A Pragmatic, Randomized Controlled Trial of Oral Antivirals for the Treatment of Chronic Hepatitis C: The PRIORITIZE Study.

BACKGROUND AND AIMS: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. APPROACH AND RESULTS: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. CONCLUSIONS: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.

HIV testing in patients who are HCV positive: Compliance with CDC guidelines in a large healthcare system.

BACKGROUND: There are approximately 300,000 people in the United States who are co-infected with HIV and HCV. Several organizations recommend that individuals who are HCV infected, as well as persons over the age of 13, should be HIV tested. Comorbidities associated with HCV can be reduced with early identification of HIV. Our objective was to determine whether providers routinely followed HIV testing guidelines for patients who tested HCV positive (HCV+). METHODS: A retrospective chart review was conducted of all patients in primary care at an academic health system from 7/2015-3/2017 who tested HCV+. As part of a primary database, HCV testing data was collected; HIV testing data was abstracted manually. We collected and described the intervals between HCV and HIV tests. To determine associations with HIV testing univariable and multivariable analyses were performed. RESULTS: We identified 445 patients who tested HCV+: 56.6% were tested for HIV, the mean age was 57 ± 10.9 years, 77% were from the Birth Cohort born 1945-1965 (BC); 61% were male; and 51% were Black/AA. Patients in the BC were more likely to be HIV tested if they were: male (p = 0.019), Black/AA (p<0.001), and had Medicaid (p = 0.005). These differences were not found in the non-BC. Six patients who were tested for both HIV and HCV were found to be newly HIV positive at the time of testing. CONCLUSION: As demonstrated, providers did not routinely follow CDC recommendations as almost half of the HCV+ patients were not correctly tested for HIV. It is important to emphasize that six persons were tested HIV positive simultaneously with their HCV+ diagnosis. If providers did not follow the CDC guidelines, then these patients may not have been identified. Improvements in EHR clinical decision support tools and provider education can help improve the HIV testing rate among individuals who are HCV+.

Leveraging the electronic health record to eliminate hepatitis C: Screening in a large integrated healthcare system.

Highly efficacious and tolerable treatments that cure hepatitis C viral (HCV) infection exist today, increasing the feasibility of disease elimination. However, large healthcare systems may not be fully prepared for supporting recommended actions due to knowledge gaps, inadequate infrastructure and uninformed policy direction. Additionally, the HCV cascade of care is complex, with many embedded barriers, and a significant number of patients do not progress through the cascade and are thus not cured. The aim of this retrospective cohort study was to evaluate a large healthcare system's HCV screening rates, linkage to care efficiency, and provider testing preferences. Patients born during 1945-1965, not previously HCV positive or tested from within the Electronic Health Record (EHR), were identified given that three-quarters of HCV-infected persons in the United States are from this Birth Cohort (BC). In building this HCV testing EHR prompt, non-Birth Cohort patients were excluded as HCV-specific risk factors identifying this population were not usually captured in searchable, structured data fields. Once completed, the BC prompt was released to primary care locations. From July 2015 through December 2016, 11.5% of eligible patients (n = 9,304/80,556) were HCV antibody tested (anti-HCV), 3.8% (353/9,304) anti-HCV positive, 98.1% (n = 311/317) HCV RNA tested, 59.8% (n = 186/311) HCV RNA positive, 86.6% (161/186) referred and 76.4% (n = 123/161) seen by a specialist, and 34.1% (n = 42/123) cured of their HCV. Results from the middle stages of the cascade in this large healthcare system are encouraging; however, entry into the cascade-HCV testing-was performed for only 11% of the birth cohort, and the endpoint-HCV cure-accounted for only 22% of all infected. Action is needed to align current practice with recommendations for HCV testing and treatment given that these are significant barriers toward elimination.

Use of direct-acting antivirals for hepatitis C viral infection and association with intrahepatic cholangiocarcinoma: Is there a linkage?

Hepatitis C viral infection is recognized worldwide as a leading cause of cirrhosis and hepatocellular carcinoma. The goal of hepatitis C viral antiviral therapy is the permanent eradication of hepatitis C viral RNA, commonly referred to as a sustained virologic response - defined as "undetectable" RNA at 12 weeks following the completion of therapy. Hepatitis C viral treatment has dramatically advanced with the FDA approval of several new agents known as direct-acting antivirals. These drugs target specific nonstructural proteins of the virus, which disrupt viral replication, and therefore halt infection. However, recently, there has been a concern for increased risk of recurrence of treated hepatocellular carcinoma or denovo occurrence of hepatocellular carcinoma after treatment with direct-acting antivirals. We are now reporting three cases of intrahepatic cholangiocarcinoma that developed after sustained virologic response following hepatitis C viral treatment with direct-acting antivirals.

