Influence of Sex/Gender and Race on Responses to Raltegravir Combined With Tenofovir-Emtricitabine in Treatment-Naive Human Immunodeficiency Virus-1 Infected Patients: Pooled Analyses of the STARTMRK and QDMRK Studies.

BACKGROUND: Antiretroviral therapy in human immunodeficiency virus (HIV)-infected women and blacks merits particular scrutiny because these groups have been underrepresented in clinical trials. METHODS: To document the effects of raltegravir across sex and racial lines, we conducted a pooled subgroup analysis of the efficacy and safety of raltegravir 400 mg BID plus tenofovir-emtricitabine by sex (women vs men) and self-identified race (black vs non-black) using phase 3 studies in treatment-naive patients. RESULTS: Study participants included 42 black women, 102 non-black women, 48 black men, and 477 non-black men. Clade B infections were less common in women (43.8%) than men (84.6%) and in blacks (45.6%) than non-blacks (80.5%). Baseline CD4 counts were ≤200 cells/µL in 52.2% of blacks and 31.6% of non-blacks. Black men had the largest proportion of patients with baseline CD4 counts/µL and the highest nontreatment-related discontinuation rate among the 4 sex-by-race subgroups. Human immunodeficiency virus-ribonucleic acid levels/mL were achieved at week 48 in 92.7% (95% confidence interval [CI], 80.1-98.5) of black women, 93.6% (95% CI, 86.6-97.6) of non-black women, 82.9% (95% CI, 67.9-92.8) of black men, and 91.4% (95% CI, 88.4-93.8) of non-black men. Serious clinical adverse events were reported in 9.0% of women versus 8.8% of men and in 11.1% of blacks versus 8.5% of non-blacks. CONCLUSIONS: In this post hoc analysis of patients with previously untreated HIV-1 infection receiving raltegravir plus tenofovir-emtricitabine, generally comparable results were achieved across sex and racial subgroups. However, black men had a lower response rate than either black women or non-black men, partially attributable to lower baseline CD4 counts and higher discontinuation rates

Long-Term Efficacy, Safety, and Tolerability of Indinavir-Based Therapy in Protease Inhibitor—Naive Adults with Advanced HIV Infection

A double-blind, randomized study of zidovudine-experienced, PI- and lamivudine-naive adults with baseline CD4 cell counts of ⩽50 cells/mm3 had demonstrated that the HIV suppression achieved with zidovudine, lamivudine, and indinavir therapy was superior to that achieved with dual-nucleoside or indinavir-only regimens after 24 weeks of therapy. In a 192-week extension of the study, 371 participants received open-label indinavir with or without other antiretroviral drugs. One hundred and eight subjects were originally randomized to receive triple therapy. After 216 weeks, the proportion of subjects with HIV RNA levels of <500 copies/mL were 34%, according to a general estimating equation analysis, 92%, according to an observed data analysis, and 24%, according to an intention-to-treat analysis counting noncompleters as failures; the proportions of subjects with HIV RNA levels of <50 copies/mL were 31%, 85%, and 22%, respectively. Hyperbilirubinemia (experienced by 31% of subjects), nausea (17%), abdominal pain (14%), and nephrolithiasis (13%) were the most common drug-related adverse events during the extensio

Estudo duplo-cego, randômico comparando indinavir, zidovudina e indinavir mais zidovudina na terapia anti-retroviral de indivíduos HIV+ sem tratamento anterior, com contagem de células CD4 entre 50 e 250/mm3

