TURQUOISE-I Part 1b: Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir with Ribavirin for Hepatitis C Virus Infection in HIV-1 Coinfected Patients on Darunavir.

Background: Ombitasvir/paritaprevir/ritonavir with dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV) is approved for hepatitis C virus (HCV) genotype 1 (GT1) treatment in HIV-1 coinfected patients. In healthy controls, coadministration of OBV/PTV/r + DSV + darunavir (DRV) lowered DRV trough concentration (Ctrough) levels. To assess the clinical significance of this change, TURQUOISE-I, Part 1b, evaluated the efficacy and safety of OBV/PTV/r + DSV + RBV in coinfected patients on stable, DRV-containing antiretroviral therapy (ART). Methods: Patients were HCV treatment-naive or interferon-experienced, had CD4+ lymphocyte count ≥200 cells/µL or ≥14%, and plasma HIV-1 RNA suppression on once-daily (QD) DRV-containing ART at screening. Patients were randomized to maintain DRV 800 mg QD or switch to twice-daily (BID) DRV 600 mg; all received OBV/PTV/r + DSV + RBV for 12 weeks. Results: Twenty-two patients were enrolled and achieved SVR12. No adverse events led to discontinuation. Coadministration had minimal impact on DRV maximum observed plasma concentration and area under the curve; DRV Ctrough levels were slightly lower with DRV QD and BID. No patient experienced plasma HIV-1 RNA >200 copies/mL during treatment. Conclusions: HCV GT1/HIV-1 coinfected patients on stable DRV-containing ART achieved 100% SVR12 while maintaining plasma HIV-1 RNA suppression. Despite DRV exposure changes, episodes of intermittent HIV-1 viremia were infrequent.

Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial.

IMPORTANCE: Patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are at high risk for liver disease progression. However, interferon-based treatments for HCV infection have significant toxicities, limiting treatment uptake. OBJECTIVE: To assess the all-oral 3 direct-acting antiviral (3D) regimen of ombitasvir, paritaprevir (co-dosed with ritonavir [paritaprevir/r]), dasabuvir, and ribavirin in HCV genotype 1-infected adults with HIV-1 co-infection, including patients with cirrhosis. DESIGN, SETTING, AND PARTICIPANTS: TURQUOISE-I is a randomized, open-label study. Part 1a of this pilot study was conducted at 17 sites in the United States and Puerto Rico between September 2013 and August 2014 and included 63 patients with HCV genotype 1 and HIV-1 co-infection who were HCV treatment-naive or had history of prior treatment failure with peginterferon plus ribavirin therapy. The study allowed enrollment of patients, including those with cirrhosis, with a CD4+ count of 200/mm3 or greater or CD4+ percentage of 14% or more and plasma HIV-1 RNA suppressed while taking a stable atazanavir- or raltegravir-inclusive antiretroviral regimen. INTERVENTIONS: Ombitasvir/paritaprevir/r, dasabuvir, and ribavirin for 12 or 24 weeks of treatment as randomized. MAIN OUTCOMES AND MEASURES: The primary assessment was the proportion of patients with sustained virologic response (HCV RNA <25 IU/mL) at posttreatment week 12 (SVR12). RESULTS: Among patients receiving 12 or 24 weeks of 3D and ribavirin, SVR12 was achieved by 29 of 31 (94%; 95% CI, 79%-98%) and 29 of 32 patients (91%; 95% CI, 76%-97%), respectively. Of the 5 patients who did not achieve SVR, 1 withdrew consent, 2 had confirmed virologic relapse or breakthrough, and 2 patients had clinical history and phylogenetic evidence consistent with HCV reinfection. The most common treatment-emergent adverse events were fatigue (48%), insomnia (19%), nausea (18%), and headache (16%). Adverse events were generally mild, with none reported as serious or leading to discontinuation. No patient had a confirmed HIV-1 breakthrough of 200 copies/mL or greater during treatment. CONCLUSIONS AND RELEVANCE: In this open-label, randomized uncontrolled study, treatment with the all-oral, interferon-free 3D-plus-ribavirin regimen resulted in high SVR rates among patients co-infected with HCV genotype 1 and HIV-1 whether treated for 12 or 24 weeks. Further phase 3 studies of this regimen are warranted in patients with co-infection. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01939197.

Peginterferon alfa-2a plus ribavirin for HIV-HCV genotype 1 coinfected patients: a randomized international trial.

