Optimizing Care for the HIV-Hepatitis Coinfected Patient Slide #1: Major HIV/AIDS Conference Clinical Update This version of Major HIV/AIDS Conference Clinical Update the Post Conference Update Series includes clinical data from the: 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment held in July 2005. Mark Holodniy, MD Professor of Medicine Stanford University Stanford, California Sponsored by The Academy for Continued Healthcare Learning Supported by an educational grant from Abbott

Intended Audience This activity is intended for HIV specialists from a wide range of disciplines, including but not limited to internal medicine, family practice, and infectious disease physicians. Pharmacists, nurses and other healthcare professionals focusing on HIV care are also encouraged to attend. In accordance with PhRMA guidelines, this program is intended for healthcare professionals only. Activity Purpose To update physicians, pharmacists, nurses and other health care professionals, on recent advances in HIV research and the management of HIV infectious disease. Method of Participation This activity will consist of a lecture meeting with collateral slides, syllabus, and interactive question and answer session.

Accreditation The Academy for Continued Healthcare Learning (ACHL) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation The Academy for Continued Healthcare Learning (ACHL) designates this educational activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. In order to receive credit, pharmacists must complete the activity requirements and evaluation at the conclusion of the program. This activity has been approved for a maximum of 0.1 CEU. ACPE Universal Program Number (UPN): 396-000-06-013-L02 Initial Release Date: 01/20/06 The Academy for Continued Healthcare Learning (ACHL) has been reviewed and approved as an Authorized Provider by the International Association of Continuing Education and Training (IACET). ACHL has awarded 0.1 CEU to participants who successfully complete this program. IACET CEU credit may be used toward nursing credits. Contact your local accrediting body for details.

Disclosure Statements The Academy for Continued Healthcare Learning (ACHL) requires that the faculty participating in a CME/CE activity disclose to the participant any relevant affiliation or other financial relationship (1) with the manufacturers of any commercial product(s) and/or provider(s) of commercial services discussed in an educational presentation, and (2) with any commercial supporters of the activity. The ACHL also requires participating faculty to disclose when unapproved/unlabeled uses of a product are discussed in a CME/CE activity. Mark Holodniy, MD, has no relevant affiliations or financial relationships to disclose. The ACHL staff members and others involved with the planning, development, and review of the content for this activity have no relevant affiliations or financial relationships to disclose.  

Disclaimer The content for this activity was developed independently of the commercial supporter. All materials are included with permission. The opinions expressed are those of the faculty and are not to be construed as those of the publisher or grantor. This educational activity was planned and produced in accordance with the ACCME Essential Areas and Elements, Policies, and Standards for Commercial Support as well as the ACPE Criteria for Quality and Interpretive Guidelines. Recommendations involving clinical medicine in a continuing medical education (CME/CE) activity must be based on evidence that is accepted within the profession of medicine as adequate justification for their indications and contraindications in the care of patients. All scientific research referred to, reported or used in CME/CE in support or justification of a patient care recommendation must conform to the generally accepted standards of experimental design, data collection and analysis. Participants are advised that one or more presentations in this CME/CE activity may contain references to unapproved or unlabeled uses of drugs or devices. Participants should note that the use of these agents outside current approved labeling is considered investigational and are advised to consult current prescribing information for these products.

Housekeeping Information Please refer to the syllabus for complete CME/CE credit information Please return your completed enrollment/evaluation forms to the Meeting Host before you leave Please turn your cell phones to off or vibrate

Learning Objectives Upon completion of this activity, participants should be able to Describe liver-related adverse events in HIV-Hepatitis coinfected patient Examine associated hepatotoxicity with different treatment modalities Review treatment options, taking into consideration hepatic safety

Liver-Related Adverse Events Liver-related adverse events are the most common grade 4 adverse events in HIV positive patients Hospitalizations for liver related events are more common than hospitalizations for opportunistic infections or for IDU related events Liver toxicity of ARV agents should be seriously considered before initiating therapy

Most Common Grade 4 Events: CPCRA Cohort Liver 2.6 Incidence Neutropenia 1.5 per 100 Person-Years Anemia 1.1 CVD 0.9 Pancreatitis 0.9 Psychiatric 0.8 Renal 0.6 Hazard Ratio For Death by Grade 4 Event (95% CI) 3.49 (2.38-5.12) P=.0001 1.02 (0.61-1.72) P=.93 1.76 (0.99-3.09) P=.051 7.08 (4.15-12.05) P=.0001 3.40 (1.82-6.33) P=.0001 1.91 (0.79-4.63) P=.15 4.60 (2.45-8.66) P=.0001 N=2947; CPCRA=Terry Beirn Community Programs for Clinical Research on AIDS. Reisler RB, et al. JAIDS. 2003;34:379-386.

