Presentation on theme: "Opportunistic Infections Dr. Robert Harrington, M.D. December 18, 2008"— Presentation transcript:
1Opportunistic Infections Dr. Robert Harrington, M.D. December 18, 2008 I’d like to welcome everyone to the I-TECH HIV/AIDS Clinical Seminar Series. We have with us today Dr. Robert Harrington. Dr. Harrington is currently an associate professor of medicine at the University of Washington and medical director of the Harborview Medical Center HIV clinic (the Madison Clinic). His interests are in general infectious diseases, clinical HIV, and the development of laboratory assays of HIV infectivity. He’s published over 40 manuscripts and book chapters on HIV and infectious diseases.Today he will be presenting on HIV and opportunistic infections (OIs). He will review relevant facts, differential diagnoses, and treatment, as well as the timing of HAART initiation in the context of treating OIs.Before we begin, I’d like to ask all the sites to type in how many participants are at their sites. If you are an individual, please type “1”.If your site has not already provided a topic suggestion for next year’s series, please do so now. Site coordinators should solicit ideas from participants at this time During the session, Maureen will be privately chatting sites who have not responded. Your input is very important to the planning for next year’s Clinical Seminar Series.
3HIV Infection: Pathogenesis Anti-HIVT-cell responseSero-conversionAntibody responseTypical CourseIntermediate StageAIDSCD4 Cell CountPlasma RNA CopiesViral set point1,000CD4 Cells5004-8 WeeksUp to 12 Years2-3 YearsA lot of important stuff happens here
4CD4 Count and Opportunistic Infections CD4 Cell CountBacterial Pneumonia, TB,HSV, Cryptosporidiosis1,000Thrush, lymphoma, KS500PCP200100MAC, CMV, PML, PCNSL,Cryptococcus, MicrosporidiaToxo4-8 WeeksUp to 12 Years2-3 Years
5Opportunistic Infections and Geography North AmericaCommon OIsPCPMACCandidaRegional EffectsSouthwest:CoccidiodomycosisMidwest:Histoplasmosis and BlastomycosisSouth:Blastomycosis and Toxoplasmosis
6Opportunistic Infections and Geography PCP, TBCandida, MACCryptococcusLeishmaniasisThe WorldPCPTBCandidaCryptococcusPenicilliosisCandidaPCPMACTBBacteriaMalariaCryptococcusPCPTBCryptococcusIsosporaCryptosporidiosisMicrosporidiaHolmes, CID, 03Putong, SEA Trop Med, 02Margues, Med Mycol, 2000Amornkul, CID, 03
7Prophylaxis to Prevent Opportunistic Infections Considerations for ProphylaxisInfection should be common and/or predictableInfection should be clinically significantTreatment (prophylaxis) should be effective, non-toxic and affordable
8Prophylaxis to Prevent Opportunistic Infections in the Developed World PrimaryPCP CD4 < 200MTb PPD > 5mmToxo IgG+,CD4 < 100MAC CD4 < 50VZV Exposure with IgG- or no hstryS. pneumoniaeHBVHAVInfluenzaSecondaryPCPToxoMACCMVCryptococcosisHistoplasmosisCoccidioidomycosisSalmonella species bacteremiaRecurrent HSVRecurrent Candidiasis
9Prophylaxis to Prevent Opportunistic Infections in the Developing World Primary prophylaxis:Secondary prophylaxis: for PCP and CryptococcusWHO Guidelines on co-trimoxazole prophylaxis for HIV-relatedinfections among children, adolescents and adults. August, 2006
10TB prevention WHO recommendation: Treat tuberculin skin test positive HIV-infected persons without active TB with 6 month regimen isoniazid preventive therapy (IPT)Difficulties:Lack of tuberculin skin testingPeople not screenedScreen positive do not receive INHScreen positive started on INH do not complete regimen
11HIV-Associated and Opportunistic Infections PCPMACCryptosporidiosisMicrosporidiosisBacterial respiratory infectionsBacterial enteric infectionsBartonellosisCoccidiodomycosisParacoccidiomycosisHistoplasmosisCryptococcusToxoplasmosisCandidaTBAspergillosisCMVHSVVZVPML (JCV)HHV-8HPVPenicilliosisLeshmaniasis
