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Background: CYP3A4 induction by efavirenz (EFV) persists after drug cessation; we assessed the pharmacokinetics (PK), efficacy and safety of maraviroc (MVC) administered to HIV-infected individuals switching from EFV-containing therapy., Methods: Patients with R5-tropic virus and suppressed viral load on two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus EFV switched EFV to MVC 600 mg twice daily for 14 days, and then to MVC 300 mg twice daily. Following screening, three intensive PK visits were performed (sampling was pre-dose and 1, 2, 4, 6, 8 and 12 h post-dose): day 1 (VISIT 1, MVC 600 mg twice daily), day 14 (VISIT 2, steady-state MVC 600 mg twice daily) and day 28 post regimen switch (VISIT 3, steady-state MVC 300 mg twice daily); MVC trough concentration (Ctrough) was determined 3, 6 and 10 days following regimen switch and viral loads up to week 24. MVC PK parameters on visits 1 and 2 and MVC Ctrough on day 6 were compared to visit 3 (reference) via geometric mean ratios (GMR) and 95% CIs., Results: Twelve males completed the study. MVC PK parameters at visit 1 versus visit 3 were: GMR and 95% CI 12-h area under the curve (AUC0-12) 1.25 (1.00, 1.58); Cmax 1.64 (1.16, 2.31); Ctrough 0.61 (0.46, 0.80). Visit 2 MVC PK parameters were significantly higher than visit 3: GMR and 95% CI AUC0-12 2.31 (1.84, 2.90); Cmax 2.42 (1.87, 3.12); Ctrough 2.25 (1.74, 2.91). MVC was well tolerated with no grade 3/4 adverse events; all subjects maintained viral suppression to the end of the study., Conclusions: The EFV induction effect necessitated increased MVC dose to 600 mg twice daily following switch and persisted for approximately one week after EFV cessation. This is less than the 2-week induction observed when switching EFV to etravirine and highlights the importance of studying different tail interactions. Higher dose MVC was well tolerated. All measured MVC Ctrough concentrations exceeded wild-type 90% inhibitory concentration.

In the context of emerging evidence related to preexposure prophylaxis and HIV treatment as prevention, an evidence summit was held in mid-2012 to discuss the current state of the science and to provide a platform for consensus building around whether and how these prevention strategies might be implemented globally. Health care providers, researchers, policy makers, people living with HIV/AIDS, and representatives of government authorities, donor agencies, pharmaceutical companies, advocacy organizations, and professional associations attended from 52 countries. An international advisory committee was convened to identify key messages and recommendations based upon the data presented and discussed at the summit. The advisory committee further worked to develop this consensus statement meant to assist relevant stakeholders in taking stock and mapping out a route forward to enhance the HIV prevention armamentarium.

Background: Here, we aimed to investigate the pharmacokinetics of abacavir and carbovir triphosphate (CBV-TP) with darunavir/ritonavir 900/100 mg once daily or raltegravir 400 mg twice daily., Methods: HIV-infected subjects on abacavir (600 mg once daily) underwent steady-state pharmacokinetic assessments without and with darunavir/ritonavir or raltegravir. Within-subject changes in plasma and intracellular pharmacokinetic parameters were evaluated by geometric mean ratios (GMRs) and 90% CIs., Results: A total of 19 patients completed the study. With darunavir/ritonavir (versus abacavir alone), abacavir GMRs (90% CI) were 0.73 (0.66, 0.80), 0.62 (0.50, 0.77) and 0.78 (0.69, 0.87) for area under the curve (AUC), trough concentration (C(trough)) and maximum concentration (C(max)), respectively. With raltegravir, they were 1.03 (0.97, 1.10), 0.83 (0.62, 1.11) and 1.06 (0.95, 1.18), respectively. Intracellular CBV-TP GMRs (90% CI) were 0.88 (0.72, 1.07), 0.68 (0.48, 0.95) and 0.98 (0.79, 1.23) for AUC, C(trough) and C(max), respectively, with darunavir/ritonavir, and 0.96 (0.76, 1.20), 0.57 (0.33, 1.00) and 1.07 (0.85, 1.35), respectively, with raltegravir., Conclusions: There was a 27% decrease in abacavir plasma exposure with darunavir/ritonavir and no changes with raltegravir. CBV-TP C(trough) was significantly decreased with darunavir/ritonavir (32%) and showed a high inter-individual variability with raltegravir.

