Dolutegravir-Based or Low-Dose Efavirenz–Based Regimen for the Treatment of HIV-1

Abstract

BACKGROUNDAn efavirenz-based regimen (with a 600-mg dose of efavirenz, known as EFV600) was the World Health Organization preferred first-line treatment for human immunodeficiency virus type 1 (HIV-1) infection until June 2018. Given concerns about side effects, dolutegravir-based and low-dose efavirenz-based combinations have been considered as first-line treatments for HIV-1 in resource-limited settings. METHODSWe conducted an open-label, multicenter, randomized, phase 3 noninferiority trial in Cameroon. Adults with HIV-1 infection who had not received antiretroviral therapy and had an HIV-1 RNA level (viral load) of at least 1000 copies per milliliter were randomly assigned to receive either dolutegravir or the reference treatment of lowdose efavirenz (a 400-mg dose, known as EFV400), combined with tenofovir and lamivudine. The primary end point was the proportion of participants with a viral load of less than 50 copies per milliliter at week 48, on the basis of the Food and Drug Administration snapshot algorithm. The difference between treatment groups was calculated, and noninferiority was tested with a margin of 10 percentage points. RESULTSA total of 613 participants received at least one dose of the assigned regimen. At week 48, a viral load of less than 50 copies per milliliter was observed in 231 of 310 participants (74.5%) in the dolutegravir group and in 209 of 303 participants (69.0%) in the EFV400 group, with a difference of 5.5 percentage points (95% confidence interval [CI], −1.6 to 12.7; P<0.001 for noninferiority). Among those with a baseline viral load of at least 100,000 copies per milliliter, a viral load of less than 50 copies per milliliter was observed in 137 of 207 participants (66.2%) in the dolutegravir group and in 123 of 200 participants (61.5%) in the EFV400 group, with a difference of 4.7 percentage points (95% CI, −4.6 to 14.0). Virologic failure (a viral load of >1000 copies per milliliter) was observed in 3 participants in the dolutegravir group (with none acquiring drug-resistance mutations) and in 16 participants in the EFV400 group. More weight gain was observed in the dolutegravir group than in the EFV400 group (median weight gain, 5.0 kg vs. 3.0 kg; incidence of obesity, 12.3% vs. 5.4%). CONCLUSIONSIn HIV-1-infected adults in Cameroon, a dolutegravir-based regimen was noninferior to an EFV400-based reference regimen with regard to viral suppression at week 48. Among participants who had a viral load of at least 100,000 copies per milliliter when antiretroviral therapy was initiated, fewer participants than expected had viral suppression.

Impact of scaling up dolutegravir on antiretroviral resistance in South Africa: A modeling study

“…efficacy was similar to the one observed in the New Antiretroviral and Monitoring Strategies in HIV-infected Adults in Low-income countries (NAMSAL) study [12], corresponding to an OR of failure between NNRTI and DTG of 1.02, after adjusting for the different baseline characteristics of the 2 groups (see S1 Text, Section 2.5). Other DTG efficacy corresponding to an OR of 2 and 5 were investigated in an additional analysis (see supporting information S1 Text, Section 5.3).…”

“…DTG suppression and failure rates Calibrated with data from NAMSAL study [12] (see S1 Text Section 2.5)…”

“…First, real-world data on the efficacy of DTG, especially in resource-limited settings, are scarce. Therefore, we conservatively assumed that DTG has a similar efficacy as observed in the NAMSAL study [12]. Higher DTG efficacies as well as different impacts of NRTI resistance on DTG-failure are investigated in supplementary analyses (see S1 Text, Section 5.3).…”

“…The introduction of DTG has been complicated by the increased risk of neural tube defects (NTD) in women living with HIV using DTG at the time of conception [11] and other potential side effects such as weight gain [9,12]. Concerns surrounding NTD risk have delayed the rollout of DTG and, in some settings, led to recommending DTG-based regimens only for men and women who are not at risk of pregnancy [13,14].…”

First case of Dolutegravir and Darunavir/r multi drug-resistant HIV-1 in Cameroon following exposure to Raltegravir: lessons and implications in the era of transition to Dolutegravir-based regimens

“…org/drug_queries/326049/drug_query_interactions). Also, as patients on DTG-containing regimens with high baseline VL (> 500,000 copies/mL) might experience challenges in viral suppression, close monitoring as well as specific case surveillance should be required even in resource-limited settings like Cameroon [18].…”