S. Kottilil

Moderate Sustained Virologic Response Rates With 6-Week Combination Directly Acting Anti–Hepatitis C Virus Therapy in Patients With Advanced Liver Disease

BACKGROUND Treatment of genotype 1 hepatitis C virus (HCV) infection with combination directly acting antivirals (DAA) for 8-24 weeks is associated with high rates of sustained virologic response (SVR). We previously demonstrated that adding a third DAA to ledipasvir and sofosbuvir (LDV/SOF) can result in high SVR rates in patients without cirrhosis. In this study, we investigated whether a similar regimen would yield equivalent rates of cure in patients with advanced liver fibrosis. METHODS Fifty patients were enrolled at the Clinical Research Center of the National Institutes of Health and associated healthcare centers. Enrollment and follow-up data from April 2014 to June 2015 are reported here. Eligible participants were aged ≥18 years, had chronic HCV genotype 1 infection (serum HCV RNA ≥2000 IU/mL), and stage 3-4 liver fibrosis. HCV RNA was measured using a reverse-transcription polymerase chain reaction assay. RESULTS Of patients treated with LDV, SOF, and the NS3/4A protease inhibitor GS-9451 for 6 weeks, 76% (38 of 50; 95% confidence interval, 60%-85%) had SVR achieved 12 weeks after the end of treatment. There was no statistically significant difference in treatment efficacy between treatment-naive patients (72%, 18 of 25) and those with treatment experience (80%; 20 of 25) (P = .51). Overall, 11 patients (22%) experienced virologic relapse, and 1 (2%) was lost to follow-up at 4 weeks after treatment. No serious adverse events, discontinuations, or deaths were associated with this regimen. CONCLUSIONS Adding a third DAA to LDV/SOF may result in a moderate SVR rate, lower than that observed in patients without cirrhosis. Significant liver fibrosis remains an impediment to achieving SVR with short-duration DAA therapy. CHINESE CLINICAL TRIALS REGISTRATION CT01805882.

Augmentation of hepatitis C virus‐specific immunity and sustained virologic response

Treatment for chronic hepatitis C virus (HCV) infection has rapidly evolved into interferon‐free directly acting antiviral regimens (DAA) that result in high sustained virologic response. DAAs primarily work by suppressing HCV replication and rely less on the immune system than interferon‐based therapies. However, it is unclear whether the immune system recovers with suppression of HCV replication and contributes to HCV clearance with DAA therapy. We previously demonstrated HCV clearance is associated with increased HCV‐specific immunity in CHCV‐GT‐1‐infected patients during treatment with sofosbuvir (SOF)+ribavirin (RBV). Here, we aimed to analyse changes in HCV‐specific immunological responses associated with viral clearance with combination DAA therapy of SOF+ledipasvir (LDV) for 12 weeks in CHCV‐GT1 (N=14) patients who relapsed without augmentation of HCV‐specific immunity during treatment with SOF+RBV. Phenotypic and functional changes within the T‐cell compartment of PBMCs pre‐ and post‐treatment were analysed. Retreatment of relapsers with LDV/SOF resulted in all patients attaining SVR12. Suppression of HCV was associated with a decline in T‐cell exhaustion markers (CD57; Tim3; PD1) along with augmented of HCV‐specific T‐cell IFN‐gamma responses post‐treatment. Addition of LDV to SOF was associated with augmentation of HCV‐specific immunity and SVR in patients who previously failed SOF+RBV therapy without increased immunity. These findings demonstrate a novel effect of DAA in inducing host immune responses to aid HCV clearance and achieve SVR.

Elbasvir/grazoprevir for treatment of chronic hepatitis C virus infection

Hepatitis C is the leading cause of progressive liver fibrosis worldwide and results in cirrhosis, liver cancer, liver failure and death. Successful treatment for hepatitis C virus (HCV) has rapidly evolved in recent years to a well-tolerated, highly efficacious all-oral therapy. Elbasvir/grazoprevir (Zepatier) is the newest of the oral combinations of HCV direct-acting agents that was approved by the US Federal Drug Administration. This review focuses on the pharmacology, mechanism of action and clinical trial data that support the use of this new combination treatment for HCV infection. The data suggest that Zepatier offers an excellent treatment efficacy, safety and tolerability in HCV treatment naïve and experienced patients and those with and without cirrhosis across multiple genotypes. Also, it has the selective advantage of safety and efficacy in patients with renal disease, especially in those with end-stage renal disease and/or hemodialysis patients.

Racial disparity in all-cause mortality among hepatitis C virus-infected individuals in a general US population, NHANES III.

