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Hepatitis and HIV

Hepatitis and HIV Catherine Creticos, M.D. August, 2007 Case study 1

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Hepatitis and HIV

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  1. Hepatitis and HIV Catherine Creticos, M.D. August, 2007

  2. Case study 1 • D. M. is a 38 y.o. man who has recently immigrated from India to join his wife who works as a nurse in the U.S. As part of the immigration process, he was tested for HIV and found to be positive. He has a history of multiple dental surgeries in India, but otherwise no medical problems. He denies a history of any sexual partners except his wife, who is HIV negative. Upon initial evaluation in the U.S. liver enzymes are minimally elevated. Further studies reveal HAV IgG+, HBsAg+, HBsAb-, HBcAb+(IgG), HBeAg+, HBeAb-, HCVAb-

  3. Hepatitis B Virus Infection • >300 million chronically infected worldwide • Established cause of chronic hepatitis and cirrhosis • Human carcinogen—cause of up to 80% of hepatocellular carcinomas

  4. Hepatitis B Clinical Features • Incubation period 60-150 days (average 90 days) • Nonspecific prodrome of malaise, fever, headache, myalgia • Illness not specific for hepatitis B • At least 50% of infections asymptomatic

  5. Hepatitis B Complications • Fulminant hepatitis • Hospitalization • Cirrhosis • Hepatocellular carcinoma • Death

  6. Chronic Hepatitis B Virus Infection • Chronic viremia • Responsible for most mortality • Overall risk 10% • Higher risk with early infection

  7. High Viral Load Predicts Poor Outcomes • Large, long-term, prospective cohort studies have linked high viral load with poor outcomes • Haimen City Cohort Chen G, et al. Am J Gastroenterol. 2006;101:1797-1803. • Fox Chase Cancer Center Cohort Study Evans AA, et al. AASLD 2004. Abstract 144. • R.E.V.E.A.L Study GroupChen CJ, et al. JAMA. 2006;295:65-73.Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

  8. Haimen City Cohort: Viral Load and Mortality From Liver Disease • 10-year prospective cohort study in Haimen City • Permanent cohort of 83,794 subjects established 1992-1993 • 2354 subjects included in HBV mortality analysis • Serum HBV DNA tested on baseline samples • Mortality information from death certificate records • 448 deaths (231 HCC, 85 CLD, and 132 nonliver deaths) CLD, chronic liver disease; HCC, hepatocellular carcinoma. Chen G, et al. Am J Gastroenterol. 2006;101:1797-1803.

  9. Haimen City: Increased RR of HCC and CLD Mortality With High Viral Load Baseline HBV DNA (copies/mL) High (≥ 105) Low (≥ 1. 6 x 103 - < 105) 1.2 (0.6-2.3) Nonliver (n = 132) 1.0 (0.5-1.8) 15.2* (2.1-109.8) CLD (n = 85) Cause of Death 1.5 (0.2-12.1) 11.2* (3.6-35.0) HCC (n = 231) 1.7 (0.5-5.7) 20 0 5 10 15 Relative Risk† (95% CI) *P trend < .001†Reference HBV DNA: < 1.6 x 103 copies/mL, adjusted for age and sex Chen G, et al. Am J Gastroenterol. 2006;101:1797-1803.

  10. Fox Chase Center Cohort: Association Between Viral Load and HCC • 3754 HBV-infected Asian American adults in Philadelphia • Nested case-control study • 27 case subjects diagnosed with HCC • Median age: 54 years (range: 42-74) • Case entry < 1-17 years (median: 3) prior to HCC diagnosis • 51 control subjects* • Median age: 56 years (range: 44-77) • HBV DNA quantified with real-time PCR *Randomly selected from non-HCC subjects and matched for age, sex, and year of study entry but not race Evans AA, et al. AASLD 2004. Abstract 144.

  11. Fox Chase: High HBV DNA Associated With Increased Risk of HCC • Relative Risk of HCC According to Baseline Viral Load • (n = 51 controls; n = 27 cases) High HBV DNA (≥ 105 copies/mL) 9.8 (2.3-42.7) Low HBV DNA (104 - < 105 copies/mL) 2.1 (0.4-10.0) Undetectable (< 104 copies/mL) Reference 0 5 10 15 Relative Risk* (95% CI) of HCC *Conditional on the matching variables Evans AA, et al. AASLD 2004. Abstract 144.

