Cabotegravir + Rilpivirine Long-Acting Injections for HIV Treatment in the US: Real World Data from the OPERA Cohort.

INTRODUCTION: The first complete long-acting antiretroviral therapy (ART) regimen, cabotegravir + rilpivirine long-acting (CAB + RPV LA) injectable, was approved in the US for HIV-1 treatment in individuals on a stable antiretroviral regimen with a viral load < 50 copies/mL, no treatment failure history, and no resistance to either cabotegravir or rilpivirine. We describe injection schedule adherence and virologic effectiveness of CAB + RPV LA in routine clinical care in the US. METHODS: From the OPERA® cohort, all adults with HIV who received their first CAB + RPV LA injection and ≥ 1 continuation injections between 21 January 2021 and 15 March 2022 were included. The injection target date was updated monthly and set to the same date of the month as the previous injection. Continuation injections administered within 7 days before or after the target date were considered on time, as per the label. Virologic undetectability (viral load < 50 copies/mL), suppression (viral load < 200 copies/mL), and confirmed virologic failure (2 consecutive viral loads ≥ 200 copies/mL or 1 viral load ≥ 200 copies/mL followed by discontinuation) were described among individuals with a viral load < 50 copies/mL at initiation and ≥ 1 follow-up viral load. RESULTS: Among 321 individuals on CAB + RPV LA, 90% of the continuation injections were administered on time (within ± 7 days of the target date). Of the 237 individuals with a viral load < 50 copies/mL at initiation and ≥ 1 follow-up viral load, nearly all were undetectable (95%) or suppressed (99%) at their last viral load measurement, 96% maintained virologic suppression with all measured viral loads < 200 copies/mL, and four confirmed virologic failures were observed. Injection delays were infrequent, and did not affect virologic outcomes over the short term. CONCLUSION: In this large US cohort, most monthly CAB + RPV LA injections were administered on time and high levels of virologic control were achieved. These results suggest that CAB + RPB LA injectable can be administered effectively during routine clinical care.

Immune response to ART initiation in advanced HIV infection.

OBJECTIVES: Our objective was to compare the immunological responses to commonly used antiretroviral therapy (ART) regimens among people with advanced HIV in the USA and to assess virological outcomes and regimen persistence. METHODS: This study included ART-naïve adults with advanced HIV infection (CD4 cell count <200 cells/µL) initiating ART with bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), boosted darunavir (bDRV), dolutegravir (DTG), or elvitegravir (EVG/c)-containing regimens between 1 January 2018 and 31 December 2020 in the Observational Pharmaco-Epidemiology Research and Analysis (OPERA) cohort. Cox proportional hazards models and linear mixed models with random intercept were fit with inverse probability of treatment weighting. RESULTS: Overall, 1349 people with advanced HIV (816 B/F/TAF, 253 DTG, 146 EVG/c, 134 bDRV) were followed for a median of 22 months. Compared with B/F/TAF, a lower likelihood of achieving a CD4 cell count ≥200 cells/µL was observed with bDRV (hazard ratio [HR] 0.76; 95% confidence interval [CI] 0.60-0.96), DTG (HR 0.82; 95% CI 0.69-0.98), and EVG/c (HR 0.73; 95% CI 0.57-0.93). All groups had a similar pattern of CD4:CD8 ratio changes: a rapid increase in the first 6 months (ranging from +0.15 to +0.16 units), followed by a slower increase thereafter. Only 40 individuals (4%) achieved CD4:CD8 ratio normalization (≥1). B/F/TAF was associated with a faster time to virological suppression (viral load <200 copies/mL) and a slower time to discontinuation compared with other regimens. CONCLUSIONS: Among people with advanced HIV infection, B/F/TAF initiation was associated with faster CD4 cell count recovery and favourable virological outcomes compared with bDRV-, DTG-, and EVG/c-based regimens, although no difference was observed in CD4:CD8 ratio changes over time across regimens.

Advanced HIV Infection in Treatment-Naïve Individuals: Effectiveness and Persistence of Recommended 3-Drug Regimens.

