Sarah Kattakuzhy

Expansion of Treatment for Hepatitis C Virus Infection by Task Shifting to Community-Based Nonspecialist Providers: A Nonrandomized Clinical Trial

Background Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection has resulted in high rates of disease cure; however, not enough specialists currently are available to provide care. Objective To determine the efficacy of HCV treatment independently provided by nurse practitioners (NPs), primary care physicians (PCPs), or specialist physicians using DAA therapy. Design Nonrandomized, open-label clinical trial initiated in 2015. (ClinicalTrials.gov: NCT02339038). Setting 13 urban, federally qualified health centers (FQHCs) in the District of Columbia. Patients A referred sample of 600 patients, of whom 96% were black, 69% were male, 82% were treatment naive, and 20% had cirrhosis. Seventy-two percent of the patients had HCV genotype 1a infection. The baseline characteristics of patients seen by each provider type were similar. Intervention Patients were assigned in a nonrandomized but specified manner to receive treatment from 1 of 5 NPs, 5 PCPs, or 6 specialists. All providers underwent an identical 3-hour training session based on guidelines. Patients received treatment with ledipasvir-sofosbuvir, which was provided on site, according to U.S. Food and Drug Administration labeling requirements. Measurements Sustained virologic response (SVR). Results 516 patients achieved SVR, a response rate of 86% (95% CI, 83.0% to 88.7%), with no major safety signals. Response rates were consistent across the 3 provider types: NPs, 89.3% (CI, 83.3% to 93.8%); PCPs, 86.9% (CI, 80.6% to 91.7%); and specialists, 83.8% (CI, 79.0% to 87.8%). Patient loss to follow-up was the major cause of non-SVR. Limitation Nonrandomized patient distribution; possible referral bias. Conclusion In a real-world cohort of patients at urban FQHCs, HCV treatment administered by nonspecialist providers was as safe and effective as that provided by specialists. Nurse practitioners and PCPs with compact didactic training could substantially expand the availability of community-based providers to escalate HCV therapy, bridging existing gaps in the continuum of care for patients with HCV infection. Primary Funding Source National Institutes of Health and Gilead Sciences.

Successful Retreatment of Chronic HCV Genotype-1 Infection With Ledipasvir and Sofosbuvir After Initial Short Course Therapy With Direct-Acting Antiviral Regimens

BACKGROUND The optimal retreatment strategy for chronic hepatitis C virus (HCV) patients who fail directly-acting antiviral agent (DAA)-based treatment is unknown. In this study, we assessed the efficacy and safety of ledipasvir (LDV) and sofosbuvir (SOF) for 12 weeks in HCV genotype-1 (GT-1) patients who failed LDV/SOF-containing therapy. METHODS In this single-center, open-label, phase 2a trial, 34 participants with HCV (GT-1) and early-stage liver fibrosis who previously failed 4-6 weeks of LDV/SOF with GS-9669 and/or GS-9451 received LDV/SOF for 12 weeks. The primary endpoint was HCV viral load below the lower limit of quantification 12 weeks after completion of therapy (sustained virological response [SVR]12). Deep sequencing of the NS3, NS5A, and NS5B regions were performed at baseline, at initial relapse, prior to retreatment, and at second relapse with Illumina next-generation sequencing technology. RESULTS Thirty-two of 34 enrolled participants completed therapy. Two patients withdrew after day 0. Participants were predominantly male and black, with median baseline HCV viral load of 1.3 × 10(6) IU/mL and Metavir fibrosis stage 1 and genotype-1a. Median time from relapse to retreatment was 22 weeks. Prior to retreatment, 29 patients (85%) had NS5A-resistant variants. The SVR12 rate was 91% (31/34; intention to treat, ITT) after retreatment. One patient relapsed. CONCLUSIONS In patients who previously failed short-course combination DAA therapy, we demonstrate a high SVR rate in response to 12 weeks of LDV/SOF, even for patients with NS5A resistance-associated variants. CLINICAL TRIALS REGISTRATION NCT01805882.