Prevalence of HIV/HCV Coinfection Prevalence by Risk Factor Johns Hopkins HIV clinic Urban setting Prospective, longitudinal database HCV-coinfection clinic established in 1997 1742 HIV-infected patients screened for HCV infection (1997-2000) HCV+: 798 patients Prevalence of HIV/HCV Coinfection Sulkowski and colleagues assessed the prevalence of HIV/HCV coinfection among a cohort of patients from the Johns Hopkins HIV clinic.1 Urban setting. Prospective, longitudinal database. HCV-coinfection clinic established in 1997. Of the 1742 HIV-infected patients screened for HCV infection from 1997 to 2000, they identified 798 who were HCV positive (45.1%).1 The highest prevalence of HIV/HCV coinfection was among injection drug users. Reference Sulkowski MS, Brinkley-Laughton S, Thomas DL. HCV and HIV co-infection: prevalence, genotype distribution and severity of liver disease in an urban HIV clinic. Hepatology. 2000;32. Abstract 204. Prevalence of Antibody HCV+, % IDU Hetero- Homo- Entire sexual sexual Cohort Sex Sex Sulkowski MS, et al. Hepatology. 2000;32. Abstract 204.

Impact of HIV Infection on HBV and HCV Disease Progression Accelerates the course of HBV and HCV infection Liver disease associated with HBV or HCV infection A leading cause of morbidity and mortality among HIV-infected patients HBV or HCV Disease Course HBV or HCV Infection 15% 85% Recovery Chronic Impact of HIV Infection on HBV and HCV Disease Progression Data from a number of studies have consistently demonstrated that HIV infection accelerates the course of HCV and HBV infection.1-5 HIV accelerates the course of HCV and HBV infection. HCV and HBV-associated liver disease is the leading cause of morbidity and mortality among HIV-infected patients. References Thomas DL, Astemborski J, Rai RM, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA. 2000;284:450-456. 2. Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The MULTIVIRC Group. Hepatology. 1999;30:1054-1058. Graham CS, Baden LR,Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33:562-569. Bodsworth NJ, Cooper DA, Donovan B. The influence of human immunodeficiency virus type 1 infection on the development of the hepatitis B virus carrier state. J Infect Dis. 1991;163:1138-1140. Gilson RJ, Hawkins AE, Beecham MR, et al. Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection. AIDS. 1997;11:597-606. 68% 17% Stable Cirrhosis 13% 4% Slowly Progressive HCC ESLD Thomas DL, et al. JAMA. 2000;284:450-456. Benhamou Y, et al. Hepatology. 1999;30:1054-1058. Graham CS, et al. Clin Infect Dis. 2001;33:562-569. Bodsworth NJ, et al. J Infect Dis. 1991;163:1138-1140. Gilson RJ, et al. AIDS. 1997;11:597-606. HCC=hepatocellular carcinoma. ESLD=end-stage liver disease.

Rapid Progression of Liver Disease in HIV/HCV Coinfected Patients Prospective study of fibrosis progression in 67 coinfected patients 2 biopsies, median time between biopsies was 2.84 years Patients With Mild Fibrosis (≤F1) on First Biopsy >25% of patients with mild fibrosis on initial biopsy had ≥2 stage progression in fibrosis score Change in Ishak Score From First to Second Biopsy Sulkowski M, et al. 12th CROI. Boston. 2005. Oral abstract 121.

Survival of Patients Coinfected With HIV and Hepatitis B or C Virus Cohort study 472 HIV patients followed for 8343 patient-months HIV alone (n=126) HIV/HBV (n=72) HIV/HCV (n=256) HIV/HBV/HCV (n=18) Variables associated with liver death in the cohort coinfected with HCV, HBV, or both (n=346) 0 to 2 antiretroviral drugs CD4 <200 cells/µL HIV or Liver Mortality Slide #18: Survival of Patients Coinfected With HIV and Hepatitis B or C Virus Bonacini and colleagues conducted a prospective, university clinic cohort study of 472 patients with HIV infection who were followed for 8343 patient-months.1 Patients were divided into 4 subgroups:1 HIV/HBV (n=72). HIV/HCV (n=256). HIV/HBV/HCV (n=18). HIV alone (n=126). Liver deaths were significantly more common in patients with multiple hepatitides (28%), HIV/HBV (15%), and HIV/HCV (13%), versus HIV alone (6%).1 Its important to note that liver mortality was comparable in HIV/HBV as in HIV/HCV-coinfected patients. Finally, in patients with hepatitis co-infection, initial CD4 cell count higher than 200 cells/mm3 and use of HAART were independently associated with reduced mortality. These results suggest that control of immunosuppression using HAART and keeping CD4 cell count above 200 should be one of the first priorities in patients with HIV and any viral hepatitis co-infection. Control of hepatitis viruses needs to be considered after HIV is suppressed or as a primary endpoint in selected patients with early untreated HIV disease.1 Reference Bonacini M, Louie S, Bzowej N, et al. Survival in patients with HIV infection and viral hepatitis B or C: a cohort study. AIDS. 2004;18:2039-2045. Mortality, % HIV HIV/HBV HIV/HCV HIV HBV/HCV Bonacini M, et al. AIDS. 2004;18:2039-2045.

