Definition of the viral targets of protective HIV-1-specific T cell responses.

BACKGROUND: The efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity. METHODS: Here, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a "protective ratio" (PR) was calculated as the ratio of median viral loads (VL) between OLP non-responders and responders. RESULTS: For both clades, there was a negative relationship between the PR and the entropy of the OLP sequence. There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals' viral loads than their HLA class I genotypes. CONCLUSIONS: The data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.

Fatal and nonfatal AIDS and non-AIDS events in HIV-1-positive individuals with high CD4 cell counts according to viral load strata.

BACKGROUND: This study compared the incidence of fatal and nonfatal AIDS and non-AIDS events in HIV-positive individuals with a CD4 cell count more than 350  cells/µl among viral load strata: low (<500  copies/ml), intermediate (500-9999.9  copies/ml) and high (≥ 10000  copies/ml). METHODS: Individuals contributed person-years at risk if their most recent CD4 cell count was more than 350  cells/µl. Follow-up was censored if their CD4 cell count dropped below 350  cells/µl. Poisson regression analysis investigated the relationship between viraemia and the incidence of AIDS and non-AIDS events. RESULTS: Three hundred and fifty-four AIDS events occurred during 51 732  person-years of follow-up (PYFU), crude incidence rate of AIDS across the three strata was 0.53, 0.90 and 2.12 per 100 PYFU, respectively. After adjustment, a higher rate of AIDS was observed in individuals with moderate [incidence rate ratio (IRR) 1.44, 1.02-2.05, P = 0.03] and high viraemia had a higher rate (IRR 3.91, 2.89-5.89, P < 0.0001) compared with low viraemia. Five hundred and seventy-two non-AIDS events occurred during 43 784 PYFU, the crude incidence rates were 1.28, 1.52, and 1.38 per 100 PYFU, respectively. After adjustment, particularly for age, region of Europe and starting combination antiretroviral therapy, there was a 61% (IRR 1.61, 1.21-2.14, P = 0.001) and 66% (IRR 1.66, 1.17-2.32, P = 0.004) higher rate of non-AIDS in individuals with intermediate and high viraemia compared with low viraemia. CONCLUSION: In individuals with a CD4 cell count more than 350  cells/µl, an increased incidence of AIDS and a slightly increased incidence of non-AIDS was found in those with uncontrolled viral replication. The association with AIDS was clear and consistent. However, the association with non-AIDS was only apparent after adjustment and no differences were observed between intermediate and high viraemia.

Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial.

BACKGROUND: Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in-vitro activity against HIV-1 strains including those resistant to currently available antiretroviral drugs. The aim of this study was to assess the safety and efficacy of raltegravir when added to optimised background regimens in HIV-infected patients. METHODS: HIV-infected patients with HIV-1 RNA viral load over 5000 copies per mL, CD4 cell counts over 50 cells per muL, and documented genotypic and phenotypic resistance to at least one nucleoside reverse transcriptase inhibitor, one non-nucleoside reverse transcriptase inhibitor, and one protease inhibitor were randomly assigned to receive raltegravir (200 mg, 400 mg, or 600 mg) or placebo orally twice daily in this multicentre, triple-blind, dose-ranging, randomised study. The primary endpoints were change in viral load from baseline at week 24 and safety. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, with the number NCT00105157. FINDINGS: 179 patients were eligible for randomisation. 44 patients were randomly assigned to receive 200 mg raltegravir, 45 to receive 400 mg raltegravir, and 45 to receive 600 mg raltegravir; 45 patients were randomly assigned to receive placebo. One patient in the 200 mg group did not receive treatment and was therefore excluded from the analyses. For all groups, the median duration of previous antiretroviral therapy was 9.9 years (range 0.4-17.3 years) and the mean baseline viral load was 4.7 (SD 0.5) log10 copies per mL. Four patients discontinued due to adverse experiences, three (2%) of the 133 patients across all raltegravir groups and one (2%) of the 45 patients on placebo. 41 patients discontinued due to lack of efficacy: 14 (11%) of the 133 patients across all raltegravir groups and 27 (60%) of the 45 patients on placebo. At week 24, mean change in viral load from baseline was -1.80 (95% CI -2.10 to -1.50) log10 copies per mL in the 200 mg group, -1.87 (-2.16 to -1.58) log10 copies per mL in the 400 mg group, -1.84 (-2.10 to -1.58) log10 copies per mL in the 600 mg group, and -0.35 (-0.61 to -0.09) log(10) copies per mL for the placebo group. Raltegravir at all doses showed a safety profile much the same as placebo; there were no dose-related toxicities. INTERPRETATION: In patients with few remaining treatment options, raltegravir at all doses studied provided better viral suppression than placebo when added to an optimised background regimen. The safety profile of raltegravir is comparable with that of placebo at all doses studied.

Atazanavir--a once-daily HIV protease inhibitor that does not cause dyslipidemia in newly treated patients: results from two randomized clinical trials.

Protease inhibitor (PI) treatment can result in dyslipidemia in a significant proportion of patients. Atazanavir (ATV) is a once-daily PI that has not been associated with clinically relevant increases in total cholesterol (TC), fasting low-density lipoprotein cholesterol (LDL-C), or fasting triglyceride (TG) concentrations. The objectives of this paper were to evaluate lipid profiles in untreated patients, and investigate the frequency and severity of dyslipidemia in the same individuals after treatment with ATV or nelfinavir (NFV) for 48 weeks. Two multinational, randomized, active-controlled, blinded trials compared the safety and efficacy of ATV and NFV in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) in antiretroviral (ARV)-naive patients. Serum lipid concentrations were analyzed in patients who had available measurements both at baseline and at week 48. Patients who had missing data at either time point were not included. Lipid levels remained within baseline ranges at week 48 with ATV treatment, whereas clinically relevant elevations in TC, fasting LDL-C, and fasting TG concentrations occurred with NFV treatment. Mean changes from pre-treatment baseline in fasting LDL-C ranged from -6 percent to +6 percent in the ATV-treatment groups, and from +27 percent to +31 percent in the NFV-treatment groups. After 48 weeks, there was a substantive increase in the proportion of NFV-treated patients who would be recommended for lipid-lowering treatment by National Cholesterol Education Program (NCEP) guidelines, whereas a lesser proportion of ATV-treated patients would be recommended for lipid-lowering treatment. Atazanavir does not lead to dyslipidemia in ARV-naive patients, and may limit the need for lipid-lowering strategies to reduce the risk of cardiovascular disease.

Genotype and phenotype at baseline and at failure in human immunodeficiency virus-infected antiretroviral-naive patients in a randomized trial comparing zidovudine and lamivudine plus nelfinavir or nevirapine.

For the 127 Spanish patients enrolled in the Combine Study, a resistance substudy was performed with 100 (79%) plasma samples obtained at baseline and with 18 samples obtained from 19 patients at the time they experienced treatment failure. At baseline, primary mutations to nonnucleoside reverse-transcriptase inhibitors and protease inhibitors were not detected, whereas mutations to nucleoside reverse-transcriptase inhibitors were observed in 10% of patients. At failure, mutations were detected in 7 of 16 patients. An agreement in the results of virtual and real phenotypes was observed in the 93 samples in which both tests were performed.