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Background: Vitamin D deficiency is common in HIV population and has been associated with increased comorbidity risk and poor immunologic status., Objective: To evaluate the effect of protease inhibitor lopinavir/ritonavir monotherapy on changes in serum 25-hydroxyvitamin D [25(OH)D] over 48 weeks., Methods: Thirty-four treatment-naïve HIV individuals initiating lopinavir/ritonavir monotherapy and receiving clinical care from private practice in Houston, Texas, were included. Serum 25-hydroxyvitamin D levels from stored plasma samples collected from IMANI-2 pilot study at both baseline and 48 weeks were analyzed using LC-MS assays. Mean 25(OH)D at baseline and 48 weeks were compared using paired t-tests. Linear regression analysis was used to evaluate factors associated with changes in 25(OH)D. Logistic regression analyses were used to determine the effect of vitamin D status and covariates on CD4 cell count recovery., Results: Mean 25(OH)D was significantly higher at 48 weeks (26.3 ng/mL (SD + 14.9); p=0.0003) compared to baseline (19.8 ng/mL (SD +12.1), with fewer individuals having vitamin D deficiency (41.2%) and severe deficiency (11.8%). Both body mass index and baseline CD4 cell count were significant independent covariates associated with 25(OH)D changes over 48 weeks. Baseline vitamin D status did not affect CD4 cell count recovery. However, in a 24-week multivariate analysis, current tobacco use was significantly associated with a decreased odds of CD4 cell count recovery (AOR 0.106, 95% CI 0.018-0.606; p=0.012)., Conclusion: Individuals treated with lopinavir/ritonavir monotherapy had significantly higher 25(OH)D after 48 weeks. Current tobacco users had significantly diminished CD4 cell count recovery after starting treatment, warranting further clinical investigation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Most guidelines recommend rapid treatment initiation for patients with newly diagnosed human immunodeficiency virus type 1 (HIV-1) infection, but prospective US data are limited. The DIAMOND (NCT03227861) study using darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a phase 3 prospective study evaluating efficacy/safety of a single-tablet regimen in a rapid-initiation model of care., Methods: Adults aged ≥18 years began D/C/F/TAF ≤14 days from diagnosis without screening/baseline results; as results became available, participants not meeting predefined safety/resistance stopping rules continued. Primary endpoint was virologic response (HIV-1 RNA <50 copies/mL; intent-to-treat; US Food and Drug Administration [FDA] snapshot) at week 48; participant satisfaction was measured via the HIV Treatment Satisfaction Questionnaire status version (HIVTSQs)., Results: Of 109 participants, 87% were male, 32% black/African American, median (range) age was 28 (range, 19-66) years, 25% of participants had HIV-1 RNA ≥100 000 copies/mL, 21% had CD4+ cell count <200 cells/µL, and 31% enrolled ≤48 hours from diagnosis. At week 48, 97 (89%) participants completed the study and 92 (84%) achieved HIV-1 RNA <50 copies/mL (FDA snapshot). There were no protocol-defined virologic failures; incidences of adverse events (AEs) and adverse drug reactions (33%) were low, no serious AEs were study drug related, and 1 (<1%) participant discontinued due to study drug related AE(s). The overall HIVTSQs score at week 48 was 58 (maximum: 60)., Conclusions: At week 48, a high proportion of participants starting D/C/F/TAF achieved HIV-1 RNA <50 copies/mL and very few discontinued therapy. D/C/F/TAF was well tolerated, no participants discontinued due to baseline resistance stopping criteria, and high treatment satisfaction among participants was recorded., Clinical Trials Registration: NCT03227861., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Objective: To compare the efficacy, safety, and anti-inflammatory effects of cenicriviroc (CVC), an oral, once-daily C-C chemokine receptor types 5 and 2 antagonist, with those of efavirenz (EFV) in treatment-naive, HIV-1-infected adults., Design: