Background
The emergence of combination antiretroviral therapy (cART) dramatically improved outcomes for patients with human immunodeficiency virus (HIV) infection, transforming it into a manageable chronic condition with a life expectancy similar to that in the general population [
1,
2]. Generally, cART results in durable virologic suppression (VS) and CD4
+ cell repletion, with reduced morbidity, decreased hospitalization rates, and reduced mortality, in addition to preventing HIV transmission [
1,
3‐
5]. However, all ARTs are associated with adverse effects, which are the most common reasons for switching or discontinuing therapy and for treatment non-adherence [
6].
Current guidelines from the World Health Organization (WHO), the US Department of Health and Human Services (DHHS), and the European AIDS Clinical Society (EACS) recommend first-line cART comprising a core agent (integrase strand inhibitor [INSTI], boosted protease inhibitor [PI], or non-nucleoside reverse transcriptase inhibitor [NNRTI]) in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) for treatment-naïve patients with HIV-1 [
7‐
10]. Recommended or commonly used core agents include the INSTIs bictegravir (BIC), dolutegravir (DTG), cobicistat-boosted elvitegravir (EVG/c), and raltegravir (RAL); the ritonavir-boosted PIs atazanavir (ATV/r), darunavir (DRV/r), and lopinavir (LPV/r); or the NNRTIs efavirenz (EFV) and rilpivirine (RPV).
Network meta-analyses (NMAs) allow the evaluation of the comparative efficacy and safety of the increasing numbers of treatment choices for treatment-naïve patients with HIV-1 to be evaluated in the absence of head-to-head clinical studies. An NMA conducted in 2016 compared INSTIs with EFV (the preferred core agent at that time according to the WHO [
9]) in treatment-naïve patients with HIV-1 and found a clear hierarchy within the INSTI class, with DTG being the most efficacious followed by RAL, then EVG/c. DTG was statistically superior to EFV, ATV/r, DRV/r, LPV/r, NVP, and RPV for VS at Week 48, and to EFV, EVG/c, ATV/r, DRV/r, LPV/r, and NVP for VS at Week 96. DTG was also statistically superior to EFV, EVG/c, ATV/r, LPV/r, and NVP with regards to rates of discontinuation due to adverse events (AEs) [
11]. These results were consistent with those of an earlier NMA conducted in 2013, in which DTG had similar or superior efficacy to the recommended core agents at that time (EVG/c, RAL, ATV/r, DRV/r, LPV/r, EFV, and RPV) [
12]
.
DTG is an INSTI approved for the treatment of HIV-1 in combination with other antiretroviral agents [
13,
14]. DTG is recommended once daily for adult patients infected with HIV-1 who do not have documented or clinically suspected resistance to INSTIs [
13,
14]. In randomized controlled trials (RCTs) DTG had a higher barrier to resistance than RAL [
15], was superior to once-daily EFV and once-daily DRV/r, and non-inferior to twice-daily RAL for the treatment of treatment-naïve patients with HIV-1 [
15‐
18]. As a result of the 2016 NMA that compared INSTIs with EFV [
11], the WHO now recommends a DTG-based regimen as a preferred first-line therapy for treatment-naïve patients with HIV-1 [
10]. The EACS and the US DHHS now recommend INSTIs, including DTG, as first-line core agents for treatment-naïve patients with HIV-1 [
7,
8].
With the publication of new data and updates to guideline recommendations, we conducted a systematic review and NMA to evaluate DTG against other guideline-recommended core agents in treatment-naïve patients with HIV-1 infection, to update the earlier (2013) NMA [
12].
Discussion
DTG is among the most effective core agents available for the initial treatment of patients with HIV-1 infection, according to the results of this NMA. In treatment-naïve patients, the odds of achieving VS at Week 48 were significantly higher with DTG than all ritonavir-boosted PIs and NNRTIs, and numerically higher than other INSTIs, although not significantly so, after adjustment for the choice of NRTI. These results were consistent with those of previous NMAs [
11,
12]. Furthermore, DTG was more likely to result in patients achieving VS at Week 48 versus all other core agents, including ritonavir-boosted PIs (100%), NNRTIs (99–100%), and other INSTIs (94–97%) (NNRTI-adjusted, FE model). The change in CD4
+ cell count from baseline to Week 48 in patients receiving DTG was also significantly higher or similar to that with other core agents. The benefits of DTG were achieved without any additional risk, such as AEs, discontinuations, discontinuations due to AEs, and changes in lipid levels compared with other core agents. Generally consistent results were observed in all models used (NRTI-adjusted and -unadjusted, FE and RE, with and without connector studies). These data suggest that INSTIs are a superior core agent class, and that DTG is among the most effective core agents available.
