HIV-infected and uninfected adolescents aged 12–19 years in the United States, the prevalence of syphilis was 9% among HIV-infected girls and 6% among HIV-infected boys. In a meta-analysis of 30 studies, the median HIV seroprevalence among persons infected with syphilis in the United States was 15.7% (27.5% among men and 12.4% among women with syphilis). July 2009

Syphilis: Clinical Manifestations
Untreated early syphilis in pregnancy leads to spontaneous abortion, stillbirth, hydrops, preterm delivery, death in up to 40% of pregnancies 47% of infants born to mothers with inadequately treated syphilis have clinical, radiographic, or laboratory findings consistent with congenital syphilis July 2009

Syphilis: Clinical Manifestations (2)
60% of infants with congenital syphilis have hepatomegaly, jaundice, skin rash, nasal discharge, anemia, thrombocytopenia, osteitis, periostitis, osteochondritis, or pseudoparalysis Late manifestations include mental retardation, keratitis, deafness, frontal bossing, Hutchinson teeth, saddle nose, Clutton joints July 2009

Syphilis: Diagnosis Use combination of physical, radiologic, serologic, and direct microscopic results, as standard serologic tests detect only IgG All infants born to mothers with reactive nontreponemal and treponemal tests should be evaluated with a quantitative nontreponemal test (eg, slide test, RPR, automated reagin test) July 2009

Syphilis: Diagnosis (2)
Darkfield microscopy or direct fluorescent antibody staining Presumptive diagnosis – any infant, regardless of physical findings, born to an untreated or inadequately treated mother with syphilis All infants born to women with reactive nontreponemal and treponemal test results should be evaluated with a quantitative nontreponemal test (e.g., VDRL slide test, rapid plasma regain (RPR), and the automated regain test). Testing should be performed on neonatal serum because of the potential for maternal blood contamination of the umbilical cord blood specimens. Performing specific treponemal tests, such as the fluorescent treponemal antibody absorption (FTA-ABS) test and T. pallidum particle agglutination (TP-PA) test, is not necessary for evaluation of congenital syphilis in the neonate. No commercially available IgM test is recommended for diagnostic use. A proven case of congenital syphilis requires the visualization of spirochetes by darkfield microscopy or fluorescent antibody testing of body fluids. A fourfold quantitative serologic titer higher than the mother’s titer is suggestive of infection. July 2009

Syphilis: Prevention – Congenital Syphilis
Routinely screen all pregnant women with serologic testing during first prenatal visit Obtain information regarding the treatment of sexual partners for sexually transmitted diseases Serologic testing of mothers serum is preferable Routine screening of newborns’ serum or umbilical cord blood is not recommended No HIV exposed infant should leave the hospital unless the maternal serologic status has been documented at least once during pregnancy and at delivery in communities where the risk of congenital syphilis is high. July 2009

Syphilis: Prevention – Acquired Syphilis
Routine discussion of sexual behaviors that place individuals at risk of syphilis and HIV Routine serologic screening for syphilis annually for all sexually active HIV-infected individuals The occurrence of syphilis in an HIV infected individual is an indication of high-risk behavior Individuals undergoing screening or treatment for syphilis should be evaluated for all sexually transmitted diseases July 2009

Syphilis: Treatment – Congenital Syphilis
Treat all infants whose mothers have untreated or inadequately treated syphilis; not treated or initiated treatment 4 weeks prior to delivery Treat if mother treated with penicillin but no 4-fold decrease in nontreponemal antibody titer, or a 4-fold increase suggesting relapse or reinfection Treat infants regardless of maternal history if examination suggests syphilis; darkfield or fluorescent antibody test positive or nontreponemal serologic titer = 4-fold higher than maternal level (A II) July 2009

Syphilis: Treatment – Congenital Syphilis (2)
Aqueous crystalline penicillin G: 100, ,000 units/kg/day given as 50,000 units/kg/dose IV Q12H for 7 days, followed by Q8H for a total of 10 days (A II) Diagnosis after 1 month of age, increase dosage to 50,000 units/kg IV Q6H for 10 days Some recommend treating asymptomatic infants born to mothers who have had adequate treatment and response to therapy with a single dose of benzathine penicillin G 50,000 units/kg/dose IM with careful clinical and serologic follow-up. July 2009

Syphilis: Treatment – Acquired Syphilis
Treat acquired syphilis with single dose of benzathine penicillin G 50,000 units/kg IM Treat late latent disease with benzathine penicillin G 50,000 units/kg IM once weekly for 3 doses (A III) Alternative therapies among HIV-infected patients have not been evaluated Treat neurosyphilis with aqueous penicillin G 200,000 to 300,000 units/kg IV Q6H for days Follow up with examinations at 1, 2, 3, 6, and 12 months and serologic tests at 3, 6, and 12 months; if titers continue to be positive or increase, consider retreatment (A III) Retreatment of patients with early-stage syphilis should be considered for those who do not experience at least a four fold decrease in serum nontreponemal antibody 6 to 12 months after therapy or those who have a sustained four fold increase in antibody titers after an initial post reduction treatment or those having persistent or recurrent clinical signs and symptoms. Patients with late latent syphilis should be retreated if they have clinical signs or symptoms of syphilis or have a fourfold increase in serum nontreponemal antibody or experience and inadequate serologic response. Retreatment of neurosyphilis should be considered if the CSF WBC count is not decreased six months after treatment completion or if the CSF-VDRL remains reactive two years after treatment. July 2009

Mycobacterium tuberculosis: Epidemiology
14,000 new cases of TB in United States in 2006 (6% among children <15 years of age) 1.1% of these were HIV infected Incidence of TB in HIV-infected children 100 times higher than in uninfected In South Africa, as many as 48% of children with TB were coinfected with HIV Incident case rates of TB disease among HIV-exposed or -infected children were reported in one study from the early 1990s to be up to 100-fold higher than those in comparably aged children in the general U.S. population. Data from international studies indicate an increased risk for TB disease among HIV-infected children; coinfection with HIV occurred in up to 48% of hospitalized South African children with culture-proven TB. In New York City, 3% of approximately 1,400 HIV-infected children and 0.5% of HIV-exposed uninfected children had active TB diagnosed during 1989–1995. July 2009

Mycobacterium tuberculosis:
Epidemiology (2) CD4 count is not a sufficient indicator of TB risk Primarily infection by contact with adults in daily environment In most cases, TB represents the progression of primary infection rather than a reactivation of disease All confirmed and suspected TB cases should be reported to health authorities Disease due to Mycobacterium bovis has reemerged in New York and California. Cases have been associated with the consumption of unpasteurized milk products. The distinction between tuberculosis species is important for determining the source of infection and treatment as M bovis isolates are resistant to pyrazinamide. July 2009

Epidemiology (3) BCG induced M tuberculosis has been reported in HIV-infected children vaccinated at birth In the United States, resistance to any of the first-line anti-TB drugs occurs in 15% of children Internationally, rate of multiple drug-resistant (MDR) TB is increasing July 2009

Epidemiology (4) Extrapulmonary and miliary TB more common in children <4 years old Congenital TB has been reported Drug-resistant TB can be transmitted Patients should be treated under assumption that drug resistance profiles of source and patient are similar Extrapulmonary and miliary TB are more common among younger children (aged <4 years) who do not have HIV infection. Younger children are also more likely to progress more rapidly from infection to active disease than older children and adults and might not be recognized as having TB disease because they might have negative skin tests and fewer symptoms of disease. Despite evidence that extrapulmonary TB occurs more frequently among HIV-infected rather than uninfected adults, this is less clear among children in areas where TB is endemic. July 2009

Mycobacterium tuberculosis: Clinical Manifestations
Younger children progress more rapidly (possibly due to delayed diagnosis) Nonspecific symptoms: fever, weight loss, failure to thrive Pulmonary TB most likely appears as infiltrate with hilar adenopathy Clinical presentation of TB similar in HIV-infected and HIV-uninfected children Extrapulmonary: marrow, lymph node, bone, pleura, pericardium, peritoneal Children with pulmonary TB might have little or no symptoms. Symptoms, when present, might be nonspecific (e.g., weight loss, fever, and failure to thrive). TB among young children rarely manifests with the typical apical lung infiltrates and late cavitation observed among adults with TB. More commonly, pulmonary TB appears as a localized pulmonary infiltrate with associated hilar lymphadenopathy. Multiple lobes are involved in up to 25% of children. Concomitant atelectasis might result from hilar adenopathy compressing bronchi or from Endobronchial granulomas. July 2009

Mycobacterium tuberculosis: Diagnosis
Difficult to diagnose; maintain a degree of suspicion M tuberculosis detected in up to 50% of gastric aspirate in HIV-uninfected children (obtain 3 consecutive morning gastric aspirates) Usually requires linking TB in child to contact along with positive radiograph, positive skin test (TST), or physical examination Because of the difficulty in obtaining a definitive culture- proven diagnosis of TB disease among children, the diagnosis of TB disease usually involves linking the child to an adult with confirmed pulmonary TB together with a positive tuberculin skin test (TST) and an abnormal radiograph or physical examination in the child. However, a negative TST result cannot exclude TB disease among children because approximately 10% of children without HIV infection but with culture-positive TB disease do not react initially to a TST. HIV infection further decreases TST reactivity. Therefore, a TST result among children, particularly HIV-infected children, is less useful than in adults. Although a positive test is useful to confirm the diagnosis, a negative test would not rule out the possibility of TB disease. July 2009

Mycobacterium tuberculosis: Diagnosis (2)
Cornerstone for latent TB is the TST TST not of value if BCG immunization has been administered Annual TB testing recommended for HIV-infected children HIV-infected children may have a negative TST Sensitivity to TST may be reduced if other viral infection, such as measles, is present July 2009

Assays for interferon gamma release following stimulation of lymphocytes have been approved by the FDA for diagnosis of TB (eg, QuantiFERON-TB) Tests for sputum using nucleic acid amplification approved but not fully evaluated in children Patients with a positive test for latent TB infection (LTBI) should have any chest radiograph and clinical evaluation to rule on active disease A definitive diagnosis of TB disease requires isolation of M. tuberculosis from expectorated sputum, bronchoalveolar lavage (BAL) fluid, aspirated gastric fluid (obtained in the early morning after the child fasts overnight), biopsied lung, peripheral lymph node or other tissue (depending on location of disease), or mycobacterial blood culture. In addition, availability of an isolate allows drug susceptibility testing to be performed. July 2009

MDR TB should be suspected in a child with TB disease if the child has: Close contact with the patient with MDR TB Contact with a TB patient who died while on treatment when there is reason to suspect MDR TB Bacteriologically proven TB that has not responded to first-line drugs Exposure to source cases that remain smear or culture positive 2 months after treatment History of living in a region with a high prevalence of MDR TB July 2009

Mycobacterium tuberculosis: Prevention
Children who are homeless, live in institutional settings, or have close family contacts in communities with high rates of coinfection with TB and HIV are particularly susceptible BCG immunization is not routinely administered in the United States and should NOT be administered to HIV-infected children because of risk of BCG dissemination Treat HIV-infected children for LTBI if they have a positive TST result July 2009

Mycobacterium tuberculosis: Prevention (2)
HIV-infected children should be treated if they are exposed to a person who has contagious TB Duration of preventive treatment for children should be 9 months with isoniazid mg/kg/day (A II) or mg/kg twice weekly (B II) If isoniazid resistance is suspected, use rifampin for 4-6 months A randomized, double-blind, controlled trial of isoniazid in HIV-infected children in South Africa was halted when isoniazid was administered daily or twice daily and found to have benefit in reducing mortality. The findings were found across all ages and classifications of AIDS and were independent of TST results. July 2009

Mycobacterium tuberculosis: Treatment
Treatment principles similar in HIV-infected and HIV-uninfected children Initiate treatment as soon as possible in children with suspected TB If already on ART, review drug interactions Use of DOT increases adherence, decreases resistance, treatment failure, and relapse Because of the high risk for dissemination among children TB treatment should be initiated as soon as the diagnosis of TB is suspected (AII). For children already receiving antiretroviral therapy who have had TB diagnosed, the child’s antiretroviral regimen should be reviewed and altered, if needed, to ensure optimal treatment for both TB and HIV and to minimize potential toxicities and drug-drug interactions (BIII). July 2009

Mycobacterium tuberculosis: Treatment (2)
Initial treatment (induction phase) 4 drugs: isoniazid, rifampin, pyrazinamide, plus either ethambutol or streptomycin (A I) If the organism is found to be susceptible to isoniazid, rifampin, and pyrazinamide during the 2-month intensive phase, ethambutol (or streptomycin) can be discontinued Use ethionamide as alternative to ethambutol for CNS disease (A III) July 2009

If clinical response occurs and organism is susceptible to isoniazid and rifampin after 2 months, continue treatment with isoniazid and rifampin 2-3 times weekly or daily during the continuation phase Children with severe immunosuppression should receive only daily or 3-times-weekly treatment during the continuation phase Ethionamide can be used as alternative to ethambutol for TB meningitis Minimum treatment is 6-9 months for children with active pulmonary TB and 12 months for extrapulmonary disease (A III) July 2009

Isoniazid Dosage: mg/kg orally once daily (maximum 300 mg daily) Hepatic toxicity increases with rifampin Peripheral neuritis, mild CNS toxicity, gastric upset July 2009

Rifampin Dosage: mg/kg orally once daily (maximum 600 mg daily) Side effects include rash; hepatitis; jaundice; GI upset; orange coloring of urine, tears, sweat Rifampin can accelerate clearance of PIs (except RTV) and NNRTIs July 2009

Rifabutin (B III) Dosage: mg/kg orally once daily Limited data in children Peripheral leukopenia, elevated liver enzymes, pseudojaundice, GI upset Increases hepatic metabolism of certain PIs: reduce rifabutin dosage by 50% when given with RTV, IDV, NFV, APV Increase dosage of rifabutin by % when given with EFV July 2009

Pyrazinamide Dosage: mg/kg orally once daily (maximum 2 g daily) Hepatic toxicity, rash, arthralgia, GI upset Ethambutol Dosage: mg/kg orally daily (maximum 2.5 g daily) Toxicity includes optic neuritis, rash, nausea July 2009

Secondary drugs Ethionamide: mg/kg orally divided into 2 or 3 doses daily (maximum dosage 1 g daily) Streptomycin: mg/kg daily IM (maximum dosage 1 g daily) Alternatives: kanamycin, amikacin, capreomycin, quinolones, cycloserine, paraaminosalicylic acid Steroids may be indicated for TB meningitis July 2009

Treatment of TB in setting of ART may be complicated by unfavorable pharmacokinetic interactions and overlapping toxicities Use of rifampin precludes treatment with protease inhibitors but may allow treatment with NNRTIs Starting treatment with NNRTIs is preferred because of fewer interactions with rifampin-based TB therapy (B II) Efavirenz is the preferred NNRTI for children >3 years of age whereas nevirapine is preferred for children <3 years of age Some experts argue that the role of rifamycins for treatment of TB is so important, the effect on protease inhibitors so unpredictable, and the subsequent risk of HIV resistance so great that antiretroviral therapy in a an antiretroviral naïve child should be deferred until completion of TB therapy. Others argue that treatment of TB in an antiretroviral naïve infected child should be initiated two to eight weeks before initiating antiretroviral medications to improve adherence and differentiate side effects. Studies in adult indicate that delaying antiretroviral treatment and coinfected individuals may increase mortality. July 2009

Children already receiving ART should receive immediate treatment for TB accompanied by a review of overlapping toxicities and drug-drug interactions Drug-resistant TB should be treated with a minimum of 3 drugs, including 2 or more bactericidal isolate-susceptible drugs Regimens may include 3-6 drugs Adjunct treatment with corticosteroids may be indicated for children with TB meningitis Children with MDR TB should be managed in consultation with infectious disease experts. Extensively drug-resistant tuberculosis (XDR TB) has emerged globally as an important new threat particularly in patients with HIV infection. XDR TB is a strain of TB resistant to isoniazid and rifampin plus additional resistance to any fluoroquinolone and greater than 1 of 3 injectable drugs. July 2009