BACKGROUND: Approximately 20% of newly diagnosed people with HIV (PWH) in the United States have advanced HIV infection, yet the literature on current antiretroviral therapy (ART) options is limited. The discontinuation/modification and effectiveness of common regimens were compared among ART-naïve people with advanced HIV infection (CD4 cell count <200 cells/µL). METHODS: ART-naïve adults with advanced HIV infection initiating bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) or a boosted darunavir (bDRV)-, dolutegravir (DTG)-, or elvitegravir/cobicistat (EVG/c)-based 3-drug regimen between January 1, 2018, and July 31, 2019, in the OPERA cohort were included. The association between regimen and discontinuation or viral suppression (<50 or <200 copies/mL) was assessed using Cox proportional hazards models with inverse probability of treatment weights. RESULTS: Overall, 961 PWH were included (416 B/F/TAF, 106 bDRV, 271 DTG, 168 EVG/c); 70% achieved a CD4 cell count ≥200 cells/µL over a 16-month median follow-up. All regimens were associated with a statistically higher likelihood of discontinuation than B/F/TAF (bDRV: adjusted hazard ratio [aHR], 2.65; 95% CI, 1.75-4.02; DTG: aHR, 2.42; 95% CI, 1.75-3.35; EVG/c: aHR, 3.52; 95% CI, 2.44-5.07). Compared with B/F/TAF, bDRV initiators were statistically less likely to suppress to <50 copies/mL (aHR, 0.72; 95% CI, 0.52-0.99) and <200 copies/mL (aHR, 0.55; 95% CI, 0.43-0.70); no statistically significant difference was detected with DTG or EVG/c. CONCLUSIONS: Among people with advanced HIV infection, those initiating B/F/TAF were less likely to discontinue/modify their regimen than those on any other regimen, and more likely to achieve viral suppression compared with those on bDRV but not compared with those on other integrase inhibitors.

Lipid metabolism and lipodystrophy in HIV-1-infected patients: the role played by nonnucleoside reverse transcriptase inhibitors.

Dyslipidemia and lipodystrophy represent significant healthcare concerns in HIV-infected patients due to their association with diabetes mellitus and increased cardiovascular disease risk. Since the lipid effects of the nonnucleoside reverse transcriptase inhibitors are not well characterized, we systematically summarized the effects of nonnucleoside reverse transcriptase inhibitor treatment on dyslipidemia and lipodystrophy in HIV-1 infection. As with other classes of antiretroviral agents, the nonnucleoside reverse transcriptase inhibitors are associated with lipid changes, although individual agents exhibit differing effects on lipid profiles. Comparative trials have shown that the risk for hypertriglyceridemia is lower with efavirenz than with the use of ritonavir-boosted lopinavir, but there is a greater likelihood of hypercholesterolemia compared to ritonavir-boosted atazanavir. Data also suggest that efavirenz results in greater increases in plasma lipid levels than integrase inhibitors and CC-chemokine-receptor-5 antagonists. Lipid disturbances are less frequent with the newer nonnucleoside reverse transcriptase inhibitors than with efavirenz. However, in most cases, no change in the total:high-density lipoprotein-cholesterol ratio was seen between the efavirenz and comparator groups. Switching from efavirenz to etravirine or rilpivirine, or the integrase inhibitors raltegravir or elvitegravir, resulted in significant reductions in lipid levels. There appears to be minimal potential for efavirenz or rilpivirine to result in development of lipodystrophy. Overall, nonnucleoside reverse transcriptase inhibitors have a smaller impact on plasma lipids than ritonavir-boosted protease inhibitors, with the newer agents exhibiting more favorable lipid profiles than efavirenz. When considering antiretroviral regimens, awareness of the different lipid effect profiles of the third agent is important, without forgetting the critical contribution of the background antiretrovirals.

Lipid levels and changes in body fat distribution in treatment-naive, HIV-1-Infected adults treated with rilpivirine or Efavirenz for 96 weeks in the ECHO and THRIVE trials.