A 48-week, randomized, double-blind, double-dummy phase 2b trial at 43 institutions (USA and Puerto Rico)., Methods: Study participants (HIV-1 RNA ≥1000 copies/ml, CD4 cell count ≥200 cells/μl, C-C chemokine receptor type 5-tropic virus) were randomized 2 : 2 : 1 to CVC 100 mg (CVC100), CVC 200 mg (CVC200), or EFV 600 mg, each administered with emtricitabine/tenofovir disoproxil fumarate. Key end points were virologic success (HIV-1 RNA <50 copies/ml) at week 24 (primary) and week 48 (secondary), safety/tolerability at weeks 24 and 48. Study sites and patients remained blinded until week 48., Results: A total of 143 patients were randomized (CVC100, n = 59; CVC200, n = 56; EFV, n = 28). Virologic success was obtained at week 24 in 76, 73, and 71% of study participants for CVC100, CVC200, and EFV, respectively (all P > 0.05 versus EFV), and at week 48 in 68, 64, and 50%, respectively (all P > 0.05 versus EFV). Resistance mutations emerged in five and zero CVC and EFV-treated study participants, respectively. Virologic nonresponse and nucleoside reverse transcriptase inhibitor resistance decreased when CVC minimum plasma concentration was at least 47.8 ng/ml. Treatment-related adverse events of at least grade 2 and discontinuations because of adverse events were less frequent in CVC-treated study participants. Total and low-density lipoprotein cholesterol decreased with CVC, but increased with EFV. C-C chemokine ligand type 2 (CCL2) (aka monocyte chemotactic protein-1) increased in a dose-dependent manner, whereas soluble CD14 levels decreased with CVC., Conclusion: CVC showed efficacy and favorable safety in treatment-naive HIV-1-infected study participants, supporting selection of CVC200 for phase 3 studies., Trial Registration: NCT01338883.

Objective: We reviewed the current literature regarding antiretroviral (ARV)-sparing therapy strategies to determine whether these novel regimens can be considered appropriate alternatives to standard regimens for the initial treatment of ARV-naive patients or as switch therapy for those patients with virologically suppressed HIV infection., Methods: A search for studies related to HIV dual therapy published from January 2000 through April 2014 was performed using Biosis, Derwent Drug File, Embase, International Pharmaceutical Abstracts, Medline, Pascal, SciSearch, and TOXNET databases; seven major trial registries, and the abstracts of major conferences. Using predetermined criteria for inclusion, an expert review committee critically reviewed and qualitatively evaluated all identified trials for efficacy and safety results and potential limitations., Results: Sixteen studies of dual therapy regimens were critiqued for the ARV-naive population. Studies of a protease inhibitor/ritonavir in combination with the integrase inhibitor raltegravir or the nucleoside reverse transcriptase inhibitor lamivudine provided the most definitive evidence supporting a role for dual therapy. In particular, lopinavir/ritonavir or darunavir/ritonavir combined with raltegravir and lopinavir/ritonavir combined with lamivudine demonstrated noninferiority to standard of care triple therapy after 48 weeks of treatment. Thirteen trials were critiqued in ARV-experienced, virologically suppressed patients. The virologic efficacy outcomes were mixed. Although overall data regarding toxicity are limited, when compared with standard triple therapy, certain dual therapy regimens may offer advantages in renal function, bone mineral density, and limb fat changes; however, some dual combinations may elevate lipid or bilirubin levels., Conclusions: The potential benefits of dual therapy regimens include reduced toxicity, improved tolerability and adherence, and reduced cost. Although the data reviewed here provide valuable insights into the effectiveness and tolerability of dual therapy regimens, it remains unclear whether these potential benefits can be maintained long-term. Appropriately powered studies with longer follow-up periods are needed to more definitively assess potential toxicity reduction advantages with dual therapy.

