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Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study

https://doi.org/10.1016/S1473-3099(11)70032-9Get rights and content

Summary

Background

The effect of transmitted drug resistance (TDR) on first-line combination antiretroviral therapy (cART) for HIV-1 needs further study to inform choice of optimum drug regimens. We investigated the effect of TDR on outcome in the first year of cART within a large European collaboration.

Methods

HIV-infected patients of any age were included if they started cART (at least three antiretroviral drugs) for the first time after Jan 1, 1998, and were antiretroviral naive and had at least one sample for a genotypic test taken before the start of cART. We used the WHO drug resistance list and the Stanford algorithm to classify patients into three resistance categories: no TDR, at least one mutation and fully-active cART, or at least one mutation and resistant to at least one prescribed drug. Virological failure was defined as time to the first of two consecutive viral load measurements over 500 copies per mL after 6 months of therapy.

Findings

Of 10 056 patients from 25 cohorts, 9102 (90·5%) had HIV without TDR, 475 (4·7%) had at least one mutation but received fully-active cART, and 479 (4·8%) had at least one mutation and resistance to at least one drug. Cumulative Kaplan-Meier estimates for virological failure at 12 months were 4·2% (95% CI 3·8–4·7) for patients in the no TDR group, 4·7% (2·9–7·5) for those in the TDR and fully-active cART group, and 15·1% (11·9–19·0) for those in the TDR and resistant group (log-rank p<0·0001). The hazard ratio for the difference in virological failure between patients with TDR and resistance to at least one drug and those without TDR was 3·13 (95% CI 2·33–4·20, p<0·0001). The hazard ratio for the difference between patients with TDR receiving fully-active cART and patients without TDR was 1·47 (95% CI 0·19–2·38, p=0·12). In stratified analysis, the hazard ratio for the risk of virological failure in patients with TDR who received fully-active cART that included a non-nucleoside reverse transcriptase inhibitor (NNRTI) compared with those without TDR was 2·0 (95% CI 0·9–4·7, p=0·093).

Interpretation

These findings confirm present treatment guidelines for HIV, which state that the initial treatment choice should be based on resistance testing in treatment-naive patients.

Funding

European Community's Seventh Framework Programme FP7/2007-2013 and Gilead.

Introduction

In Europe, widespread use of combination antiretroviral therapy (cART) has been associated with a substantial improvement in survival. However, this improvement is paralleled by increased transmission of antiretroviral drug resistance: an estimated 10–15% of antiretroviral-naive patients in Europe1, 2, 3, 4, 5 and the USA6 carry viruses with at least one drug resistance mutation.

Mutations in the HIV genome that confer drug resistance are a major reason for virological failure and can affect immunological response to ART. Treatment guidelines recommend genotypic testing in antiretroviral-naive patients to detect the presence of transmitted drug resistance (TDR) and to adapt their first-line treatment accordingly.7, 8 However, the effect of TDR on virological and immunological response remains controversial and has not been fully described. In particular, the effect of TDR on virological response in patients treated with a fully-active regimen has not been assessed in large datasets in the context of systematic genotypic testing before treatment initiation.

We assessed the effect of TDR on virological and immunological response in the first year of cART in adults and children within a large European collaboration of HIV observational cohorts (EuroCoord) and the European Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN).

Section snippets

Study population

The collaborative HIV cohorts CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe), COHERE (Collaboration of Observational HIV Epidemiological Research Europe), EuroSIDA, and PENTA-EPPICC (Paediatric European Network for Treatment of AIDS—European Pregnancy and Paediatric HIV Cohort Collaboration) are the four founding networks of EuroCoord. CHAIN and EuroCoord joined their collaborative efforts for this project.

25 cohorts that participated through the EuroCoord network

Results

Of 12 016 eligible patients, 10 056 had sufficient follow-up data and were included in the main analysis (table 1); 6126 (60·9%) of 10 056 patients had at least one nucleotide sequence available and for 3930 (39%) the result of the resistance test was reported as a list of mutations. The plasma sample for genotypic testing was taken before ART initiation in all patients but the date of testing was after initiation in some patients: 37% of patients were tested before initiation (median 2 months,

Discussion

In this large assessment, TDR was associated with virological failure in patients who received at least one drug to which the virus had lost susceptibility, which confirms results from previous studies (panel).14, 15, 16 We reported that the prescription of a drug classified even with low-level resistance is associated with a significantly higher risk for virological failure, which underscores the need for at least three fully-active antiretroviral drugs to optimise the virological response to

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