ABSTRACT
Background: Tenofovir-lamivudine-dolutegravir (TLD) is the WHO-preferred first-line regimen for people with HIV, but drug-drug interactions between dolutegravir (DTG) and rifampin (RIF) require an additional 50mg DTG (TLD+50) in people receiving tuberculosis (TB)/HIV co-treatment. RIF is a key drug in TB treatment, but is a potent inducer of metabolizing enzymes and efflux transporters, which can markedly lower drug concentrations. There are limited data on the effectiveness of TLD+50 in people with TB/HIV from program settings. Method(s): We conducted a prospective, observational study at 12 sites in 6 countries (Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe). Participants received concomitant TLD+50 and RIF-based TB treatment provided as standard of care by HIV and TB treatment programs. Primary outcome was HIV-1 RNA <1000 copies/mL (cpm) at end of TB treatment. New DTG resistance mutations were defined as those present at end of TB treatment but not present at start. Result(s): From 11/2019-6/2021, we enrolled 91 participants with TB/HIV, including 75 ART-naive participants (82%) starting TLD+50 after a median of 15 days on TB treatment, 10 ART-naive participants (11%) starting TLD+50 and RIF together, 5 (5%) starting TB treatment and changing to TLD+50 after a median of 3.3y on TLD, and 1 (1%) starting RIF and TLD+50 after changing from EFV/3TC/TDF. Median age was 37y (IQR 32-43), 35% were female, 100% cis-gender, median CD4 count was 120 cells/mm3 (IQR 50-295), 87% had HIV-1 RNA >1000 copies/mL. Two participants died during TB treatment (week 4 disseminated TB, week 12 suspected COVID-19), 1 interrupted TLD+50 due to jaundice;and 1 discontinued TB treatment due to drug-induced liver injury. Among 89 surviving participants, 6 were lost to follow-up and a further 10 had no HIV-1 RNA result due to missed or remote visits. Primary virologic outcome was therefore assessed in 73 (80%), of whom 69 (95%, Wald 95% CI 89-100%) had HIV-1 RNA <=1000 cpm;68 (93%) had HIV-1 RNA <200 cpm. No sex specific differences in viral suppression were observed. No DTG resistance mutations were detected among 4 participants with HIV-1 RNA >1000 cpm. Conclusion(s): Concomitant RIF-containing TB treatment and TLD+50 was welltolerated and achieved excellent viral suppression in a cohort of predominantly ART-naive people with TB/HIV. These multi-country data from program settings support feasibility and effectiveness of current treatment approaches for TB/ HIV co-infection.
ABSTRACT
Background: Single-tablet tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) has been rapidly adopted as 1st-line ART for patients initiating treatment and switching from virally-suppressive NNRTI-based 1st regimens in PEPFAR programs. There are limited data, however, on effectiveness and emergence of resistance to TLD in programmatic settings where plasma HIV-1 RNA and drug resistance testing are not used widely. Methods: A prospective observational study is being performed at 13 ACTG sites in six countries (Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe) coincident with TLD rollout to assess efficacy and emergence of HIV drug resistance following TLD for 1st, 2nd or 3rd-line ART. This report focuses on the 2 Groups that completed enrollment and 6 months of follow-up: Group 1b (Gp1b) participants on NNRTI-based ART for at least 6 months with HIV-1 RNA ≤1000 cps/mL before switch to TLD;and Group 4 (Gp4) ART-naïve participants initiating 1st-line TLD. The primary objective was to estimate the proportions of participants on TLD with HIV-1 RNA ≤1000 cps/mL and with new DTG resistance mutations at 6 months. Results:\From 10/2019-10/2020, we enrolled 600 participants who started TLD: 421 in Gp1b (median age 41years;80% female) and 179 in Gp4 (median age 35years;42% female). In Gp1b, median time on ART was 6.6y (IQR 3.3-10.3);88% were taking EFV with 3TC+TDF or FTC+TDF. In Gp4, median baseline HIV-1 RNA was 4.4 log10 cps/mL (IQR 3.5-5.1). Six participants in Gp1b (1.4%) and 6 in Gp4 (3.4%) discontinued TLD by 6 months, due to withdrawal or loss to follow-up (6 participants), adverse events considered related to TLD (4), and death (2;both Gp4;1 from TB, 1 unknown cause). Among participants followed on TLD to 6 months, 90% in Gp1b (373/415) and 86% in Gp4 (149/173) had a 6-month HIV-1 RNA result (missing values mainly due to COVID-related virtual visits). HIV-1 RNA ≤1000, <200 and <50 cps/mL was achieved in 99%, 98.4%, and 96% of participants in Gp1b and in 90%, 87.2%, and in 84.6% of Gp4, respectively (Table). A new mutation possibly selected by DTG was observed in 1 participant in Gp1b (T97AT) and none in Gp4. Conclusion: TLD was well tolerated and achieved excellent viral suppression in ART-naïve participants and in participants who switched from virally-suppressive 1st-line ART. An emerging InSTI mutation of uncertain significance was seen in only one participant. These data support early tolerability and efficacy of TLD transition in the public sector.