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The causal effect of switching to second-line ART in programmes without access to routine viral load monitoring.

ABSTRACT: We examined the effect of switching to second-line antiretroviral therapy (ART) on mortality in patients who experienced immunological failure in ART programmes without access to routine viral load monitoring in sub-Saharan Africa.Collaborative analysis of two ART programmes in Lusaka, Zambia and Lilongwe, Malawi.We included all adult patients experiencing immunological failure based on WHO criteria. We used Cox proportional hazards models weighted by the inverse probability of switching to compare mortality between patients who switched and patients who did not; and between patients who switched immediately and patients who switched later. Results are expressed as hazard ratios with 95% credible intervals (95% CI).Among 2411 patients with immunological failure 324 patients (13.4%) switched to second-line ART during 3932 person-years of follow-up. The median CD4 cell count at start of ART and failure was lower in patients who switched compared to patients who did not: 80 versus 155 cells/?l (P < 0.001) and 77 versus 146 cells/?l (P < 0.001), respectively. Adjusting for baseline and time-dependent confounders, mortality was lower among patients who switched compared to patients remaining on failing first-line ART: hazard ratio 0.25 (95% CI 0.09-0.72). Mortality was also lower among patients who remained on failing first-line ART for shorter periods: hazard ratio 0.70 (95% CI 0.44-1.09) per 6 months shorter exposure.In ART programmes switching patients to second-line regimens based on WHO immunological failure criteria appears to reduce mortality, with the greatest benefit in patients switching immediately after immunological failure is diagnosed.

SUBMITTER: Gsponer T

PROVIDER: S-EPMC3759359 | biostudies-other | 2012 Jan

REPOSITORIES: biostudies-other

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The causal effect of switching to second-line ART in programmes without access to routine viral load monitoring.

Gsponer Thomas T Petersen Maya M Egger Matthias M Phiri Sam S Maathuis Marloes H MH Boulle Andrew A Musondad Patrick P Tweya Hannock H Peter Karin K Chi Benjamin H BH Keiser Olivia O

AIDS (London, England) 20120101 1

<h4>Objectives</h4>We examined the effect of switching to second-line antiretroviral therapy (ART) on mortality in patients who experienced immunological failure in ART programmes without access to routine viral load monitoring in sub-Saharan Africa.<h4>Design and setting</h4>Collaborative analysis of two ART programmes in Lusaka, Zambia and Lilongwe, Malawi.<h4>Methods</h4>We included all adult patients experiencing immunological failure based on WHO criteria. We used Cox proportional hazards m ...[more]

PMID: 22089376

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Project description:BackgroundViral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand.Methods and findingsThe Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50-250/mm(3)) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm(3). The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6-11.4) in VL versus 7.4% (5.1-10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2-8.4) in VL versus 7.5% (5.0-11.1) in CD4 (p=0.097). Median time from treatment initiation to switch was 11.7 months (7.7-19.4) in VL and 24.7 months (15.9-35.0) in CD4 (p=0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8-8.0) in VL versus 15.8 months (8.5-20.4) in CD4 (p=0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported.ConclusionsThe 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings.Trial registrationClinicalTrials.govNCT00162682 Please see later in the article for the Editors' Summary.

Dataset Information

The causal effect of switching to second-line ART in programmes without access to routine viral load monitoring.

Publications

The causal effect of switching to second-line ART in programmes without access to routine viral load monitoring.

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