BACKGROUND: Pooled ECHO/THRIVE lipid and body fat data are presented from the ECHO (Efficacy Comparison in Treatment-Naïve, HIV-Infected Subjects of TMC278 and Efavirenz) and THRIVE (TMC278 Against HIV, in a Once-Daily Regimen Versus Efavirenz) trials. METHODS: We assessed the 96-week effects on lipids, adverse events (AEs), and body fat distribution (dual-energy x-ray absorptiometry) of rilpivirine (RPV) and EFV plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs) in treatment-naive adults infected with human immunodeficiency virus type 1 (HIV-1). RESULTS: Rilpivirine produced minimal changes in total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Compared with RPV, EFV significantly (P < .001) increased lipid levels. Decreases in the TC/HDL-C ratio were similar with RPV and EFV. Background N[t]RTI affected RPV-induced lipid changes; all levels increased with zidovudine/lamivudine (3TC) and abacavir/3TC (except triglycerides, which were unchanged). With emtricitabine/tenofovir, levels of HDL-C were increased, TC and LDL-C were unchanged, and triglycerides were decreased. With EFV, lipid levels increased in each N[t]RTI subgroup (except triglycerides were unchanged with abacavir/3TC). Fewer (P < .001) RPV-treated patients than EFV-treated patients had TC, LDL-C, and triglyceride levels above National Cholesterol Education Program cutoffs. More RPV- than EFV-treated patients had HDL-C values below these cutoffs (P = .02). Dyslipidemia AEs were less common with RPV than with EFV. Similar proportions of patients had a ≥10% decrease in limb fat (16% with RPV and 17% with EFV). Limb fat was significantly (P < .001) increased to a similar extent (by 12% with RPV and 11% with EFV). At week 96, patients receiving zidovudine/3TC had lost limb fat, and those receiving emtricitabine/tenofovir had gained it. CONCLUSIONS: Over the course of 96 weeks, RPV-based therapy was associated with lower increases in lipid parameters and fewer dyslipidemia AEs than EFV-based treatment. Body fat distribution changes were similar between treatments. The N[t]RTI regimen affected lipid and body fat distribution changes.

Safety, tolerability, and efficacy of KP-1461 as monotherapy for 124 days in antiretroviral-experienced, HIV type 1-infected subjects.

Treatment of HIV infection with conventional antiretroviral therapy (ART) is a lifelong challenge with significant long-term risks of adverse events and treatment failure-induced HIV resistance being major concerns. One potential alternative to standard treatment is the use of viral decay accelerators, antiviral agents that theoretically can drive the rate of viral mutation beyond the compensatory capacity of the virus, thereby inducing viral extinction. One such drug, KP-1461, was tested in a population of HIV-infected persons not receiving ART to assess the safety, tolerability, and efficacy of the strategy in vivo. Of 24 highly treatment-experienced HIV-infected patients who received at least one dose of KP-1461, 13 completed the planned 4 months of monotherapy. The drug was generally well tolerated; it did not significantly affect either HIV viral load or CD4 lymphocyte count over the period of dosing. Pharmacokinetic sampling suggested adequate drug exposure was achieved. There were no new mutations induced by KP-1461 that changed viral susceptibility to standard antiretroviral agents. After the study was completed, analysis of more than 7 million base pairs of HIV samples from study patients and controls demonstrated changes in the pattern of viral mutations that differed significantly from what would be encountered naturally. The identified alterations were consistent with an effect resulting from KP-1461's proposed mechanism of action. These findings suggest that the novel antiretroviral approach illustrated by this study should be further investigated, particularly given the relatively good tolerability and the demonstrated excellent safety in this limited cohort study.

Efficacy, safety, and tolerability of etravirine with and without darunavir/ritonavir or raltegravir in treatment-experienced patients: analysis of the etravirine early access program in the United States.

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.

Improvement in lipid profiles in antiretroviral-experienced HIV-positive patients with hyperlipidemia after a switch to unboosted atazanavir.

OBJECTIVE: The primary objective was to compare the change in fasting low-density lipoprotein (LDL) cholesterol from baseline to week 12 between patients receiving an atazanavir-containing regimen and those receiving comparator protease inhibitor (PI) regimens. DESIGN: AI424-067 was a 48-week, open-label, randomized, prospective study of 246 patients on PI-based regimens with hyperlipidemia [fasting LDL cholesterol >130 mg/dL (>3.4 mmol/L)] and with HIV RNA <50 copies per milliliter. Patients were randomized to switch to atazanavir (400 mg once daily) on day 1 (immediate switch) or maintain current PI regimen for the first 24 weeks, then switch to atazanavir (delayed switch). METHODS: Plasma lipid levels were compared with baseline values at weeks 12, 24, and 48. Safety, viral load, and CD4 profiles were also evaluated. RESULTS: At week 12, the mean percent changes in LDL cholesterol from baseline for the immediate-switch and delayed-switch groups were -15% and +1%, respectively (P < 0.0001). Favorable LDL cholesterol levels in the immediate-switch group were sustained through week 48. Both groups maintained comparable virologic control. Switching to atazanavir did not produce a significant change in safety or tolerability. CONCLUSIONS: A switch-either immediate or delayed-from a boosted or unboosted PI to unboosted atazanavir in patients with hyperlipidemia was associated with improvements in plasma lipid parameters without loss of virological suppression.

