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Hepatitis and HIV Catherine Creticos, M.D. August, 2007 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- 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 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 Hepatitis B Complications Fulminant hepatitis Hospitalization Cirrhosis Hepatocellular carcinoma Death Chronic Hepatitis B Virus Infection Chronic viremia Responsible for most mortality Overall risk 10% Higher risk with early infection High Viral Load Predicts Poor Outcomes Large, long-term, prospective cohort studies have linked high viral load with poor outcomes 1. Haimen City Cohort Chen G, et al. Am J Gastroenterol. 2006;101:1797-1803. 2. Fox Chase Cancer Center Cohort Study Evans AA, et al. AASLD 2004. Abstract 144. 3. R.E.V.E.A.L Study Group Chen CJ, et al. JAMA. 2006;295:65-73. Iloeje UH, et al. Gastroenterology. 2006;130:678-686. 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. Haimen City: Increased RR of HCC and CLD Mortality With High Viral Load Baseline HBV DNA (copies/mL) Cause of Death High (≥ 105) Low (≥ 1. 6 x 103 - < 105) 1.2 (0.6-2.3) 1.0 (0.5-1.8) Nonliver (n = 132) 15.2* (2.1-109.8) CLD (n = 85) 1.5 (0.2-12.1) 11.2* (3.6-35.0) HCC (n = 231) 1.7 (0.5-5.7) 0 5 10 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. 15 20 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. 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) (104 9.8 (2.3-42.7) Low HBV DNA - < 105 copies/mL) 2.1 (0.4-10.0) Undetectable Reference (< 104 copies/mL) 0 5 10 Relative Risk* (95% CI) of HCC *Conditional on the matching variables Evans AA, et al. AASLD 2004. Abstract 144. 15 Risk Evaluation of Viral Load Elevation & Associated Liver Disease/Cancer Study REVEAL: prospective, multicenter, observational cohort study 1991-1992: recruitment 7 Taiwanese townships; individuals aged 30-65 years eligible (N = 89,293) HCC-free individuals enrolled (N = 23,820) HCV seropositive HCC follow-up: 41,779 PYs Cirrhosis follow-up: 40,038 PYs HBsAg(+) with adequate baseline HBV DNA sample (N = 3851) HCC analysis (n = 3653) Cirrhosis analysis (n = 3582) Chen CJ, et al. JAMA. 2006;295:65-73. Iloeje UH, et al. Gastroenterology. 2006;130:678-686. Insufficient serum for tests or HBsAg(-) HCV seropositive or diagnosed with cirrhosis or died within 6 months of entry REVEAL: High HBV DNA Associated With Increased HCC Incidence Relationship Between Baseline HBV DNA and HCC Incidence: All Participants (N = 3653) Cumulative Incidence of HCC at Year 13 Follow-up (%) 50 40 30 20 14.89 12.17 10 1.30 0 < 300 Chen CJ, et al. JAMA. 2006;295:65-73. 1.37 3.57 100030010,0009999 999 99,999 HBV DNA at Baseline (copies/mL) ≥ 100,000 Cumulative Incidence of Cirrhosis at Year 13 Follow-up (%) 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 20 10 0 4.5 < 300 5.9 9.8 10,000300100,000- ≥ 1,000,000 99,999 9999 999,999 HBV DNA at Baseline (copies/mL) Iloeje UH, et al. Gastroenterology. 2006;130:678-686. 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 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 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 Reversal of Fibrosis With Long-term Nucleos(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. Reversal of Fibrosis With Long-term Nucleos(t)ide Analogue Therapy 47 HBeAg-negative patients treated with up to 2 years of adefovir Inflammation change 96 Wks Continued Adefovir (n = 19) 48 Wks Adefovir → 48 Wks Placebo (n = 8) 48 Wks Placebo → 48 Wks Adefovir (n = 20) Wk 48 Wk 96 Wk 48 Wk 96 Wk 48 Wk 96 - 4.2 - 4.3 - 3.8 - 0.9 - 0.6 - 2.3 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. Delayed Disease Progression With Continued Suppression: Cirrhotics 651 cirrhosis patients with evidence of viral replication Placebo (n = 215) Patients With Disease Progression at Follow-up P = .001 25 Lamivudine (n = 436) 21 20 15 10 5 0 *5 cases of HCC in Year 1 excluded, P = .052 Liaw YF, et al. N Engl J Med. 2004;351:1521-1531. 