Association Between CD4 Cell Count and Liver-Related Death D:A:D Study Prospective study with 23 441 people with HIV 1248 deaths between 2000-February 2004 Leading causes of death: AIDS, 30% Liver-related death 14% (79% associated with chronic hepatitis) Heart disease 9% Non-AIDS malignancies, 8% Relative risk of death for persons with CD4 <50 cells/mm3 as compared with persons with CD4 >500 cells/mm3 Category RR 95% CI P AIDS 96.4 61.6-150.7 <.0001 Liver-Related 26.6 12.9-54.7 Non-AIDS Malignancies 23.5 9.4-58.7 Weber, R, et al. 12th CROI. Boston. 2005. Abstract 595.

HAART and the Impact of HIV RNA, CD4, or Both on Liver Fibrosis 0.196 P=.005 P=.005 P=.04 0.162 0.155 0.145 P=.005 0.122 0.121 0.123 Ishak Fibrosis Units/Year <400 400-99K ≥100K ≥350 <350 <400 ≥400 HIV RNA (copies/mL) CD4 (cells/mm3) HIV RNA (copies/mL) + <500 CD4 cells/mm3 Brau N, et al. 39th EASL. Berlin, 2004. Abstract 99.

HAART and Liver Fibrosis in HIV/HCV Coinfected Patients HAART may slow fibrosis progression HIV/HCV coinfection versus HCV monoinfection post-HAART: No difference in: Fibrosis progression rate (P=.29) Fibrosis stage (P=.87) Necroinflammatory grade (P=.89) Fibrosis progression rate (FPR) in Coinfected patients: Strongly correlated with HIV RNA levels Coinfected patients with any HIV RNA >400 copies/mL had a faster FPR than coinfected patients with HIV RNA <400 copies/mL (P=.004) Coinfected patients with HIV RNA <400 copies/mL had a similar FPR to HCV monoinfected patients (P=.253) Increased with CD4 cell counts <500 cells/mm3 combined with HIV RNA >400 copies/mL (P=.005) HAART and Liver Fibrosis in HIV/HCV Coinfected Patients Brau and colleagues’ retrospective chart review found that HAART may slow fibrosis progression Post-HAART:1 HIV/HCV coinfection versus HCV monoinfection, there was no difference in: Fibrosis progression rate (P=0.29). Fibrosis stage (P=0.87). Necroinflammatory grade (P=0.89). Fibrosis progression rate (FPR) in HIV/HCV-coinfected patients was strongly correlated with HIV RNA levels and was increased with CD4 cell counts <500 cells/mm3 combined with HIV RNA>400 copies/mL (P=0.005). HIV/HCV coinfected patients with any HIV RNA < 400 copies/mL had a faster FPR than coinfected patients with HIV RNA < 400 copies/mL (p=0.004) HIV/HCV coinfected patients with HIV RNA < 400 copies/mL had a similar FPR to HCV monoinfected patients (p=0.253) Reference Brau N, Rogdriquez-Torres M, Salatore M, et al. Control of viral HIV load through highly active antiretroviral therapy (HAART) slows down liver fibrosis in HIV/HCV-coinfection and makes it the same as in HCV-monoinfection. Program and abstracts of the 39th Annual Meeting of the European Association for the Study of the Liver. April 14-19, 2004. Berlin, Germany. Abstract 91. Brau N, et al. 39th EASL. Berlin, 2004. Abstract 99.

Impact of HAART and ART on Mortality in HIV/HCV Coinfected Patients Days Overall Mortality Cumulative Survival 0 1000 2000 3000 4000 5000 6000 ART HAART* No therapy *P<.001 Bonn cohort (1990-2002) 285 HIV/HCV coinfected patients Liver-related mortality rates per 100 person-years HAART: 0.45 ART: 0.69 No therapy: 1.70 Predictors for liver-related mortality No HAART Low CD4 cell count Increasing age Impact of ART on Overall Liver Mortality in HIV/HCV-Coinfected Patients Qurishi and colleagues studied liver-related mortality and overall mortality in 285 patients who were regularly treated during the period 1990-2002. This Bonn cohort comprised 285 HIV/HCV coinfected patients.1 Overall survival was significantly improved among those receiving HAART.1 Liver-related mortality rates per 100 person-years:1 HAART use: 0.45. ART use: 0.69. No therapy: 1.70. Predictors for liver-related mortality.1 No use of HAART. Low CD4 cell count. Increasing age. Reference Qurishi N, Kreuzberg C, Luchters G, et al. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet. 2003;362:1708-1713. Days Liver-Related Mortality Cumulative Survival 0 1000 2000 3000 4000 5000 6000 HAART* ART No therapy *P=.018 Qurishi N, et al. Lancet. 2003;362:1708-1713.

