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Background: Adherence to therapy with pegylated interferon and ribavirin for hepatitis C virus (HCV) infection has been incompletely examined.Objective: To evaluate the relationship between adherence to HCV therapy and early and sustained virologic response, assess changes in adherence over time, and examine risk factors for nonadherence.Design: Retrospective cohort study.Setting: National Veterans Affairs Hepatitis C Clinical Case Registry.Patients: 5706 HCV-infected patients (genotypes 1, 2, 3, or 4) with at least 1 prescription for both pegylated interferon and ribavirin between 2003 and 2006 and HCV RNA results before and after treatment initiation.Measurements: Adherence was calculated over 12-week intervals by using pharmacy refill data. End points included early virologic response (decrease of ≥2 log(10) HCV RNA at 12 weeks) and sustained virologic response (undetectable HCV RNA 24 weeks after the end of treatment).Results: Early virologic response increased with higher levels of adherence to ribavirin therapy over the initial 12 weeks (patients with HCV genotype 1 or 4, 25 of 68 [37%] with ≤40% adherence vs. 1367 of 2187 [63%] with 91% to 100% adherence [P < 0.001]; patients with HCV genotype 2 or 3, 12 of 18 [67%] with ≤40% adherence vs. 651 of 713 [91%] with 91% to 100% adherence [P < 0.001]). Among patients with HCV genotype 1 or 4, sustained response increased with higher adherence to ribavirin therapy over the second, third, and fourth 12-week intervals. Results were similar for adherence to interferon therapy. Mean adherence to therapy with interferon and ribavirin decreased by 3.4 and 6.6 percentage points per 12-week interval, respectively (P for trend < 0.001 for each drug). Patients who received growth factors or thyroid medications during treatment had higher mean adherence to antiviral therapy.Limitation: This was an observational study without standardized timing for outcome measurements.Conclusion: Early and sustained virologic responses increased with higher levels of adherence to interferon and ribavirin therapy. Adherence to therapy with both antivirals decreased over time, but more so for ribavirin. [ABSTRACT FROM AUTHOR]

Attitudes of patients as well as infectious disease, gastroenterology, and primary care providers need to be addressed to improve surveillance rates for high-risk patients with chronic hepatitis B infections., Competing Interests: Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.

A combination of nitazoxanide (NTZ), peginterferon (PegIFN), and ribavirin (RBV) may result in higher sustained virologic response (SVR) rates in hepatitis C virus (HCV) monoinfected patients. This study evaluated the effect of NTZ on interferon-stimulated gene (ISG) expression in vitro and in vivo among HIV/HCV genotype-1 (GT-1) treatment-naive patients. The ability of NTZ to enhance host response to interferon (IFN) signaling using the HCV cell culture system was initially evaluated. Second, ISG expression in 53 patients with treatment outcomes [21 SVR and 32 nonresponders (NR)] in the ACTG A5269 trial, a phase-II study (4-week lead in of NTZ 500 mg daily followed by 48 weeks of NTZ, PegIFN, and weight-based RBV), was assessed. The relative expression of 48 ISGs in peripheral blood mononuclear cells (PBMCs) was measured at baseline, week 4, and week 8 of treatment in a blinded manner. In vitro NTZ produced a direct and additive antiviral effect with IFN-alfa, with pretreatment of NTZ resulting in maximal HCV suppression. NTZ augmented IFN-mediated ISG induction in PBMCs from relapsers and SVRs (p < 0.05), but not NR. In ACTG A5269, baseline expression of most ISGs was similar between NR and SVR. NTZ minimally induced 17 genes in NR and 13 genes in SVR after 4 weeks of therapy. However, after initiation of PegIFN and RBV, ISG induction was predominantly observed in the SVR group and not NR group. NTZ treatment facilitates IFN-induced suppression of HCV replication. Inability to achieve SVR with IFN-based therapy in this clinical trial is associated with diminished ISG response to therapy that is refractory to NTZ.

