Kristen M. Marks

Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1

BACKGROUND Effective treatment for hepatitis C virus (HCV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains an unmet medical need. METHODS We conducted a multicenter, single-group, open-label study involving patients coinfected with HIV-1 and genotype 1 or 4 HCV receiving an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine, or raltegravir. All patients received ledipasvir, an NS5A inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor, as a single fixed-dose combination for 12 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Of the 335 patients enrolled, 34% were black, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 322 patients (96%) had a sustained virologic response at 12 weeks after the end of therapy (95% confidence interval [CI], 93 to 98), including rates of 96% (95% CI, 93 to 98) in patients with HCV genotype 1a, 96% (95% CI, 89 to 99) in those with HCV genotype 1b, and 100% (95% CI, 63 to 100) in those with HCV genotype 4. Rates of sustained virologic response were similar regardless of previous treatment or the presence of cirrhosis. Of the 13 patients who did not have a sustained virologic response, 10 had a relapse after the end of treatment. No patient had confirmed HIV-1 virologic rebound. The most common adverse events were headache (25%), fatigue (21%), and diarrhea (11%). No patient discontinued treatment because of adverse events. CONCLUSIONS Ledipasvir and sofosbuvir for 12 weeks provided high rates of sustained virologic response in patients coinfected with HIV-1 and HCV genotype 1 or 4. (Funded by Gilead Sciences; ION-4 ClinicalTrials.gov number, NCT02073656.).

Histological Findings and Clinical Characteristics Associated with Hepatic Steatosis in Patients Coinfected with HIV and Hepatitis C Virus

BACKGROUND Hepatic steatosis, a common histological finding in hepatitis C virus (HCV)-infected patients, is associated with severity of fibrosis. The prevalence and significance of steatosis in patients coinfected with human immunodeficiency virus (HIV) and HCV are not well characterized. METHODS To determine the prevalence and severity of steatosis, a single pathologist evaluated liver-biopsy samples from 106 patients coinfected with HIV and HCV but without hepatitis B infection (negative results for hepatitis B surface antigen) for findings associated with steatosis or steatohepatitis and viral hepatitis. Medical records were reviewed retrospectively to elucidate risk factors for steatosis. RESULTS Steatosis was present in 56% of biopsy samples, with moderate to severe grades in 9%. Severity of steatosis was associated with fibrosis (odds ratio [OR], 1.84 [95% confidence interval (CI), 1.06-3.20]; P=.03) but not with necroinflammation. In multivariate analysis, the severity of steatosis was associated with lower levels of high-density lipoprotein cholesterol (OR, 0.71 per 10-mg/dL increase [95% CI, 0.52-0.95]; P=.02), higher body-mass index (OR, 1.30 per kg/m2 increase [95% CI, 1.13-1.49]; P<.001), and the presence of lipodystrophy (OR, 3.82 [95% CI, 1.13-12.88]; P=.03). There was a trend toward an association between the severity of steatosis and fibrosis in multivariate analysis (OR, 1.69 [95% CI, 0.91-3.16]; P=.10). CONCLUSIONS In patients coinfected with HIV and HCV, hepatic steatosis is common and associated with more-advanced fibrosis. Lower levels of high-density lipoprotein cholesterol, higher body-mass index, and lipodystrophy are potentially modifiable risk factors associated with the severity of steatosis.

Rapid Progression to Decompensated Cirrhosis, Liver Transplant, and Death in HIV-Infected Men After Primary Hepatitis C Virus Infection

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.

Integrated internist — addiction medicine — hepatology model for hepatitis C management for individuals on methadone maintenance

Summary.  Despite a high prevalence of hepatitis C virus (HCV) among drug users, HCV evaluation and treatment acceptance are extremely low among these patients when referred from drug treatment facilities for HCV management. We sought to increase HCV treatment effectiveness among patients from a methadone maintenance treatment program (MMTP) by maintaining continuity of care. We developed, instituted and retrospectively assessed the effectiveness of an integrated, co‐localized care model in which an internist‐addiction medicine specialist from MMTP was embedded in the hepatitis clinic. Methadone maintenance treatment program patients were referred, evaluated by the internist and hepatologist in hepatitis clinic and provided HCV treatment with integration between both sites. Of 401 evaluated patients, anti‐HCV antibody was detected in 257, 86% of whom were older than 40 years. Hepatitis C virus RNA levels were measured in 222 patients, 65 of whom were aviremic. Of 157 patients with detectable HCV RNA, 125 were eligible for referral to the hepatitis clinic, 76 (61%) of whom accepted and adhered with the referral. Men engaged in MMTP <36 months were significantly less likely to be seen in hepatitis clinic than men in MMTP more than 36 months (odds ratio = 7.7; 95% confidence interval 2.6–22.9) or women. We evaluated liver histology in 63 patients, and 83% had moderate to advanced liver disease. Twenty‐four patients initiated treatment with 19 completing and 13 (54%) achieving sustained response. In conclusion, integrated care between the MMTP and the hepatitis clinic improves adherence with HCV evaluation and treatment compared to standard referral practices.