BACKGROUND: The safety and efficacy of weight-based ribavirin (RBV) dosing regimens in patients with HIV-HCV coinfection has not been demonstrated in randomized clinical trials. OBJECTIVE: This randomized, double-blind, international, parallel-group study in specialist outpatient clinics in the United States, Spain, and Portugal compares the efficacy and safety of 2 RBV dose regimens (800 mg/day and 1000/1200 mg/day) combined with peginterferon alfa-2a (40KD) in patients with HIV-HCV (genotype 1) coinfection. METHODS: Patients with HIV-HCV coinfection, quantifiable HCV RNA in serum, HCV genotype-1 infection, compensated liver disease, and stable HIV disease (CD4+ count ≥100 cells/µL) with or without ongoing antiretroviral therapy were randomized to 48 weeks' treatment with RBV at standard dose (800 mg/day) or weight-based dose (1000 mg/day for patients weighing <75 kg; 1200 mg/day for patients weighing ≥75 kg) in combination with peginterferon alfa-2a (40KD) 180 µg once a week. Planned enrollment was 400 patients with ≥100 non-Latino African Americans. The primary endpoint was sustained virological response (SVR) (undetectable HCV RNA [<20 IU/mL] at the end of a 24-week untreated follow-up period [week 72]). RESULTS: SVR rates were 19% (26/135) and 22% (60/275) in patients randomized to RBV 800 mg/day and 1000/1200 mg/day, respectively (odds ratio, 1.15; 95% CI, 0.68-1.93; P = .6119). In the 1000/1200 mg/day RBV dose group, the incidence of hemoglobin reductions <100 g/L and anaemia reported as an adverse event were higher versus the standard 800 mg/day RBV dose group. CONCLUSIONS: Compared with the standard RBV dose (800 mg/day), weight-based RBV dosing (1000/1200 mg/day) did not significantly increase SVR rates, but did increase the incidence of anemia in HIV-HCV (genotype 1) coinfected patients.

Once-daily nevirapine XR: a brief overview of the safety and efficacy of a new formulation.

Nevirapine (NVP) was the first nonnucleoside reverse transcriptase inhibitor (NNRTI) approved by the US Food and Drug Administration (FDA) in 1996, for the treatment of HIV infection. Current treatment guidelines include NVP as a component of a recommended alternative NNRTI regimen, which may be the preferred regimen for patients with established cardiovascular risk factors since NVP has minimal untoward effects on serum lipids. Two randomized and controlled clinical trials established the noninferior virologic efficacy of twice-daily NVP versus ritonavir-boosted atazanavir (ATV/r), a protease inhibitor with limited effects on serum lipids, each drug on a background regimen of once-daily (QD) tenofovir (TDF)/emtricitabine (FTC). An extended-release (XR) formulation of NVP was developed since QD dosing and reduced pill burdens have been shown to improve regimen adherence. This formulation (Viramune XR 400 mg) was recently FDA approved based on the results of 2 randomized, controlled clinical trials. The XR formulation will provide additional treatment options for patients who may benefit from NVP-based regimens.

Provider and patient correlates of provider decisions to recommend HCV treatment to HIV co-infected patients.

Despite low uptake of hepatitis C virus (HCV) treatment among HIV co-infected patients, few studies have examined the factors that contribute to provider decisions to recommend treatment. Surveys of 173 co-infected patients and their primary care providers, as well as patient chart data, were collected at 3 HIV clinics in Los Angeles; 73% of the patients had any history of being recommended HCV treatment. Multivariate predictors of being offered treatment included being Caucasian, greater HCV knowledge, receiving depression treatment if depressed, and one's provider having a lower weekly patient load and more years working at the study site. These findings suggest that provider decisions to recommend HCV treatment are influenced by patient factors including race and psychosocial treatment readiness, as well as characteristics of their own practice and treatment philosophy. With changes to HCV treatment soon to emerge, further evaluation of factors influencing treatment decisions is needed to improve HCV treatment uptake.

Simplification to abacavir/lamivudine + atazanavir maintains viral suppression and improves bone and renal biomarkers in ASSURE, a randomized, open label, non-inferiority trial.

