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THE BODY PRO The HIV Resource for Health Professionals New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 Faculty: Daniel Fierer, M.D. Assistant Professor of Medicine at the Mount Sinai School of Medicine The Body PRO Covers ICAAC/IDSA 2008 Washington, D.C.; October 25-28, 2008 This activity is jointly sponsored by Postgraduate Institute for Medicine and The Body PRO. Copyright © 2009 The HealthCentral Network, Inc. All rights reserved. Daniel Fierer, M.D. 1 Faculty for This Activity The Body PRO Daniel Fierer, M.D. Daniel Fierer, M.D., is an assistant professor of medicine and infectious diseases at the Mount Sinai School of Medicine in New York City. Dr. Fierer earned his medical doctorate from the Yale University School of Medicine in 1986. He trained in internal medicine at the University of California, San Diego, and completed postgraduate fellowships in infectious diseases at the National Institutes of Health and the University of California Hospitals. Dr. Fierer's research interests focus primarily on HIV/hepatitis C (HCV) coinfection, and he is the co-author of numerous journal articles and studies in this area. He initiated a study evaluating HIV-infected patients referred by their physicians for acute HCV infection. The aim of the study was to further investigate the early effects of HCV infection on liver pathology, the natural history of the disease, the effectiveness of treatment and the mode of transmission. Disclosures Dr. Fierer has no real or apparent financial relationship to disclose related to the topic of this activity. This activity is supported by an educational grant from New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 The Body PRO HCV in the HIV-Infected Patient: Case Study, 56-Year-Old Caucasian Male With HIV and Hepatitis C Exposure to HIV and HCV: Late 1970s Diagnosis: Early 1990s No ART CD4+ lymphocyte 782/mm3 HIV RNA < 400 copies/ml HCV genotype 1a; HCV RNA 6.4 log IU/ml ALT 77; INR 1, TB 1.9; creat 1; plts 219K Liver biopsy 2001: mild fat; no fibrosis Adapted from David Thomas. ICAAC/IDSA 2008; abstract 849. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 2 3 HCV in the HIV-Infected Patient: ACTG 5178 No Benefit of Maintenance The Body PRO No benefit of 18 months of maintenance N = 21 DSMB stopped study Cirrhosis 18% and 21% of maintenance and observation arms N = 24 Change in Metavir Fibrosis Sherman and ACTG 5178 team, CROI 2008 Adapted from David Thomas. ICAAC/IDSA 2008; abstract 849. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 The Body PRO 4 Ritonavir-Boosted PI and Not Abacavir Adversely Impacts HCV Treatment: Treatment Response by Regimen Type (n = 27) P Value (chi-square) Non-Ritonavir Containing Regimens Ritonavir Containing Regimens EVR 0.03 12/18 (67%) 2/9 (22%) SVR 0.03 7/18 (39%) 0/9 (0%) Non-Abacavir Abacavir EVR 0.34 5/12 (42%) 9/15 (60%) SVR 0.33 2/12 (17%) 5/15 (33%) Non-PI Any PI EVR 0.18 10/16 (63%) 4/11 (36%) SVR 0.06 6/16 (38%) 1/11 (9%) EVR = early virologic response; SVR = sustained virologic response Adapted from Rohit Talwani et al. ICAAC/IDSA 2008; abstract V-1632. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 5 The Body PRO Infectious Complications During Peg-IFN Plus Ribavirin in HIV-Infected Patients With Chronic Hepatitis C: Patients and Methods • Prospective cohort of 174 consecutive HIV/HCV-coinfected patients who started their first course of treatment with peg-IFN α-2a (53%) or peg-IFN α-2b(47%) plus weight-adjusted ribavirin, between January 2001 and March 2006. • Monthly visits during the treatment period were performed. All adverse effects, including infectious complications, were systematically recorded. • The frequency of infectious complications was compared between patients with or without neutropenia WHO grade 3 or 4 (< 750/mm3) and with or without CD4+ cells below 200/mm3 by means of Chi square test. Ana Moreno et al. ICAAC/IDSA 2008; abstract V-1633. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 6 The Body PRO Infectious Complications During Peg-IFN Plus Ribavirin in HIV-Infected Patients With Chronic Hepatitis C: Results • During the study period almost half the population developed an infectious complication during therapy (117 infections in 84 patients, 48%). • The median time to an infectious event was 12 weeks (IQR 8; 24). • Grade 3-4 neutropenia was observed in 51 subjects (29%), but only in 2% led to peg-IFN dose reduction. There were no treatment withdrawals. 30 of 51 patients received G-CSF (59%), with favorable response. • The most frequent infectious complications were respiratory tract infections (31% of patients). • Patients with WHO grade 3 or 4 neutropenia, or with CD4+ counts below 200 cells/ml during therapy, did not have more frequency of infectious events. Ana Moreno et al. ICAAC/IDSA 2008; abstract V-1633. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 7 The Body PRO HAART Is Associated With a Lower Level of Hepatic Necroinflammatory Activity: Characteristics of Study Population Jose F. Pascual Pareja et al. ICAAC/IDSA 2008; abstract H-2319. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 8 The Body PRO HAART Is Associated With a Lower Level of Hepatic Necroinflammatory Activity: Factors Associated With Necroinflammatory Activity ≥ 3 Jose F. Pascual Pareja et al. ICAAC/IDSA 2008; abstract H-2319. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 9 The Body PRO HCV Treatment Eligibility in ERCHIVES: Characteristics of HCV and HCV/HIV-Coinfected Subjects With and Without HCV RNA Availability Adeel A. Butt et al. ICAAC/IDSA 2008; abstract V-1634. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 The Body PRO HCV Treatment Eligibility in ERCHIVES: Flowchart of Treatment Eligibility and Contraindications in the HCV/HIVCoinfected Subjects Adeel A. Butt et al. ICAAC/IDSA 2008; abstract V-1634. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 10 The Body PRO 11 Low HCV Treatment Rates After a Liver Biopsy: Liver Biopsy Findings Batts-Ludwig Scale F0-F4 (n = 163) All HCV+ pts (n = 163) HIV+/HCV+ (n = 83) HIV-/HCV+ (n = 80) 20 53 24 3 19 55 24 1 21 51 24 4 42 31 16 11 58% 38 34 16 12 62% 45 29 16 9 55% Inflammation (%) Grade 1 Grade 2 Grade 3 Grade 4 Fibrosis (%) F 0-1 F2 F3 F 4 (Cirrhosis) [Fibrosis > F2] There were no significant differences in liver histology between HIV-positive and HIV-negative patients Oluwatoyin M. Adeyemi et al. ICAAC/IDSA 2008; abstract V-1637. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 The Body PRO Low HCV Treatment Rates After a Liver Biopsy: Predictors of HCV Treatment Post-Liver Biopsy 61 patients (37%) received HCV treatment post-liver biopsy 31 (37%) of HIV-positive patients and 30 (38%) of HIV-negative patients received HCV treatment 49% of all patients with significant fibrosis (≥ F2) received HCV treatment Women were more likely to receive treatment: 50% vs. 32% (P = .05) African Americans less likely to receive treatment: 27% vs. 50% (P = .01) Patients with more advanced histology were more likely to receive HCV treatment Fibrosis ≥ F2: 49% vs. 22% (P = .001) Fibrosis F4 (cirrhosis): 70% vs. 34% (P = .001) Oluwatoyin M. Adeyemi et al. ICAAC/IDSA 2008; abstract V-1637. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 12 The Body PRO Low HCV Treatment Rates After a Liver Biopsy: Reasons for Non-Treatment Post-Liver Biopsy n = 102: 52 HIV+, 50 HIV- Oluwatoyin M. Adeyemi et al. ICAAC/IDSA 2008; abstract V-1637. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 13 The Body PRO 14 PERICO: Main Results at Week 4 of Hepatitis C Therapy According to Treatment Arm RBV 1.0 – 1.2 g/day (N = 75) RBV 2.0 g/day (N = 74) P 12.7 [11.1 to 14.2] 13.4 [11.1 to 15.6] 0.04 Mean Δ Hb [Baseline to Week 4] (g/dL) -2.4 [1.5 to 3.2] -1.8 [0.3 to 3.7] 0.06 Mean Δ HCV-RNA [Baseline to Week 4] (log IU/mL) -2.4 [-1.2 to -4.1] -2.6 [-1.6 to -3.6] 0.5 Mean RBV Plasma Concentration (µg/mL) 1.9 [1.4 to 2.6] 2.4 [1.7 to 3] 0.2 Patients With Severe Anemia at Week 4 [Hb < 10 g/dL] (%) 4 (6.6%) 2 (3.3%) 0.4 16 (22%) 16 (22%) 1 1 (1.3) 2 (2.8) 0.6 Mean Hb at Week 4 (g/dL) Patients With RVR (%) Treatment Discontinuation or RBV Dose Reduction Due to Anemia (%) Adapted from Vicente Soriano et al. ICAAC/IDSA 2008; abstract H-2321. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 The Body PRO 15 New HCV Drugs in the Pipeline: Sustained Virological Response in Subgroups of Interest Race Baseline Viral Load METAVIR Fibrosis Score African American Caucasian Low ≤ 600,000 IU/mL High > 600,000 IU/mL 0/1/2 3/4 PEG-IFN -2b 1.0/RBV N = 1016 17% 44% 59% 33% 39% 30% PEG-IFN -2b 1.5/RBV N = 1019 23% 44% 61% 35% 42% 21% PEG-IFN -2a 180/RBV N = 1035 26% 44% 66% 36% 44% 24% Adapted from Mark Sulkowski. ICAAC/IDSA 2008; abstract 850. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 The Body PRO Does the Choice of peg-IFN Formulation Affect Safety or Efficacy in HIV/HCV-Coinfected Patients Receiving Weight-Adjusted Ribavirin?: Overall Outcomes According to peg-IFN Formulation Peg-IFN! -2a (n=93) Peg-IFN! -2b (n=81) 16 P HCV-RNA (log10IU/ml; mean±SD) Week 4 2,96 ± 2,42 2,83 ± 2,51 0.72 Week 12 1,80 ± 2,28 2,40 ± 2,6 0.21 Week 24 1,31 ± 2,20 1,84 ± 2,6 0.27 Week 4 33 41 0.28 Week 12 54 48 0.44 Week 24 68 62 0.46 EVR (%) 70 57 0.07 SVR (%) 49,5 41 0.24 Early withdrawals (%) 15 18 0.54 Negative HCV-RNA (%) Ana Moreno et al. ICAAC/IDSA 2008; abstract V-1631. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 The Body PRO 17 New HCV Drugs in the Pipeline: Multiple Direct Antiviral Agents Have Entered Clinical Development Polymerase Protease Other GS 9190 BILN 2061* A-831 HCV-796* Boceprevir (phase 3) BMS R1626 (phase 2)* ITMN-191 (phase 1) GS 9132* R7128 (phase 2) MK7009 (phase 1) Valopicitabine* Telaprevir (phase 3) VCH-759 TMC435350 (phase 2) *Development is on hold. Adapted from Mark Sulkowski. ICAAC/IDSA 2008; abstract 850. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 18 SMART*: Primary and Major Secondary End Points The Body PRO Adapted from Wafaa El-Sadr et al. N Engl J Med. 2006;355(22):2283-2296. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 19 Hepatitis C Virus Infection and the Risk of Coronary Disease: Results The Body PRO A flow chart depicting the number of subjects included in the study. Adeel A. Butt et al. ICAAC/IDSA 2008; abstract V-4219. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 20 The Body PRO Hepatitis C Virus Infection and the Risk of Coronary Disease: Results: Factors Associated With CAD (Multivariable Cox) Adeel A. Butt et al. ICAAC/IDSA 2008; abstract V-4219. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 The Body PRO HIV Infection and the Risk of Diabetes Mellitus: Baseline Characteristics of HIV-Infected and Uninfected Persons in the Veterans Aging Cohort Study Age at study entry, mean (SD) years HIV + (n=3,227) HIV – (n=3,240) Pvalue 49.6 (8.8) 50.8 (10.0) <0.001 HIV + (n=3,227) HIV – (n=3,240) White 19.9 24.3 Black 66.7 62.1 4.6 5.1 35-39 7.4 6.7 Hispanic 9.5 10.0 Other/Unknown 3.9 3.6 40-44 14.9 12.9 45-49 23.5 21.6 Hepatitis C infection (%) 31.2 15.4 <0.001 50-54 22.3 22.1 55-59 16.4 16.3 60-64 5.4 6.0 65-69 2.9 4.3 ≥70 2.5 5.0 97.5 92.1 Gender (% male) <0.001 Diabetes (%) 14.9 21.4 <0.001 Height (SD) (meters) 1.77 (0.07) 1.77 (0.08) 0.6 Weight (SD) (kilograms) 79.1 (15.4) 90.6 (19.4) <0.001 Body mass index, mean (SD) <0.001 25.2 (4.5) 28.9 (5.6) <0.001 Pvalue Race Age at study entry (years) <35 21 <0.001 Adeel A. Butt et al. ICAAC/IDSA 2008; abstract H-2306. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 The Body PRO HIV Infection and the Risk of Diabetes Mellitus: Baseline Characteristics of HIV-Infected and Uninfected Persons in the Veterans Aging Cohort Study (Continued) HIV + (n=3,227) HIV – (n=3,240) Pvalue Body mass index Drug use (%) <20 9.2 3.2 20-24.9 41.2 20.2 25-29.9 37.3 39.2 ≥30 12.3 37.4 23.7 20.9 1-4 25.3 25.1 5-10 13.3 12.7 11-30 17.1 17.2 31-60 7.1 8.0 13.5 16.2 >60 HIV + (n=3,227) HIV – (n=3,240) Pvalue 50.7 38.3 <0.001 HIV+ <0.001 CD4+ lymphocyte count/mm3, N (%) ≤200 695 (23.9) * 1,331 (45.7) * 886 (30.4) * Median (SD) CD4+ lymphocyte count 366 (264) * Median HIV RNA (SD), Log10 copies/ml 3.08 (1.87) * 201-500 Alcohol use (average number of drinks per month) 0 22 >500 0.01 * Not included in the model, since HIV-uninfected subjects were included Adeel A. Butt et al. ICAAC/IDSA 2008; abstract H-2306. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 23 HIV Infection and the Risk of Diabetes Mellitus: Discussion The Body PRO • We found that HIV infection per se was not associated with a higher risk of diabetes mellitus (DM). In fact, the risk of DM at baseline was lower in the HIV-infected (OR 0.84, 95% CI 0.72-0.97) compared with HIV-uninfected persons. • There were many differences in the prevalence of risk factors for DM in the HIV-infected and uninfected persons. HIVinfected persons were younger and had a lower body mass index (BMI), which decreases the risk for DM, but were more likely to be racial minorities and had a higher prevalence of HCV, which increases risk. • We found that HCV infection is associated with a higher risk of DM in the HIV-infected group, and demonstrated a similar trend in the uninfected group in multivariable analysis (although this trend did not reach statistical significance, the effect size was similar). • We found that use of combination antiretroviral therapy (CART) was associated with a significantly higher risk of DM in the HIV-infected group. • Our finding of a lower risk of DM associated with increasing alcohol use and drug use is intriguing. Increasing quantity/frequency of alcohol use was associated with increasing protection except in HIV-infected persons who consumed > 60 drinks per month. Increasing alcohol use is associated with increasing liver damage, and may be expected to increase the risk of diabetes. We conducted separate analyses including liver damage (defined as alanine or aspartate aminotransferase levels > 5 times upper limit of normal) with and without HCV in the models and found no significant association with liver damage. It is also plausible that increased alcohol consumption and drug abuse or dependence may lead to poor nutrition and lower BMI which may indirectly afford protection from DM. However, we found no significant association between quantity and frequency of alcohol use and BMI. Another possibility is that people with alcohol and drug abuse may not seek medical care and the opportunity to diagnose DM may have been missed. We did find that non-drinkers were older, while moderate to heavy drinkers were more likely to be younger. These data suggest that while some of the protective effect of alcohol is due to the alcohol consuming population being younger, there are other likely mechanisms that modulate this effect. Adeel A. Butt et al. ICAAC/IDSA 2008; abstract H-2306. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 24 The Body PRO Sharp Decline in the Seroprevalence of Hepatitis C Virus Among HIV-Infected Patients in Spain: Baseline Characteristics Baseline Characteristics CoRIS-MD (n=2,611) (1997-2003) CoRIS (n=2,559) (2004-2006) Total (n=5,170) n Freq. n Freq. n Freq. 721 27.61% 598 23.37% 1,319 25.51% 1,522 58.29% 532 20.79% 2,054 39.73% Gender Female HCV status Infected Transmission pathway MSM 378 14.48% 979 38.26% 1,357 26.25% IVDU 1,394 53.39% 473 18.48% 1,867 36.11% Heterosexual 624 23.90% 968 37.83% 1,592 30.79% Other 215 8.23% 139 5.43% 354 6.85% 591 22.64% 608 23.76% 1,199 23.19% 1,580 60.51% 1,151 44.98% 2,731 52.82% 440 16.85% 800 31.26% 1,240 23.99% Age (categorical) Less than 30 30 to 39.9 40 or more MSM: males who have sex with males; IVDU: intravenous drug user. Santiago Moreno et al. ICAAC/IDSA 2008; abstract V-1629. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 The Body PRO Acute Hepatitis C: Management and New Epidemiology: Risk Factors for Acute HCV: Case-Control Study • Unprotected receptive anal intercourse with (P = .04) or without (P = .03) ejaculation • Unprotected receptive oral sex with ejaculation (P = .03) • Use of sex toys (P = .03) • “Sex while high” (P = .01) • Use of marijuana (P = .04) Daniel Fierer. ICAAC/IDSA 2008; abstract 851. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 25 The Body PRO Acute Hepatitis C: Management and New Epidemiology: Fibrosis During Acute HCV Infection in HIV-Positive Men 20 patients underwent liver biopsy: • Median 4 months after detection of ALT elevation (range 3 weeks to 4 1/3 years) • 17 (85%) had stage 2 of 4 fibrosis (Scheuer) • 2 had stage 1 • 1 had stage 0 Daniel Fierer. ICAAC/IDSA 2008; abstract 851. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 26 27 The Body PRO Acute Hepatitis C: Management and New Epidemiology: Acute HCV Infection of HIV-Positive Men Who Have Sex With Men (MSM): Conclusions • Acute HCV infection of HIV-positive men is a newly described clinical syndrome: — Route of transmission related to sex — Moderately advanced fibrosis occurs within weeks to months and does not regress in years • Emerging infection in the US as well as in Europe • Enhanced surveillance in HIV-positive MSM should be performed to enable detection and curative treatment in the acute phase to prevent further progression of already significant liver fibrosis. — LFTs every 3 months, Ab every 6-12 months Daniel Fierer. ICAAC/IDSA 2008; abstract 851. Reprinted with permission. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008 28 The Body PRO • This presentation was created to accompany The Body PRO's summaries of key research presented at ICAAC/IDSA 2008, by Daniel Fierer, M.D. • The Body PRO's extensive coverage of ICAAC/IDSA 2008 also includes: – Summaries and analyses of research on a wide array of clinical subjects. – Interviews with top researchers discussing the results of noteworthy studies. – Audio podcasts you can play online or download to your computer or MP3 player. – Narrated, online slide presentations highlighting major study results. • Visit TheBodyPRO.com/ICAAC2008 today for a full listing of our conference coverage! Disclaimer: The Body PRO is designed for educational purposes only and is not engaged in rendering medical advice or professional services. The information provided through The Body PRO should not be used for diagnosing or treating a health problem or a disease. New Developments in HIV/Hepatitis C Coinfection Management and Epidemiology: Highlights From ICAAC/IDSA 2008