High Hepatitis C Infection Rate Among Baby Boomers in an Urban Primary Care Clinic: Results from the HepTLC Initiative.

OBJECTIVE: CDC recommends that all people born between 1945 and 1965 be tested for hepatitis C virus (HCV). We hypothesized that HCV testing in a large, urban primary care clinic would reveal higher rates of HCV infection than previously published. METHODS: Through the Hepatitis Testing and Linkage to Care initiative, the primary care clinic at MedStar Washington Hospital Center in Washington, DC, provided HCV antibody (anti-HCV) testing and linkage to care from October 2012 through September 2013 for patients born between 1945 and 1965 without previously noted risk factors. We collected data on age, race/ethnicity, sex, anti-HCV and HCV ribonucleic acid (RNA) results, risk factors in those who tested anti-HCV positive, and health insurance type and made comparisons using c(2) and Student's t-tests. RESULTS: Of 1,123 patients tested, the mean age was 57 years, 742 (66.1%) were women, 969 (86.3%) were black/African American, and 654 (58.2%) had public health insurance. Of the 99 (8.8%) patients who tested anti-HCV positive, the mean age was 58 years, 54 were men, and 93 were black/African American; 41 of 74 anti-HCV-positive patients were intravenous drug users. Of 82 anti-HCV-positive patients, 51 were HCV RNA positive. Of the black/African American patients tested, 49 of 317 men (15.5%) and 44 of 652 women (6.7%) were anti-HCV positive (p,0.001). The HCV prevalence rate in the birth cohort (8.8%) was significantly higher than the U.S. (3.3%) and DC (2.5%) rates (p,0.001), and the HCV prevalence rate among black/African American men in DC (15.5%) was substantially higher than the prevalence rate reported by CDC (8.1%). CONCLUSION: Testing initiatives in primary care settings need to be more rigorously upheld, and internal champions are needed to advocate for increased screening to ensure linkage to care and engagement in the HCV care cascade.

Effects of Angiotensin Converting Enzyme Inhibitors on Liver Fibrosis in HIV and Hepatitis C Coinfection.

Background. Liver fibrosis is accelerated in HIV and hepatitis C coinfection, mediated by profibrotic effects of angiotensin. The objective of this study was to determine if angiotensin converting enzyme inhibitors (ACE-Is) attenuate liver fibrosis in coinfection. Methods. A retrospective review of 156 coinfected subjects was conducted to analyze the association between exposure to ACE-Is and liver fibrosis. Noninvasive indices of liver fibrosis (APRI, FIB-4, Forns indices) were compared between subjects who had taken ACE-Is and controls who had not taken them. Linear regression was used to evaluate ACE-I use as an independent predictor of fibrosis. Results. Subjects taking ACE-Is for three years were no different than controls on the APRI and the FIB-4 but had significantly higher scores than controls on the Forns index, indicating more advanced fibrosis. The use of ACE-Is for three years remained independently associated with an elevated Forns score when adjusted for age, race, and HIV viral load (P < 0.001). There were significant associations between all of the indices and significant fibrosis, as determined clinically and radiologically. Conclusions. There was not a protective association between angiotensin inhibition and liver fibrosis in coinfection. These noninvasive indices may be useful for ruling out significant fibrosis in coinfection.

Low rates of hepatitis A and B vaccination in patients with chronic hepatitis C at an urban methadone maintenance program.

Patients with chronic hepatitis C virus (HCV) are at increased risk for complications of liver disease if they become infected with the hepatitis A (HAV) or hepatitis B (HBV) viruses. The authors examined the rates of testing for HAV, HBV, and HCV, as well as rates of vaccination against HAV and HBV in patients with chronic HCV in a random sample (N = 207) of medical records of patients enrolled in a methadone maintenance program. Almost all patients reviewed were tested for HAV, HBV, and HCV. Of the 111 patients with chronic HCV, 53 (48.6%) and 68 (63%) lacked immunity to HAV and HBV, respectively. Of those lacking immunity, 29 (54.7%) and 2 (2.9%) were vaccinated for HAV and HBV, respectively. Despite high rates of testing for HAV, HBV, and HCV at a methadone maintenance program, approximately half of those with chronic HCV eligible for the HAV vaccine received it, and few of those eligible for HBV vaccine received it.

Prevalence and patient awareness of medical comorbidities in an urban AIDS clinic.

