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Welcome to I-TECH HIV/AIDS Clinical Seminar Series Opportunistic Infections Dr. Robert Harrington, M.D. December 18, 2008.

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Presentation on theme: "Welcome to I-TECH HIV/AIDS Clinical Seminar Series Opportunistic Infections Dr. Robert Harrington, M.D. December 18, 2008."— Presentation transcript:

1 Welcome to I-TECH HIV/AIDS Clinical Seminar Series Opportunistic Infections Dr. Robert Harrington, M.D. December 18, 2008

2 MMWR 1981

3 Plasma RNA Copies CD4 Cells 4-8 WeeksUp to 12 Years2-3 Years CD4 Cell Count 1, Intermediate StageAIDS HIV Infection: Pathogenesis Typical Course Viral set point Anti-HIV T-cell response Sero-conversion Antibody response A lot of important stuff happens here

4 MAC, CMV, PML, PCNSL, Cryptococcus, Microsporidia Toxo PCP 4-8 WeeksUp to 12 Years2-3 Years CD4 Cell Count 1, CD4 Count and Opportunistic Infections Bacterial Pneumonia, TB, HSV, Cryptosporidiosis Thrush, lymphoma, KS

5 Opportunistic Infections and Geography Common OIs PCP MAC Candida Regional Effects Southwest: –Coccidiodomycosis Midwest: –Histoplasmosis and Blastomycosis South: –Blastomycosis and Toxoplasmosis North America

6 Opportunistic Infections and Geography The World TB Bacteria Malaria Cryptococcus Candida PCP MAC Holmes, CID, 03 Putong, SEA Trop Med, 02 Margues, Med Mycol, 2000 Amornkul, CID, 03 PCP TB Candida Cryptococcus Penicilliosis PCP TB Cryptococcus Isospora Cryptosporidiosis Microsporidia PCP, TB Candida, MAC Cryptococcus Leishmaniasis

7 Prophylaxis to Prevent Opportunistic Infections Considerations for Prophylaxis Infection should be common and/or predictable Infection should be clinically significant Treatment (prophylaxis) should be effective, non-toxic and affordable

8 Prophylaxis to Prevent Opportunistic Infections in the Developed World Primary PCPCD4 < 200 MTbPPD > 5mm ToxoIgG+,CD4 < 100 MACCD4 < 50 VZVExposure with IgG- or no hstry S. pneumoniae HBV HAV Influenza Secondary PCP Toxo MAC CMV Cryptococcosis Histoplasmosis Coccidioidomycosis Salmonella species bacteremia Recurrent HSV Recurrent Candidiasis

9 Prophylaxis to Prevent Opportunistic Infections in the Developing World WHO Guidelines on co-trimoxazole prophylaxis for HIV-related infections among children, adolescents and adults. August, 2006 Primary prophylaxis: Secondary prophylaxis: for PCP and Cryptococcus

10 TB 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 testing –People not screened –Screen positive do not receive INH –Screen positive started on INH do not complete regimen

11 HIV-Associated and Opportunistic Infections PCP MAC Cryptosporidiosis Microsporidiosis Bacterial respiratory infections Bacterial enteric infections Bartonellosis Coccidiodomycosis Paracoccidiomycosis Histoplasmosis Cryptococcus Toxoplasmosis Candida TB Aspergillosis CMV HSV VZV PML (JCV) HHV-8 HPV Penicilliosis Leshmaniasis

12 HIV ASSOCIATED MALIGNANCIES AIDS Defining Malignancies Kaposi’s sarcoma Primary CNS lymphoma (PCNSL) Non-Hodgkin’s lymphoma (NHL) Invasive cervical cancer

13 HIV ASSOCIATED MALIGNANCIES Hodgkin’s disease Anal cancer Multiple myeloma Leukemia Lung cancer Head and neck tumors GI malignancies Genital cancers Hypernephroma Soft tissue tumors Increased Rates of Other Cancers in HIV

14 EFFECTS OF HAART ON OPPORTUNISTIC INFECTIONS Declining incidence Reduced need for prophylaxis (primary and secondary) Spontaneous improvements and cure Immune reconstitution effects

