Changes In HIV-1 RNA Levels Research Articles

The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial

Most HIV-1-infected patients on effective antiretroviral therapy (ART) with plasma HIV-1 RNA levels below the detection limits of commercial assays have residual viremia measurable by more sensitive methods. We assessed whether adding raltegravir lowered the level of residual viremia in such patients. Patients receiving ART who had plasma HIV-1 RNA levels below 50 copies/mL but detectable viremia by single copy assay (SCA) were randomized to add either raltegravir or placebo to their ART regimen for 12 weeks; patients then crossed-over to the other therapy for an additional 12 weeks while continuing pre-study ART. The primary endpoint was the plasma HIV-1 RNA by SCA averaged between weeks 10 and 12 (10/12) compared between treatment groups. Fifty-three patients were enrolled. The median screening HIV-1 RNA was 1.7 copies/mL. The HIV-1 RNA level at weeks 10/12 did not differ significantly between the raltegravir-intensified (n = 25) and the placebo (n = 24) groups (median 1.2 versus 1.7 copies/mL, p = 0.55, Wilcoxon rank sum test), nor did the change in HIV-1 RNA level from baseline to week 10/12 (median -0.2 and -0.1 copies/mL, p = 0.71, Wilcoxon rank sum test). There was also no significant change in HIV-1 RNA level from weeks 10/12 to weeks 22/24 after patients crossed-over. There was a greater CD4 cell count increase from baseline to week 12 in the raltegravir-intensified group compared with the placebo group (+42 versus -44 cells/mm(3), p = 0.082, Wilcoxon rank sum test), which reversed after the cross-over. This CD4 cell count change was not associated with an effect of raltegravir intensification on markers of CD4 or CD8 cell activation in blood. In this randomized, double-blind cross-over study, 12 weeks of raltegravir intensification did not demonstrably reduce low-level plasma viremia in patients on currently recommended ART. This finding suggests that residual viremia does not arise from ongoing cycles of HIV-1 replication and infection of new cells. New therapeutic strategies to eliminate reservoirs that produce residual viremia will be required to eradicate HIV-1 infection. ClinicalTrials.gov NCT00515827

Comparison of Clinical Response to Initial Highly Active Antiretroviral Therapy in the Patients in Clinical Care in the United States and Brazil

US and Brazilian studies indicate that highly active antiretroviral therapy (HAART) has been effective in reducing morbidity and mortality from HIV/AIDS. Differences exist in the adoption and patterns of antiretroviral drug use and in the incidence of AIDS-defining illness (ADI) between the 2 countries, however, and there has not been a direct comparison of clinical response between Brazil and the United States. We sought to determine if there have been differences in the clinical response to HAART from HIV clinical practices in the United States and Brazil. We compared 2 similarly designed clinical cohorts from Baltimore, Maryland and Rio de Janeiro, Brazil. Patients who started HAART from 1997 to 2004 were compared for HIV-1 RNA suppression and CD4+ T-lymphocyte count change by 1 year of therapy and for development of an ADI up to 6 years of follow-up. A total of 1368 patients from Baltimore and 1045 patients from Rio de Janeiro were studied. There was no difference by location in achieving an HIV-1 RNA level <400 copies/mL (46.9% in Rio de Janeiro, 50.8% in Baltimore), in the log change in HIV-1 RNA level (-1.65 log in Rio de Janeiro, - 1.63 log in Baltimore), or in the change in CD4 count (116 cells/mm3 in Rio de Janeiro, 122 cells/mm3 in Baltimore) by 12 months after starting HAART. By Kaplan-Meier analysis and Cox regression adjusted for demographic and clinical prognostic factors, there was no difference by location in development of the first ADI after starting HAART (relative hazard = 1.02; 95% confidence interval: 0.82 to 1.25 for Rio de Janeiro vs. Baltimore). The most commonly occurring ADI in Rio de Janeiro was tuberculosis (27.7% of patients), and the most commonly occurring ADI in Baltimore was esophageal candidiasis (36.8% of patients). There were only minor differences in clinical response to the use of HAART comparing Rio de Janeiro with Baltimore, despite differences in patterns of antiretroviral drug use and ADI incidence. This analysis indicates that HAART can be similarly effective in treating HIV/AIDS in countries with different economies.

Impact of Enhanced Services on Virologic Outcomes in a Directly Administered Antiretroviral Therapy Trial for HIV-Infected Drug Users

Directly administered antiretroviral therapy (DAART) is a promising intervention for improving HIV outcomes among active drug users, but the elements associated with successful DAART programs remain largely unknown. This study aimed to assess the impact of colocated medical, case management, and referral to substance abuse services (DAART-Plus) among the subjects receiving DAART as part of a larger randomized controlled trial comparing DAART with self-administered therapy. The health services utilization of 72 subjects receiving DAART was analyzed for its impact on changes in HIV-1 RNA levels at 6 months. The primary outcome was virologic success, defined as achieving an HIV-1 RNA level </=400 copies/mL or a >/=1.0 log10 reduction in HIV-1 RNA level. A second analysis consisted of linear regression assessing the effect of covariates on log10 HIV-1 RNA reduction from baseline to 6 months. In multivariate analyses, achieving virologic success at 6 months was associated with high medical services utilization [adjusted odds ratio [AOR] = 10.0 (1.4, 73.9); P = 0.02] and with the use of case management services [AOR = 5.8 (1.1, 30.5); P = 0.04]. Both services resulted in a larger reduction in log10 HIV-1 RNA from baseline (difference in slopes: -0.9 and -1.0, respectively; P = 0.02 for both). Referral to off-site substance abuse services treatment did not significantly predict either virologic outcome. Among individuals who receive DAART, the utilization of on-site medical and case management services was independently associated with improved virologic outcomes. These results suggest the potential utility of integrating these services into DAART interventions (DAART-Plus) targeting HIV-infected drug users with problematic adherence.