Risk factors for thrombocytopenia in HIV-infected persons in the era of potent antiretroviral therapy.

Objective:Before potent antiretroviral therapy, thrombocytopenia was observed frequently. Little is known about risk factors for or severity and consequences of thrombocytopenia since establishment of highly effective therapy for HIV. Methods:We conducted a retrospective-matched case-control study of HIV-infected adult outpatients with and without thrombocytopenia to elucidate the contribution of HIV viremia, hepatitis C infection, and other potential risk factors for thrombocytopenia. Seventy-three cases with thrombocytopenia (platelet count <100 × 109/L persistent for >3 months) were matched by age, sex, and first clinic visit with 73 nonthrombocytopenic controls. Risk factors and outcomes were assessed using conditional logistic regression. Results:Nadir platelet counts in cases were ≤50 × 109/L in 58% and ≤30 × 109/L in 38%. In multivariate modeling, HIV RNA >400 copies/ml, hepatitis C virus infection, and cirrhosis were significantly associated with thrombocytopenia with adjusted odds ratios of 5.3 [confidence interval (CI) 1.6-17.1, P = 0.006], 6.1 (CI 1.6-22.6, P = 0.007), and 24.0 (CI 1.7-338, P = 0.019), respectively. Thrombocytopenia was significantly associated with major bleeding events and nonbleeding-related death. Conclusions:Thrombocytopenia in the era of potent antiretroviral therapy is associated with hepatitis C virus infection, cirrhosis, and uncontrolled HIV replication, and serious complications including major bleeding and death.

The first wave: HCV NS3 protease inhibitors telaprevir and boceprevir.

Boceprevir and telaprevir are peptidomimetic serine protease inhibitors that have been recently approved for the treatment of HCV chronic infection. The addition of these drugs to the prior standard of care, pegylated interferon and ribavirin, improves sustained virological response rates for treatment-naive and treatment-experienced patients and shortens the duration of treatment for over half of treatment-naive patients. This review describes the clinical data supporting the approval and use of telaprevir and boceprevir, the algorithm for the use of these drugs, their adverse effects, as well as their important drug-drug interactions.

Sofosbuvir Plus Ribavirin Without Interferon for Treatment of Acute Hepatitis C Virus Infection in HIV-1–Infected Individuals: SWIFT-C

Background Historically, acute hepatitis C virus (HCV) infection was treated with shorter durations of interferon-containing therapies. In the era of direct-acting antivirals (DAAs), it is unclear whether the efficacy of treatment achieved in chronic infection can be maintained with abbreviated courses of therapy during the acute phase. Methods The sofosbuvir-containing regimens without interferon for treatment of acute HCV in HIV-1 infected individuals (SWIFT-C) is an open-label, 2-cohort clinical trial in which the first cohort assessed for the safety and efficacy of 12 weeks of sofosbuvir plus ribavirin for the treatment of acute HCV infection in participants with chronic human immunodeficiency virus type 1 (HIV-1) infection. This is a preplanned analysis of the first cohort, which had a planned accrual of 17 participants. Results Seventeen men (11 Hispanic, 6 white, median age 45 years) were enrolled. Most (88%) had HCV genotype-1 infection and few (24%) had the favorable IL28B CC genotype. Median baseline HCV RNA was 2 280 000 IU/mL (interquartile range, 272 000-4 230 000). Ten participants (59%) achieved the primary outcome of SVR12 (90% confidence interval, 36%-78%), failing to establish noninferiority. All treatment failures were due to viral relapse (41%). There were no premature treatment discontinuations. The only factor that differed between participants who achieved SVR vs those who relapsed was ribavirin concentration at the end of treatment. Conclusion Sofosbuvir-ribavirin for 12 weeks for the treatment of acute HCV genotype-1 infection in HIV-1-infected persons results in a high relapse rate. Preliminary studies of DAA combination therapies suggest improved response rates, although the adequate duration of therapy remains unclear. Clinical Trials Registration NCT02128217.

