Effects of once-daily darunavir/ritonavir versus atazanavir/ritonavir on insulin sensitivity in HIV-infected persons over 48 weeks: results of an exploratory substudy of METABOLIK, a phase 4, randomized trial.

BACKGROUND: The phase 4, METABOLIK trial demonstrated that changes in metabolic parameters with darunavir with low-dose ritonavir (DRV/r) were comparable to those observed with atazanavir with low-dose ritonavir (ATV/r). A comprehensive assessment of the effects of these agents on insulin sensitivity will provide additional, relevant clinical information. METHODS: In this substudy of METABOLIK, HIV-1-infected, antiretroviral agent-naïve male subjects aged ≥18 years with a viral load of >1,000 copies/mL were randomized to receive DRV/r 800/100 mg once daily (qd) or ATV/r 300/100 mg qd, both with a fixed dose of tenofovir disoproxil fumarate/emtricitabine 300/200 mg qd. The effects of DRV/r versus ATV/r on insulin sensitivity over 48 weeks were compared using the euglycemic hyperinsulinemic clamp, the preferred method to assess insulin sensitivity; primary end point was the effect on insulin sensitivity during the first 12 weeks. RESULTS: Twenty-seven subjects completed the study. In the DRV/r arm (n=14), median glucose disposal from baseline through weeks 12 and 48 was 9.3, 11.4, and 9.9 mg/kg*min, respectively; in the ATV/r arm (n=13), these values were 8.9, 8.6, and 9.1 mg/kg*min, respectively. Median insulin sensitivity in the DRV/r arm at baseline, week 12, and week 48 was 24.0, 25.0, and 21.5 mg/kg*min per µIU/mL×100, respectively; these values in the ATV/r arm were 20.7, 22.0, and 22.0 mg/kg*min per µIU/mL×100, respectively. Most subjects had ≥1 adverse event, including three serious adverse events (n=2 [DRV/r], n=1 [ATV/r]). CONCLUSIONS: DRV/r and ATV/r displayed similar modest effects on insulin sensitivity using a euglycemic hyperinsulinemic clamp.

Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257.

BACKGROUND: Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24). METHODS: Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression. RESULTS: Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1). CONCLUSIONS: Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation. CLINICAL TRIALS REGISTRATION: NCT 00811954.

Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial.

BACKGROUND: Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons. OBJECTIVE: To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability. DESIGN: A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954). SETTING: 57 sites in the United States and Puerto Rico. PATIENTS: Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors. INTERVENTION: Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d. MEASUREMENTS: Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability. RESULTS: Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir. LIMITATION: The trial was open-label, and ritonavir was not provided. CONCLUSION: Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

HIV testing practices among black primary care physicians in the United States.

BACKGROUND: The Centers for Disease Control and Prevention recommends routine HIV testing in all healthcare settings, but it is unclear how consistently physicians adopt the recommendation. Making the most of each interaction between black physicians and their patients is extremely important to address the HIV health disparities that disproportionately afflict the black community. The goal of this survey-based study was to evaluate the perceptions and practices of black, primary care physicians regarding HIV testing. METHODS: A physician survey was administered at the 2010 National Medical Association Annual Convention, via online physician panels, and by email. Physician eligibility criteria: black race; practicing at least 1 year in the US; practice comprised of at least 60% adults and 20% black patients. Contingency tables and ordinary least squares regression were used for comparisons and statistical analyses. A Chi-square test compared percentages of physicians who gave a particular response and a t-test compared the means of values provided by physicians. RESULTS: Physicians over-estimated HIV prevalence and believed that HIV is a crisis in the black community, yet reported that only 34% of patients were HIV tested in the past year. Physicians reported that 67% of those patients tested did so due to a physician recommendation. Physicians who were younger, female, obstetricians/gynecologists, and had a higher proportion of black, low-socioeconomic status, and Medicaid patients reported higher testing rates. Most testing was risk-based rather than routine, and three of the five most commonly reported barriers to testing were related to disease stigma and perceived value judgments. Physicians reported that in-office patient informational materials, increased media attention, additional education and training on HIV testing, government mandates requiring routine testing, and accurate pre-packed tests would most help them test more frequently for HIV. CONCLUSIONS: In this sample of black, primary care physicians, HIV testing practices differed according to physician characteristics and practice demographics, and overall reported testing rates were low. More physician education and training around testing guidelines is needed to enable more routine testing, treatment, and long-term management of patients with HIV.