The lancet. HIV · 2025
Virological and drug-resistance outcomes for people living with HIV initiating or switching to tenofovir, lamivudine, and dolutegravir in six PEPFAR-supported countries: a prospective cohort study.
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Marc Jean Bernard, McCarthy Caitlyn, Wallis Carole L, Kityo Cissy, Hughes Michael D, Godfrey Catherine, Shah N Sarita, Parikh Urvi M, Maartens Gary, Kanyike Francis, Van Schalkwyk Marije, Kihumuro Raymond Bernard, Asiimwe Philip, Tsikhutsu Isaac, Munyanga Cornelius, Some Fatma F, Joseph Yvetot, Flowers Tracy, Mohapi Lerato, Samaneka Wadzanai P, Mponda Kelvin, Rassool Mohammed S, Pierre Samuel, Woolley Elizabeth, Manabe Yukari C, Mellors John W, Flexner Charles, Koenig Serena P, Mngqibisa Rosie, ACTG A5381–Hakim Study Team
Аннотация
BACKGROUND: A combined regimen of tenofovir disoproxil fumarate, lamivudine, and dolutegravir is widely prescribed for people living with HIV in programmes supported by the US President's Emergency Plan for AIDS Relief (PEPFAR). This study aimed to assess long-term virological and drug-resistance outcomes in response to initiation of or switching to the tenofovir-lamivudine-dolutegravir combination among individuals receiving care through such programmes.
METHODS: The Advancing Clinical Therapeutics Globally (ACTG) A5381-Hakim Study was a prospective cohort study of participants aged 10 years or older initiating or switching to tenofovir-lamivudine-dolutegravir therapy at 13 PEPFAR-supported sites in Haiti, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Group 1 switched from non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART), group 2 switched from protease inhibitor-based ART, and group 3 was ART-naive; before switching, group 1A and group 2A had HIV-1 RNA of more than 1000 copies per mL and group 1B and group 2B had 1000 copies per mL or less. Viral suppression (HIV-1 RNA ≤1000 copies per mL), emergence of dolutegravir-resistance mutations, and adverse events were assessed up to 36 months. Adherence, based on tenofovir diphosphate concentrations in dried blood spots, was evaluated in a nested case-control study.
FINDINGS: Between Oct 28, 2019, and Sept 27, 2022, 1241 participants were enrolled in the study, four of whom were excluded (two in group 2B who started tenofovir-lamivudine-dolutegravir before enrolment and two in group 3 who did not start tenofovir-lamivudine-dolutegravir). Therefore, 1237 participants were included in the full analysis population: 44 in group 1A, 425 in group 1B, 173 in group 2A, 416 in group 2B, and 179 in group 3. 65% were female, 35% were male. 12 (1%) participants discontinued tenofovir-lamivudine-dolutegravir therapy because of adverse events. Among participants for whom viral load data were available and who did not discontinue tenofovir-lamivudine-dolutegravir before viral load measurement, HIV-1 RNA of 1000 copies per mL or less was recorded in 88% (37 of 42 participants) at 6 months and 76% (16 of 21 participants) at 24 months in group 1A; 99% (380 of 384 participants) and 98% (368 of 375 participants) in group 1B; 72% (118 of 165 participants) and 70% (45 of 64 participants) in group 2A; 95% (376 of 395 participants) and 93% (190 of 204 participants) in group 2B; and 90% (136 of 151 participants) and 90% (128 of 143 participants) in group 3. Mutations associated with decreased dolutegravir susceptibility were detected in three participants in group 2A (G118R, R263K) and in no participants in the other groups. Of 87 case-control pairs analysed at 6 months, tenofovir diphosphate concentrations were lower among participants with HIV-1 RNA of more than 1000 copies per mL than among those with 1000 copies per mL or less (p<0·0001).
INTERPRETATION: High rates of viral suppression in response to tenofovir-lamivudine-dolutegravir therapy in individuals who had suppression before switching support international treatment guidelines for this population. Findings on resistance mutations and tenofovir diphosphate concentrations suggest that incomplete adherence was a key factor in the suboptimal outcomes of people with virological failure at the time of switching treatment.
FUNDING: National Institutes of Health and PEPFAR.
METHODS: The Advancing Clinical Therapeutics Globally (ACTG) A5381-Hakim Study was a prospective cohort study of participants aged 10 years or older initiating or switching to tenofovir-lamivudine-dolutegravir therapy at 13 PEPFAR-supported sites in Haiti, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Group 1 switched from non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART), group 2 switched from protease inhibitor-based ART, and group 3 was ART-naive; before switching, group 1A and group 2A had HIV-1 RNA of more than 1000 copies per mL and group 1B and group 2B had 1000 copies per mL or less. Viral suppression (HIV-1 RNA ≤1000 copies per mL), emergence of dolutegravir-resistance mutations, and adverse events were assessed up to 36 months. Adherence, based on tenofovir diphosphate concentrations in dried blood spots, was evaluated in a nested case-control study.
FINDINGS: Between Oct 28, 2019, and Sept 27, 2022, 1241 participants were enrolled in the study, four of whom were excluded (two in group 2B who started tenofovir-lamivudine-dolutegravir before enrolment and two in group 3 who did not start tenofovir-lamivudine-dolutegravir). Therefore, 1237 participants were included in the full analysis population: 44 in group 1A, 425 in group 1B, 173 in group 2A, 416 in group 2B, and 179 in group 3. 65% were female, 35% were male. 12 (1%) participants discontinued tenofovir-lamivudine-dolutegravir therapy because of adverse events. Among participants for whom viral load data were available and who did not discontinue tenofovir-lamivudine-dolutegravir before viral load measurement, HIV-1 RNA of 1000 copies per mL or less was recorded in 88% (37 of 42 participants) at 6 months and 76% (16 of 21 participants) at 24 months in group 1A; 99% (380 of 384 participants) and 98% (368 of 375 participants) in group 1B; 72% (118 of 165 participants) and 70% (45 of 64 participants) in group 2A; 95% (376 of 395 participants) and 93% (190 of 204 participants) in group 2B; and 90% (136 of 151 participants) and 90% (128 of 143 participants) in group 3. Mutations associated with decreased dolutegravir susceptibility were detected in three participants in group 2A (G118R, R263K) and in no participants in the other groups. Of 87 case-control pairs analysed at 6 months, tenofovir diphosphate concentrations were lower among participants with HIV-1 RNA of more than 1000 copies per mL than among those with 1000 copies per mL or less (p<0·0001).
INTERPRETATION: High rates of viral suppression in response to tenofovir-lamivudine-dolutegravir therapy in individuals who had suppression before switching support international treatment guidelines for this population. Findings on resistance mutations and tenofovir diphosphate concentrations suggest that incomplete adherence was a key factor in the suboptimal outcomes of people with virological failure at the time of switching treatment.
FUNDING: National Institutes of Health and PEPFAR.