12HIV ASSOCIATED MALIGNANCIES AIDS Defining MalignanciesKaposi’s sarcomaPrimary CNS lymphoma (PCNSL)Non-Hodgkin’s lymphoma (NHL)Invasive cervical cancer
13HIV ASSOCIATED MALIGNANCIES Increased Rates of Other Cancers in HIVHodgkin’s diseaseAnal cancerMultiple myelomaLeukemiaLung cancerHead and neck tumorsGI malignanciesGenital cancersHypernephromaSoft tissue tumors
14EFFECTS OF HAART ON OPPORTUNISTIC INFECTIONS Declining incidenceReduced need for prophylaxis (primary and secondary)Spontaneous improvements and cureImmune reconstitution effects
15EFFECT OF HAART ON INCIDENCE OF OPPORTUNISTIC INFECTIONS J.E. Kaplan et al. CID 2000;30:S5-S14(Kovacks, NEJM, 2000)
16Effect of HAART on Opportunistic Infections: Reduced Need for Prophylaxis Primary ProphylaxisPCP When CD4 > 200 for 3 monthsMAC When CD4 > 100 for 3 monthsToxo When CD4 > 200 for 3 months
17Secondary Prophylaxis or Maintenance Therapy Effect of HAART on Opportunistic Infections: Reduced Need for ProphylaxisSecondary Prophylaxis or Maintenance TherapyPCP When CD4 > 200 for 3 monthsCMV When CD4 > for 6 monthsMAC When CD4 > 100 for 6 months, no symptoms of MAC and after 12 months of MAC RxToxo When CD4 > 200 for 6 months and completed initial Toxo RxCryptococcus When CD4 > for 6 months and completed initial Crypto Rx
19Case 1A 40 yo male with severe bipolar disease presents with cough, weight loss, dyspnea and low grade fever.His PMH is notable for recurrent bacterial pneumonia, methamphetamine and alcohol abuse. He has refused all medications.On exam he is thin and in mild respiratory distress. T 38C, BP 100/70, HR 100, RR 18, O2 saturation 89% at rest. Lung exam reveals fine rales at lung bases.
21Case 1What diagnostic studies do you want?(www.tulane.edu)
22Case 1 How would you treat this patient? Treatment: TMP-SMX, pentamidineTimethoprim-dapsone, clindamycin and primaquine, atovoqoneTrimetrexate and leucovorinSevere disease (paO2 < 70 or Aa gradient > 35): add steroidsHow would you treat this patient?
23Case 1 Over the next 10 days the patient slowly improves. His CD4 T-cell count returns at 60 cells/uL.Should he receive HAART and, if so, when should he start?
24Timing of HAART#142: Immediate Vs Delayed ART in Setting of Acute OI, Zolopa, Powderly, et.al. (ACTG 5164)Randomized study of ARV given within 14 days of Rx for OI Vs delayed (at least 4 wks)Patients with TB excludedPrimary endpoint: 48 week combination of 3 categorical variables1. Death or alive with new AIDS diagnosis2. Alive with HIV RNA > 50 and no new AIDS diagnosis3. Alive with HIV RNA < 50 and no new AIDS diagnosis
25Timing of HAART#142: Immediate Vs Delayed ART in Setting of Acute OI, Zolopa, Powderly, et.al. (ACTG 5164)Patients (N=282)Median age 38Median CD4 = 29 and log10 HIV RNA level = 5.07OIsPCP 63%Cryptococcal meningitis 13%Pneumonia 10%Median time to starting ART 12 Vs 45 days
26Timing of HAART ACTG 5164: Results No significant difference between immediate Vs delayed for the composite endpointImmediate arm had fewer deaths/new AIDS diagnosisImmediate arm had longer time to death/new AIDS diagnosis (HR 0.53)P=0.035
27Case 2RT is an asymptomatic 47 yo Asian male with newly diagnosed HIV who presents for care.His PMH is notable for multiple STDs and “hepatitis”PE is notable only for thrush, mild cervical adenopathy and seborrheic dermatitis.CD4 is 380, HIVRNA is 80K, ALT is 240, HepAAB+, HepCAB and RNA negative, HepBsAG+, cAB+, eAG+ and HBV DNA 40 million
28Case 2How common is chronic Hepatitis B infection and why do you suppose he has it?What about co-infection with HIV?