Four-Week Direct-Acting Antiviral Regimens in Noncirrhotic Patients With Hepatitis C Virus Genotype 1 Infection: An Open-Label, Nonrandomized Trial

BACKGROUND Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) for 6 weeks achieves sustained virologic response (SVR) rates of 95% in some patients. If effective, shorter therapeutic courses could improve adherence and treatment costs. OBJECTIVE To determine factors predictive of SVR to 4 weeks of DAA treatment in patients with stage F0 to F2 liver fibrosis. DESIGN Open-label, nonrandomized, phase 2a trial. (Clinical Trials.gov: NCT01805882). SETTING Single-center. PATIENTS 50 treatment-naive and predominantly African American patients with HCV genotype 1 infection and early-stage liver fibrosis were sequentially enrolled into 2 treatment groups. INTERVENTION 25 participants received a 3-drug regimen consisting of ledipasvir and sofosbuvir plus GS-9451 for 4 weeks, and 25 received a 4-drug regimen consisting of ledipasvir, sofosbuvir, GS-9451, and GS-9669 for 4 weeks. MEASUREMENTS The primary efficacy end point was SVR12 (HCV RNA level below the lower limit of quantification at posttreatment week 12). RESULTS Forty percent (10 of 25) (95% CI, 21% to 61%) of patients in the 3-drug group and 20% (5 of 25) (CI, 7% to 41%) of those in the 4-drug group achieved SVR12. Exploratory analysis suggested that lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12. Ten patients had baseline HCV variants conferring greater than 20-fold resistance in vitro to at least 1 study DAA; all had viral relapse. Forty-eight percent (12 of 25) of patients receiving the 3-drug regimen and 72% (18 of 25) of those receiving the 4-drug regimen had adverse events, most of which were mild. One participant was lost to follow-up. LIMITATION Nonrandomized study design and small sample of patients with early-stage fibrosis. CONCLUSION Combination DAA therapy with 3 or 4 drugs for 4 weeks was well-tolerated but resulted in limited cure rates. PRIMARY FUNDING SOURCE National Institute of Allergy and Infectious Diseases, National Cancer Institute, and Clinical Center Intramural Program; supported in part by a cooperative research and development agreement between the National Institutes of Health and Gilead Sciences.

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.

Sofosbuvir for treatment of chronic hepatitis C

Chronic hepatitis C is a leading cause of liver-related morbidity and mortality worldwide. If untreated, chronic hepatitis C can progress to advanced liver fibrosis, cirrhosis, liver failure, hepatocellular carcinoma and death. Until recently, treatment of hepatitis C predominantly constituted an immunomodulatory agent, peg-interferon-alfa and ribavirin. In 2011, the first class of directly acting antiviral agents, HCV NS3/4A serine protease inhibitors, was added to peg-interferon-alfa and ribavirin with increased efficacy. In the past year, an NS5B inhibitor, sofosbuvir, has emerged as a potent agent with pangenotypic efficacy, resulting in the first interferon-free regimen for the treatment of hepatitis C. This review summarizes the data that resulted in regulatory approval of sofosbuvir and highlights the future of hepatitis C therapy with sofosbuvir as the backbone of a highly effective antiviral regimen.

Diabetes Mellitus Type 2 and Abnormal Glucose Metabolism in the Setting of Human Immunodeficiency Virus

As the modern era of combination antiretroviral therapy has increased life expectancy for individuals infected with the human immunodeficiency virus (HIV), type 2 diabetes mellitus and disorders of glucose metabolism have emerged as an important issue in the care of this population. Multiple mechanisms, both specific and nonspecific to HIV, underlie a significant prevalence. Although best-practice diagnostic testing remains unclear, the risks associated with diabetes in the setting of HIV are well characterized, ranging from organ-specific damage to socioeconomic decline. As population-specific treatment data are limited, current guidelines serve as a basis for ongoing management.

Safe and effective sofosbuvir-based therapy in patients with mental health disease on hepatitis C virus treatment

