Safety, Tolerability, Pharmacokinetics, and Acceptability of Oral and Long-Acting Cabotegravir in HIV-Negative Chinese Men.

Long-acting (LA) cabotegravir demonstrated superior efficacy versus daily oral standard-of-care for HIV-1 preexposure prophylaxis. This phase 1 study assessed safety, tolerability, pharmacokinetics, and acceptability of cabotegravir in 47 HIV-negative adult Chinese men at low risk of acquiring HIV-1. Participants received once-daily oral cabotegravir 30 mg for 4 weeks and, after a 1-week washout, five 600-mg (3-mL) intramuscular cabotegravir LA injections at weeks 5, 9, 17, 25, and 33. Pharmacokinetic plasma samples were intensively collected on day 27 (n = 17) and sparsely collected before each injection until 56 weeks after final injection (n = 47). Cabotegravir LA injections were acceptable and well tolerated. Common adverse events included injection site pain, injection site swelling, and upper respiratory tract infection. No drug-related serious adverse events or deaths occurred. Mean cabotegravir concentration remained above 1.33 µg/mL (8× in vitro protein-adjusted concentration for 90% of the maximum inhibition of viral growth [PA-IC90]) before each injection and above 0.166 µg/mL (PA-IC90) for >32 weeks after final injection. Trough concentrations remained above PA-IC90 in nearly all participants and showed minimal accumulation. Noncompartmental pharmacokinetic analysis was performed. Geometric mean of terminal half-life was 1.89 and 47 days after oral and LA dosing, respectively. Cabotegravir concentrations were estimated to remain quantifiable for 48.7 weeks after final injection. Steady-state area under the concentration-time curve (AUC), peak concentration, trough concentration, terminal half-life, time to peak concentration, and apparent clearance after cabotegravir oral and LA dosing were similar to those estimated in non-Asian men in historical studies. These results support further clinical development of cabotegravir LA in China. (This study has been registered at ClinicalTrials.gov under registration no. NCT03422172.).

Unexpected finding of delayed-onset seizures in HIV-positive, treatment-experienced subjects in the Phase IIb evaluation of fosdevirine (GSK2248761).

BACKGROUND: Fosdevirine (GSK2248761) is a non-nucleoside reverse transcriptase inhibitor with HIV-1 activity against common efavirenz-resistant strains. Two partially blind, randomized, Phase IIb studies were initiated (1 in treatment-naive and 1 in treatment-experienced subjects with HIV) to select a once-daily dose of fosdevirine for Phase III trials. METHODS: In the SIGNET study, treatment-naive subjects were randomized 1:1:1 to receive once-daily fosdevirine 100 or 200 mg or efavirenz 600 mg, each along with tenofovir disoproxil fumarate/emtricitabine 300 mg/200 mg or abacavir/lamivudine 600 mg/300 mg. In the SONNET study, treatment-experienced subjects with non-nucleoside reverse transcriptase inhibitor-resistant HIV-1 were randomized 1:1:1 to treatment with fosdevirine 100 or 200 mg once daily or etravirine 200 mg twice daily, each along with twice-daily darunavir/ritonavir 600/100 mg and raltegravir 400 mg. The primary efficacy end point was the proportion of subjects with HIV-1 RNA<50 copies/ml. Safety and pharmacokinetics were also addressed. RESULTS: A total of 35 subjects were exposed to fosdevirine 100 or 200 mg. Trials were halted when 5 treatment-experienced subjects (1 receiving fosdevirine 100 mg, 4 receiving fosdevirine 200 mg) developed new-onset seizures after ≥4 weeks of exposure to fosdevirine. There was no clear association between seizures and fosdevirine plasma drug levels. Time to seizure onset ranged from 28 to 81 days, and all 5 subjects experienced ≥1 seizure after drug discontinuation. CONCLUSIONS: The delayed onset of seizures after fosdevirine exposure and persistence after discontinuation is without precedent in antiretroviral drug development, leading to additional investigation and underscoring the need for careful subject monitoring.

Similar virologic and immunologic efficacy with fosamprenavir boosted with 100 mg or 200 mg of ritonavir in HIV-infected patients: results of the LESS trial.