15 EFFECT OF HAART ON INCIDENCE OF OPPORTUNISTIC INFECTIONS J.E. Kaplan et al. CID 2000;30:S5-S14 (Kovacks, NEJM, 2000)

16 Effect of HAART on Opportunistic Infections: Reduced Need for Prophylaxis Primary Prophylaxis PCPWhen CD4 > 200 for 3 months MACWhen CD4 > 100 for 3 months ToxoWhen CD4 > 200 for 3 months

17 Effect of HAART on Opportunistic Infections: Reduced Need for Prophylaxis Secondary Prophylaxis or Maintenance Therapy PCPWhen CD4 > 200 for 3 months CMVWhen CD4 > for 6 months MACWhen CD4 > 100 for 6 months, no symptoms of MAC and after 12 months of MAC Rx ToxoWhen CD4 > 200 for 6 months and completed initial Toxo Rx CryptococcusWhen CD4 > for 6 months and completed initial Crypto Rx

18 Opportunistic Infections Treatable with HAART alone Progressive Multifocal Leukoencephalopathy (PML) Cryptosporidiosis Microsporidiosis Kaposi’s sarcoma Mycobacterium avium complex (sometimes)

19 Case 1 A 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.

20 Case 1 CXR of Case 1 (www.learningradiology.com)www.learning

21 Case 1 What diagnostic studies do you want? (www.tulane.edu)

22 Case 1 Treatment: –TMP-SMX, pentamidine –Timethoprim-dapsone, clindamycin and primaquine, atovoqone –Trimetrexate and leucovorin –Severe disease (paO2 35): add steroids How would you treat this patient?

23 Case 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?

24 Timing 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 excluded Primary endpoint: 48 week combination of 3 categorical variables –1. Death or alive with new AIDS diagnosis –2. Alive with HIV RNA > 50 and no new AIDS diagnosis –3. Alive with HIV RNA < 50 and no new AIDS diagnosis

25 Timing of HAART #142: Immediate Vs Delayed ART in Setting of Acute OI, Zolopa, Powderly, et.al. (ACTG 5164) Patients (N=282) –Median age 38 –Median CD4 = 29 and log 10 HIV RNA level = 5.07 –OIs PCP 63% Cryptococcal meningitis 13% Pneumonia 10% –Median time to starting ART 12 Vs 45 days

26 Timing of HAART No significant difference between immediate Vs delayed for the composite endpoint Immediate arm had fewer deaths/new AIDS diagnosis Immediate arm had longer time to death/new AIDS diagnosis (HR 0.53) P=0.035 ACTG 5164: Results

27 Case 2 RT 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

28 Case 2 How common is chronic Hepatitis B infection and why do you suppose he has it? What about co-infection with HIV?

29 Outcome of Hepatitis B by Age of Acquisition Symptomatic Infection Chronic Infection Age at Infection Chronic Infection (%) Symptomatic Infection (%) Birth 1-6 months7-12 months 1-4 years Older Children and Adults

30 IgM anti-HBc Total anti- HBc HBsAg Acute (6 months) HBeAg Chronic (Years) anti-HBe Years Natural History: Acute HBV Infection with Progression to Chronic Infection Weeks after Exposure Titer

31 Natural History: Chronic HBV Definitions: NIH Workshop (Hoofnagle, Hepatology 2007;45: ) Immune Tolerant Immune Active (Clearance) Inactive Chronic Carrier Perinatal Transmission 60-80% 20-40% Horizontal Transmission

32 Natural History: Chronic HBV Definitions: NIH Workshop HBsAg-positive for at least 6 months Phases of Chronic hepatitis B –Immune 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-HBe –Inactive Hepatitis B carrier: anti-HBe, ALT WNL, HBV DNA < 2,000 IU/ml Reactivation of hepatitis Clearance of HBsAg (Hoofnagle, Hepatology 2007;45: )

33 Hepatitis B: Epidemiology  2 billion people have evidence of HBV infection  1/3 of world’s populations  350 million people chronically infected  15% to 25% will develop HBV-related chronic liver disease (cirrhosis, hepatocellular carcinoma) and die without intervention  Up to 1 million deaths worldwide each year from HBV- related chronic liver disease

