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

Once-a-day highly active antiretroviral therapy: a systematic review

J Ena and F Pasquau.

Review published: 2003.

CRD summary

The review assessed once-a-day highly active antiretroviral therapy (HAART) in patients infected with the human immunodeficiency virus. The authors concluded that some once-a-day HAART regimens had a virological efficacy at least similar to that of conventional HAART, an overall CD4 cell increase of at least 114 lymphocytes/microlitre, and good tolerability. The conclusions of this well-conducted systematic review are supported by the evidence presented.

Authors' objectives

To evaluate the efficacy and tolerability of once-a-day highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV)-infected patients.

Searching

MEDLINE (from 1996 to January 2002), AIDSLINE (from 1980 to December 2000) and EMBASE (search dates not given) were searched; the search terms were reported. The authors also handsearched abstracts presented at major infectious disease meetings between 1998 and 2002. The authors did not restrict their search by the language of publication.

Study selection

Study designs of evaluations included in the review

Clinical trials with at least 80% participant follow-up were eligible for inclusion. The trials included in the review had between 96 and 100% complete follow-up; follow-up was for 24 to 64 weeks.

Specific interventions included in the review

Studies that investigated once-a-day administration of at least three antiretroviral drugs were eligible for inclusion in the review. A low dose of ritonavir (RTV) to boost other protease inhibitors was not considered to be an additional drug to the regimen. The included studies used the following combinations in their once-a-day HAART regimen:

didanosine (ddI), emtricitabine (FTC) and efavirenz (EFV);

ddI, lamivudine (3TC) and EFV;

ddI, 3TC, EFV and adefovir dipivoxil;

ddI, nevirapine and EFV;

ddI, 3TC, indinavir and RTV; and

ddI, 3TC, saquinavir and RTV.

Details of the doses used in the studies were given. Directly observed therapy was used in one study.

Participants included in the review

Patients infected with HIV with detectable virus loads were eligible for inclusion. The majority of the participants in the studies were male. All participants were naive to antiretroviral therapy. The average baseline CD4 lymphocyte cell count of the participants was 164 to 471 cells/microL. The average baseline HIV-1 RNA load of the participants was 4.47 to 5.56 log10 copies/mL. Three studies reported that they included patients who were intravenous drug users.

Outcomes assessed in the review

Studies that reported undetectable HIV-1 RNA load at 24 and 48 weeks of follow-up were eligible for inclusion. The included studies reported the HIV-1 RNA load at 24 weeks (2 studies), 32 weeks (1 study), 48 weeks (4 studies), or 64 weeks (1 study). Seven studies had a lower limit of detection of 50 copies/mL, while the remaining study had a lower limit of detection of 400 copies/mL. The included studies also reported the average CD4 cell count increase. The adherence rate was measured in 5 studies: by pill count in one study and by self-report in the other 4 studies. Adverse events were also reported.

How were decisions on the relevance of primary studies made?

Two reviewers independently assessed the titles or abstracts of the identified studies to assess their relevance to the review. Both reviewers then independently assessed the full articles (or abstracts when full articles were not produced) for potential relevance. Any disagreements were resolved by consensus. The authors of 14 articles were asked to provide additional data to clarify ambiguities before including their data; 5 authors replied. For the other 9 studies, the decision on whether the study was eligible for inclusion in the review was based on the available information.

Weighted kappa statistics were used to measure the level of agreement between reviewers for the selection and inclusion of studies in the review. For duplicated or updated publications, only the most complete data set was included in the review.

Assessment of study quality

The authors did not state that they assessed validity.

Data extraction

Two reviewers independently extracted data from the primary studies. Data were extracted on patient characteristics, HAART regimen, numbers of patients with undetectable HIV-1 RNA load at the end of follow-up, CD4 lymphocyte increase, adverse events, adherence rates, and whether treatment administration was directly observed. Adverse events associated with death, or requiring drug withdrawal, were classified as severe.

The proportions, along with 95% confidence intervals (CIs), of patients with an undetectable HIV-1 RNA load at the end of follow-up were calculated. Virological failure was imputed in all patients lost to follow-up; the analysis was conducted on an intention-to-treat basis.

Methods of synthesis

How were the studies combined?

A narrative synthesis of the studies was undertaken. More detailed results were presented for the 2 RCTs.

How were differences between studies investigated?