  12. Risk Evaluation of Viral Load Elevation & Associated Liver Disease/Cancer Study • REVEAL: prospective, multicenter, observational cohort study 7 Taiwanese townships; individuals aged 30-65 years eligible (N = 89,293) 1991-1992: recruitment HCC-free individuals enrolled (N = 23,820) Insufficient serum for tests or HBsAg(-) HBsAg(+) with adequatebaseline HBV DNA sample (N = 3851) HCV seropositive ordiagnosed with cirrhosis or died within 6 months of entry HCV seropositive HCC analysis (n = 3653) Cirrhosis analysis (n = 3582) HCC follow-up: 41,779 PYs Cirrhosis follow-up: 40,038PYs Chen CJ, et al.JAMA. 2006;295:65-73. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

  13. REVEAL: High HBV DNA Associated With Increased HCC Incidence Relationship Between Baseline HBV DNA and HCC Incidence:All Participants (N = 3653) 50 40 30 Cumulative Incidence of HCC at Year 13 Follow-up (%) 20 14.89 12.17 10 3.57 1.37 1.30 0 1000- 9999 300- 999 10,000- 99,999 ≥ 100,000 < 300 HBV DNA at Baseline (copies/mL) Chen CJ, et al.JAMA. 2006;295:65-73.

  14. REVEAL: High HBV DNA Associated With Increased Incidence of Cirrhosis Relationship Between Baseline HBV DNA and Cirrhosis Incidence: All Participants (N = 3582) 50 40 36.2 30 23.5 Cumulative Incidence of Cirrhosis at Year 13 Follow-up (%) 20 9.8 10 5.9 4.5 0 10,000- 99,999 300- 9999 100,000- 999,999 ≥ 1,000,000 < 300 HBV DNA at Baseline (copies/mL) Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

  15. HBV viral load and disease progression - summary • The higher the viral load, the greater the risk for development of cirrhosis, its complications, and HCC • Disease can progress even when HBV DNA is < 104 copies/mL (~ 2000 IU/mL) • Continued suppression of HBV DNA decreases fibrosis and delays disease progression

  16. Goals of Hepatitis B Therapy • Primary goal: suppress HBV DNA to the lowest possible level to achieve • Prevention of liver disease progression to cirrhosis • Prevention of liver failure and HCC • Prevention of liver disease–related transplantation or death • HBV DNA suppression leads to • Histologic improvement • ALT normalization • HBeAg loss and seroconversion • HBsAg loss and seroconversion

  17. Goals of Therapy: 2 Distinct Patient Populations • HBeAg positive (wild type) • HBeAg loss  seroconversion • Durable suppression of HBV DNA to lowest possible levels • Therapy discontinued after seroconversion; durability of response ~ 80% • HBeAg negative (precore and core promoter mutants) • HBeAg seroconversion not an endpoint • Durable suppression of HBV DNA to lowest possible levels • Relapse common after stopping oral therapy; therapy usually administered long term

  18. Reversal of Fibrosis With Long-termNucleos(t)ide Analogue Therapy • Paired biopsies from before, after 3 years of lamivudine(N = 63) • HAI necroinflammatory scores • 56% improved by ≥ 2 points • 33% had no change • 11% had worsening (YMDD mutations blunted the response) • Fibrosis • 63% (12/19) had improvement in bridging fibrosis by ≥ 1 • 73% (8/11) had improvement in cirrhosis (score 4 → ≤ 3) • Only 2% (1/52) had progression to cirrhosis and 9% (3/34) to bridging fibrosis—all with YMDD mutations Dienstag J, et al. Gastroenterology. 2003;124:105-117.

  19. Reversal of Fibrosis With Long-termNucleos(t)ide Analogue Therapy • 47 HBeAg-negative patients treated with up to 2 years of adefovir • Fibrosis by rank assessment at Week 96 • Mean reduction with continued adefovir 0.63 ± 1.07 (P = .031 compared with adefovir → placebo group) Hadziyannis SJ, et al. N Engl J Med. 2005;352:2673-2681.