Objectives: To evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of the first protease inhibitor-based single-tablet regimen (STR) for initial treatment of HIV-1 infection., Methods: Antiretroviral therapy (ART)-naive adults with estimated glomerular filtration rate ≥ 70 mL/min were randomized 2:1 to receive the darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) STR (TAF: N = 103) or darunavir + cobicistat + emtricitabine/tenofovir disoproxil fumarate (TDF: N = 50) once daily with matched placebos for 48 weeks., Results: At week 24, viral suppression (HIV-1 RNA <50 copies/mL) rates were similar (TAF 74.8% vs. TDF 74.0%). At week 48, rates were TAF 76.7% vs. TDF 84.0%; the difference was driven by higher rate of discontinuations in TAF (6.8%) vs. TDF (2%). Among those with virologic failure, none developed resistance. Most adverse events were of mild/moderate severity. The mean change in serum creatinine from baseline at week 48 was 0.06 mg/dL (95% confidence interval: 0.04 to 0.08) for TAF vs. 0.09 mg/dL (95% confidence interval: 0.05 to 0.14) for TDF (P = 0.053). The % change in retinol binding protein/Cr ratio was +9 (TAF) vs. +54 (TDF), P = 0.003; the % change in urine β-2 microglobulin/Cr ratio was -42.0 (TAF) vs. +2.3 (TDF), P = 0.002. The % change in hip bone mineral density (BMD) was -0.84 (TAF) vs. -3.82 (TDF), P < 0.001 and in spine BMD was -1.57 (TAF) vs. -3.62 (TDF), P = 0.003. There were no fractures in either group., Conclusions: The TAF arm had significantly improved renal and bone safety parameters: less proteinuria and less change in hip and spine BMD, consistent with results from a similarly designed study of the elvitegravir/C/F/TAF STR. This D/C/F/TAF STR offers a promising option for initial HIV treatment, with the high barrier to resistance of darunavir, and the potential for improved long-term renal and bone safety with TAF.

This ongoing, randomized, double-blind, active-controlled phase 3 international trial demonstrated the noninferior efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF) compared with atazanavir boosted by ritonavir (ATV/RTV) plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) at 48 weeks. Here, we report the week 96 results. Of 708 treated subjects, virological success (Food and Drug Administration snapshot) was maintained at week 96 with EVG/COBI/FTC/TDF and ATV/RTV + FTC/TDF (83% vs 82%, difference 1.1%, 95% confidence interval -4.5% to 6.7%). Study drug discontinuations due to adverse events were low (4% vs 6%). Median increases from baseline in serum Cr (mg/dL) in EVG/COBI/FTC/TDF vs ATV/RTV + FTC/TDF at week 96 (0.12 vs 0.08) were similar to those at week 48 (0.12 vs 0.08). EVG/COBI/FTC/TDF showed similar mean decreases (%) in bone mineral density from baseline vs ATV/RTV + FTC/TDF (hip: -3.16 vs -4.19, P = 0.069; spine: -1.96 vs -3.54, P = 0.049). Overall, week 96 results support durable efficacy and safety of EVG/COBI/FTC/TDF in HIV-1-infected patients.

Background: Vicriviroc, a novel HIV CCR5 antagonist, demonstrated significant efficacy and favorable tolerability in phase II trials in treatment-experienced subjects, supporting further evaluation in phase III studies., Methods: Two identical double-blind, placebo (PBO)-controlled trials in CCR5-tropic HIV-infected subjects with documented resistance to two antiretroviral classes were conducted. Subjects were randomized to vicriviroc 30 mg QD (N = 571) or PBO (N = 286) with open-label optimized background therapy (OBT) containing ≥2 fully active antiretroviral drugs. The primary endpoint was percentage of subjects with <50 copies/mL HIV RNA at 48 weeks. It was analyzed in a logistic regression with treatment (vicriviroc + OBT/PBO + OBT), use of enfuvirtide in baseline OBT (yes/no), and baseline HIV RNA (≤100,000/>100,000 copies/mL) as covariates. In addition, a pre-planned analysis to examine other efficacy and safety endpoints was conducted., Results: Baseline characteristics of the pooled mITT population (vicriviroc, n = 486; PBO, n = 235) included mean HIV RNA of 4.6 log(10) copies/mL and mean CD4 count of 257 cells/μL. Approximately 60% of subjects received ≥3 active drugs in the OBT. The percentage of subjects with <50 copies/mL HIV RNA was not significantly different between vicriviroc and PBO at week 48 (64% vs 62%, p = 0.6). However, in subjects receiving ≤2 active drugs in their OBT, the proportion achieving <50 copies/mL HIV RNA was higher in those receiving vicriviroc compared with PBO (70% vs 55%, p = 0.02)., Conclusions: The studies failed to show significant efficacy gains when vicriviroc was added to OBT. However, given the efficacy results of earlier vicriviroc trials and other CCR5 antagonist, studies are needed to define the role of this class of drugs in the treatment of HIV. Clinical trial identifier: