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1.  Rapid Progression to Decompensated Cirrhosis, Liver Transplant, and Death in HIV-Infected Men After Primary Hepatitis C Virus Infection 
Four men from a cohort of HIV-infected men who did not achieve cure after primary hepatitis C virus infection developed decompensated cirrhosis within 17 months to 6 years after infection, with subsequent rapid progression to liver transplant and death.
Background. We and others have shown that primary hepatitis C (HCV) infection in men infected with human immunodeficiency virus (HIV) causes early-onset liver fibrosis; however, little is known about the long-term natural history of the liver disease in these HIV-infected men.
Methods. We followed a cohort of HIV-infected men with primary HCV infection in New York City.
Results. Four men who were not cured after their primary HCV infection developed decompensated cirrhosis within 17 months to 6 years after primary HCV infection. Three died within 8 years of primary HCV infection, and 1 survived after liver transplant done 2 years after primary HCV infection. Three of the 4 men had AIDS at the time of primary HCV infection, and the most rapid progression occurred in the 2 men with the lowest CD4 counts at the time of HCV infection. Liver histopathology was most consistent with HCV-induced damage even though some had exposures to other potential hepatotoxins.
Conclusions. Primary HCV infection resulted in decompensated cirrhosis and death within 2–8 years in 4 HIV-infected men. The rapid onset of fibrosis due to primary HCV infection in HIV-infected men cannot therefore be considered benign. The rate of continued progression to liver failure may be proportional to the degree of underlying immunocompromise caused by HIV infection. More research is needed to better define the mechanisms behind accelerated liver damage.
PMCID: PMC3588118  PMID: 23264364
liver failure; primary acute hepatitis C infection; HIV infection/AIDS; immunocompromise; men who have sex with men
3.  Direct-Acting Antiviral Agents in Patients with Hepatitis C Cirrhosis 
Gastroenterology & Hepatology  2012;8(11):727-765.
Patients with cirrhosis who are infected with hepatitis C virus (HCV) are the most in need of antiviral treatment. Virologic cure improves fibrosis and quality of life while reducing liver-related morbidity and mortality. In mid-2011, the addition of direct-acting antiviral agents (DAAs)—the protease inhibitors boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex)—to pegylated interferon α-2a/b and ribavirin revolutionized the treatment of HCV infection by increasing cure rates across all fibrosis scores in patients with genotype 1 HCV infection. However, patients with advanced fibrosis or cirrhosis are the most difficult to treat, and the addition of DAAs increases treatment side effects as well as potency. Five phase III DAA trials have been published to date, but they contain limited data on patients with cirrhosis. This review will examine the available data and will describe the evolution of HCV therapy in patients with cirrhosis from the standard-of-care therapy of the past decade into the new era of DAAs.
PMCID: PMC3966169  PMID: 24672409
Chronic hepatitis C virus infection; cirrhosis; protease inhibitors; direct-acting antiviral agents; boceprevir; telaprevir; sustained virologic response; anemia; decompensation
4.  Mortality in Hepatitis C Virus–Infected Patients With a Diagnosis of AIDS in the Era of Combination Antiretroviral Therapy 
Chronic hepatitis C increased mortality by approximately 50% in patients with Centers for Disease Control and Prevention–defined AIDS, despite the competing mortality risks in these patients. About 20% of the deaths were liver-related, suggesting that greater hepatitis C virus awareness and treatment could increase survival.
Background. Before the introduction of combination antiretroviral therapy (cART), patients infected with the human immunodeficiency virus (HIV) rarely died of liver disease. In resource-rich countries, cART dramatically increased longevity. As patients survived longer, hepatitis C virus (HCV) infection became a leading cause of death; however, because patients with AIDS continue to have 5-fold greater mortality than non-AIDS patients, it is unclear whether HCV infection increases mortality in them.
Methods. In this investigation, which is part of the Longitudinal Studies of the Ocular Complications of AIDS, plasma banked at enrollment from 2025 patients with AIDS as defined by the Centers for Disease Control and Prevention were tested for HCV RNA and antibodies.