  20. Delayed Disease Progression With Continued Suppression: Cirrhotics • 651 cirrhosis patients with evidence of viral replication Placebo (n = 215) Lamivudine (n = 436) P = .001 25 21 20 15 Patients With Disease Progression at Follow-up 9 10 • Child-Pugh score P = .02; HCC P = .047* • Benefit reduced with YMDD emergence 5 0 *5 cases of HCC in Year 1 excluded, P = .052 Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.

  21. Delayed Disease Progression With Continued Suppression: Noncirrhotics • 142 noncirrhotic patients on continuous lamivudine for a median of 89.9 months vs 124 untreated controls Placebo Lamivudine P = .005 14 12 10 8 Percentage of Patients With Cirrhosis/HCC 6 4 2 0 Yuen MF, et al. AASLD 2005. Abstract 985.

  22. Conclusions • Prolonged viral suppression with nucleos(t)ide analogues • Reduces necroinflammation • Reverses fibrosis and cirrhosis • Decreases cirrhotic complications and HCC in both cirrhotic and precirrhotic patients

  23. HBV DNA as a Marker of Efficacy During Treatment of HBV • Literature analysis of 26 prospective studies • Investigation of the relationship between treatment-induced changes in HBV DNA, histology, other disease activity markers • Results • Statistically significant and consistent correlations between HBV DNA, histology, biochemical and serologic responses • HBV DNA had broader dynamic range than histology • Conclusion • Treatment-induced reduction in HBV DNA can be used to assess efficacy • Treatment goal should be profound and durable suppression of HBV DNA Mommeja-Marin H, et al. Hepatology. 2003;37:1309-1319.

  24. Correlation Between HBV DNA Levels and Markers of Liver Disease (cont’d) • Necroinflammation correlated with • HBV DNA levels in untreated patients (r = 0.78; P = .001) • HBV DNA levels at the end of treatment (r = 0.71; P = .003) • HBeAg seroconversion correlate with change in median HBV DNA from baseline to end of treatment (r = 0.72, P < .0002) • Normalized ALT post treatment correlated with HBV DNA level (r = 0.62, P = .0004) Mommeja-Marin H, et al. Hepatology. 2003;37:1309-1319.

  25. Entecavir Superior to Lamivudine in HBeAg-Positive Patients Entecavir (n = 354) Lamivudine (n = 355) HBV DNA < 300 copies/mL Through Week 96* HBeAg Seroconversion Through Week 96† Histologic Improvement Through Week 48 100 100 100 P < .0001 P = .009 80 80 80 80 72 62 60 60 60 P = NS Patients (%) 39 40 40 40 31 26 20 20 20 (n = 354) (n = 355) (n = 354) (n = 355) (n = 314) (n = 314) 0 0 0 *Cumulative confirmed data: 2 data points or last observation on therapy. †Cumulative confirmed data through last observation and 6 months off treatment. Gish RG, et al. Hepatology. 2005;42:267A.

  26. Long-term Entecavir in HBeAg-Negative Patients Entecavir Lamivudine Histologic Improvement Through Week 48 HBV DNA < 300 copies/mL Through Week 96* P < .0001 100 100 94 P = .01 77 80 80 70 61 60 60 Patients (%) 40 40 20 20 (n = 287) (n = 313) (n = 296) (n = 325) 0 0 *Cumulative confirmed data: 2 data points or last observation on therapy. Shouval D, et al. EASL 2006. Abstract 45. Lai C, et al. N Engl J Med. 2006;354:1011-1020.

  27. Clinical Efficacy 2-Year Results:Telbivudine vs Lamivudine *P ≤ .05 vs lamivudine. Lai C, et al. AASLD 2006. Abstract 91.

  28. Week 52 Histologic Outcomes:Telbivudine vs Lamivudine HBeAg Positive Patients HBeAg Negative Patients 100 7 8 12 15 Missing Week 52 23 25 80 19 biopsy 26 Histologic Response (%) 60 No improvement 40 69 69 68 60 Improvement 20 0 LdT LdT LAM LAM Lai C, et al. AASLD 2006. Abstract 91.

  29. Peginterferon alfa-2a in HBeAg-Positive Chronic Hepatitis B Patients HBV DNA Levels 1 Year Post treatment According to Type of Initial Response 100 HBV DNA 1 year post treatment (copies/mL) 21 29 80 7 60 29 33 > 100,000 96 Patients (%) 10,001-100,000 40 21 401-10,000 20 39 ≤ 400 21 0 Early, Sustained HBeAg Seroconversion Late HBeAg Seroconversion No HBeAg Seroconversion (n=61) (n=15) (n=88) Lau GK, et al. EASL 2006. Abstract 50.