http://www.clinicaltrial.gov/: VICTOR-E3 (NCT00523211) and VICTOR-E4 (NCT00474370)., (Copyright © 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: A week 48 efficacy and safety analysis with respect to gender and race was conducted using pooled data from the phase III, double-blind, double-dummy efficacy comparison in treatment-naïve, HIV-infected subjects of TMC278 and efavirenz (ECHO) and TMC278 against HIV, in a once-daily regimen versus efavirenz (THRIVE) trials., Methods: Treatment-naïve, HIV-1-infected adults were randomized to receive rilpivirine (RPV; TMC278) 25 mg once a day (qd), or efavirenz (EFV) 600 mg qd, plus tenofovir/emtricitabine (ECHO) or tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine (THRIVE)., Results: A total of 1368 participants (76% male and 61% White, of those with available race data) were randomized and treated. No gender-related differences in response rate (percentage of patients with HIV-1 viral load < 50 HIV-1 RNA copies/mL, using an intent-to-treat, time-to-loss-of-virological-response algorithm) were observed (RPV: men, 85%; women, 83%; EFV: men, 82%; women, 83%). Response rates were lower in Black compared with Asian and White participants (RPV: 75% vs. 95% and 85%, respectively; EFV: 74% vs. 93% and 83%, respectively); this finding was mostly a result of higher discontinuation and virological failure rates in Black patients. Safety findings were generally similar across race and gender subgroups. However, nausea occurred more commonly in women than in men in both treatment groups. In men, diarrhoea was more frequent in the EFV group, and abnormal dreams/nightmares were more frequent in men in both the EFV and RPV groups., Conclusions: Overall response rates were high for both RPV and EFV. No gender differences were observed. However, response rates were lower among Black patients, regardless of treatment group. Gender appeared to influence the incidence of gastrointestinal adverse events and abnormal dreams/nightmares for both treatments., (© 2012 British HIV Association.)

Background: The HIV integrase strand transfer inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) into a once-daily, single tablet. We compared EVG/COBI/FTC/TDF with a ritonavir-boosted (RTV) protease inhibitor regimen of atazanavir (ATV)/RTV+FTC/TDF as initial therapy for HIV-1 infection., Methods: This phase 3, non-inferiority study enrolled treatment-naive patients with an HIV-1 RNA concentration of 5000 copies per mL or more and susceptibility to atazanavir, emtricitabine, and tenofovir. Patients were randomly assigned (1:1) to receive EVG/COBI/FTC/TDF or ATV/RTV+FTC/TDF plus matching placebos, administered once daily. Randomisation was by a computer-generated random sequence, accessed via an interactive telephone and web response system. Patients, and investigators and study staff who gave treatments, assessed outcomes, or analysed data were masked to the assignment. The primary endpoint was HIV RNA concentration of 50 copies per mL or less after 48 weeks (according to the US FDA snapshot algorithm), with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov, number NCT01106586., Findings: 1017 patients were screened, 715 were enrolled, and 708 were treated (353 with EVG/COBI/FTC/TDF and 355 with ATV/RTV+FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to ATV/RTV+FTC/TDF for the primary outcome (316 patients [89·5%] vs 308 patients [86·8%], adjusted difference 3·0%, 95% CI -1·9% to 7·8%). Both regimens had favourable safety and tolerability; 13 (3·7%) versus 18 (5·1%) patients discontinued treatment because of adverse events. Fewer patients receiving EVG/COBI/FTC/TDF had abnormal results in liver function tests than did those receiving ATV/RTV+FTC/TDF and had smaller median increases in fasting triglyceride concentration (90 μmol/L vs 260 μmol/L, p=0·006). Small median increases in serum creatinine concentration with accompanying decreases in estimated glomerular filtration rate occurred in both study groups by week 2; they generally stabilised by week 8 and did not change up to week 48 (median change 11 μmol/L vs 7 μmol/L)., Interpretation: If regulatory approval is given, EVG/COBI/FTC/TDF would be the first integrase-inhibitor-based regimen given once daily and the only one formulated as a single tablet for initial HIV treatment., Funding: Gilead Sciences., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: Current antiretroviral regimens recommended for treatment-naïve patients include 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). The purpose of this study is to evaluate whether a new NRTI-sparing regimen may provide an alternative for persons for whom traditional regimens may not be the best option., Methods: PROGRESS is a 96-week, randomized, open-label, multicenter trial comparing the efficacy and