Background: To determine the prevalence of patient-reported joint pain among patients with human immunodeficiency virus (HIV)/chronic hepatitis C virus (HCV) coinfection, chronic HCV monoinfection, and HIV monoinfection followed in hepatology and infectious disease outpatient practices., Methods: Standardized interviews were performed among 79 HIV/HCV-coinfected, 93 HCV-monoinfected, and 30 HIV-monoinfected patients in a cross-sectional study within hepatology and infectious disease clinics at three centers. The Multi-Dimensional Health Assessment Questionnaire was used to ascertain joint pain and associated symptoms. Information on potential risk factors for joint pain was obtained during the interview and by chart review. Logistic regression was used to determine adjusted odds ratios (aORs) with 95% confidence intervals (CIs) of joint pain associated with risk factors of interest among chronic HCV-infected and HIV-infected patients., Results: Joint pain was more commonly reported in HCV-monoinfected than HIV/HCV-coinfected (71% versus 56%; p = 0.038) and HIV-monoinfected (71% versus 50%; p = 0.035) patients. A previous diagnosis of arthritis and current smoking were risk factors for joint pain among HCV-infected patients (arthritis: aOR, 4.25; 95% CI, 1.84-9.81; smoking: aOR, 5.02; 95% CI, 2.15-11.74) and HIV-infected (arthritis: aOR, 5.36; 95% CI, 2.01-14.25; smoking: aOR, 6.07; 95% CI, 2.30-16.00) patients., Conclusion: Patient-reported joint pain was prevalent among all three groups, but more common among chronic HCV-monoinfected than either HIV/HCV-coinfected or HIV-monoinfected patients. A prior diagnosis of arthritis and current smoking were risk factors for patient-reported joint pain among both HCV-infected and HIV-infected patients.

Given that low muscle mass can lead to worse health outcomes in patients with chronic infections, we assessed whether chronic hepatitis C virus (HCV) infection was associated with low muscle mass among US adults. We performed a cross-sectional study of the National Health Examination and Nutrition Study (1999-2010). Chronic HCV-infected patients had detectable HCV RNA. Low muscle mass was defined as <10th percentile for mid-upper arm circumference (MUAC). Multivariable logistic regression was used to determine adjusted odds ratios (aORs) with 95% confidence intervals (CIs) of low muscle mass associated with chronic HCV. Among 18 513 adults, chronic HCV-infected patients (n = 303) had a higher prevalence of low muscle mass than uninfected persons (13.8% vs 6.7%; aOR, 2.22; 95% CI, 1.39-3.56), and this association remained when analyses were repeated among persons without significant liver fibrosis (aOR, 2.12; 95% CI, 1.30-3.47). This study demonstrates that chronic HCV infection is associated with low muscle mass, as assessed by MUAC measurements, even in the absence of advanced liver disease., (© 2014 John Wiley & Sons Ltd.)

Persistent viral infections including HCV, HBV, and HIV are associated with increased immune regulatory pathways including the extrinsic FoxP3+CD4+ regulatory T cells (Tregs) and intrinsic inhibitory pathways such as programed death-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) with potentially reversible suppression of antiviral effector T cells (1-12). Immunological consequences of viral coinfections relative to these immune regulatory pathways and their interplay are not well-defined. In this study, we examined the frequency, phenotype, and effector function of circulating T cell subsets in patients with chronic HCV and/or HIV infection, hypothesizing that HCV/HIV coinfection will result in greater immune dysregulation with pathogenetic consequences (13, 14). We show that multiple T cell inhibitory pathways are induced in HCV/HIV coinfection including FoxP3+ Tregs, PD-1, and CTLA-4 in inverse association with overall CD4 T cell frequency but not with liver function or HCV RNA titers. The inverse association between CD4 T cell frequency and their FoxP3, PD-1, or CTLA-4 expression remained significant in all subjects combined regardless of HCV and/or HIV infection, suggesting a global homeostatic mechanism to maintain immune regulation relative to CD4 T cell frequency. PD-1 blockade rescued T cell responses to HIV but not HCV without significant impact by CTLA-4 blockade in vitro. Collectively, these findings highlight complex immune interactions in viral coinfections and differential regulatory pathways influencing virus-specific T cells that are relevant in immunotherapeutic development.