9 Child-Pugh score P = .02; HCC P = .047* Benefit reduced with YMDD emergence Delayed Disease Progression With Continued Suppression: Noncirrhotics 142 noncirrhotic patients on continuous lamivudine for a median of 89.9 months vs 124 untreated controls Percentage of Patients With Cirrhosis/HCC 14 12 10 8 6 4 2 0 Yuen MF, et al. AASLD 2005. Abstract 985. P = .005 Placebo Lamivudine 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 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. 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. Entecavir Superior to Lamivudine in HBeAg-Positive Patients Entecavir (n = 354) HBV DNA < 300 copies/mL Through Week 96* 100 Patients (%) 80 P < .0001 Lamivudine (n = 355) HBeAg Seroconversion Through Week 96† 100 Histologic Improvement Through Week 48 100 P = .009 80 80 80 72 62 60 60 39 40 20 0 60 P = NS 40 31 40 26 20 (n = 354) (n = 355) 0 20 (n = 354) (n = 355) 0 (n = 314) *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. (n = 314) 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 77 80 Patients (%) 100 94 P = .01 80 60 60 40 40 20 20 0 (n = 325) (n = 313) 0 70 61 (n = 296) *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. (n = 287) Clinical Efficacy 2-Year Results: Telbivudine vs Lamivudine HBeAg(+) Response Mean HBV DNA reduction, log10 copies/mL HBV DNA undetectable, % HBeAg(-) LdT LAM LdT LAM (n = 458) (n = 463) (n = 222) (n = 224) -5.7* -4.4 -5.0* -4.2 56* 39 82* 57 ALT normalization, % 70* 62 78 70 Therapeutic response, % 64* 48 78* 66 HBeAg loss, % 35 29 - - HBeAg seroconversion, % 30 25 - - 4.0* 12.3 0* 2.7 Primary treatment failure, % *P ≤ .05 vs lamivudine. Lai C, et al. AASLD 2006. Abstract 91. Histologic Response (%) Week 52 Histologic Outcomes: Telbivudine vs Lamivudine HBeAg Positive Patients 100 12 80 HBeAg Negative Patients 19 7 8 23 15 26 25 60 No improvement 40 69 69 60 68 20 0 Missing Week 52 biopsy LdT Lai C, et al. AASLD 2006. Abstract 91. LAM LdT LAM Improvement Peginterferon alfa-2a in HBeAgPositive Chronic Hepatitis B Patients HBV DNA Levels 1 Year Post treatment According to Type of Initial Response 100 21 Patients (%) 80 60 HBV DNA 1 year post treatment (copies/mL) 29 7 33 29 96 10,001-100,000 40 21 20 > 100,000 401-10,000 39 ≤ 400 21 0 Early, Sustained Late HBeAg HBeAg Seroconversion Seroconversion (n=61) (n=15) Lau GK, et al. EASL 2006. Abstract 50. No HBeAg Seroconversion (n=88) Histologic Improvement (%) Histologic Improvement With Peginterferon Therapy 100 HBeAg-Positive Patients HBeAg-Negative Patients 80 60 49 52 59 51 40 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. 58 48 PegIFN PegIFN + LAM LAM HBV DNA and HBeAg Seroconversion at Year 1 in HBeAg(+) Patients 30 27 20 18 21 23 12 10 0 0 -3.6 -4.0 -6.9 -6.5 -5.8 -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. Log10 Decrease in HBV DNA HBeAg Seroconversion, % Data from individual studies, not direct comparisons (different populations, baseline values, HBV DNA assays) 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 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 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/HBVcoinfected patients beginning tenofovirbased HAART Lacombe K, Gozlan J, Boelle PY, et al. AIDS. 2005;19:907-915 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 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) 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], 