Comparison of once-daily fosamprenavir boosted with either 100 or 200 mg of ritonavir, in combination with abacavir/lamivudine: 96-week results from COL100758.

The long-term efficacy of once-daily (qd) fosamprenavir (FPV) 1400 mg boosted by ritonavir 100 mg (FPV/r100) has not been evaluated previously. A 96-week open-label, randomized, multicenter study compared the efficacy/safety of FPV/r100 with FPV 1400 mg boosted by ritonavir 200 mg qd (FPV/r200), plus abacavir/lamivudine 600 mg/300 mg qd, in antiretroviral-naive, HIV-infected patients with viral load (VL)> or =1000 copies/ml. Primary endpoints were proportion of patients achieving VL <400 copies/ml or discontinuing for drug-related reasons. In the intent-to-treat:exposed (ITT-E) population, missing = failure (M = F), and observed approaches were used to assess between-arm differences in VL responses by Cochran-Mantel-Haenszel test and CD4(+) count by Wilcoxon rank-sum test. One hundred and fifteen (115) patients enrolled, with 58 on FPV/r100 (median VL 4.7 log(10) copies/ml; CD4(+) count 259 cells/mm(3)) and 57 on FPV/r200 (median VL 4.9 log(10) copies/ml; CD4(+) count 179 cells/mm(3)). Fewer FPV/r100-treated patients discontinued treatment prematurely (12 vs. 24) and experienced virologic failure (5 vs. 8, none developing major protease inhibitor resistance mutations). At week 96, more FPV/r100-treated patients had VL <400 copies/ml [ITT-E,M = F: 78% (45/58) vs. 53% (30/57), p = 0.006; observed: 98% (45/46) vs. 94% (30/32)] and VL<50 copies/ml [ITT-E,M = F: 66% (38/58) vs. 53% (30/57); observed: 83% (38/46) vs. 94% (30/32)]. The FPV/r100 and FPV/r200 arms were similar at week 96 regarding median change from baseline in CD4(+) count (+265 vs. +260 cells/mm(3)) and total cholesterol (+33 vs. +35 mg/dl), and in total-cholesterol:HDL-cholesterol ratio (4.0 vs. 4.1) and type/frequency of treatment-related grade 2-4 adverse events, although FPV/r100 was associated with a lower elevation in triglycerides (+27 vs. +48 mg/dl). In conclusion, through 96 weeks, FPV/r100 was more effective and prompted less elevation in triglycerides than FPV/r200.

Once-daily abacavir/lamivudine and ritonavir-boosted atazanavir for the treatment of HIV-1 infection in antiretroviral-naïve patients: a 48-week pilot study.

PURPOSE: To assess the efficacy and safety of a once-daily (QD) regimen consisting of the co-formulation of abacavir/lamivudine (ABC/3TC) and atazanavir plus ritonavir (ATV-RTV) in antiretroviral (ART)-naïve patients with plasma HIV-1 RNA >5,000 copies/mL. METHOD: This open-label, multicenter study conducted between September 2004 and June 2006 included 112 patients who received ABC 600 mg/3TC 300 mg and ATV 300 mg-RTV 100 mg QD. Drug switches were permitted for ABC hypersensitivity and ATV-related hyperbilirubinemia. Primary endpoints were proportion of patients achieving HIV-1 RNA <50 copies/mL at Week 48 and treatment discontinuation due to study drugs. RESULTS: A total of 111 patients were treated. At Week 48, the proportion of patients achieving HIV-1 RNA <50 copies/mL was 77% (85/111) by intent-to-treat (ITT) missing=failure, switch included response rate. Drug substitutions occurred in 8 (7%) patients for suspected ABC hypersensitivity reaction (HSR) and in 6 (5%) patients for ATV-related toxicities; only 1 patient discontinued study due to ABC HSR. Four patients met confirmed virologic nonresponse (HIV RNA >or= 400 copies/mL). Treatment-emergent drug resistance was rare, and no patient had virus that developed reduced susceptibility to ATV. Median change from baseline (95% confidence interval) in fasting lipids at Week 48 was 39 (26-66) mg/dL for triglycerides, 28 (22-38) mg/dL for total cholesterol (C), 14 (10.5-16) mg/dL for HDL-C, and 8 (2-16.5) mg/dL for LDL-C. CONCLUSION: ABC/3TC and ATV-RTV QD is an effective and well-tolerated regimen in ART-naïve patients through 48 weeks, with a modest impact on fasting lipids.