The results of this NMA were consistent in subgroups of patients with high VL or low CD4
+ cell counts at baseline, who can be difficult to treat. In patients with VL > 100,000 RNA copies/mL at baseline, the odds of achieving VS at Week 48 were statistically superior with DTG compared with all core agents except RAL and BIC, and DTG was associated with a 93–100% probability of patients achieving VS at Week 48 versus all other core agents, including RAL and BIC, in this subgroup. Results in patients with VL > 500,000 RNA copies/mL at baseline were generally consistent with these findings, although highly variable due to the low number of patients in this subgroup. The subgroup with a VL > 500,000 RNA copies/mL also included studies for which data were reported at a different threshold (> 400,000 RNA copies/mL in the two studies evaluating BIC). In patients with CD4
+ ≤ 200 cells/μL at baseline, the odds of achieving VS at Week 48 were statistically superior with DTG compared with ATV/r and LPV/r, and similar to all other core agents. DTG was associated with a 62–99% probability of patients achieving VS at Week 48 versus all other core agents in this subgroup. These results support the continued use of DTG as a preferred core agent, including in resource-constrained settings; indeed, by the end of 2017, approximately 70 lower and middle-income countries had already included/were planning to include DTG in their national formularies and to shift to a DTG-based first-line regimen [
10].
Given the cost and complications associated with conducting further RCTs to directly compare the increasing number of core agents available for the treatment of HIV-1 infection, it is appropriate to use robust methods such as an NMA to synthesize the available evidence for new and established agents in a single analysis [
97]
. The NMA methods used here were generally consistent with those of previous studies [
11,
12], with the addition of probabilistic results to rank therapies. Unlike previous NMAs, which did not include data for the NRTI TAF as it was not recommended at the time, this NMA included grouped data on TDF or TAF in combination with core agents. The grouping of TDF and TAF could be perceived as a limitation of this analysis, due to the possibility of these NRTIs having different effects independent of the core agent. However, data from head-to-head studies in which TAF and TDF (both with EVG/c and FTC) were compared in treatment-naïve patients with HIV-1 support this approach, as TAF was shown to be non-inferior to TDF in terms of VS, with similar safety profiles [
34]. No previous NMA has included BIC, as they were undertaken before its approval in 2018 [
11,
12]. The US DHHS and EACS now recommend the INSTIs BIC in addition to DTG and RAL as preferred first-line core agents for treatment-naïve adults, while the WHO does not recommend BIC or RAL, recommending a DTG-based regimen [
7,
8,
10]. The current analyses included all recently published studies evaluating core agents for treatment-naïve patients with HIV, including BIC, and allowed them to be ranked based on their ability to achieve VS relative to DTG
. Overall, the results of this analysis are in line with those of previous NMAs, with INSTIs having superior efficacy to ritonavir-boosted PIs and NNRTIs in treatment-naïve patients [
11,
12]
. The 2016 NMA by Kanters et al found a clear hierarchy within the INSTI class with regard to their ability to achieve VS, with DTG being the most efficacious followed by RAL, then EVG/c [
11]. The VS results at Week 48 from the current analysis are very similar to those reported by Kanters et al, with DTG being the most efficacious followed by RAL, BIC, then EVG/c.
Conclusions
In conclusion, our systematic literature review and NMA provide further evidence to support INSTIs as the superior class of core agent for first-line treatment of HIV-1 infection in treatment-naïve patients. They further suggest that DTG is among the most effective first-line core agents, with a safety profile similar to other core agents at Week 48. In NRTI-adjusted models in treatment-naïve patients with HIV-1, the odds of achieving VS at Week 48 were significantly higher with DTG than with all ritonavir-boosted PIs and NNRTIs and similar to other INSTIs, and increases in CD4+ cell count with DTG were significantly higher than with all ritonavir-boosted PIs and EFV and similar to other core agents. Higher odds of achieving VS at Week 48 were also seen with DTG compared with all other core agents in patients with VL > 100,000 RNA copies/mL or CD4+ cell counts ≤200 cells/μL at baseline, who can be difficult to treat. Overall, the results of this NMA confirm that DTG should remain a preferred core agent in treatment-naïve patients infected with HIV-1.
Acknowledgments
Editorial support (in the form of writing assistance during development of the initial draft, assembling tables and figures, collating authors’ comments, grammatical editing, and referencing) was provided by Chrystelle Rasamison and Meghan Betts, PhD of Fishawack Indicia Ltd., UK, and was funded by ViiV Healthcare and GlaxoSmithKline.