Mycobacterium tuberculosis: Monitoring and Adverse Effects
Monthly monitoring of clinical and bacteriological responses to treatment Side effects of drugs include nausea, vomiting, hepatotoxicity, nephrotoxicity, and optic neuritis with ethambutol IRIS associated with new onset of systemic symptoms in HIV-infected individuals receiving ART Data on occurrence of IRIS in children are incomplete Treatment with corticosteroids has been used in severe cases IRIS has not been well studied in a children and incidents not well established. There are no controlled trials on the use of corticosteroids to modify the course of IRIS July 2009

Mycobacterium avium Complex Disease: Epidemiology
Multiple related species of non-TB mycobacteria: M avium, M intracellulare, M paratuberculosis Second most common OI in children after PCP but decreases in incidence with ART Associated with soil exposure and racial susceptibility Acquired by means of inhalation, ingestion, or inoculation Mycobacterium avium complex (MAC) refers to multiple related species of nontuberculous mycobacteria (e.g., M. avium, M. intracellulare, M. paratuberculosis) that are widely distributed in the environment. MAC is the cause of the second most common opportunistic infection among children with HIV infection after PCP, and is presumably acquired by common environmental exposures through inhalation, ingestion, or inoculation. Respiratory and gastrointestinal colonization can act as portals of entry that can lead to disseminated infection. July 2009

Mycobacterium avium Complex Disease: Epidemiology (2)
72% of children with isolated pulmonary MAC develop disseminated MAC by 8 months May appear as isolated lymphadenitis Frequency increases with age and declining CD4 T-cell count July 2009

Mycobacterium avium Complex Disease: Prevention
Most effective means of prevention is to preserve immune function with ART Offer prophylaxis for MAC as follows: (A II) CD4 T-cell risk factor for occurrence: <750 cells/µL <1 year; <500 cells/µL 1-2 years; <75 cells/µL 2-5 years; < 50 cells/µL >6 years Use either clarithromycin or azithromycin (A II) Studies suggest that prophylaxis may be discontinued when CD4 percentages reach 20% to 25% while on stable ART MAC can appear as isolated lymphadenitis among HIV infected children. Presentation with isolated MAC pulmonary disease is a marker of high risk for dissemination; 72% of children develop disseminated MAC within a mean time of 8 months. Disseminated infection with MAC in pediatric HIV infection rarely occurs during the first year of life; its frequency increases with age and declining CD4+ count, and it is a frequent complication of advanced immunologic deterioration among HIV-infected children. Disseminated MAC can occur at higher CD4+ cell counts among younger HIV-infected children than older children or adults, especially among children aged <2 years. Age-related CD4+ cell counts levels considered as high risk for MAC warranting consideration of prophylaxis are <750/mm3 among HIV-infected children <1 year old; <500/mm3 for children aged 1–2 years; <75/mm3 for children aged 2–6 years; and <50/mm3 for children aged >6 years. There is no available data indicating that the presence of MAC in stool or respiratory samples precedes disseminated disease. Routine screening of respiratory or gastrointestinal tract specimens for MAC is not recommended as a means of determining when prophylaxis should be initiated. July 2009

Mycobacterium avium Complex Disease: Clinical Manifestations
Recurrent fever, weight loss, failure to thrive, neutropenia, night sweats, chronic diarrhea, malabsorption, abdominal pain Lymphadenopathy, hepatomegaly, splenomegaly Respiratory symptoms uncommon among children Laboratory abnormalities include anemia, leukopenia, and thrombocytopenia July 2009

Mycobacterium avium Complex Disease: Diagnosis
Isolation of organism from biopsy, blood, bone marrow, lymph node, or other tissue Histology demonstrating macrophage containing acid-fast bacilli strongly indicates MAC Culture is essential for differentiating from TB Isolation from stool or respiratory does not necessarily indicate invasive disease July 2009

Mycobacterium avium Complex Disease: Treatment
Preserve immune function through optimal treatment of HIV infection Initiate treatment with 2 or more drugs (eg, clarithromycin or azithromycin plus ethambutol) (A I) Consider rifabutin as third drug in severely ill patients (C I) Caution in using rifabutin as it may increase toxicity of other ARVs and increase clearance of PIs and NNRTIs As with other opportunistic infections there is debate as to whether treatment with HAART should be delayed to avoid the occurrence of IRIS. July 2009

Mycobacterium avium Complex Disease: Treatment (2)
Note cautions in use of these drugs with ARVs If rifabutin cannot be used or if drug failure occurs, consider ciprofloxacin, amikacin, streptomycin, and a quinolone Lifelong suppressive therapy required after initial therapy IRIS may occur as indicated by new onset of symptoms Toxicities of drugs include nausea, vomiting, liver toxicity, hypersensitivity reactions and, with ethambutol, optic neuritis July 2009

Clarithromycin: mg/kg orally twice daily (maximum 500 mg twice daily) (A I) Azithromycin: mg/kg once daily (maximum 500 mg daily) (A II) Ethambutol: mg/kg single oral dose (maximum 1 g) (A I) July 2009

Rifabutin: mg/kg orally once daily (maximum 300 mg daily) (A I) Ciprofloxacin: mg/kg IV or orally once daily (maximum 1.5 g) Amikacin: mg/kg/day IV divided every hours (maximum 1.5 g) (C III) July 2009

Aspergillosis: Epidemiology
Aspergillus species are ubiquitous molds found in soil, on plants, and in decomposing organic materials The most common species causing aspergillosis are A fumigatus and A flavus Rare but frequently lethal infection Risk factors include low CD4 count, neutropenia, corticosteroids, concurrent malignancy with chemotherapy, HIV-related phagocytic impairment, previous respiratory infections, broad-spectrum antibiotic exposure July 2009

Aspergillosis: Clinical Manifestations
Pulmonary aspergillosis is the most common presentation Invasive pulmonary aspergillosis associated with fever, cough, dyspnea, pleuritic pain Additional manifestations include necrotizing tracheobronchitis, pseudomembranous tracheobronchitis, CNS involvement, cutaneous, sinus, middle ear and mastoid infection July 2009

Aspergillosis: Diagnosis
Usually isolated from the blood but also readily isolated from lung, sinus, brain, and skin biopsy Definitive diagnosis includes histopathologic demonstration of organisms in biopsy specimens Presumptive diagnosis of respiratory tract infection can be made if Aspergillus species is recovered from respiratory sample July 2009

Aspergillosis: Diagnosis (2)
Chest radiograph demonstrates either diffuse interstitial pneumonitis or localized wedge-shaped infiltrates CT of chest may be used to identify a “halo” sign Cavitation and air crescent formation in chest CDT more frequent in older children and adults The Halo sign is a macronodule surrounded by a perimeter of ground glass opacity which is an early sign of invasive pulmonary aspergillosis. July 2009 79

Aspergillosis: Prevention
Consider excluding plants and flowers from rooms and avoiding food items such as nuts and spices Erect suitable barriers between patient care and construction sites, clean shower heads routinely as well as hot-water faucets and air-handling systems July 2009

Aspergillosis: Treatment
Voriconazole is recommended for treatment of invasive aspergillosis Adult data indicate that voriconazole is superior to amphotericin B but data in children are limited Recommended dosage for children is 6-8 mg/kg IV (or 8 mg/kg orally) Q12H, followed by 7 mg/kg IV or orally twice daily Treatment is continued for 12 weeks Voriconazole has not been studied in HIV-infected children. It should be used cautiously when using PIs and efavirenz because of potential interactions. Amphotericin B, either conventional or lipid formulation, is an alternative regimen. Surgical excision of localized invasive lesions may be warranted. July 2009 81

Aspergillosis: Adverse Effects and Treatment Failure
Voriconazole side effects include reversible dose-dependent visual disturbances, elevated liver enzymes, and occasional skin rash Amphotericin toxicity is associated primarily with fever, chills, and nephrotoxicity Efficacy of antifungal therapy for aspergillosis is poor Experimental approaches include evaluation of caspofungin July 2009

Candida Infections: Epidemiology
Most common fungal infections in HIV-infected children Thrush and diaper dermatitis occur in 50-85% of HIV-infected children In pre-ART era, oropharyngeal candidiasis found in 94% of children with Candida esophagitis Disseminated candidiasis rare in children except those with CMV or HSV coinfection, and those with central venous catheter Disseminated candidiasis is infrequent among HIV-infected children, but Candida can disseminate from the esophagus particularly when coinfection with HSV or CMV is present. Fungemia occurs in up to 12% of HIV-infected children with chronically indwelling central venous catheters for total parental nutrition or intravenous antibiotics. Approximately 50% of reported cases of fungemia among HIV-infected children are caused by non-albicans Candida species including C. tropicalis, C. pseudotropicalis, C. parapsilosis, C. glabrata, C. krusei, and C. dubliniensis. A substantial number of children who develop fungemia have received systemically absorbed oral antifungal azole compounds (ketoconazole or fluconazole) for control of oral and esophageal candidiasis. July 2009 83

Candida Infections: Epidemiology (2)
A substantial percentage of children with fungemia receive oral, systemically absorbable azole antifungals (eg, ketoconazole) Complications include disseminated infection of bone, liver, and kidney; endophthalmitis Mortality from disseminated candidiasis >90% in children with fever and symptoms >14 days July 2009

Candida Infections: Clinical Manifestations
Thrush and erythematous, hyperplastic, and angular cheilitis Esophageal candidiasis may present with odynophagia, dysphagia, or retrosternal pain Children may develop nausea, vomiting, or weight loss and dehydration New onset of fever in individuals with central venous catheters Systemic fungemia may lead to endophthalmitis July 2009

Candida Infections: Diagnosis
Culture and KOH preparation with microscopic demonstration of budding yeast cells in wet mounts or biopsy Blood culture using lysis centrifugation “Cobblestone” appearance on barium swallow Perform endoscopy in refractory cases to look for CMV, HSV, MAC coinfections Research studies or evaluating detection of candidate antigens for early diagnosis Diagnosis of candidemia is best made with blood cultures using lysis-centrifugation techniques or automated broth based systems. When fungemia is present, retinal examination for endophthalmitis, abdominal CT or ultrasound for hepatic or renal involvement, and bone scans if osteomyelitis is clinically suspected might be appropriate. July 2009 86

Candida Infections: Prevention
Routine primary prophylaxis of candidiasis in HIV-infected children is not indicated Candida organisms are common commensals on mucosal surfaces in healthy individuals and no measures are available to reduce exposure July 2009 87

Candida Infections: Treatment
Treat early uncomplicated oropharyngeal candidiasis (OPC) with topical therapy Cotrimoxazole: 10 mg troches 4-5 times/day for 2 weeks (B II) Nystatin suspension: 4-6 mL (400, ,000 units/mL) 4 times/day Amphotericin B suspension: (100 mg/mL) 1 mL 4 times/day July 2009 88

Candida Infections: Treatment (2)
Oral systemic therapy for OPC Fluconazole: 3-6 mg/kg orally once daily for 7-14 days (A I) Itraconazole: 2.5 mg/kg orally BID for 7-14 days (A I) Ketoconazole: 5-10 mg/kg/day orally divided into 2 doses given for 14 days (D II) Amphotericin oral suspension or IV for OPC refractory to other treatment July 2009

Esophageal disease Treat both diagnosed esophageal disease and children with OPC and esophageal symptoms (A I) Initiate treatment with: Fluconazole 6 mg/kg/day orally or IV on day 1 followed by 3-6 mg/kg for days (A I) Itraconazole oral solution 2.5 mg/kg/dose given twice daily or 5 mg/kg once daily for days (A I) Consider low-dose IV amphotericin B minimum of 7 days for refractory disease (B II) July 2009

Esophageal disease Other therapies not fully evaluated in children Voriconazole: loading dose of 6 mg/kg IV Q12H on day 1, followed by 4 mg/kg Q12H thereafter; after stabilization, change to oral dosing Caspofungin: available only in IV form; <50 kg dosage range mg/kg daily; >50 kg, adult dosing July 2009

Invasive disease Remove central venous catheter Amphotericin B (A I) mg/kg once daily IV over course of 1-2 hours, administered in 5% dextrose at final concentration of 0.1 mg/mL For mild to moderate disease, begin at mg/kg and increase as tolerated to 1.5 mg/kg Once stabilized, administer 1.5 mg/kg every other day (B III) Treat for 3 weeks after last positive blood culture of symptoms July 2009

Invasive disease: alternative therapy Fluconazole in stable patients with uncomplicated candidemia without previous azole treatment (identification of Candida species essential; C krusei and C glabrata are resistant) (E III) Amphotericin lipid formulations (limited pediatric experience) Amphotericin lipid complex (ABLC, Abelcet) Liposomal amphotericin lipid complex (AmBisome) Amphotericin B cholesteryl sulfate complex (ABCD) July 2009

Treatment under development Caspofungin, micafungin, and anidulafungin have been studied in battles with HIV infection, neutropenic children at risk of fungal infection in children with documented candidiasis Data on HIV-infected children are limited July 2009 94

Amphotericin toxicity Nephrotoxicity: azotemia, hypokalemia Nephrotoxicity can be minimized by hydration with 0.9% saline intravenously 30 minutes before amphotericin B infusion Infusion-related chills, fever, and vomiting; pretreat with acetaminophen or diphenhydramine Rarely: hypotension, arrhythmias, neurotoxicity, hepatic toxicity Amphotericin undergoes renal excretion. Adverse effects of amphotericin B are primarily nephrotoxicity, defined by substantial azotemia from glomerular damage and can be accompanied by hypokalemia from tubular damage; nephrotoxicity is exacerbated by use of concomitant nephrotoxic drugs. Permanent nephrotoxicity is related to cumulative dose. Nephrotoxicity can be ameliorated by hydration with 0.9% saline intravenously over 30 minute before the amphotericin B infusion. July 2009 95

Fluconazole, itraconazole, ketoconazole toxicity Inhibition of CYP450-dependent hepatic enzymes can result in either decreased levels of azole when administered with other drugs with hepatic metabolism or increased levels of other drugs with hepatic metabolism Nausea, vomiting, rash, pruritus, Stevens-Johnson syndrome (rare), increased liver enzymes, hepatitis, leukopenia, anemia, hemolytic anemia, alopecia (fluconazole) July 2009

Candida Infections: Treatment Failure
Oral pharyngeal and esophageal candidiasis Initial failure should be treated with oral fluconazole, itraconazole, oral amphotericin B, or low-dose IV amphotericin B Invasive disease Amphotericin B lipid formulations can be used for children who cannot tolerate amphotericin B, have disseminated Candida infection that is resistance to amphotericin B, or are at risk of nephrotoxicity Amphotericin B lipid complex (ABELCET) and amphotericin B liposome (AmBisome) have been evaluated in adults but have not been well studied in HIV-infected children. July 2009 97

Coccidioidomycosis: Epidemiology
Increased risk of infection with Coccidioides immitis and Coccidioides posadasii among HIV-infected children in endemic areas (eg, southwestern United States, northern Mexico, Central and South America) Primary infection of newborn rare In utero and perinatal transmission of C immitis reported Reports of infection in nonendemic areas usually due to reactivation July 2009

Coccidioidomycosis: Clinical Manifestations
Fever and dyspnea most common presentation Chills, weight loss, lymphadenopathy, chest pain, diffuse reticulonodular pulmonary infiltrates, meningitis Disseminated disease associated with erythema multiforme; erythema nodosum; erythematous maculopapular rash; arthralgia; bone, joint, and CNS infection July 2009