29Outcome of Hepatitis B by Age of Acquisition 10010080806060Chronic Infection (%)Chronic InfectionSymptomatic Infection (%)40402020Symptomatic InfectionBirth1-6 months7-12 months1-4 yearsOlder Childrenand AdultsAge at Infection
30Natural History: Acute HBV Infection with Progression to Chronic Infection (6 months)Chronic(Years)HBeAganti-HBeHBsAgTotal anti-HBcTiterIgM anti-HBcWeeks after Exposure481216202428323652Years
32Natural History: Chronic HBV Definitions: NIH Workshop HBsAg-positive for at least 6 monthsPhases of Chronic hepatitis BImmune Tolerant Phase: HBeAg+, normal ALT, HBV DNA > 200,000 IU/ml (>1 million copies)Immune Active or Clearance Phase: elevated ALT, HBV DNA > 2,000 IU/ml, HBeAg or anti-HBeInactive Hepatitis B carrier: anti-HBe, ALT WNL, HBV DNA < 2,000 IU/mlReactivation of hepatitisClearance of HBsAg(Hoofnagle, Hepatology 2007;45: )
33Hepatitis B: Epidemiology 2 billion people have evidence of HBV infection1/3 of world’s populations350 million people chronically infected15% to 25% will develop HBV-related chronic liver disease (cirrhosis, hepatocellular carcinoma) and die without interventionUp to 1 million deaths worldwide each year from HBV-related chronic liver diseaseWorldwide Burden of DiseaseWorldwide, approximately 2,000 million individuals, or X% of the world’s population, have serologic evidence of current or past HBV infection. Over 200 million individuals are chronically infected with HBV, and are at risk of developing and dying from HBV-related chronic liver disease, including cirrhosis and primary hepatocellular carcinoma. Each year 1 million people die from HBV-related chronic liver disease making it one of the major causes of mortality worldwide. (Kane M. Global status of HB Immjnization, Acta Gastro-Enterologica Belgica, LXI, April-June 1998)
34Hepatitis B: Epidemiology Geographic Distribution of Chronic HBV InfectionThe world can be divided into areas of high, intermediate, and low endemicity based on the prevalence of HBsAg in the population. Areas of high endemicity are those in which the prevalence of HBsAg >8%. Southeast Asia, East Asia, many of the Pacific Islands, and parts of South America and Africa are areas of high endemicity. Areas of intermediate endemicity are those in which the prevalence of HBsAg is 2%-7%, and include Eastern Europe, the Middle East, and central Asia. Areas of low endemicity, in which <2% of the population is HBsAg positive, include Australia, North America, and Western Europe.HBsAg Prevalence8% - High2-7% - Intermediate<2% - Low
35Hepatitis B: Epidemiology Among all the chronic hepatitis B carriers worldwide, 75% are AsiansWhile the overall incidence of chronic hepatitis B in the US population is less than 1 in 200, the incidence among Asian Americans is 1 in 10 (Source: Asian Liver Center of Stanford University)9-16% of HIV infected patients in the US are co-infected with HBV
36Case 2….back to the caseHe is not inclined to start HAART but wants to discuss it with you.Should you be worried about his HBV infection and why?Does it influence your decision to recommend HAART?
37Natural History: Long-Term Outcome of Chronic HBV Hepatocellular carcinoma (HCC)25%-40% of males10-15% femalesCirrhosis10% to 20% of males and femalesBeasley. Cancer 1988;61:McMahon. Ann Intern Med 2001;135:
38Elevated HBV DNA as Risk for HCC: R.E.V.E.A.L.-HBV Study* 23,820 residents 7 townships in Taiwan4,155 HBsAg-positive3,653 tested for HBV DNA at entryMedian age 46 years; follow-up 11.4 yearsFindings: Risk factors for HCC at study entry using Regression analysisHBV DNA > 104 copies/mlLiver cirrhosisAgeAPPLIES TO ADULTS > 40WITH GENOTYPES B&CChen, C.-J. et al. JAMA 2006;295:65-73.Chen JAMA 2006;295:65-73*Funded by Bristol Myers Squib
39Cumulative Incidence of Hepatocellular Carcinoma by Serum HBV DNA Level at Study Entry Chen, C.-J. et al. JAMA 2006;295:65-73.