Autoimmune hepatitis in the HIV-infected patient: a therapeutic dilemma.

Autoimmune hepatitis (AIH) is a progressive, chronic hepatitis that has rarely been reported in HIV-infected individuals. Among patients who are candidates for hepatitis C virus (HCV) treatment, screening for AIH should be considered, because interferon has the potential to cause fulminant hepatic failure in the setting of immune-mediated injury. During a 4-year period, we identified four HIV-infected patients who were referred for evaluation of persistently elevated aminotransferases, two of whom were also infected with HCV. Serologic testing and the hepatic histologic appearance were consistent with AIH. Although each patient initiated treatment with corticosteroids and immunosuppressive agents, all four eventually developed life-threatening infectious or adverse metabolic effects that resulted in treatment discontinuation. Of note, one HIV/HCV co-infected patient was able to initiate HCV treatment with interferon after AIH remission was documented. While these cases illustrate that AIH can produce hepatic injury in virally infected individuals, we recommend that treatment for AIH in HIV-infected patients should be individualized after careful consideration of the potential risks and likely benefits.

Depression and Fatigue in Chronic Hepatitis C Patients With and Without HIV Co-Infection

BACKGROUND Depression and fatigue are common in chronic hepatitis C (CHC). OBJECTIVE We report clinical predictors of these conditions in patients seen in a university clinic. METHODS A total of 167 CHC patients completed the Patient Health Questionnaire-9 (PHQ-9) and Fatigue Severity Scale (FSS). Major depressive disorder (MDD) suggested by PHQ-9 was confirmed by clinical interview. FSS scores ≥41 were considered clinically significant fatigue. Logistic and multiple regression models were employed for analysis. RESULTS Thirty-three percent of patients had MDD and 52% had clinically significant fatigue. Sixty-one percent were HIV-infected, among whom both MDD and clinically significant fatigue were significantly less prevalent (OR = 0.47 and 0.46, respectively). MDD was least common in patients without a history of IV drug use (OR = 0.28), and highest in methadone users (OR = 3.57). Compared with methadone users, patients with no history of IV drug use and former IV drug users had less severe fatigue (coefficients = -31.0, -34.0, respectively). Lack of a history of hepatitis treatment was also associated with less severe fatigue (coefficient= -7.6). CONCLUSION Our study confirms high prevalence of fatigue and depression in CHC. HIV-positivity was associated with lower rates of MDD and clinically significant fatigue, arguably due to support systems for people living with HIV. Higher rates of depression in methadone users might be due to intrinsically higher rates of psychopathology in this group. Being on hepatitis treatment was associated with higher rates of fatigue, probably due to the adverse effects of interferon. Our findings emphasize the importance of routine screening and evaluation of depression and fatigue in CHC populations.

Risk factors for hepatitis C seropositivity among young people who inject drugs in New York City: Implications for prevention

Background Hepatitis C virus (HCV) infection remains a significant problem in the United States, with people who inject drugs (PWID) disproportionately afflicted. Over the last decade rates of heroin use have more than doubled, with young persons (18–25 years) demonstrating the largest increase. Methods We conducted a cross-sectional study in New York City from 2005 to 2012 among young people who injected illicit drugs, and were age 18 to 35 or had injected drugs for ≤5 years, to examine potentially modifiable factors associated with HCV among young adults who began injecting during the era of syringe services. Results Among 714 participants, the median age was 24 years; the median duration of drug injection was 5 years; 31% were women; 75% identified as white; 69% reported being homeless; and 48% [95% CI 44–52] had HCV antibodies. Factors associated with HCV included older age (adjusted odds ratio [AOR], 1.99 [1.52–2.63]; p<0.001), longer duration of injection drug use (AOR, 1.68 [1.39–2.02]; p<0.001),more frequent injection (AOR, 1.26 [1.09–1.45]; p = 0.001), using a used syringe with more individuals (AOR, 1.26 [1.10–1.46]; p = 0.001), less confidence in remaining uninfected (AOR, 1.32 [1.07–1.63]; p<0.001), injecting primarily in public or outdoors spaces (AOR, 1.90 [1.33–2.72]; p<0.001), and arrest for carrying syringes (AOR, 3.17 [1.95–5.17]; p<0.001). Conclusions Despite the availability of harm reduction services, the seroprevalence of HCV in young PWID in New York City remained high and constant during 2005–2012. Age and several injection behaviors conferred independent risk. Individuals were somewhat aware of their own risk. Public and outdoor injection and arrest for possession of a syringe are risk factors for HCV that can be modified through structural interventions.