Coccidioidomycosis: Diagnosis
Direct examination and culture of respiratory secretions and CSF or biopsy of lesions Blood cultures positive in 15% of cases Complement fixation assay detects IgG antibody, positive IgM assays suggest active or recent infection, complement fixation titers > 1:16 correlate with presence and severity of extrapulmonary infection IgM antibody detected by latex agglutination, enzyme immunoassay, immunodiffusion, or tube precipitin appears early and is an indication of acute infection. IgG antibody gradually appears over the first few months after primary infection and does not disappear in the presence of disseminated disease. Titers of >1:16–1:32 are associated with disseminated disease, except in cases of isolated meningitis. Serological tests (e.g., complement fixation, tube precipitation and immunodiffusion assays) might have reduced diagnostic use in severely immunosuppressed HIV infected patients. July 2009 100

Coccidioidomycosis: Prevention
Difficult to avoid exposure in endemic areas Exposure can be reduced by avoiding activities that predispose to inhalation of spores such as disturbing contaminated soil, being outdoors during dust storms IgM antibody detected by latex agglutination, enzyme immunoassay, immunodiffusion, or tube precipitin appears early and is an indication of acute infection. IgG antibody gradually appears over the first few months after primary infection and does not disappear in the presence of disseminated disease. Titers of >1:16–1:32 are associated with disseminated disease, except in cases of isolated meningitis. Serological tests (e.g., complement fixation, tube precipitation and immunodiffusion assays) might have reduced diagnostic use in severely immunosuppressed HIV infected patients. July 2009 101

Coccidioidomycosis: Treatment
Limited data in children; recommendations based on adult data Treat diffuse pulmonary disease or disseminated disease with amphotericin B dosage of mg/kg/day until clinical improvement occurs (A II) Follow with chronic suppressive fluconazole or itraconazole therapy (A II) Alterative therapy: fluconazole 5-6 mg/kg BID or itraconazole 4-10 mg/kg BID for 3 days followed by 2-5 mg/kg BID (B III) See Appendix A, page 71. July 2009 102

Coccidioidomycosis: Treatment (2)
CNS infection, including meningitis High-dose fluconazole 5-6 mg/kg BID If unresponsive to fluconazole, use IV amphotericin B augmented by intrathecal amphotericin B (C I) July 2009

Coccidioidomycosis: Monitoring, Adverse Events and Toxicity
Monitoring of complement fixing IgG antibody is useful Toxicity of antifungal drugs includes fevers, chills, nausea and vomiting, nephrotoxicity Interaction of all antifungal agents with ARVs should be investigated; fluconazole and itraconazole appear to be safe in combination with ARVs Voriconazole should be avoided in patients on PIs or NNRTIs July 2009

Cryptococcosis: Epidemiology
Most infections caused by Cryptococcosis neoformans and Cryptococcosis gattii Infection occurs primarily in tropical and subtropical areas Low incidence of infection in children, especially with use of ART Children usually infected during 6-12 year age range Usually severely immunosuppressed July 2009

Cryptococcosis: Clinical Manifestations
Meningoencephalitis most common manifestation Fever, headache, altered mental status evolving over days to weeks Acute illness with nuchal rigidity, seizures, focal neurologic signs observed in developing countries Translucent, umbilicated, papules, nodules, ulcers, infiltrated plaques seen in disseminated disease Pulmonary cryptococcosis unusual in children Pulmonary cryptococcus without dissemination is unusual among children but can present as unexplained recurrent fever, cough with scant sputum, intrathoracic lymphadenopathy, and focal or diffuse pulmonary infiltrates. It might be asymptomatic with pulmonary nodules found on routine chest radiograph. July 2009 106

Cryptococcosis: Diagnosis
Microscopic examination of CSF on India ink-stained wet mounts Detection of cryptococcal antigen in CSF, serum, bronchoalveolar lavage fluid (can be negative in culture-positive meningitis) Fungal cultures from CSF, sputum, and blood cultures can identify the organism Antigen levels useful in evaluating response to treatment and relapse Pulmonary disease diagnosed by bronchoalveolar lavage and direct examination of India ink-stained specimens July 2009

Cryptococcosis: Prevention
No proven strategies to prevent exposure Believed to be acquired by inhalation of aerosolized particles from the environment July 2009

Cryptococcosis: Treatment
Not well studied in children; infection is often fatal in the absence of treatment CNS Disease Amphotericin B induction ( mg/kg/day IV) combined with 2 weeks of flucytosine (25 mg/kg/dose given 4 times daily) followed by fluconazole for a minimum of 8 weeks After symptoms are controlled, treat with fluconazole or itraconazole maintenance Use amphotericin B alone if flucytosine is not tolerated Fluconazole plus flucytosine is an alternative to amphotericin B (limited data in children) July 2009 109

Cryptococcosis: Treatment (2)
Pulmonary and extrapulmonary cryptococcosis No clinical trials on the outcome of non-CNS cryptococcosis in HIV-infected patients Treat with amphotericin B with or without the addition of fluconazole (A III) Fluconazole or itraconazole should be continued long-term July 2009

Cryptococcosis: Monitoring and Drug Toxicity
Amphotericin toxicity Nephrotoxicity: azotemia, hypokalemia Nephrotoxicity can be minimized by hydration with 0.9% saline intravenously 30 minutes before amphotericin B infusion Infusion-related chills, fever, and vomiting; pretreat with acetaminophen or diphenhydramine Rarely: hypotension, arrhythmias, neurotoxicity, hepatic toxicity July 2009

Cryptococcosis: Monitoring and Drug Toxicity (2)
Flucytosine toxicity Bone marrow: anemia, leukopenia, thrombocytopenia Liver, GI, and renal toxicity Fluconazole toxicity Potential interaction with ARV should be evaluated before initiating treatment (A III) July 2009

Cryptococcosis: IRIS and Treatment Failure
IRIS related to cryptococcosis can present within weeks Optimal treatment of patients experiencing treatment failure has not been defined Patients failing initial azole treatment should be switched to amphotericin B in combination with flucytosine Consider use of liposomal amphotericin B Experience with posaconazole or voriconazole is limited In one study of HIV infected adults 30% of HAART treated patients were readmitted to the hospital with symptoms of IRIS. The optimal time to initiate treatment with HAART in a patient with cryptococcosis has not been defined. July 2009 113

Histoplasmosis: Epidemiology
Pathogen is Histoplasma capsulatum Incidence of disseminated histoplasmosis in HIV-infected children in the United States is <0.4% Incidence is higher in countries such as Brazil, Argentina, and Mexico (2.7% to 3.8%) No evidence of dissemination of maternal infection to the fetus or greater severity of infection during pregnancy July 2009 114

Histoplasmosis: Clinical Manifestations
Prolonged fever is the most common presentation Malaise, weight loss, and nonproductive cough Primary pulmonary focus leads to widespread dissemination in children Pulmonary manifestations common Physical findings include hepatosplenomegaly, erythematous nodular coetaneous lesions, CNS involvement with meningitis Anemia, thrombocytopenia, elevated liver transaminases Progressive disseminated histoplasmosis (PDH) is fatal if untreated The most common presenting symptom among children and adults with AIDS with disseminated histoplasmosis is prolonged fever. In comparison with adults, children Predominantly have malaise, weight loss, and nonproductive cough. In addition, interstitial pneumonitis as seen in adults is rarely observed among children, but a primary pulmonary focus frequently leads to widespread dissemination among HIV-infected children. The most frequent physical finding is hepatosplenomegaly (89% in infants). Cutaneous lesions that are erythematous and nodular might occur. CNS involvement with meningitis and focal brain lesions is common among HIV-infected adults and might result from reactivated infection in the setting of low CD4+ cell number. Anemia and thrombocytopenia are the most common hematologic abnormalities found, although pancytopenia has been reported. Elevated liver transaminases also occur. Progressive disseminated histoplasmosis (PDH) is fatal if untreated. It is the most common presentation in HIV infected children. July 2009 115

Histoplasmosis: Diagnosis
Serologic testing using CF and immunodiffusion is insensitive in the presence of HIV infection. Positive in most patients but not useful for diagnosis of acute infection For diagnosis of CNS disease, a combination of CSF antibody, antigen, and culture is most sensitive Skin testing not recommended for diagnosis July 2009

Histoplasmosis: Diagnosis (2)
Culture of Histoplasma from blood or other sources Detection of H capsulatum polysaccharide antigen in urine, blood, CSF, or bronchoalveolar lavage using EIA EIA sensitivity greater in disseminated disease or acute pulmonary disease; greater in urine than in serum Antigen levels decline with treatment and correlate with both response to treatment and relapse Culture of the organism is the definitive method of diagnosis. Blood cultures using lysis-centrifugation blood cultured system are highly sensitive in HIV-associated disseminated histoplasmosis, but the organism might require up to 6 weeks to grow. Identification of Histoplasma capsulatum can be shortened in cultures through the use of a DNA probe. Although PCR and DNA probes have been studied for detection of H. capsulatum DNA in tissues and body fluids, they have not been validated and are used only for research. July 2009 117

Histoplasmosis: Prevention
Most infections occur without a recognized history of exposure Sites and conditions commonly implicated include outbreaks of soil contamination with bird or bat droppings, older urban and rural structures, and decaying vegetation See Appendix A, page 70. July 2009 118

Histoplasmosis: Treatment
Limited data for children; recommendations based on adult data PDH is fatal without treatment and should be treated with either amphotericin B or itraconazole Fluconazole has been used successfully as an alternative for patients with mild disease and for those who cannot tolerate itraconazole July 2009 119

Histoplasmosis: Treatment (2)
Amphotericin B for patients with severe disseminated disease requiring hospitalization and for those who are immunocompromised Amphotericin B induction dosage: 1 mg/kg for 4-6 weeks followed by itraconazole chronic suppressive therapy for 12 months (A I) After successful treatment of acute disease, use chronic lifelong suppressive therapy with itraconazole Liposomal amphotericin B alternative in event of amphotericin B intolerance Central nervous system infection that accompanies PDH is expected to respond to the regimen recommended for moderately severe to severe PDH. Liposomal amphotericin B is preferred for central nervous system disease as it achieves high concentrations in the brain and penetration into the central nervous system than with other formulations. Amphotericin B should be given for four to six weeks followed by itraconazole for 12 months until central nervous system abnormalities including histoplasmosis generic resolve. July 2009 120

Histoplasmosis: Monitoring and Adverse Effects
Antigen levels should be monitored during treatment and for 1 year thereafter Adverse effects of amphotericin B include nephrotoxicity, infusion related fever, chills, nausea, and vomiting Azole drugs inhibit CYP450-dependent hepatic enzymes, warranting careful review of drug interactions when using ARVs As with other opportunistic infection concomitant treatment of HIV with ARVs and opportunistic infection with antimicrobial may result in IRIS. Data on a recurrence of IRIS in HIV-infected children with histoplasmosis is limited. July 2009 121

Pneumocystis jiroveci (carinii): Epidemiology
Organisms are found worldwide in the lungs of humans and lower animals Antibody in 80% of normal children by 4 years Most common AIDS indicator disease in children Incidence highest in first year of life, peaking at 3-6 months Accounted for 57% of AIDS-defining illnesses in infants age <1 year pre-ART CD4 T-cell count not a good indicator of risk in infants <1 year old Infection now unusual owing to routine prophylaxis with TMP-SMX There has been a 95% decline in PCP in the HAART era. The decline is likely to be due to multiple factors including increased use of antiretroviral therapy to prevent HIV transmission from mothers to children, the introduction of HAART and chemoprophylaxis for PCP. July 2009 122

Pneumocystis jiroveci (carinii): Clinical Manifestations
Fever, tachypnea, cough, dyspnea, poor feeding, weight loss Abrupt or insidious onset Bibasilar rales with evidence of hypoxia and respiratory distress Extrapulmonary locations: spleen, liver, colon, pancreas, ear, eye, GI tract, bone marrow, heart, kidney, lymph nodes, CNS In HIV-infected children with pneumonia, 4 clinical variables independently associated with PCP are: age less than six months, respiratory rate greater than 59 breaths per minute, arterial percentage hemoglobin saturation less than 92%, and the absence of vomiting. July 2009 123

Pneumocystis jiroveci (carinii): Diagnosis
Hypoxia with low arterial oxygen pressure (alveolar-arterial oxygen gradient >30 mmHg) Definitive diagnosis requires demonstrating organism Induced sputum (difficult <2 years) Bronchoscopy with bronchoalveolar lavage Fiberoptic bronchoscopy with biopsy – generally not recommended Bronchoscopy with bronchoalveolar lavage is the diagnostic procedure of choice for infants. Sensitivity ranges from 55%–97% and might be positive for at least 72 hours after PCP treatment has been initiated; treatment should not be delayed while awaiting results. Complications included hemoptysis, pneumothorax, transient increase in hypoxemia, transient increase in pulmonary infiltrates at the lavage site, and post bronchoscopy fever. July 2009 124

Pneumocystis jiroveci (carinii): Diagnosis (2)
Open lung biopsy most sensitive Requires thoracotomy, chest tube drainage Organisms seen on biopsy with: Gomori methenamine silver stain Toluidine blue stain Giemsa or Wright stain Monoclonal antibody DNA PCR for Pneumocystis MSG gene in fluids, lavage – sensitive but less specific than histology July 2009

Pneumocystis jiroveci (carinii): Prevention
Need for isolation of hospitalized patients has not been demonstrated, but when prophylaxis cannot be given, may need to isolate patient or susceptible contacts Infants born to HIV-infected mothers should be considered for prophylaxis at 4-6 weeks of age and continued until 1 year of age (A II) July 2009

Pneumocystis jiroveci (carinii): Prevention (2)
Chemoprophylaxis with TMP-SMX recommended as follows, based on CD4 counts and patient age: 6 years: CD4 count <200 cells/µL or CD4 percentage <15% 1 to 5 years: CD4 count <500 cells/µL or CD4 percentage <15% All HIV-infected infants <12 months of age regardless of CD4 count or percentage TMP-SMX is recommended as the drug of choice for prophylaxis because of its high efficacy, low cost, safety, and broad antimicrobial spectrum. (AI) The prophylactic dose is 150 mg/meter2 body surface area/day TMP and 750 mg/meter2 body surface area/day SMX. Alternatively TMP-SMX can be administered daily seven days a week. (AI) Alternative therapy in the presence of hypersensitivity or intolerance includes atovaquone and dapsone. Nationalized pentamidine is recommended for children who cannot take oral medication. Fansadar has been used in adults but not recently evaluated for PCP in HIV-infected children. July 2009 127

Pneumocystis jiroveci (carinii): Treatment
TMP-SMX (A I) >2 months mg/kg/day of TMP component IV in 3-4 divided doses Infuse over course of 1 hour Administer for 21 days Can be given orally in children with mild to moderate disease Lifelong prophylaxis indicated Trimethoprim/sulfamethoxazole (TMP/SMX) is the recommended treatment for PCP (AI). The dose for HIV-infected children aged >2 months is 15–20 mg/kg body weight/day of the TMP component (75–100 mg/kg of SMX component) administered intravenously in 3–4 divided doses, with the dose infused over 1 hour for 21 days (AI). After the acute pneumonitis has resolved, children with mild to moderate disease who do not have malabsorption or diarrhea can be administered oral treatment with the same dose of TMP/SMX in 3–4 divided doses to complete a 21–day course. July 2009 128

Pneumocystis jiroveci (carinii): Treatment (2)
Adverse reactions: Rash Stevens-Johnson syndrome (rare) Neutropenia, thrombocytopenia, megaloblastic or aplastic anemia July 2009

