Summary
The availability of effective, simple, well‐tolerated oral direct‐acting antiviral (DAA) hepatitis C regimens has raised optimism for hepatitis C virus (HCV) elimination at the population ...level. HCV reinfection in key populations such as people who inject drugs (PWID) and HIV‐infected men who have sex with men (MSM) however threatens the achievement of this goal from a patient, provider and population perspective. The goal of this review was to synthesize our current understanding of estimated rates and factors associated with HCV reinfection. This review also proposes interventions to aid understanding of and reduce hepatitis C reinfection among PWID and HIV‐infected MSM in the oral direct‐acting antiviral era.
Interferon (IFN)-α treatment for infectious diseases and cancer is associated with significant depressive symptoms that can limit therapeutic efficacy. Multiple mechanisms have been implicated in ...IFN-α-induced depression including immune, neuroendocrine and neurotransmitter pathways. To further explore mechanisms of IFN-α-induced depression and establish associated genetic risk factors, single nucleotide polymorphisms in genes encoding proteins previously implicated in IFN-α-induced depression were explored in two self-reported ethnic groups, Caucasians (n=800) and African Americans (n=232), participating in a clinical trial on the impact of three pegylated IFN-α treatment regimens on sustained viral response in patients with chronic hepatitis C. Before treatment, all subjects were free of psychotropic medications and had a score ≤20 on the Center for Epidemiologic Studies Depression Scale (CES-D), which was used to assess depressive symptom severity throughout the study. In Caucasians, a polymorphism (rs9657182) in the promoter region of the gene encoding indoleamine-2,3-dioxygenase (IDO1) was found to be associated with moderate or severe IFN-α-induced depressive symptoms (CES-D>20) at 12 weeks of IFN-α treatment (P=0.0012, P<0.05 corrected). Similar results were obtained for treatment weeks 24, 36 and 48. In subjects homozygous for the risk allele (CC, n=150), the odds ratio for developing moderate or severe depressive symptoms at treatment week 12 was 2.91 (confidence interval: 1.48-5.73) compared with TT homozygotes (n=270). rs9657182 did not predict depression in African Americans, who exhibited a markedly lower frequency of the risk allele at this locus. The findings in Caucasians further support the notion that IDO has an important role in cytokine-induced behavioral changes.
Summary
Background
Chronic hepatitis C virus therapy in patients with advanced liver disease remains a clinical challenge. HCV‐TARGET collects data in patients treated at tertiary academic and ...community centres.
Aim
To assess efficacy of all‐oral HCV therapy in advanced liver disease.
Methods
Between December 2013 and October 2014, 240 patients with a MELD score of ≥10 initiated HCV treatment with an all‐oral regimen. Data from the 220 patients who completed 12‐week follow‐up were analysed.
Results
Genotype 1 (GT1) patients had higher sustained virological response (SVR) when treated with sofosbuvir plus simeprevir ± ribavirin than with sofosbuvir plus ribavirin (66–74% vs. 54%); GT1b vs GT1a (84% vs. 64%). SVR for GT2 was 72% with sofosbuvir plus ribavirin, while GT3 patients had a substantially lower response (35%). A decrease in MELD score was not clearly related to SVR over the short course of follow‐up although some had improvements in MELD score, serum bilirubin and albumin. A predictor of virological response was albumin level while negative predictors were elevated bilirubin level and GT1a. Most patients with GT1 were treated with approximately 12‐week duration of sofosbuvir and simeprevir ± ribavirin therapy while GT2 and GT3 patients were treated with approximately 12 and 24 weeks of sofosbuvir plus ribavirin respectively.
Conclusions
All‐oral therapies are effective among patients with advanced liver disease with high levels of success in GT2 and GT1b, and may serve to reduce the severity of liver disease after SVR. Treatment for GT3 patients remains an unmet need.
