Journal Article > ReviewFull Text
Lancet HIV. 1 November 2024; Online ahead of print; DOI:10.1016/S2352-3018(24)00233-9
Cortes CP, Sued O, Wong WCW, Borquez A, Ssonko C, et al.
Lancet HIV. 1 November 2024; Online ahead of print; DOI:10.1016/S2352-3018(24)00233-9
Journal Article > LetterAbstract Only
Lancet HIV. 1 October 2024; Volume 11 (Issue 10); e711-e716.; DOI:10.1016/S2352-3018(24)00173-5
Venter WDF, Gandhi M, Sokhela S, Sikwese K, Bygrave H, et al.
Lancet HIV. 1 October 2024; Volume 11 (Issue 10); e711-e716.; DOI:10.1016/S2352-3018(24)00173-5
Journal Article > CommentaryFull Text
Lancet HIV. 21 August 2024; Online ahead of print; DOI:10.1016/S2352-3018(24)00207-8
Flores A, Tut Chol B, Alphonse J, Hewett T
Lancet HIV. 21 August 2024; Online ahead of print; DOI:10.1016/S2352-3018(24)00207-8
Journal Article > ResearchFull Text
Lancet HIV. 22 May 2023; Volume S2352-3018 (Issue 23); 00081-4.; DOI:10.1016/S2352-3018(23)00081-4
Griesel R, Zhao Y, Simmons B, Omar Z, Wiesner L, et al.
Lancet HIV. 22 May 2023; Volume S2352-3018 (Issue 23); 00081-4.; DOI:10.1016/S2352-3018(23)00081-4
BACKGROUND
The drug-drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, which is difficult to implement in high-burden settings. We aimed to test whether virological outcomes with standard-dose dolutegravir-based antiretroviral therapy (ART) are acceptable in people with HIV on rifampicin-based antituberculosis therapy.
METHODS
RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial at a single site in Khayelitsha, Cape Town, South Africa. Participants were older than 18 years of age, with plasma HIV-1 RNA greater than 1000 copies per mL, CD4 count greater than 100 cells per μL, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than 3 months. By use of permuted block (block size of 6) randomisation, participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50 mg dolutegravir 12 h later or tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus matched placebo 12 h later. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first 2 months followed by isoniazid and rifampicin for 4 months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 24 analysed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03851588.
FINDINGS
Between Nov 28, 2019, and July 23, 2021, 108 participants (38 female, median age 35 years [IQR 31-40]) were randomly assigned to supplemental dolutegravir (n=53) or placebo (n=55). Median baseline CD4 count was 188 cells per μL (IQR 145-316) and median HIV-1 RNA was 5·2 log10 copies per mL (4·6-5·7). At week 24, 43 (83%, 95% CI 70-92) of 52 participants in the supplemental dolutegravir arm and 44 (83%, 95% CI 70-92) of 53 participants in the placebo arm had virological suppression. No treatment-emergent dolutegravir resistance mutations were detected up to week 48 in the 19 participants with study-defined virological failure. Grade 3 and 4 adverse events were similarly distributed between the study arms. The most frequent grade 3 and 4 adverse events were weight loss (4/108 [4%]), insomnia (3/108 [3%]), and pneumonia (3/108 [3%]).
INTERPRETATION
Our findings suggest that twice-daily dolutegravir might be unnecessary in people with HIV-associated tuberculosis.
The drug-drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, which is difficult to implement in high-burden settings. We aimed to test whether virological outcomes with standard-dose dolutegravir-based antiretroviral therapy (ART) are acceptable in people with HIV on rifampicin-based antituberculosis therapy.
METHODS
RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial at a single site in Khayelitsha, Cape Town, South Africa. Participants were older than 18 years of age, with plasma HIV-1 RNA greater than 1000 copies per mL, CD4 count greater than 100 cells per μL, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than 3 months. By use of permuted block (block size of 6) randomisation, participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50 mg dolutegravir 12 h later or tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus matched placebo 12 h later. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first 2 months followed by isoniazid and rifampicin for 4 months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 24 analysed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03851588.
FINDINGS
Between Nov 28, 2019, and July 23, 2021, 108 participants (38 female, median age 35 years [IQR 31-40]) were randomly assigned to supplemental dolutegravir (n=53) or placebo (n=55). Median baseline CD4 count was 188 cells per μL (IQR 145-316) and median HIV-1 RNA was 5·2 log10 copies per mL (4·6-5·7). At week 24, 43 (83%, 95% CI 70-92) of 52 participants in the supplemental dolutegravir arm and 44 (83%, 95% CI 70-92) of 53 participants in the placebo arm had virological suppression. No treatment-emergent dolutegravir resistance mutations were detected up to week 48 in the 19 participants with study-defined virological failure. Grade 3 and 4 adverse events were similarly distributed between the study arms. The most frequent grade 3 and 4 adverse events were weight loss (4/108 [4%]), insomnia (3/108 [3%]), and pneumonia (3/108 [3%]).