Pneumocystis jiroveci (carinii): Treatment (3)
Pentamidine isethionate Recommended for patients with intolerance to TMP-SMX or clinical failure with TMP-SMX (A I); do not combine use 4 mg/kg/day IV once daily over period of minutes Consider oral atovaquone after 7-10 days (B III) Pentamidine isothionate (4 mg/kg/day once daily administered intravenously over 60–90 minutes) is recommended for patients intolerant of TMP/SMX or who demonstrate clinical treatment failure after 5–7 days of TMP/SMX therapy (AI). No evidence exists for synergistic or additive effects on efficacy of these agents; therefore, because of potential increased toxicity, their combined use is not recommended (DIII). Among patients with clinical improvement after 7–10 days of intravenous therapy with pentamidine, an oral regimen (e.g., atovaquone) might be considered to complete a 21–day course (BIII). July 2009 130

Pneumocystis jiroveci (carinii): Treatment Alternatives
Atovaquone (B I) Limited data in children 30-40 mg/kg/day divided into 2 doses, given with fatty foods Infants 3-24 months may require 45 mg/kg/day divided into 2 doses, given with fatty foods (A II) Adverse reactions include rash, nausea, diarrhea, increased liver enzymes July 2009

Pneumocystis jiroveci (carinii): Treatment Alternatives (2)
Clindamycin/primaquine Used for mild to moderate PCP in adults; no data in children (C III) Primaquine contraindicated in G6PD deficiency July 2009

Clindamycin/primaquine Pediatric clindamycin dosing based on other uses: mg/kg/day IV divided into 3 or 4 doses, administered for 21 days Primaquine dosing based on malaria: 0.3 mg/kg daily of the base, administered orally for 21 days Adverse reactions include rash, nausea, diarrhea, pseudomembranous colitis July 2009

Dapsone/TMP Use for mild to moderate PCP in adults; no data in children (C III) Dapsone dosage <13 years 2 mg/kg/day orally once daily (A II) for 21 days TMP 15/mg/kg/day orally divided into 3 daily doses for 21 days Adverse reactions include rash, anemia, thrombocytopenia, increased liver enzymes July 2009

Pneumocystis jiroveci (carinii): Treatment Adjunct
Corticosteroids Consider use in moderate to severe PCP Use within 72 hours of diagnosis Results in reduced respiratory failure, decreased ventilation requirements, and decreased mortality On the basis of studies in adults, a short course of corticosteroids might be indicated in some cases of PCP of moderate or great severity, started within 72 hours of diagnosis (AI). Pediatric studies have indicated reduction in acute respiratory failure, decreased need for ventilation, and decrease in mortality with early use of corticosteroids in HIV infected children with PCP. Indications for corticosteroid treatment include a PaO2 value of <70 mm Hg or an alveolar-arterial gradient of >35 mm Hg. Doses in children varied between studies. Alternative regimens include 1) prednisone on days 1–5, 40 mg twice daily; days 6–10, 40 mg once daily; days 11–21, 20 mg once daily; 2) prednisone (or methylprednisolone sodium) on days 1–5, 1 mg/kg twice daily; day 6–10, 0.5 mg/kg twice daily; days 11–21, 0.5 mg/kg once daily; or 3) methylprednisolone (intravenous) on days 1–7, 1 mg/kg every 6 hours; days 8–9, 1 mg/kg twice daily; days 10–11, 0.5 mg/kg twice daily; days 12–16, 1 mg/kg once daily. July 2009 135

Pneumocystis jiroveci (carinii): Treatment Adjunct (2)
Corticosteroids Dosing recommendations vary Prednisone: 40 mg BID for 1-5 days; 40 mg once daily days 6-10; 20 mg once daily days 11-21 Alternative: prednisone 1 mg/kg BID days 1-5; 0.5 mg/kg BID days 6-10; 0.5 mg/kg once daily days 11-21 July 2009

Pneumocystis jiroveci (carinii): Monitoring and Adverse Events
Short courses of corticosteroids have been used in some cases of PCP of moderate to severe intensity starting within 72 hours of diagnosis (A I) As with other coinfection, IRIS may occur following initiation of ART but has been described infrequently in PCP Most common adverse reaction to TMP-SMX includes rash and rarely erythema multiforme or Stevens-Johnson syndrome Pentamidine is associated with renal toxicity, usually occurring 2 weeks after initiation of treatment Dapsone and trimethoprim are associated with neutropenia and skin rashes. Skin rashes, nausea and diarrhea may occur with atovaquone treatment. July 2009 137

Cryptosporidiosis/Microsporidiosis: Epidemiology
Protozoal parasites that cause enteric illness in humans and animals Human infection primarily caused by C hominis, C parvum, C meleagridis Microsporida include E bieneusi and E intestinalis Infection results from ingestion of oocysts excreted in feces of humans or animals Invade intestinal tract mucosa causing watery, nonbloody diarrhea, dehydration, malnutrition Cryptosporidium species are protozoal parasites that mainly cause enteric illness in humans and animals. The three most common species infecting humans are C. hominis (formerly C. parvum genotype 1 or human genotype), C. parvum (formerly C. parvum genotype 2 or bovine genotype), and C. meleagridis. In addition, infections with C. canis, C. felis, C. muris, and Cryptosporidium pig genotype have been reported in immunocompromised patients. Cryptosporidium parasites invade the gut mucosa, causing severe profuse, nonbloody, watery diarrhea leading to dehydration and malnutrition in immunocompromised hosts. Microspora species are obligate, intracellular, spore-forming protozoa that primarily cause moderate to severe diarrhea among children. Enterocytozoon bieneusi and Encephalitozoon intestinalis are the most common microsporidia that cause infection among patients with HIV infection. In addition to the Enterocytozoon and Encephalitozoon microsporidia genera, Nosema, Pleistophora, Trachipleistophora, Brachiola, and Vittaforma species have been implicated in human infections. The Microspora parasites develop in enterocytes and are excreted with feces and, like C. parvum, are transmitted by the fecal-oral route, which can include ingestion of contaminated food or water. Microsporidiosis has been reported in up to 7% of HIV-infected Thai children with acute and chronic diarrhea. July 2009 138

Cryptosporidiosis/Microsporidiosis: Epidemiology (2)
Person-to-person transmission in child care centers Oocysts can contaminate water supplies Outbreaks associated with contaminated drinking water and swimming pools Incidence declined since advent of ART July 2009 139

Cryptosporidiosis/Microsporidiosis: Clinical Manifestations
Frequent watery, nonbloody diarrhea Abdominal cramps, fatigue, vomiting, anorexia, weight loss, poor weight gain Fever and vomiting more common in children Liver involvement causes abdominal pain and elevated alkaline phosphatase Less common: myositis, cholangitis, sinusitis, hepatitis, CNS disease Different species may cause different clinical syndromes (eg, Encephalitozoon hellem associated with keratoconjunctivitis, sinusitis, prostatic abscess) July 2009

Cryptosporidiosis/Microsporidiosis: Diagnosis
Concentrated stool samples demonstrating oocysts Evaluate at least 3 separate stool samples Monoclonal antibody fluorescein stain and EIA for antigen have enhanced specificity and sensitivity July 2009

Cryptosporidiosis/Microsporidiosis: Diagnosis (2)
Microsporidia Use thin smears of unconcentrated stool-formalin suspension or duodenal aspirates stained with trichrome or chemofluorescent agents Consider endoscopy in all patients with diarrhea >2 months duration PCR techniques still in research Endoscopy should be considered for all patients with chronic diarrhea of >2 months duration and negative stool examinations. Touch preparations are useful for rapid diagnosis (i.e., within 24 hours). Sensitive assays using PCR amplification of parasite DNA sequences extracted from stool or biopsy specimens have been developed for Cryptosporidium and Enterocytozoon bieneusi, but are research tools and not commercially available. July 2009 142

Cryptosporidiosis/Microsporidiosis: Prevention
Avoid direct contact with fecal material from adults, diaper-age children, and infected animals Carefully investigate sources of drinking water and recreational activities involving water HIV-infected children should not be allowed to drink water directly from lakes or rivers Outbreaks of cryptosporidiosis occasionally have been linked to municipal water contamination Some experts recommend that severely immunocompromised HIV-infected patients should not share a room with patients who have cryptosporidiosis July 2009 143

Cryptosporidiosis/Microsporidiosis: Treatment
Immune restoration following antiretroviral treatment frequently results in clearing Supportive care, hydration, electrolyte replenishment, nutritional supplements Available treatment inconsistently effective Immune reconstitution resulting from HAART frequently results in clearance of Cryptosporidium and Microsporidium infections. Effective HAART is the recommended treatment for these infections (AII). Supportive care with hydration, correction of electrolyte abnormalities, and nutritional supplementation should be provided (AIII). Antimotility agents should be used with caution among young children (CIII). July 2009 144

Cryptosporidiosis: Treatment
No agents have been consistently effective Nitazoxanide: effective for Cryptosporidium and Giardia lamblia (B I for children and C III for HIV-infected children) Nitazoxanide dosage: 100 mg orally BID for children 1-3 years; 200 mg BID for children 4-11 years Limited data: paromomycin, azithromycin July 2009 145

Microsporidiosis: Treatment
Albendazole: 7.5 mg/kg orally BID; maximum dosage 400 mg orally BID (A II) Fumagillin: limited data for adults, no data for HIV-infected children See Appendix A, page 66. July 2009 146

Malaria: Epidemiology
Malaria is caused by the obligate intracellular protozoa Plasmodium 4 species account for most human infections: P falciparum (60%), P vivax (25-30%), P ovale and P malariae In the United States, 1,200 to 1,400 cases are reported annually Most cases of malaria infection in U.S. citizens are a result of not taking appropriate malaria chemoprophylaxis Over 30% of malaria cases in children are found in newly arrived immigrants This section will discuss only malaria in the United States and will not address the greater malaria epidemic in developing countries. Refer to WHO guidelines on malaria for additional information. The field of malaria chemoprophylaxis and treatment is rapidly evolving with new treatments available. Currently there is no vaccine available to prevent malaria infection. July 2009 147

Malaria: Clinical Manifestations
Clinical studies of malaria present differing conclusions on whether parasitemia, frequency of malaria, recurrence, and severity of infection differ in HIV-infected vs HIV-uninfected children Fever is the most common symptom of malaria, accompanied by chills, sweating, headache, myalgias, malaise, nausea, vomiting, diarrhea, and cough Chronic symptoms include splenomegaly, fever, thrombocytopenia, and anemia Congenital malaria is rare Malaria may be misdiagnosed as a viral infection or HIV (HIV also may be misdiagnosed as malaria) July 2009 148

Malaria: Diagnosis Thick blood smears are the most sensitive technique for detecting infection but are not helpful in determining the infectious species Giemsa-stained thin blood smear gives the malaria parasite’s distinctive appearance Blood smear examination taken at hour intervals may be needed to rule out a diagnosis A rapid malaria antigen capture assay (Binax Now) has been approved by the FDA The test is less sensitive for asymptomatic individuals The Binax Now assay for malaria has decreased sensitivity for species other than P. falciparum. There’s also less sensitive when a single blood smear is used. Guidelines for use of the test are available at a July 2009 149

Malaria: Prevention HIV-infected children who travel to regions of endemic malaria should use clothing impregnated with permethrin DEET mosquito repellent (30-50% concentration) is practical and effective Insecticide-treated bed nets should be provided Recommendations for chemoprophylaxis are the same for HIV-infected children and HIV-uninfected children July 2009 150

Malaria: Prevention (2)
Prevention includes mefloquine (Lariam) and Malarone Mefloquine chemoprophylaxis is less expensive and more convenient (once a week) but may be associated with central nervous system effects Doxycycline is an alternative chemoprophylaxis agent Emerging evidence suggests that TMP-SMX may protect against new or recurrent cases of malaria July 2009 151

Malaria: Treatment HIV infection status should not determine the choice of treatment (A II) Chloroquine-sensitive P falciparum should be treated with chloroquine In the United States, resistant P falciparum treatment choices include atovaquone-proguanil, quinine with clindamycin, or doxycycline or mefloquine A full discussion on the choice of treatment is available at July 2009 152

Malaria: Treatment (2) Severe P falciparum should be treated with IV quinidine gluconate (or IV quinine when available) Ritonavir inhibits quinidine metabolism and is contraindicated Artemisinin, artesunate and other derivatives combined with additional antimalarial drugs have not been approved in the United States but may be available through the CDC July 2009 153

Malaria: Treatment (3) P vivax, P ovale, P malariae
The drug of choice for non-P falciparum is chloroquine The drug is well tolerated and side effects are usually limited to itching Resistance to chloroquine may exist, warranting treatment with quinine plus clindamycin or doxycycline, atovaquone-proguanil, or mefloquine To prevent relapses of P. vivax or P ovale patients should receive presumptive anti-relapse therapy with primaquine following the primary blood stage treatment. Glucose-6-phosphate dehydrogenase deficiency must be excluded. July 2009 154

Malaria: Adverse Events
Severe malaria commonly induces hypoglycemia in children, especially when treated with IV quinine/quinidine Cardiac monitoring and intensive care monitoring are recommended when using quinine/quinidine July 2009 155

Toxoplasmosis: Epidemiology
Primarily perinatal transmission from primary infection of mothers during pregnancy Older children acquire toxoplasmosis from poorly cooked food and from ingestion of sporulated oocysts in soil, water, or food The overall risk for maternal-fetal transmission in women without HIV infection who acquire primary Toxoplasma infection during pregnancy is 29% (95% confidence interval [CI] = 25%–33%). The risk for congenital infection is low among infants born to women who become infected during the first trimester (range: 2%–6%) but increases sharply thereafter, with a risk as high as 81% for women acquiring infection during the last few weeks of pregnancy. Infection of the fetus in early gestation usually results in more severe involvement, compared with milder disease when infection occurs late in gestation. July 2009 156

Toxoplasmosis: Epidemiology (2)
Risk of transmission in HIV-uninfected mothers with primary infection during pregnancy = 29% (lower if maternal infection in 1st trimester) Perinatal toxoplasmosis infection may occur in HIV-positive women with chronic infection <1% of AIDS-defining illnesses in children July 2009

Toxoplasmosis: Clinical Manifestations
Non-immunocompromised infants are usually asymptomatic at birth but majority develop late manifestations: retinitis, neurologic impairment Newborn symptoms can include: Rash, lymphadenopathy, jaundice, hematologic abnormalities, seizures, microcephaly, chorioretinitis, hydrocephalus Isolated ocular toxoplasmosis is rare and usually occurs in association with CNS infection. As a result, a neurologic examination is indicated for children who have had Toxoplasma chorioretinitis diagnosed. Ocular toxoplasmosis appears as white retinal lesions with little associated hemorrhage; visual loss might be observed initially. July 2009 158

Toxoplasmosis: Clinical Manifestations (2)
Toxoplasmosis acquired after birth is initially asymptomatic, followed by infectious mononucleosis-like syndrome Chronic toxoplasmosis can reactivate in HIV-infected children Isolated ocular toxoplasmosis is rare is usually associate with CNS disease Less frequently observed presentations include pneumonitis, hepatitis, myocarditis July 2009

Toxoplasmosis: Diagnosis
Test all HIV-infected pregnant women for toxoplasmosis If positive, evaluate infant for congenital toxoplasmosis Use antibody assay to detect IgM-, IgA-, or IgE-specific antibody in first 6 months or persistence of IgG antibody after 12 months HIV-infected women might be at increased risk for transmitting Toxoplasma gondii to their fetuses, and serologic testing for Toxoplasma should be performed on all HIV infected pregnant women. All infants whose mothers are both HIV-infected and seropositive for Toxoplasma should be evaluated for congenital toxoplasmosis. Congenital toxoplasmosis can be diagnosed by using enzyme immunoassay or an immunosorbent assay to detect the presence of Toxoplasma-specific IgM, IgA, or IgE in neonatal serum within the first 6 months of life or persistence of specific IgG antibody beyond age 12 months. IgA might be more sensitive for detection of congenital infection than IgM or IgE. However, approximately 20%–30% of infants with congenital toxoplasmosis will not be identified in the neonatal period with IgA or IgM assays. July 2009 160

