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The development of direct-acting antiviral (DAA) agents has reinvigorated the treatment of hepatitis C virus infection. The availability of multiple DAA agents and drug combinations has enabled the transition to interferon-free therapy that is applicable to a broad range of patients. However, these DAA combinations are not without drug-drug interactions (DDIs). As every possible DDI permutation cannot be evaluated in a clinical study, guidance is needed for healthcare providers to avoid or minimize drug interaction risk. In this review, we evaluated the DDI potential of the novel three-DAA combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir (the 3D regimen) with more than 200 drugs representing 19 therapeutic drug classes. Outcomes of these DDI studies were compared with the metabolism and elimination routes of prospective concomitant medications to develop mechanism-based and drug-specific guidance on interaction potential. This analysis revealed that the 3D regimen is compatible with many of the drugs that are commonly prescribed to patients with hepatitis C virus infection. Where interaction is possible, risk can be mitigated by paying careful attention to concomitant medications, adjusting drug dosage as needed, and monitoring patient response and/or clinical parameters.

Background: We aimed to characterize the natural history of hepatitis C virus (HCV) reinfection and spontaneous clearance following reinfection (reclearance), including predictors of HCV reclearance., Methods: Data were synthesized from the 9 prospective cohorts of the International Collaboration of Incident Human Immunodeficiency Virus and HCV in Injecting Cohorts study, which evaluated HCV infection outcomes among people who inject drugs. Participants with primary HCV infection were classified as having achieved viral suppression if they had negative results of at least 1 subsequent HCV RNA test. Those with positive results of an HCV RNA test following viral suppression were investigated for reinfection. Viral sequence analysis was used to identify reinfection (defined as detection of heterologous virus with no subsequent detection of the original viral strain)., Results: Among 591 participants with acute primary HCV infection, 118 were investigated for reinfection. Twenty-eight participants were reinfected (12.3 cases/100 person-years; 95% confidence interval [CI], 8.5-17.8). Peak HCV RNA level was lower during reinfection than primary infection (P = .011). The proportion of individuals with reclearance 6 months after reinfection was 52% (95% CI, 33%-73%). After adjustment for study site, females with the IFNL4 (formerly IFNL3 and IL28B) rs12979860 CC genotype detected were more likely to have reclearance (hazard ratio, 4.16; 95% CI, 1.24-13.94; P = .021)., Conclusions: Sex and IFNL4 genotype are associated with spontaneous clearance after reinfection., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: In 2010, the incidence of hepatitis C virus (HCV) infection in the United States was estimated to be 17 000 cases annually, based on 850 acute HCV cases reported to the Centers for Disease Control and Prevention by local public health authorities. Absence of symptomatic disease and lack of a specific laboratory test for acute infection complicates diagnosis and surveillance., Objective: To validate estimates of the incidence of acute HCV infection by determining the reporting rate of clinical diagnoses of acute infection to the Massachusetts Department of Public Health (MDPH) and Centers for Disease Control and Prevention., Design: Case series and chart review., Setting: Two hospitals and the state correctional health care system in Massachusetts., Patients: 183 patients clinically diagnosed with acute HCV infection from 2001 to 2011 and participating in a research study., Measurements: Rate of electronic case reporting of acute HCV infection to the MDPH and rate of subsequent confirmation according to national case definitions., Results: 149 of 183 (81.4%) clinical cases of acute HCV infection were reported to the MDPH for surveillance classification. The MDPH investigated 43 of these reports as potential acute cases of HCV infection based on their surveillance requirements; ultimately, only 1 met the national case definition and was counted in nationwide statistics published by the Centers for Disease Control and Prevention. Discordance in clinical and surveillance classification was often related to missing clinical or laboratory data at the MDPH as well as restrictive definitions, including requirements for negative hepatitis A and B laboratory results., Limitation: Findings may not apply to other jurisdictions because of differences in resources for surveillance., Conclusion: Clinical diagnoses of acute HCV infection were grossly underascertained by formal surveillance reporting. Incomplete clinician reporting, problematic case definitions, limitations of diagnostic testing, and imperfect data capture remain major limitations to accurate case ascertainment despite automated electronic laboratory reporting. These findings may have implications for national estimates of the incidence of HCV infection., Primary Funding Source: National Institutes of Health.