34 HBsAg Prevalence  8% - High 2-7% - Intermediate <2% - Low Hepatitis B: Epidemiology

35 Among all the chronic hepatitis B carriers worldwide, 75% are Asians While 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 Hepatitis B: Epidemiology

36 Case 2 ….back to the case He 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?

37 Natural History: Long-Term Outcome of Chronic HBV Hepatocellular carcinoma (HCC) –25%-40% of males –10-15% females Cirrhosis –10% to 20% of males and females Beasley. Cancer 1988;61: McMahon. Ann Intern Med 2001;135:

38 Elevated HBV DNA as Risk for HCC: R.E.V.E.A.L.-HBV Study* 23,820 residents 7 townships in Taiwan –4,155 HBsAg-positive –3,653 tested for HBV DNA at entry –Median age 46 years; follow-up 11.4 years –Findings: Risk factors for HCC at study entry using Regression analysis HBV DNA > 10 4 copies/ml Liver cirrhosis Age Chen JAMA 2006;295:65-73 *Funded by Bristol Myers Squib Chen, C.-J. et al. JAMA 2006;295: APPLIES TO ADULTS > 40 WITH GENOTYPES B&C

39 Chen, C.-J. et al. JAMA 2006;295: Cumulative Incidence of Hepatocellular Carcinoma by Serum HBV DNA Level at Study Entry

40 Natural History: Chronic HBV: Factors Associated with Progression HBV –HBV DNA level –Genotype –Pre-core mutant –Core Promoter mutations Other viruses: HIV, DELTA, HCV Demographic: Age, male sex Environmental and Social –Alcohol –NAFLD –Aflatoxin

41 Natural History: Chronic HBV/HIV Co-infection Co-infected patients have –Higher HBV DNA levels –Lower rates of spontaneous HBeAg clearance –More severe liver disease and higher liver-related mortality –May experience severe hepatitis flares due to immune reconstitution after HAART –May 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

42 Long-Term Goals of Antiviral Therapy Decrease risk of development of cirrhosis If cirrhosis is present, decrease risk of decompensation If decompensated cirrhosis present, treat to revert patient to compensated cirrhosis Decrease risk of development of hepatocellular carcinoma

43 HBsAg + HBeAg Positive ALT < 1 X ULNALT 1-2 X ULNALT >2 X ULN Q 6 mo ALT Q 12 mo HBeAg Q 3 mo ALT Q 6 mo HBeAg Liver bx if persistent or age > 40, Rx as needed Q 1-3 mo ALT, HBeAg If persistent, Liver bx & Rx; Immediate Rx if jaundice or decompensated * HCC surveillance if indicated AASLD Practice Guidelines, 2007* Lok & McMahon. Hepatology 2007;45: Available at aasld.org

44 HBsAg + Negative ALT > 2X ULN DNA > 20,000 IU/mL ALT 1-2X ULN DNA 2,000-20,000 IU/ml ALT < 1X ULN DNA < 2,000 IU/mL Liver bx & Rx Q 3 mo ALT & DNA If results persist, liver bx, treat as needed Q 3 mo ALT X 3, Then Q 6-12 mo If ALT still WNL * HCC surveillance if indicated AASLD Practice Guidelines, 2007* HBeAg Lok & McMahon. Hepatology 2007;45: Available at aasld.org

45 Treatment of HBV/HIV Co-infection All HBV/HIV patients should be offered HAART If treating HBV only can use IFN or adefovir When treating both HIV and HBV - Rx with TDF and FTC is preferred Patients already on HAART with agents not active against HBV can be treated with the addition of IFN, adefovir or entecavir Patients with lamivudine resistant HBV can be treated with the addition of TDF When altering HAART, consider the need to continue HBV therapy unless the patient has cleared HBeAg