INTERPRETATION
Our findings suggest that twice-daily dolutegravir might be unnecessary in people with HIV-associated tuberculosis.
Journal Article > ResearchFull Text
Lancet HIV. 1 August 2022; Volume 9 (Issue 8); e544-e553.; DOI:10.1016/S2352-3018(22)00136-9
Schramm B, Temfack E, Descamps D, Nicholas S, Peytavin G, et al.
Lancet HIV. 1 August 2022; Volume 9 (Issue 8); e544-e553.; DOI:10.1016/S2352-3018(22)00136-9
BACKGROUND
Many countries are now replacing non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy (ART) with a regimen containing tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). Recognising laboratory limitations, Malawi opted to transition those on NNRTI-based first-line ART to TLD without viral load testing. We aimed to assess viral load and HIV drug resistance during 1 year following transition to TLD without previous viral load testing.
METHODS
In this prospective cohort study, we monitored 1892 adults transitioning from NNRTI-based first-line ART to the TLD regimen in the Médecins Sans Frontières-supported decentralised HIV programme in Chiradzulu District, Malawi. Eligible adults were enrolled between Jan 17 and May 11, 2019, at Ndunde and Milepa health centres, and between March 8 and May 11, 2019, at the Boma clinic. Viral load at the start of the TLD regimen was assessed retrospectively and measured at month 3, 6, and 12, and additionally at month 18 for those ever viraemic (viral load ≥50 copies per mL). Dolutegravir minimal plasma concentrations (Cmin) were determined for individuals with viraemia. Drug-resistance testing was done at the start of TLD regimen and at viral failure (viral load ≥50 copies per mL, followed by viral load ≥500 copies per mL; resistance defined as Stanford score ≥15).
FINDINGS
Of 1892 participants who transitioned to the TLD regimen, 101 (5·3%) were viraemic at TLD start. 89 of 101 had drug-resistance testing with 31 participants (34·8%) with Lys65Arg mutation, 48 (53·9%) with Met184Val/Ile, and 42 (40·4%) with lamivudine and tenofovir disoproxil fumerate dual resistance. At month 12 (in the per-protocol population), 1725 (97·9% [95% CI 97·1–98·5]) of 1762 had viral loads of less than 50 copies per mL, including 83 (88·3% [80·0–94·0]) of 94 of those who were viraemic at baseline. At month 18, 35 (97·2% [85·5–99·9]) of 36 who were viraemic at TLD start with lamivudine and tenofovir disoproxil fumarate resistance and 27 (81·8% [64·5–93·0]) of 33 of those viraemic at baseline without resistance had viral load suppression. 14 of 1838 with at least two viral load tests upon transitioning had viral failure (all with at least one dolutegravir Cmin value <640 ng/mL; active threshold), suggesting suboptimal adherence. High baseline viral load was associated with viral failure (adjusted odds ratio [aOR] 14·1 [2·3–87·4] for 1000 to <10 000 copies per mL; aOR 64·4 [19·3–215·4] for ≥10 000 copies per mL). Two people with viral failure had dolutegravir resistance at 6 months (Arg263Lys or Gly118Arg mutation), both were viraemic with lamivudine and tenofovir disoproxil fumarate resistance at baseline.
INTERPRETATION
High viral load suppression 1 year after introduction of the TLD regimen supports the unconditional transition strategy in Malawi. However, high pre-transition viral load, ongoing adherence challenges, and possibly existing nucleoside reverse transcriptase inhibitor resistance can lead to rapid development of dolutegravir resistance in a few individuals. This finding highlights the importance of viral load monitoring and dolutegravir-resistance surveillance after mass transitioning to the TLD regimen.
Many countries are now replacing non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy (ART) with a regimen containing tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). Recognising laboratory limitations, Malawi opted to transition those on NNRTI-based first-line ART to TLD without viral load testing. We aimed to assess viral load and HIV drug resistance during 1 year following transition to TLD without previous viral load testing.
METHODS
In this prospective cohort study, we monitored 1892 adults transitioning from NNRTI-based first-line ART to the TLD regimen in the Médecins Sans Frontières-supported decentralised HIV programme in Chiradzulu District, Malawi. Eligible adults were enrolled between Jan 17 and May 11, 2019, at Ndunde and Milepa health centres, and between March 8 and May 11, 2019, at the Boma clinic. Viral load at the start of the TLD regimen was assessed retrospectively and measured at month 3, 6, and 12, and additionally at month 18 for those ever viraemic (viral load ≥50 copies per mL). Dolutegravir minimal plasma concentrations (Cmin) were determined for individuals with viraemia. Drug-resistance testing was done at the start of TLD regimen and at viral failure (viral load ≥50 copies per mL, followed by viral load ≥500 copies per mL; resistance defined as Stanford score ≥15).