Clinical trial number: NCT01474811
CONTEXT Use of antiretroviral drugs, including protease inhibitors, for treatment
of human immunodeficiency virus (HIV) infection has been anecdotally associated
with hepatotoxicity, particularly in ...persons coinfected with hepatitis C or
B virus. OBJECTIVES To ascertain if incidence of severe hepatotoxicity during antiretroviral
therapy is similar for all antiretroviral drug combinations, and to define
the role of chronic viral hepatitis in its development. DESIGN Prospective cohort study. SETTING University-based urban HIV clinic. PATIENTS A total of 298 patients who were prescribed new antiretroviral therapies
between January 1996 and January 1998, 211 (71%) of whom received protease
inhibitors as part of combination therapy (median follow-up, 182 days) and
87 (29%) of whom received dual nucleoside analog regimens (median follow-up,
167 days). Chronic hepatitis C and B virus infection was present in 154 (52%)
and 8 (2.7%) patients, respectively. MAIN OUTCOME MEASURE Severe hepatotoxicity, defined as a grade 3 or 4 change in levels of
serum alanine aminotransferase and aspartate aminotransferase, evaluated before
and during therapy. RESULTS Severe hepatotoxicity was observed in 31 (10.4%) of 298 patients (95%
confidence interval CI, 7.2%-14.4%). Ritonavir use was associated with a
higher incidence of toxicity (30%; 95% CI, 17.9%-44.6%). However, no significant
difference was detected in hepatotoxicity incidence in other treatment groups,
ie, nucleoside analogs (5.7%; 95% CI, 1.2%-12.9%), nelfinavir (5.9%; 95% CI,
1.2%-16.2%), saquinavir (5.9%; 95% CI, 0.15%-28.7%), and indinavir (6.8%;
95% CI, 3.0%-13.1%). Although chronic viral hepatitis was associated with
an increased risk of severe hepatotoxicity among patients prescribed nonritonavir
regimens (relative risk, 3.7; 95% CI, 1.0-11.8), most patients with chronic
hepatitis C or B virus infection (88%) did not experience significant toxic
effects. Rate of severe toxicity with use of any protease inhibitor in patients
with hepatitis C infection was 12.2% (13/107; 95% CI, 6.6%-19.9%). In multivariate
logistic regression, only ritonavir (adjusted odds ratio AOR, 8.6; 95% CI,
3.0-24.6) and a CD4 cell count increase of more than 0.05 × 109/L (AOR, 3.6; 95% CI, 1.0-12.9) were associated with severe hepatotoxicity.
No irreversible outcomes were seen in patients with severe hepatotoxicity. CONCLUSIONS Our data indicate that use of ritonavir may increase risk of severe
hepatotoxicity. Although hepatotoxicity may be more common in persons with
chronic viral hepatitis, these data do not support withholding protease inhibitor
therapy from persons coinfected with hepatitis B or C virus.
The importance of treating hepatitis C virus (HCV)‐associated morbidities in a growing population of patients coinfected with human immunodeficiency virus (HIV) has increased since the introduction ...of highly active antiretroviral therapy. As a result, investigative attention is turning to HCV‐related liver disease and treatment‐associated issues in coinfection. HIV/HCV‐coinfected patients have higher HCV RNA loads and show more rapid progression of fibrosis than do monoinfected patients. Combination therapy with pegylated interferon plus ribavirin (RBV) is the standard of care for HCV in coinfected patients. Therapy slows fibrosis progression, but toxicity prevents identification of the most effective RBV dose. Coinfected patients have about a threefold greater risk of antiretroviral therapy‐associated hepatotoxicity than patients with HIV only. Other challenges include anaemia, mitochondrial toxicity, drug–drug interactions and leucopenia. Thus, chronic hepatitis C should be treated in HIV/HCV‐coinfected patients, but steps must be taken to prevent and treat potential toxicities. The first European Consensus Conference on the Treatment of Chronic Hepatitis B and C in HIV Co‐infected Patients was held March 2005 in Paris to address these issues. This article reviews the peer‐reviewed literature and expert opinion published from 1990 to 2005, and compares results with presentations and recommendations from the Consensus Conference to best present current issues in coinfection.
The aim of this work was to estimate the future disease burden of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections in the United States until the year 2030. Two ...back‐calculation models of the HIV and the HCV epidemic were developed. They were based on US epidemiological data regarding prevalence, age and gender of incident cases, AIDS, hepatocellular carcinoma (HCC) mortality and general population mortality from the Centers for Disease Control and WHO. Based on the HCV back‐calculation model, HCV incidence peaked in 1984 at 350 000 new infections and then fell to about 77 000 in 1998. Based on the HIV back‐calculation model, HIV incidence reached its maximum in 1989 at 142 000 new infections and then declined to 79 000 in 1998. Mortality related to HCV (death from liver failure or HCC) rose from about 3700 in 1998 and is expected to peak at about 13 000 in 2030. Predicted HCV mortality would fall only if increased access to or more effective antiviral therapy occurs. For comparison, observed HIV‐related mortality was 14 400 in 1998 and projected to be 4200 for 2030. With the availability of effective highly active antiretroviral therapy for HIV infection, mortality from HIV appears to have declined substantially, whereas HCV‐related deaths as a result of pre‐1999 infections will likely continue to increase over the next 25 years.
Hepatitis C virus (HCV) infection may contribute to the development of diabetes mellitus. This relationship has not been investigated at the population level, and its biological mechanism remains ...unknown.
To examine the prevalence of type 2 diabetes among persons with HCV infection in a representative sample of the general adult population of the United States.
Cross-sectional national survey.
The Third National Health and Nutrition Examination Survey, 1988-1994.
