The Design of Single-Arm Clinical Trials of Combination Antiretroviral Regimens for Treatment-Naive HIV-Infected Patients

Single-arm clinical trials are useful to evaluate antiretroviral regimens in certain populations of HIV-infected treatment-naive patients for whom a randomized controlled trial is not feasible or desirable. They can also be useful to establish initial estimates of efficacy and safety/tolerability of novel regimens to inform the design of large phase III trials. In this article, we discuss key design considerations for such single-arm studies

Boceprevir and Antiretroviral Pharmacokinetic Interactions in HIV/HCV Co-infected Persons: AIDS Clinical Trials Group Study A5309s

Objective: The objective of this study was to determine the magnitude of drug interactions between the hepatitis C virus (HCV) protease inhibitor boceprevir (BOC) and antiretroviral (ARV) agents in persons with HIV/HCV co-infection. Methods: Participants taking two nucleos(t)ide analogs with either efavirenz, raltegravir, or ritonavir-boosted atazanavir, darunavir, or lopinavir underwent intensive pharmacokinetic (PK) sampling for ARV 2 weeks before (week 2) and 2 weeks after initiating BOC (week 6) and for BOC at week 6. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare ARV PK at weeks 2 and 6 and BOC PK at week 6 to historical data (HD) in healthy volunteers and HCV mono-infected patients. Results: ARV PK was available for 55 participants. BOC reduced atazanavir and darunavir exposures by 30 and 42%, respectively. BOC increased raltegravir maximum concentration (C max) by 71%. BOC did not alter efavirenz PK. BOC PK was available for 53 participants. BOC exposures were similar in these HIV/HCV co-infected participants compared with HD in healthy volunteers, but BOC minimum concentrations (C min) were lower with all ARV agents (by 34–73%) compared with HD in HCV mono-infected patients. Conclusions: Effects of BOC on ARV PK in these HIV/HCV co-infected individuals were similar to prior studies in healthy volunteers. However, some differences in the effects of ARV on BOC PK were observed, indicating the magnitude of interactions may differ in HCV-infected individuals versus healthy volunteers. Findings highlight the need to conduct interaction studies with HCV therapies in the population likely to receive the combination

Dynamics of Immune Reconstitution and Activation Markers in HIV+ Treatment-Naïve Patients Treated with Raltegravir, Tenofovir Disoproxil Fumarate and Emtricitabine

Background: The dynamics of CD4+ T cell reconstitution and changes in immune activation and inflammation in HIV-1 disease following initiation of antiretroviral therapy (ART) are incompletely defined and their underlying mechanisms poorly understood. Methods: Thirty-nine treatment-naïve patients were treated with raltegravir, tenofovir DF and emtricitabine. Immunologic and inflammatory indices were examined in persons with sustained virologic control during 48 weeks of therapy. Results: Initiation of ART increased CD4+ T cell numbers and decreased activation and cell cycle entry among CD4+ and CD8+ T cell subsets, and attenuated markers of coagulation (D-dimer levels) and inflammation (IL-6 and TNFr1). These indices decayed at different rates and almost all remained elevated above levels measured in HIV-seronegatives through 48 weeks of viral control. Greater first and second phase CD4+ T cell restoration was related to lower T cell activation and cell cycling at baseline, to their decay with treatment, and to baseline levels of selected inflammatory indices, but less so to their changes on therapy. Conclusions: ART initiation results in dynamic changes in viral replication, T cell restoration, and indices of immune activation, inflammation, and coagulation. These findings suggest that determinants of T cell activation/cycling and inflammation/coagulation may have distinguishable impact on immune homeostasis. Trial Registration Clinicaltrials.gov NCT0066097

Comparison of Once‐Daily versus Twice‐Daily Combination Antiretroviral Therapy in Treatment‐Naive Patients: Results of AIDS Clinical Trials Group (ACTG) A5073, a 48‐Week Randomized Controlled Trial

Dosing frequency is an important determinant of regimen effectiveness

Phase I/II Trial of the Anti-HIV Activity of Mifepristone in HIV-Infected Subjects ACTG 5200

Mifepristone is a glucocorticoid receptor inhibitor shown in vitro to have anti-HIV activity and anti-simian immunodeficiency virus activity in a macaque model. A phase I/II trial was performed to assess the drug’s safety and anti-HIV activity

Program manager perspectives on the service system to meet the needs of youth with concurrent disorders: findings from a Canadian national survey

Abstract Background Concurrent mental health and substance use issues are a serious problem for adolescents and transition-aged youth. Service providers across sectors must be involved in informing system change to meet youth needs. This study examines stakeholder perspectives on services for youth with concurrent disorders including 1) clinical issues in youth services; 2) priority system issues; and 3) optimal knowledge translation strategies to enhance researcher-stakeholder communication. Methods A database of youth clinical services across Canada was developed. Program managers (n = 481) at cross-sectoral (mental health, addictions, justice, child welfare, advocacy, and outreach) youth-serving (aged 12–24) programs were invited to complete an online survey; 232 responded. Survey questions concerned youth needs, program characteristics, priorities for service system enhancement; and usual and preferred knowledge translation methods. Results Across service sectors, the mean estimated proportion of youth using services with concurrent mental health and substance use problems was 55 %. Program managers reported routine screening for mental health and substance use concerns (66 %), referring to other agencies to meet the concurrent disorder needs of youth (54 %), offering specific programming for concurrent disorders (42 %), and program evaluation (48 %). Notably, mental health programs were significantly less likely to offer concurrent disorders services than addictions programs. Where services do exist, most are targeted at youth aged 12–18 years, with fewer services available for transition-aged youth. Endorsement of various system change goals exceeded 80 %, with a particular emphasis on improving access to services (49 %), ensuring a continuum of services for varying levels of severity (37 %), and improved integration across sectors (36 %). Preferred knowledge exchange methods were workshops and websites for receiving information; and focus groups or surveys, rather than intensive participation on research teams, to inform research. Conclusions There is a high need to build capacity across most sectors for meeting the needs of youth with co-occurring mental health and substance use problems, especially for transition-aged youth. In addition, limits in program evaluation should be addressed. Innovative knowledge exchange strategies are needed to better meet the needs of youth with concurrent disorders. Although service providers expressed readiness to participate in service enhancement and knowledge translation activities, effective, feasible approaches must integrate strategies likely to result in desired clinical outcomes, given clinical workload challenges

The Design of Single-Arm Clinical Trials of Combination Antiretroviral Regimens for Treatment-Naive HIV-Infected Patients

Single-arm clinical trials are useful to evaluate antiretroviral regimens in certain populations of HIV-infected treatment-naive patients for whom a randomized controlled trial is not feasible or desirable. They can also be useful to establish initial estimates of efficacy and safety/tolerability of novel regimens to inform the design of large phase III trials. In this article, we discuss key design considerations for such single-arm studies