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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Emergence of drug resistance in HIV type 1-infected patients after receipt of first-line highly active antiretroviral therapy: a systematic review of clinical trials

R Gupta, A Hill, AW Sawyer, and D Pillay.

Review published: 2008.

Link to full article: [Journal publisher]

CRD summary

This review compared drug resistance profiles of patients with HIV type 1 infection after treatment with first-line antiretroviral therapy. The authors concluded that initial treatment with a boosted protease inhibitor-based regimen was associated with less resistance within and across drug classes. The reliability of this conclusion is unclear due to potential methodological weaknesses and gaps in the reporting process.

Authors' objectives

To compare the drug resistance profiles of patients with HIV (human immunodeficiency virus) type infection after treatment with first-line antiretroviral therapy.

Searching

MEDLINE was searched for relevant articles published from January 1994 to November 2007 and for abstracts published from 1999 to 2007. Search terms were reported. Six relevant conference proceedings were reviewed and reference lists of included studies were searched for additional articles of interest. Full-length articles were included in the review.

Study selection

Clinical trials with a minimum of 50 treatment-naive HIV-1-infected adults (aged over 13 years) in each treatment arm of highly active antiretroviral therapy (HAART) were eligible for inclusion in the review. HAART had to consist of two nucleoside reverse-transcriptase inhibitors (NRTIs) in combination with a third agent, such as a non-NRTI (NNRTI), or in combination with a ritonavir-boosted protease inhibitor (bPI). Trials had to measure viral load at least every 16 weeks and contain genotypic resistance data on virological failures, with a minimum of 48 weeks follow-up. The varied inclusion criteria for virologic failure were reported in the paper. Prevention studies of maternal-to-child transmission were excluded, as were those that used non-recommended agents (didanosine, delaviridine, zalcitabine, nelfinavir, indinavir, full dose ritonavir), or those that did not use lamivudine or emtricitabine. Mean age of included participants ranged from 35.5 to 37.3 years. Females represented approximately 22% of the study population. Follow-up ranged from 48 to 144 weeks. Two independent reviewers selected studies for inclusion in the review. Disagreements were resolved in consultation with a third reviewer.

Assessment of study quality

The authors did not state that they assessed validity, although the blinding status of trials was reported.

Data extraction

Data were extracted on: baseline median and/or mean CD4 cell count and log 10 viral load; viral suppression rates at weeks 48 and 96 (using intention to treat data from patients who had been randomised to receive at least one dose of the study drug); increases in CD4 cell count; definition and number of virologic failures; and number of genotypes successfully determined in patients with virologic failures. Data were collected on: virologic failure and genotypic resistance in patients infected with wild-type virus, or who experienced no change from the baseline genotype; patients with NNRTI mutations of the HIV reverse-transcriptase (defined in the paper); and PI mutations (defined in the paper). Data were also collected on measures of NRTI resistance: M184V mutation; at least one thymidine analogue mutation (TAM) (defined in the paper); and K65R mutation.

Two independent reviewers performed the data extraction. Where necessary, trial co-ordinators or study authors were contacted to obtain additional data.

Methods of synthesis

Results were synthesised in a meta-analysis. Group mean values for CD4 cell count and log 10 viral load were compared using inverse-variance weighting. Rates of specific resistance mutations were compared across the groups (NNRTI versus bPI); and the number of patients with M184V, at least one TAM, and greater or equal to one major NNRTI or PI mutation per treatment arm at week 48. The two main populations for analysis were genotype population (total number of patients with genotype resistance data available after virologic failure) and the intention-to-treat population. For each group, 95% confidence intervals (CI) were reported using the exact interval. Subgroup analyses were conducted to explore the impact of the NRTI backbone on the development of resistance. Newer NRTIs (abacavir or tenofovir) were compared with older agents (stavudine or zidovudine) in terms of resistance rates to lamivudine and NNRTIs.

Results of the review

Twenty clinical trials (n=7,970 patients) were included in the review; 4,560 patients received NNRTI-based regimens and 3,410 patients received bPI-based regimens. Fifteen trials were open label and five were double blind.

At 48 weeks, virologic failure was reported in 4.9% (95% CI 3.9% to 6.1%) of NNRTI patients compared with 5.3 % (95% CI 4.4% to 6.4%, p=0.50) of bPI patients. Where failures were successfully genotyped (80% in NNRTI-based and 83% of patients in bPI-based regimens), the M184V mutation in the HIV reverse transcriptase (lamivudine resistance) was reported in 35.3% (95% CI 29.3% to 41.6%) of patients who started NNRTI-based HAART compared with 21.0% (95% CI 14.4% to 28.8%, p<0.001) of those treated with a bPI.

Incidences of virologic failure for the K65R mutation in the HIV reverse transcriptase (multi-nucleoside resistance) were 5.3% (95% CI 2.4% to 9,9%) for NNRTI and 0.0% (95% CI 0.0% to 3.6%, p=0.01) for BPI where patients were treated with non-zidovudine-based regimens. Resistance to the third agent was reported in 53% (95% CI 46% to 60%) of NNRTI patients and 0.9% (95% CI 0.0% to 6.2%, p<0.001) of bPI patients.

Newer NRTIs combined with an NNRTI were not associated with lower rates of NNRTI resistance than older thymidine analogues, nor was the rate of lamivudine resistance different.

Authors' conclusions

Initial therapy with bPI-based regimens was associated with less resistance within and across drug classes.

CRD commentary

The review addressed a clear question supported by comprehensive inclusion criteria that were potentially reproducible. The search strategy relied largely on one electronic database, which may mean that relevant studies were missed. It appeared that attempts were made to locate unpublished material from various sources, which reduced the threat of publication bias. The processes of study selection and data extraction were carried out with sufficient attempts to minimise error and bias. No formal assessment of study quality was reported, which limited the interpretation of the reliability of the authors' conclusions. Study details were provided. No details were available to verify the authors statement about the absence of heterogeneity and it was not possible to assess the appropriateness of the chosen method of meta-analysis. The authors' conclusion reflected the evidence presented, but the reliability of the conclusion was unclear due to the potential methodological weaknesses and gaps in the reporting process. The authors declared some potential conflicts of interest in terms of receipts of funding from drug manufacturers.

Implications of the review for practice and research

Practice: The authors stated that bPIs may be appropriate for use in resource-poor settings.

Research: The authors stated that first-line treatment using generic bPIs should be evaluated as part of a global public health approach to HAART.

Funding

British Infection Society Clinical Research Training Fellowship. UCLH/UCL Comprehensive Biomedical Research Centre. Wellcome Trust.

Bibliographic details

Gupta R, Hill A, Sawyer AW, Pillay D. Emergence of drug resistance in HIV type 1-infected patients after receipt of first-line highly active antiretroviral therapy: a systematic review of clinical trials. Clinical Infectious Diseases 2008; 47(5): 712-722. [PubMed: 18662137]

Indexing Status

Subject indexing assigned by NLM

MeSH

Adult; Anti-HIV Agents /pharmacology /therapeutic use; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Drug Resistance, Viral; HIV Infections /drug therapy /virology; HIV Reverse Transcriptase /genetics; HIV-1 /drug effects /genetics; Humans; Incidence; Mutation, Missense; Treatment Failure; Treatment Outcome; Young Adult

AccessionNumber

12009100315

Database entry date

17/02/2010

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 18662137

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