Treatment with indinavir has been shown to result in marked decreases in viral load and increases in CD4 cell counts in HIV-infected individuals. A randomized double-blind study to evaluate the efficacy of indinavir alone (800 mg q8h), zidovidine alone (200 mg q8h) or the combination was performed to evaluate progression to AIDS. 996 antiretroviral therapy-naive patients with CD4 cell counts of 50-250/mm3 were allocated to treatment. During the trial the protocol was amended to add lamivudine to the zidovudine-containing arms. The primary endpoint was time to development of an AIDS-defining illness or death. The study was terminated after a protocol-defined interim analysis demonstrated highly significant reductions in progression to a clinical event in the indinavir-containing arms, compared to the zidovudine arm (p&lt;0.0001). Over a median follow-up of 52 weeks (up to 99 weeks), percent reductions in hazards for the indinavir plus zidovudine and indinavir groups compared to the zidovudine group were 70% and 61%, respectively. Significant reductions in HIV RNA and increases in CD4 cell counts were also seen in the indinavir-containing groups compared to the zidovudine group. Improvement in both CD4 cell count and HIV RNA were associated with reduced risk of disease progression. All three regimens were generally well tolerated.Foi demonstrado que o tratamento com indinavir resulta em importante redução da carga viral e aumentos das células CD4 em pacientes infectados pelo HIV. Foi realizado um estudo duplo-cego, randômico para avaliar a eficácia do indinavir isoladamente (800 mg cada 8h), zidovudina isoladamente (200 mg cada 8h) ou a combinação, para avaliar a progressão para AIDS. Foram distribuidos para tratamento 996 pacientes virgens de tratamento antiretroviral, com contagens de CD4 entre 50 e 250 células/mm3. Durante o estudo, o protocolo foi modificado para adicionar lamivudina aos braços contendo zidovudina. O "endpoint" primário foi o tempo para o desenvolvimento de uma doença-definidora de AIDS ou morte. O estudo foi interrompido após uma análise preliminar definida no protocolo ter demonstrado reduções significativas na progressão para um evento clínico nos grupos contendo indinavir, comparado ao grupo da zidovudina (p&lt; 0,0001). Após uma mediana de seguimento de 52 semanas (chegando a 99 semanas), as reduções percentuais nas ocorrências para indinavir+zidovudina e indinavir, comparado com zidovudina foram de 70% e 61%, respectivamente. Reduções significativas na medida do RNA viral e aumentos nas contagens de CD4 também foram observadas nos grupos contendo indinavir, em relação ao da zidovudina. A melhora nas células CD4 e RNA viral foram ambas associadas a risco reduzido de progressão da doença. Os três tratamentos foram geralmente bem tolerados

Relationship of the genes for Chediak-Higashi syndrome (beige) and the T-cell receptor [gamma] chain in mouse and man

The genetic linkage of Chediak-Higashi syndrome and its murine analog, beige (bg), to the T-cell receptor (TCR-[gamma]) [gamma] chain gene is further defined. Previous studies using recombinant inbred strains of mice demonstrated that the murine bg gene is genetically linked to a murine TCR-[gamma] gene. We report that in the mouse the frequency of recombination between these two markers is 0.025. Further, we tested the hypothesis that these two genes are linked in the human genome by analyzing restriction fragment length polymorphisms (RFLPs) in five families with children afflicted with Chediak-Higashi syndrome. In three families, RFLPs in TCR-[gamma] genes were inherited discordantly from Chediak-Higashi syndrome, demonstrating nonlinkage. We postulate that there is an evolutionary chromosomal breakpoint between the bg gene and the TCR-[gamma] gene.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26520/1/0000058.pd

Comparison of the Metabolic Effects of Ritonavir-Boosted Darunavir or Atazanavir Versus Raltegravir, and the Impact of Ritonavir Plasma Exposure: ACTG 5257

Background. Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24)

Comparison of the Metabolic Effects of Ritonavir-Boosted Darunavir or Atazanavir Versus Raltegravir, and the Impact of Ritonavir Plasma Exposure: ACTG 5257

Background. Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24)

Safety and Immunogenicity of the Merck Adenovirus Serotype 5 (MRKAd5) and MRKAd6 Human Immunodeficiency Virus Type 1 Trigene Vaccines Alone and in Combination in Healthy Adults▿