Ritonavir-boosted protease inhibitors: impact of ritonavir on toxicities in treatment-experienced patients.

The purpose of this review is to discuss the basis for ritonavir boosting of protease inhibitors as well as the complications and benefits associated with ritonavir boosting when designing an antiretroviral regimen for treatment-experienced patients. Such patients have fewer viable options because of cross-resistance arising from previous regimen failures. Ritonavir administered at a low dose to boost another protease inhibitor may be a useful strategy for achieving virological efficacy while minimizing the toxicities associated with full-dose ritonavir. There may be an increased risk of adverse events associated with increased plasma concentration of the concurrent protease inhibitor. Still, the incidence of these adverse events is generally low, and clinical trials have suggested that they rarely result in discontinuation or alteration of the regimen. In highly treatment-experienced patients in particular, the potential benefits associated with ritonavir boosting usually outweigh the risks.

Long-Term suppression of HIV infection: benefits and limitations of current treatment options.

HIV type 1, a causative agent of AIDS, is a source of worldwide morbidity and mortality. There are an estimated 1 million people in North America currently living with HIV infection, and more than 40,000 new cases occur annually. Before the advent of highly active antiretroviral therapy (HAART), the mortality rate of HIV infection was nearly 100%, and life expectancy was short. However, successful HAART delays the onset of AIDS, allowing patients to live with chronic HIV infection for 20 years or more. HAART usually consists of a combination of protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), and/or nonnucleoside reverse transcriptase inhibitors (NNRTIs). Although these agents are highly efficacious in delaying the onset of AIDS, their clinical utility is limited by viral resistance, nonadherence to therapy, and drug toxicity. Consequently, multidrug regimens are necessary for successful treatment. Initial NNRTI-based HAART regimens are effective at reducing viral load and boosting CD4(+) cell counts. NNRTI resistance is uncommon, but should it occur, the NNRTI-based therapy needs to be quickly replaced by a PI-based therapy. Triple NRTI-based regimens are recommended only if NNRTI- or PI-based regimens cannot be used. When developing a multidrug regimen, it is also important to select HAART agents with limited adverse effects. Because each HAART agent has its own unique adverse effect profile, selecting a regimen with a favorable profile may be difficult. For example, certain PIs produce adverse metabolic effects that may increase the risk of developing cardiovascular disease. In contrast, NNRTI-based therapies have a different side effect profile. Because each HAART agent has specific limitations, tailoring a regimen to the individual patient is of paramount importance for achieving optimal outcomes.

Substituting abacavir for hyperlipidemia-associated protease inhibitors in HAART regimens improves fasting lipid profiles, maintains virologic suppression, and simplifies treatment.