  30. Histologic Improvement With Peginterferon Therapy HBeAg-Negative Patients HBeAg-Positive Patients 100 80 59 58 PegIFN 52 60 51 49 48 Histologic Improvement (%) PegIFN + LAM 40 LAM 20 0 Lau GK, Piratvisuth T, Luo KX, et al. N Engl J Med. 2005. 30;352:2682-2695. Marcellin P, Lau GK, Bonino F, et al. N Engl J Med. 2004. 16;351:1206-1217.

  31. HBV DNA and HBeAg Seroconversion at Year 1 in HBeAg(+) Patients Data from individual studies, not direct comparisons (different populations, baseline values, HBV DNA assays) PegIFN LAM ADV ETV LdT 30 27 23 21 HBeAg Seroconversion, % 20 18 12 10 0 0 Log10 Decrease in HBV DNA -3.6 -4.0 -5.8 -6.5 -6.9 -10 Lau et al. N Engl J Med. 2005;352:2682-2695. Dienstag et al. N Engl J Med. 1999;341:1256-1263. Marcellin et al. EASL 2005. Abstract 73. Lai et al. AASLD 2005. Abstract 72404. Chang et al. AASLD 2004. Abstract 70. Entecavir package insert. Telbivudine package insert.

  32. Emtricitabine impact on HBV in HBV/HIV coinfection • Data analyzed from HIV/HBV coinfected individuals enrolled in three Gilead studies designed to evaluate the safety and efficacy of FTC as part of HAART in treatment-naïve patients • Anti-HIV and anti-HBV effects of FTC in these individuals evaluated

  33. Emtricitabine effective against HBV • 39 patients from 3 studies • Baseline median HBV viral load >500,000 copies/mL • Week 24 HBV viral load undetectable in 45%; 59% at week 48 • HIV viral load undetectable at week 24 in 97%, 94% at week 48 • In a separate study, undetectable HBV viral load was achieved in 59% of monoinfected individuals at 48 weeks. • 12% incidence of drug-resistant HBV at week 48 in coinfected individuals with detectable HBV viral load at baseline Snow A, Harris J, Borroto-Esoda K, et al. CROI 2004; Poster 836

  34. Tenofovir active against HBV in coinfected individuals • Tenofovir has potent activity against HBV in vitro and in retrospectively analyzed HIV/HBV-coinfected patients • Study to assess long-term HBV dynamics and influence of baseline factors on HBV load in HIV/HBV-coinfected patients beginning tenofovir-based HAART Lacombe K, Gozlan J, Boelle PY, et al. AIDS. 2005;19:907-915

  35. Summary of Study Design • Subgroup of patients enrolled in French multicenter prospective HIV-HBV Cohort Study used in analysis • Child-Pugh score determined in cirrhotic patients at beginning and end of follow-up • HBV DNA and biochemical data measured at least once during first month and then at least once every 3 months thereafter

  36. Baseline Characteristics • N = 28 • Median duration HIV infection, 11.1 years (range, 0.01-17.7 years) • Median duration HBV infection, 7.0 years (range, 0.01-16.9 years) • Median HIV-1 RNA, 3.81 log10 copies/mL (range, 1.4-5.7 log10 copies/mL) • Median HBV DNA, 7.75 log10 copies/mL (range, 3-10 log10 copies/mL)

  37. Main Findings • HBV DNA declined from baseline by mean of 4.6 log10 copies/mL with tenofovir treatment (P < .001) • HBV DNA undetectable (< 200 copies/mL) in 21 (87.5%) patients • Median time until undetectable, 272.5 days (95% confidence interval [CI], 203.5-416.0) • 4 of 24 (16.7%) HBeAg-positive patients at baseline lost HBeAg and seroconverted to hepatitis B antibodies • No incidence of grade 3/4 adverse events

  38. Main Findings • Tenofovir-based HAART also had significant impact on HIV-1 RNA, ALT • HIV-1 RNA declined from baseline by mean of 1.4 log10 copies/mL (P < .0001) • Undetectable HIV-1 RNA (< 50 copies/mL) increased from 22% of patients at baseline to 75% • Mean ALT declined from 125 to 50 IU/mL (P < .05)

