An open-label, randomized comparative pilot study of a single-class quadruple therapy regimen versus a 2-class triple therapy regimen for individuals initiating antiretroviral therapy.

OBJECTIVE: To examine the antiviral potency and tolerability profile of a single-class four drug (quadruple) nucleoside reverse transcriptase inhibitor (NRTI) regimen compared with a 2-class standard-of-care regimen. METHODOLOGY: A three-centre, randomized, open-label comparative pilot study of zidovudine/lamivudine/efavirenz (triple) versus abacavir/lamivudine/zidovudine/tenofovir (quadruple) therapy in HIV-1-infected, treatment-naive individuals. Both regimens were taken without regard to food and consisted of a twice-daily regimen and 3 pills/day. The study power was based on time-weighted average changes in HIV-1 RNA load. RESULTS: A total of 114 individuals (56 triple, 57 quadruple) received at least one dose of medication. Patients were well matched at baseline for viral load (mean 5.26 log10 versus 5.13 log10, respectively) and CD4 cell count (median 193 versus 153 cells/mm3, respectively). The two regimens performed similarly with regards to all endpoints. At week 48, by intention-to-treat, missing=failure analysis, 68% of triple- and 67% of quadruple-drug treated patients had an HIV-1 RNA <50copies/ml (P>0.05). On-treatment analysis showed 40/40 (100%) of triple- and 39/40 (97.5%) of quadruple-drug treated patients (P=0.996) had responded to <50copies/ml. No unexpected adverse events were reported. Changes in total cholesterol and triglycerides were modest but significantly favoured the quadruple therapy regimen at multiple time points. CONCLUSION: This pilot study suggests a quadruple NRTI-based regimen provides similar antiviral potency, tolerability and administrative characteristics to a 2-class triple therapy regimen. These findings should be confirmed in a more fully powered study. Potent quadruple NRTI-based regimens may have advantages for some individuals with regards to salvageability, tolerability and drug interactions.

Short Communication: The Impact of Switching from Atripla to Darunavir/Ritonavir Monotherapy on Neurocognition, Quality of Life, and Sleep: Results from a Randomized Controlled Study.

We investigated whether a treatment switch from Atripla® (tenofovir, emtricitabine, and efavirenz) to DRV/r monotherapy may improve neuropsychological performance, health-related quality of life, and sleep function. Virologically suppressed subjects and asymptomatic on Atripla for ≥6 months were randomized 1:1 to continue Atripla or switch to boosted darunavir (DRV/r) 800/100 mg once daily for 48 weeks. Neurocognitive tests, the International HIV Dementia Scale (IHDS), Medical Outcomes Study HIV Health Survey (MOS-HIV), EQ-5D-3L, and the Hospital Anxiety and Depression Scale (HADS) were completed at baseline and at week 48. Sleep function was evaluated at week 48. Twenty-six patients on DRV/r and 31 on Atripla completed the 48-week study. No significant difference in the change in scores from week 0 to week 48 between the two arms was observed in neurocognitive outcomes, IHDS, health outcomes (EQ-5D-3L and QOL), and HADS score. By contrast, the HADS score and sleep quality were both significantly better in the DRV/r arm. In conclusion, switching to DRV/r monotherapy did not affect neurocognitive function or quality of life but improved anxiety, and sleep quality was significantly better than in continued Atripla.

Effects on vitamin D, bone and the kidney of switching from fixed-dose tenofovir disoproxil fumarate/emtricitabine/efavirenz to darunavir/ritonavir monotherapy: a randomized, controlled trial (MIDAS).