HIV infection accelerates the course of viral hepatitis Summary: Clinical Implications of Liver Damage and Benefits of HAART in Coinfected Patients Liver damage in HIV-infected patients causes significant morbidity and mortality HIV infection accelerates the course of viral hepatitis Patients with low CD4 cell counts have an increased risk of liver-related death HAART Can be tolerated by coinfected patients Controls HIV May slow the progression of fibrosis, especially PIs Improves immune status Improves survival Slide #43: Summary: Benefits of HAART in HIV/HCV-Coinfected Patients In summary, the use of HAART in HIV/HCV-coinfected patients has a number of benefits. HAART in HIV/HCV-coinfected patients can be well tolerated and it: Controls HIV disease. May slow fibrosis progression. Improves immune status. Improves survival: both overall mortality and liver-specific mortality.

Balancing HAART and Hepatic Safety NRTIs

NRTI-Related Hepatotoxicity Syndrome of mitochondrial toxicity Mitochondria have their own DNA (mtDNA) that encodes 13% of mitochondrial proteins NRTIs inhibit mitochondrial DNA synthesis, causing mitochondrial dysfunction and cellular toxicity High-risk drugs Stavudine, didanosine, zalcitabine Low-risk drugs Abacavir, zidovudine, lamivudine Fleischer R, et al. Clin Infect Dis. 2004;38:e79-e80.

Association of Dideoxynucleoside Analogues With Hepatic Steatosis Retrospective chart review of 179 HIV/HCV coinfected patients Univariate analysis Factors associated with steatosis; Dideoxynucleosides (P=.029) and the number of nucleoside analogues (P=.042) Use of protease inhibitors was not associated with steatosis Multivariate analysis Odds Ratio 95% CI P Dideoxynucleosides 6.0 (1.9-18.9) .002 Other nucleoside analogues 3.0 (1.05-8.4) .04 HCV genotype 3 3.7 (0.92-14.5) .065 McGovern B, et al. 12th CROI. Boston. 2005. Abstract 950.

Balancing HAART and Hepatic Safety NNRTIs

NNRTI-Related Hepatotoxicity Incidence of ALT or AST elevations in randomized trials Grade 3 (>5 x ULN) and 4 (>10 x ULN): 8% to 16% Hepatitis coinfection increases the risk of hepatotoxicity Nevirapine Fatal hepatic necrosis US FDA “warning” Sulkowski MS, et al. Hepatology. 2002;35:182-189. Reisler R, et al. 1st IAS Conference. Buenos Aires, 2001. Abstract 43. Stern J, et al. JAIDS. 2003;34(suppl 1):S21-S33. Wit FW, et al. J Infect Dis. 2002;186:23-31. van Leth F, et al. Lancet. 2004;363:1253-1263. Gallant JE, et al. JAMA. 2004;29:191-201.

Risk Factors for Severe, Life-Threatening Hepatotoxicity With Nevirapine Women with CD4 cell counts >250 cells/mm3 Have a 12-fold higher risk versus women with <250 cells/mm3 Can be fatal Greatest risk of severe and potentially fatal hepatic events often associated with rash Occurs in first 6 weeks of nevirapine therapy Close monitoring recommended. In some cases, hepatic injury progresses despite discontinuation of treatment Nevirapine should not be used for chronic therapy among women with CD4 >250 cells/mm3 when other options exist Viramune [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2005.

Meta-Analysis of AACTG Studies: Odds Ratio of Severe Hepatotoxicity Retrospective analysis of 21 AACTG studies 9003 patients Single and double NRTIs Triple regimens including NRTIs, NNRTIs, and PI Overall incidence Severe hepatotoxicity: 10% 23% discontinued due to severe hepatotoxicity Liver-related mortality: 0.3% NRTI-based regimen: 0.46% NNRTI or PI-based regimen: 0.13% Incidence of Severe Hepatotoxicity (95% CI) Efavirenz (n=65) 10.8 (3.3-18.3) Nevirapine (n=594) 8.9 (6.6-11.2) Delavirdine (n=137) 3.6 (0.5-6.7) Total NNRTI (n=796) 8.2 (6.3-10.1) Grade 3 or 4 elevations (>5 x ULN). Reisler R, et al. 1st IAS Conference. Buenos Aires. 2001. Abstract 43.

Grade 3/4 Hepatotoxicity 2NN Study: Severe Hepatotoxicity in Patients Receiving NNRTI-Based Regimens Treatment-naïve patients 1216 enrolled HBV coinfected: 5.2% HCV coinfected: 9.5% NNRTI + d4T + 3TC Nevirapine qd (400 mg) Nevirapine bid (200 mg) Efavirenz qd (600 mg) Nevirapine + efavirenz qd (400 + 800 mg) 2 nevirapine-attributed deaths Fulminant hepatitis, pancreatitis, renal failure Stevens-Johnson syndrome (recovered) Later developed septicemia due to a methicillin-resistant Staphylococcus aureus infection Grade 3/4 Hepatotoxicity 13.6% 9.1% 8.3% Patients, % 4.5% QD BID Efavirenz Efavirenz + (n=220) (n=387) (n=400) Nevirapine (n=209) Nevirapine van Leth F, et al. Lancet. 2004;363:1253-1263.

