Comparative efficacy, safety and durability of dolutegravir relative to common core agents in treatment-naïve patients infected with HIV-1: an update on a systematic review and network meta-analysis

Abstract

Background The objective of this study was to assess the durability of response of dolutegravir (DTG) as an antiretroviral core agent by comparing its efficacy and safety with other recommended or commonly used core agents up to 96-weeks (W96). Methods A previously published systematic review was updated to identify phase 3/4 randomised controlled trials (RCTs) of core agents in treatment-naïve HIV-1 patients. Efficacy [virologic suppression (VS), CD4+ cell change from baseline] and safety [adverse events [AEs], discontinuations, drug-related AEs [DRAEs]] were analysed at W96 using Bayesian network meta-analysis (NMA) adjusting for nucleoside/nucleotide reverse transcriptase inhibitors' (NRTIs') backbone. Subgroups of patients with VL > 100,000 copies/mL or CD4+ ≤ 200 cells/μL at baseline were analysed separately. Results The NMA included 20 studies reporting data at W96. A higher proportion of patients receiving DTG achieved VS compared to those on protease inhibitors [PI:Range:8.7%(CrI:3.1,16.0)-19.9%(10.8,30.5)], efavirenz [EFV:6.9%(1.3,10.8)] and cobicistat-boosted elvitegravir [EVG/c:8.2%(0.2,17.4)], and similar but numerically higher compared to rilpivirine [RPV:5.0%(− 2.8,12.5)], raltegravir [RAL:2.9%(− 1.6,7.7)] and bictegravir [BIC:2.7%(− 2.7,10.6)]. The probability that more patients on DTG would achieve VS at W96 compared to any other core agent was greater than 80%. A higher proportion of patients on DTG achieved VS compared to PI/rs [Range:33.1%(13.6,50.4)-45.3%(24.1,61.6)] and RAL [16.7%(3.3,31.2)] in patients with VL > 100,000 copies/mL at baseline, and similar VS was achieved in patients with CD4+ ≤ 200 cells/μL at baseline. DTG also achieved greater increase in CD4+ cells from baseline compared to EFV [32.6(10.7,54.7)], ritonavir-boosted darunavir [DRV/r:25.7(3.6,48.1)] and BIC [24.7(1.5,47.7)]. Patients receiving DTG had lower odds of discontinuing therapy by W96 compared to PI/rs, EFV, RAL and EVG/c. Patients on DTG had lower odds of experiencing an adverse event (AE) compared to patients on EFV [odds ratio:0.6(0.3,0.9)], ATV/r [0.4(0.3,0.6)] and LPV/r [0.3(0.2,0.5)]. For patients on DTG, the odds of experiencing a drug-related AE were lower than the odds for patients on EFV [0.3(0.2,0.4)], comparable to patients on RAL [1.1(0.8,1.4)] and higher than those on BIC [1.5(1.1,2.0)]. Conclusion Un-boosted integrase inhibitors had better efficacy and similar safety compared to PI/rs at W96 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious core agent, particularly in patients with baseline VL > 100,000 copies/mL or ≤ 200 CD4+ cells/μL, who can be difficult to treat.

Once-daily dolutegravir-based antiretroviral therapy in infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the randomised ODYSSEY trial

“…Virological suppression in the dolutegravir group at 96 weeks according to the FDA snapshot algorithm (which incorporates information on treatment changes, deaths, and losses to follow-up) was similar (32 [76%] of 42 children with viral load <400 copies per mL) to that in older children in the dolutegravir group in the main ODYSSEY trial (82%) 15 and adults receiving dolutegravir (around 80-90% on first-line ART at 96 weeks and around 75% on second-line ART at 48 weeks). [6][7][8][9][10][11]13 A lower proportion of participants in the dolutegravir group had NRTI-resistant mutations after treatment failure than in the standard of care group; this finding is likely to be due to the combination of faster suppression and a lower rate of viral rebound with dolutegravir. One child in the below 14 kg cohort who experienced virological failure on second-line dolutegravir-based ART had potential low-level resistance to dolutegravir at treatment failure, with resistance also to zidovudine and lamivudine; the child achieved viral suppression again after failure without a change in ART.…”

“…4,5 Previous trials have shown that dolutegravir-based ART regimens are safe and effective at achieving high rates of virological suppression among adults living with HIV. [6][7][8][9][10] Dolutegravir-based regimens are also more durable with a lower risk of developing major drug resistance mutations compared with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART regimens. 8,9,[11][12][13] The ODYSSEY trial aimed to compare the efficacy and safety of dolutegravir-based ART versus standard of care in children starting first-line or secondline ART.…”

“…[6][7][8][9][10] Dolutegravir-based regimens are also more durable with a lower risk of developing major drug resistance mutations compared with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART regimens. 8,9,[11][12][13] The ODYSSEY trial aimed to compare the efficacy and safety of dolutegravir-based ART versus standard of care in children starting first-line or secondline ART. 14 The main trial recruited children weighing at least 14 kg and showed superiority of dolutegravir-based ART.…”

Medicine and the Law

“…In a recent systematic review and meta-analysis, DTG was found to be the most effective treatment for patients with HIV, even in difficultto-treat individuals. [15] Moreover, in patients with a high viral load (>100 000 copies/mL), DTG was associated with a higher proportion of patients achieving viral suppression at 96 weeks compared with those on other ART regimens. [15] Rapid viral suppression is a critical public health goal to reduce HIV transmission.…”

A Phase IV Study on Safety, Tolerability and Efficacy of Dolutegravir, Lamivudine, and Tenofovir Disoproxil Fumarate in Treatment Naïve Adult Indian Patients Living with HIV-1

“…15 In 2017, the generic DTG was introduced in India. All major guidelines [16][17][18][19] and network meta-analysis (NMA) [20][21][22] recommend DTG based regimens as preferred first-line ART in treatment naïve HIV patients. Also, DTG based regimens are now the standard of care in HIV treatment as per WHO guidelines.…”