There are few long‐term nationally representative studies of all‐cause mortality among those infected with hepatitis C virus (HCV). When an additional 5 years of data were made publicly available in 2015, the Third National Health and Nutrition Examination Survey Linked Mortality File became the longest nationally representative study in the United States. Our objective was to update the estimated HCV‐associated all‐cause mortality in the general US population and determine any differences by sex, age and race/ethnicity. HCV status was assessed in 9117 nationally representative adults aged 18‐59 years from 1988 to 1994, and mortality follow‐up of the same individuals was completed through 2011 and made publicly available in 2015. There were 930 deaths over a median follow‐up of 19.8 years. After adjusting for all covariate risk factors, chronic HCV had 2.63 times (95% CI: 1.59‐4.37; P=.0002) higher all‐cause mortality rate ratio (MRR) compared with being HCV negative. All‐cause MRR was stratified by sex, age and race/ethnicity. Only race/ethnicity was a significant effect modifier of MRR (P<.0001) as the highest MRR of chronic HCV compared to HCV negative was 7.48 (95% CI: 2.15‐26.10, P=.001) among Mexican Americans, 2.67 (95% CI: 2.67‐5.56, P=.009) among non‐Hispanic Whites and 2.02 (95% CI: 1.20‐3.40, P=.007) among non‐Hispanic Blacks. Racial disparity was seen in the all‐cause mortality as Mexican Americans with chronic HCV had approximately seven times higher mortality rate than HCV‐negative individuals. This suggests that these at‐risk individuals should be targeted for HCV screening and treatment, given the availability of new highly effective HCV therapies.

A pilot study to expand treatment of chronic hepatitis C in resource-limited settings

The past five years have seen a revolution in the treatment of chronic hepatitis C, as short duration oral regimens of direct-acting antiviral drugs (DAAs), with nearly 100% cure rates for all genotypes, have replaced longer courses of ribavirin and injected interferon. Although initially very expensive, these DAAs are now becoming available in generic equivalents in countries with large numbers of chronically infected people, such as India. However, a number of obstacles may hinder the delivery of these drugs in resource-limited settings, including lack of access to diagnostic testing and the restriction of treatment to a small number of medical specialists. New approaches are therefore needed to make DAAs available to the estimated 71 million infected people, many of whom disproportionately live in low- or middle-income countries. A recent pilot study (ASCEND) of hepatitis C management in a low-income population in Washington, D.C., demonstrated that trained nurse practitioners, primary care physicians and hepatologists were equally successful in diagnosing and treating patients, indicating that such an approach might be successful in resource-limited regions of the world. Members of the Global Virus Network have received funding to carry out a similar training project in a region of India with a high prevalence of hepatitis C. This paper reviews the challenges of delivering DAA therapy in low- and middle-income countries, describes plans for performing and evaluating the effectiveness of a training program in India, and discusses future needs for the eventual elimination of hepatitis C.

Dual sofosbuvir and ribavirin therapy for chronic hepatitis C infection

Sofosbuvir is the first pan-genotypic direct acting antiviral agent to be approved. This article provides an overview of the pharmacology of sofosbuvir and ribavirin and a comprehensive summary of the phase 2 and 3 studies supporting dual sofosbuvir and ribavirin therapy for chronic hepatitis C infection. With the production of generic formulations of sofosbuvir, we anticipate this regimen leading the first wave for widespread, IFN-free treatment and becoming first line for all genotypes (including genotype 1) for much of the world—in particular in developing and middle income countries. We discuss the continued challenges with this regimen including among patients with decompensated liver disease and post-liver transplant, and renal failure. We address concerns of emerging resistance. We also discuss the future prospects including the global uptake of sofosbuvir and ribavirin for the treatment of all genotypes.

Durable Sustained Virologic Response After Oral Directly Acting Antiviral Therapy Despite Immunosuppressive Treatment.

Treatment for hepatitis C has evolved from interferon-based therapy to all oral, directly acting antiviral (DAA) therapy. The influence of immunosuppression on maintaining sustained virologic response (SVR) in patients who have been treated with these directly acting agents is unknown. In this study, we report sustained hepatitis C virus (HCV) suppression in 3 patients undergoing various immunosuppressive treatments after achieving SVR with DAA therapy. Three patients, who were enrolled in 1 of 2 single-center National Institutes of Health clinical trials, achieved SVR12. Each patient had undergone between 6 and 24 weeks of DAA therapy with or without ribavirin. Immunosuppression was varied among the 3 patients. Therapy included adalimumab, carboplatin/irinotecan, or capecitabine. In all 3 cases, patients maintained HCV RNA levels below detection after immunosuppression. All patients had undetectable viral load and normalized liver-related enzymes during immunosuppressive therapy. This report suggests that SVR as a result of novel DAA therapy is durable and likely not affected by immunosuppressive therapy. Larger studies are required to confirm these results, but findings are promising for the treatment of large numbers of HCV-infected patients who may require subsequent immunosuppressive or immunomodulating therapies.

Underutilization of statins for prevention of cardiovascular disease among primarily African-American HIV-infected patients.