40Natural History: Chronic HBV: Factors Associated with Progression HBV DNA levelGenotypePre-core mutantCore Promoter mutationsOther viruses: HIV, DELTA, HCVDemographic: Age, male sexEnvironmental and SocialAlcoholNAFLDAflatoxin
41Natural History: Chronic HBV/HIV Co-infection Co-infected patients haveHigher HBV DNA levelsLower rates of spontaneous HBeAg clearanceMore severe liver disease and higher liver-related mortalityMay experience severe hepatitis flares due to immune reconstitution after HAARTMay have “occult” HBV infection with high HBV DNA levels but with negative HBsAg.Any HIV+ patient who tests + for either HBsAg or HBcAB should be tested for HBV DNA
42Long-Term Goals of Antiviral Therapy Decrease risk of development of cirrhosisIf cirrhosis is present, decrease risk of decompensationIf decompensated cirrhosis present, treat to revert patient to compensated cirrhosisDecrease risk of development of hepatocellular carcinoma
43AASLD Practice Guidelines, 2007* HBsAg +HBeAgPositiveALT < 1 X ULNALT 1-2 X ULNALT >2 X ULNQ 6 mo ALTQ 12 mo HBeAgQ 3 mo ALTQ 6 mo HBeAgLiver bx if persistent or age > 40, Rx as neededQ 1-3 mo ALT, HBeAgIf persistent, Liver bx & Rx;Immediate Rx if jaundice ordecompensatedLok & McMahon. Hepatology 2007;45: Available at aasld.org* HCC surveillance if indicated
44AASLD Practice Guidelines, 2007* HBsAg +HBeAgNegativeALT > 2X ULNDNA > 20,000 IU/mLALT 1-2X ULNDNA 2,000-20,000 IU/mlALT < 1X ULNDNA < 2,000 IU/mLQ 3 mo ALT & DNAIf results persist,liver bx, treat as neededQ 3 mo ALT X 3,Then Q 6-12 moIf ALT still WNLLiver bx & Rx* HCC surveillance if indicatedLok & McMahon. Hepatology 2007;45: Available at aasld.org
45Treatment of HBV/HIV Co-infection All HBV/HIV patients should be offered HAARTIf treating HBV only can use IFN or adefovirWhen treating both HIV and HBV - Rx with TDF and FTC is preferredPatients already on HAART with agents not active against HBV can be treated with the addition of IFN, adefovir or entecavirPatients with lamivudine resistant HBV can be treated with the addition of TDFWhen altering HAART, consider the need to continue HBV therapy unless the patient has cleared HBeAg
46Case 3A 38 yo South African male presents with a 10 kg weight loss, 10 weeks of cough and intermittent fever. He has no past medical history.On exam he is thin, T 38.8 C, BP 100/70, HR 104, RR 20. He has prominent cervical adenopathy, oral thrush and course breath sounds over his R upper and mid lung zones.
47Case 3 HIV test is + and Sputum smear stains 3+ for AFB What diagnostic testing do you want?HIV test is + and Sputum smear stains 3+ for AFB
48Case 3He is admitted to a hospital ward with similar patients and started on “RIPE” therapy.After a week his constitutional symptoms improve. His CD4 T-cell count measures 15 cells/uL.Should he be offered HAART?If so, when should HAART be started?Are there TB and HIV drug interactions of concern?