BACKGROUND: Efavirenz (EFV) has been associated with reductions in vitamin D (25[OH]D) and tenofovir (TDF) with increased bone turnover, reductions in bone mineral density (BMD) and renal tubular dysfunction. We hypothesized that switching from fixed-dose TDF/emtricitabine (FTC)/EFV to darunavir/ritonavir monotherapy (DRV/r) might increase 25(OH)D and BMD, and improve renal tubular function. METHODS: Subjects with HIV RNA <50 copies/ml on TDF/FTC/EFV for ≥6 months were randomized 1:1 to ongoing TDF/FTC/EFV or DRV/r (800/100 mg once daily) for 48 weeks. The primary end point was change from baseline in 25(OH)D at week 48. Secondary end points included changes in BMD, bone turnover markers and renal tubular function. RESULTS: A total of 64 subjects (86% male, 66% white, mean [sd] CD4(+) T-cell count 537.3 [191.5]/mm(3)) were analysed. After adjustment for baseline 25(OH)D and demographics, at week 48 DRV/r monotherapy was associated with a +3.6 (95% CI 0.6, 6.6) ng/ml increase in 25(OH)D compared to TDF/FTC/EFV (P=0.02). DRV/r monotherapy was associated with an increase in BMD (+2.9% versus -0.003% at the neck of femur and +2.6% versus +0.008% at the lumbar spine for DRV/r versus TDF/FTC/EFV; P<0.05 for all) and reductions in bone biomarkers compared with those remaining on TDF/FTC/EFV. No significant difference in renal tubular function was observed. Reasons for discontinuation in the DRV/r arm included side effects (n=4) and viral load rebound (n=3), all of which resolved with DRV/r discontinuation or regimen intensification. CONCLUSIONS: Switching from TDF/FTC/EFV to DRV/r in patients with suppressed HIV RNA resulted in significant improvements in 25(OH)D and bone biomarkers, and a 2-3% increase in BMD.

Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin's lymphoma.

PURPOSE: Immunosuppression induced by HIV-1 increases the risk of developing non-Hodgkin's lymphoma (NHL). We measured the influence of immunologic factors and highly active antiretroviral therapy (HAART) on this risk. As there are no data demonstrating that specific antiretroviral regimens are effective at protecting from NHL, we compared different HAART regimens. PATIENTS AND METHODS: The protective effect of HAART regimens, containing protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the development of NHL was examined in a prospectively recorded cohort of 9,621 HIV-infected individuals. Lymphocyte and natural killer subset data were also entered in univariate and multivariate analyses to establish and stratify the risk of NHL. RESULTS: From this cohort of 9,621 patients, 102 have been diagnosed with systemic AIDS-related NHL since 1996, when HAART became freely available here. By univariate analysis, increased age, higher nadir CD4 and CD8 T-cell counts, CD19 B-cell count, CD16/56 natural killer count and exposure to NNRTI or PI containing HAART conferred significant protection against NHL (P <.05). In a multivariate analysis, age, nadir CD4 and CD8 T-cell counts, and exposure to HAART were independent predictors of risk of NHL (P <.02). NNRTI-based HAART (adjusted rate ratio, 0.4; 95% CI, 0.3 to 0.5) was as protective as PI-based HAART, and these were significantly more protective than nucleoside analogues alone (rate ratio, 0.5; 95% CI, 0.4 to 0.7) or no antiretrovirals (P <.001). CONCLUSION: Effective HAART-induced maintenance of CD4 and CD8 counts protects from systemic AIDS-related NHL.

Prognostic significance of immune subset measurement in individuals with AIDS-associated Kaposi's sarcoma.

PURPOSE: A prognostic index for AIDS-associated Kaposi's sarcoma (KS) diagnosed in the era of highly active antiretroviral therapy (HAART) was based on routine clinical and laboratory characteristics. Because immune subset measurement is often performed in HIV-positive individuals, we examined whether these were predictive of mortality independently of the prognostic index, or could predict time to progression of KS. PATIENTS AND METHODS: We performed univariate and multivariate Cox regression analyses on a data set of 326 individuals with AIDS-associated KS to identify immune subset covariates predictive of overall survival and time to progression. Adaptive (CD8 T cell and CD19 B cell) and innate (CD16/56 natural-killer cell) immune parameters were studied by flow cytometry. RESULTS: In univariate analyses, all three immune subsets had significant effects on overall survival (P < .025). In multivariate analyses including the prognostic index, only CD8 counts remained significant (P = .026), although its effect on the overall prognostic index is small. An increase of 100 cells/mm3 in the CD8 count confers a 5% improvement in overall survival. Individuals with a higher CD8 count did not have an increased time to progression. Patients who were already on HAART at the time of KS diagnosis did not have a shorter time to progression than those who were antiretroviral naïve at KS diagnosis. CONCLUSION: The CD8 count appears to provide independent prognostic information in individuals with AIDS-associated KS. Measurement of the CD8 count is clinically useful in patients with KS.