Calvin Cohen

Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease

Summary Background Ritonavir is a potent, orally bioavailable inhibitor of HIV-1 protease. We undertook an international, multicentre, randomised, double-blind, placebo-controlled trial of ritonavir in patients with HIV-1 infection and CD4-lymphocyte counts of 100 cells/u, L or less, who had previously been treated with antiretroviral drugs. Methods 1090 patients were randomly assigned twice-daily liquid oral ritonavir 600 mg (n=543) or placebo (n=547) while continuing treatment with up to two licensed nucleoside agents. The primary study outcome was any first new, or specified recurrent, AIDS-defining event or death. Open-label ritonavir was provided after 16 weeks in the study to any patient who had an AIDS-defining event. Findings The baseline median CD4-lymphocyte count was 18 (IQR 10-43)/μ in the ritonavir group and 22 (10-47) /μL in the placebo group. Study medication was discontinued in 114 (21·1%) ritonavir-group patients and 45 (8·3%) placebo-group patients mainly because of initial adverse symptoms. Outcomes of AIDS-defining illness or death occurred in 119 (21·9%) ritonavir-group patients and 205 (37·5%) placebo-group patients (hazard ratio 0·53 [95% Cl 0·42-0·66]; log-rank p Interpretation Although earlier intervention with combination therapy may provide much more effective treatment, ritonavir in patients with advanced disease and extensive previous antiretroviral use is safe and effective, lowers the risk of AIDS complications, and prolongs survival.

Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials.

BACKGROUND The continuing, randomised, multinational, phase IIB POWER 1 and 2 studies aim to evaluate efficacy and safety of darunavir in combination with low-dose ritonavir in treatment-experienced HIV-1-infected patients. We did a pooled subgroup analysis to update results at week 48 for patients receiving the recommended dose of darunavir-ritonavir compared with those receiving other protease inhibitors (PIs). METHODS After 24-week dose-finding phases and primary efficacy analyses, patients randomised to receive darunavir-ritonavir were given 600/100 mg twice daily, and patients receiving control PIs continued on assigned treatment into the longer-term, open-label phase; all patients continued on optimised background regimen. We assessed patients who had reached week 48 or discontinued earlier at the time of analysis; for the darunavir-ritonavir group, only patients who received 600/100 mg twice daily from baseline were included. Analyses were intention-to-treat. The POWER 2 study (TMC114-C202) is registered with ClinicalTrials.gov (NCT00071097). FINDINGS At week 48, 67 of 110 (61%) darunavir-ritonavir patients compared with 18 of 120 (15%) of control PI patients had viral load reductions of 1 log10 copies per mL or greater from baseline (primary endpoint; difference in response rates 46%, 95% CI 35%-57%, p<0.0001). Based on a logistic regression model including stratification factors (baseline number of primary PI mutations, use of enfuvirtide, baseline viral load) and study as covariates, the difference in response was 50% (odds ratio 11.72, 95% CI 5.75-23.89). In the darunavir-ritonavir group, rates of adverse events were mostly lower than or similar to those in the control group when corrected for treatment exposure. No unexpected safety concerns were identified. INTERPRETATION Efficacy responses with darunavir-ritonavir 600/100 mg twice daily plus optimised background regimen were greater than those with control PI and were sustained to at least week 48, with favourable safety and tolerability in treatment-experienced patients. This regimen could expand the treatment options available for such patients.

The Cost Effectiveness of Combination Antiretroviral Therapy for HIV Disease

BACKGROUND Combination antiretroviral therapy with a combination of three or more drugs has become the standard of care for patients with human immunodeficiency virus (HIV) infection in the United States. We estimated the clinical benefits and cost effectiveness of three-drug antiretroviral regimens. METHODS We developed a mathematical simulation model of HIV disease, using the CD4 cell count and HIV RNA level as predictors of the progression of disease. Outcome measures included life expectancy, life expectancy adjusted for the quality of life, lifetime direct medical costs, and cost effectiveness in dollars per quality-adjusted year of life gained. Clinical data were derived from major clinical trials, including the AIDS Clinical Trials Group 320 Study. Data on costs were based on the national AIDS Cost and Services Utilization Survey, with drug costs obtained from the Red Book. RESULTS For patients similar to those in the AIDS Clinical Trials Group 320 Study (mean CD4 cell count, 87 per cubic millimeter), life expectancy adjusted for the quality of life increased from 1.53 to 2.91 years, and per-person lifetime costs increased from

Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks

45,460 to

Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study.