Preexisting immunity to adenovirus serotype 5 (Ad5) diminishes immune responses to vaccines using Ad5 as a vector. Alternate Ad serotypes as vaccine vectors might overcome Ad5-specific neutralizing antibodies and enhance immune responses in populations with a high prevalence of Ad5 immunity. To test this hypothesis, healthy human immunodeficiency virus (HIV)-seronegative adults were enrolled in a blinded, randomized, dose-escalating, placebo-controlled study. In part A, subjects with baseline Ad6 titers of ≤18 received the Merck Ad6 (MRKAd6) HIV type 1 (HIV-1) trigene vaccine at weeks 0, 4, and 26. In part B, subjects stratified by Ad5 titers (≤200 or >200) and Ad6 titers (≤18 or >18) received the MRKAd5-plus-MRKAd6 (MRKAd5+6) HIV-1 trigene vaccine at weeks 0, 4, and 26. Immunogenicity was assessed by an enzyme-linked immunospot (ELISPOT) assay at week 30. No serious adverse events occurred. MRKAd6 trigene vaccine recipients responded more often to Nef than to Gag or Pol. In part A, ELISPOT response rates to ≥2 vaccine antigens were 14%, 63%, and 71% at 109, 1010, and 1011 viral genomes (vg)/dose, respectively. All responders had positive Nef-specific ELISPOT results. In part B, Nef-ELISPOT response rates at 1010 vg/dose of the MRKAd5+6 trigene vaccine were 50% in the low-Ad5/low-Ad6 stratum (n = 8), 78% in the low-Ad5/high-Ad6 stratum (n = 9), 75% in the high-Ad5/low-Ad6 stratum (n = 8), and 44% in the high-Ad5/high-Ad6 stratum (n = 9). The MRKAd6 and MRKAd5+6 trigene vaccines elicited dose-dependent responses predominantly to Nef and were generally well tolerated, indicating that Ad6 should be considered a candidate vector for future vaccines. Although small sample sizes limit the conclusions that can be drawn from this exploratory study, combining two Ad vectors may be a useful vaccine strategy for circumventing isolated immunity to a single Ad serotype

Estudo duplo-cego, randômico comparando indinavir, zidovudina e indinavir mais zidovudina na terapia anti-retroviral de indivíduos HIV+ sem tratamento anterior, com contagem de células CD4 entre 50 e 250/mm3

Treatment with indinavir has been shown to result in marked decreases in viral load and increases in CD4 cell counts in HIV-infected individuals. A randomized double-blind study to evaluate the efficacy of indinavir alone (800 mg q8h), zidovidine alone (200 mg q8h) or the combination was performed to evaluate progression to AIDS. 996 antiretroviral therapy-naive patients with CD4 cell counts of 50-250/mm3 were allocated to treatment. During the trial the protocol was amended to add lamivudine to the zidovudine-containing arms. The primary endpoint was time to development of an AIDS-defining illness or death. The study was terminated after a protocol-defined interim analysis demonstrated highly significant reductions in progression to a clinical event in the indinavir-containing arms, compared to the zidovudine arm (p&lt;0.0001). Over a median follow-up of 52 weeks (up to 99 weeks), percent reductions in hazards for the indinavir plus zidovudine and indinavir groups compared to the zidovudine group were 70% and 61%, respectively. Significant reductions in HIV RNA and increases in CD4 cell counts were also seen in the indinavir-containing groups compared to the zidovudine group. Improvement in both CD4 cell count and HIV RNA were associated with reduced risk of disease progression. All three regimens were generally well tolerated.Foi demonstrado que o tratamento com indinavir resulta em importante redução da carga viral e aumentos das células CD4 em pacientes infectados pelo HIV. Foi realizado um estudo duplo-cego, randômico para avaliar a eficácia do indinavir isoladamente (800 mg cada 8h), zidovudina isoladamente (200 mg cada 8h) ou a combinação, para avaliar a progressão para AIDS. Foram distribuidos para tratamento 996 pacientes virgens de tratamento antiretroviral, com contagens de CD4 entre 50 e 250 células/mm3. Durante o estudo, o protocolo foi modificado para adicionar lamivudina aos braços contendo zidovudina. O endpoint primário foi o tempo para o desenvolvimento de uma doença-definidora de AIDS ou morte. O estudo foi interrompido após uma análise preliminar definida no protocolo ter demonstrado reduções significativas na progressão para um evento clínico nos grupos contendo indinavir, comparado ao grupo da zidovudina (p&lt; 0,0001). Após uma mediana de seguimento de 52 semanas (chegando a 99 semanas), as reduções percentuais nas ocorrências para indinavir+zidovudina e indinavir, comparado com zidovudina foram de 70% e 61%, respectivamente. Reduções significativas na medida do RNA viral e aumentos nas contagens de CD4 também foram observadas nos grupos contendo indinavir, em relação ao da zidovudina. A melhora nas células CD4 e RNA viral foram ambas associadas a risco reduzido de progressão da doença. Os três tratamentos foram geralmente bem tolerados.273