OBJECTIVE: Simplification of antiretroviral therapy in patients with suppressed viremia may minimize long-term adverse effects. The study's primary objective was to determine whether abacavir/lamivudine + atazanavir (ABC/3TC+ATV) was virologically non-inferior to tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC+ATV/r) over 24 weeks in a population of virologically suppressed, HIV-1 infected patients. DESIGN: This open-label, multicenter, non-inferiority study enrolled antiretroviral experienced, HIV-infected adults currently receiving a regimen of TDF/FTC+ATV/r for ≥ 6 months with no history of virologic failure and whose HIV-1 RNA had been ≤ 75 copies/mL on 2 consecutive measurements including screening. Patients were randomized 1 ∶ 2 to continue current treatment or simplify to ABC/3TC+ATV. METHODS: The primary endpoint was the proportion of patients with HIV-RNA<50 copies/mL at Week 24 by the Time to Loss of Virologic Response (TLOVR) algorithm. Secondary endpoints included alternative measures of efficacy, adverse events (AEs), and fasting lipids. Exploratory endpoints included inflammatory, coagulation, bone, and renal biomarkers. RESULTS: After 24 weeks, ABC/3TC+ATV (n = 199) was non-inferior to TDF/FTC+ATV/r (n = 97) by both the primary analysis (87% in both groups) and all secondary efficacy analyses. Rates of grade 2-4 AEs were similar between the two groups (40% vs 37%, respectively), but an excess of hyperbilirubinemia made the rate of grade 3-4 laboratory abnormalities higher in the TDF/FTC+ATV/r group (30%) compared with the ABC/3TC+ATV group (13%). Lipid levels were stable except for HDL cholesterol, which increased significantly in the ABC/3TC+ATV group. Bone and renal biomarkers improved significantly between baseline and Week 24 in patients taking ABC/3TC+ATV, and the difference between groups was significant at Week 24. No significant changes occurred in any inflammatory or coagulation biomarker within or between treatment groups. CONCLUSIONS: After 24 weeks, simplification to ABC/3TC+ATV from TDF/FTC+ATV/r maintained viral suppression was well-tolerated, and led to improvements in bone and renal biomarkers and HDL cholesterol. TRIAL REGISTRATION: ClinicalTrials.gov NCT01102972 GlaxoSmithKline Clinical Study Register #113734.

Patient and provider characteristics associated with the decision of HIV coinfected patients to start hepatitis C treatment.

Hepatitis C (HCV) and HIV coinfection is common and liver disease is a leading cause of morbidity and mortality among coinfected patients. Despite advances in HCV treatment, few HIV coinfected patients actually initiate treatment. We examined patient and provider characteristics associated with a patient's decision to accept or refuse HCV treatment once offered. We conducted patient chart abstraction and surveys with 127 HIV coinfected patients who were offered HCV treatment by their provider and surveys of their HCV care providers at three HIV clinics. Participants were mostly male (87%), minority (66%), and had a history of injection drug use (60%). Most had been diagnosed with HIV for several years (X=13.7 years) and reported HIV transmission through unprotected sex (47%). Of the 127 patients, 79 accepted treatment. In multivariate analysis, patients who had a CD4 greater than 200 cells/mm(3) and a provider with more confidence about HCV treatment were more likely to accept the recommendation to start treatment; younger age was marginally associated with treatment acceptance. In bivariate analysis, added correlates of treatment acceptance included male gender, no recent drug use, and several provider attitudes regarding treatment and philosophy about determination of patient treatment readiness. Patient and provider characteristics are important when understanding a patient's decision to start or defer HCV treatment. Further research is needed to better understand barriers to treatment uptake as new and more effective HCV treatments will soon be available.

Patient Characteristics Associated with HCV Treatment Adherence, Treatment Completion, and Sustained Virologic Response in HIV Coinfected Patients.

Background. Hepatitis C (HCV) treatment efficacy among HIV patients is limited by poor treatment adherence and tolerance, but few studies have examined the psychosocial determinants of treatment adherence and outcomes. Methods. Chart abstracted and survey data were collected on 72 HIV patients who had received pegylated interferon and ribavirin to assess correlates of treatment adherence, completion, and sustained virologic response (SVR). Results. Nearly half (46%) the sample had active psychiatric problems and 13% had illicit drug use at treatment onset; 28% reported <100% treatment adherence, 38% did not complete treatment (mostly due to virologic nonresponse), and intent to treat SVR rate was 49%. Having a psychiatric diagnosis was associated with nonadherence, while better HCV adherence was associated with both treatment completion and SVR. Conclusions. Good mental health may be an indicator of HCV treatment adherence readiness, which is in turn associated with treatment completion and response, but further research is needed with new HCV treatments emerging.