Background: We analysed the influence of gender on use and outcomes of first-line HAART in a UK cohort., Methods: Analyses included heterosexuals starting HAART from 1998-2007 with pre-treatment CD4(+) T-cell count<350 cells/mm(3) and viral load (VL)>500 copies/ml. Virological suppression (<50 copies/ml), virological rebound (>500 copies/ml), CD4(+) T-cell counts at 6 and 12 months, clinical events and treatment discontinuation/switch in the first year of HAART were compared using linear, logistic and Cox regression., Results: Compared with women (n=2,179), men (n=1,487) were older and had lower CD4(+) T-cell count and higher VL at start of HAART. Median follow-up was 3.8 years (IQR 2.0-6.2). At 6 and 12 months, 72.7% and 75.3% had VL≤50 copies/ml, with no large differences between genders at either time after adjustment for confounders (6 months, OR 0.92 [95% CI 0.76-1.13]; 12 months, OR 1.06 [95% CI 0.85-1.31]). Overall, 79.4% patients achieved virological suppression and 19.2% experienced virological rebound, without gender differences, although men had an increased risk of rebound after excluding pregnant women (adjusted relative hazard [RH] 1.33 [95% CI 1.04-1.71]). Mean CD4(+) T-cell count increases at 6 and 12 months were, respectively, 112 and 156 cells/mm(3) overall, with mean differences between men and women of -14.6 cells/mm(3) (95% CI -24.6--4.5) and -12.1 cells/mm(3) (95% CI -24.4-0.2) at 6 and 12 months, respectively. Clinical progression was similar in men and women, but men were less likely to experience treatment discontinuation/switch (adjusted RH 0.72 [95% CI 0.63-0.83])., Conclusions: Despite higher discontinuation rates among women, men had an increased risk of virological rebound and slightly poorer CD4(+) T-cell count responses. Identifying the reasons underlying treatment discontinuation/switch may help optimize treatment strategies for both genders., (© 2011 International Medical Press)

Background: There is conflicting evidence on specific reverse transcriptase inhibitors to which the N348I mutation in the connection domain of HIV type-1 reverse transcriptase confers resistance. Here, we examined associations between the emergence of N348I and antiretroviral history in a large clinical database., Methods: We analysed 5,353 resistance tests (that were sequenced beyond codon 348) among 2,266 antiretroviral-experienced patients. Associations between N348I and individual antiretroviral drug exposure were estimated using a matched case-control approach. Cases were defined as the first resistance test where N348I was detected; for each case, the 10 closest (in calendar time) N348N tests were selected as controls. Odds ratios (ORs) adjusted for effects of all other drugs were estimated by conditional logistic regression., Results: N348I was detected in 198 (8.7%) cases. Drugs that were statistically significantly positively associated with N348I were efavirenz (OR 1.55, 95% confidence interval [CI] 1.08-2.23; P=0.017) and nevirapine (OR 2.06, 95% CI 1.49-2.85; P<0.001). Tenofovir disoproxil fumarate (TDF) was significantly negatively associated (OR 0.27, 95% CI 0.15-0.48; P<0.001) with N348I. Similar findings were observed when the analysis was repeated to include only those tests within 2 years of the resistance test. Effects for zidovudine and stavudine were evident only in an additional analysis, which considered exposure to both drugs jointly within 2 years prior to the resistance test: exposure to zidovudine alone (OR 4.61, 95% CI 1.83-11.61; P<0.001) and exposure to stavudine alone (OR 3.39, 95% CI 1.32-8.71; P=0.011)., Conclusions: This is the first clinical evidence to suggest that efavirenz might select for N348I in addition to nevirapine, that stavudine might select for N348I in addition to zidovudine and that TDF might protect against the mutation.