Study 006: Patients With Hepatitis C and/or Hep B Coinfection Seropositive for hepatitis B and C at study entry 137 patients treated with efavirenz-containing regimens 84 patients treated with indinavir + 2 NRTIs Discontinuations due to liver or biliary system disorders were similar (2% to 3%) ALT and AST >5 Times ULN Efavirenz-containing regimens Indinavir + 2 NRTIs 20% 13% Patients (%) 7% 7% ALT AST Sustiva [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2003.

Summary of NNRTIs and Hepatic Safety There appears to be a modest class effect of NNRTIs on abnormal liver enzyme levels Rate of serious clinical (symptomatic) hepatotoxicity, ALT and/or AST levels >5 times ULN is relatively low May be significantly higher in patients coinfected with HBV or HCV Unique hepatic event associated with nevirapine Immune-mediated Associated with rash Occurs almost exclusively within the first 6 weeks of nevirapine treatment

Balancing HAART and Hepatic Safety PIs

PI-Related Hepatotoxicity Incidence of ALT and/or AST elevations in registration trials Grade 3 (>5 x ULN) and 4 (>10 x ULN): 1% to 9% Full-dose ritonavir Only PI identified as an independent risk factor for severe hepatic injury Boosting doses of ritonavir (≤200 mg/d) Not associated with significantly higher incidence of severe hepatotoxicity versus other PIs Less data on newer PIs Atazanavir or fosamprenavir Sulkowski MS, et al. Clin Infect Dis. 2004:38(suppl 2):S90-S97.

Incidence and Risk Factors of HAART-Associated Hepatotoxicity Retrospective cohort analysis (n=560) Risk factors for grade 4 liver enzyme elevations (HR [95% CI]) Female sex: 2.8 [1.3-5.8] Baseline ALT levels (per 10 U/L increase): 1.05 [1.01-1.11] Chronic HCV infection: 5.0 [2.3-10.7] Chronic HBV infection: 9.2 [4.1-20.6] Recent discontinuation of lamivudine: 6.8 [2.1-22.7] Recent start of nevirapine:* 9.6 [3.2-28.3] Recent start of full-dose ritonavir:* 4.9 [2.0-12.1] No increased risk if ritonavir dose ≤200 mg bid *12-week period after start of drug. †Patients without NRTIs experience using first-line ARV versus subsequent regimens. Wit FW, et al. J Infect Dis. 2002;186:23-31.

1st PI-Containing Regimen Hepatotoxicity Associated with PI-Based Regimens ± Low-Dose Ritonavir: Design Prospective study (n=1161) Evaluate grade 3/4 AST/ALT elevations of PIs Median follow-up: 211−365 days Baseline characteristics Age*: 37 years Male: 73% African American: 77% HCV+: 46% HbsAg+: 10% ALT*: 30 IU/L CD4*: 168 cells/mm3 HIV RNA*: 4.7 log10 copies/mL 1st PI-Containing Regimen Saquinavir/r Nelfinavir Indinavir/r Indinavir Lopinavir/r *median Sulkowski MS, et al. Hepatology. 2003;38:698A. Sulkowski MS, et al. AIDS. 2004;18:2277-2284.

Risk Factors for PI-Associated Drug-Induced Liver Injury Relative Risk of Severe Hepatotoxicity (95% CI) HCV+ 1.73 (1.14-2.63) CD4 >50 cells/mm3 0.51 (0.33-0.79) HIV RNA >10,000 copies/mL 2.59 (1.08-6.18) Indinavir 2.30 (1.06-4.98) Indinavir/RTV 2.73 (1.33-5.63) Saquinavir/RTV 2.39 (1.47-3.89) No increased risk observed with lopinavir/r and nelfinavir Results consistent with data from the randomized control trial by Walmsley (Study 863) HIV/HCV-coinfected patients 84% had no drug-induced liver injury Multivariate analysis Sulkowski MS, et al. Hepatology. 2003;38:698A. Sulkowski MS, et al. AIDS. 2004;18:2277-2284.

Study 863: 60-Week Safety of Lopinavir/r and Nelfinavir by Hepatitis Status Hepatitis B/C-positive patients Patients with ALT/AST >3x ULN were excluded at screening regardless of hepatitis status Lopinavir/r patients (n=57) tended to have a lower incidence of grade 3/4 AST and ALT elevations compared with nelfinavir-treated patients (n=68) AST: lopinavir/r 4% versus nelfinavir 13% ALT: lopinavir/r 12% versus nelfinavir 17% Similar incidence of discontinuations due to hepatic adverse events in both groups (4%) No discontinuations due to elevated liver enzymes in either group No hepatic-related events resulted in death Bernstein B, et al. 1st IAS Conference. Buenos Aires. 2001. Abstract 525.

Study 863: Selected Adverse Events and Laboratory Abnormalities Patients (%) Lopinavir/r HBV/HCV+ (n=57) HBV/HCV– (n=269) Nelfinavir (n=68) (n=259) Glucose (250 mg/dL) 2 3 1 AST (>5 x ULN) 4 13 2† ALT (>5 x ULN) 12 3* 17 <1† Total cholesterol (>300) 10 11 8 6 Triglycerides (>750 mg/dL) Amylase (>2 x ULN) *P<.05 and †P<.001 vs hepatitis positive Bernstein B, et al. 1st IAS Conference. Buenos Aires. 2001. Abstract 525.

