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      Improved virologic outcomes over time for HIV-infected patients on antiretroviral therapy in a cohort from Rio de Janeiro, 1997–2011

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          Abstract

          Background

          Previous cohort studies have demonstrated the beneficial effects of antiretroviral therapy (ART) on viral load suppression. We aimed to examine the factors associated with virologic suppression for HIV-infected patients on ART receiving care at the Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation in Rio de Janeiro, Brazil.

          Methods

          HIV-1 RNA levels and CD4+ T-cell counts at the date closest to midyear (1 July) were evaluated for 1,678 ART-naïve patients ≥18 years of age initiating ART between 1997 and 2010. The odds ratios (OR) and 95% confidence intervals (CI) for having an undetectable viral load (≤400 copies/mL) were estimated using generalized estimating equations regression models adjusted for clinical and demographic factors. Time-updated covariates included age, years since HIV diagnosis, hepatitis C diagnosis and ART interruptions.

          Results

          Between 1997 and 2011, the proportion of patients with an undetectable viral load increased from 6% to 78% and the median [interquartile range] CD4+ T-cell count increased from 207 [162, 343] to 554 [382, 743] cells/μL. Pre-treatment median CD4+ T-cell count significantly increased over the observation period from 114 [37, 161] to 237 [76, 333] cells/μL (p < .001). The per-year adjusted OR (aOR) for having undetectable viral load was 1.18 (95% CI = 1.16-1.21). ART interruptions >1 month per calendar significantly decreased the odds [aOR = 0.32 (95% CI = 0.27-0.38)] of having an undetectable viral load. Patients initiating on a protease inhibitor (PI)-based first-line regimen were less likely to have undetectable viral load [aOR = 0.72 (95% CI = 0.63-0.83)] compared to those initiating on a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen.

          Conclusions

          Our results demonstrate significant improvements in virologic outcomes from 1997 to 2011, which persisted after adjusting for other factors. This may in part be due to improvements in care and new treatment options. NNRTI- versus PI-based first-line regimens were found to be associated with increased odds of having an undetectable viral load, consistent with previous studies. Treatment interruptions were found to be the most important determinant of not having an undetectable viral load. Studies are needed to characterize the reasons for treatment interruptions and to develop subsequent strategies for improving adherence to ART.

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          Most cited references18

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          Class-sparing regimens for initial treatment of HIV-1 infection.

          The use of either efavirenz or lopinavir-ritonavir plus two nucleoside reverse-transcriptase inhibitors (NRTIs) is recommended for initial therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection, but which of the two regimens has greater efficacy is not known. The alternative regimen of lopinavir-ritonavir plus efavirenz may prevent toxic effects associated with NRTIs. In an open-label study, we compared three regimens for initial therapy: efavirenz plus two NRTIs (efavirenz group), lopinavir-ritonavir plus two NRTIs (lopinavir-ritonavir group), and lopinavir-ritonavir plus efavirenz (NRTI-sparing group). We randomly assigned 757 patients with a median CD4 count of 191 cells per cubic millimeter and a median HIV-1 RNA level of 4.8 log10 copies per milliliter to the three groups. At a median follow-up of 112 weeks, the time to virologic failure was longer in the efavirenz group than in the lopinavir-ritonavir group (P=0.006) but was not significantly different in the NRTI-sparing group from the time in either of the other two groups. At week 96, the proportion of patients with fewer than 50 copies of plasma HIV-1 RNA per milliliter was 89% in the efavirenz group, 77% in the lopinavir-ritonavir group, and 83% in the NRTI-sparing group (P=0.003 for the comparison between the efavirenz group and the lopinavir-ritonavir group). The groups did not differ significantly in the time to discontinuation because of toxic effects. At virologic failure, antiretroviral resistance mutations were more frequent in the NRTI-sparing group than in the other two groups. Virologic failure was less likely in the efavirenz group than in the lopinavir-ritonavir group. The virologic efficacy of the NRTI-sparing regimen was similar to that of the efavirenz regimen but was more likely to be associated with drug resistance. (ClinicalTrials.gov number, NCT00050895 [ClinicalTrials.gov].). Copyright 2008 Massachusetts Medical Society.
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            Association between adherence to antiretroviral therapy and human immunodeficiency virus drug resistance.

            Nonadherence to highly active antiretroviral therapy (HAART) is a major cause of human immunodeficiency virus (HIV) drug resistance; however the level of nonadherence associated with the greatest risk of resistance is unknown. Beginning in February 2000, 195 patients at the Johns Hopkins Outpatient Center (Baltimore, MD) who were receiving HAART and who had HIV loads of <500 copies/mL were recruited into a cohort study and observed for 1 year. At each visit, adherence to HAART was assessed and plasma samples were obtained and stored for resistance testing, if indicated. The overall incidence of viral rebound with clinically significant resistance was 14.5 cases per 100 person-years. By multivariate Cox proportional hazards regression, a cumulative adherence of 70%-89%, a CD4 cell nadir of <200 cells/microL, and the missing of a scheduled clinic visit in the past month were independently associated with an increased hazard of viral rebound with clinically significant resistance. Clinicians and patients must set high adherence goals to avoid the development of resistance.
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              The combined effect of modern highly active antiretroviral therapy regimens and adherence on mortality over time.

              To characterize the impact of longitudinal adherence on survival in drug-naive individuals starting currently recommended highly active antiretroviral therapy (HAART) regimens. Eligible study participants initiated HAART between January 2000 and November 2004 and were followed until November 2005 (N = 903). HAART regimens contained efavirenz, nevirapine, or ritonavir-boosted atazanavir or lopinavir. Marginal structural modeling was used to address our objective. The all-cause mortality was 11%. Individual adherence decreased significantly over time, with the mean adherence shifting from 79% within the first 6 months of starting HAART to 72% within the 24- to 30-month period (P value <0.01). Nonadherence over time (<95%) was strongly associated with higher risk of mortality (hazard ratio: 3.13; 95% confidence interval (CI): 1.95 to 5.05). Nonadherent (<95%) patients on nonnucleoside reverse transcriptase inhibitor (NNRTI)-based and boosted protease inhibitor-based regimens were, respectively, 3.61 times (95% CI: 2.15 to 6.06) and 3.25 times (95% CI: 1.63 to 6.49) more likely to die than adherent patients. Within the NNRTI-based regimens, nonadherent individuals on efavirenz were at a higher risk of mortality. Incomplete adherence to modern HAART over time was strongly associated with increased mortality, and patients on efavirenz-based NNRTI therapies were particularly at a higher risk if nonadherent. These results highlight the need to develop further strategies to help sustain high levels of adherence on a long-term basis.
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                Author and article information

                Contributors
                Journal
                BMC Infect Dis
                BMC Infect. Dis
                BMC Infectious Diseases
                BioMed Central
                1471-2334
                2014
                11 June 2014
                : 14
                : 322
                Affiliations
                [1 ]University of California, Los Angeles, Los Angeles, USA
                [2 ]Fundação Oswaldo Cruz, Instituto de Pesquisa Clínica Evandro Chagas, HIV/AIDS Clinical Research Center, Rio de Janeiro, Brazil
                Article
                1471-2334-14-322
                10.1186/1471-2334-14-322
                4067376
                24919778
                d3b57543-4cc5-4af5-bdae-bd20cd67155a
                Copyright © 2014 Martin et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 29 January 2014
                : 4 June 2014
                Categories
                Research Article

                Infectious disease & Microbiology
                antiretroviral therapy,cohort studies,brazil,viral load,adherence

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