Background: We investigated the pharmacokinetics of atazanavir/ritonavir once daily and lopinavir/ritonavir twice and once daily over 72 h following drug intake cessation., Methods: This was an open-label, three-session, pharmacokinetic trial. Healthy volunteers received atazanavir/ritonavir 300/100 mg once daily and lopinavir/ritonavir 400/100 mg twice daily and 800/200 mg once daily separately for 10 days. Pharmacokinetic profiles were assessed for each phase on day 10 over 72 h. Pharmacokinetic parameters were determined over 12 or 24 h and to the last measurable concentration by non-compartmental methods., Results: Sixteen participants completed the study. Geometric mean terminal elimination half-life to 72 h of atazanavir was 8.35 h and not different from the 0-24 h half-life (9.91 h). Terminal elimination halflife of lopinavir was 2.33 h (twice daily) and 2.44 h (once daily). These values were lower compared with the half-life over the respective dosing intervals (7.15 and 4.88 h for 0-12 and 0-24 h, respectively). No participant on atazanavir had concentrations below the minimum effective concentration (MEC) of 150 ng/ml at 24 h. In total, 44% of the participants on lopinavir once daily had concentrations below the MEC of 1,000 ng/ml at 24 h. At 16 h and 20 h, 13% and 63% of participants were below target for twice daily lopinavir, respectively. At 36 h, all participants on lopinavir and 31% on atazanavir were below target. Ritonavir area under the plasma concentration-time curve was 30% lower and 26% higher when dosed at 100 mg or 200 mg with lopinavir versus atazanavir., Conclusions: This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Whereas the decline in lopinavir concentrations occured rapidly as the boosting effect of ritonavir diminished, the rate of decline of atazanavir remained constant to 72 h.

Background: Significant interactions between abacavir and other antiretrovirals have not been reported. This study investigated the steady-state plasma pharmacokinetics of abacavir when co-administered with atazanavir/ritonavir or lopinavir/ritonavir in HIV-infected individuals., Methods: HIV-infected subjects on abacavir (600 mg once daily) plus two nucleoside reverse transcriptase inhibitors (NRTIs) (excluding tenofovir) underwent a 24 h pharmacokinetic assessment for plasma abacavir concentrations. Atazanavir/ritonavir (300/100 mg once daily; arm (1) or lopinavir/ritonavir (400/100 mg twice daily; arm (2) were then added and the 24 h pharmacokinetic assessment repeated. Arm 3 included subjects stable on atazanavir/ritonavir or lopinavir/ritonavir and two NRTIs (excluding tenofovir or abacavir). These patients underwent a pharmacokinetic assessment for atazanavir/ritonavir or lopinavir/ritonavir concentrations on day 1, abacavir (600 mg once daily) was then added to the regimen and the pharmacokinetic assessment repeated. Within-subject changes in drug exposure were evaluated by geometric mean (GM) ratios and 95% confidence intervals (CI)., Results: Twenty-four patients completed the study. GM (95% CI) abacavir area under the curve (AUC) was 18,621 (15,900-21,807) and 15,136 (13,339-17,174) ng.h/ml without and with atazanavir/ritonavir and 15,136 (12,298-18,628) and 10,471 (9,270-11,828) ng.h/ml without and with lopinavir/ritonavir. GM (95% CI) atazanavir AUC without and with abacavir was 26,915 (13,252-54,666) and 28,840 (19,213-43,291) ng.h/ml; lopinavir AUC without and with abacavir was 60,253 (48,084-75,509) and 63,096 (48,128-82,718) ng.h/ml., Conclusions: No changes in atazanavir or lopinavir exposures were observed following the addition of abacavir; however, decreases in abacavir plasma exposure of 17% and 32% were observed following the addition of atazanavir/ritonavir or lopinavir/ritonavir, respectively.

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.

Objective: To assess the rate of protocol-defined treatment failure and safety of lopinavir/ritonavir (LPV/r) and saquinavir/ritonavir (SAQ/r)., Design: Open-label, prospective, randomized (1:1), international multi-centre trial., Methods: Adult HIV-1-infected patients were assigned LPV/r 400/100 mg twice daily or SAQ/r 1000/100 mg twice daily with two or more nucleoside reverse transcriptase inhibitors (NRTIs)/non-NRTIs. All patients, whether on or off the assigned treatment, were followed for 48 weeks., Results: Of 339 randomized patients, 324 initiated assigned treatment (intention-to-treat/exposed [ITT/e] population). At 48 weeks, treatment failure occurred in 29/163 (18%) and 53/161 (33%) of patients in the LPV/r and SAQ/r arms, respectively (ITT/e, P = 0.002, log rank test). In an analysis that also considered those patients who discontinued treatment as having failed treatment (ITT/e/discontinuation = failure), 40/161 (25%) LPV/r-treated individuals versus 63/161 (39%) SAQ/R-treated individuals failed treatment (P = 0.005, log rank test). Discontinuation of the assigned treatment occurred in 23/163 (14%) patients in the LPV/r-treated group, compared with 48/161 (300%) in the SAQ/r-treated group (ITT/e; P = 0.001). The primary reasons for premature discontinuation were non-fatal adverse events (LPV/r: 12/163; SAQ/r: 21/161) and patients' choice (LPV/r: 7/163; SAQ/r: 8/161). In the on-treatment analysis of time to treatment failure, no difference was observed between the two arms (P = 0.27, log rank test)., Conclusion: LPV/r had better antiretroviral effects compared with SAQ/r at the doses and in the formulations studied. This may have been a result of patients' preferences and ability to adhere to assigned therapy, rather than a result of differences in the intrinsic potency of the study protease inhibitors.