46 Case 3 A 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.

47 Case 3 HIV test is + and Sputum smear stains 3+ for AFB What diagnostic testing do you want?

48 Case 3 He 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?

49 WHO/DHHS: Treatment Start TB therapy HAART as soon as TB Rx tolerated (b/n 2-8 wks) Some experts would wait until 8 weeks (avoid IRIS) Start TB therapy HAART after intensive phase of TB Rx (HAART earlier if severely immunocompromised) Start TB therapy Monitor CD4 count and start HAART when indicated TB therapyImproving, no OIsHAART when TB Rx complete CD4 not available CD CD CD4 > 350 HIV-TB Extrapulmonary TBPulmonary TB Start TB therapy, start HAART in 2 weeksCD4 < 100

50 Treatment and Outcome Thailand Retrospective study of 1103 HIV+ patients with TB 411 received HAART Risk factors for death –No HAART –Delay of HAART > 6 months –MDR TB –Gastrointestinal TB Survival (Manosuthi, J Acquir Immune Defic Syndr 2006;43:42-46)

51 Timing of HAART and TB CROI 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) TB MV analysis: mortality associated only with CD4 < 100 and WHO stage 4 Among 73 patients who had TB diagnosed prior to HAART there were 14 deaths –10 occurred among patients waiting for HAART –4 occurred after HAART - 2 due to IRS

52 COD in Patients with TB CROI 2007: Abst # 82: Cause of Death in HIV + Patients with TB in Soweto, South Africa, Martinson, et.al. Results of complete autopsies, N=47 Immediate Cause of Death Pulmonary TB19 Bacterial pneumonia4 Disseminated TB 4* CMV pneumonia7 PCP3 * Contributed to another 28

53 Immune Reconstitution Syndrome TB-associated IRS in South Africa –160 patients receiving Rx for TB at the time HAART initiated –Median CD4 68 –IRS in 12% overall, 32% in those who started HAART within 2 months of TB Rx –MV analysis: IRS risks Low CD4 Early HAART – OR for starting HAART < 30 days = 69.5 –2 IRS deaths (both had disseminated TB TB-IRS and CD4 and HAART (Lawn, AIDS 2007;21:335-41)

54 TB/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 months If using regimens without INH or a rifamycin - duration should be 12 to 15 months

55 Principles of Treatment: Importance of Rifamycin Treatment with NON rifamycin-containing regimens is associated with: Higher relapse rates Higher mortality Wallis, et al. (1996) Tuber Lung Dis 77: Hawken, et al. (1993) Lancet 342: Perriens, et al. (1991) AM Rev Resp Dis 144: Korwnromp, et al. (2003) CID 37:101-12

56 Principles of Treatment Be wary of drug interactions between the rifamycins and HIV medications Do not use TB treatment regimens that are dosed weekly (e.g. INH-rifapentine) or even twice weekly in patients with CD4 counts < 100 Consider measuring drugs levels if there is concern for malabsorption or increased elimination of TB therapies

57 Principles of Treatment Drug Interactions: The P450 system Isoform CYP 3A is affected and/or involved in the metabolism of rifamycins, NNRTI and PIs Rifamycins: Induce CYP 3A –Rifampin > rifapentine > rifabutin –Rifampin 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)

58 Principles of Treatment Drug Interactions: The P450 system NNRTIs (efavirenz and nevirapine) –Induce CYP 3A Protease Inhibitors (many) –Inhibit CYP 3A

59 Principles of Treatment If using rifampin - avoid PI-based HAART - use NNRTIs instead If using rifabutin - can use PIs or NNRTI - but will have to dose adjust the rifabutin in most cases

60 Principles of Treatment Drug Interactions: Rifamycins and PIs PIRifabutinRifampin ATZ 400/d150 QOD No AMP 1200 BID 150 QD (300 3x/wk) No IDV 1000 q8hr 150 QD (300 3x/wk) No LPV/r 3 caps BID 150 QD (150 3x/wk) 600 QD +R* NLF 1250 BID 150 QD (300 3x/wk) No (*Extra RTV 300 BID)

61 Principles of Treatment Drug Interactions: Rifamycins and PIs PIRifabutin Rifampin SQV/RTV 400/400 BID150 QOD (150 3x/wk) No IDV/RTV 800/200 BID150 QOD (150 3x/wk) No ATZ/RTV 300/100 QD150 QOD (150 3x/wk) No data APV/RTV 600/100 BID150 QOD (150 3x/wk) No data TPV/RTV 500/200 BID150 QOD (150 3x/wk) No data DRV/RTV 600/100 BID150 QOD (150 3x/wk) No data