PURPOSE: ritonavir (RTV) effectively boosts most protease inhibitors but is associated with significant dose-dependent adverse events (AEs). In an effort to better manage toxicities through a reduced dose of RTV, this study compared fosamprenavir (FPV) boosted with RTV 100 mg (FPV/r100) or with RTV 200 mg (FPV/r200) daily. METHODS: this 24-week, open-label study enrolled patients taking a FPV/r 200-containing regimen who had HIV RNA <400 copies/mL and randomized them 1:2 to continue that regimen or simplify to FPV/r100 once daily. Other medications were not altered. The primary endpoint was the percentage of patients without suspected or confirmed virologic failure (HIV RNA ≥ 400 copies/mL) through week 24 by a missing/discontinuation equals failure (M/D=F) analysis. Noninferiority criteria were demonstrated if the lower bound of the 95% confidence interval (CI) for the difference in the primary endpoint rates between groups was greater than -12. RESULTS: the 2 regimens met prespecified noninferiority criteria (FPV/r100, 92%; FPV/r 200, 94%; 95% CI, -9.36 to 5.12). At week 24, the percentage of patients with HIV RNA <50 copies/mL by M/ D=F was 83% in the FPV/r100 group and 85% in the FPV/r 200 group. Drug-related grade 2-4 AEs were uncommon (FPV/r100, 4%; FPV/r 200, 7%). Median changes in lipids were similar in both groups, with the exception of triglycerides (FPV/r100, -21 mg/dL; FPV/r 200, -2 mg/dL). CONCLUSIONS: this 24-week study demonstrated that among previously suppressed patients, once-daily FPV/r100 was similar to FPV/r 200 in virologic and immunologic effects but was associated with greater decreases from baseline in triglyceride levels.

Similar efficacy and tolerability of atazanavir compared with atazanavir/ritonavir, each with abacavir/lamivudine after initial suppression with abacavir/lamivudine plus ritonavir-boosted atazanavir in HIV-infected patients.

BACKGROUND: Treatment simplification strategies involving induction with a ritonavir (RTV)-boosted (/r) protease inhibitor regimen followed by simplification (without RTV) are appealing because they may offer sustained virologic suppression while minimizing potential long-term adverse effects associated with RTV. METHODS: This open-label, randomized, noninferiority study enrolled 515 antiretroviral therapy-naive patients to receive abacavir/lamivudine plus atazanavir/RTV (ATV/r) followed by randomization at week 36 (N = 419) to maintain or discontinue RTV for an additional 48 weeks. Eligibility for randomization required confirmed HIV RNA level below 50 copies/ml and no virologic failure. Protocol-defined virologic failure after week 36 was confirmed rebound of HIV RNA level at least 400 copies/ml. The primary endpoint was the proportion of patients with HIV RNA level below 50 copies/ml at week 84 (time to loss of virologic response). This study is registered with ClinicalTrials.gov number NCT00440947. RESULTS: At week 84, noninferiority of ATV to ATV/r (95% confidence interval around the treatment difference -1.75 to 12.48%) was demonstrated with 181 of 210 (86%) patients in the ATV group and 169 of 209 (81%) in the ATV/r group maintaining HIV RNA level below 50 copies/ml. During the randomized phase (weeks 36-84), 10 versus 14% of patients in the ATV and ATV/r arms, respectively, experienced a drug-related grades 2-4 adverse event with hyperbilirubinemia being the most frequently reported (4 versus 10%). The overall rate of protocol-defined virologic failure was 2%; no patient had virus that developed a major protease inhibitor mutation. CONCLUSION: ATV in combination with abacavir/lamivudine is a potent and well tolerated regimen in patients who have achieved initial suppression on an induction regimen and represents a viable treatment simplification strategy.

Safety and efficacy of a 36-week induction regimen of abacavir/lamivudine and ritonavir-boosted atazanavir in HIV-infected patients.