Objective: To evaluate the steady-state pharmacokinetics and safety of two once-daily saquinavir/ritonavir (SQV/RTV) regimens, 1600/100 and 2000/100 mg, in HIV-positive patients., Methods: Eighteen HIV-infected adults treated with the standard twice-daily SQV/RTV 1000/100 mg regimen were enrolled in this open-label, two-phase, crossover pharmacokinetic study. The steady-state pharmacokinetics of SQV administered with 100 mg RTV were investigated following once-daily doses of 1600 mg or 2000 mg or a twice-daily dose of 1000 mg. Plasma drug concentrations were determined by high performance liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were calculated using a non-compartmental model., Results: Compared with SQV 1000 mg twice daily, the Cmax of SQV following a 1600 mg and 2000 mg dose increased in a dose-proportional manner [geometric mean (95% CI) 1915 (1656-2850) ng/ml for 1000 mg, 2782 (2249-4330) ng/ml for 1600 mg and 4179 (3429-6105) ng/ml for 2000 mg doses, respectively]. SQV Ctrough values were 539 (453-1011), 106 (76-223) and 231 (75-822) ng/ml, respectively. A SQV Ctrough value greater than 100 ng/ml was achieved in all subjects on the twice-daily regimen, in 9/18 (50%) subjects on the 1600/100 mg once-daily regimen, and in 14/17 (82%) subjects on the 2000/100 mg once-daily regimen. The once-daily regimens were well tolerated, with mild-to-moderate gastrointestinal symptoms being the only events reported by a small number of patients., Conclusion: This is the first study to evaluate the pharmacokinetics of once-daily SQV/RTV 2000/100 mg in HIV-infected subjects. Our findings suggest that this regimen may be an alternative to twice-daily 1000/100 mg doses and should be further evaluated in efficacy studies. The data indicate that most patients (14/17) on once-daily 2000/100 mg achieve trough concentrations above target values (determined for HIV wild-type) for efficacy of SQV with the use of just 100 mg RTV/day and with good tolerability.

Background: Strong virus-specific helper and cytotoxic T-cell responses correlate with non-progression during HIV-1 infection. Administration of antiretroviral therapy (ART) during the chronic phases of HIV-1 infection fails to restore these responses in most patients., Design and Methods: We assessed the changes in immune function of 12 HIV-1-positive individuals treated with ART for over 4 years, who received 4 mg/day of recombinant human growth hormone (rhGH) for 12 weeks and were then randomized into groups receiving either placebo, twice weekly or alternate day dosing of rhGH. Peripheral blood was drawn for phenotypic analysis and functional assays at time points 0, 12 and 24 weeks., Results: At week 12, we observed significant increases in naive CD4 T cells (P<0.01) and effector CD8 T cells based on CD45RA and CCR7 expression (P<0.02). In addition, we observed a rise in HIV-1 antigen-specific CD4 (P<0.005) and CD8 (P<0.05) T-cell responses. Twelve weeks post-randomization into placebo, alternate day or twice weekly dosing (24 weeks post-baseline), the phenotype and function of the virus-specific effector CD8 T cells seen at week 12 was maintained in most patients regardless of randomization arm and despite the disappearance of HIV-1-specific CD4 T-cell responses., Conclusions: Concomitant administration of rhGH at 4 mg/day with highly active ART appears to partially reverse some of the defects exerted on the immune system by HIV-1. This combination may represent a valuable immunotherapeutic intervention aiding in the treatment of chronic HIV-1 infection.