Results. Three hundred thirty-seven patients had HCV RNA (chronic infection), 91 had HCV antibodies and no HCV RNA (cleared infection), and 1597 had no HCV markers. Median CD4+ T-cell counts/µL were 200 (chronic), 193 (cleared), and 175 (no markers). There were 558 deaths. At a median follow-up of 6.1 years, patients with chronic HCV had a 50% increased risk of mortality compared with patients with no HCV markers (relative risk [RR], 1.5; 95% confidence interval [CI], 1.2–1.9; P = .001) in an adjusted model that included known risk factors. Mortality was not increased in patients with cleared infection (RR, 0.9; 95% CI, .6–1.5; P = .82). In patients with chronic HCV, 20.4% of deaths were liver related compared with 3.8% in patients without HCV.
Conclusions. Chronic HCV infection is independently associated with a 50% increase in mortality among patients with a diagnosis of AIDS, despite competing risks. Effective HCV treatment may benefit HIV/HCV-coinfected patients with AIDS.
PMCID: PMC3369565  PMID: 22534149
5.  Insulin Resistance Predicts Retreatment Failure in an Efficacy Study of Peginterferon-α-2a and Ribavirin in HIV/HCV Co-infected Patients 
Journal of hepatology  2010;54(1):41-47.
Background and Aims
Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. To evaluate safety and efficacy of pegylated interferon-α-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response including insulin resistance, and the relationship between insulin resistance and liver histology.
This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-α-2a and ribavirin for 48 weeks. Serum HCV RNA was measured 24 weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR >2. Correlations between baseline insulin resistance and steatosis and/or cirrhosis were determined.
Sustained virological response was achieved by 14/96 (15%) patients. Of those with HOMA-IR <2, 35% (6/17) achieved sustained virological response vs 14% (15/36) of those with HOMA-IR between 2–4 and 7% (3/41) of those with HOMA-IR >4 (p=0.01). In multivariable analysis, insulin resistance and log10 HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95%CI 0.05–0.64, p=0.009, and AOR 0.36; 95%CI 0.14–0.93, p=0.04, respectively). Steatosis and cirrhosis correlated with insulin resistance (p=0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% and 2 patients died of unrelated cause.
In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those without insulin resistance are significantly more likely to achieve sustained virological response.
PMCID: PMC2994950  PMID: 20974502
Insulin resistance; hepatitis C virus; chronic; HIV; retreatment; antiviral therapy; pegylated interferon alfa-2a; ribavirin
6.  Short Communication: Inadequate Vitamin D Exacerbates Parathyroid Hormone Elevations in Tenofovir Users 
Parathyroid hormone (PTH) elevations are associated with reduced bone mineral density and adverse health outcomes and have been reported in patients with HIV infection. We aimed to examine the impact of vitamin D status and tenofovir (TDF) use on PTH levels among HIV-infected patients receiving combination antiretroviral therapy (cART). Demographics, medication and supplement use, and clinical data, including 25-hydroxyvitamin D [25(OH)D] and PTH, were collected on 45 HIV-infected men on ART. Suboptimal vitamin D status was defined as 25(OH)D < 30 ng/ml. The relationship between antiretroviral agents, suboptimal 25(OH)D, and PTH levels was examined. Among subjects with suboptimal vitamin D status, PTH values greater than or equal to the ULN (87 pg/ml) were more common among TDF users than nonusers: 41% versus 0% (p = 0.018); and median PTH was higher in TDF users: 80 pg/ml versus 55 pg/ml (p = 0.02). Among TDF users, PTH was higher in the group with suboptimal 25(OH)D (p = 0.045). Multivariable linear regression showed that PTH was independently and directly related to TDF use (p = 0.017) and inversely related to 25(OH)D (p = 0.017). PTH was not related to the estimated glomerular filtration rate (p = 0.9). In this cross-sectional study of HIV-infected men on ART, the use of TDF and the level of 25(OH)D were independently associated with PTH levels. Because TDF is a potent and widely used antiretroviral drug, information about cofactors that may exacerbate its side effects is of significant clinical value.
PMCID: PMC2957627  PMID: 20672993
7.  Hepatitis C Patients' Self-reported Adherence to Pegylated Interferon and Ribavirin 
Prior research on adherence to Hepatitis C treatment has documented rates of dose reductions and early treatment discontinuation, but little is known about patients' dose-taking adherence.