Background: Studies have consistently demonstrated that statin therapy reduces CHD-related mortality, but HIVinfected individuals are frequently undertreated for hyperlipidemia. Therefore, we sought to: 1. determine whether the numbers of patients recommended for statin therapy differed using the 2004 and 2013 guidelines; 2. evaluate the proportion of recommended patients who were actually receiving statins; and 3. evaluate the factors associated with statin prescription. Methods: Conducted cross-sectional analysis of a retrospective cohort. 100 patients receiving care at an academic inner-city HIV clinic in 2008 were reviewed. The atherosclerotic vascular disease (ASCVD) risk score was calculated using the 2013 Pooled Cohort Equation and the 2004 and 2013 guidelines were applied to evaluate numbers of patients recommended for statin therapy. Proportions were used to report patients receiving statins among those who were recommended for treatment and several unadjusted logistic regression analyses were performed to identify factors associated with utilization of statins in recommended patients. Results: 81 participants were included in the final analysis. Substantially larger numbers of HIV-infected individuals were recommended to receive statin therapy for CHD risk reduction when applying the 2013 guidelines compared to the 2004 guidelines, but less than half received statins for primary prevention as recommended. Prescription of statins was not associated with either ASCVD risk score or many traditional CHD risk factors. Diabetes mellitus was associated with increased odds of receiving statin therapy whereas hepatitis C co-infection and current smoking status were associated with decreased odds of receiving statins. Conclusions: There is an increased, large and unmet need to increase statin use for prevention of CHD. Underutilization of statins was most pronounced among HIV-hepatitis C co-infected patients and HIV-infected smokers.

Treatment of hepatitis C with 8 weeks of ledipasvir/sofosbuvir: Highly effective in a predominantly black male patient population

The combination directly acting antiviral regimen of ledipasvir and sofosbuvir (LDV/SOF) produces high rates of hepatitis C cure in both clinical trials and realworld studies.1–3 The phase 3 studies reported comparable efficacy of 8 and 12 weeks of LDV/SOF in treatment naïve patients without cirrhosis.2,3 Subset analyses of the ION3 study reported cure rates following 8 weeks of therapy were optimized in patients with baseline HCV RNA levels of <6 million4 or favourable genetics,5 although independent analyses differed.6 The Food and Drug Administration LDV/SOF label advised prescribers to consider 8 weeks of LDV/SOF therapy in noncirrhotic, treatment naïve patients with HCV RNA <6 000 000 IU/mL.7 Reallife experiences have shown conflicting results following 8 weeks of therapy among Black patients.8-10 Subsequently, current American Association for the Study of Liver Diseases/Infectious Disease Society of America (AASLD/IDSA) HCV treatment guidelines recommend against 8week LDV/SOF treatment durations in Black patients.11 Given the potential cost savings with reduced treatment durations, the VA guidelines continue to allow for 8 weeks of LDV/SOF in those who can be treated for shortened durations without sacrificing effectiveness: treatment naïve, noncirrhotic patients with HCV RNA levels <6 000 000 IU/mL.12 Here, we report our experience with 8week LDV/SOF therapy among predominantly Black Veterans treated by the VA Maryland Healthcare System (VAMHCS).

Global Burden of Atherosclerotic Cardiovascular Disease in People Living with the Human Immunodeficiency Virus: A Systematic Review and Meta-Analysis

Background: With advances in antiretroviral therapy, most deaths in people with HIV are now attributable to noncommunicable illnesses, especially cardiovascular disease. We determine the association between HIV and cardiovascular disease, and estimate the national, regional, and global burden of cardiovascular disease attributable to HIV. Methods: We conducted a systematic review across 5 databases from inception to August 2016 for longitudinal studies of cardiovascular disease in HIV infection. A random-effects meta-analysis across 80 studies was used to derive the pooled rate and risk of cardiovascular disease in people living with HIV. We then estimated the temporal changes in the population-attributable fraction and disability-adjusted life-years (DALYs) from HIV-associated cardiovascular disease from 1990 to 2015 at a regional and global level. National cardiovascular DALYs associated with HIV for 2015 were derived for 154 of the 193 United Nations member states. The main outcome measure was the pooled estimate of the rate and risk of cardiovascular disease in people living with HIV and the national, regional, and global estimates of DALYs from cardiovascular disease associated with HIV. Results: In 793 635 people living with HIV and a total follow-up of 3.5 million person-years, the crude rate of cardiovascular disease was 61.8 (95% CI, 45.8–83.4) per 10 000 person-years. In comparison with individuals without HIV, the risk ratio for cardiovascular disease was 2.16 (95% CI, 1.68–2.77). Over the past 26 years, the global population–attributable fraction from cardiovascular disease attributable to HIV increased from 0.36% (95% CI, 0.21%–0.56%) to 0.92% (95% CI, 0.55%–1.41%), and DALYs increased from 0.74 (95% CI, 0.44–1.16) to 2.57 (95% CI, 1.53–3.92) million. There was marked regional variation with most DALYs lost in sub-Saharan Africa (0.87 million, 95% CI, 0.43–1.70) and the Asia Pacific (0.39 million, 95% CI, 0.23–0.62) regions. The highest population-attributable fraction and burden were observed in Swaziland, Botswana, and Lesotho. Conclusions: People living with HIV are twice as likely to develop cardiovascular disease. The global burden of HIV-associated cardiovascular disease has tripled over the past 2 decades and is now responsible for 2.6 million DALYs per annum with the greatest impact in sub-Saharan Africa and the Asia Pacific regions. Clinical Trial Registration: URL: https://www.crd.york.ac.uk/prospero. Unique identifier: CRD42016048257.