safety of a boosted protease inhibitor (PI) and an integrase inhibitor (lopi-navir/ritonavir [LPV/r] + raltegravir [RAL]) to a boosted PI and 2 NRTIs (LPV/r + tenofovir/ emtricitabine [TDF/FTC]) in antiretroviral (ARV)-naïve HIV-1-infected adults., Results: A total of 206 subjects were randomized to receive LPV/r + RAL (n=101) or LPV/r + TDF/FTC (n=105) and analyzed for ARV efficacy using the US Food and Drug Administration time to loss of virologic response (FDA-TLOVR) algorithm. The percentage of subjects with plasma HIV-1 RNA <40 copies/mL at week 48 was 83.2% in the LPV/r + RAL group and 84.8% in the LPV/r + TDF/FTC group (P = .850; difference -1.6%; exact 95% CI, -12.0% to 8.8%). As the lower limit of the exact 95% CI for the difference between regimens was at or above the protocol-defined threshold of -20% (as well as the more stringent threshold of -12%), LPV/r + RAL was noninferior to LPV/r + TDF/FTC. The occurrence of treatment-related, moderate/severe adverse events was similar between treatment groups through 48 weeks of treatment., Conclusions: The HIV treatment regimen of LPV/r + RAL resulted in noninferior efficacy and comparable safety and tolerability compared with a traditional NRTI-containing regimen through 48 weeks of treatment. These results support further evaluation of the LPV/r + RAL regimen.

Objectives: To determine the antiviral activity, pharmacokinetics, pharmacodynamics, safety, and tolerability of several dose levels of oral TBR-652 monotherapy in HIV-1-infected, antiretroviral experienced, CCR5 antagonist-naive subjects., Design: Double-blind placebo-controlled study in the United States and Argentina., Methods: Subjects were randomized in a ratio of 4:1 per dose level to TBR-652 (25, 50, 75, 100, or 150 mg) or placebo, taken once daily for 10 days. Changes from baseline in HIV-1 RNA and CD4 cell counts were measured through day 40 and for monocyte chemotactic protein-1 (MCP-1), high-sensitivity C-reactive protein (hs-CRP), and IL-6 at day 10. Pharmacokinetic data were analyzed using noncompartmental statistics. Laboratory and clinical adverse events (AEs) and electrocardiogram changes were recorded., Results: Maximum median reductions in HIV-1 RNA values for the 25, 50, 75, and 150 mg doses were -0.7, -1.6, -1.8, and -1.7 log10 copies per milliliter, respectively. All changes were significant. Median time to nadir was 10-11 days. Suppression persisted well into the posttreatment period. Mean MCP-1 increased significantly by day 10 in the 50-mg and 150-mg dose groups. Effects on CD4 cell counts, hs-CRP, and IL-6 levels were negligible. TBR-652 was generally safe and well tolerated, with no withdrawals due to AEs., Conclusions: TBR-652 caused significant reductions in HIV-1 RNA at all doses. Significant increases in MCP-1 levels suggested a strong CCR2 blockade. TBR-652 was generally well tolerated with no dose-limiting AEs. Pharmacodynamics indicate that TBR-652 warrants further investigation as an unboosted once-daily oral CCR5 antagonist with potentially important CCR2-mediated anti-inflammatory effects.

Background: This study (VERxVE) compared the efficacy and safety of the new nevirapine extended-release (NVP XR) formulation dosed once daily with NVP immediate release (IR) twice daily in treatment-naive patients., Methods: Randomized, double-blind, double-dummy, parallel group study of HIV-1-infected adult patients with baseline viral load (VL) ≥ 1,000 copies/ml and CD4(+) T-cell count of >50-<400 (males) and >50-<250 cells/mm(3) (females). Patients stratified by baseline VL (≤ 100,000/>100,000 copies/ml) were randomized 1:1 to NVP XR 400 mg once daily (plus placebo) or NVP IR 200 mg twice daily (plus placebo), both combined with tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine 200 mg once daily. Primary endpoint was sustained virological response (<50 copies/ml) through week 48 using the time to loss of virological response algorithm. Non-inferiority of NVP XR to NVP IR was tested using Cochran's statistic incorporating baseline VL stratum with pre-specified, non-inferiority margin of -10%., Results: Among 1,011 patients randomized and treated, virological response at week 48 was 81.0% (409/505) for NVP XR and 75.9% (384/506) for NVP IR with adjusted difference of 4.9% in favour of NVP XR (95% CI -0.1-10.0%), demonstrating non-inferiority of NVP XR to NVP IR. This finding was supported by secondary endpoints. The safety profile of NVP XR was similar to NVP IR, but showed numerically fewer treatment-related adverse events., Conclusions: NVP XR in combination with TDF and emtricitabine was shown to be non-inferior in efficacy to NVP IR with a similar safety and adverse event profile, with the potential for the added convenience of once-daily dosing., Trial Registration: ClinicalTrials (NCT): NCT00561925.

