 |
Introduction |
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
Influential clinical guidelines tend to be based on individual selected
clinical trials, often published as conference
abstracts.
3 4 7
Early results from individual studies
can be unrepresentative.8 Support for the clinical benefit
of increasing drug combinations comes from well conducted cohort
studies,9-14 but the length of follow up is still too
short to assess the long term clinical benefit of triple therapy.
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.15-20 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 |
Search strategy and inclusion criteria
This review was conducted to the suggested QUOROM guidelines
standards.21 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. There was no language
restriction. 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.22 Data were extracted by two independent
reviewers. We included and listed in the review those trials that did
not provide any useful measure of variance or had no events, but the
data from these trials could not be used in the analyses.
Data 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 of the total number of patients
in each arm remained.
Meta-analysis
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 calculated
the standard error of the weighted mean difference by adding the
variances of the change in outcome in both groups and taking the square
root. For triple therapy we also present data on viral load as the
proportion of patients in whom concentrations of plasma virus became
too low to be detected (<50 copies per ml). We pooled data using the
inverse variance method of weighting (for continuous outcomes) and the
fixed effects Peto method for event rates.23 Significance
was set at P<0.05. We assessed statistical heterogeneity using the
2 test.
24 25
When there were several arms
within a trial that allowed more than one comparison per arm 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 (Stata 5.0 software), 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
(mean/median/change/end point), 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 (Stata
5.0).
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Fig 1.
Funnel plots of CD4 count results for
monotherapy versus placebo, double therapy versus monotherapy, and
triple therapy versus double therapy
|
|
| |
Results |
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 trials26-86 and 20 404 patients. The trials were
generally of good quality and randomised. Concealment of allocation was
confirmed in a third, most were double blind, and participants in each
arm were comparable within trials. 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.
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Fig 2.
Effect of zidovudine monotherapy versus placebo
on disease progression or death. Figures are number of events/number of
participants
|
|
The table lists the comparisons available for the analyses. Zidovudine
was the only monotherapy compared with placebo or no treatment. The
most common double 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 (two nucleosides plus ritonavir plus saquinavir at lower doses
given to boost each other rather than as a true full dose quadruple
combination) and therefore was not incorporated into the
analyses.78 Other unusual interventions (such as cyclical
or intermittent therapies) were not included in the analyses. We
classified immediate versus deferred zidovudine as zidovudine versus
placebo.
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Fig 4.
Effect of zidovudine monotherapy versus placebo
on change in mean (SD) viral load (log copies per ml)
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Fig 5.
Duration of trial and odds of disease
progression or death with zidovudine monotherapy versus
placebo
|
|
Potential publication bias
We found no consistent visual or statistical evidence of
publication bias (that is, the tendency that small studies are more
likely to be published if they have significant positive results)
except for CD4 count for triple versus double therapy, where there was
a clear lack of small studies with negative results (fig1). The
limitations of the techniques, particularly when there are few trials
and there is heterogeneity present, mean we cannot exclude publication
bias.
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Fig 6.
Effect of double therapy versus monotherapy on
disease progression or death. Figures are number of events/number of
participants
|
|
Main outcomes
Monotherapy compared with placebo
Fifteen trials compared monotherapy with
placebo.
26 32-34 36-39 41-45 50 51
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 2). Zidovudine also resulted in an
improvement in CD4 count of 47 cells per µl (29 to 65) with no
important heterogeneity (fig 3) and a viral load reduction of 0.56 log
copies per ml (0.71 to 0.41) with some unexplained heterogeneity (fig
4). The heterogeneity present in the clinical outcome data (range of
odds ratio 0.1-1.1, fig 2) 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,42 the beneficial effect of zidovudine
was virtually eliminated (fig 5).
Double therapy compared with monotherapy
We found 14 trials that compared double therapy with monotherapy
(figs 6-8).
52 53 55-62 66 77 79 80
Double therapy
resulted in significantly better clinical outcomes than monotherapy did
(fig 6) (odds ratio for disease progression/death was 0.6, 0.5 to 0.7).
There was some heterogeneity, but this seemed to be largely accounted
for by one large trial of protease inhibitors.79 Sensitivity analysis in which we excluded this trial did not alter the
effect size or confidence intervals. In contrast with the results for
monotherapy the trial duration did not explain the heterogeneity,
despite ranging from six months to three years.
Results for surrogate markers were significantly better with double
therapy than with monotherapy (figs 7 and 8). Subgroup analyses showed
that heterogeneity in the CD4 counts was wholly accounted for by
the presence of zidovudine or protease inhibitors (fig 7), which
suggests that combinations that contain protease inhibitors may be more
effective than other double therapies and that monotherapy with
zidovudine is less effective compared with other monotherapies.
Heterogeneity was present in the analysis of viral load, but
exploratory analyses were not informative.
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Fig 8.
Effect of double therapy versus monotherapy on
change in mean (SD) viral load (log copies per ml)
|
|
Triple therapy compared with double therapy
We found 12 trials of triple therapy compared with double therapy
(fig 9-12).
68-70 72 73 75 81-86
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 9),
although most trials had few events. Only one large trial lasted over a
year, and this contributed most events.86 The
heterogeneity was attributable to one open label study with few
events.73 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. Regression analyses of both the CD4
count and the change in viral load indicated that possible causes of
this heterogeneity were issues of quality (concealment of allocation
and non-blinding) and types of drugs used.
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Fig 9.
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.
30 33 34 36 37 39 42-45 51 55 58 60 61 63 68 69 72 73 75 76 81 82 84 86
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. Subgroup classification of trials according to presence of protease inhibitors suggested that 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. The exception to this was the PISCES
trial,86 the only trial that included saquinavir in the
triple arm (fig 13). Only four trials gave useful information regarding
quality of life related to health,
27-29 47 71
and they
had inconsistent
results.
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Fig 11.
Effect of triple therapy versus double therapy
on change in mean (SD) viral load (log copies per ml)
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Fig 12.
Effect of triple therapy versus double therapy
on proportion of participants reaching undetectable viral load. Figures
are number of events/number of participants
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Fig 13.
Triple therapy versus double therapy and
withdrawals due to adverse events related to drug treatment
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|
| |
Discussion |
Principal findings
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. Marked variation in the results for
many outcomes was greater than could be accounted for by chance alone.
When we investigated the effects of potential confounders on the
results we found that the heterogeneity for monotherapy was largely
explained by decreasing effectiveness over time, which is consistent
with the development of drug resistance. For double and triple therapy,
the heterogeneity was mainly accounted for by the drugs tested
(possible greater effectiveness of protease inhibitors and weaker
effect of zidovudine) and issues of quality (blinding and concealment
of allocation) for particular trials but was not always consistent
between different surrogate and clinical outcomes. We found no
published trials on the effectiveness of true full dose quadruple therapy.
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.87 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.
19 20
Also, the overall findings are supported by the results of cohort studies.9-14 However,
there is no fully published evidence on the effectiveness of quadruple or higher combinations.
Exploratory analyses of the variation in results showed that
differences resulted from the specific drugs used. Both effectiveness and cost considerations indicate that 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.
Better evidence is required. 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. The research community must respond. 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.
We thank Jeremy Hawker, Paul Aveyard, Matthias Egger, Sarah
Walker, and Abdel Babiker for their valuable comments.
Contributors: RJ was the main reviewer; conducted the search,
data extraction, evaluation, and analyses; and wrote the paper. LG
performed the double data extraction, advised on direction, and
commented on the text. CC advised on and performed the statistics and
cowrote the text. CH advised on direction and interpretation of the
analyses, made substantial comments on the text, and is guarantor.
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