Genotypic resistance and HIV-1 subtype in Brazilian children on dual and triple combination therapy.

Antiretroviral therapy is provided by the Brazilian Ministry of Health to eligible HIV-infected individuals. Based on clinical and immunological classification, the Brazilian guidelines recommend dual or triple therapy for children. However, the development of drug-resistant strains or poor adherence to therapy could impact the efficacy of this approach. We examined relationships between RNA levels, CD4+ T-cell counts, treatment history, and the prevalence of drug-resistant variants in a cohort of HIV-1-infected children in Rio de Janeiro, Brazil. Direct sequencing of reverse transcriptase and protease genes from plasma was performed. Virologic and CD4+ T-cell counts responses to therapy were assessed by changes in HIV-1 RNA levels and CD4+ T-cell counts from baseline. Thirty-seven patients were receiving dual therapy and 38 were on triple therapy at enrollment, segregated by antiretroviral history. Both groups had a higher increase in CD4+ T cell counts and a lower viral load in pre-treatment antiretroviral-naïve subjects. Notably, there was a direct correlation between the higher frequencies of drug-resistance mutations and cross-resistance with previous usage of antiretroviral (ARV) therapy in both groups. Non-B subtypes isolates were found in 21.3% of samples. A smaller increase in CD4+ T cell counts was found between non-B subtypes when compared to B-subtypes. These results suggest that less immunological recovery and a higher number of mutations related to drug resistance were associated with previous usage of ARV and consequent higher time under drug selective pressure in these HIV-infected Brazilian children. These facts suggest the preferential use of triple drug combination as first line regimen in children.

Gag-Specific Immune Responses after Immunization with pl7/p24:Ty Virus-Like Particles in HIV Type 1-Seropositive Individuals

Gag-specific immune responses and changes in HIV-1 RNA levels were evaluated in eight HIV-1-infected persons, in order to assess the immunotherapeutic potential HIV-1 p17/p24: Ty virus-like particles (p24-VLP). All treated subjects showed transient and dose-dependent proliferative responses to the Ty-VLP carrier (stimulation index [SI], 2.0-119.5). Three of four individuals who received either 500 or 1,000 micrograms of p24-VLP also showed proliferative responses to p17 or p24 (SI, 2.0-15.7). In 2 subjects who were treated with either 500 or 1,000 micrograms of p24-VLP, enhanced Gag-specific CTL precursor (CTLp) frequencies were observed after immunization (10- to 14-fold). Both subjects had low baseline Gag-specific CTL activity (< 25 cTLp/10(6) PBMCs). In the other participants studied no significant boosting of preexisting Gag-specific CTL responses was observed. Short-term elevation of HIV-1 RNA levels at weeks 2 and 4 was observed in two subjects treated with the highest dose of p24-VLP. However, HIV-1 RNA levels at week 24 did not significantly differ from those found in the placebo group. In conclusion, p24-VLP induced marginal Gag-specific immune responses in limited numbers of HIV-1-seropositive individuals, with some showing transient elevation of HIV-1 viral load. Further studies are needed to establish potential clinical effects of these observations.

Impact of PUVA therapy on HIV viremia: a pilot study.

Treatment by ultraviolet radiation (UV) during human immunodeficiency virus (HIV) infection is controversial, since exposure of HIV-infected cells in vitro to UV enhances HIV replication in vitro. Four consecutive AIDS patients with psoriasis and CD4 count lower than 20/mm3 were treated with 8-methoxypsoralen and UVA (PUVA). HIV viremia expressed as long of HIV-1 RNA copies/ml of plasma was quantified 10 min before and 1 h following UVA exposure, every week during PUVA therapy and at the end of treatment. The Psoriasis Area Surface Index (PASI) score was used to quantify the severity of psoriasis. No significant change in HIV-1 RNA level was observed in the 18 paired samples analyzed before and 1 h after PUVA (median: -0.05 log HIV-1 RNA, range: -0.50-0.21, p = 0.10). After 12-31 UVA exposure for a total dose of 15.5-196 J/cm2 over a period of 6-15 weeks, viremia changes from baseline in the 4 patients were -0.61, -0.07, 0.36 and 0.39 log HIV RNA. In 1 patient without antiviral treatment, a persistent decrease in viremia and transient increase in CD4 cell count were observed. PUVA was well tolerated and associated with significant improvement of the PASI score in 3 patients. HIV viremia is not significantly modified by PUVA therapy in AIDS patients with psoriasis.

Association of plasma human immunodeficiency virus type 1 RNA level with risk of clinical progression in patients with advanced infection. AIDS Clinical Trials Group (ACTG) 116B/117 Study Team. ACTG Virology Committee Resistance and HIV-1 RNA Working Groups.

Human immunodeficiency virus (HIV)-1 RNA level in plasma was evaluated as a surrogate marker for disease progression in a clinical trial of advanced HIV-1 infection. Baseline HIV-1 RNA level was an independent predictor of disease progression (relative hazard [RH] for each doubling of HIV-1 RNA level, 1.26; 95% confidence interval [CI], 1.03-1.54; P = .02), after adjusting for the week 4 change in HIV-1 RNA level, baseline CD4 cell count, syncytium-inducing phenotype, clinical status at study entry, and therapy randomization. A 50% reduction in HIV-1 RNA level was associated with a 27% decrease in the adjusted risk of disease progression during the study (RH, 0.73; 95% CI, 0.52-1.02; P = .07). The partial validation of HIV-1 RNA as a predictor for clinical end points has implications for the use of HIV-1 RNA in clinical trials and practice.