Toxoplasmosis: Diagnosis (2)
Additional methods include isolation of toxoplasmosis from body fluids or blood Negative antibody does not exclude toxoplasmosis – may require CT, MRI, or brain biopsy in case of encephalitis In the United States, routine screening for Toxoplasma is not recommended in HIV-infected children when the mother does not have Toxoplasma infection A presumptive diagnosis of CNS toxoplasmosis is based on clinical symptoms, serologic evidence of infection, and the presence of a space-occupying lesion on imaging studies of the brain. Cases of Toxoplasma encephalitis have been reported in persons without Toxoplasma-specific IgG antibodies; therefore, negative serology does not exclude that diagnosis. Computerized tomography of the brain might indicate multiple, bilateral, ring-enhancing lesions in CNS toxoplasmosis, especially in the basal ganglia and cerebral corticomedullary junction. Magnetic resonance imaging is more sensitive and will confirm basal ganglia lesions in the majority of patients. F-fluoro-2-deoxyglucose-positive emission tomography can be helpful in distinguishing Toxoplasma abscesses from primary CNS lymphoma, but the accuracy is not high and this test is not widely available. July 2009 161

Toxoplasmosis: Prevention
Council all HIV-infected children and their caregivers regarding sources of Toxoplasma gondii infection Advise not to eat raw or undercooked meat Hands should be washed after contact with raw meat or when gardening or in contact with soil Vegetables should be washed well and never eaten raw Stray cats should not be handled or adopted Toxoplasma-seropositive adolescents and adult patients with CD4 counts of <100 cells/µL and Toxoplasma-seropositive children with CD4 percentage <15% should be administered prophylaxis with TMP-SMX Alternative prophylaxis for Toxoplasma includes dapsone-pyrimethamine and atovaquone with or without pyrimethamine. July 2009 162

Toxoplasmosis: Treatment
If HIV-infected mother has symptomatic toxoplasmosis during pregnancy, infant should be treated (B III) Preferred treatment – congenital toxoplasmosis: Pyrimethamine loading dose of 2 mg/kg orally once daily for 2 days; then 1 mg/kg orally once daily for 2-6 months; then 1 mg/kg orally 3 times/week with sulfadiazine 50 gm/kg/dose BID and with leucovorin (folinic acid) 10 mg orally with each dose of sulfadiazine (A II) Optimal duration of treatment: 12 months July 2009 163

Toxoplasmosis: Treatment (2)
Treatment of HIV-infected children with acquired CNS, ocular, or systemic toxoplasmosis Pyrimethamine: 2 mg/kg/day (maximum 50 mg/kg) orally for 3 days; then 1 mg/kg/day orally and leucovorin mg/day plus sulfadiazine mg/kg/dose orally, given 4 times daily Continue acute therapy for 6 weeks Lifelong therapy should be provided Alternative to pyrimethamine and leucovorin in sulfa- sensitive individuals is clindamycin HIV-infected children with acquired CNS, ocular, or systemic toxoplasmosis should be treated with pyrimethamine (2 mg/kg/day for 3 days, followed by 1 mg/kg/day) and leucovorin (10–25 mg/day) plus sulfadiazine (25–50 mg/ kg/dose given four times daily) (AI). Acute therapy should be continued for 6 weeks, assuming clinical and radiological improvement (BII). Longer courses of treatment might be required in cases of extensive disease or poor response after 6 weeks. July 2009 164

Toxoplasmosis: Alternative Treatment
Azithromycin: 900-1,200 mg/kg/day with pyrimethamine and leucovorin (B II), but not evaluated in children Clindamycin with pyrimethamine leucovorin Adults – atovaquone: 1,500 mg orally BID plus pyrimethamine and leucovorin (C III), but not evaluated in children Limited use of corticosteroids as adjuvant therapy with CNS disease Corticosteriods (e.g., dexamethasone or prednisone) have been used among children with CNS disease when CSF protein is very elevated (i.e., >1,000 mg/dL) or with focal lesions with substantial mass effects (BIII). Because of the potential immunosuppressive effects of steroids, they should be discontinued as soon as possible. July 2009 165

Toxoplasmosis: Adverse Events
Pyrimethamine: rash, Stevens-Johnson syndrome, nausea, reversible bone marrow toxicity Sulfadiazine: rash, fever, leukopenia, hepatitis, nausea, vomiting, diarrhea, crystalluria IRIS rare in patients with HIV in toxoplasmosis July 2009 166

Cytomegalovirus: Epidemiology
Infection with CMV common and often inapparent 50-80% of women of childbearing age in United States are CMV antibody positive 90% of HIV-infected women are CMV antibody positive Infection occurs: During infancy, early childhood, adolescence Via contact with virus-containing salvia, urine, sexual fluid, blood, transplanted organ Perinatally – most common In the United States, the overall prevalence of CMV infection among women of childbearing age is 50%–80%, with the highest prevalence in women in lower socioeconomic strata. The prevalence of CMV infection among HIV-infected pregnant women is higher than in the general population, with approximately 90% of HIV infected pregnant women coinfected with CMV. HIV-infected women with CMV infection have a higher rate of CMV shedding from the cervix than women without HIV infection (52%–59% compared with 14%–35% in HIV-uninfected cohorts). The risk for mother to child transmission of CMV might be increased among infants born to women dually infected with CMV and HIV. In one study of 440 infants born to HIV-infected women in the United States, the overall rate of in utero infection was 4.5%, higher than the <2% rate of in utero infection in the general U.S. population. July 2009 167

Cytomegalovirus: Epidemiology (2)
In utero infection occurs most commonly among infants born to mothers with primary infection during pregnancy 30-40% rate of CMV transmission to fetus following primary infection during pregnancy 0.2-1% rate of CMV transmission to fetus following recurrent infection during pregnancy (reactivation of infection or reinfection with a different strain of CMV) July 2009

CMV may be transmitted intrapartum or postpartum 57% of infants whose mothers shed CMV become infected 53% of infants who are breast-fed with milk that contains CMV become infected July 2009

HIV-coinfected women have a higher rate of CMV shedding HIV-coinfected women have a higher rate of HIV transmission HIV-infected children at greater risk of acquiring CMV during early childhood CMV causes 8-10% of AIDS-defining illnesses Children with positive CMV urine cultures have lower survival rates A higher percentage of HIV/CMV-coinfected children shed CMV than do CMV-infected, HIV-uninfected children July 2009

Cytomegalovirus: Clinical Manifestations
10% of infants infected in utero are symptomatic at birth with congenital CMV syndrome Infants with congenital infection: small for gestational age, purpura/petechiae, jaundice, hepatosplenomegaly, chorioretinitis, microcephaly, intracranial calcification, hearing loss Delayed manifestations of congenital infections include developmental abnormalities, sensorineural hearing loss, chorioretinitis, neurologic defects July 2009

Cytomegalovirus: Clinical Manifestations (2)
HIV-infected children with CMV coinfection have accelerated HIV progression Coinfected children more likely to develop HIV CNS disease CMV retinitis most frequent severe manifestation of CMV disease, accounting for 25% of CMV AIDS-defining illnesses CMV retinitis is frequently asymptomatic Older children may have floaters or loss of peripheral central vision Diagnosis of CMV retinitis is based on clinical appearance with white and yellow retinal infiltrates and associated retinal hemorrhages. A more indolent, granular retinitis also might occur. HIV-infected children with CD4+ cell counts <100/µL are more likely to develop CMV retinitis than those with higher CD4+ cell counts, but CD4+ cell count is less predictive of risk for CMV disease in young infants, and systemic and localized CMV disease also can occur among HIV-infected infants with higher age-adjusted CD4+ cell counts. July 2009 172

Cytomegalovirus: Clinical Manifestations (3)
End organ disease reported in liver, lung, GI tract, pancreas, kidney, sinuses, CNS Nonspecific symptoms include weight loss, loss of developmental milestones, fever, anemia, thrombocytopenia Also observed: oral and esophageal ulcers, ascending cholangiopathy, CMV colitis, CMV pneumonia with shortness of breath and dry nonproductive cough CNS manifestations include encephalopathy, myelitis, polyradiculopathy with nonspecific or normal CSF July 2009

Cytomegalovirus: Diagnosis
Antibody assays indicative of maternal transfer of IgG in children <12 months; indicative of previous infection in children >12 months Positive cell culture from urine, tissues, blood leukocytes DNA PCR assays more sensitive than buffy coat or urine culture Quantitative DNA PCR can be used to monitor disease and treatment Other methods include monoclonal antibody staining and immunostaining for antigen Different methods have been used to detect viral antigen or DNA directly and identify patients at risk for development of CMV disease, including detection of pp65 antigenemia, qualitative and quantitative PCR, and DNA hybridization. The DNA assays are more sensitive than buffy-coat or urine cultures for detecting CMV and can be used to identify patients at higher risk for development of clinically recognizable disease. CMV DNA detection in CSF by DNA PCR is highly sensitive for CMV disease. Quantitative DNA PCR can be used as a marker of risk for disease and to monitor response to therapy. July 2009 174

Cytomegalovirus: Diagnosis (2)
Recommendations include: Testing all HIV-infected infants with urine culture for CMV in the first months of life to identify congenital, perinatal, or early postnatal infection Testing annually for CMV antibody in infants previously negative by culture and antibody to identify occult CMV infections permitting appropriate screening for retinitis Dilated retinal examinations for coinfected children every 4-6 months; older children should report floaters and visual changes July 2009

Cytomegalovirus: Prevention
Administer CMV antibody-negative blood and blood products if transfusion is required Begin CMV antibody testing at 1 year of age in seronegative HIV-infected infants and children who are severely immunosuppressed Inform parents and care providers that HIV-infected children are at risk of CMV in daycare settings Minimize risk of acquiring CMV infection with optimal hygienic practices July 2009 176

Cytomegalovirus: Treatment
Symptomatic congenital CMV Ganciclovir: 6 mg/kg IV Q12H for 6 weeks (B I) Alternative treatment for ganciclovir-resistant CMV is foscarnet July 2009 177

Cytomegalovirus: Treatment (2)
Initial and maintenance treatment of disseminated CMV and CMV retinitis Ganciclovir: 5 mg/kg/dose IV over period of 1-2 hours BID for days, followed by lifelong maintenance therapy (A I) Combination treatment with ganciclovir and foscarnet delays progression of retinitis inpatients failing monotherapy (B III) Maintenance treatment with oral valganciclovir with a ganciclovir sustained-release ocular implant can be considered for chronic suppression of CMV retinitis in older children and adults Liquid formulations of valganciclovir are not commercially available. Intraocular implants are not practical in children less than three years of age because of the small size of the eyes. July 2009 178

Alternative treatment for ganciclovir resistance Foscarnet (A I) at 60 mg/kg/dose IV (infused at 1 mg/kg/minute) over period of 1-2 hours Q8H for days, followed by lifelong therapy Foscarnet plus ganciclovir delays progression of retinitis in certain patients failing monotherapy Toxicity: decreased renal function, metabolic abnormalities, electrolyte imbalances with secondary seizures, cardiac dysrhythmia, abnormal liver enzymes, and CNS symptoms July 2009

Treatments for adults (inadequate pediatric data) Valganciclovir: prodrug of ganciclovir, given orally, effective in retinitis in adults Oral ganciclovir (or valganciclovir) plus ganciclovir sustained-release intraocular implant used for retinitis Cidofovir for retinitis Fomivirsen: antisense nucleotide used as intravitreous injection July 2009

Cytomegalovirus: Adverse Events
Ganciclovir and valganciclovir Neutropenia may occur and may require dosage modification Resistance and myelosuppression can occur Other toxic effects include renal impairment, CNS effects, GI dysfunction, increased liver enzymes Metabolic disturbances can be minimized by slow infusion rates Immune recovery uveitis, and immunologic reaction to CMV, is related to the occurrence of IRIS and other coinfections following initiation of ART July 2009

Cytomegalovirus: Discontinuing Secondary Prophylaxis
Multiple studies indicate that maintenance therapy can be discontinued in adults with CMV retinitis whose CD4 counts have increased and who are on ART Safety of discontinuing maintenance therapy in children has not been well studied Discontinuing prophylaxis and children 1-6 years of age receiving ART and with CD4 percentage of >15% or CD4 count >500 cells/L can be considered (C III) Patients who have had CMV maintenance therapy discontinued should undergo ophthalmologic monitoring at 3-6 month intervals July 2009

Hepatitis B: Epidemiology
Acquired by perinatal or mother-to-infant transmission Unknown whether there is a greater risk of HBV transmission to infants from HIV-coinfected mothers Chronic hepatitis B infection is defined as persistence of hepatitis B surface antigen (HbsAg) for >6 months July 2009

Hepatitis B: Epidemiology (2)
HBV-infected household members may pose risk of infection Infection occurs through contact with infected blood or body fluids and through sharing of objects such as toothbrushes Adolescents are at risk of HBV infection through sexual activity or injection drug use All infants previously unimmunized should receive routine childhood HBV vaccine Humoral response to hepatitis B vaccination is reduced in children with HIV infection. In multiple studies, Approximately 25%–35% of HIV-infected children vaccinated with hepatitis B vaccine have protective antibody titers. Younger children and those with higher CD4+ cell counts are more likely to respond to vaccination than older, symptomatic, and immunodeficient HIV-infected children. Booster doses might increase response rates. HIV-infected infants, children, and adolescents should be tested for anti-HBs 1–2 months after completing the vaccination series, and if anti-HBs negative, revaccinated. July 2009 184

Hepatitis B: Epidemiology (3)
HBV infection risk increased through sexual activity in adolescents who are HIV coinfected Immunize HBV-susceptible adolescents Limited data on the prevalence of HBV infection in HIV-infected children Risk of chronic HBV infection in children without HIV infection is inversely related to age at time of infection Chronic hepatitis B infection develops in less than 90% of infants, 25-50% children 1-5 years of age and 6-10% of older children and adolescents July 2009

Hepatitis B: Clinical Manifestations
Majority of children are asymptomatic Children who are coinfected with HIV may have smoldering chronic infection along with lethargy, malaise, fatigue, and anorexia Jaundice is sometimes present with hepatosplenomegaly July 2009

Hepatitis B: Clinical Manifestations (2)
Young children may experience a serum sickness-like illness consisting of asymmetrical arthropathy and skin lesions Papular acrodermatitis and urticarial or purpuric skin lesions may occur Aplastic anemia, polyarteritis nodosa, glomerulonephritis are occasionally seen Rarely, fulminant hepatic failure may occur during childhood 25% of infants and children with chronic HBV will eventually develop cirrhosis or hepatocellular carcinoma July 2009

Hepatitis B: Diagnosis
HBsAg is the first detectible marker and it precedes an increase in liver enzymes Anti-HBV core antibody (anti-HBc) appears 2 weeks after HBsAg and persists for life Passively transferred anti-HBc present in infants up to 12 months of age IgM anti-HBc highly specific for acute infection In self-limited infections, HBsAg is eliminated in 1–2 months, and anti-HBs develop during convalescence. Anti- HBs indicate immunity from HBV infection. After recovery from natural infection, both anti-HBs and anti-HBc are usually present; only anti-HBs develop in response to the hepatitis B vaccine. In persons who become chronically infected (i.e., persistently positive for HBsAg [and anti-HBc] beyond 24 weeks), anti-HBs is not detectable. Hepatitis B e antigen (HBeAg) correlates with viral replication, DNA polymerase activity, increased infectivity, and increased severity of liver disease. With clearance of HBeAg, antibody to HBeAg might be detectable. HBV DNA can be detected in serum and peripheral blood mononuclear cells by PCR or branched chain DNA amplification. Quantitative DNA assays can be helpful in evaluating response to therapy. July 2009 188

Hepatitis B: Diagnosis (2)
In self-limited infections, HBsAg is eliminated in 1-2 months Anti-HBsAg during convalescence, indicating immunity to HBV After recovery, both anti-HBs and anti-HBc usually are present Following immunization, only anti-HBs develops July 2009