To assess the prevalence of missed doses of pegylated interferon and ribavirin and examine the correlates of dose-taking adherence in clinic settings.
180 patients on treatment for Hepatitis C (23% co-infected with HIV) completed a cross-sectional survey at the site of their Hepatitis C care.
Seven percent of patients reported missing at least one injection of pegylated interferon in the last four weeks and 21% reported missing at least one dose of ribavirin in the last 7 days. Dose-taking adherence was not associated with HCV viral load.
Self-reported dose nonadherence to Hepatitis C treatment occurs frequently. Further studies of dose nonadherence (assessed by method other than self-report) and its relationship to HCV virologic outcome are warranted.
PMCID: PMC2891196  PMID: 19086329
Adherence; HCV; HIV; co-infection; interferon; ribavirin
8.  Hepatic profile analyses of tipranavir in Phase II and III clinical trials 
The risk and course of serum transaminase elevations (TEs) and clinical hepatic serious adverse event (SAE) development in ritonavir-boosted tipranavir (TPV/r) 500/200 mg BID recipients, who also received additional combination antiretroviral treatment agents in clinical trials (TPV/r-based cART), was determined.
Aggregated transaminase and hepatic SAE data through 96 weeks of TPV/r-based cART from five Phase IIb/III trials were analyzed. Patients were categorized by the presence or absence of underlying liver disease (+LD or -LD). Kaplan-Meier (K-M) probability estimates for time-to-first US National Institutes of Health, Division of AIDS (DAIDS) Grade 3/4 TE and clinical hepatic SAE were determined and clinical actions/outcomes evaluated. Risk factors for DAIDS Grade 3/4 TE were identified through multivariate Cox regression statistical modeling.
Grade 3/4 TEs occurred in 144/1299 (11.1%) patients; 123/144 (85%) of these were asymptomatic; 84% of these patients only temporarily interrupted treatment or continued, with transaminase levels returning to Grade ≤ 2. At 96 weeks of study treatment, the incidence of Grade 3/4 TEs was higher among the +LD (16.8%) than among the -LD (10.1%) patients. K-M analysis revealed an incremental risk for developing DAIDS Grade 3/4 TEs; risk was greatest through 24 weeks (6.1%), and decreasing thereafter (>24-48 weeks: 3.4%, >48 weeks-72 weeks: 2.0%, >72-96 weeks: 2.2%), and higher in +LD than -LD patients at each 24-week interval. Treatment with TPV/r, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+ > 200 cells/mm3 at baseline were found to be independent risk factors for development of DAIDS Grade 3/4 TE; the hazard ratios (HR) were 2.8, 2.0, 2.1 and 1.5, respectively. Four of the 144 (2.7%) patients with Grade 3/4 TEs developed hepatic SAEs; overall, 14/1299 (1.1%) patients had hepatic SAEs including six with hepatic failure (0.5%). The K-M risk of developing hepatic SAEs through 96 weeks was 1.4%; highest risk was observed during the first 24 weeks and decreased thereafter; the risk was similar between +LD and -LD patients for the first 24 weeks (0.6% and 0.5%, respectively) and was higher for +LD patients, thereafter.
Through 96 weeks of TPV/r-based cART, DAIDS Grade 3/4 TEs and hepatic SAEs occurred in approximately 11% and 1% of TPV/r patients, respectively; most (84%) had no significant clinical implications and were managed without permanent treatment discontinuation. Among the 14 patients with hepatic SAE, 6 experienced hepatic failure (0.5%); these patients had profound immunosuppression and the rate appears higher among hepatitis co-infected patients. The overall probability of experiencing a hepatic SAE in this patient cohort was 1.4% through 96 weeks of treatment. Independent risk factors for DAIDS Grade 3/4 TEs include TPV/r treatment, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+ > 200 cells/mm3 at baseline.
Trial registration
US-NIH Trial registration number: NCT00144170
PMCID: PMC2803791  PMID: 20003457
9.  Hepatitis B 
Gastroenterology & Hepatology  2007;3(9):724-726.
PMCID: PMC3104263  PMID: 21960885

Results 1-10 (10)