49WHO/DHHS: Treatment HIV-TB Pulmonary TB Extrapulmonary TB CD4 < 100 Start TB therapy, start HAART in 2 weeksStart TB therapyHAART as soon as TB Rx tolerated (b/n 2-8 wks)Some experts would wait until 8 weeks (avoid IRIS)CDStart TB therapyHAART after intensive phase of TB Rx(HAART earlier if severely immunocompromised)CDStart TB therapyMonitor CD4 count and start HAART when indicatedCD4 > 350CD4 notavailableTB therapyImproving, no OIsHAART when TB Rxcomplete
50Treatment and Outcome Thailand Survival Retrospective study of 1103 HIV+ patients with TB411 received HAARTRisk factors for deathNo HAARTDelay of HAART > 6 monthsMDR TBGastrointestinal TB(Manosuthi, J Acquir Immune Defic Syndr 2006;43:42-46)
51Timing of HAART and TBCROI 2007: Abst # 81: Early Mortality Among Patients with HIV and TB in Africa, Lawn, et, al.Observational study of mortality before and during first 16 weeks of ART in patients with (n=213) and without (n=675) TBMV analysis: mortality associated only with CD4 < 100 and WHO stage 4Among 73 patients who had TB diagnosed prior to HAART there were 14 deaths10 occurred among patients waiting for HAART4 occurred after HAART - 2 due to IRS
52COD in Patients with TBCROI 2007: Abst # 82: Cause of Death in HIV + Patients with TB in Soweto, South Africa, Martinson, et.al.Results of complete autopsies, N=47Immediate Cause of DeathPulmonary TB19Bacterial pneumonia4Disseminated TB4*CMV pneumonia7PCP3* Contributed to another 28
53Immune Reconstitution Syndrome TB-associated IRS in South Africa160 patients receiving Rx for TB at the time HAART initiatedMedian CD4 68IRS in 12% overall, 32% in those who started HAART within 2 months of TB RxMV analysis: IRS risksLow CD4Early HAART – OR for starting HAART < 30 days = 69.52 IRS deaths (both had disseminated TBTB-IRS and CD4 and HAART(Lawn, AIDS 2007;21:335-41)
54TB/HIV Co-infection: Principles of Treatment Treatment generally the same as in HIV- patients (4 drugs for 2 months and 2 drugs for 4 months)Sub-optimal response (culture + after 2 months) – give 9 months, skeletal TB – 6 to 9 months, CNS TB – 9 to 12 monthsIf using regimens without INH or a rifamycin - duration should be 12 to 15 months
55Principles of Treatment: Importance of Rifamycin Treatment with NON rifamycin-containing regimens is associated with:• Higher relapse rates• Higher mortalityWallis, et al. (1996) Tuber Lung Dis 77:516-23Hawken, et al. (1993) Lancet 342:332-38Perriens, et al. (1991) AM Rev Resp Dis 144:750-55Korwnromp, et al. (2003) CID 37:101-12
56Principles of Treatment Be wary of drug interactions between the rifamycins and HIV medicationsDo not use TB treatment regimens that are dosed weekly (e.g. INH-rifapentine) or even twice weekly in patients with CD4 counts < 100Consider measuring drugs levels if there is concern for malabsorption or increased elimination of TB therapies
57Principles of Treatment Drug Interactions: The P450 systemIsoform CYP 3A is affected and/or involved in the metabolism of rifamycins, NNRTI and PIsRifamycins: Induce CYP 3ARifampin > rifapentine > rifabutinRifampin is not metabolized by CYP 3A (level not affected by other drugs that influence CYP 3A)Rifabutin is metabolized by CYP 3A (level is affected by other drugs that also affect CYP 3A)
58Principles of Treatment Drug Interactions: The P450 systemNNRTIs (efavirenz and nevirapine)Induce CYP 3AProtease Inhibitors (many)Inhibit CYP 3A
59Principles of Treatment If using rifampin - avoid PI-based HAART - use NNRTIs insteadIf using rifabutin - can use PIs or NNRTI - but will have to dose adjust the rifabutin in most cases
61Principles of Treatment Drug Interactions: Rifamycins and PIsPI Rifabutin RifampinSQV/RTV 400/400 BID 150 QOD (150 3x/wk) NoIDV/RTV 800/200 BID 150 QOD (150 3x/wk) NoATZ/RTV 300/100 QD 150 QOD (150 3x/wk) No dataAPV/RTV 600/100 BID 150 QOD (150 3x/wk) No dataTPV/RTV 500/200 BID 150 QOD (150 3x/wk) No dataDRV/RTV 600/100 BID 150 QOD (150 3x/wk) No data
62Principles of Treatment Drug Interactions: Rifamycins and NNRTIsNNRTI Rifabutin RifampinEFV 600 QD QD (600 3x/wk) QDNVP 200 BID QD QDDLV No NoWeb site for more complete table showing dosages:
63Case 3…back to the case10 days into his TB therapy he is started on HAART.3 weeks later his fever and cough return
64Case 3What are you worried about and what are you going to do?
