This systematic review pooled data from 12 studies and showed that the effects of quadruple cART were not better than standard triple cART for first line treatment of people with HIV. Although marginally substantial heterogeneity was observed for two outcomes (undetectable HIV-1 RNA and severe adverse effects), prespecified subgroup and sensitivity analyses suggested that the primary results were robust across various scenarios. The study 13 that was excluded from this systematic review owing to insufficient follow-up time showed that the addition of a fourth drug did not lead to a greater increase in the CD4 T cell count at 36 weeks, which was consistent with our findings. The findings were also supported by mechanism studies conducted in animals. 42

Strengths, weaknesses, and implications of the study

The systematic review by Jordan and colleagues11 showed that escalating the number of antiretroviral drugs was an effective strategy to improve clinical outcomes. However, it did not evaluate quadruple cART because of the sparse data. The present systematic review is an important addition in this regard. Taking the results from the two systematic reviews together, we found that the effectiveness of cART increases as the number of drugs escalates up to three, but does not continue increasing at four, while the risk of adverse effects seems to keep increasing as the number of drugs increases.

In the included studies, the triple therapies consisted of two NRTI drugs plus one NNRTI, protease inhibitor, or integrase strand transfer inhibitor as recommended, and the added fourth drug varied across studies, involving five classes of antiretroviral drugs. Although different drug combinations could influence the effects of quadruple or triple cART themselves, they would not necessarily lead to a big difference between the two types of regimen,1143 as shown by the subgroup analyses of this systematic review. In addition, the meta-analyses with no or very low heterogeneity (that is, fig 3, fig 4, fig 5, fig 6) showed that the effects of quadruple cART were not better than those of triple cART. Furthermore, adding a fourth drug to first line treatment not only increases financial and pill burden, which might lead to lower adherence to treatment and consequently drug resistance and treatment failure, but also limits drug options for second line treatments and beyond.4445 Thus, triple cART regimens could be seen as being superior to quadruple regimens. This finding lends support to current guidelines recommending triple therapy as first line treatment.14151617

The generalisability of the findings could be a concern, owing to the many potential drug combinations for quadruple and triple cART, with only a few of these combinations evaluated in this systematic review. However, the tested cART regimens have been designed according to good evidence, beliefs, and scientific theories, so they are more likely to be better than other possible combinations. Given this assumption, it is unlikely that other combinations would be better than those tested in the trials. In fact, none of the tested quadruple therapies was statistically significantly better than any of the triple therapies in any trial on any of the outcomes assessed (fig 2, fig 3, fig 4, fig 5, fig 6, fig 7). This finding suggests strongly that these quadruple therapies be highly consistently not better than triple ones.

If the assumption does not hold that the tested cART regimens are better than any untested possible cART regimens, we would need new guiding rules that are better than current ones in designing combination therapies to increase the chance of success and improve cost effectiveness. Without a new guiding rule, there is only a faint possibility that more effective combinations have not been designed and tested so far. In addition, the cost of proving this belief would be huge, because of the large number of possible four drug and three drug combinations; the number of possible comparisons (pairs) between these combinations would be even larger. Given the currently available evidence shown in this study, further testing of new combinations might not be worthwhile.

Even if future studies comparing other drug combinations show a difference, quadruple cART regimens are more likely to be inferior to triple cART regimens, rather than the other way around, because none of the point estimates of effect from our meta-analyses favoured quadruple cART. This argument is especially tenable in view of the additional financial and pill burden and consequent issues associated with quadruple cART. Thus, the cost effectiveness of huge investment in such trials could be a concern. However, this systematic review cannot exclude the possibility that quadruple therapies would be better than triple ones when new classes of antiretroviral drugs are made available.

The above findings have important implications for future research. According to clinical trial registries, large trials to compare quadruple cART with triple cART are still being conducted, with primary interest in surrogate outcomes.46 Some researchers have gone even further and compared quintuple cART regimens with triple cART regimens, which has unsurprisingly shown no difference in effects between the two regimens.4748 Thus, the idea of evidence based research deserves more emphasis in the proposal of further trials, which are generally expensive and pose potential harms to study participants. Network analysis could also be used to compare regimens across different trials in a principled and cost effective way.

This systematic review had a few limitations. Firstly, it was not pre-registered. However, the review was conducted and reported following the widely accepted guidelines to reduce manipulation and increase transparency. Furthermore, as all major clinical outcomes were studied and reported, the impact of potential incomplete reporting in this review (if any) on the main conclusions was reduced to minimum. Therefore, the validity of this systematic review is unlikely to have been influenced by the lack of pre-registration. Secondly, some of the included studies had potential bias because of no blinding of outcome assessment and incomplete outcome data, which might have undermined the reliability of the results. However, the effect estimates remained unchanged in sensitivity analyses that removed those studies, indicating that the potential bias in studies did not affect the results much. Finally, due to the small number of studies, funnel plots and Egger’s test were not performed. Thus, we cannot rule out the possibility of publication bias.