Heterogeneity was not formally assessed. The authors stated that there was a lot of variability among the populations, the follow-up periods and the lower limits of HIV-1 RNA detection.

Results of the review

Eight studies with a total of 864 participants were included in the review: 2 randomised controlled trials (RCTs; 673 participants) and 6 non-comparative clinical trials (191 participants). Four of the studies were published and four were unpublished.

The agreement between the two reviewers was 0.91 for the selection and 0.84 for the inclusion of studies in the review.

Undetectable virus load: once-a-day HAART regimens had a virological efficacy (proportion of study patients with undetectable HIV-1 RNA) of 70 to 91%.

One RCT that randomised 34 patients to a once-a-day regimen of ddI, 3TC and EFV, 34 patients to a twice-a-day regimen of zidovudine (ZDV), 3TC and nelfinavir, and 34 patients to a twice-a-day regimen of ZDV, 3TC and EFV, found that the once-a-day regimen had a greater virological efficacy than twice-a-day ZDV, 3TC and nelfinavir (79% versus 50%; P=0.02), but a similar virological efficacy to twice-a-day ZDV, 3TC and EFV (81% versus 79%; P non significant).

The other RCT was double-blind and randomised 286 patients to a once-a-day regimen of ddI, FTC and EFV, and 285 patients to ddI, stavudine immediate-release twice daily plus EFV. The RCT found that the once-a-day regimen had a greater virological efficacy (81% versus 65%; P<0.001).

CD4 lymphocyte recovery: the average CD4 cell count increase at the end of follow-up ranged from 114 to 438 cells/microL.

Adherence: the proportion of patients adherent to the regimen was 89% in the study that measured adherence by pill count, and between 90 and 98% in the 4 studies that measured adherence by self-report.

Side-effects: the authors reported that few studies provided data on the safety of once-a-day HAART regimens. They stated that overall tolerance was fair, with a low number of severe adverse events requiring discontinuation of therapy, and no deaths directly associated with once-a-day HAART were observed. However, 7 out of 10 patients developed nephrotoxicity on the adefovir dipivoxil, ddI, 3TC and EFV regimen, while a high proportion of patients who received a once-a-day HAART regimen with EFV or nevirapine showed methadone withdrawal symptoms. A high proportion of patients who received regimens containing EFV had central nervous system adverse events during the first days of therapy. Such adverse events included sleep disturbances, dizziness, depression and mood changes.

Authors' conclusions

Preliminary RCTs showed that some once-a-day HAART regimens had a virological efficacy at least similar to that of conventional HAART, an overall CD4 cell increase of at least 114 lymphocytes/microL, and good tolerability with a low discontinuation rate.

CRD commentary

The review question was clear in terms of the study designs, participants, interventions and outcomes of interest. The authors searched three relevant electronic databases, and handsearched abstracts presented at major infectious disease meetings in an attempt to identify unpublished literature; the search resulted in the inclusion of four published and four unpublished studies. Language restrictions were not applied to the search strategy. It is therefore less likely that publication or language bias was introduced into the review. Two reviewers independently assessed the studies for inclusion in the review and the level of agreement between the reviewers was high. Two reviewers also performed the data extraction, thus reducing the chance of bias or error occurring. The authors did not assess the included studies for quality; however, only clinical trials with at least 80% participant follow-up were eligible for inclusion in the review.

Adequate details of the included studies were presented. The authors did not assess statistical heterogeneity, but commented that there was a lot of variability between studies; therefore, the narrative synthesis was appropriate. This was a well-conducted systematic review and the authors' conclusions are supported by the evidence presented.

Implications of the review for practice and research

The authors did not state any implications for practice or further research.

Bibliographic details

Ena J, Pasquau F. Once-a-day highly active antiretroviral therapy: a systematic review. Clinical Infectious Diseases 2003; 36(9): 1186-1190. [PubMed: 12715315]

Indexing Status

Subject indexing assigned by NLM

MeSH

Adolescent; Adult; Anti-HIV Agents /administration & dosage /adverse effects /therapeutic use; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Clinical Trials as Topic; Drug Therapy, Combination; Drug Tolerance; Female; HIV /physiology; HIV Infections /drug therapy; Humans; Lymphocytes /immunology; Male; RNA, Viral /analysis; Randomized Controlled Trials as Topic; Treatment Outcome; Viral Load

AccessionNumber

12003000941

Database entry date

31/01/2005

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: 12715315