Suppression of hepatitis B virus (HBV)-DNA to undetectable levels is an important goal for HIV/HBV-co-infected patients receiving anti-HBV-active antiretroviral therapy (ART), and current guidelines recommend that this outcome should be reached by 1 year of treatment. However, the proportion of patients that fail to achieve an undetectable HBV DNA at this time point and its determinants remain unknown in clinical practice. The objective of this study was to determine the incidence and risk factors for incomplete HBV suppression following 1 year of tenofovir-based ART. We performed a cohort study among tenofovir-treated HIV/HBV-co-infected patients. Patients had HBV viraemia, initiated tenofovir-based ART and had HBV DNA measured at 1 year of therapy. The primary outcome was incomplete HBV suppression (HBV DNA ≥2.6 log IU/mL) at 1 year. Logistic regression determined odds ratio (ORs) of incomplete HBV suppression for risk factors of interest. Among 133 patients, 54% (95% CI, 46-63%) had incomplete HBV suppression at 1 year. Incomplete suppression was associated with higher baseline HBV DNA (OR, 1.46 per log IU/mL increase; 95% CI, 1.1-1.94) and detectable HIV viraemia at 1 year (OR, 2.52; 95% CI, 1.19-5.32). Among 66 patients with suppressed HIV RNA at 1 year, 28 (42%) failed to achieve an undetectable HBV DNA. Failure to suppress HBV DNA by 1 year occurred in a sizeable proportion of tenofovir-treated HIV/HBV-co-infected patients. Higher HBV DNA and detectable HIV viraemia were risk factors for incomplete HBV suppression., (© 2013 John Wiley & Sons Ltd.)

Background: We hypothesized that nitazoxanide (NTZ) added to pegylated interferon alfa-2a (PEG-IFN) and weight-based ribavirin (WBR) would improve hepatitis C virus (HCV) virologic responses in HCV treatment-naïve HIV-1/HCV genotype 1 coinfected persons., Methods: Prospective, single-arm study in which subjects received 4-week lead-in (NTZ 500 mg twice daily) followed by 48 weeks of NTZ, PEG-IFN, and WBR. We compared the HCV virologic responses of these subjects to historical controls from the completed ACTG study A5178 who received PEG-IFN and WBR and had similar subject characteristics. Primary endpoints were early virologic response and complete early virologic response (EVR and cEVR)., Results: Among 67 subjects (78% male; 48% Black; median age, 50 years), EVR was achieved in 65.7% (90% CI, 55.0%-75.3%), cEVR in 38.8% (28.8%-49.6%). and SVR in 32.8% (23.4%-43.5%). EVR was higher with NTZ (51.4% in A5178; P = .03), but the sustained virologic response (SVR) proportion was similar (27.3% in A5178; P = .24). In contrast to A5178, SVR was similar across IL28B genotypes. Overall, NTZ was safe and well-tolerated., Conclusion: Whereas EVR proportion improved significantly in this pilot study, the addition of NTZ to PEG-IFN/WBR did not significantly improve SVR compared to historical controls. NTZ may be associated with an attenuation of the effect of IL28B on HCV treatment response.