Background: Understanding the patterns of HCV RNA levels during acute hepatitis C virus (HCV) infection provides insights into immunopathogenesis and is important for vaccine design. This study evaluated patterns of HCV RNA levels and associated factors among individuals with acute infection., Methods: Data were from an international collaboration of nine prospective cohorts of acute HCV (InC3 Study). Participants with well-characterized acute HCV infection (detected within three months post-infection and interval between the peak and subsequent HCV RNA levels ≤ 120 days) were categorised by a priori-defined patterns of HCV RNA levels: i) spontaneous clearance, ii) partial viral control with persistence (≥ 1 log IU/mL decline in HCV RNA levels following peak) and iii) viral plateau with persistence (increase or <1 log IU/mL decline in HCV RNA levels following peak). Factors associated with HCV RNA patterns were assessed using multinomial logistic regression., Results: Among 643 individuals with acute HCV, 162 with well-characterized acute HCV were identified: spontaneous clearance (32%), partial viral control with persistence (27%), and viral plateau with persistence (41%). HCV RNA levels reached a high viraemic phase within two months following infection, with higher levels in the spontaneous clearance and partial viral control groups, compared to the viral plateau group (median: 6.0, 6.2, 5.3 log IU/mL, respectively; P = 0.018). In the two groups with persistence, Interferon lambda 3 (IFNL3) CC genotype was independently associated with partial viral control compared to viral plateau (adjusted odds ratio [AOR]: 2.75; 95%CI: 1.08, 7.02). In the two groups with viral control, female sex was independently associated with spontaneous clearance compared to partial viral control (AOR: 2.86; 95%CI: 1.04, 7.83)., Conclusions: Among individuals with acute HCV, a spectrum of HCV RNA patterns is evident. IFNL3 CC genotype is associated with initial viral control, while female sex is associated with ultimate spontaneous clearance.

Background and Objectives: Hepatitis C virus (HCV) RNA level in acute HCV infection is predictive of spontaneous clearance. This study assessed factors associated with HCV RNA levels during early acute infection among people who inject drugs with well-defined acute HCV infection., Study Design: Data were from International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC(3)) Study, an international collaboration of nine prospective cohorts studying acute HCV infection. Individuals with available HCV RNA levels during early acute infection (first two months following infection) were included. The distribution of HCV RNA levels during early acute infection were compared by selected host and virological factors., Results: A total of 195 individuals were included. Median HCV RNA levels were significantly higher among individuals with interferon lambda 3 (IFNL3, formerly called IL28B) CC genotype compared to those with TT/CT genotype (6.28 vs. 5.39logIU/mL, respectively; P=0.01). IFNL3 CC genotype was also associated with top tertile HCV RNA levels (≥6.3log IU/mL; vs. TT/CT genotype; adjusted Odds Ratio: 4.28; 95%CI: 2.01, 9.10; P<0.01)., Conclusions: This study indicates that IFNL3 CC genotype predicts higher HCV RNA levels in early acute HCV infection., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Unlabelled: Although 20%-40% of persons with acute hepatitis C virus (HCV) infection demonstrate spontaneous clearance, the time course and factors associated with clearance remain poorly understood. We investigated the time to spontaneous clearance and predictors among participants with acute HCV using Cox proportional hazards analyses. Data for this analysis were drawn from an international collaboration of nine prospective cohorts evaluating outcomes after acute HCV infection. Among 632 participants with acute HCV, 35% were female, 82% were Caucasian, 49% had interleukin-28 (IL28)B CC genotype (rs12979860), 96% had injected drugs ever, 47% were infected with HCV genotype 1, and 7% had human immunodeficiency virus (HIV) coinfection. Twenty-eight percent were HCV antibody negative/RNA positive at the time of acute HCV detection (early acute HCV). During follow-up, spontaneous clearance occurred in 173 of 632, and at 1 year after infection, 25% (95% confidence interval [CI]: 21, 29) had cleared virus. Among those with clearance, the median time to clearance was 16.5 weeks (IQR: 10.5, 33.4), with 34%, 67%, and 83% demonstrating clearance at 3, 6, and 12 months. Adjusting for age, factors independently associated with time to spontaneous clearance included female sex (adjusted hazards ratio [AHR]: 2.16; 95% CI: 1.48, 3.18), IL28B CC genotype (versus CT/TT; AHR, 2.26; 95% CI: 1.52, 3.34), and HCV genotype 1 (versus non-genotype 1; AHR: 1.56; 95% CI: 1.06, 2.30). The effect of IL28B genotype and HCV genotype on spontaneous clearance was greater among females, compared to males., Conclusions: Female sex, favorable IL28B genotype, and HCV genotype 1 are independent predictors of spontaneous clearance. Further research is required to elucidate the observed sex-based differences in HCV control., (© 2013 by the American Association for the Study of Liver Diseases.)