PURPOSE: The ARIES study assessed safety and efficacy of an induction regimen with atazanavir/ritonavir (ATV/RTV) + abacavir/lamivudine (ABC/3TC) followed by simplification to ATV + ABC/3TC in antiretroviral-naïve patients. METHODS: This report includes a noncomparative analysis of all patients in the induction phase of the ARIES study through 36 weeks (clinicaltrials.gov: NCT00440947). This open-label study included 515 antiretroviral-naïve,HLA-B*5701-negative patients receiving a regimen of ATV 300 mg, RTV 100 mg, and ABC/3TC 600 mg/300 mg once daily for 36 weeks; eligible patients were then randomized to continue the induction regimen or simplify to ATV 400 mg plus ABC/3TC 600 mg/300 mg once daily. RESULTS: Eighty-six percent (442/515) of patients completed 36 weeks on study; 80% (410/515) achieved HIV RNA <50 copies/mL (84% and 76% of patients with baseline HIV RNA of < and >or=100,000 copies/mL achieved this endpoint). Virologic failure (VF) was uncommon (3%); treatment-emergent major protease inhibitor and nucleoside reverse transcriptase inhibitor mutations were detected in 0/15 and 4/15 patients, respectively. Median CD4+ cell increase was 171 (range, -176 to 718) cells/mm(3). Hyperbilirubinemia (13%), diarrhea (4%), nausea (2%), and rash (2%) were the most frequent drug-related Grade 2-4 adverse events. Few adverse events (3%) led to study discontinuation. CONCLUSIONS: Induction with ATV/RTV + ABC/3TC once daily provides an efficacious and well-tolerated regimen for the initial treatment of HIV.

A study of HIV provider attitudes toward HLA-B 5701 testing in the United States.

Screening for HLA-B 5701 reduces the risk of developing an abacavir hypersensitivity reaction (ABC HSR) and is recommended in all patients before initiating highly active antiretroviral therapy (HAART) with abacavir. Between September 2007 and March 2008 we conducted a study of the attitudes and practice patterns of HIV providers in the United States to identify barriers to HLA-B 5701 testing in clinical practice. Study participants who completed an educational program could receive HLA-B 5701 test kits for use in their clinical practice. Surveys were administered before and after the educational program. A total of 477 HIV providers registered to participate in the survey, and 134 providers tested a total of 874 HIV-infected subjects, of which 6% (49/874) were HLA-B 5701 positive. Of 433 providers who completed the preeducation survey, 97% indicated that the test provided clinical value and 77% anticipated barriers to testing, with cost/reimbursement the most frequently cited. Among 202 providers who completed the posteducation survey, perceptions of the test's value remained largely unchanged while the proportion of providers who anticipated or encountered barriers to testing decreased. Of providers who used HLA-B 5701 test kits, 86% (115/134) found it "very easy" or "easy" to obtain test results, 95% (127/134) found it "very easy" or "easy" to interpret results, and 89% (119/134) indicated that they planned to continue HLA-B 5701 testing after the study. The results of this study suggest that HLA-B 5701 testing is easy to use in clinical practice and is a valuable tool to help reduce the risk of developing ABC HSR.

Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment.

BACKGROUND: Abacavir sulfate/lamivudine (ABC/3TC) and tenofovir DF/emtricitabine (TDF/FTC) are widely used nucleoside reverse transcriptase inhibitors for initial HIV-1 treatment. This is the first completed, randomized clinical trial to directly compare the efficacy, safety, and tolerability of these agents, each in combination with lopinavir/ritonavir in antiretroviral-naive patients. METHODS: Six hundred and eighty-eight antiretroviral-naive, HIV-1-infected patients were randomized in this double-blind, placebo-matched, multicenter, noninferiority study to receive a once-daily regimen of either ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg, both with lopinavir/ritonavir 800 mg/200 mg. Primary endpoints were the proportion of patients with HIV-1 RNA below 50 copies/ml at week 48 (missing = failure, switch included analysis) and the proportion of patients experiencing adverse events over 96 weeks. RESULTS: At week 48, 68% in the ABC/3TC group vs. 67% in the TDF/FTC group achieved an HIV-1 RNA below 50 copies/ml (intent-to-treat exposed missing = failure, 95% confidence interval on the difference -6.63 to 7.40, P = 0.913), demonstrating the noninferiority of ABC/3TC to TDF/FTC at week 48. Noninferiority of the two regimens was sustained at week 96 (60% vs. 58%, respectively, 95% confidence interval -5.41 to 9.32, P = 0.603). In addition, efficacy of both regimens was similar in patients with baseline HIV-1 RNA >or= 100 000 copies/ml or CD4 cell counts below 50 cells/microl. Median CD4 recovery (ABC/3TC vs. TDF/FTC, cells/microl) was +250 vs. +247 by week 96. Premature study discontinuation due to adverse events occurred in 6% of patients in both groups. Protocol-defined virologic failure occurred in 14% of patients in both groups. CONCLUSION: Both ABC/3TC and TDF/FTC provided comparable antiviral efficacy, safety, and tolerability when each was combined with lopinavir/ritonavir in treatment-naive patients.

First large, multicenter, open-label study utilizing HLA-B*5701 screening for abacavir hypersensitivity in North America.

