Introduction

Top Abstract Introduction Methods Results Discussion References

In 1987 zidovudine was introduced for the treatment of HIV infection. Since then there has been an escalation in the number of antiretroviral agents. Sequentially, treatment with two and then three drugs has become rapidly accepted.^1-5 Treatment with four or more drugs has also been proposed. ^{3 6}

Systematic reviews have examined questions about the effectiveness of specific drugs and combinations or have included trials with a mixture of patients who have and have not received drug treatment.^7-12 We carried out a systematic review on the effectiveness of increasing numbers of drugs used in combination. To reduce the potential for confounding by established drug resistance we looked only at those patients who had not previously received antiretroviral therapy.

	Methods

Top Abstract Introduction Methods Results Discussion References

Search strategy and inclusion criteria
We looked for randomised controlled trials of antiretroviral therapy in HIV patients (up to the end of February 2001) in Medline, the Cochrane Library, Embase, CINAHL, PsycLIT, Healthstar, appropriate internet sites such as AIDSTRIALS, and citation lists. We also contacted pharmaceutical companies. We included studies only if they included patients who were HIV positive (any stage) and were aged 12 years with less than six months' previous antiretroviral therapy or if less than 30% of patients had previous therapy or if patients who had never had therapy were reported separately. The accepted interventions were any licensed (United Kingdom or United States) antiretroviral drug (or combination) compared with any other antiretroviral drug or placebo or no treatment. We excluded studies if they lasted less than 12 weeks. We assessed studies for quality using a standard checklist.¹³

Analysis
Data were collected on all relevant outcomes, with disease progression and deaths as clinical outcomes and CD4 count and viral load as surrogate markers. To take account of the large dropout rates but to maximise the length of time in the trial we measured CD4 count and viral load at the longest time point when at least half the total number of patients in each arm remained. For continuous outcomes (CD4 count and viral load change) we calculated the treatment effect for individual trials as the treatment effect (that is, mean change) minus the control effect. We pooled data using the inverse variance method of weighting (for continuous outcomes) and the fixed effects Peto method for event rates.¹⁴ Significance was set at P<0.05. We assessed statistical heterogeneity using the ² test. ^{15 16} When there were several arms within a trial we weighted the number of events and the number of participants so that each participant was used only once.

We explored heterogeneity using sensitivity and subgroup analyses and fixed effects weighted regression techniques, with the covariates of trial duration, baseline CD4 count/viral load, dropout rates, drug dose, specific drug or drugs (presence of protease inhibitors or zidovudine), change in CD4/viral load, sensitivity of the viral load assay, and blinding and concealment of allocation.

We assessed publication bias visually using a funnel plot and statistically using Egger's and Begg's tests.

	Results

Top Abstract Introduction Methods Results Discussion References

Quantity, quality, and characteristics of trials
Out of over 2000 search "hits" we retrieved 700 papers and finally included 90, which referred to 54 different trials and 20 404 patients (references for these 54 trials can be found in the long version of this paper on bmj.com; selected references are cited here). Over 80% of the participants were men, with an average age ranging between 27 and 40 years. More patients were asymptomatic than at any other clinical stage, mean baseline CD4 counts ranged from 83-660 cells per µl, and mean viral load ranged from 2.35 to 7.35 log copies per ml. The length of the trials varied from 12 weeks to 4.8 years, although follow up was not always clearly reported.

Zidovudine was the only monotherapy compared with placebo or no treatment. The most common dual therapies were two nucleosides, most which were compared against zidovudine or didanosine monotherapy. Triple therapies were mainly based on the currently advised pattern of two nucleosides (usually zidovudine plus didanosine or lamivudine) with the addition of a protease inhibitor or a non-nucleoside. One trial compared quadruple therapy with protease inhibitors at lower doses to boost each other rather than as true quadruple combination and therefore was not incorporated into the analyses.¹⁷

Potential publication bias
We found no consistent visual or statistical evidence of publication bias except for CD4 count for triple versus double therapy, where there was a clear lack of small studies with negative results.

Main outcomes

Monotherapy compared with placebo
Compared with placebo, zidovudine significantly reduced disease progression or death (odds ratio 0.7, 95% confidence interval 0.6 to 0.8), although there was substantial heterogeneity (fig 1). Zidovudine also resulted in an improvement in CD4 count of 47 cells per µl (29 to 65) with no important heterogeneity and a viral load reduction of 0.56 log copies per ml (0.71 to 0.41) with some unexplained heterogeneity. The heterogeneity present in the clinical outcome data (range of odds ratio 0.1-1.1, fig 1) was in part explained by the variable duration of the trials: as the trials increased in length zidovudine had a smaller relative effect. At 152 weeks (about three years), as in the Concorde trial,¹⁸ the beneficial effect of zidovudine was virtually eliminated (fig 2).