The International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC(3)) Study is an international multi-cohort project of pooled biological and behavioural data from nine prospective cohorts of people who inject drugs (PWID). InC(3) brings together researchers from Australia, Canada, USA and the Netherlands with expertise in epidemiology, biostatistics, clinical and behavioural sciences, virology and immunology to investigate research questions relevant to hepatitis C virus (HCV) and HIV outcomes. InC(3) was established to: (i) create a merged multi-cohort study of pooled data from well-characterized cohorts of PWID with prospective data on HIV and HCV infections, with a particular focus on HCV; (ii) facilitate new studies not possible within individual cohorts; and (iii) bring together researchers across disciplines to answer a broad range of research questions. Study cohorts identify acute HCV cases through follow-up of high-risk HCV antibody-negative PWID or through clinical referral networks. To date, data from 1986 to 2010 have been received from all contributing cohorts, with 821 HCV-infected and 1216 HCV-uninfected participants (overall, n = 2037). Data collected include demographics, host genetics, HCV ribonucleic acid testing, alanine aminotransferase testing, HIV/hepatitis B virus testing, HCV therapy, loss to follow-up and mortality. Potential collaborators should contact the InC(3) PI Dr Kimberley Page (kPage@psg.ucsf.edu) for further information.

Unlabelled: Acute hepatitis C virus (HCV) infection is underdiagnosed because most patients are asymptomatic. The majority of new infections occur among people who inject drugs (PWID), many of whom have a history of incarceration. In a previous pilot study, we identified symptomatic HCV cases, mainly among Caucasian inmates. We designed a cross-sectional study to evaluate whether risk factor-based screening of newly incarcerated inmates would enhance identification of asymptomatic acute HCV infection and elucidate any demographic shifts in HCV acquisition. From October 2006 to March 2008, 6,342 inmates underwent health assessments and 3,470 inmates (55%) were screened. The racial distribution was as follows: African American, 24.0%; Caucasian, 49.5%; Hispanic, 22.2%. One hundred seventy-one inmates (4.9%) were classified as high-risk. After further evaluation, 35 (20.5%) inmates were diagnosed with acute HCV with a mean age of 29 years; 62.9% were female and 91% were Caucasian. No African Americans were diagnosed with acute HCV. Our case-finding rate was 1.9 patients/month nearly a three-fold increase compared with our historical control period with a higher proportion of asymptomatic cases. We estimate a prevalence of ∼1.0% (95% confidence interval, 0.7%-1.4%) of acute HCV infections among newly incarcerated inmates., Conclusion: Within the correctional system, systematic screening based on risk factors successfully identifies acute HCV infection among PWID, including asymptomatic patients. Our data also reflect changing nationwide patterns of injection drug use that vary by age, ethnicity, and race, leading to a marked reduction of acute HCV infections among African Americans compared with non-Hispanic whites. The nationwide implementation of this simple low-cost strategy in prison-based settings could identify more than 7,000 acute HCV infections among PWID, provide insight into changing epidemiologic trends, and facilitate appropriate therapeutic and preventive interventions., (Copyright © 2012 American Association for the Study of Liver Diseases.)

We report a case of acute hepatitis C virus infection that occurred after a traumatic altercation among prison inmates. This report has significant implications for infection control policies and procedures in prisons and jails, where the estimated prevalence of hepatitis C virus infection is ∼20 times that of the general population.

Background: The diagnosis of acute hepatitis C virus (HCV) infection is imprecise because antibody testing does not differentiate between acute and chronic infection. Although virologic features, such as viral load fluctuations and low levels of viremia, have been noted to be characteristic of acute HCV infection, these parameters have not been used for diagnosis., Methods: We validated the use of these novel parameters (ie, viral load fluctuations >1 log and HCV RNA levels <100,000 IU/mL) in a cohort of acute HCV seroconverters. We then applied standard diagnostic criteria for acute HCV infection in a cohort of high-risk injection drug users entering prison with suspected acute HCV infection (n=37). We subsequently assessed whether these novel virologic parameters, measured serially over a 10-week period, could enhance the diagnosis of acute infection., Results: Low-level viremia and viral load fluctuations were highly prevalent in our cohort of acute seroconverters (81% and 86%, respectively), whereas low-level viremia occurred in only 13% of control patients with chronic infection. With use of standard criteria, 37 inmates received a diagnosis of acute HCV infection. Among the 35 patients with HCV RNA detectable at baseline, we found low-level viremia to be highly prevalent (n=27; 77%); among patients with a minimum of 2 HCV RNA samples, we demonstrated viral fluctuations in more than one-third (n=9; 36%)., Conclusions: The diagnosis of acute infection in HCV-seropositive patients is strengthened by the use of virologic parameters that are uncommon in chronic disease. Viral load fluctuations and low levels of HCV RNA should be incorporated into standard diagnostic criteria.

