|Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data
|Ioannidis J P, Collier A C, Cooper D A, Corey L, Fiddian A P, Gazzard B G, Griffiths P D, Contopoulos-Ioannidis D G, Lau J, Pavia A T, Saag M S, Spruance S L, Youle M S
To determine the efficacy of high-dose acyclovir in patients with the human immunodeficiency virus (HIV).
The trials were identified by searching MEDLINE, abstracts from meetings and trial directories, and through correspondence with experts, investigators of the identified trials and industry personnel.
Study designs of evaluations included in the review
The review included individual patient data (IPD) from randomised controlled trials (RCTs).
Specific interventions included in the review
Studies that compared high-dose acyclovir (defined as at least 3,200 mg/day) with no therapy or placebo were eligible for inclusion. The dose of acyclovir ranged from 3,200 to 4,800 mg/day and the median treatment duration ranged from 0.4 to 1.8 years.
Participants included in the review
Studies of patients with HIV infection were eligible for inclusion. Patients with or without a diagnosis of acquired immune deficiency syndrome (AIDS) were included. The median CD4 cell count ranged from 34 to 607 cells/mm3 and the median haemoglobin level ranged from 12 to 14.8 g/dL.
Outcomes assessed in the review
The main outcome of interest was survival. Secondary outcomes were herpes simplex virus (HSV) or varicella zoster virus (VZV) infections, the occurrence of new cytomegalovirus (CMV) end-organ disease, and death from lymphoma and from Kaposi's sarcoma.
How were decisions on the relevance of primary studies made?
The authors did not state how the papers were selected for the review, or how many reviewers performed the selection. The authors stated that no patients were excluded from the analysis.
Assessment of study quality
The authors stated that data inconsistencies were clarified by contact between the meta-analysis team, local data managers and trial investigators.The validity of the data was established centrally by contact between the meta-analysis team, local data managers and trial investigators.
The trial investigators and sponsoring agencies provided IPD for their trial. IPD were obtained on the following: patient identification number, treatment assignment, data of randomisation (start), latest date known to be alive and survival status, age, gender, ethnicity, baseline CD4 count, haemoglobin level and diagnosis of AIDS. Data on the occurrence of secondary outcomes were extracted, based on group data from each trial, using an intention-to-treat format.
Methods of synthesis
How were the studies combined?
IPD mortality data were analysed using Kaplan-Meier survival curves for each individual trial and for all trials combined. Comparisons between treatment groups were performed using the log rank test.
A meta-analysis of IPD was used to calculate the pooled odds ratios (ORs) and 95% confidence intervals (CIs) for survival at 6, 12, 24, 36 and 48 months, and complete follow-up, on the basis of the number of deaths occurring within each time interval among patients at risk at the beginning of that time interval. Fixed-effect and random-effects meta-analyses were used. Pooled relative risks (RRs) and 95% CIs were calculated for the analysis of the complete follow-up.
Cox proportional hazard regression was used to obtain hazard ratios (HRs) to determine the influence of age, gender, ethnicity, baseline CD4 count, baseline haemoglobin level and diagnosis of AIDS (stratified by trial) on survival.
For secondary outcomes, pooled ORs and 95% CIs were calculated from summary data using fixed-effect and random-effects meta-analyses. A significance threshold of P equal to 0.1 was used to account for multiple comparisons.
How were differences between studies investigated?
Subgroup analyses were performed for age of entry (below 30 versus greater than 30 years), gender, ethnicity (white versus other), baseline CD4 count (more than 100/mm3 versus less than 100/mm3), baseline haemoglobin level (less than 11 g/dL versus more than 11 g/dL) and reported diagnosis of AIDS. A chi-squared test for statistical heterogeneity was applied to all meta-analyses (significance threshold P<0.1). A separate analysis was performed to explore whether survival differed according to the incidence of HSV and VZV.
Results of the review
IPD from 8 RCTs (n=1,792) were included in the analysis. Three other trials were identified, but these were not included because of their use of intravenous acyclovir (1 RCT) or focus on pathogenesis (2 RCTs).
Survival (n=1,792; 2,946 patient-years).
Kaplan-Meier survival curves suggested that acyclovir was associated with a significant increase in survival compared with no treatment in patients with HIV (P=0.006).
The IPD meta-analysis found a marginal significant reduction in mortality associated with acyclovir compared with no treatment (OR 0.75, 95% CI: 0.57, 1.00, P=0.05; RR 0.81, 95% CI: 0.68, 0.96, P=0.016) for the complete follow-up. No evidence of statistical heterogeneity was found for complete follow-up or at specific time intervals. The subgroup analyses suggested that survival did not differ significantly for age of entry, gender, ethnicity, CD4 count, haemoglobin level, or reported diagnosis of AIDS.
The regression analysis found that mortality was significantly reduced in patients treated with acyclovir (HR 0.78, 95% CI: 0.65, 0.93). Higher CD4 count, higher haemoglobin count and younger age were associated with reduced mortality (P<0.001).
Significantly fewer patients treated with acyclovir had clinically evidence of HSV infection (OR 0.28, 95% CI: 0.21, 0.37, P<0.001) and VZV infection (OR 0.29, 95% CI: 0.13, 0.63, P<0.002). No significant difference was found on the occurrence of CMV-related disease, or mortality from lymphoma or Kaposi's sarcoma. No statistical heterogeneity was found for any of the secondary outcomes (P>0.2). Survival was increased in studies with a high incidence (more than 25% per year) of HSV or VZV (OR 0.64, 95% CI: 0.44, 0.93, P=0.02).
Acyclovir offered a small survival benefit in patients at low risk of death, the clinical significance of which was uncertain given recent changes in HIV therapeutics, but caution should be applied in the interpretation of the results given their apparent imprecision. However, the results supported the importance of pathogenic interaction between HIV and herpes viruses.
The review was clear in terms of the participants, interventions, outcomes and study design. A comprehensive search was undertaken to identify relevant published and unpublished trials. Methods were used to assess the accuracy and completeness of data through correspondence with trial investigators, although the authors did not explicitly state how decisions of relevance were made. Information was given on the trials excluded from the review. Appropriate methods were used to analyse the data, and the authors clearly stated which analyses were based on IPD and which were based on summary data. Heterogeneity was assessed statistically and appropriate subgroup analyses were performed. The authors' suitably cautious conclusion appear to be based on the evidence presented.
Implications of the review for practice and research
Practice: The authors stated that the use of acyclovir in current practice is not clear given the current range of HIV treatments.
Research: The authors stated that further research into the pathogenesis of still unknown viral interactions in co-infected HIV patients is warranted.
Ioannidis J P, Collier A C, Cooper D A, Corey L, Fiddian A P, Gazzard B G, Griffiths P D, Contopoulos-Ioannidis D G, Lau J, Pavia A T, Saag M S, Spruance S L, Youle M S. Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data. Journal of Infectious Diseases 1998; 178(2): 349-359
Subject indexing assigned by NLM
Acyclovir /therapeutic use; Adult; Anti-HIV Agents /therapeutic use; Dose-Response Relationship, Drug; Female; Follow-Up Studies; HIV Infections /drug therapy; Humans; Male; Randomized Controlled Trials as Topic
Date bibliographic record published
Date abstract record published
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.