65XDR TB# 143: Exogenous Re-infection with MDR and XDR TB Among TB/HIV Infected Patients in Rural South Africa, Andrews, et.al.Case control study of patient with pulmonary TB at Church of Scotland Hospital, South Africa fromN=170; 43 had baseline and follow-up cultures; 23 developed MDR or XDR TB
66XDR TB# 143: Exogenous Re-infection with MDR and XDR TB Among TB/HIV Infected Patients in Rural South Africa, Andrews, et.al.170 patients with TB43 had both initial andfollow up cultures done23 developed MDR or XDR TB17 had paired spoligotypes performed17/17 pairs were NOT matched
67XDR TB# 143: Exogenous Re-infection with MDR and XDR TB Among TB/HIV Infected Patients in Rural South Africa, Andrews, et.al.23 developed MDR or XDR TB17 had paired spoligotypes performed17/17 pairs were NOT matchedAll 17 patients had been hospitalized15/17 who were HIV tested were +
68Treatment and Outcome MDR and XDR TB (Raviglione, NEJM 2007;356:656-59)
69Treatment and Outcome Survival XDR TB Report of 53 cases in rural South Africa55% had never been treated for TB67% had recently been hospitalized44 (100%)/44 tested for HIV were + (median CD4 63)52 (98%)/53 died, median survival of 16 days49 cases in USA: HIV+: 74% ( ) Vs 10% ( )Survival(Gandhi, Lancet, 2006; 368: )(MMWR, 2007; 56(11): )
70# 112: Confronting the Catastrophe of M/XDR TB, Gerald Friedland Infection with resistant organisms acquired in healthcare settings is central to recent MDR/XDR outbreaksNeedBetter diagnosis and infection control proceduresDe-centralization of careBetter integration of HIV and TB careBetter diagnosis and infection control proceduresDe-centralization of careBetter integration of HIV and TB care
71Case 4A 46 yo Ethiopian male with untreated HIV and a CD4 T-cell count of 110 presents with mild dysphagia, weight loss, abdominal fullness and fatigue.On exam he appears chronically ill. T 38 C, BP 110/60, HR 98, RR12. He has thrush, a palpable liver and spleen tip and several nodular skin lesions.His Hct is 24, WBC 1800, plts 90. AST 110, ALT 123, AP 200, bili 2.3.
72Case 4Skin lesions for Case 4(www.dermatology.cdlib.org)
73Case 4 What is your differential diagnosis for this patient? What diagnostic tests will you perform?
74Case 4Blood smear or buffy coat or BM of Leishmania amastigotes
75Leishmaniasis and HIV An intracellular protozoa Transmitted to humans by phlebotomine sand fliesMost cases reported in southern Europe (Spain, Italy, France), Ethiopia, central and south America
76Leishmaniasis and HIVReported cases of Leishmania and HIV Co-infection(www.who.int)
77Leishmaniasis and HIV Clinically Cutaneous, mucosal or visceral diseaseHIV patients:Disseminated visceral diseaseCytopeniasAtypical locations: GI, lung, pleura and peritoneal spaces, unusual cutaneous lesions
78Leishmaniasis and HIV Treatment: HAART + AmB 0.5 to 1.0mg/kg/d (to total dose of gms)Liposomal AmB 2-4mg/kg/d (to total dose of 20 to 60 mg/kg)Pentavalent antimony 20 mg/kg/d for 3-4 weeksSecondary prophylaxis q 3 to 4 weeksConsider discontinuing if CD4 > 350
80SummaryOpportunistic infections are predictable based on a patients immune status and environmentDisseminated and atypical presentations are the rule with extreme immune suppressionProphylaxis against certain OIs is indicated if the OI is common and the prophylaxis is affordable, effective and well toleratedHAART alone is treatment enough for certain OIs and can eliminate the need for prophylaxisThe timing of HAART relative to OI therapy is controversial but should probably be early…..however, watch out for IRIS!
82Next session: January 8th, 2009 Lisa Frenkel Pediatric HIV Thank you for attending the session. Please type in again how many participants are at your site. We will answers to the questions that we were unable to get to today to the Distance Learning listserv. If you have additional questions, please them to the listserv. That listserv is:Please contact if you would like to get on this listserv or if you have any more topic suggestions for next year's series.