Treatment of acute hepatitis C virus (HCV) infection leads to a sustained virologic response (SVR) in the vast majority of patients, although the clinical predictors of these favorable responses are not well understood. In chronic infection, the most potent predictor of a SVR is complete viral suppression after 4 weeks of treatment, also known as a rapid virologic response (RVR). However, few patients with HCV genotype 1 infection and high-level viremia ever achieve this benchmark. In 2 separate cohorts of patients with acute HCV infection, we demonstrate that rapid virologic clearance and low-level viremia (HCV RNA level, <400,000 IU/mL) are highly prevalent, regardless of HCV genotype.

The development of specifically targeted antiviral agents against hepatitis C is a major therapeutic advance that promises to markedly improve treatment response rates in patients with chronic infection. However, rapid emergence of drug resistance has already been described, the consequences of which are not yet understood. Although there are important differences between hepatitis C (HCV) and human immunodeficiency virus (HIV) infection, the judicious use of candidate agents against HCV should be guided by principles that have been established in the HIV therapeutic arena. In this review, we attempt to draw useful parallels between the development of antiretroviral therapy for HIV and preliminary data on antiviral agents for hepatitis C virus infection. Applying concepts learned in HIV therapeutics will hopefully lead to a prudent and cautious path in HCV treatment paradigms, particularly with respect to drug resistance.

Background: Human immunodeficiency virus (HIV)-infected patients with hepatitis C virus (HCV) coinfection are at increased risk for drug-induced liver injury (DILI) compared with patients with HIV infection alone. The mechanism underlying this observation is unknown. We hypothesized that interferon (IFN) would induce biochemical improvement through its anti-inflammatory properties and thereby facilitate the reintroduction of antiretroviral therapy (ART) in patients with DILI., Methods: Patients with symptomatic DILI were referred for evaluation; biopsy of a liver sample was performed for all patients, except 1 with clinical cirrhosis., Results: Twelve patients with acquired immunodeficiency syndrome and symptomatic grade 3/4 hepatotoxicity received treatment with IFN and ribavirin (RBV). Seven of these patients had a history of recurrent DILI. The mean baseline CD4(+) T cell counts and HIV RNA levels were 124 cells/mm(3) and 115,369 copies/mL, respectively. Biopsies of liver samples demonstrated significant necroinflammation (mean grade, 10.3) and fibrosis (mean stage, 2.9). Three patients continued to receive ART when they began treatment with IFN-RBV; 9 reinitiated ART within an average of 12 weeks (range, 4-20 weeks) of HCV treatment initiation. All patients attained marked improvement in aminotransferases and continued to receive ART treatment during a mean follow-up regimen of 26.5 months, with subsequent virologic suppression and immunologic reconstitution (mean CD4(+) cell count increase, 251/mm(3)). However, only 1 patient maintained HCV suppression after completion of treatment with IFN-RBV., Conclusions: In patients with symptomatic DILI, treatment with IFN-ribavirin (RBV) led to decreases in aminotransferase levels, which enabled the reinitiation of ART. The beneficial effects of IFN-based therapy may be modulated through the suppression of proinflammatory cytokines, even in virologic nonresponders. Herein, we propose a novel mechanism for DILI, whereby HCV- and HIV-associated inflammatory mediators induce liver injury synergistically.