62 Principles of Treatment Drug Interactions: Rifamycins and NNRTIs NNRTIRifabutinRifampin EFV 600 QD450 QD (600 3x/wk) 600 QD NVP 200 BID300 QD 600 QD DLVNo No Web site for more complete table showing dosages:

63 Case 3 …back to the case 10 days into his TB therapy he is started on HAART. 3 weeks later his fever and cough return

64 Case 3 What are you worried about and what are you going to do?

65 XDR 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 from N=170; 43 had baseline and follow-up cultures; 23 developed MDR or XDR TB

66 XDR 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 TB 43 had both initial and follow up cultures done 23 developed MDR or XDR TB 17 had paired spoligotypes performed 17/17 pairs were NOT matched

67 XDR 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 TB 17 had paired spoligotypes performed 17/17 pairs were NOT matched All 17 patients had been hospitalized 15/17 who were HIV tested were +

68 Treatment and Outcome (Raviglione, NEJM 2007;356:656-59) MDR and XDR TB

69 Treatment and Outcome XDR TB –Report of 53 cases in rural South Africa –55% had never been treated for TB –67% had recently been hospitalized –44 (100%)/44 tested for HIV were + (median CD4 63) –52 (98%)/53 died, median survival of 16 days 49 cases in USA: HIV+: 74% ( ) Vs 10% ( ) Survival (Gandhi, Lancet, 2006; 368: ) (MMWR, 2007; 56(11): )

70 XDR TB # 112: Confronting the Catastrophe of M/XDR TB, Gerald Friedland Infection with resistant organisms acquired in healthcare settings is central to recent MDR/XDR outbreaks Need –Better diagnosis and infection control procedures –De-centralization of care –Better integration of HIV and TB care –Better diagnosis and infection control procedures –De-centralization of care –Better integration of HIV and TB care

71 Case 4 A 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.

72 Case 4 Skin lesions for Case 4 (www.dermatology.cdlib.org)

73 Case 4 What is your differential diagnosis for this patient? What diagnostic tests will you perform?

74 Case 4 Blood smear or buffy coat or BM of Leishmania amastigotes

75 Leishmaniasis and HIV An intracellular protozoa Transmitted to humans by phlebotomine sand flies Most cases reported in southern Europe (Spain, Italy, France), Ethiopia, central and south America

76 Leishmaniasis and HIV (www.who.int) Reported cases of Leishmania and HIV Co-infection

77 Leishmaniasis and HIV Clinically Cutaneous, mucosal or visceral disease HIV patients: –Disseminated visceral disease –Cytopenias –Atypical locations: GI, lung, pleura and peritoneal spaces, unusual cutaneous lesions

78 Leishmaniasis 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 weeks Secondary prophylaxis q 3 to 4 weeks Consider discontinuing if CD4 > 350

79 Opportunistic Infections - not discussed MAC Cryptosporidiosis Microsporidiosis Bacterial respiratory infections Bacterial enteric infections Bartonellosis Coccidiodomycosis Paracoccidiomycosis Histoplasmosis Cryptococcus Toxoplasmosis Candida Aspergillosis CMV HSV VZV PML (JCV) HHV-8 HPV Penicilliosis Malaria

80 Summary Opportunistic infections are predictable based on a patients immune status and environment Disseminated and atypical presentations are the rule with extreme immune suppression Prophylaxis against certain OIs is indicated if the OI is common and the prophylaxis is affordable, effective and well tolerated HAART alone is treatment enough for certain OIs and can eliminate the need for prophylaxis The timing of HAART relative to OI therapy is controversial but should probably be early…..however, watch out for IRIS!

81 Thank you! Next session: January 8 th, 2009 Listserv:

82 Welcome to I-TECH HIV/AIDS Clinical Seminar Series Next session: January 8 th, 2009 Lisa Frenkel Pediatric HIV


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