T-1249 retains potent antiretroviral activity in patients who had experienced virological failure while on an enfuvirtide-containing treatment regimen.

BACKGROUND: T-1249 is a 39-amino acid synthetic peptide fusion inhibitor (FI) shown to preserve antiretroviral activity in vitro against human immunodeficiency virus (HIV) isolates that have decreased susceptibility to enfuvirtide (ENF). METHODS: A 10-day phase 1/2 study of the safety and antiretroviral activity of T-1249 was conducted in 53 HIV-1-infected adults with detectable viremia while on an ENF-containing treatment regimen. RESULTS: From FI-naive baseline levels, the geometric mean (GM) decrease in susceptibility to ENF was 116.3-fold, and the GM decrease in susceptibility to T-1249 was 2.0-fold. Patients continued to administer their failing treatment regimen but replaced ENF with T-1249 at a dose of 192 mg/day. T-1249 was generally well tolerated; injection site reactions, which were generally mild, were the most commonly reported adverse event (64% of patients). The median change from levels of HIV-1 RNA at baseline to levels on day 11 was -1.26 log(10) copies/mL (95% confidence interval, -1.40 to -1.09 log(10) copies/mL); on day 11, a decrease from baseline HIV-1 RNA levels of >/=1.0 log(10) copies/mL was seen in 73% of patients. Antiretroviral activity, as measured by levels of HIV-1 RNA, was not predicted by baseline susceptibility to T-1249 or to ENF; genotypic substitutions that emerged during T-1249 treatment were identified in virus from some patients. CONCLUSIONS: These results indicate that FIs constitute an expanding class of antiretroviral agents with the potential to be sequenced.

Prevalence of chemokine and chemokine receptor polymorphisms in seroprevalent children with symptomatic HIV-1 infection in the United States.

Several chemokines and chemokine receptors are involved in HIV-1 infection, disease progression, and transmission. We studied the prevalence of genetic variations in CCR2, SDF1, and the CCR5 gene and its promoter region at positions 59029, 59353, and 59356 in a seroprevalent cohort of 1057 children with symptomatic HIV-1 infection in the United States. The percentage of children with the CCR5-wt/Delta32 genotype was significantly higher for white, non-Hispanic children (15%) than for Hispanic (6%) or black, non-Hispanic children (4%). For the CCR5-59029-G/A, CCR5-59353-T/C, and CCR5-59356-C/T polymorphisms, there were significant or marginally significant differences in genotype frequencies across race/ethnicity groups. For the CCR2-wt/64I polymorphism, both black, non-Hispanic and Hispanic children had a higher frequency of the CCR2-wt/64I genotype (24% and 21%, respectively) and CCR2-64I/64I genotype (4% and 3%, respectively) than white, non-Hispanic children (14% and 2%, respectively). For the SDF1-3'-G/A polymorphism, black, non-Hispanic children had a lower combined frequency of the SDF1-3'-G/A and SDF1-3'-A/A genotypes (15%) than did Hispanic children (33%) and white, non-Hispanic children (37%). These analyses show that the distribution of chemokine receptor and chemokine genetic polymorphisms varies significantly across race/ethnicity subgroups of HIV-1-infected children in the United States.

Short-term safety and antiretroviral activity of T-1249, a second-generation fusion inhibitor of HIV.

T-1249 is a 39-aa synthetic peptide that inhibits fusion of human immunodeficiency virus (HIV) to the host target cell. A 14-day open-label, phase 1/2 dose-escalation monotherapy study of the safety and antiretroviral activity of T-1249 was performed on 115 HIV-1-infected adults. At baseline, the majority of the patients had advanced HIV disease (baseline median CD4(+) cell count, 57 cells/microL) and had extensive pretreatment (i.e., pre-T-1249) experience with antiretroviral medications (median, 11 antiretroviral drugs). Patients received T-1249 monotherapy by subcutaneous injection, for 14 days, at doses ranging from 6.25 to 192 mg/day. T-1249 was generally well tolerated, and no dose-limiting toxicity was identified. Injection-site reactions were the most commonly reported adverse event (57%). Dose-dependent decreases in plasma HIV-1 RNA load were observed; the median maximum change from baseline across dose groups ranged from -0.29 log(10) copies/mL (95% confidence interval [CI], -0.43 to -0.05 log(10) copies/mL) for the lowest dose to -1.96 log(10) copies/mL (95% CI, -2.02 to -1.37 copies/mL) for the highest dose. These results indicate that T-1249 is a potent new therapeutic agent for HIV-1 infection.

Mutations linked to drug resistance, human immunodeficiency virus type 1 biologic phenotype and their association with disease progression in children receiving nucleoside reverse transcriptase inhibitors.

BACKGROUND: Few data are available concerning the impact of antiretroviral resistance in response to antiviral therapy in children. We evaluated the development of antiretroviral genotypic resistance and clinical outcome in a subgroup of children involved in a prospective antiretroviral therapy trial (Pediatric AIDS Clinical Trials Group Protocol 152). DESIGN: We studied 26 matched case/control pairs. A case was defined as having clinical disease progression during the study period; controls did not have disease progression. Cases and controls were matched by age and CD4+ cell count at baseline. Matched pairs received treatment with zidovudine (9 pairs), didanosine (12 pairs) or combined therapy (5 pairs). Multiple codons of the reverse transcriptase coding region (41, 67, 70, 74, 151, 184, 210, 215 and 219) were analyzed. Patients were evaluated for CD4+ cell count, HIV-1 viral load and HIV-1 biologic phenotype at baseline and clinical endpoint. RESULTS: The presence of mutations associated with resistance after nucleoside antiretroviral therapy (P = 0.039) and syncytium-inducing phenotype (P = 0.031), were significantly associated with increased risk of clinical disease progression. The mean difference in HIV-1 RNA levels between cases and their matched controls after nucleoside antiretroviral therapy was 0.77 log10 copies/ml higher for cases (P = 0.003). The median difference between cases and controls for CD4+ cell count after nucleoside antiretroviral therapy was 349 cells/mm3 lower for cases (P < 0.001). CONCLUSIONS: In this small prospective study of HIV-infected children, mutations in the reverse transcriptase coding region, syncytium-inducing viral phenotype, higher HIV-1 RNA load and lower CD4+ cell count were significantly correlated with increased risk of HIV clinical disease progression.

Genetic influence of CCR5, CCR2, and SDF1 variants on human immunodeficiency virus 1 (HIV-1)-related disease progression and neurological impairment, in children with symptomatic HIV-1 infection.

The role that host genetics plays in the modification of the rate of human immunodeficiency virus 1 (HIV-1)-related disease progression was evaluated in a seroprevalent cohort of 1049 children with symptomatic HIV-1 infection who participated in 2 clinical trials in the United States. Variants including CCR2-V64I, CCR5-wt/Delta32, CCR5-59029-G/A, CCR5-59353-T/C, CCR5-59356-C/T, and SDF1-3'-G/A were identified by polymerase chain-reaction genotyping. Children with the CCR5-wt/Delta32 genotype experienced significantly delayed disease progression, including less neurocognitive impairment. In the CCR5-wt/wt group, the most rapid disease progression was in those with the CCR5-59029-A/A genotype, which was present in 23% of the children. Although the SDF1-3'-A/A variant was associated with more-rapid disease progression, it occurred in <2% of the children studied. Modest or little impact was associated with the CCR5-59353, CCR5-59356, or CCR2 genotypes. Thus, in children with the CCR5-wt/wt genotype, variants at CCR5-59029 have the broadest impact on disease progression. These data suggest that, in children, host genetics plays an important role in HIV-1-related disease progression and neurological impairment.