77,300 with three-drug therapy as compared with no therapy. The incremental cost per quality-adjusted year of life gained, as compared with no therapy, was

Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial

23,000. On the basis of additional data from other major studies, the cost-effectiveness ratio for three-drug therapy ranged from

Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients

13,000 to

Use of Genotypic Resistance Testing To Guide HIV Therapy: Clinical Impact and Cost-Effectiveness

23,000 per quality-adjusted year of life gained. The initial CD4 cell count and drug costs were the most important determinants of costs, clinical benefits, and cost effectiveness. CONCLUSIONS Treatment of HIV infection with a combination of three antiretroviral drugs is a cost-effective use of resources.

Ritonavir and saquinavir combination therapy for the treatment of HIV infection.

BACKGROUND The integrase inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) in a single tablet given once daily. We compared the efficacy and safety of EVG/COBI/FTC/TDF with standard of care-co-formulated efavirenz (EFV)/FTC/TDF-as initial treatment for HIV infection. METHODS In this phase 3 trial, treatment-naive patients from outpatient clinics in North America were randomly assigned by computer-generated allocation sequence with a block size of four in a 1:1 ratio to receive EVG/COBI/FTC/TDF or EFV/FTC/TDF, once daily, plus matching placebo. Patients and study staff involved in giving study treatment, assessing outcomes, and collecting and analysing data were masked to treatment allocation. Eligibility criteria included screening HIV RNA concentration of 5000 copies per mL or more, and susceptibility to efavirenz, emtricitabine, and tenofovir. The primary endpoint was HIV RNA concentration of fewer than 50 copies per mL at week 48. The study is registered with ClinicalTrials.gov, number NCT01095796. FINDINGS 700 patients were randomly assigned and treated (348 with EVG/COBI/FTC/TDF, 352 with EFV/FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF; 305/348 (87·6%) versus 296/352 (84·1%) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 (difference 3·6%, 95% CI -1·6% to 8·8%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group). Nausea was more common with EVG/COBI/FTC/TDF than with EFV/FTC/TDF (72/348 vs 48/352) and dizziness (23/348 vs 86/352), abnormal dreams (53/348 vs 95/352), insomnia (30/348 vs 49/352), and rash (22/348 vs 43/352) were less common. Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (median 13 μmol/L, IQR 5 to 20 vs 1 μmol/L, -6 to 8; p<0·001). INTERPRETATION If regulatory approval is given, EVG/COBI/FTC/TDF would be the only single-tablet, once-daily, integrase-inhibitor-based regimen for initial treatment of HIV infection. FUNDING Gilead Sciences.

The Safety, Plasma Pharmacokinetics, and Antiviral Activity of Subcutaneous Enfuvirtide (T-20), a Peptide Inhibitor of gp41-Mediated Virus Fusion, in HIV-Infected Adults

BACKGROUND The SMART study randomized 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL to intermittent antiretroviral therapy (ART; the drug conservation [DC] group) versus continuous ART (the viral suppression [VS] group). In the DC group, participants started ART when the CD4+ cell count was <250 cells/microL. Clinical outcomes in participants not receiving ART at entry inform the early use of ART. METHODS Patients who were either ART naive (n=249) or who had not been receiving ART for >or= 6 months (n=228) were analyzed. The following clinical outcomes were assessed: (i) opportunistic disease (OD) or death from any cause (OD/death); (ii) OD (fatal or nonfatal); (iii) serious non-AIDS events (cardiovascular, renal, and hepatic disease plus non-AIDS-defining cancers) and non-OD deaths; and (iv) the composite of outcomes (ii) and (iii). RESULTS A total of 477 participants (228 in the DC group and 249 in the VS group) were followed (mean, 18 months). For outcome (iv), 21 and 6 events occurred in the DC (7 in ART-naive participants and 14 in those who had not received ART for >or= 6 months) and VS (2 in ART-naive participants and 4 in those who had not received ART for 6 months) groups, respectively. Hazard ratios for DC vs. VS by outcome category were as follows: outcome (i), 3.47 (95% confidence interval [CI], 1.26-9.56; p=.02); outcome (ii), 3.26 (95% CI, 1.04-10.25; p=.04); outcome (iii), 7.02 (95% CI, 1.57-31.38; p=.01); and outcome (iv), 4.19 (95% CI, 1.69-10.39; p=.002 ). CONCLUSIONS Initiation of ART at CD4+ cell counts >350 cells/microL compared with <250 cells/microL may reduce both OD and serious non-AIDS events. These findings require validation in a large, randomized clinical trial.Background. The SMART study randomized 5472 human immunodeficiency virus (HIV)-infected patients with CD4 + cell counts >350 cells/μL to intermittent antiretroviral therapy (ART; the drug conservation [DC] group) versus continuous ART (the viral supression [VS] group). In the DC group, participants started ART when the CD4 + cell count was 350 cells/μL compared with <250 cells/μL may reduce both OD and serious non-AIDS events. These findings require validation in a large, randomized clinical trial.