Background: Etravirine, a nonnucleoside reverse transcriptase inhibitor, was provided through an international early access program (EAP) prior to regulatory approval., Methods: The Phase III, nonrandomized, open-label EAP investigated etravirine 200 mg twice daily plus a background regimen (BR) in patients who had failed multiple antiretroviral regimens. Efficacy and safety are reported for HIV-infected adults from the United States through week 48, including subgroups receiving etravirine +/- darunavir/ritonavir and/or raltegravir., Results: The intent-to-treat population included 2578 patients; 62.4% and 56.7% of patients received darunavir/ritonavir and raltegravir, respectively, in their BR. At week 48, 62.3% of patients achieved viral loads <75 copies per milliliter; responses across subgroups were similar. Median CD4 count increase from baseline was >100 cells per cubic millimeter. No unexpected safety concerns emerged; serious AEs and deaths due to AEs, considered possibly related to etravirine, occurred in 2.0% and 0.3% of patients, respectively. Discontinuations due to AEs were low overall (4.4%) and comparable across subgroups., Conclusions: Etravirine combined with a BR, often including other new antiretrovirals, such as darunavir/ritonavir and/or raltegravir, provided an effective treatment option in treatment-experienced patients with HIV-1.

Purpose: To assess the safety and efficacy of a 4-drug, 3-tablet, once-daily (qd) regimen consisting of abacavir/lamivudine/zidovudine (ABC/3TC/ZDV; 2 tablets) and tenofovir (TDF) in antiretroviral-naïve patients with plasma HIV-1 RNA 30,000 copies/mL at 48 weeks., Method: All participants received ABC/3TC/ZDV (300/150/300 mg) and TDF (300 mg) qd in this pilot, open-label, multicenter study. Intent-to-treat (ITT) analyses were conducted to evaluate virologic and immunologic efficacy., Results: Of the 123 participants enrolled, 52 (42%) prematurely discontinued study for adverse events (14), were lost to follow-up (13), had virologic nonresponse (12), and withdrew for other reasons (13). At week 48, by ITT missing=failure analysis, 41% (51/123) and 51% (63/123) of participants had plasma HIV-1 RNA <50 copies/mL and <400 copies/mL, respectively; by ITT-observed analysis, 75% (51/68) and 93% (63/68) had plasma HIV-1 RNA <50 copies/mL and <400 copies/mL, respectively; 11% (14/123) met virologic nonresponse criteria. Median week 48 change in CD4+ cell count from baseline was +127 cells/mm3. Median week 48 changes from baseline for fasting lipids were as follows: cholesterol (-9 mg/dL), HDL (+1 mg/dL), LDL (-9 mg/dL), and triglycerides (-4 mg/dL)., Conclusion: A high rate of premature discontinuations contributed to the overall suboptimal virologic response to ABC/3TC/ZDV+TDF qd; however, the regimen was not associated with high rates of virologic failure previously observed with TDF+ABC/3TC.