Background: The Centers for Disease Control and Prevention has emphasized the need for interventional programs regarding hepatitis C virus (HCV) infection for injection drug users, the group of persons who are at highest risk of acquiring acute infection., Methods: We designed a pilot study to assess the feasibility of identifying injection drug users with acute HCV infection in correctional and detoxification facilities. On-site medical providers were educated regarding risk factors and signs and symptoms of infection and were instructed to refer all patients with hepatitis to our specialty clinic., Results: Over a 30-month period, 21 patients received a diagnosis of acute hepatitis C, 3 received a diagnosis of hepatitis B, and 1 received a diagnosis of hepatitis A. Of the 21 patients with acute hepatitis C, 19 were identified in the prison setting shortly after incarceration. Of the 17 patients who were observed serially (mean duration of observation, 6.3 months), 8 had spontaneous virologic clearance. Early therapy with pegylated interferon was initiated for 5 patients with persistent viremia and led to a sustained virologic response in 2 individuals. All patients agreed to undergo human immunodeficiency virus counseling and testing, as well as to receive immunization for hepatitis A and B., Conclusions: Incarceration presents a unique opportunity to identify injection drug users with acute HCV infection, to initiate counseling regarding other bloodborne pathogens, and to facilitate immunizations and HCV treatment.

The article offers a report relating to the effects of hepatitis C in the HIV-infected patient. The section shows that concomitant HIV infection alters hepatitis C virus (HCV) virology in ways that are relevant for treatment. According to the study, increased HCV viral load may be associated with HIV progression.

Background. Studies of the progression liver fibrosis in human immunodeficiency virus (HIV) and hepatitis C virus-coinfected patients suggest that cirrhosis is associated with immunosuppression, as measured by low absolute CD4+ T cell counts. However, we hypothesized that, in patients with advanced liver disease, low CD4+ T cell counts may occur secondary to portal hypertension and splenic sequestration, regardless of the presence or absence of HIV infection. Methods. Sixty HIV-seronegative outpatients with cirrhosis were enrolled during the period 2001-2003 in a prospective, cross-sectional study of the association between liver disease and CD4+ T cell counts and percentages. Demographic characteristics, liver disease-related characteristics, and laboratory results-including CD4+ T cell parameters-were collected. Results. A total of 39 patients (65%) had a low CD4+ T cell count; 26 patients (43%) and 4 patients (7%) had CD4+ T cell counts <350 and <200 cells/mm³, respectively. Abnormal CD4+ T cell counts were associated with splenomegaly (P = .03 ), thrombocytopenia (P = .002), and leukopenia (P < .001 ). The percentage of CD4+ T cells was normal in 95% of patients who had a low absolute CD4+ T cell count. CD4+ T cell counts were significantly lower among cirrhotic patients than among 7638 HIV-seronegative historic control subjects without liver disease. Conclusions. Cirrhosis is associated with low CD4+ T cell counts in the absence of HIV infection. Discordance between low absolute CD4+ T cell counts and normal CD4+ T cell percentages may be attributable to portal hypertension and splenic sequestration. Our findings have significant implications for the use and interpretation of absolute CD4+ T cell counts in HIV-infected patients with advanced liver disease. [ABSTRACT FROM AUTHOR]

Background. We conducted a study to determine the prevalence and factors associated with hepatic steatosis in human immunodeficiency virus (HIV)-seropositive patients with hepatitis C and to investigate whether steatosis is associated with liver fibrosis. Methods. Retrospective chart reviews were conducted in 4 hospitals that serve community-based and incarcerated HIV-infected patients who had undergone a liver biopsy for evaluation of hepatitis C virus (HCV) infection during the period of 2000–2003. Demographic characteristics and medication and laboratory data were collected from the time of the biopsy. A pathologist blinded to all clinical data evaluated the specimens. The primary outcome was presence or absence of steatosis. Results. Of 260 HIV-HCV-coinfected patients, 183 met inclusion criteria and had a biopsy specimen adequate for review. Steatosis was present in 69% of patients (graded as minimal in 31%, mild in 27%, moderate in 18%, and severe in 1%). Factors associated with steatosis included use of dideoxynucleoside analogues, such as didanosine and stavudine (odds ratio [OR], 4.63; 95% confidence interval [CI], 1.55–13.82). There was a trend toward presence of steatosis and use of other nucleoside analogues or infection with HCV genotype 3 (OR, 2.65 [95% CI, 0.95–7.41] and 3.38 [95% CI, 0.86–13.28], respectively). The presence of steatosis was associated with fibrosis (OR, 1.37; 95% CI, 1.03–1.81). Conclusions. In this multiracial population of HIV-HCV-coinfected patients, steatosis was prevalent and was associated with severity of liver fibrosis. Use of nucleoside analogues (particularly didanosine and stavudine) and HCV genotype 3 infection were associated with hepatic steatosis. The development of steatosis is multifactorial in nature and may play a contributory role in the progression of liver disease in HIV-infected patients. [ABSTRACT FROM AUTHOR]