HIV and Viral Hepatitis (B & C) H. Nina Kim, MD MSc University of Washington July 9, 2009

1. HIV and Viral Hepatitis (B & C) H. Nina Kim, MD MSc University of Washington July 9, 2009

2. 36 yo man to establish care • HIV infection: Risk factor: unprotected heterosexual sex. Dx 2004 with CD4 155, HIV RNA 222,000. No hx OIs. • Started Combivir & Efavirenz 9/2004 • Switched to Atripla in Jan 2007 • Chronic hepatitis B • Started on adefovir Jan 2007 • Normal alpha-fetoprotein, abdominal ultrasound March 2007 • PMH otherwise notable for: • BRBPR – negative EGD/colonoscopy; attributed to hemorrhoids • Hypertriglyciridemia

3. Additional Hx Medications • Truvada • Efavirenz • Omeprazole • Gemfibrozil Soc Hx Works as cleaner in Chinese restaurant. Born in Mexico; immigrated to US 15 yrs ago. Lives with several coworkers in hotel. Smokes 2 cigs per day. Used cocaine 1 mon ago. Rare EtOH.

4. PEx & Labs T 36.3 C, 117/66, HR 84, RR 20 Wt 68.5 kg Well-appearing young Latino in NAD. Exam normal; no stigmata of cirrhosis; no palpable hepatosplenomegaly. Hep B surface Ag positive, HB surface Ab negative, HBV core Ab+, HAV Ab+, HBV Ab negative. CD4 375/28%, HIV RNA <30 copies/mL. HBV PCR 240,000 IU/mL – no prior values available. ALT 42, AST 30, alk phos 91. Normal total bilirubin & albumin.

5. Questions • Does this patient need treatment for chronic hepatitis B? • How would you risk stratify this patient? • If tx, what agent(s) would you use? • What is natural hx in this HIV-HBV coinfected patient? • Special considerations esp re HAART • Does this patient need screening for HCC?

6. Chronic Hepatitis B:Epidemiology • Definition: HBsAg+ for >6 months • US – Low endemic • Most infections occur in adolescents, young adults • Sexual transmission > percutaneous • Asia – High endemic • Perinatal transmission predominates • Genotypes B, C • Africa – Intermediate to High endemic • Childhood • Vertical transmission less important role (possibly b/c lower prevalence of HBeAg+ mothers)

7. Chronic HBV: Worldwide prevalence www.cdc.gov

8. www.hepwebstudy.com

9. Chronic Hepatitis B:Stage the infection

10. Chronic Hepatitis B & HIV:Epidemiology & Natural Hx • Prevalence 6-17% depending on population • Consequences of coinfection: • Higher risk of developing chronic hepatitis B when exposed (estimated 5X greater c/w HIV-unininfected) • Higher HBV viremia  higher risk of reactivation & transmission • Higher rates of disease progression w/ adverse outcomes, i.e. cirrhosis • Poorer response to standard therapies? • Increased risk of HAART-related hepatoxicity Colin JF, et al. Hepatology. 1999;29:1306-1310. Puoti M, et al. AIDS Rev. 2002;4:27-35. Hadler SC, et al. J Infect Dis. 1991;163:454-459.

11. HBV DNA Associated With Increased Risk of HCC & Cirrhosis REVEAL: Long-term follow-up of untreated HBsAg+ individuals in Taiwan 50 Cumulative Incidence of HCC at Year 13 Follow-up[1] (N = 3653) Cumulative Incidence of Cirrhosis at Year 13 Follow-up[2] (N = 3582) 40 36.2 30 23.5 Patients (%) 20 14.9 12.2 9.8 10 5.9 4.5 3.6 1.4 1.3 0 < 300 < 300 100,000- 999,999 ≥ 1 million 300- 999 1000- 9999 10,000- 99,999 300- 9999 ≥ 100,000 10,000- 99,999 Baseline HBV DNA (copies/mL) 1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

12. Risk of Liver-related Mortality among MSM in MACS Cohort 14.2 1.7 0.8 Thio, et. al. Lancet 2002; 360: 1921-26.

13. Treatment End-points for HIV-uninfected chronic Hep B • HBeAg seroconversion to anti-Hbe (if eAg+) • Spontaneous in HIV-negative pt: 8-12% per yr • Treatment-associated rate: 15-27% • HBV DNA suppression: ideally, complete (prior threshold goal <20,000 IU/mL) • ALT normalization • HBsAg loss & seroconversion These pts need to be monitored after tx discontinued: q6 mon ALT, annual HBV DNA. 30% over 10 years can reactivate viral replication. So what about HIV-infected?

14. Treatment of HBV in HIV+ Patient • Interferon (standard or pegylated) • Pros: HBsAb loss, short duration, no drug resistance • Cons: SC, freq adverse effects, HBeAg seroconversion rate lower than in HIV-negative population (11.5% vs. 28%) • Lamivudine • Use in ESLD, pregnant women • High rate resistance (~20%/yr  approaches 100% x 5 yr if only anti-HBV drug) • Adefovir • Use in ESLD • Drug resistance: delayed, less common than 3TC • Entecavir • Potent • Drug resistance rare in nucleoside-naïve pt (<1% in 4 yrs), higher if treatment-experienced (14% at year 2) • Telbivudine • Drug resistance: intermediate (~22% at year 2). • Category B pregnancy • Tenofovir • Potent with high genetic barrier for HBV resistance