Mortality in HIV-positive persons is increasingly due to non-HIV-related medical comorbidities. There are limited data on the prevalence and patient awareness of these comorbid conditions. Two hundred subjects at an urban HIV clinic were interviewed in 2005 to assess their awareness of 15 non-HIV-related medical comorbidities, defined as medical problems that are neither AIDS-defining by standard definitions, nor a direct effect of immune deficiency. Medical charts were subsequently reviewed to establish prevalence and concordance between self-report and chart documentation. Eighty-four percent of subjects self-reported at least 1 of 15 medical comorbidities and 92% had at least 1 condition chart-documented. The top 5 chart-documented conditions were hepatitis C (51.5%), pulmonary disease (28.5%), high blood pressure (27%), high cholesterol (24.5%), and obesity (22.5%). In multivariate analysis, higher number of non-HIV-related medical comorbidities was associated with older age, female gender, and intravenous drug use as route of HIV transmission. Across self-reported non-HIV-related medical comorbidities, the absolute concordance rate ranged from 67% to 96%, the sensitivity ranged from 0% to 79%; the positive predictive value ranged from 0% to 100%. While the vast majority of largely urban minority HIV-positive subjects were diagnosed with non-HIV-related medical comorbidities, there is significant room for improvement in patient awareness. In order to help patients optimally access and adhere to medication and medical care for these non-HIV-related medical comorbidities, interventions and educational campaigns to improve patient awareness that take cultural background, literacy, and educational level into account should be developed, implemented, and evaluated.

Chronic kidney disease in HIV infection: an urban epidemic.

Kidney disease is an important complication of HIV, particularly in minority populations. We describe the burden of chronic kidney disease among 1239 adults followed at an urban AIDS center, with an estimated prevalence of 15.5% (n = 192). Independent predictors of kidney disease included older age, black race, hepatitis C virus exposure, and lower CD4 cell count. These data suggest that chronic kidney disease remains a common complication of HIV infection in the era of antiretroviral therapy.

Predictors of hepatitis C virus RNA levels in a prospective cohort study of drug users.

High levels of hepatitis C virus (HCV) RNA are associated with a poor response to treatment of chronic hepatitis C, and a substantial reduction in HCV RNA levels predicts a favorable treatment response. We prospectively studied time-dependent and time-independent predictors of HCV RNA levels in 264 drug users with chronic HCV infection. Interviews on medical history and high-risk behaviors, phlebotomy for HIV viral load, serum HCV RNA levels as measured by the COBAS Amplicor HCV Monitor (Roche Diagnostics, Branchburg, NJ), and a lymphocyte subset assay were performed. Factors associated with HCV RNA levels over time were analyzed using a linear mixed model. Nearly 70% of the participants were men, two thirds were Hispanic, and the mean age was 46 years. HCV RNA levels increased over time. Older age (P < 0.001), HIV seropositivity (P = 0.03), and HCV nongenotype 1 (P = 0.05) were predictors of higher HCV RNA levels on multivariate analysis. Among 142 HIV-seropositive participants, a detectable HIV-1 viral load (P < 0.001) and recent alcohol use (P = 0.02) were predictors of higher HCV RNA levels. The predictors of higher HCV RNA levels found in this longitudinal study are consistent with those of prior cross-sectional studies. Further studies are warranted to determine if treatment of alcohol use affects HCV RNA levels.

Factors associated with successful referral for clinical care of drug users with chronic hepatitis C who have or are at risk for HIV infection.

The objective of this study was to determine outcomes of referring drug users (DUs) with chronic hepatitis C for clinical evaluation and care. Two hundred twenty-eight persons with detectable hepatitis C virus RNA were given expedited referrals for evaluation and possible treatment of hepatitis C from a prospective study cohort of current and former opiate-addicted DUs. Four outcomes were analyzed: accepted referral, arrived for clinical evaluation, had liver biopsy, and received treatment. One hundred twenty-seven participants (56%) accepted referral, of whom 54 (43%) arrived for evaluation. Of these participants, 12 (22%) had liver biopsy, and 4 (7%) were treated. Multivariate logistic regression revealed that HIV-infected DUs were significantly less likely to accept referral (adjusted odds ratio [O(Radj)], 0.51; 95% confidence interval [CI], 0.30-0.88), and older participants were more likely to keep an appointment (O(Radj), 1.06/y; 95% CI, 1.00-1.12). Of HIV-seropositive participants, those with a history of injection were more likely to accept referral (O(Radj), 3.60; 95% CI, 1.08-11.96), and those with higher HIV load (O(Radj), 0.50/log10; 95% CI, 0.26-0.94) and Hispanic ethnicity (O(Radj), 0.26; 95% CI, 0.07-0.89) were less likely to keep an appointment. Despite expedited referrals for hepatitis C care, only a few participants received an evaluation, and even far fewer were treated. Because increasingly effective treatment is available, better methods are urgently needed to improve evaluation and treatment of HCV-infected DUs, including those coinfected with HIV.