Background: Guidelines for chronic hepatitis C virus (HCV) management have recommended that a liver biopsy be repeated at 3-year intervals for HIV/HCV-coinfected patients and 5-year intervals for those with HCV monoinfection to assess fibrosis progression. However, it is unclear if patients are willing to repeat this procedure., Objective: To determine the prevalence and factors, particularly HIV coinfection, associated with willingness to repeat a liver biopsy., Methods: A questionnaire was administered to 235 HCV-infected patients (113 with HIV coinfection) between January 2008 and June 2011 who previously underwent liver biopsy. The main outcome was self-reported willingness to repeat the biopsy. The questionnaire collected data on other hypothesized determinants of willingness to repeat the biopsy. These were evaluated by logistic regression., Results: Among 235 subjects who completed the questionnaire, 32 (14%) reported unwillingness to repeat the biopsy, most commonly because of a perception that it was unimportant for care [13(41%)], concerns regarding pain [12(38%)], and a poor experience with the prior biopsy [7(21%)]. Considering biopsy to be safe [odds ratio (OR), 4.45; 95% CI, 1.50-13.27], important (OR, 4.87; 95% CI, 1.83-12.95), and knowing a person who underwent liver biopsy (OR, 3.45; 95% CI, 1.16-10.23) were associated with willingness to repeat the biopsy. HIV was not associated with willingness to repeat the biopsy (OR, 1.42; 95% CI, 0.67-3.03)., Conclusions: Eighty-six percent of chronic HCV-infected patients were willing to repeat a liver biopsy. HIV was not associated with unwillingness. In patients in whom a repeat liver biopsy is indicated, education on the utility and safety of the biopsy is important to its acceptance.

Adherence to hepatitis C virus (HCV) therapy has been incompletely examined among HIV-infected patients. We assessed changes in interferon and ribavirin adherence and evaluated the relationship between adherence and early (EVR) and sustained virologic response (SVR). We performed a cohort study among 333 HIV/HCV-coinfected patients who received pegylated interferon and ribavirin between 2001 and 2006 and had HCV RNA before and after treatment. Adherence was calculated over 12-week intervals using pharmacy refills. Mean interferon and ribavirin adherence declined 2.5 and 4.1 percentage points per 12-week interval, respectively. Among genotype 1/4 patients, EVR increased with higher ribavirin adherence, but this association was less strong for interferon. SVR among these patients was higher with increasing interferon and ribavirin adherence over the first, second, and third, but not fourth, 12-week intervals. Among HIV/HCV patients, EVR and SVR increased with higher interferon and ribavirin adherence. Adherence to both antivirals declined over time, but more so for ribavirin.

Purpose: Although limited data exist on the efficacy and potential risk of synergistic aminoglycoside therapy for persistent Staphylococcus aureus bacteremia and endocarditis, aminoglycosides are frequently used in clinical practice., Methods: As our study population, we included subjects fulfilling the modified Duke criteria for S. aureus endocarditis and/or having greater than 72 h of S. aureus bacteremia. Among these subjects, we compared patients who did and did not receive aminoglycoside therapy for their S. aureus bloodstream infection. These groups were compared for the primary outcome of recurrent bacteremia, as well as for the duration of bacteremia, mortality, complication rate, and incident renal failure., Results: Eighty-seven subjects fulfilled the inclusion criteria. Of these, 49 received aminoglycoside therapy, whereas 38 did not. There were no significant differences in the baseline characteristics when comparing groups who did or did not receive aminoglycoside therapy. Four (8.2%) subjects treated with aminoglycoside therapy experienced recurrent bacteremia versus nine (23.7%) who did not receive aminoglycoside therapy [relative risk and 95% confidence interval [RR (95%CI)] = 0.51 (0.22-1.17), p = 0.04]. In multivariable analyses, aminoglycoside use remained significantly associated with a decrease in recurrent bacteremia [adjusted odds ratio (OR) (95%CI) = 0.26 (0.07-0.98), p = 0.046]. No significant differences were seen between groups treated with and without an aminoglycoside in terms of the 6-month all-cause mortality (51.0 vs. 42.1%, p = 0.41), complication rate (71.4 vs. 73.7%, p = 0.82), or incident renal failure (54.5 vs. 46.9%, p = 0.54)., Conclusions: The use of combination therapy with an aminoglycoside in persistent S. aureus bacteremia and/or endocarditis may be associated with a lower rate of recurrent bacteremia without significant differences in the incident renal failure.