15. Antiviral agents active against HBV • Lamivudine (3TC) or Emtricitabine (FTC) • Adefovir (ADF) • Entecavir (ETV) • Telbivudine (LDT) • Tenofovir (TDF) … & HIV

16. Lamivudine (3TC) Resistance in HIV-HBV infected patients on 3TC monotherapy Matthews, AIDS 2006. 20:863-870.

17. Treatment of HBV in HIV+ Patient

18. Combination Therapy • Not yet the paradigm the way it is for HIV infection • Dual nucleos/tide analogues: more widely used in • Cirrhotic patients • HIV-coinfected patients • s/p OLT after HBV infection • Combination Peg-IFN & lamivudine – results disappointing • No additional efficacy c/w Peg-IFN alone

19. HCC Screening for HBV+ Pts • Asian males >40 years • Asian females >50 years • All cirrhotic hepatitis B carriers (stage 3+ fibrosis) • Family history of HCC • Africans over age 20 • Other risks – severity of liver disease as measured by current & hx inflammation, esp +ongoing HBV viremia, ?coinfection HCV, alcohol AASLD Practice Guidelines 2005, Hepatology 42(5): 1208.

20. Sensitivity of AFP >20 is 60% PPV = 41% Still see false positives with this cutoff Cutoff = 20 ng/ml Alpha-fetoprotein: Imperfect screening tool for HCC

21. CONTEST: Most Interesting Dermatology Case • Submit a dermatology case by Friday, July 24 using the case referral form • Instructions will be sent in a follow-up email • Dr Roy Colven will be the judge and announce the winner during his session on July 30 • The winner will receive a 2 GB I-TECH thumb drive!

22. 42 yo woman with remote hx IVDU • HIV Hx: • Dx 1996, nadir CD4 120 • Has been undetectable on Kaletra + Combivir x several years, most recent CD4 250 (25%) • Tested positive for HCV Ab • Hx of alcohol & heroin dependence • Hx depression with psychotic features • PEx: T 37 BP 104/80 HR 86 RR 12 • Well-appearing woman, alert & conversant • No stigmata of advanced liver disease (No spider telangiectasia, palmar erythema, scleral icterus, abd distension, no appreciable HSM

23. Lab Data • ALT 35-45, AST 25-35 • Normal alk phos, total bilirubin, serum albumin • HCV RNA 2.8 million IU/mL • HCV genotype 1a • Hepatitis A & B immune • CBC: WBC 3.5, Hgb 11.0, Hct 35% with MCV 110, platelets 160K.

24. Chronic Hep C & HIVEpidemiology • 1/4 to 1/3 of HIV-infected pts in US & Europe are coinfected with chronic hepatitis C • Much higher prevalence (75%) in high-risk groups with hx blood exposure: IVDU & hemophiliacs • HCV one of the major causes of morbidity & mortality in HIV-infected pts • More rapid disease progression • Higher risk of hepatotoxicity from HAART Rockstroh, J Infect Dis. 2005; 192:992-1002. Pol, Clin Infect Dis. 2008; 47: 94-101.

26. Factors to ConsiderTo Treat or not Treat? • HIV-related • CD4 count • Antiretroviral therapy • Liver-related • HCV genotype • Liver enzymes? • Histology • Other • Neuropsychiatric history • Substance dependence & Alcohol consumption

27. Normal ALTLess Predictive of Benign Histology in HIV-HCV Coinfected patients Percentage of patients with grade 3-4 necroinflammation Gonzalez, et. al. J Acquir Immune Defic Syndr. 2006; 41(5): 582-9.

28. HCV Treatment & Risk of Mitochondrial Toxicity Odds Ratio (95%CI) • US FDA Adverse Event Reporting 2002 • 31 patients had 58 events c/w MT: • Pancreatitis • Lactic acidosis • Elevated LFTs • Hepatic steatosis • Elevated CK • Neuropathy Ribavirin + ddI ddI + d4T d4T ABC 3TC AZT 12.4 8.0 3.3 1.1 0.2 0.06 0.01 0.1 1.0 10 100 Fleischer, R. Clin Infect Dis. 2004; 38: e79-80.

29. Anemia & HCV TreatmentRole of AZT • AZT use associated with higher incidence of anemia in 1st 12 wks • Not associated with lower rates of EVR or higher rates of tx discontinuation Alvarez, D. J Viral Hepat. 2006; 13(10):683-9.

30. Current Standard Therapies for HIV-HCV coinfected pts • Peg-IFN + RBV more effective than standard IFN + RBV combination or peg-IFN alone • Genotype 1, 2, 3 or 4 • Peg-IFN + RBV 1000 mg/day if wt <75 kg or 1200 mg/day if wt >75 kg → 48 weeks • Goal of treatment is sustained virologic response (SVR) defined as • No detectable serum HCV RNA 24 weeks after the end of treatment • Tested using sensitive HCV RNA assay with lower limit of detection of 50 IU/mL

31. Definitions of Virologic Response on HCV Treatment

32. Percentage of HIV-HCV patients achieving treatment response

33. Clinical Trials of HIV-HCV Coinfected

34. Pegylated InterferonSide Effects

35. Reality of Treating HIV-HCV Coinfected Pts: Few eligible Fleming, et. al. Clin Infect Dis 2003; 36:99-101.

36. Questions?

37. Next session: July 30, 2009 Dr. Roy Colven HIV Dermatology: Virtual Office Hours

38. Next session: July 30, 2009 Listserv: itechdistlearning@u.washington.edu Email: DLinfo@u.washington.edu