Objective: To assess and compare the activity and safety of capsules containing enteric-coated beadlets of didanosine given once daily with stavudine and nelfinavir with that of a standard reference triple drug regimen of zidovudine plus lamivudine and nelfinavir., Design: Multinational, 49-site, prospective, open-label, randomized, two-arm comparison study., Participants: HIV-infected subjects with limited or no previous antiretroviral therapy who had plasma HIV RNA levels of >or=2000 copies/mL and CD4 cell counts of >or=200/mm3 (511 were randomized to treatment groups, and 352 completed the study)., Interventions: Triple antiretroviral therapy for 48 weeks: didanosine EC (400 mg once daily), stavudine (40 mg twice daily), and nelfinavir (750 mg three times daily) or a twice-daily coformulation of zidovudine (300 mg) plus lamivudine (150 mg) and nelfinavir (750 mg three times daily)., Main Outcome Measure: Proportion of subjects with HIV RNA levels of <400 copies/mL at week 48 based on an "intent-to-treat, missing = treatment failure" analysis., Results: The two treatment groups were similar in the proportion of treatment responders (i.e., HIV RNA level of <400 copies/mL), with 54% of subjects in the didanosine EC and zidovudine plus lamivudine treatment groups responding at week 48. Results of other analyses supported those of the primary analysis. The two study regimens were associated with similar numbers of adverse events., Conclusions: The antiviral efficacy of a triple combination regimen containing once-daily didanosine EC is similar to that of a reference triple combination regimen.

Context: Abacavir, a nucleoside analogue, has demonstrated suppression of human immunodeficiency virus (HIV) replication alone and in combination therapy. However, the role of abacavir in a triple nucleoside combination regimen has not been evaluated against a standard protease inhibitor-containing regimen for initial antiretroviral treatment., Objective: To evaluate antiretroviral equivalence and safety of an abacavir-lamivudine-zidovudine regimen compared with an indinavir-lamivudine-zidovudine regimen., Design and Setting: A multicenter, phase 3, randomized, double-blind trial with an enrollment period from August 1997 to June 1998, with follow-up through 48 weeks at 73 clinical research units in the United States, Canada, Australia, and Europe., Patients: Five hundred sixty-two antiretroviral-naive, HIV-infected adults with a plasma HIV RNA level of at least 10 000 copies/mL and a CD4 cell count of at least 100 x 10(6)/L., Interventions: Patients were stratified by baseline HIV RNA level and randomly assigned to receive a combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine twice daily plus either 300 mg of abacavir twice daily and indinavir placebo or 800 mg of indinavir every 8 hours daily plus abacavir placebo. After 16 weeks, patients with confirmed HIV RNA levels greater than 400 copies/mL were eligible to continue receiving randomized treatment or receive open-label therapy., Main Outcome Measure: Virologic suppression, defined as HIV RNA concentration of 400 copies/mL or less at week 48., Results: The proportion of patients who met the end point of having an HIV RNA level of 400 copies/mL or less at week 48 was equivalent in the abacavir group (51% [133/262]) and in the indinavir group (51% [136/265]) with a treatment difference of -0.6% (95% confidence interval [CI], -9% to 8%). In patients with baseline HIV RNA levels greater than 100 000 copies/mL, the proportion of patients achieving less than 50 copies/mL was greater in the indinavir group than in the abacavir group with 45% (45/100) vs 31% (30/96) and a treatment diference of -14% (95% CI, -27% to 0%). The 2 treatments were comparable with respect to their effects on CD4 cell count. There was no difference between groups in the frequency of treatment-limiting adverse events or laboratory abnormalities. One death in the abacavir group was attributed to hypersensitivity reaction, which occurred following rechallenge with abacavir, approximately 3 weeks after initiating study treatment., Conclusions: In this study of antiretroviral-naive HIV-infected adults, the triple nucleoside regimen of abacavir-lamivudine-zidovudine was equivalent to the regimen of indinavir-lamivudine-zidovudine in achieving a plasma HIV RNA level of less than 400 copies/mL at 48 weeks.

The safety and antiretroviral effects of didanosine and stavudine in combination were evaluated in 86 people infected with HIV with CD4 counts between 200 and 500 cells/mm3 who had received <7 days of prior nucleoside analogue antiretroviral treatment. Patients were randomized to receive blinded treatments with one of five weight-adjusted, twice-daily regimens of didanosine and stavudine (100 + 10 mg, 100 + 20 mg, 100 + 40 mg, 200 + 20 mg, and 200 + 40 mg) for up to 1 year. Dosages were adjusted appropriately for patients weighing <60 kg and reduced in response to adverse effects. No clear dose-related differences among treatment groups were detected with regard to suppression of plasma HIV RNA level or reduction in infectious titers in peripheral blood mononuclear cells (PBMCs), improvement in CD4 count, or adverse effects. However, trends toward greater decreases in viral load and increases in CD4 count were detected when treatment groups containing the full recommended dosage of one or both agents (high-dose subgroup; arms 3, 4, and 5) were compared with the groups receiving lower dosages. At 28 weeks the mean log 10 HIV RNA decrease was 1.12 (n = 52) and at 52 weeks it was 0.97 (n = 32). Combination therapy was well tolerated, with no apparent dose-related adverse effects. Peripheral neuropathy occurred in 2 of 86 (2.3%) of patients. Didanosine and stavudine together appear to be a good nucleoside analogue foundation for aggressive triple- or quadruple-drug therapy. Full therapeutic doses of each of these two agents should be used to achieve optimal suppression of HIV replication.