AIM To study impact of baseline mental health disease on hepatitis C virus (HCV) treatment; and Beck’s Depression Inventory (BDI) changes with sofosbuvir- and interferon-based therapy. METHODS This is a retrospective cohort study of participants from 5 studies enrolled from single center trials conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, MD, United States. All participants were adults with chronic HCV genotype 1 infection and naïve to HCV therapy. Two of the studies included HCV mono-infected participants only (SPARE, SYNERGY-A), and 3 included human immunodeficiency virus (HIV)/HCV co-infected participants only (ERADICATE, PFINPK, and ALBIN). Patients were treated for HCV with 3 different regimens: Sofosbuvir and ribavirin in the SPARE trial, ledipasvir and sofosbuvir in SYNERGY-A and ERADICATE trials, and pegylated interferon (IFN) and ribavirin for 48 wk in the PIFNPK and ALBIN trials. Participants with baseline mental health disease (MHD) were identified (defined as either a DSM IV diagnosis of major depression, bipolar disorder, schizophrenia, generalized anxiety, and post-traumatic stress disorder or requiring anti-depressants, antipsychotics, mood stabilizers or psychotropics prescribed by a psychiatrist). For our first aim, we compared sustained virologic response (SVR) and adherence (pill counts, study visits, and in 25 patients, blood levels of the sofosbuvir metabolite, GS-331007) within each study. For our second aim, only patients with HIV coinfection were evaluated. BDI scores were obtained pre-treatment, during treatment, and post-treatment among participants treated with sofosbuvir-based therapy, and compared to scores from participants treated with interferon-based therapy. Statistical differences for both aims were analyzed by Fisher’s Exact, and t-test with significance defined as a P value less than 0.05. RESULTS Baseline characteristics did not differ significantly between all participants with and without MHD groups treated with sofosbuvir-based therapy. Among patients treated with sofosbuvir-based therapy, the percentage of patients with MHD who achieved SVR was the same as those without (SPARE: 60.9% of those MHD compared to 67.6% in those without, P = 0.78; SYNERGY-A: 100% of both groups; ERADICATE: 100% compared to 97.1%). There was no statistically significant difference in pill counts, adherence to study visits between groups, nor mean serum concentrations of GS-331007 for each group at week 2 of treatment (P = 0.72). Among patients with HIV co-infection, pre-treatment BDI scores were similar among patients treated with sofosbuvir, and those treated with interferon (sofosbuvir-based 5.24, IFN-based 6.96; P = 0.14); however, a dichotomous effect on was observed during treatment. Among participants treated with directly acting antiviral (DAA)-based therapy, mean BDI scores decreased from 5.24 (pre-treatment) to 3.28 during treatment (1.96 decrease, P = 0.0034) and 2.82 post-treatment. The decrease in mean score from pre- to post-treatment was statistically significant (-2.42, P = 0.0012). Among participants treated with IFN-based therapy, mean BDI score increased from 6.96 at pre-treatment to 9.19 during treatment (an increase of 2.46 points, P = 0.1), and then decreased back to baseline post-treatment (mean BDI score 6.3, P = 0.54). Overall change in mean BDI scores from pre-treatment to during treatment among participants treated with DAA-based and IFN-therapy was statistically significant (-1.96 and +2.23, respectively; P = 0.0032). This change remained statistically significant when analysis was restricted to participants who achieved SVR (-2.0 and +4.36, respectively; P = 0.0004). CONCLUSION Sofosbuvir-based therapy is safe and well tolerated in patients with MHD. A decline in BDI associated with sofosbuvir-based HCV treatment suggests additional MHD benefits, although the duration of these effects is unknown.

P0875 : Predictors of sustained viral response to 4–6 week duration therapy with ledipasvir + sofosbuvir + GS-9451 +/− GS-9669 in early and advanced fibrosis (NIH/UMD synergy trial)

Dietrich D et al., 2014 Mixed Multicenter Yes 276 Mean 59 181 (57) 145 (45) Modi AA et al., 2014 Community Multicenter Yes 32 Median 59 34 (76) − Bichoupan K et al., 2014 University Single center No 181 Median 62 96 (53) Capraru CI et al., 2014 University Single center No 34 Mean 57.7 31 (66) − Roytman M et al., 2014 University Single center No 52 Mean 61.5 63 (64) 63 (64) Lin MV et al., 2014 University Multicenter No 121 Mean 57.7 103 (70) 84 (57) Lingala S et al., 2014 University Single center No 19 Mean 59 16 (64) −

No Improvement in Hemoglobin A1c Following Hepatitis C Viral Clearance in Patients With and Without HIV

Hepatitis C clearance with directly acting antivirals (DAAs) may be associated with acute decreases in hemoglobin A1c (HbA1c). We prospectively evaluated 251 chronic hepatitis C virus (HCV)-infected subjects (31% human immunodeficiency virus [HIV] positive) pre- and post-DAA therapy (median follow-up 28 months). Changes in HbA1c and glucose were minimal and did not differ by sustained virologic response (SVR), HIV, diabetes, or fibrosis. Following SVR, mean change in HbA1c was -0.022 ± 0.53%; however, total and low-density lipoprotein cholesterol increased significantly. Subjects with HIV had smaller transaminase reductions after SVR. Sustained benefits in glycemia were not identified following HCV clearance irrespective of HIV, diabetes, or fibrosis stage, whereas lipid alterations may warrant further investigation.

HIV/HCV Co-infection: Overcoming Barriers to Treatment

A critical step in the eradication of hepatitis C virus (HCV) infection is access to effective therapy. With the advent of interferon‐free regimens, HCV providers and patients gained hope that the success seen in clinical trials could be translated to the real world. However, the exorbitant cost of the new direct‐acting antivirals limits access to these medications to the general HCV population, especially underserved patients with public insurance. We used a descriptive qualitative approach to detail the measures necessary and challenges faced by an inner‐city nursing team in Washington, DC to obtain the new direct‐acting antivirals. Significant time and dedication on the part of providers and staff was required to assist patients with the process of obtaining direct‐acting antivirals.