  39. Key Conclusions • Tenofovir demonstrates potent activity against HBV in HIV/HBV-coinfected patients and shows marked impact on liver function by decreasing ALT activity • Significant decline in HIV-1 RNA also observed • Tenofovir well tolerated • Long-term HBV dynamics not affected by concomitant receipt of lamivudine, HBV genotype, or HIV-related immunosuppression

  40. Treatment of HBV with TDF or ADV • Nonrandomized, open label study of TDF vs. ADV in 85 HIV-HBV co-infected patients • ADV (n=29), TDF (n=56) • Tx-naive, except for past or current 3TC as part of ARV regimen. • TDF superior regarding antiviral and biochemical responses • More rapid HBV DNA decline and a greater decline at 12 mos. (p<0.0001) • Greater decreases in transaminases • After adjustment of HBeAg status, HBV-DNA at baseline and level of ALT at baseline, TDF associated with a higher rate of patients achieving undetectable HBV-DNA levels 1.00 P=0.04 0.75 Proportion with <200 copies/mL 0.50 TDF .025 ADV 0.00 0 1 0 2 0 3 0 4 0 Time to HBV-DNA undetectability (months) Lacombe Burman W, et al. 14th CROI, Los Angeles, CA, February 25-28, 2007. Abst. 945.

  41. Conclusions • HBV DNA suppression with anti-HBV therapy improves patient outcomes • Continued benefits are observed with long-term HBV therapy • Resistance diminishes the benefits of treatment • More potent viral suppression can lead to greater patient outcomes • HBeAg seroconversion • ALT normalization • Long-term virologic response • Lower risk of resistance

  42. HBV Resistance • HBV resistance can be delayed • By using highly potent antivirals • By improving adherence • By using combination therapies • When resistance occurs • Consider add-on therapy rather than switching to second monotherapy • Consider using the most potent available antiviral combination

  43. 2006 NIH Workshop on the Management of CHB:Who Should Receive Treatment? HBsAg Positive HBeAg Decompensated cirrhosis Inactive carrier/mild chronic hepatitis Neg Pos HBV DNA < 104 IU/mL; ALT normal 3-6 months Grey zone HBV DNA > 104 IU/mL; elevated ALT 3-6 months Consider antiviral therapy/ refer for OLT Consider Liver biopsy Consider antiviral therapy Monitor every 3-6 months

  44. Interferon Therapy • Pros • Finite duration of therapy • Durable response • No resistance or cross resistance • Cons • Route of administration—injection • Frequent side effects • Cost

  45. Ideal Clinical Situation for IFN Therapy • High ALT (> 5 x ULN) and low HBV DNA level (< 200,000 IU/mL) • Younger patient • Black • Well-compensated cirrhosis • No contraindications to use of interferon • ? Genotype A or B • ?HIV/HBV with high CD4, low HIV-RNA

  46. Lamivudine • Pros • Oral • Negligible side effects • Excellent safety profile • Low cost • Cons • High rate of resistance and cross-resistance with other nucleoside analogues • Long/indefinite duration of therapy • Cannot be used as monotherapy in HIV/HBV

  47. Ideal Clinical Situation for Lamivudine Use • Short duration of therapy • Prevention of disease flares/reactivation during chemotherapy • Protracted or severe acute hepatitis • Safety a concern • During pregnancy • Cost a concern • HBeAg-negative CHB in developing countries

  48. Lamivudine in HAART Regimen • Lamivudine used in HAART regimen for coinfected individual may result in the development of HBV resistance mutations • If HAART interrupted or changed, anticipate flare in HBV/hepatitis if lamivudine also stopped

  49. Adefovir • Pros • Route of administration: oral • Low rate of resistance • Effective against lamivudine resistant virus • Can be used as monotherapy in HIV/HBV without inducing HIV resistance mutations • Cons • Slow response and high rate of primary nonresponse • ? Renal toxicity with long-term use • Long/indefinite duration of therapy

  50. Ideal Clinical Situation for Adefovir Use • HBeAg-positive and HBeAg-negative chronic hepatitis B with low HBV DNA • Management of lamivudine-resistant chronic hepatitis B • HIV/HBV coinfected individual not requiring HAART

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