Susceptibility of HIV-1 to tipranavir and other antiretroviral agents in treatment-experienced patients: The UTILIZE Study.

OBJECTIVES: The primary objective was to assess HIV-1 susceptibility to the protease inhibitor (PI) tipranavir and other antiretroviral (ARV) agents among treatment-experienced patients (TEP). Secondarily, clinicians' use of resistance testing was examined. METHODS: UTILIZE was an observational study conducted at 40 sites in the United States. Patients currently failing a PI-based regimen were randomized to receive either a genotype (GT) or combined phenotype-genotype test (PGT) and a treatment decision was made at the second study visit. RESULTS: 246 patients enrolled, 236 had resistance test results, and 139 (59%) had evidence of HIV-1 resistance to >or=1 PI. Among these 139 patients, more than 50% had viruses that remained sensitive to tipranavir and darunavir, whereas susceptibility to other PIs was markedly lower (<22%). Increasing prior PI exposure was associated with reduced susceptibility to most ARV agents. After obtaining resistance test results, 83% of patients changed therapy. Newly available or investigational ARVs were used frequently. The reason investigators most often cited for changing therapy was the patient resistance test results (82%) and the most common reason for not changing therapy was the inability to construct an active regimen. The majority of patients who exhibited PI resistance received two or more active agents in the new regimen. CONCLUSIONS: Overall, 59% of TEPs failing a PI-based regimen had HIV-1 with PI resistance. The majority of these patients' viruses remained sensitive to either tipranavir or darunavir. Investigators used results from resistance assays to construct a new regimen, frequently with newer agents. In PI-experienced patients, tipranavir and darunavir remain the most likely available active PIs.

Treat early or wait and monitor? A qualitative analysis of provider hepatitis C virus treatment decision-making in the context of HIV coinfection.

Liver disease is a leading cause of death among patients with HIV coinfected with hepatitis C (HCV); yet, studies show that less than 10% receive HCV treatment, in part because of limited treatment response, high treatment toxicity, and psychosocial barriers to treatment readiness. Using a process model framework, we sought to explore the factors and processes by which providers make HCV treatment decisions for HIV-coinfected patients. We conducted 22 semistructured interviews with primary care providers and support staff at three HIV clinics in Los Angeles, California, in which rates of HCV treatment uptake varied from 10% to 38%. Providers agreed that stable HIV disease, favorable genotype, and significant signs of liver disease progression are all signs of need for treatment. However, two divergent treatment approaches emerged for genotype 1 and 4 patients with minimal disease, and in definitions of patient readiness. Providers with lower treatment rates preferred to delay treatment in hopes of better future treatment options, and were more conservative in requiring complete mental health screens and treatment and abstinence from substance use. Conversely, providers with higher treatment rates viewed all patients as needing treatment as soon as possible, and defined readiness more leniently, with some willing to treat even in the context of untreated depression and drug use, so long as ability to adhere well was demonstrated. Regardless of whether an aggressive or cautious approach to treatment is used, development of effective programs for promoting patient treatment readiness is critical to ensuring greater treatment uptake.

Factors that influence an HIV coinfected patient's decision to start hepatitis C treatment.

Liver disease is a leading cause of morbidity and mortality among patients coinfected with HIV and hepatitis C (HCV), yet few HIV coinfected patients actually receive HCV treatment. Providers must first be willing to prescribe treatment, but the patient ultimately makes the decision to accept or decline a treatment recommendation. We used a process model framework to explore the factors influencing patients' treatment decision-making. We conducted semistructured interviews with 35 HIV coinfected patients and 11 primary care providers at three HIV clinics in Los Angeles, California. Patients reported that stability of HIV disease, perceived need for HCV treatment, treatment readiness, willingness to deal with side effects, absence of substance abuse, and stability of mental health and overall life circumstances are key factors influencing treatment decision-making. Patients also spoke of the influence of the trusting relationship that many had with their provider, and providers acknowledged an awareness of the influence of how they present the risks and benefits of HCV treatment and the overall tone of their recommendation (encouraging, dissuasive, or neutral). These results speak to a social decision-making process between the patient and provider-a partnership that involves sequential interactions whereby both the patient and provider may influence the other's evaluation of the patient's readiness for treatment, with treatment initiation dependent on both agreeing on the need for treatment and the patient's readiness for treatment.