One important goal of antiretroviral therapy should be simplification of treatment regimens whenever possible, in order to enhance adherence and potentially improve treatment outcome. While the nucleoside didanosine (ddI) has generally been dosed twice daily in clinical trials, the long intracellular half-life (>12 h) of its active metabolite, dideoxyadenosine triphosphate, should permit once-daily administration of this antiretroviral agent. The STADI trial evaluated this possibility by administering once-daily ddI and twice-daily stavudine (d4T) to antiretroviral-naive patients with human immunodeficiency virus type 1 (HIV-1) infection. This combination was well tolerated and at the end of 24 weeks of therapy, viral load was reduced by -1.48 log copies/ml and HIV-1 RNA was below the lower limit of quantification (500 copies/ml) in 62% of patients. Twenty-four weeks of treatment with d4T plus once-daily ddI increased average CD4 cell counts by 139/ml. The effectiveness of once-daily administration of ddI will be evaluated further in a new multinational clinical trial, AI454-148, in which it will be combined with d4T and the protease inhibitor, nelfinavir. The primary endpoint of this trial will be durable reduction of plasma HIV-1 RNA below 400 copies/ml. Such a change in the treatment regimen for this nucleoside has the potential to improve patient adherence and, thus, treatment outcome.

Background: Stavudine is a promising antiretroviral agent, but its clinical efficacy has not been determined., Objective: To evaluate the clinical effect of stavudine (2',3'-didehydro-3'-deoxythymidine) monotherapy in patients with human immunodeficiency virus (HIV) infection., Design: Randomized, controlled, double-blind trial., Setting: 56 outpatient clinics in private practices, universities, and contract research organizations in the United States, France, and Italy., Patients: 822 HIV-infected adults who had 50 to 500 CD4+ cells/mm3 and had previously received at least 6 months of zidovudine treatment., Intervention: Monotherapy with peroral stavudine capsules or peroral zidovudine capsules., Measurements: The primary end point was clinical progression, which was defined as all occurrences of acquired immunodeficiency syndrome (AIDS)-defining events or death., Results: Patients receiving stavudine reached clinical end points at a rate of 26 per 100 person-years, compared with 32 per 100 person-years for patients receiving zidovudine (relative risk, 0.75 [95% CI, 0.58 to 0.98]; P = 0.03). The risk for death alone was 26% lower in the stavudine group than in the zidovudine group, but the comparison was not statistically significant (relative risk, 0.74 [CI, 0.53 to 1.02]; P = 0.066). The benefit of stavudine therapy was seen in all CD4+ cell strata (< or = 100 cells/mm3, 101 to 300 cells/mm3, and > 300 cells/mm3) and clinical stages of HIV disease (asymptomatic, symptomatic, and AIDS). Four weeks after treatment began, CD4+ cell counts were 30 cells/mm3 higher in the stavudine group than in the zidovudine group; this difference was sustained for 96 weeks (P < 0.001). Nausea and vomiting were more common in patients receiving zidovudine (P < 0.01), and neuropathy occurred more frequently in those receiving stavudine (12% in the stavudine group compared with 4% in the zidovudine group; P < 0.001). Neuropathy resolved completely in many patients (63%) after interruption of stavudine treatment; these patients could resume stavudine therapy at a lower dose., Conclusions: Stavudine was well tolerated and delayed progression of HIV disease in patients who had previously received 6 or more months of zidovudine treatment. Benefits were apparent in all CD4+ cell strata and clinical stages of HIV disease. Stavudine is an important agent to consider for trials of combination chemotherapy.