A hypersensitivity reaction is associated with abacavir in approximately 2-8% of exposed patients. The frequency of the HLA-B*5701 allele varies across racial groups and significantly correlates with risk of hypersensitivity. Studies in Europe and Western Australia demonstrated that prospective screening can significantly reduce the rate of hypersensitivity by avoiding the use of abacavir in patients carrying the HLA-B*5701 allele. Prospective HLA-B*5701 screening in a large, racially diverse North American population resulted in less than 1% of individuals diagnosed with a suspected abacavir hypersensitivity reaction (ABC HSR) and no positive skin patch test through 30 weeks among HLA-B*5701-negative individuals.

High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients.

BACKGROUND: Although the human leukocyte antigen (HLA)-B*5701 is highly associated with a hypersensitivity reaction (HSR) to abacavir (ABC), variable sensitivities have been reported when clinical data alone have been used to define an ABC HSR. This study evaluated the sensitivity of detection of the HLA-B*5701 allele as a marker of ABC HSRs in both white and black patients, using skin patch testing to supplement clinical diagnosis. METHODS: White and black patients, identified through chart review, were classified as having received a diagnosis of an ABC HSR based on clinical findings only (a clinically suspected ABC HSR) or based on clinical findings and a positive skin patch test result (an immunologically confirmed [IC] ABC HSR). Control subjects were racially matched subjects who tolerated ABC for >/=12 weeks without experiencing an ABC HSR. Patients and control subjects were tested for the presence of HLA-B*5701. Sensitivity, specificity, and odds ratios for the detection of HLA-B*5701 as a marker for an ABC HSR were calculated for white and black participants. RESULTS: Forty-two (32.3%) of 130 white patients and 5 (7.2%) of 69 black patients who met the criteria for clinically suspected HSRs had IC HSRs. All 42 white patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 1945; 95% confidence interval, 110-34,352). Among all white patients with clinically suspected HSRs, sensitivity was 44% (57 of 130 patients tested positive for HLA-B*5701); specificity among white control subjects was 96%. Five of 5 black patients with IC HSRs were HLA-B*5701 positive (sensitivity, 100%; odds ratio, 900; 95% confidence interval, 38-21,045). Among black patients with clinically suspected HSRs, the sensitivity was 14% (10 of 69 tested positive for HLA-B*5701); specificity among black control subjects was 99%. CONCLUSIONS: Although IC ABC HSRs are uncommon in black persons, the 100% sensitivity of HLA-B*5701 as a marker for IC ABC HSRs in both US white and black patients suggests similar implications of the association between HLA-B*5701 positivity and risk of ABC HSRs in both races.

The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial.

BACKGROUND: Lopinavir-ritonavir is a preferred protease inhibitor co-formulation for initial HIV-1 treatment. Fosamprenavir-ritonavir has shown similar efficacy and safety to lopinavir-ritonavir when each is combined with two nucleoside reverse transcriptase inhibitors. We compared the two treatments directly in antiretroviral-naive patients. METHODS: This open-label, non-inferiority study included 878 antiretroviral-naive, HIV-1-infected patients randomised to receive either fosamprenavir-ritonavir 700 mg/100 mg twice daily or lopinavir-ritonavir 400 mg/100 mg twice daily, each with the co-formulation of abacavir-lamivudine 600 mg/300 mg once daily. Primary endpoints were proportion of patients achieving HIV-1 RNA less than 400 copies per mL at week 48 and treatment discontinuations because of an adverse event. The intent-to-treat analysis included all patients exposed to at least one dose of randomised study medication. This study is registered with ClinicalTrials.gov, number NCT00085943. FINDINGS: At week 48, non-inferiority of fosamprenavir-ritonavir to lopinavir-ritonavir (95% CI around the treatment difference -4.84 to 7.05) was shown, with 315 of 434 (73%) patients in the fosamprenavir-ritonavir group and 317 of 444 (71%) in the lopinavir-ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two treatment groups (fosamprenavir-ritonavir 53, 12%; lopinavir-ritonavir 43, 10%). Diarrhoea, nausea, and abacavir hypersensitivity were the most frequent drug-related grade 2-4 adverse events. Treatment-emergent drug resistance was rare; no patient had virus that developed reduced susceptibility to fosamprenavir-ritonavir or lopinavir-ritonavir. INTERPRETATION: Fosamprenavir-ritonavir twice daily in treatment-naive patients provides similar antiviral efficacy, safety, tolerability, and emergence of resistance as lopinavir-ritonavir, each in combination with abacavir-lamivudine.