Background: Transplant centers are reluctant to perform heart transplantation in patients with hepatitis C virus (HCV) infection because augmented immunosuppression could potentially increase mortality. However, there have been few studies examining whether HCV infection reduces survival after heart transplantation., Methods: We used data from the the U.S. Scientific Registry of Transplant Recipients to perform a multicenter cohort study evaluating the association between recipient pre-transplant HCV status and survival after heart transplantation. Adults undergoing heart transplantation between January 1, 1993 and December 31, 2007 were eligible to participate., Results: Among 20,687 heart transplant recipients (443 HCV-positive and 20,244 HCV-negative) at 103 institutions followed for a mean of 5.6 years, mortality was higher among HCV-positive than HCV-negative recipients (177 [40%] vs 6,367 [31.5%]; p = 0.0001). After matching on propensity score, hospital and gender, the hazard ratio (HR) of death for HCV-positive heart transplant recipients was 1.32 (95% confidence interval [CI] 1.08 to 1.61). Mortality rates were higher among HCV-positive heart transplant recipients at 1 year (9.4% vs 8.2%), 5 years (26.3% vs 22.9%), 10 years (53.1% vs 43.4%) and 15 years (74.8% vs 62.3%) post-transplantation. HRs did not vary by gender or overall number of heart transplantations performed at the center., Conclusions: Pre-transplant HCV positivity is associated with decreased survival after heart transplantation., (2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Hepatitis C virus (HCV) leads to disproportionate morbidity and mortality in the HIV-positive population. A new era of anti-HCV therapeutics is emerging, with many direct antiviral agents and immunomodulating drugs in clinical development. This review discusses HCV treatments in development, with special attention to four agents being studied actively among HIV/HCV-co-infected persons.

Background: HIV-monoinfected patients may be at risk for significant liver fibrosis, but its prevalence and determinants in these patients are unknown. Since HIV-monoinfected patients do not routinely undergo liver biopsy, we evaluated the prevalence and risk factors of significant hepatic fibrosis in this group using the aspartate aminotransferase (AST)-to-platelet ratio index (APRI)., Methods: We conducted a cross-sectional study among HIV-infected patients negative for hepatitis B surface antigen and hepatitis C antibody in the Penn Center for AIDS Research Adult/Adolescent Database. Clinical and laboratory data were collected from the database at enrollment. Hypothesized determinants of significant fibrosis were modifiable risk factors associated with liver disease progression, hepatic fibrosis, or hepatotoxicity, including immune dysfunction (i.e., CD4 T lymphocyte count <200 cells/mm(3), HIV viremia), diseases associated with hepatic steatosis (e.g., obesity, diabetes mellitus), and use of antiretroviral therapy. The primary outcome was an APRI score >1.5, which suggests significant hepatic fibrosis. Multivariable logistic regression identified independent risk factors for significant fibrosis by APRI., Results: Among 432 HIV-monoinfected patients enrolled in the CFAR Database between November 1999 and May 2008, significant fibrosis by APRI was identified in 36 (8.3%; 95% CI, 5.9-11.4%) patients. After controlling for all other hypothesized risk factors as well as active alcohol use and site, detectable HIV viremia (adjusted OR, 2.56; 95% CI, 1.02-8.87) and diabetes mellitus (adjusted OR, 3.15; 95% CI, 1.12-10.10) remained associated with significant fibrosis by APRI., Conclusions: Significant fibrosis by APRI score was found in 8% of HIV-monoinfected patients. Detectable HIV viremia and diabetes mellitus were associated with significant fibrosis. Future studies should explore mechanisms for fibrosis in HIV-monoinfected patients.