Hepatitis B: Diagnosis (3)
Chronically infected individuals are persistently positive for HBsAg and anti-HBc beyond 24 weeks; anti-HBs not detectible HBe antigen (HBeAg) correlates with viral replication, DNA polymerase activity, increased infectivity, increased severity of liver disease HBV DNA can be detected in serum and blood mononuclear cells by PCR or branched DNA Quantitative DNA assays may be useful for evaluating responses to treatment July 2009

Hepatitis B: Prevention
All pregnant women should be tested for HBV surface antigen (HBsAg) Repeat test late in pregnancy for women at high risk for HBV infection Pregnancy is not a contraindication for hepatitis B immunization July 2009

Hepatitis B: Prevention (2)
All infants born to HBV-infected mothers should receive HBV vaccine and HBV immune globulin (HBIG) within 12 hours of birth Second dose of vaccine at 1-2 months of age; third dose at 6 months of age Test for antibody to HBsAg at 9-15 months of age; if negative, reimmunize Immunize HBV-susceptible adolescents All children, including HIV-infected children and those with HBV coinfection, should receive hepatitis A immunization HBV-infected children should not share toothbrushes or other personal items Although the efficiency of sexual transmission of HBV is low, safe sex practitioners should be encouraged for HIV-infected adolescents and young adults July 2009 192

Hepatitis B: Treatment
Indications for treatment are the same as those for children coinfected with HBV and HIV: Evidence of ongoing viral replication as indicated by presence of detectible HBV DNA with or without HBeAg positivity for at least 6 months Persistent elevation of transaminases (2 times upper limit of normal) Evidence of chronic hepatitis on liver biopsy (B II) July 2009 193

Hepatitis B: Treatment (2)
Correlates of successful treatment not well defined Current correlates: improved liver histology, normalization of hepatic transaminases, decrease in HBV DNA levels, loss of e antigen with development of anti-HBe No target HBV DNA level has been defined July 2009

6 drugs have been approved for the treatment of HBV IFN-alfa (standard and pegylated), lamivudine (3TC), telbivudine, entecavir, and adefovir approved for treatment of HBV in adults IFN-alfa and 3TC approved for children Preferred initial treatment for adults for chronic hepatitis B infection without HIV infection include pegylated interferon-alfa, adefovir, or entecavir monotherapy Some experts would initiate fully suppressive treatment for HIV/HBV coinfection with 2 drugs that have activity against both HIV and HBV plus a third agent with activity against HIV Six therapies have been approved for chronic hepatitis B in adults: interferon-alfa, lamivudine (3TC), and adefovir. Interferon-alfa and 3TC are also approved for treatment of chronic hepatitis B in children. For treatment of chronic hepatitis B in HIV-HBV coinfected adults, some specialists recommend that interferon-alfa is the therapy of choice in persons who do not yet require antiretroviral therapy for HIV infection to preserve use of 3TC and tenofovir for later treatment of HIV infection (CIII). For HIV-HBV coinfected adults who are antiretroviral-naïve and require both HBV and HIV treatment, 3TC is considered by some specialists to be the therapy of choice for HBV, administered in HIV-suppressive doses and in combination with other antiretroviral drugs for treatment of HIV infection (BIII). Considerations would be similar for HIV-HBV coinfected children. Additional antiretroviral drugs which have activity against HBV include tenofovir and am emtricitabine but they have not been approved for this indication. July 2009 195

If treatment of chronic HBV, but not HIV, is indicated, standard interferon-alfa is preferred (B III) Adefovir should be considered in older children If treatment of HIV, but not chronic HBV, is indicated, use of ART that avoids drugs with activity against HBV is suggested If treatment of both HIV and chronic HBV is indicated and the patient is naive to 3TC, use an ARV regimen that includes 3TC (or emtricitabine) (B III) July 2009 196

If treatment for HIV and chronic HBV is indicated and the child is receiving ART including 3TC or emtricitabine with HIV suppression but detectable plasma HBV DNA, HBV 3TC resistance can be assumed Treatment options for children who require HBV therapy include the addition of interferon therapy to the ARV regimen (B III), tenofovir, or adefovir if the child can receive adult dosing (B III) July 2009 197

IFN-alfa Most widely studied for treatment of compensated HBV liver disease Studies of HBV/HIV coinfection in children have not been performed Dosage range in children for IFN-alfa 2a or 2b: 3-10 million units/m2 subcutaneously 3 times weekly for 3-12 months Commonly used regimen is 5 million units/m2 3 times weekly for 6 months Prolonged and higher dosages improve responses In instances where HIV treatment is not an option but treatment of hepatitis B is needed, pegylated interferon-alpha may be used alone. The use of tenofovir, lamivudine, or emtricitabine without fully suppressive HAART regimen should be avoided because of the rapid development of drug-resistant mutations July 2009 198

3TC Results in rapid decline in HBV DNA levels Used for HBV-infected, HIV-uninfected children but sustained virologic response rates are low Used as both primary and secondary treatment in HBV-infected, HIV-uninfected children Extended monotherapy treatment can lead to resistance July 2009

3TC (cont’d) Do not use 3TC monotherapy in HIV/HBV-coinfected children (3TC resistance develops) Dosage: 3 mg/kg once daily (lower than dosage required for HIV treatment) If 3TC is used to treat HBV/HIV-coinfected children, treat with 4 mg/kg BID in the context of ART (A III) Extended treatment with 3TC can lead to the development of 3TC-resistant HBV, with base pair substitutions at the YMDD locus of DNA polymerase. In one pediatric study, 19% of HBV-infected patients treated with 3TC for 1 year had emergence of the YMDD HBV-variant; a more recent study reported mutant variants in 65% of 3TC treated children unresponsive to interferon, compared with 16%–32% in HBV-infected adults treated with 3TC for 1 year, and 49% after 3 years. However, the emergence of variants containing the YMDD motif mutation did not prevent HBeAg seroconversion or result in substantial worsening of liver histology. 3TC resistance should be suspected if HBV replication (as measured by HBV DNA levels) increases or recurs while receiving treatment. Among children with HIV-HBV coinfection, 3TC should not be administered as monotherapy because resistance of HIV to 3TC develops (EI). The dose of 3TC approved to treat HBV infection (3 mg/kg body weight once daily) is lower than that required to treat HIV (4 mg/kg twice daily, maximum dose 150 mg twice daily). If 3TC is administered to HIV-HBV co-infected children at the lower dose, the resulting subtherapeutic blood levels of 3TC will result in the development of 3TC-resistant HIV; emergence of the M184V 3TC resistance mutation is observed after only 1–2 weeks of single drug therapy. In contrast, the dose of 3TC used to threat HIV as part of combination antiretroviral therapy is adequate to treat HBV. Thus, among HIV-HBV coinfected children, if 3TC is used to treat chronic hepatitis B, 3TC should be administered at the dose of 4 mg/kg twice daily in the context of a potent combination antiretroviral regimen (BIII). July 2009 200

Adefovir Some experts recommend combined adefovir or TDF in addition to 3TC as part of suppressive ART to reduce development of resistance Development of resistance is less common with adefovir than with 3TC Adefovir dipivoxil (10 mg once daily in adults) active against HBV with minimal anti-HIV effect (insufficient data in children) July 2009 201

Tenofovir Shown to reduce HBV DNA levels in adult patients with 3TC-resistant virus as well as wild-type HBV infection Not approved for use in treatment of chronic HBV infection or for use in HIV-infected children <18 years of age Should not be used for HBV/HIV-coinfected patients who are not receiving ART Tenofovir, a nucleotide analogue similar to adefovir, has in vitro activity against HBV, but data is limited in subjects with HIV-HBV coinfection. It has been administered in certain adult patients at a dose used for treatment of HIV (tenofovir administered as 300 mg once daily). Similar to 3TC, tenofovir, when used for treatment of chronic hepatitis B among HIV-infected patients, should be administered as part of a fully suppressive HAART regimen and not as monotherapy (CIII). No data are available on safety and appropriate dosing of tenofovir among children. July 2009 202

Entecavir Compared with 3TC, treatment results in a greater effect on indicators of chronic HBV infection Preferred for 3TC-resistant HBV infection Use only in patients receiving ART in HIV/HBV coinfection Telbivudine Approved for treatment of chronic HBV and adults Emergence of resistance over time No data available on HIV/HBV-coinfected adults and no data on children July 2009 203

Hepatitis B: Adverse Events
IFN-alfa Flulike syndrome most severe during first month of therapy, consisting of fever, chills, headache, myalgia, arthralgia, abdominal pain, nausea, vomiting Epistaxis associated with thrombocytopenia or prolonged prothrombin time The most common adverse effect of interferon-alfa is an influenza-like syndrome that can consist of fever, chills, headache, myalgia, arthralgia, abdominal pain, nausea, and vomiting. Fever usually appears within 2–6 hours after Interferon injection, and rarely febrile seizures have occurred; the influenza-like symptoms are most severe during the first month of treatment. Relapsing cases of epistaxis (not associated with thrombocytopenia or prolonged prothrombin time) have been reported in certain children and occurred more frequently in the first months of treatment. Certain children experience loss of appetite and a transient weight loss and impairment in height growth, which resolves after completion of therapy. Transient mild alopecia, usually first occurring after 2–3 months of therapy, also has been reported. Subtle personality changes have been reported in 42% of children that resolve when therapy is discontinued. Neutropenia, which resolves after discontinuation of therapy, is the most common laboratory abnormality; anemia and thrombocytopenia are less common. Certain children have experienced antinuclear autoantibodies. Periodic monitoring of a complete blood count is recommended in children receiving interferon-alfa therapy. July 2009 204

Hepatitis B: Adverse Events (2)
Adverse effects: IFN-alfa Neutropenia, anemia, thrombocytopenia Personality changes Abnormalities of thyroid function Treatment contraindicated in decompensated liver disease, cytopenias, cardiac disease, and autoimmune disease Monitor patients with complete blood count and serum TSH level every 3 months July 2009

Hepatitis C: Epidemiology
Low seroprevalence among children in United States: % Seroprevalence higher among HIV-infected children: 1.5% in one study Risk of MTCT about 6% Mother-to-child transmission is the dominant mode of HCV infection HCV infection in older children results from injection drug use, body piercing, tattoos, accidental needlestick injury, household contacts, and sexual exposure Most infections occur at or near time of delivery July 2009

Hepatitis C: Epidemiology (2)
Higher risk of MTCT if mother is HIV coinfected, IV drug user, or viremic; and with intrapartum exposure to infected blood, perineal or vaginal laceration, and fetal hypoxia No reduction of transmission with cesarean section No increased risk from breast-feeding Transmission risk of HIV may be increased with HCV coinfection Chronic HCV infection, defined as the presence of HCV RNA for >6 months, resolves spontaneously in 15-40% of adults There are more than 6 HCV genotypes, with genotype 1 being most common in the United States No association of HCV perinatal transmission with mode of delivery has been demonstrated in most studies. On the basis of current evidence, routine Cesarean delivery is not recommended for women with chronic HCV infection. Although vaginal delivery itself might not be a risk factor for HCV transmission, higher risk for transmission among vaginally delivered infants has been described with higher maternal HCV quantitative viral load, intrapartum exposure to virus-contaminated maternal blood by the occurrence of perineal or vaginal laceration, or neonatal hypoxia. Although HCV can be detected in breast milk, studies of infants born to HCV-infected women have not demonstrated an increased risk for HCV transmission in infants who are breastfed compared with those who were formula fed. Therefore, breastfeeding is not contraindicated on the basis of HCV status alone. July 2009 207

Hepatitis C: Epidemiology (3)
Viremia in HCV-infected, HIV-uninfected children: persistent 52%; intermittent 42%; not detectable 6% Spontaneous clearing has been reported in MTCT of HCV >40% of those who are viremic have persistent features of hepatitis Patterns of HCV viremia observed among HCV-infected children without HIV infection vary widely and include persistent viremia (52%), intermittent viremia (42%), and lack of detectable viremia despite persistent HCV antibody positivity (6%). Compared with HCV-infected adults without HIV infection, in which 2% demonstrated a loss of HCV RNA over follow-up of 3 years, spontaneous HCV clearance or transient viremia in infants has been reported in 17% of cases of mother-to-child HCV transmission. However, whether this represents true clearance of infection is unknown; >40% of those who become persistently HCV RNA-negative continue to demonstrate biochemical signs of hepatitis. July 2009 208

Hepatitis C: Clinical Manifestations
Most children are asymptomatic with minor abnormalities including hepatomegaly, fatigue, myalgia, and poor weight gain Children have less frequent and slower progression than adults In a study of posttransfusion HCV, 55% of antibody-positive children had detectable HCV in blood July 2009

Hepatitis C: Clinical Manifestations (2)
Histologic changes can be present in the absence of symptoms No correlation between persistent viremia or elevated liver enzymes and liver disease No evidence of clinical differences between HIV-coinfected and HIV-uninfected children No evidence exists to indicate that children with HIV/HCV co-infection appear differently from HCV-infected children. Approximately 90% of children with vertically Acquired HCV infection are asymptomatic and appear to grow normally. Serum ALT levels are high during the first 2 years of life and decline substantially thereafter. Among children, ALT concentrations can fluctuate substantially. Among 16% of children, no abnormalities in ALT concentration are ever observed. After age 2 years, mean ALT concentrations are slightly higher among children with persistent viremia compared with those with intermittent or no viremia. However, ALT activity is not a reliable index of ongoing viral replication in HCV-infected children. July 2009 210

Hepatitis C: Diagnosis
Testing is recommended for all children whose mothers are known to have HCV and for all HIV-infected adults and adolescents Serologic and nucleic acid tests are used to diagnose HCV infection HCV antibody passively transferred; not useful for diagnosis of infection until >18 months of age A third-generation anti-HCV EIA is available for detection of antibody HCV RNA first becomes detectable 1-3 weeks following infection A single HCV RNA test is not sufficient for diagnosis; testing should be repeated on 2 separate occasions between 2-6 months of age Liver transaminase levels are not elevated in direct Proportion to the extent of liver disease and correlate only loosely with biopsy findings. Persistent elevation indicates liver inflammation and warrants further evaluation. Hepatotoxicity resulting from antiretroviral therapy or from a possible immune reconstitution syndrome after initiation of HAART also can contribute to an elevation in liver enzymes. Liver biopsy is the most specific test for diagnosis and assessment of hepatic pathology and is used to quantitate the amount of hepatic fibrosis present and stage the extent of disease. A liver biopsy should be strongly considered before initiating therapy for chronic hepatitis C. July 2009 211

Hepatitis C: Diagnosis (2)
A positive anti-HCV antibody test result in a child >18 months of age is indicative of infection A positive HCV RNA test confirms the presence of infection, and if positive for >6 months, suggests chronic infection Liver biopsy best for evaluation of hepatic disease; should be considered before initiating treatment July 2009

Hepatitis C: Prevention
All HIV-infected individuals, including HIV-infected pregnant women, should be screened for HCV There is no reliable method for preventing perinatal HCV transmission; cesarean delivery is not associated with decreased HCV transmission Adolescents should be warned about the risks of tattooing, body piercing, and intravenous drug use HCV-infected individuals should not share toothbrushes, razors, and other personal items July 2009

Hepatitis C: Treatment
Limited studies on the treatment of HCV-infected children Consideration for treatment includes: symptomatic disease, advanced pathologic features (bridging necrosis, active cirrhosis) (B I) Response to treatment better with HCV 2 and HCV 3 than with HCV 1 Use quantitative HCV RNA to access treatment response July 2009

Hepatitis C: Treatment (2)
HIV/HCV-coinfected adults and adolescents Consider treatment of any nonpregnant HCV-infected adult with abnormal liver enzymes or a liver biopsy showing chronic hepatitis or significant fibrosis Recommended treatment is pegylated interferon-alfa 2a or 2b or daily oral ribavirin for 48 weeks Note: HCV treatment generally is not recommended during pregnancy because ribavirin is teratogenic July 2009