Study 863: Demographics of HIV/HCV Coinfected Patients Lopinavir/r (n=29) Nelfinavir (n=41) HIV RNA (log10 copies/mL) Median (range) 5.12 (3.02-6.28) 5.02 (2.98-6.72) CD4 (cells/mm3) 205 (2.5-868) 186 (15-818) HCV RNA (log10 IU/mL) 6.28 (1.70-7.32) (n=22) 6.45 (2.95-7.36) (n=35) ALT (IU/L) 44 (16-265) 39 (14-100) All patients received lamivudine + stavudine. HCV Genotype 1: 71% of patients. Sherman KE, et al. 11th CROI. San Francisco. 2004. Abstract 811.

CD4 Change From Baseline Study 863 HIV/HCV-Coinfected Patients: CD4 Cell Counts Through 48 Weeks On-Treatment 234 Lopinavir/r + d4T + 3TC Nelfinavir + d4T + 3TC 184 CD4 Change From Baseline (cells/mm3) P=0.247 0 8 16 24 32 40 48 LPV/r (n=29) (n=23) (n=20) Nelfinavir (n=41) (n=34) (n=35) Weeks Sherman KE, et al. 11th CROI. San Francisco. 2004. Abstract 811.

Study 863 HIV/HCV-Coinfected Patients: Time to HIV RNA <400 and <50 Copies/mL 100% 87% 100% 73% Lopinavir/r (n=29) Nelfinavir (n=41) Patients, % Patients, % Lopinavir/r (n=29) Nelfinavir (n=41) First evaluated at 24 weeks P=.274 P=.308 Weeks Weeks All patients received lamivudine + stavudine. Sherman KE, et al. 11th CROI. San Francisco. 2004. Abstract 811.

Study 863 HIV/HCV-Coinfected Patients: Mean ALT Through 48 Weeks On-Treatment † * 63 * Mean ALT, IU/L 44 Lopinavir/r + d4T + 3TC Nelfinavir + d4T + 3TC 0 8 16 24 32 40 48 LPV/r (n=29) (n=24) (n=21) Nelfinavir (n=41) (n=37) (n=35) Weeks *P<.05 and †P<.01 vs LPV/r. Sherman KE, et al. 11th CROI. San Francisco. 2004. Abstract 811.

Meta-Analysis of Lopinavir/Ritonavir Efficacy in HIV/HCV Coinfected Patients 48-week exposure data from 8 clinical trials 819 adult HIV-infected patients Hepatitis positive: 132 patients with HCV and/or HBV coinfection Hepatitis negative: 687 patients 5-year exposure data from Study M97-720 Lopinavir/ritonavir At least as safe as nelfinavir 6.9% to 12.8% experienced grade 3+ ALT elevations Overall coinfected patients did have 3 to 4 fold higher risk of ALT and AST elevations versus those without hepatitis Slide #107: Meta-Analysis: Lopinavir/Ritonavir Efficacy in HIV/HCV-Coinfected Patients da Silva and colleagues retrospectively compared 819 HIV/HCV and/or HBV-coinfected patients to 687 non-coinfected patients in several clinical trials of lopinavir/ ritonavir, with respect to virologic and immunologic response, and the risk of AST/ALT elevations. In addition, 5-year exposure data from Study M97-720 was also evaluated.1 Lopinavir/ritonavir was found to be at least as safe as nelfinavir.1 6.9% to 12.8% experienced grade 3+ ALT elevations. Overall coinfected patients did have 3 to 4 fold higher risk of ALT and AST elevations versus those without hepatitis. Reference da Silva B, King B, Cernohous P, et al. Lopinavir/ritonavir safety, tolerability, and efficacy in HIV patients co-infected with hepatitis C and/or B: review of clinical trials. Program and abstracts of the 15th International AIDS Society Conference. July 11-16, 2004. Bangkok, Thailand. Abstract MoPeB3285. da Silva, et al. 15th IAC. Bangkok, 2004. Abstract MoPeB3285.

Meta-Analysis: Virologic Outcomes With Lopinavir/Ritonavir 0 8 16 24 32 40 48 HIV RNA <400 copies/mL, % Hepatitis positive (n=75) Week Treatment-Naïve Hepatitis negative (n=433) P=0.205 HIV RNA <400 copies/mL % (n=57) Treatment-Experienced (n=254) P=0.562 Slide #108: Virologic Outcomes With Lopinavir/Ritonavir In the meta-analysis of da Silva and colleagues, clinically significant and similar virologic outcomes were achieved in patients treated with lopinavir/ritonavir regardless of hepatitis status.1 Reference da Silva B, King B, Cernohous P, et al. Lopinavir/ritonavir safety, tolerability, and efficacy in HIV patients co-infected with hepatitis C and/or B: review of clinical trials. Program and abstracts of the 15th International AIDS Society Conference. July 11-16, 2004. Bangkok, Thailand. Abstract MoPeB3285. All patients received lamivudine + stavudine. da Silva, et al. 15th IAC. Bangkok, 2004. Abstract MoPeB3285.