203.5416.0) 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 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) 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 Treatment of HBV with TDF or ADV Proportion with <200 copies/mL Nonrandomized, open label study of TDF vs. ADV in 85 HIV-HBV coinfected 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 1.00 of ALT at baseline, TDF associated with a higher rate of patients achieving undetectable HBV-DNA levels 0.75 P=0.04 0.50 TDF .025 ADV 0.00 0 10 20 30 Time to HBV-DNA undetectability (months) Lacombe Burman W, et al. 14th CROI, Los Angeles, CA, February 25-28, 2007. Abst. 945. 40 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 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 2006 NIH Workshop on the Management of CHB: Who Should Receive Treatment? HBsAg Positive HBeAg Inactive carrier/mild chronic hepatitis Neg HBV DNA < 104 IU/mL; ALT normal 3-6 months Monitor every 3-6 months Decompensated cirrhosis Pos Grey zone Consider Liver biopsy HBV DNA > 104 IU/mL; elevated ALT 3-6 months Consider antiviral therapy Consider antiviral therapy/ refer for OLT Interferon Therapy Pros – – – Finite duration of therapy Durable response No resistance or cross resistance Cons – – – Route of administration—injection Frequent side effects Cost 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 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 Ideal Clinical Situation for Lamivudine Use Short duration of therapy – – Safety a concern – Prevention of disease flares/reactivation during chemotherapy Protracted or severe acute hepatitis During pregnancy Cost a concern – HBeAg-negative CHB in developing countries 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 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 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 Entecavir Pros – Route of administration: oral – Potent with low rate of resistance – Effective against LAM-R Cons – Long-term safety unknown – Long/indefinite duration of therapy – Cannot be used in HIV/HBV coinfected patient not on HAART – will select for M184V mutation Ideal Clinical Situation for Entecavir Use HBeAg-positive or HBeAg-negative chronic hepatitis B with high viral load Management of lamivudine resistance Can be used in HIV/HBV coinfection in patients who are on HAART if preferable to other HBV agents FTC and TDF for HIV/HBV Coinfected Individuals Evidence supports benefit of this combination for coinfected individuals requiring both HIV and HBV treatment Should be used in combination with a fully HIV suppressive regimen If HAART regimen interrupted or altered, anticipate potential HBV flare if FTC and/or TDF withdrawn without continued HBV suppression Case Study 1 – cont. Additional laboratories: CD4 372 HIV RNA 86,000 HBV DNA >500,000 Treatment options: Treat HBV, not HIV Adefovir Telbivudine Interferon Treat both HBV and HIV Tenofovir and epivir or emtricitabine in a HAART regimen Monitor both HBV and HIV off treatment Case Study 2 C. T. is a 53 y.o. man with a history of paranoid schizophrenia and alcohol and cocaine use. He continues to actively use both substances, but not IV cocaine. He has been HIV and HCV positive for the last 10 years; CD4 nadir at time of diagnosis was 125. He has been extremely adherent to HAART over the last 10 years, including a difficult indinavir-containing regimen, maintaining an undetectable HIV RNA for the last 9 years, and CD4 above 600 for most of that time. He has had 2 liver biopsies for staging of liver disease (3 and 1 year ago), that have both show stage 1 fibrosis. His transaminases fluctuate in the 80-100 range. He is anxious to treat