9841 persons older than 20 years of age for whom data on HCV infection and diabetes were complete.
The presence of diabetes was ascertained by using American Diabetes Association guidelines based on fasting plasma glucose measurement and medication history. Presence of HCV infection was assessed by testing for serum HCV-specific antibodies (anti-HCV).
Of the 9841 persons evaluated, 8.4% had type 2 diabetes and 2.1% were anti-HCV positive. Type 2 diabetes occurred more often in persons who were older, were nonwhite, had a high body mass index, and had low socioeconomic status. Type 2 diabetes was less common in persons who acknowledged previous illicit drug use. After adjustment for these factors, persons 40 years of age or older with HCV infection were more than three times more likely than those without HCV infection to have type 2 diabetes (adjusted odds ratio, 3.77 95% CI, 1.80 to 7.87). None of the 19 persons with type 1 diabetes were anti-HCV positive.
In the United States, type 2 diabetes occurs more often in persons with HCV infection who are older than 40 years of age.
To define the incidence of fibrosis progression among hepatitis C virus (HCV)/HIV-co-infected adults, to assess whether HCV or HIV treatment alters the risk of progression, and to determine the ...utility of liver biopsy to predict future disease.
This prospective cohort evaluated 184 HIV/HCV-co-infected individuals who had at least two liver biopsies (median interval 2.9 years).
Biopsies were scored according to the Ishak modified histological activity index scoring system by a single pathologist blind to biopsy sequence. Significant fibrosis progression was defined as an increase of at least two Ishak fibrosis units between the first and second liver biopsy. Logistic regression analysis was used to assess determinants of fibrosis progression.
A total of 174 non-cirrhotic patients were eligible; the majority were African-American men undergoing HIV treatment. On initial biopsy, no or minimal fibrosis was identified in 136 patients (77%). Significant fibrosis progression occurred in 41 patients (24%). Measures of HIV disease and its treatment before and after initial biopsy were not significantly different in progressors and non-progressors. Fibrosis progression was not associated with HCV treatment, which was received by 37 patients (21%) but only three sustained HCV-RNA suppression. In adjusted analysis, only an elevated serum aspartate aminotransferase level between biopsies was associated with progression (odd ratio 3.4, 95% confidence interval 1.4-7.9).
Over a 3-year interval, significant fibrosis progression can occur in co-infected individuals even if minimal disease was detected on initial biopsy. In this context, factors other than treatment for HIV or HCV modify the risk of fibrosis progression.
Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family and is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Owing to shared routes of transmission, HCV and ...human immunodeficiency virus (HIV) coinfection are common, affecting approximately one-third of all HIV-infected persons in the United States. In addition, HIV coinfection is associated with higher HCV RNA level and a more rapid progression of HCV-related liver disease, which leads to an increased risk of cirrhosis. HCV infection may also impact the course and management of HIV disease, particularly by increasing the risk of antiretroviral drug-induced hepatotoxicity. Thus, chronic HCV infection acts as an opportunistic disease in HIV-infected persons, because the incidence of infection is increased and the natural history of HCV infection is accelerated in coinfected persons. Strategies to prevent primary HCV infection and to modify the progression of HCV-related liver disease are urgently needed for HIV-HCV-coinfected individuals.
As a result of shared routes of transmission, coinfection with hepatitis C virus (HCV) is common in human immunodeficiency virus (HIV)—infected patients. The prevalence of HIV/HCV coinfection is ...particularly high among persons who have used injection drugs; however, more recently, sexual transmission of HCV has been recognized among HIV-infected men who have sex with men (MSM). Over the past decade, the effectiveness of HIV treatment improved substantially, leading to a substantial reduction in HIV/AIDS-related deaths; in this context, liver disease due to HCV infection has emerged as major concern for co-infected patients. Over the same period, treatment of HCV remained stagnant, with pegylated interferon alfa (PegIFN) plus ribavirin (RBV; PegIFN/RBV) entrenched as the standard treatment for HCV infection for coinfected patients, who have the greatest risk for liver disease. However, the effectiveness of HCV treatment in this population has been disappointing because of low rates of treatment initiation and success. In 2011, novel HCV NS3/4A PIs (PIs), telaprevir and boceprevir, were approved for use in combination with PegIFN/RBV for the treatment of HCV genotype 1 infection; at the time of approval, important questions regarding the efficacy, safety, and potential for drug interactions with telaprevir and boceprevir had not been answered. More recently, data from drug-interaction studies and 2 small, phase II clinical trials indicate that these HCV treatment regimens may lead to higher rates of HCV eradication in HIV/HCV-coinfected patients, with manageable toxicity and pharmacologic interactions with antiretroviral drugs. As such, these HCV PI-based regimens have emerged as the standard for the treatment of HCV genotype 1 infection in carefully selected HIV-infected patients.
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