View larger version (35K): [in this window] [in a new window]   Fig 1.   Effect of zidovudine monotherapy versus placebo on disease progression or death. Figures are number of events/number of participants

View larger version (11K): [in this window] [in a new window]   Fig 2.   Duration of trial and odds of disease progression or death with zidovudine monotherapy versus placebo

Double therapy compared with monotherapy
Double therapy resulted in significantly better clinical outcomes than monotherapy did (odds ratio for disease progression/death was 0.6, 0.5 to 0.7, fig 3). There was some heterogeneity, but this seemed to be largely accounted for by one large trial of protease inhibitors.¹⁹ Sensitivity analysis in which we excluded this trial did not alter the effect size or confidence intervals. The trial duration did not explain the heterogeneity.

View larger version (38K): [in this window] [in a new window]   Fig 3.   Effect of double therapy versus monotherapy on disease progression or death. Figures are number of events/number of participants

Triple therapy compared with double therapy
Triple therapy significantly improved clinical outcomes compared with double therapy (odds ratio for disease progression/death was 0.6, 0.5 to 0.8, fig 4), although most trials had few events. Only one large trial lasted over a year, and this contributed most events.²⁰ The heterogeneity was attributable to one open label study with few events.²¹ In a sensitivity analysis that excluded this study we found no change in the estimates of effect size. The results for the surrogate markers (CD4 and viral load) were consistent with those for the clinical outcomes, showing that triple therapy was significantly better than double therapy, though there was substantial heterogeneity in all analyses. Possible causes of this heterogeneity were issues of quality (concealment of allocation and non-blinding) and types of drugs used.

View larger version (25K): [in this window] [in a new window]   Fig 4.   Effect of triple therapy versus double therapy on disease progression or death. Figures are number of events/number of participants

Other outcomes
Twenty six trials gave information on drug related withdrawals. Dropout rates were higher with monotherapy than with placebo but no different between double therapy and monotherapy. The results of triple compared with double therapy were heterogeneous. There was no significant difference in dropout rates between triple therapy without a protease inhibitor and double therapy without a protease inhibitor. Trials of therapies that contained a protease inhibitor in the triple but not the double arm had significantly higher withdrawals, with one exception.²⁰ Only four trials gave useful information regarding quality of life related to health,^22-26 and they had inconsistent results.

	Discussion

Top Abstract Introduction Methods Results Discussion References

This systematic review of combination therapy for people with HIV showed a consistently and significantly greater benefit for increasing numbers of drugs up to, and including, triple therapy for clinical outcomes and surrogate markers. There was, however, marked heterogeneity, mainly accounted for by the drugs tested and issues of quality.

Strengths and weaknesses
HIV patients who have never received antiretroviral drugs comprise only a part of clinical practice, but establishment of the effectiveness of such treatment in these patients is fundamental to understanding the overall relative benefit of the drugs, and subsequent treatment decisions are contingent on the initial choice. Though choice of this study population reduced confounding, other potential causes of clinical heterogeneity were reflected in the results. Exploration of heterogeneity with regression techniques suggested that different drugs might explain some of the variation. This conclusion must be tempered with caution as post hoc analyses are purely exploratory and the techniques used are limited, with small numbers of observations. Data on individual patients would allow better exploration of the effect of patient characteristics, although such techniques are usually too expensive and time consuming.²⁷ In addition, some of these findings are based on surrogate end points and should be confirmed by clinical end points, which are less well reported in published trials. Data on adverse events are difficult to interpret in the context of HIV trials in which patient behaviour may differ from clinical practice, and a full evaluation of adverse events should include postmarketing surveillance. Despite a rigorous search for trials, the possibility of publication bias cannot be completely excluded.

Implications and future research
This systematic review provides new evidence that the escalation of combinations of antiretroviral drugs up to triple therapy is an effective strategy. Our results for the relative effectiveness of monotherapy versus placebo and double therapy versus monotherapy are consistent with the results of smaller meta-analyses. ^{11 12} Also, the overall findings are supported by the results of cohort studies.^28-33 However, there is no fully published evidence on the effectiveness of quadruple or higher combinations.

Future work to clarify which triple combination is the most effective is as important as investigating the effectiveness of quadruple or higher combinations. As the number of drugs increases, quality of life and safety assume relatively greater importance but are currently inadequately reported.

The exploratory analyses of heterogeneity indicate that the design of future trials must be more rigorous and less variable (for example, in trial duration, test drugs, comparators, and clinical stage at entry) and should not rely on surrogate outcomes alone. There are still important questions to be answered about the effectiveness of existing agents. This may require publicly funded trials which should be carried out within a clear well supported collaborative framework.