FINDINGS
Of 1892 participants who transitioned to the TLD regimen, 101 (5·3%) were viraemic at TLD start. 89 of 101 had drug-resistance testing with 31 participants (34·8%) with Lys65Arg mutation, 48 (53·9%) with Met184Val/Ile, and 42 (40·4%) with lamivudine and tenofovir disoproxil fumerate dual resistance. At month 12 (in the per-protocol population), 1725 (97·9% [95% CI 97·1–98·5]) of 1762 had viral loads of less than 50 copies per mL, including 83 (88·3% [80·0–94·0]) of 94 of those who were viraemic at baseline. At month 18, 35 (97·2% [85·5–99·9]) of 36 who were viraemic at TLD start with lamivudine and tenofovir disoproxil fumarate resistance and 27 (81·8% [64·5–93·0]) of 33 of those viraemic at baseline without resistance had viral load suppression. 14 of 1838 with at least two viral load tests upon transitioning had viral failure (all with at least one dolutegravir Cmin value <640 ng/mL; active threshold), suggesting suboptimal adherence. High baseline viral load was associated with viral failure (adjusted odds ratio [aOR] 14·1 [2·3–87·4] for 1000 to <10 000 copies per mL; aOR 64·4 [19·3–215·4] for ≥10 000 copies per mL). Two people with viral failure had dolutegravir resistance at 6 months (Arg263Lys or Gly118Arg mutation), both were viraemic with lamivudine and tenofovir disoproxil fumarate resistance at baseline.
INTERPRETATION
High viral load suppression 1 year after introduction of the TLD regimen supports the unconditional transition strategy in Malawi. However, high pre-transition viral load, ongoing adherence challenges, and possibly existing nucleoside reverse transcriptase inhibitor resistance can lead to rapid development of dolutegravir resistance in a few individuals. This finding highlights the importance of viral load monitoring and dolutegravir-resistance surveillance after mass transitioning to the TLD regimen.
Journal Article > ResearchFull Text
Lancet HIV. 11 August 2015; Volume 2 (Issue 10); DOI:10.1016/S2352-3018(15)00137-X
Ford NP, Shubber Z, Meintjes GA, Grinsztejn B, Eholie SP, et al.
Lancet HIV. 11 August 2015; Volume 2 (Issue 10); DOI:10.1016/S2352-3018(15)00137-X
Journal Article > CommentaryFull Text
Lancet HIV. 8 September 2018; Volume 392 (Issue 10150); 797-798.; DOI:10.1016/S0140-6736(18)31670-2
Reuter A, Furin J
Lancet HIV. 8 September 2018; Volume 392 (Issue 10150); 797-798.; DOI:10.1016/S0140-6736(18)31670-2
Journal Article > CommentaryFull Text
Lancet HIV. 7 December 2021; Volume S2352-3018 (Issue 21); 00321-0.; DOI:10.1016/S2352-3018(21)00321-0
Barber M, Sarpatwari A, Cepuch C
Lancet HIV. 7 December 2021; Volume S2352-3018 (Issue 21); 00321-0.; DOI:10.1016/S2352-3018(21)00321-0
Journal Article > CommentaryFull Text
Lancet HIV. 2 July 2020; DOI:32621871
Reuter A, Furin J
Lancet HIV. 2 July 2020; DOI:32621871
“We were hungry all the time”, is the first thing a 28-year-old tuberculosis survivor from rural Haiti told one of us (JF) when asked in 2017 about his experience of being treated for the disease. This patient had been cutting sugar cane to support his family of seven—all of whom lived in a one-room shack—but had to stop his gruelling labour once he became sick with tuberculosis, both because of his physical symptoms and because he had to go to the clinic daily for directly observed therapy. Without his income, his family fell into ruin and the pressing need to feed his children became his most urgent priority. “It was hard to take my treatment when the little ones were holding their bellies and crying. We lost so much to TB.”
Journal Article > CommentaryFull Text
Lancet HIV. 24 September 2015; Volume 2 (Issue 10); DOI:10.1016/S2352-3018(15)00180-0
Isaakidis P, Gupta S, Das M, Ferrer D, Nalinikanta R, et al.
Lancet HIV. 24 September 2015; Volume 2 (Issue 10); DOI:10.1016/S2352-3018(15)00180-0