his hepatitis C, but although he is extremely adherent to his HAART regimen, refuses to take any psychiatric medications. Hepatitis C Identified in 1989 Now recognized as the primary cause of non-A/non-B hepatitis Most common blood borne infection in the US 3.9 million people infected 36,000 new cases annually 10,000 deaths annually Causes 40% of chronic liver disease in the US Leading indication for liver transplantation - 10,000 per year Screening for HCV disease EVERYONE who is HIV positive should be screened for HCV - similar risk factors Children born to women with suspected chronic HCV infection at the time of the delivery should be screened for HCV infection (risk approximately 5%) History of acute hepatitis - HAV, HBV, and HCV Injection drug users Serologic Tests for HCV Anti-HCV by EIA-3 May be negative in immunocompromised patients or acute HCV infection HCV RNA by PCR Recombinant Immunoblot Assay (RIBA) Quantitative PCR and branched DNA (bDNA) Acute HCV Infection Asymptomatic - 60-70% Jaundice - 20-30% Non-specific symptoms - 20-30% Anorexia, malaise, or abdominal pain Time from exposure to symptoms - 6-7 weeks Time from exposure to seroconversion 8-9 weeks Anti-HCV can be detected in 80% of patients within 15 weeks after exposure >90% within 5 months >97% within 6 months Rarely is seroconversion delayed >9 months Serologic Pattern of Acute HCV Infection with Recovery antiHCV Symptoms +/- Titer HCV RNA ALT Normal 0 1 2 6 1 2 3 3 4 5 Years Months Time after Exposure 4 Chronic HCV Infection HCV RNA detectable in the blood for > 6 months 60-85% of acutely infected will become chronic Most do not have symptoms Some may experience: fatigue, mild RUQ discomfort or tenderness, nausea, poor appetite, muscle and joint pains Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection antiHCV Symptoms +/- Titer HCV RNA ALT Normal 0 1 2 6 1 2 3 3 4 5 Years Months Time after Exposure 4 Factors Influencing the Progression of HCV Older age at time of infection Male gender Immunocompromised state Concurrent infection with HBV Alcohol intake Men - 30 g/day (2 beers, 2 glasses of wine, 2 mixed drinks) Women - 20 g/day Other - iron overload, nonalcoholic fatty liver disease, schistosomal co-infection, hepatotoxic medications, environmental contaminants Prognosis of Untreated HCV Variable Course and Outcome No symptoms - 50-80% Liver biopsy with some chronic hepatitis changes Good prognosis Severe hepatitis - 20-50% HCV RNA detectable Elevated liver enzymes Within 10-20 years, 15% will develop cirrhosis and ESLD 1-4% will develop hepatocellular carcinoma Epidemiology and Natural History of HIV/HCV Co-infection Prevalence - 33% of all HIV infected persons have HCV Injection drug users - 60 - 90% Persons with hemophilia - 85% (blood products prior to 1985) Homosexual men - 4 - 8% Natural History of HCV disease in HIV-infected persons HIV infection - significant co-factor for HCV-related liver disease and mortality HCV-related fibrosis is accelerated in persons with HIV-infection Impact of HCV disease will increase as HIV-related mortality declines due to the use of HAART and OI prophylaxis Effect of HCV on HIV HCV may hasten progression to AIDS or death May impair immune reconstitution following initiation of HAART More frequent vertical transmission Increased risk of hepatotoxicity from HAART Effect of HIV on HCV May have false negative anti-HCV EIA results Vertical transmission of HCV in increased May increase sexual transmission of HCV Higher HCV viremia Associated with higher HIV RNA levels and lower CD4 counts Increases rate of fibrosis Increased rate of HCV-related liver disease (cirrhosis, ESLD, HCC) In the Co-Infected Patient Higher