Background: It remains unclear if certain antiretroviral medications, particularly abacavir, compromise response to HCV therapy. Such data could inform the selection of appropriate antiretrovirals in HIV/HCV-coinfected patients. The aim of this study was to determine if use of abacavir, as well as other antiretrovirals, was associated with reduced response to pegylated interferon (PEG-IFN) plus ribavirin., Methods: A cohort study was performed among antiretroviral-treated HIV/HCV-coinfected patients initiating PEG-IFN plus ribavirin between January 2001 and June 2007 at six sites in the United States. Abacavir and other antiretrovirals represented exposures of interest. Study outcomes included an early virological response (> or =2 log IU/ml decrease in HCV viral load at 12 weeks) and sustained virological response (undetectable HCV viral load 24 weeks after treatment discontinuation)., Results: Among 212 patients, 74 (35%) received abacavir. For patients infected with HCV genotype 1 or 4, no differences were observed between abacavir users and non-users in early virological response (26 [40%] versus 53 [44%]; adjusted odds ratio [OR] 1.00; 95% confidence interval [CI] 0.50-2.00) or sustained virological response (8 [13%] versus 13 [12%]; adjusted OR 1.34; 95% CI 0.50-3.62). Among genotype 2 and 3 patients, rates of early virological response (7 [78%] versus 16 [89%]; OR 0.44; 95% CI 0.05-3.76) and sustained virological response (3 [33%] versus 8 [44%]; OR 0.63; 95% CI 0.12-3.32) were also similar between abacavir users and non-users. No association was found between other antiretrovirals and a lack of early or sustained response., Conclusions: Use of abacavir or other antiretroviral medications was not associated with reduced early or sustained virological response rates.

Background: Suboptimal drug exposure attributable to physician-directed dosage reductions of pegylated interferon and/or ribavirin are associated with decreased sustained virologic response rates. However, data are limited with regard to suboptimal drug exposure that is attributable to missed doses by patients with chronic hepatitis C virus (HCV) infection. We examined the relationship between adherence to pegylated interferon and ribavirin therapy, measured by pharmacy refill, and HCV suppression during the initial 12 weeks of therapy., Methods: We conducted a cohort study involving 188 patients with chronic HCV infection who were treated with pegylated interferon plus ribavirin. Adherence was calculated using pharmacy refill data and could exceed 100%. The primary outcome was decrease in HCV load at 12 weeks; early virologic response was a secondary outcome. Mixed-effects regression models estimated the association between adherence and HCV suppression during the initial 12 weeks. Subanalyses were performed among patients who received optimal weight-based dosages., Results: The mean decrease in HCV load at 12 weeks was 0.66 log IU/mL greater for patients with > or =85% adherence than for those with <85% adherence (3.23 vs. 2.57 log IU/mL; P = .04). When patients who received a suboptimal ribavirin dosage were excluded, the decrease in viral load was 1.00 log IU/mL greater for persons with > or =85% adherence (3.32 vs. 2.32 log IU/mL; P = .01). Early virologic response was more common among patients with > or =85% adherence than it was among those with <85% adherence to treatment with pegylated interferon (73% vs. 29%; P = .02) and ribavirin (73% vs. 55%; P = .08)., Conclusions: Adherence of > or =85% to pegylated interferon and ribavirin treatment was associated with increased HCV suppression. Decreases in HCV load became greater when patients with > or =85% adherence to their regimen continued to receive their recommended weight-based ribavirin dosage.

Because of shared routes of transmission, hepatitis C virus (HCV) coinfection is common among HIV-infected persons. Because of the effectiveness of antiretroviral therapy, chronic HCV has now emerged as a major cause of morbidity and mortality in this population. Because chronic HCV is highly prevalent among HIV-infected patients and has a rapid disease progression, antiviral therapy with pegylated interferon plus ribavirin is critical for the long-term survival of HIV/HCV-coinfected patients. In this article, the authors review the (1) epidemiology of HCV among HIV-infected individuals, (2) effect of HIV on the natural history of chronic HCV, (3) impact of antiretroviral therapy on HCV coinfection, and (4) management of chronic HCV in the HIV-infected person.

Concerns about the possible release of smallpox by bioterrorists has led to policies that recommend smallpox vaccination of some health care providers, and, in the near future, the vaccine may become available to the general population on a voluntary basis. Both smallpox virus (variola virus) and the smallpox vaccine (vaccinia virus) will have a significant impact on people infected with human immunodeficiency virus (HIV). Given that populations with acquired immunodeficiency syndrome and populations with immunosuppressed conditions due to solid organ and bone marrow transplantation were not present in the days when smallpox was prevalent, we will speculate on how smallpox might present in immunodeficient patients, and we will review the adverse events expected from the smallpox vaccine in hosts with HIV infection.