HCV-infected children without HIV infection Treatment of HIV-uninfected children with HCV infection who are <3 years of age is not recommended Only interferon-alfa 2b and ribavirin are approved by the FDA for treatment of children 3-17 years of age A 24-week course of treatment is recommended for genotypes 2 and 3; 48-week course for other HCV genotypes July 2009

HIV/HCV-coinfected children Recommendations for treatment are based primarily on adult data Consider treatment for all HIV/HCV-coinfected individuals including children >3 years of age who have no contraindication to treatment (B III) Treatment of HCV-infected children regardless of HIV status should include combination therapy with interferon-alfa and ribavirin (B III) Based on adult studies, 48 weeks of treatment is recommended for coinfected children July 2009

Adults and children with HIV disease Combination therapy with interferon and ribavirin (A I) Pegylated interferon-alfa 2a: subcutaneously 180 mcg/kg weekly or alfa 2b subcutaneously 1.5 mcg/kg weekly (adults) Ribavirin: 400 mg orally BID (adults) Limited data on use of interferon with children See Appendix A, page 73. July 2009 218

HCV RNA levels in serum transaminase should be monitored every 6-12 months alone with an annual hemogram and serum AFP Patients who are on treatment should be monitored at baseline, and after 12 and 24 weeks of antiviral therapy Individuals with undetectable levels of HCV RNA following treatment should be retested after 24 weeks In HIV-coinfected patients, testing can be continued for an additional 1-5 years July 2009

Interferon-alfa 2a and alfa 2b Pediatric dosage in studies ranged from 1.75 to 5 million units/m2 (maximum dosage 3-5 million units) administered subcutaneously or intramuscularly 3 times weekly for 4-12 months Treatment contraindicated in decompensated liver disease, cytopenia, cardiac disease or autoimmune disease July 2009

Ribavirin oral solution Dosage: oral solution 40 mg/mL – 15 mg/kg/day divided into 2 doses given BID 25-36 kg: 1 capsule (200 mg) in a.m., 1 in p.m kg: 1 capsule (200 mg) in a.m., 2 in p.m kg: 2 capsules (200 mg each) in a.m., 2 in p.m. July 2009

Hepatitis C: Adverse Events
Initiation of ART in HIV/HCV coinfection may worsen hepatitis as evidenced by increased serum transaminase levels and clinical signs of liver disease (IRIS) Adverse effects: interferon-alfa Flulike syndrome most severe during first month of therapy, consisting of fever, chills, headache, myalgia, arthralgia, abdominal pain, nausea, vomiting Epistaxis associated with thrombocytopenia or prolonged prothrombin time Neutropenia, anemia, thrombocytopenia Personality changes Abnormalities of thyroid function The incidence of the majority of adverse effects decreases substantially during the first 4 months of therapy. Premedication with acetaminophen might reduce the incidence of side effects (BIII). The most common adverse effect of interferon-alfa is an influenza-like syndrome that can consist of fever, chills, headache, myalgia, and arthralgia, abdominal pain, nausea, and vomiting. Fever appears within 2–6 hours after interferon injection, and febrile seizures have occurred; influenza-like symptoms are most severe during the first month of treatment. Relapsing cases of epistaxis not associated with thrombocytopenia or prolonged prothrombin time have been reported among certain children and occurred more frequently in the first months of treatment. Certain children experience loss of appetite and a transient weight loss and impairment in height growth, which resolves after completion of therapy. Transient mild alopecia, usually first occurring after 2–3 months of therapy, also has been reported. Subtle personality changes have been reported in 42% of children; they resolve when therapy is discontinued. Neutropenia, which resolves upon discontinuation of therapy, is the most common laboratory abnormality; anemia and thrombocytopenia are less common. Certain children have experienced antinuclear autoantibodies. July 2009 222

Hepatitis C: Adverse Events (2)
Ribavirin Flulike syndrome consisting of fever, chills, headache, myalgia, arthralgia, abdominal pain, nausea, vomiting Hemolytic anemia, lymphopenia Neutropenia, anemia, thrombocytopenia Depression and suicidal ideation Do not use in combination with ddI Ribavirin inhibits intracellular phosphorylation of pyrimidine nucleoside analogues (zidovudine, stavudine, zalcitabine) in vitro, but the clinical significance of this interaction in vivo is unclear. Ribavirin enhances intracellular phosphorylation of didanosine; case reports have indicated a potential increased risk for pancreatitis and mitochondrial toxicity with concomitant use, and this combination should be used with caution. July 2009 223

Human Herpes Virus 6 and 7: Epidemiology
Human herpes virus 6 (HHV-6) and 7 (HHV-7) are closely related members of the Roseolovirus genus of herpes viruses Humans are the only known host Infection is believed to be transmitted through saliva; sexual transmission may occur and presumptive in utero infection has been described Children become infected early in childhood with 100% infected by 3 years of age July 2009

Human Herpes Virus 6 and 7: Epidemiology (2)
HHV-6 has been transmitted from mother to child Congenital HHV-6 infection has been documented in <2% of newborns HHV-7 is acquired later in life than is HHV-6 Seropositivity for HHV-7 is approximately 50% by 2 years of age Salivary shedding of HHV-7 is common and viral DNA has been found in breast milk July 2009

Human Herpes Virus 6 and 7: Clinical Manifestations
HHV-6 primary infection may be asymptomatic or accompanied by mild nonspecific symptoms Common symptoms are fever, irritability, and rhinitis HHV-6 is the causative agent of most cases of exanthem subitum (also known as roseola infantum) Primary infection and reactivation associated with severe central nervous system syndromes in immunodeficient individuals Reactivation of infection may include pneumonia, encephalitis, bone marrow suppression, fever, skin rash, and leukopenia Reactivation of HHV-7 also occurs in immunodeficient individuals July 2009

Human Herpes Virus 6 and 7: Diagnosis
Most often, the diagnosis is based on clinical features and presence of a distinctive rash Laboratory confirmation of the infection includes antibody testing, culture, antigen detection, PCR, immunohistochemistry Detection of HHV-6-specific antibodies, seroconversion, or changing antibody titer indicate infection Many of the laboratory tests for the diagnosis of HHV infection are available only on the research basis July 2009

Human Herpes Virus 6 and 7: Prevention
HHV-6 and HHV-7 infections are ubiquitous, making prevention difficult Prophylactic ganciclovir may decrease the number of episodes and severity of HHV-6 reactivation and transplantations There is no vaccine to prevent HHV-6 or HHV-7 infections July 2009

Human Herpes Virus 6 and 7: Treatment
The majority of HHV-6 primary infections are mild and self-limited There are no clear indications for treatment although treatment might be considered for severe encephalitis There are no proven therapies, but based on in vitro data, there is a suggestion that ganciclovir and foscarnet are active against HHV-6 Other treatments that have been reported are based on individual or small numbers of patients July 2009

Human Herpes Virus-8: Epidemiology
Human herpes virus-8 (HHV-8) is a transmissible DNA virus similar in DNA structure to Epstein-Barr virus Causally linked to all forms of Kaposi sarcoma (KS) Also linked to cavity-based lymphoma and multicentric Castleman disease In the United States, 1-3% of the general population is seropositive, with higher rates among homosexual men Seropositivity rate in some parts of Africa >80% July 2009

Human Herpes Virus-8: Epidemiology (2)
Transmitted through oral and genital secretions Immunocompetent HHV-8-infected adults shed HHV-8 in their oropharyngeal secretions Seroprevalence increases in endemic areas during the first 5 years of life Seropositivity in the United States among HIV-uninfected adolescents equals 11% Seropositivity in the United States among homosexual males equals 23% In the United States, KS accounts for <1% of pediatric AIDS-defining illnesses The incidence of KS appeared to decline even before the widespread use of HAART. The reason for the decline is not clear but may be related to the use of other antiviral agents with activity toward HHV-8. KS, effusion lymphoma and multicentric Castleman’s disease are describe mostly among HIV-infected individuals with advanced immunosuppression. Although KS occurs primarily in adults, the incidence in children has increased in HIV epidemic areas, particularly in Africa. July 2009 231

Human Herpes Virus 8: Clinical Manifestations
Primary infection is associated with fever, mild expiratory symptoms, and a maculopapular rash Some evidence suggests there may be a more severe clinical presentation in immunodeficient HIV-infected individuals KS presentation varies widely and includes nontender, purplish, indurated skin lesions; intraoral lesions; visceral dissemination Multicentric Castleman disease presents with generalized adenopathy and fever July 2009

Human Herpes Virus 8: Diagnosis
Diagnosis based on serologic assays including immunofluorescence, ELISA, and Western blot Sensitivity varies from 80% to 90% DNA hybridization and PCR are important for diagnosis on biologic specimens Routine screening for HHV-8 by PCR or serologic testing is not indicated for HIV-infected individuals July 2009

Human Herpes Virus 8: Prevention
Exposure to HHV-8 places HIV-infected individuals at risk of KS HIV-infected individuals should be counseled concerning transmission risk of HHV-8 to sexual partners Safe sexual practices are warranted to reduce the risk of transmission There is no effective way to prevent childhood acquisition of HHV-8 July 2009

Human Herpes Virus 8: Treatment
Effective suppression of HIV replication with ART may prevent KS progression or returns of new lesions KS requires treatment with cytotoxic chemotherapy Chemotherapy in combination with potent ART should be considered for patients with visceral KS or primary effusion lymphoma (B II) Castleman disease has been treated with anti-herpesvirus drugs (ganciclovir or oral valganciclovir), leading to substantial clinical improvement July 2009

Herpes Simplex Virus: Epidemiology
HSV-1 and HSV-2 affect all populations HSV-1 is transmitted primarily through contact with infected oral secretions HSV-2 is acquired primarily through contact with infected genital secretions Neonatal HSV infection occurs at a rate of 1/2,000-5,000 deliveries Transmitted from infected mother to infant primarily through exposure to maternal genital fluids during birth, by ascending infection, or by invasive procedures (eg, fetal scalp electrodes) Congenital (in utero) rare, but severe cutaneous, ocular, and CNS damage In the United States, 75% of neonatal infections are caused by genital herpes, HSV type 2, and HSV type 1. HSV-2 seroprevalence among the overall population of childbearing-aged women is approximately 26%. HSV-2 infection rates might be higher in HIV-infected than HIV-uninfected women. Women infected with HIV, particularly those with low CD4+ cell count, shed HSV from the vulva and cervix more commonly than women not infected with HIV; the majority of this shedding is asymptomatic. Among women who are not infected with HIV, the rate of HSV reactivation is about 25% during the last month of pregnancy, but only about 2%–3% will be shedding on the day of delivery. In comparison, in women who are coinfected with HIV and HSV, an estimated 10% have cervical shedding of HSV on the day of delivery. The risk for genital HSV reactivation and shedding increases as HIV-related immunosuppression progresses. No evidence exists to indicate that in utero HSV infection of the infant occurs more frequently in the HIV infected pregnant woman; whether infants born to women with HIV/HSV-2 coinfection have an increased risk for perinatal (intrapartum) HSV infection is unknown. July 2009 236

Herpes Simplex Virus: Epidemiology (2)
Maternal antibody to HSV predicts likelihood and severity of transmission to infant Risk of neonatal HSV greatest in infant born to mother with primary HSV infection (30-40%) Genital shedding of HSV and prolonged rupture of membranes increases risk of HSV transmission Cesarean section lowers risk of transmission July 2009

Herpes Simplex Virus: Epidemiology (3)
In the United States, 75% of neonatal HSV is caused by genital herpes (HSV-2) HSV-2 seroprevalence in women of childbearing age is 26%; rates may be higher in HIV-infected women HIV-infected women shed HSV from genital area more frequently than HIV-uninfected women (may be asymptomatic) No evidence that in utero HSV infection is more frequent in HIV-infected pregnant women HSV infection may increase the risk of MTCT July 2009

Herpes Simplex Virus: Clinical Manifestations
Neonatal HSV may appear as: Disseminated multiorgan disease (occurring in about 25% of neonates with infection) Localized CNS disease (about 35%) Localized infection of skin, eyes, mouth (about 40%) July 2009

Herpes Simplex Virus: Clinical Manifestations (2)
Disseminated disease usually manifests at 9-11 days with encephalitis in 60-70% and vesicular rash in 60% Localized disease usually appears at days Even with treatment, neonates with skin lesions may have recurrences for first 6 months of life Outside neonatal period, most common presentation is orolabial disease with fever, irritability, submandibular lymphadenopathy, painful ulcers in gingival and oral mucosa (gingivostomatitis) July 2009

Herpes Simplex Virus: Clinical Manifestations (3)
HSV-2 infection presents as painful, ulcerative lesions on the perineum as well as on the vaginal and urethral mucosa HSV keratitis, neonatal HSV, HSV encephalitis, and herpetic whitlow have similar presentations in HIV-infected and HIV-uninfected patients but may be more severe among HIV-infected patients When severely immunocompromised, may develop disseminated HIV infection including infection of esophagus, CNS, liver, lung, kidney, spleen, adrenal Outside of the neonatal period, the most common appearance of herpes virus infection in children is orolabial disease. Fever, irritability, tender submandibular lymphadenopathy, and superficial, painful ulcers in the gingival and oral mucosa and perioral area characterize primary HSV gingivostomatitis. HIV-infected children who experience primary infection when they are immunocompromised can have severe local lesions or, more rarely, disseminated HSV with visceral involvement and generalized skin lesions with primary infection. Other sites of involvement among HIV infected children with severe immunocompromise include the esophagus, CNS, and genitals and disseminated disease involving the liver, adrenals, lung, kidney, spleen, and brain. July 2009 241

Herpes Simplex Virus: Diagnosis
Appearance of typical ulcers and vesicles Isolation of HSV from lesions following culture Diagnosis of neonatal HSV based on cultures from blood, skin vesicles, mouth, eyes, urine, and stool CSF using DNA PCR sequence common to HSV-1 and HSV-2 Direct immunofluorescence for HSV antigen in samples HSV DNA PCR has replaced brain biopsy Definitive diagnosis of HSV esophagitis requires endoscopy with biopsy Among children with suspected HSV encephalitis, detection of HSV DNA by PCR in the CSF has replaced brain biopsy as the diagnostic test of choice in such patients. Cultures of the CSF for HSV usually are negative. Definitive diagnosis of HSV esophagitis requires endoscopy with biopsy (histologic evidence of multinucleated giant cells with intranuclear viral inclusion) and culture. July 2009 242

Herpes Simplex Virus: Prevention
Effective ART regimens may decrease but not prevent the frequency of maternal genital HSV shedding Use of acyclovir or valacyclovir in late pregnancy in HIV-uninfected pregnant women may reduce the need for cesarean section; not recommended for HIV-infected women who should have cesarean section Avoid sexual contact when herpetic lesions are present Use condoms to reduce transmission of HSV and other sexually transmitted infections Chronic suppressive therapy with valacyclovir may reduce HSV-2 transmission July 2009 243

Herpes Simplex Virus: Treatment
Acyclovir is the drug of choice regardless of infection status (AI) (oral and IV formulations available) Treat neonatal HSV with 20 mg/kg/dose IV TID for 21 days for CNS and disseminated diseases For skin, eye, mouth disease, treat for 14 days Do not discontinue acyclovir in neonates with CNS disease unless CSF DNA PCR is negative at days of treatment (B III) Acyclovir is the drug of choice for disseminated HSV encephalitis: treat for 21 days Trifluridine is the treatment of choice for herpes keratoconjunctivitis July 2009 244

Herpes Simplex Virus: Treatment (2)
Alternatives to acyclovir in older children include valacyclovir and famciclovir (A I) No pediatric formulation available for valacyclovir Data on the use of famciclovir in children are not available July 2009 245