risk of toxicity associated with IFN therapy with patients on HAART Early treatment is key to successful management HCV must be evaluated and treated before the development of ESLD Goals of HCV Therapy Eliminate HCV RNA Delay progression of fibrosis Prevent liver decompensation, HCC, and death Improve tolerance and effectiveness of HAART Permit aggressive ART Potentially enhance immune reconstitution HAART reduces liver fibrosis progression in HIV/HCV coinfected individuals Liver biopsies performed on 296 coinfected patients who had not received therapy for HCV Data analyzed from 213 patients on whom date of HCV infection could be ascertained Logistic regression analysis done to assess the association between time on HAART and fibrosis progression index (ratio of fibrosis stage to years of HCV infection) Results: HAART reduces the fibrosis progression rate and the development of bridging fibrosis and cirrhosis in HIV-HCV coinfected patients S Resino, J Berenguer, P Miralles et al., CROI 2007, Abstract 935 In the Co-Infected Patient Higher risk of toxicity associated with IFN therapy with patients on HAART Early treatment is key to successful management HCV must be evaluated and treated before the development of ESLD HCV/HIV Co-infection: Who should be treated? All patients with HIV and HCV should be considered for treatment Patients with well controlled HIV disease HIV RNA undetectable and CD4 count > 200 cells/mm3 Patients with advanced liver disease by biopsy HCV Treatment Options Interferon alfa monotherapy Pegylated interferon monotherapy Interferon alfa-2b (Intron A) Interferon alfa-2a (Roferon-A) Interferon alfacon-1 (Infergen) Peginterferon alfa-2b (PEG-Intron) Peginterferon alfa-2a (PEGASYS) Pegylated interferon combination therapy Peginterferon alfa-2b plus ribavirin Peginterferon alfa-2a plus ribavirin HIV/HCV Coinfection Trials: PEG IFN and RBV Study Treatment Regimen RIBAVIC France (N = 412) PEG IFN alfa-2b 1.5 μg/kg + RBV 800 mg IFN alfa-2b 3 MIU + RBV 800 mg ACTG 5071 USA (N = 133) PEG IFN alfa-2a 180 µg + RBV 600 mg x 4 wks, then 800mg x 4 wks, then 1 g/d IFN alfa-2a 6 MIU x 12 wks 3 MIU + RBV 600 mg x 4wks, then 800mg x 4wks, then 1 g/d APRICOT International (N = 868) PEG IFN alfa-2a 180 µg + RBV 800 mg IFN alfa-2a 3 MIU + RBV 800 mg PEG IFN alfa-2a 180 µg + RBV placebo 800 mg ACTG, AIDS Clinical Trials Group; APRICOT, AIDS PEGASYS® Ribavirin International CO-Infection Trial. Chung et al. N Engl J Med. 2004;351:451-459. Perronne et al. 11th CROI. February 8-11, 2004; San Francisco, Calif. Abstract 117LB. Torriani et al. N Engl J Med. 2004;351:438-450. ACTG 5071: Overall Results (N=133) Response (%) * 45 40 35 30 25 20 15 10 5 0 41 EOT SVR 27 12 ** 12 IFN 2a + RBV PEG 2a + RBV SVR: HCV<60 IU/mL 24 weeks after end of therapy (EOT). *P=.0001 versus IFN 2a + RBV. **P<.03 versus IFN 2a + RBV. Chung R et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 110. Response (%) ACTG 5071: PEG α-2a + RBV Arm by Genotype 90 80 70 60 50 40 30 20 10 0 80 * EOT SVR 73 * 29 14 Genotype 1 Genotype non-1 * P=.0007 vs Genotype 1. Chung R et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 110. ACTG 5071: Summary Predictors of sustained virologic response included PEG α-2a + RBV treatment, HCV genotype non-1, no previous IDU, and detectable HIV-1 RNA at entry PEG-IFN α-2a + RBV was more effective treatment than standard IFN + RBV Even in virologic nonresponders, 36% had a histological response IDU = injection drug use. Chung R et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 110. APRICOT: Virologic Response* End of Treatment Versus End of Follow-up (Genotype 1) End of treatment End of follow-up 60% % Response 50% 38% 40% 29% 30% 21% 20% 10% 0% 14% 8% 7% IFN α-2a + RBV PEG-IFN α-2a (40 kDa) + Placebo PEG-IFN α-2a (40 kDa) + RBV *Defined as <50 IU/mL HCV RNA. Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112. APRICOT: Virologic Response* End of Treatment Versus End of Follow-up (Genotypes 2 and 3) 70% End of treatment 64% 57% 60% % Response End of follow-up 62% 50% 36% 40% 30% 27% 20% 20% 10% 0% IFN α-2a + RBV PEG-IFN α-2a (40 kDa) + Placebo PEG-IFN α-2a (40 kDa) + RBV *Defined as <50 IU/mL HCV RNA. Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112. Median Change From Baseline in CD4+ Count (cells/L) APRICOT: Median Change in CD4+ Counts From Baseline * IFN -2a 3 MIU + RBV 800 mg (n=174) g PEG-IFN -2a (40 kDa) 180 g + Placebo (n=196) PEG-IFN -2a (40 kDa) 180 + RBV 800 mg (n=217) 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 BL 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 Time (Weeks) * Patients receiving 48 weeks of treatment. Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112. APRICOT: Change in HIV RNA From Baseline – All Patients Treated* Change in Log10 HIV RNA IFN -2a 3 MIU + RBV 800 mg (n=174) PEG-IFN -2a (40 kDa) 180g + Placebo (n=196) PEG-IFN -2a (40 kDa) 180g + RBV 800 mg (n=217) 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0 -1.5 -2.0 BL 4 8 * Patients receiving 48 weeks of treatment. 12 24 36 Time (Weeks) 48 52 Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112. 60 72 APRICOT: Summary SVR was significantly higher for PEG-IFN α-2a (40 kDa) + RBV compared with conventional combination therapy Overall: 40% versus 12%; P <.0001 Genotype 1: 29% versus 7% Genotype 2/3: 62% versus 20% Adverse event profile of PEG-IFN α-2a (40kDa) + RBV is generally similar to IFN + RBV therapy Only 15% to 16% of patients discontinued for adverse events or laboratory abnormalities Torriani FJ et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 112. French ANRS RIBAVIC Study Randomized, multicenter, open-label study in HIVHCV coinfected patients with CD4>200 and stable HIV RNA for 48 weeks on: PEG-IFN α-2b 1.5 g/kg/wk + RBV (n=205), or Standard IFN-2b 3 MIU tiw + RBV 800 mg QD (n=207) Primary efficacy end point was SVR (undetectable HCV RNA) at week 72 Perronne C et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 117LB. RIBAVIC: SVR at Week 72 50 P=.031 43 45 SVR (%) 40 35 26 (54/205) 30 25 20 18 (18/207) 15 10 11 5 0 IFN 2b/RBV PEG 2b/RBV Genotypes Genotypes 1/4 2/3 Perronne C et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 117LB. RIBAVIC: Response Rates – Patients Who Did Not Discontinue Treatment (n=245) Response Rates (%) 60 PEG-IFN -2b + RBV 54 52 IFN 2b + RBV 50 41 40 41 34 34 30 35 26 20 20 12 10 0 4 12 24 48 72 (SVR) Weeks of Treatment Perronne C et al. Presented at: 11th Conference of Retroviruses and Opportunistic Infections; No. 117LB. HIV/HCV Infection Trials: SVR (combined genotypes) RIBAVIC PEG IFN-alfa-2b and RBV: SVR = 26% ACTG 5071 PEG IFN alfa 2-a/RBV: SVR = 27% APRICOT PEG IFN alfa-2a/RBV: SVR = 40% Chung et al. N Engl J Med. 2004;351:451-459. Perronne et al. 11th CROI. February 8-11, 2004; San Francisco, Calif. Abstract 117LB. Torriani et al. N Engl J Med. 2004;351:438-450. Contraindications to Peginterferon/Ribavirin Hypersensitivity to peginterferon or ribavirin Pregnancy Hemoglobinopathies Active OI Decompensated liver disease Autoimmune disease Adverse Effects of Combination Therapy Interferon Fatigue (70%) Flu-like symptoms - self limited after initial doses Bone marrow suppression Depression, anxiety, insomnia, and irritability Alopecia Weight loss Potential exacerbation of autoimmune conditions Thyroid dysfunction (4%) Ribavirin Teratogenicity Hemolytic anemia