Treatment-Experienced Meta-Analysis: Week 48 CD4 Cell Gain With Lopinavir/Ritonavir by Hepatitis Status Treatment-Naïve CD4 Change, cells/mm3 Hepatitis Positive (n=51) Negative (n=377) 211 219 P=.69 Treatment-Experienced CD4 Change, cells/mm3 Hepatitis Positive (n=39) Negative (n=181) 82 114 P=.17 Slide #109: Week 48 CD4 Cell Gain With Lopinavir/Ritonavir by Hepatitis Status There was no significant difference between hepatitis positive and hepatitis negative patients in mean change in CD4 counts from baseline to 48 weeks in both treatment-naïve and treatment experienced patients.1 Analyses comparing hepatitis positive and negative patients within baseline CD4 subcategories yielded similar results.1 Reference da Silva B, King B, Cernohous P, et al. Lopinavir/ritonavir safety, tolerability, and efficacy in HIV patients co-infected with hepatitis C and/or B: review of clinical trials. Program and abstracts of the 15th International AIDS Society Conference. July 11-16, 2004. Bangkok, Thailand. Abstract MoPeB3285. All patients received lamivudine + stavudine. da Silva, et al. 15th IAC. Bangkok, 2004. Abstract MoPeB3285.

Meta-Analysis Findings A higher percentage of HIV/HCV coinfected patients treated with lopinavir/ritonavir maintained HIV RNA levels <400 and <50 copies/mL compared with nelfinavir-treated patients Lopinavir/ritonavir appears at least as safe as nelfinavir in HIV/HCV coinfected patients A minority of patients (6.9% to 12.8%) experienced grade 3+ ALT elevations Lopinavir/ritonavir appears to be equally effective against HIV infection in HCV positive and negative patients Slide #110: Lopinavir/Ritonavir Use in Patients With Hepatitis Coinfection Taken together, the data from da Silva and colleagues demonstrate that:1 A higher percentage of HIV/HCV-coinfected patients treated with lopinavir/ritonavir maintained HIV RNA levels <400 and <50 copies/mL compared with nelfinavir-treated patients. Lopinavir/ritonavir appears at least as safe as nelfinavir in HIV/HCV-coinfected patients. A minority of patients (6.9% to 12.8%) experienced grade 3+ ALT elevations. Lopinavir/ritonavir appears to be equally effective against HIV infection in HCV positive and negative patients.1 Reference da Silva B, King B, Cernohous P, et al. Lopinavir/ritonavir safety, tolerability, and efficacy in HIV patients co-infected with hepatitis C and/or B: review of clinical trials. Program and abstracts of the 15th International AIDS Society Conference. July 11-16, 2004. Bangkok, Thailand. Abstract MoPeB3285. da Silva, et al. 15th IAC. Bangkok, 2004. Abstract MoPeB3285.

Study 418: HIV RNA <50 Copies/mL Through Week 48 by Baseline Hepatitis Status (ITT NC=F) Easterbrook P. et al. HIV7. Glasgow, UK. 2004. Abstract 164.

Study 418: CD4 Count Mean Change From Baseline by Baseline Hepatitis Status Easterbrook P. et al. HIV7. Glasgow, UK. 2004. Abstract 164.

Study 418 Incidence of Resistance Through Week 48 LPV/r 800/200 mg QD (n=115) LPV/r 400/100 mg BID (n=75) Patients eligible for resistance testing1 Genotypic results available Lopinavir resistance2 Tenofovir resistance3 Emtricitabine resistance4 11 8/11 0/8 2/8 11 7/11 0/7 1/7 1HIV RNA >500 copies/mL any time during Weeks 12-24. All samples >500 copies/mL were submitted for testing 2LPV/r resistance: emergence of primary or active site mutation at protease positions 8, 30, 32, 46, 47, 48, 50, 54, 82, 84, 90, with phenotypic LPV resistance FC > 2.5 vs WT 3TDF resistance: emergence of K65R or any TAM (41, 67, 70, 210, 215, 219) in RT 4FTC resistance: emergence of M184V mutation in RT Molina JM, et al. XV IAC. Bangkok, Thailand. 2004. Abstract WePe5701.