Herpes Simplex Virus: Adverse Events
Acyclovir toxicity effects primarily renal function Valacyclovir toxicity is similar to acyclovir Neutropenia may occur in contents Treatment failure should be managed with IV foscarnet (A I) See Appendix A, page 72. July 2009 246

Human Papillomavirus: Epidemiology
HPV infects cutaneous and mucosal squamous epithelium Approximately 100 distinct types HPV 16, 18, 31, 33, 35, 39, 45, 51, 56, 58, 59 are considered high risk Genital HPV types can cause conjunctiva, nasal, oral, and laryngeal warts Transmission occurs by direct contact or sexual contact (genital warts in young children may be a sign of sexual abuse) HPV DNA has been detected in cord blood peripheral blood cells and amniotic fluid, indicating the potential for in utero infection. Duration of membrane rupture has been associated with mother-to-child HPV transmission, and some studies have indicated higher infant HPV infection rates among infants delivered vaginally than by cesarean section. Reported rates of HPV detection in nasopharyngeal aspirates, buccal brush swabs, or genital swabs from infants born to HPV-infected mothers have varied (range: 2%–80%). In general, no neonatal clinical abnormalities have been associated with HPV detection. The presence of HPV DNA in newborn nasopharyngeal samples could represent contamination with infected maternal cells; however, persistence of HPV DNA in oral secretions or buccal swabs has been reported in 0–80% of infants with initially positive specimens who were followed through age 6 months. Infant laryngeal papillomas and juvenile laryngeal Papillomatosis are thought to be secondary to HPV transmitted from mother to child through aspiration of infectious maternal genital secretions during delivery. July 2009 247

Human Papillomavirus: Epidemiology (2)
Latent HPV seen in 5-42% of pregnant women without HIV infection HPV infection rates higher among HIV-infected women (up to 95%) Mother-to-child HPV transmission occurs and can result in infant laryngeal and juvenile laryngeal papillomatosis In general, no neonatal abnormalities are associated with detection of HPV in neonates July 2009

Human Papillomavirus: Epidemiology (3)
HPV detected in 13-60% of sexually active adolescent girls 40-80% of infections in HIV uninfected are transient Persistent infection with HPV 16, 81, 31, and 33 associated with high risk of developing cervical, vulvovaginal, and anal carcinoma; cervical and anal intraepithelial neoplasia Increased risk if HIV infected July 2009 249

Human Papillomavirus: Clinical Manifestations
Hyperplastic, papillomatosis and verrucous squamous epithelial lesions on the skin and mucous membranes including anal, genital, oral, nasal, conjunctiva, GI, and respiratory tract mucosa Lesions are soft, pink or white “cauliflower-like” sessile growths July 2009

Human Papillomavirus: Diagnosis
Most cutaneous and anogenital warts diagnosable on physical examination Diagnosis of laryngeal papillomatosis requires laryngoscopy DNA PCR can be used for detection of HPV types but is not necessary for diagnosis or management of anogenital or cutaneous warts or papillomas July 2009

Human Papillomavirus: Prevention
A vaccine to prevent HPV types 6, 11, 16, and 18 has been approved HPV 6 and 11 cause 90% of the external genital warts HPV 16 and 18 cause 70% of invasive cervical cancers To be fully effective, the HPV vaccine should be administered before the onset of sexual activity July 2009 252

Human Papillomavirus: Prevention (2)
Data on safety, immunogenicity and duration of immunity of HPV vaccine is not available in HIV-infected individuals Current recommendations are to immunize all females aged years: a secondary should be given 2 months after the first dose; a third dose should be administered 6 months after the first dose The HPV vaccine has not been shown to have a therapeutic benefit HIV infected sexually active women should have a pelvic examination and cervical cancer screening twice during the first year after diagnosis of HIV infection and annually thereafter. HIV-infected men who have sex with men and women may benefit from screening and treatment of anal HSILs July 2009 253

Human Papillomavirus: Treatment
Topical Treatment (B III) Standard topical treatment often ineffective in HIV-infected children as underlying infection persists and results in recurrence Podofilox 0.5% (antimitotic agent) Imiquimod cream 5% (immune enhancer) Trichloroacetic or bichloracetic acid 80-90% aqueous solution (caustic agent) See Appendix A, page 73. July 2009 254

Human Papillomavirus: Treatment (2)
Cidofovir topical gel 1% evaluated primarily in adults; used successfully for molluscum contagiosum in children with HIV infection Cryotherapy and electrodessication applied to each lesion; treatment can be repeated every 1-2 weeks Treatment of laryngeal papillomatosis directed primarily to removal of obstructions ART not consistently associated with reduced risk of HPV-related cervical abnormalities July 2009

Genital warts Standard topical treatment often ineffective in HIV-infected children as underlying infection persists and results in recurrence Podofilox 0.5% (antimitotic agent) Imiquimod cream 5% (immune enhancer) Trichloroacetic or bichloracetic acid 80-90% aqueous solution (caustic agent) Podophyllin resin 10-25% in a compound of tincture of benzoin Veregen, intraregional interferon or 5-fluorouracil/epinephrine gel implant, and cidofovirtopical gel. Lesions can be removed by cryotherapy or surgery (BIII). July 2009 256

Respiratory papillomatosis Should be managed by a specialist Treatment is directed toward removing lesions constructing the airway rather than eliminating the disease Lesions are removed by debridement or laser treatment Systemic interferon-alfa therapy or intralesional cidofovir has been used with limited success (C III) July 2009 257

Treatment of histologic CIN Follow-up with annual cytologic assessment is recommended for adolescents with CIN 1 (A II) Either treatment or observation should be implemented for up to 24 months using both colposcopy and cytology for CIN 2 or 3 not otherwise specified Treatment recommended for histologic diagnosis of CIN 3 Persistent CIN 1, 2, and 3 lesions in HIV-infected women should be treated as in HIV-uninfected women Treatment includes cryotherapy, laser therapy, cone biopsy, and loop electrosurgical excision July 2009 258

Human Papillomavirus: Role of ART, IRIS, and Adverse Events
ART has not been consistently associated with a reduced risk of HPV-related cervical abnormalities in HIV-infected women Major toxicities are associated with local skin irritation from topical therapy Pain is a frequent side effect of surgical procedures Interferon treatment may induce fever, fatigue, myalgia, and depression IRIS associated with oral warts has been observed in adults July 2009 259

PML: Epidemiology Rare demyelinating disease of the CNS in immunocompromised patients First described in association with chronic lymphocytic leukemia and Hodgkin disease Caused by the Jamestown Canyon polyoma virus (JCV) 50% of children are seropositive by 9-11 years of age Infection results in chronic asymptomatic carriage of the virus in kidneys, lymphoid tissue, bone marrow, and lymphocytes Reactivation of the virus in immunocompromised individuals results; virus is spread to the brain by lymphocytes July 2009

PML: Clinical Manifestations
No known symptoms of acute infection exist PML may initially present with focal neurologic deficits involving different regions of the brain Steady progression over course of weeks or months characterized by ataxia, aphasia, cranial nerve deficits, visual abnormalities, hemiparesis or quadriparesis, and eventually coma Survival has improved with ART July 2009

PML: Diagnosis Criteria for a clinical diagnosis include signs and symptoms on neurologic examination, focal white matter lesions on MRI or CT, and exclusion of other causes Brain biopsy with characteristic pathologic findings JCV may be demonstrated by in situ hybridization or by electron microscopy Brain biopsy demonstrates a characteristic triad of pathologic foci of demyelination, enlarged hyperchromatic oligodendrocytes with enlarged nuclei and basophilic staining of intranuclear material, and enlarged astrocytes with bizarre hyperchromatic nuclei. July 2009 262

There is no known means of preventing exposure to JCV
PML: Prevention There is no known means of preventing exposure to JCV The use of ART can prevent or reverse the development of severe immunosuppression, which may stabilize the disease July 2009

PML: Treatment and Adverse Events
There is no effective treatment for JCV or PML Survival of HIV-infected adults has been substantially improved with ART in adults but there are no data in children A number of studies have evaluated various forms of treatment, including cytosine arabinoside, cidofovir, and interferon-alfa, but none have been reported to be successful Following ART, patients may have improvement in their neurologic symptoms, remain stable, or have worsening of symptoms attributed to IRIS July 2009

Varicella-Zoster Virus: Epidemiology
9% of children <10 years of age experience varicella infection (before vaccine use) 95% of adults have antibody to VZV Rare perinatal VZV transmission Congenital VZV occurs in 2% of infants whose mothers have primary VZV in first trimester Zoster occurs only when previously VZV infected Rate of zoster as high as 70% in HIV-infected children who are immunocompromised at time of primary VZV infection VZV can be transmitted to the fetus in later gestation, resulting in neonatal varicella. When the mother develops varicella from 4 days before to 2 days after delivery without passive antibody prophylaxis, the attack rate for infants is approximately 20% and mortality is approximately 30%. In comparison, if maternal varicella precedes delivery long enough to allow transfer of VZV IgG antibodies across the placenta, infants might be born with cutaneous varicella lesions or have them in the first 5 days of life, but they are usually not at risk for serious complications. July 2009 265

Varicella-Zoster Virus: Epidemiology (2)
VZV is transmitted primarily from skin lesions during illness and is highly contagious Mother-to-child transmission can occur but is unusual Congenital varicella occurs in <1% of infants born to women who have VZV before 13 weeks’ gestation and in approximately 2% of infants born to women who have VZV between 13 and 20 weeks’ gestation VZV can be transmitted to the fetus in later gestation, resulting in acute neonatal infection Zoster was common in HIV-infected children prior to the widespread use of ART July 2009 266

Varicella-Zoster Virus: Clinical Manifestations
Prodrome of malaise and fever, followed by the appearance of a pruritic vesicle papular lesion Complications include superinfection of the skin, neurologic manifestations, transverse myelitis, and on occasion, vascular stroke, hepatitis, and pneumonia Uncommonly, HIV-infected children may experience persistent chronic infection with continued lesions for >1 month Zoster presents with painful pruritic unilateral vesicular eruptions in a dermatomal distribution The classical clinical presentation of varicella (i.e., a generalized pruritic vesicular rash and fever) is diagnostic. However, persistent lesions might be atypical and lack a vesicular component. The classical clinical presentation of zoster (i.e., a frequently painful vesicular eruption with a dermatomal distribution) is diagnostic. However, less typical rashes, including those that extend beyond dermatomal boundaries or that are bilaterally distributed or are generalized, also might represent zoster in HIV-infected children. HIV-infected children can have recurrent episodes of reactivated VZV infection that present with a disseminated rash more similar to chickenpox than zoster but without visceral dissemination; they might have multiple episodes of recurrent disease. July 2009 267

Varicella-Zoster Virus: Clinical Manifestations (2)
Congenital infection characterized by cicatricial skin scarring, limb hypoplasia, microcephaly, seizures, mental retardation, chorioretinitis, cataracts, microphthalmia, neurogenic bladder, hydroureter, abnormalities of swallowing Duration of disease longer and complications more frequent in HIV-infected children May develop VZV retinitis Acute in retinal necrosis occurs as a peripheral necrotizing retinitis July 2009 268

Varicella-Zoster Virus: Diagnosis
Clinical diagnosis based on typical generalized pruritic vesicular rash and fever Direct immunofluorescence for VZV antigen on cells from skin, conjunctiva, mucosal lesions VZV PCR sensitive and specific, can differentiate wild-type and vaccine-type virus VZV antibody response positive 2-3 weeks after onset of illness; IgM indicates acute infection or recurrent infection PCR can be used to detect VZV in samples, is extremely sensitive and specific, and can differentiate wild-type and vaccine VZV, but is available only in research laboratories. Serologic tests can be used to diagnose VZV infection, noting a substantial increase in antibody titer during convalescence (2–3 weeks after onset of illness) or the presence of VZV IgM antibody. VZV reactivation can induce VZV IgM antibodies in many patients so their presence does not differentiate primary from recurrent VZV infections. July 2009 269

Varicella-Zoster Virus: Prevention
HIV-infected individuals who have no history or laboratory evidence of VZV should avoid exposure to individuals with varicella or zoster Household contacts without evidence of previous varicella should be immunized with varicella vaccine HIV-infected children 1-8 years of age with CD4 percentage >15% should be considered for immunization Limited data indicate that varicella vaccine in HIV-infected children is well tolerated and that >80% of subjects have detectable antibody Varicella vaccine is administered as two doses of single antigen vaccine given three months apart. If varicella immunized, HIV infected individuals, develop severe symptoms following immunization, acyclovir treatment should be considered. If varicella immunoglobulin is not available or > 96 hours have elapsed since exposure some individuals recommend the administration of acyclovir, 80 mg/kg per day administered four times per day for five to seven days. July 2009 270

Varicella-Zoster Virus: Prevention (2)
HIV-infected children with low CD4 counts may develop pneumonia and neurologic manifestations following immunization Immunization of such children may be considered following treatment with ART and evidence of immune restoration Postexposure prophylaxis against varicella in HIV-infected children should be provided within 96 hours after close contact using varicella zoster immunoglobulin Data are lacking regarding the effectiveness of acyclovir for preventing varicella in HIV-infected susceptible children July 2009 271

Varicella-Zoster Virus: Treatment
Acyclovir is the drug of choice for HIV-infected children; should be initiated as soon as possible after diagnosis (A I) New lesions may continue to appear several days after initiation of treatment Dosing <1 year of age: 10 mg/kg/dose IV Q8H as 1-hour infusion for 7-10 days >1 year of age: dosage as above or 500 mg/m2/dose IV Q8H as 1-hour infusion for 7-10 days If new lesions continue to appear during treatment it is recommended that treatment continue until no new lesions have appeared for 48 hours. July 2009 272

Varicella-Zoster Virus: Treatment (2)
Children with HIV coinfection and normal or minimal decrease in CD4 T-cell counts Acyclovir: 20 mg/kg per dose orally 4 times daily; maximum dose 800 mg (B III) Children with zoster and HIV infection Oral acyclovir Use IV if severely immunocompromised, trigeminal nerve involvement, or extensive multidermatomal zoster July 2009

Oral acyclovir data limited in children <2 years of age; infants who receive long-term suppressive therapy (300 mg/kg/m2/dose administered TID) frequently develop neutropenia (usually self-limited) Acute retinal necrosis: high-dose acyclovir (10-15 mg/kg IV Q8H for days Progressive retinal necrosis: combination of ganciclovir (5 mg/kg Q12H) and foscarnet (90 mg/kg IV Q12H plus twice weekly intravitreal ganciclovir (2 mg/0.5 mL or foscarnet 1.2 mg/0.5 mL) July 2009

Use IV foscarnet for treatment of children with acyclovir-resistant VZV (B II) Dosage: mg/kg/dose IV over period of 1-2 hours administered TID for 7 days or until no new lesions appear Modify dosage in patients with renal insufficiency Valacyclovir and famciclovir are alternative treatments (not active against acyclovir-resistant VZV) but data in children are limited July 2009

Varicella-Zoster Virus: Adverse Events
Acyclovir toxicities include phlebitis, nausea, vomiting, rash, impaired renal function, neutropenia Foscarnet toxicities include decreased renal function IRIS has been described in adults and children following initiation of ART July 2009

About This Slide Set This presentation was prepared by Arthur Ammann, MD, Clinical Professor of Pediatrics University of California and President of Global Strategies for HIV Prevention for the AETC National Resource Center, in July 2009 See the AETC NRC website for the most current version of this presentation: July 2009

Recommendations from Centers for Disease Control and Prevention,

Similar presentations

Presentation on theme: "Recommendations from Centers for Disease Control and Prevention,"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Recommendations from Centers for Disease Control and Prevention,

Similar presentations

Presentation on theme: "Recommendations from Centers for Disease Control and Prevention,"— Presentation transcript:

Similar presentations

About project

Feedback