Dose-dependent and completely reversible Average 2-3 grams hemoglobin over the first four weeks of therapy Nausea - take with food Managing Side Effects Evening injections Increase fluid intake Aerobic exercise Prophylactic acetaminophen or ibuprofen Support groups Psychiatric medications Erythropoetin and G-CSF International, US, and Canadian Guidelines Test ALL HIV-infected patients for HCV antibodies To treat HCV consider Liver biopsy score CD4+ cell count HIV RNA viral load Substance abuse History of depression Active Opportunistic Infection Treatment of choice is PEG IFN/RBV AASLD Practice Guidelines HCV RNA testing for: confirmation of HCV infection in HIV-infected persons who are positive for anti-HCV those who are negative and have evidence of unexplained liver disease HCV treatment for the HIV/HCV coinfected person in whom the likelihood of serious liver disease and a treatment response are judged to outweigh the risk of morbidity from the adverse effects of therapy Initial treatment of HCV in most HIV-infected persons is PEG IFN alfa/RBV for 48 weeks AASLD Practice Guidelines (cont) Monitor coinfected patients on HCV treatment closely Use RBV with caution in persons with limited myeloid reserves and in those taking AZT and D4T Patients receiving ddI should be switched to an equivalent ART before beginning therapy with RBV if possible HIV-infected patients with decompensated liver disease may be candidates for OLT AZT, zidovudine; OLT, orthotopic liver transplantation. Strader et al. Hepatology. 2004;39:1147-1171. International Guidelines Parameter HCV Treatment Recommendation Elevated ALT, CD4+ >350 cells/mm3, HIV RNA <50,000 copies/mL Begin therapy Normal ALT, fibrosis CD4+ <350 cells/mm3 CD4+ <200 cells/mm3 Begin therapy Treat with caution Hold treatment Cirrhosis without hepatic decompensation Hepatic decompensation Begin therapy ALT, alanine aminotrasferase. Soriano et al. J Viral Hepat. 2004;11:2-17. Liver transplant New International Guidelines for Management of HIV/HCV Coinfection 25-40% of coinfected patients with persistently normal ALT may have fibrosis and thus should be considered for HCV treatment regardless of ALT Non-invasive methods for assessing liver fibrosis accurately predict fibrosis in most cases, so that liver biopsy is not necessary for considering HCV treatment New International Guidelines – cont. RVR at week 4 predicts SVR in coinfected individuals as it does in monoinfected Coinfected patients on treatment who do not achieve EVR by week 12 or who still have detectable HCV RNA at week 24 should stop treatment early Guidelines – cont. Weight-based RBV superior to fixed dose 48 weeks PEG IFN + RBV for all HCV genotypes; 24 weeks may be adequate for HCV 2 or 3 Slow responders may benefit from 6072 week courses of therapy Guidelines – cont. Coinfected non-responders and relapsers must be evaluated on and individual basis and considered for retreatment or interferon maintenance monotherapy to slow liver disease HAART may benefit patients with ESLD Acute HCV in HIV-infected Individuals – International Guidelines Outbreaks in Europe among MSM – presumably sexually transmitted HIV infected individuals less likely to clear acute hepatitis C Early treatment especially indicated in patients with HIV Treatment should be initiated after 12 weeks to allow for possible spontaneous clearance, then initiated with PEG IFN and weightbased RBV for 24 weeks Case Study 2 C.T. is a candidate for Peg IFN and RBV therapy, but active substance use and psychiatric issues may complicate treatment Lack of progression in liver fibrosis on 2 consecutive biopsies reassuring Non-invasive studies to monitor fibrosis may be helpful