The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1-infected patients.

OBJECTIVE: To compare the efficacy, durability, and tolerability of GW433908 (908), 1400 mg twice-daily (BID), with nelfinavir (NFV), 1250 mg BID. METHODS: This was an international, multicenter, randomized, open-label study (NEAT) in antiretroviral therapy (ART)-naive HIV-infected adults with plasma HIV-1 RNA (vRNA) at screening > or =5000 copies/mL (c/mL). Patients were randomly assigned to 908 or NFV (2:1) for a minimum of 48 weeks, with a background of abacavir (ABC) and lamivudine (3TC). RESULTS: A total of 166 patients received randomized treatment with 908 BID and 83 received NFV BID. The population was diverse with regard to race and gender (76% Hispanics and blacks, 31% female) and had advanced HIV disease at screening (45% had vRNA >100,000 c/mL, 48% had CD4 cell counts <200 cells/mm3, 20% had a history of Centers for Disease Control class C events). After 48 weeks of study by an intention-to-treat rebound or discontinuation = failure analysis, a greater proportion of patients in the 908 BID group (66%) than the NFV BID group (51%) achieved vRNA <400 c/mL. Furthermore, more patients with screening vRNA >100,000 c/mL (67 vs. 35%) or CD4 <50 cells/mm3 (48 vs. 24%) achieved undetectable viral loads taking 908 BID compared with NFV BID, respectively. Favorable immunologic responses were observed for both groups. Diarrhea, which was more common in the NFV BID group (18 vs. 5%), was the only drug-related grade 2-4 adverse event with a significant difference (P = 0.002) in incidence between groups. CONCLUSION: Administration of 908 BID resulted in a potent and sustained antiretroviral response, notably in ART-naive patients with advanced HIV disease. GW433908 was generally well tolerated and provides a convenient dosing option without food or fluid restrictions.

Twice-daily Trizivir versus Combivir-abacavir in antiretroviral-experienced adults with human immunodeficiency virus-1 infection: a formulation-switch trial.

STUDY OBJECTIVE: To establish the clinical equivalence (noninferiority) of one tablet containing abacavir 300 mg-lamivudine 150 mg-zidovudine 300 mg (Trizivir) versus a tablet containing lamivudine 150 mg-zidovudine 300 mg (Combivir) given with one abacavir (ABC) 300-mg tablet, administered twice/day, in antiretroviral-experienced, human immunodeficiency virus (HIV)-1-infected patients. DESIGN: Randomized, open-label, parallel-group, multicenter, formulation-switch study. SETTING: Twenty seven outpatient treatment sites. PATIENTS: Adults with HIV-1 RNA levels of 400 copies/ml or less and CD4+ cell counts above 200 cells/mm3 who had been treated for 16 weeks or more with highly active antiretroviral therapy containing Combivir-ABC. INTERVENTION: Patients were randomized 1:1 to Trizivir (97 patients) or Combivir-ABC (98) for 24 weeks. MEASUREMENTS AND MAIN RESULTS: The primary study end point was the proportion of patients who maintained less than a 0.5-log10 increase from baseline in HIV-1 RNA (virologic success) through week 24. Clinical equivalence of the treatments was established if the 95.1% lower confidence limit (LCL) for the difference in proportion of virologic success with Trizivir minus Combivir-ABC was -0.12 or greater. Trizivir was clinically equivalent to Combivir-ABC. The intent-to-treat observed analysis at week 24 with Trizivir and Combivir-ABC showed a similar rate of virologic success (83% [80/97] and 77% [75/98], respectively, 95.1% LCL -0.026), of patients with HIV-1 RNA levels of 400 or fewer copies/ml (99% [82/83] and 93% [77/83], respectively, 95.1% LCL 0.021), and of patients with HIV-1 RNA levels of fewer than 50 copies/ml (89% [74/83] and 77% [64/83], respectively, 95.1% LCL 0.038). The intent-to-treat missing = failure analysis showed comparable results. Changes in CD4+ cell count from baseline, overall mean self-reported adherence (Trizivir 97%, Combivir-ABC 92%), and adverse events did not differ significantly between treatments. No ABC-related hypersensitivity reactions occurred. CONCLUSION: Trizivir was clinically equivalent to Combivir-ABC and may be substituted for the latter to simplify treatment and reduce pill burden.