BACKGROUND: Hyperlipidemia secondary to protease inhibitors (PI) may abate by switching to anti-HIV medications without lipid effects. METHOD: An open-label, randomized pilot study compared changes in fasting lipids and HIV-1 RNA in 104 HIV-infected adults with PI-associated hyperlipidemia (fasting serum total cholesterol >200 mg/dL) who were randomized either to a regimen in which their PI was replaced by abacavir 300 mg twice daily (n = 52) or a regimen in which their PI was continued (n = 52) for 28 weeks. All patients had undetectable viral loads (HIV-1 RNA <50 copies/mL) at baseline and were naive to abacavir and non-nucleoside reverse transcriptase inhibitors. RESULTS: At baseline, the mean total cholesterol was 243 mg/dL, low density lipoprotein (LDL)-cholesterol 149 mg/dL, high density lipoprotein (HDL)-cholesterol 41 mg/dL, and triglycerides 310 mg/dL. Mean CD4+ cell counts were 551 and 531 cells/mm3 in the abacavir-switch and PI-continuation arms, respectively. At week 28, the abacavir-switch arm had significantly greater least square mean reduction from baseline in total cholesterol (-42 vs -10 mg/dL, P < 0.001), LDL-cholesterol (-14 vs +5 mg/dL, P = 0.016), and triglycerides (-134 vs -36 mg/dL, P = 0.019) than the PI-continuation arm, with no differences in HDL-cholesterol (+0.2 vs +1.3 mg/dL, P = 0.583). A higher proportion of patients in the abacavir-switch arm had decreases in protocol-defined total cholesterol and triglyceride toxicity grades, whereas a smaller proportion had increases in these toxicity grades. At week 28, an intent-to treat: missing = failure analysis showed that the abacavir-switch and PI-continuation arms did not differ significantly with respect to proportion of patients maintaining HIV-1 RNA <400 or <50 copies/mL or adjusted mean change from baseline in CD4+ cell count. Two possible abacavir-related hypersensitivity reactions were reported. No significant changes in glucose, insulin, insulin resistance, C-peptide, or waist-to-hip ratios were observed in either treatment arm, nor were differences in these parameters noted between treatments. CONCLUSION: In hyperlipidemic, antiretroviral-experienced patients with HIV-1 RNA levels <50 copies/mL and CD4+ cell counts >500 cells/mm3, substituting abacavir for hyperlipidemia-associated PIs in combination antiretroviral regimens improves lipid profiles and maintains virologic suppression over a 28-week period, and it simplifies treatment.

Once-daily versus twice-daily lamivudine, in combination with zidovudine and efavirenz, for the treatment of antiretroviral-naive adults with HIV infection: a randomized equivalence trial.

A randomized, double-blind, double-dummy controlled, multicenter trial was conducted that involved 554 antiretroviral-naive human immunodeficiency virus-infected adults (plasma HIV type 1 [HIV-1] RNA level, >or=400 copies/mL; CD4(+) cell count, >100 cells/mm(3)) and compared a 300-mg once-daily (q.d.) regimen of lamivudine (3TC) versus a 150-mg twice-daily (b.i.d.) regimen of 3TC, combined with zidovudine (300 mg b.i.d.) and efavirenz (600 mg q.d.), during a 48-week period. Treatments were considered equivalent if the 95% confidence interval (CI) for the difference in proportions of patients achieving an HIV-1 RNA level of <400 copies/mL was within the bound of -12% to 12%. At week 48 of the study, an intent-to-treat analysis in which patients with missing data were considered to have experienced treatment failure showed that the 3TC q.d. and 3TC b.i.d. regimens were equivalent (HIV-1 RNA level <400 copies/mL, 178 [64%] of 278 vs. 174 [63%] of 276; treatment difference, 1% [95% CI, -7.1% to 8.9%]; HIV-1 RNA level <50 copies/mL, 165 [59%] of 278 vs. 168 [61%] of 276; treatment difference, 1.7% [95% CI, -9.7% to 6.6%]). Median increase above baseline in CD4(+) cell count was similar (q.d. group, +144 cells/mm(3); b.i.d. group, +146 cells/mm(3)), and the incidences of adverse events, disease progression, and HIV-associated conditions were comparable.

Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV.

BACKGROUND: Atazanavir, an azapeptide protease inhibitor (PI), has pharmacokinetics that allow once-daily dosing, and it is not associated with significant PI-associated dyslipidemia. METHODS: A randomized, double-blind, double-dummy, active-controlled, 2-arm study comparing the antiviral efficacy and safety of atazanavir 400 mg administered once daily with efavirenz 600 mg administered once daily in combination with open-label fixed-dose zidovudine plus lamivudine twice daily. The 810 treatment-naive patients were stratified by HIV RNA level. The primary efficacy end point was the proportion of treated patients with HIV RNA levels <400 copies/mL through week 48. RESULTS: At week 48, HIV RNA levels were <400 copies/mL in 70% of patients receiving atazanavir and 64% of patients receiving efavirenz (intent-to-treat, difference; 95% confidence interval: 5.2%; -1.2%, 11.7%). Median CD4 cell counts increased at comparable magnitudes and rates in the 2 treatment arms (mean change at week 48: 176 cells/mm with atazanavir, 160 cells/mm with efavirenz). Atazanavir-treated patients relative to comparator-treated patients did not demonstrate significant increases in total cholesterol, fasting low-density lipoprotein cholesterol, or fasting triglycerides over 48 weeks of therapy. Atazanavir-linked bilirubin elevations infrequently resulted in treatment discontinuation (<1%). Atazanavir treatment did not increase fasting glucose or insulin levels. CONCLUSIONS: For initial HIV treatment, a highly active antiretroviral therapy regimen of atazanavir/zidovudine/lamivudine is as efficacious and well tolerated as the combination of efavirenz/zidovudine/lamivudine.

Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir.

The purpose of the study was to determine long-term efficacy, safety, and tolerability of atazanavir plus stavudine/lamivudine in 346 HIV-infected patients previously treated with atazanavir or nelfinavir. BMS AI424-044 is an ongoing, multicenter, international, open-label, rollover/switch study initiated in June 2001. Patients completing >or=48 weeks in trial BMS AI424-008 with a plasma HIV RNA viral load <10,000 copies/mL were eligible to continue on atazanavir (400 or 600 mg) or to switch from nelfinavir to atazanavir (400 mg) once daily. Antiviral efficacy, change in CD4 cell counts, and effect on lipid parameters were measured. After 24 weeks of atazanavir use in BMS AI424-044, 83%, 85%, and 87% of the atazanavir 400-mg, atazanavir 600-mg, and nelfinavir-to-atazanavir-switched patients, respectively, had HIV RNA levels <400 copies/mL compared with 76%, 76%, and 63%, respectively, at week 48 of BMS AI424-008. Atazanavir-treated patients showed minimal changes in lipid levels compared with baseline. Patients switched from nelfinavir to atazanavir showed significant mean percent decreases in total cholesterol (-16%), fasting low-density lipoprotein cholesterol (-21%), and fasting triglycerides (-28%) (P<0.0001) by week 12 of atazanavir treatment. No new safety issues were identified, and the overall incidence of treatment-emergent adverse events during BMS AI424-044 was comparable across treatment groups. Atazanavir was safe, tolerable, and effective during extended use and in patients switched from nelfinavir. Extended atazanavir use resulted in continued viral suppression and lipid changes that were not clinically relevant. In virologically suppressed nelfinavir-treated patients switched to atazanavir, virologic improvement continued, whereas nelfinavir-induced lipid elevations were reversed within 12 weeks, approaching pretreatment values.

Initial therapy for human immunodeficiency virus: broadening the options.

The goal of investigation into new therapeutic options for HIV/AIDS is to further the achievements of highly active antiretroviral therapy by developing new drugs with improved efficacy. Although several therapies are currently available for initial therapy in HIV-infected patients, ongoing research focuses on additions to existing and novel drug classes that might have improved pharmacokinetic and tolerability profiles, as well as on new therapeutic combinations that might result in synergistic activity. To retain activity against resistant strains, novel drugs need to target the numerous critical points in the life cycle of HIV, inhibiting different enzyme subsites than those affected by antiretroviral agents currently in use. An improvement in patient adherence to therapy is another key objective of efforts in HIV treatment, as suboptimal drug levels are a main determinant of antiretroviral regimen failure. This article reviews the current classes of antiretroviral agents in development, describing the clinical data obtained to date. These agents may have potential use as initial therapy in HIV patients.

Improvement in lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virus-infected patients switched from stavudine to abacavir or zidovudine: the results of the TARHEEL study.

Stavudine use is a contributing factor for lipoatrophy, whereas use of abacavir or zidovudine is less likely to cause this complication. The TARHEEL study was a 48-week, open-label study that assessed changes in lipoatrophy after abacavir (86 patients [73%]) or zidovudine (32 patients [27%]), 300 mg twice daily, was substituted for stavudine for 118 human immunodeficiency virus (HIV)-infected patients (HIV type 1 RNA level, <400 copies/mL) with virological suppression who had developed lipoatrophy after > or =6 months of stavudine-based treatment. At week 48, full-body dual-energy x-ray absorptiometry demonstrated a median increase in arm fat of 35%, leg fat of 12%, and trunk fat of 18%, compared with the baseline level. These improvements coincided with fat gain in lipoatrophic areas that was documented by computerized tomography. Results of a "body image" questionnaire showed that a substantial percentage of patients reported some or a lot of fat gain in the arms (22%), legs (18%), buttocks (19%), and face (27%). HIV suppression was maintained over the study period. In conclusion, replacing stavudine with abacavir or zidovudine resulted in improvement in stavudine-induced lipoatrophy.