Summary of PIs and Hepatic Safety Rate of serious clinical (symptomatic) hepatotoxicity, ALT and/or AST levels >5 times ULN is relatively low Boosting doses of ritonavir not associated with significantly higher incidence of severe hepatotoxicity versus other PIs Patients coinfected with HBV and/or HCV Greater risk of hepatotoxicity Lopinavir/ritonavir appears at least as safe as nelfinavir Boosted PIs can help suppress resistance to other ARV agents More data for atazanavir and fosamprenavir are needed in this patient population

Conclusions

Conclusions High prevalence of HIV-hepatitis coinfection HIV RNA and CD4 are correlated with fibrosis progression in coinfected patients Use of NNRTIs is associated with increased risk of hepatotoxicity For PI regimens, no increased risk if ritonavir dose <200 mg bid

Conclusions, cont. Patients treated with boosted PIs tend to have a lower incidence of grade 3/4 AST and ALT elevations than patients treated with nelfinavir Boosted PIs tend to suppress HIV RNA better than nelfinavir in HIV/HCV coinfected patients Boosted PIs can help suppress resistance to other ARV agents (eg, tenofovir DF)

Recommended Regimens for Treatment-Naïve Patients: DHHS 2006 Preferred Regimens Lopinavir/ritonavir (400/100 mg [2 tablets] bid or 800/200 mg [4 tablets] qd) + ZDV + (3TC or FTC) Efavirenz* + (ZDV or TDF) + (3TC or FTC) Alternative Regimens PI-Based Atazanavir†, fosamprenavir, ritonavir‡-boosted fosamprenavir, ritonavir‡-boosted indinavir, nelfinavir, or ritonavir‡-boosted saquinavir¶: All used in conjunction with (3TC or FTC) + (ZDV or d4T or ABC or TDF or ddI) Lopinavir/ritonavir + (3TC or FTC) + (d4T or ABC or TDF or ddI) NNRTI-Based Efavirenz* + (3TC or FTC) + (ABC or ddI or d4T) Nevirapine§ + (3TC or FTC) + (ZDV or d4T or ddI or ABC or TDF) Triple NRTI Abacavir + 3TC + ZDV (only when a preferred or an alternative NNRTI- or PI-based regimen cannot or should not be used) Slide #9: Recommended Regimens for Treatment-Naïve Patients: DHHS 2006 On May 4, 2006, the Panel on Clinical Practices for Treatment of HIV Infection, sponsored by the DHHS, provided its recommendations for the use of antiretroviral agents in treatment-naïve HIV-infected patients.1 Data from the growing number of clinical trials allowed the panel to recommend the use of specific antiretroviral combination regimens as being preferred for first-line use or for alternative regimens. Preferred regimens:1 PI-based: lopinavir/ritonavir + zidovudine + (lamivudine or emtricitabine). NNRTI-based: efavirenz + (zidovudine or tenofovir DF) + (lamivudine or emtricitabine). Administration of this NNRTI-based regimen is not recommended during pregnancy, particularly during the first trimester, or in women with high pregnancy potential. The panel also identified a number of alternative regimens that may be useful under conditions when the preferred regimens may not be the best choice for an individual patient.1 Reference 1. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Default.aspx. Revision: May 4, 2006. *Not recommended for use in 1st trimester, or in women with high pregnancy potential. †Ritonavir 100 mg/day recommended when tenofovir DF is used with atazanavir. ‡ Low-dose: 100 to 400 mg/day as a pharmacologic booster. §Adult females and males with CD4 cell counts <250 and <400 cells/mm3, respectively. ¶Soft-gel or hard gel capsules, or tablets. Available at: http://aidsinfo.nih.gov/Default.aspx.

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Thank You!

Case 1- HCV Diagnosis in HIV Infected Patient 43 y/o WM, unemployed, h/o IDU, found to be HIV positive last year. No f/u until today when he presents to clinic for evaluation You obtain labs and determine that his CD4 count is 227 (14%), HIV VL 84,000, Hemoglobin 13, ALT 51 and HCV Ab, HBV sAg are negative. No current meds. Given his HIV VL and CD4 count ARV Rx is recommended. In your consideration about ARV regimens in this patient, you discuss potential liver toxicity. Despite negative hepatitis serologies is any further or repeat testing warranted?

Case 2- HIV Treatment in the HIV/HCV Coinfected Patient 37 y/o AAF was diagnosed with HIV/HCV about 4 years ago. Remote h/o IDU and minimal ETOH intake. Has ongoing depression. Works as a medical assistant. Current meds are Zoloft and as needed ibuprofen. Current Labs today: HCV VL 7.1M genotype 1b, Chol 220 (LDL 131), ALT 51 CD4 count has been in the 400s, HIV VL 12,000, but over the last couple of years has drifted down to 300 (17%) and the HIV VL is now 47,500. What type of ARV regimen would you consider using in this patient?

Case 3- HCV Treatment in the HIV/HCV Coinfected Patient 51 y/o HM with HIV/HCV for over 10 years. Intermittently employed as a house painter. H/o HTN, smoker, on ARV Rx (Sustiva, Truvada) with an undetectable HIV VL and CD4 count 451 (21%). His BMI is 29. Other labs include HCV VL 27.5M genotype 1a, ALT 67, Chol 247 (LDL 185), TG 97 Liver biopsy 2 years ago showed grade 2 fibrosis and no cirrhosis. Although adherent to meds, he has missed a few appointments. Is this patient a candidate for HCV Treatment? What factors go into your decision?