COVID-19 Publications

Authors: T.G Jacobs, A. Colbers, H. Waalewijn, P. Amuge, D. Bbuye, E. Kaudha, A. Nanduudu, S. Makumbi, L. Atwine, S. Mudzingwa, K. Nathoo, J. Hakim, A. Liberty, A.J. Van Rensburg, M. Archary, D.M Gibb, D. Ford, A. Turkova, D.M Burger, ODYSSEY trial team

Published in: IAS 2021

Abstract

Background: ODYSSEY and IMPAACT-P1093 found lower and more variable dolutegravir (DTG) exposure in children compared to adults based on mg/kg dose. Investigating the main metabolic pathway (UGT1A1) for DTG could help to explain these findings. Estimates of DTG glucuronide/DTG molar metabolic ratio (DTG-MR) are 0.05-0.08 in adults but this has not been studied in children.

Methods: A subset of children was selected from PK substudies within the ODYSSEY trial, including all children aged <2 years and a random sample of older children receiving DTG film-coated tablets (FCT; >=20kg) or dispersible tablets (DT; 3-<25kg). DTG and DTG-glucuronide concentrations were measured with a validated UPLC-MS/MS assay and geometric mean (GM) DTG-MR was determined using 3 plasma samples per PK curve (t=2, 6 and 24h).   We assessed correlation between DTG-MR and DTG clearance in children, as clearance adjusted for formulation is independent of DTG dose, and it is associated with DTG exposure. Pearson’s correlation coefficient was used on log-transformed data to assess the relationships between DTG-MR and DTG clearance/kg (corrected for higher bioavailability of DT), and DTG-MR and age (not logtransformed).

Results: In total, 37 children (age 3 months – 18 years) were included in this study. There was positive relationship between DTG-MR and DTG clearance/kg in children (r(37)=0.64, p<.001) (Figure). No association was found between DTG-MR and age (r(37)=-0.12, p=0.50). GM(CV%) DTG-MR in children was 0.051(66%), in line with adult values.

Conclusions: Intersubject variability in DTG-MR was high in children and as the ratio correlates with clearance, this may explain high variability of DTG exposure between children. DTG-MR was similar to adult values and did not change with age, hence increased glucuronidation does not appear to explain the relatively low DTG exposure observed in children aged >3 months. Further studies are needed to assess the role other factors contributing to differences in DTG exposure in children.

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Authors: L. Barlow-Mosha, G. Ahimbisibwe, E. Chappell, P.M. Amuge, A. Nanduudu, E. Kaudha, T. Amukele, D. Balamusani, B. Kafufu, A. Nimwesiga, C. Kityo, A.R Kekitiinwa, R. Namwanje, G. Kasangaki, A. Mulindwa, G.A. Muzorah, D. Bbuye, M. Nolan, C. Giaquinto, D.M Gibb, D. Ford, P. Musoke, A. Turkova, The ODYSSEY Trial Team

Published in: International workshop on HIV pediatrics 2021

Abstract

Background: Neural tube defects (NTDs) are known to be associated with maternal folate and vitamin B12 deficiency, and initial surveillance studies suggested an increased risk of NTDs among infants conceived by women taking dolutegravir (DTG). We, therefore, compared folate and vitamin B12 levels among HIV-infected children aged 6-<18 years starting first- or second-line DTG-based antiretroviral treatment (ART) versus Standard of Care (SOC) at 3 Ugandan sites in the ODYSSEY trial.

Methods: Plasma folate was measured on stored samples at baseline and 4 weeks. Red blood cell (RBC) folate and vitamin B12 levels were measured using samples collected prospectively at ≥96 weeks. Samples were analysed in one laboratory using Elecys assays. Normal regression was used to compare change in plasma folate from baseline to 4 weeks (adjusted for baseline) and cross-sectional RBC folate and vitamin B12 between randomised arms, adjusting for site, sample date, first-/ second-line ART and randomisation stratification factors

Results: 229 children ≥6 years were randomised; 51% female, median(IQR) age was 12.3 years (9.0,14.7), CD4  501cells/mm3  (228,795); 67% started second-line ART; 114 started DTG, 115 started SOC (40% lopinavir/ritonavir-, 37% efavarinez-, 23% atazanavir/ritonavir-based ART). By 4 weeks, mean plasma folate was higher in DTG arm versus SOC (difference (DTG-SOC) 1.6 ng/mL; 95%CI 0.8, 2.3; p<0.01). At week ≥96, mean RBC folate was higher in the DTG arm vs SOC (difference 73 ng/mL; 95%CI 3, 143; p=0.04). Plasma and RBC folate levels varied by site, but there was no evidence for heterogeneity of treatment effects (Table). Vitamin B12 levels were similar between arms (p=0.42). 

Conclusions: We found no evidence that DTG-based ART was associated with decreased levels of plasma folate or RBC folate; levels were higher than on NNRTI-/PI-based ART though the mechanism is unclear. Vitamin B12 levels were similar in both arms. These results suggest any increased risk of NTDs in infants conceived on DTG is unlikely to be due to DTG causing decreased folate and vitamin B12 levels.   

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Authors: E White, A Turkova, HA Mujuru, I Nankya, B Wynne, S Ali, A Kekitiinwa, A Lugemwa, E Kaudha, A Liberty, H Cassim, M Archary, M Cotton, L Barlow-Mosha, TR Cressey, C Ngampiyasakul, U Srirompotong, O Behuhuma, Y Saidi, A Bamford, R Kobbe, P Rojo, C Giaquinto, DM Gibb, D Ford on behalf of the ODYSSEY trial team

Published in: International Workshop on HIV pediatrics

Abstract

Background: ODYSSEY, a multi-country randomised trial, demonstrated superior treatment efficacy for dolutegravir (DTG) plus two NRTIs versus standard-ofcare (SOC) in children ≥14kg (median age 12 years [range:3-18]) starting first- and second-line ART. We describe virological and drug resistance outcomes by 96 weeks.

Methods: Virological failure (VF) was defined as confirmed viral load (VL)≥400c/mL after week 36 or lack of virological response by week 24 with ART switch. Participants with VF were retrospectively tested for post-failure resistance up to week 96, using the latest sample with VL≥1000c/mL after failure and prior to treatment change; the corresponding baseline sample was sequenced if ≥1 major IAS mutation was identified

Results: 311 children started first-line ART (154 DTG, 157 SOC [92% efavirenz]) and 396 started second-line (196 DTG, 200 SOC [72% lopinavir/r, 25% atazanavir/r]). NRTI backbones were ABC/3TC (80% first-line, 54% second-line), TDF/XTC (19%, 26%), ZDV/3TC (1%, 19%), and ABC/TDF (0%, 0.8%). On firstline, 11(7%) DTG vs. 30(19%) SOC experienced VF by 96 weeks, and on second-line, 31(16%) DTG vs. 40(20%) SOC. Samples were tested for all 112 failures: median time from VF to resistance test was 24[IQR:12-47] weeks. 47(42%) had post-failure resistance test at week 96, 60(54%) were tested earlier (16 due to treatment change, 44 no later sample available with VL≥1000c/mL or later sample failed to amplify); the remaining 5(4%) failed to amplify on all samples. On first-line, post-failure resistance tests were available as follows: reverse transcriptase (RT)/protease (PR) (11 DTG, 29 SOC), integrase (IN) (10 DTG); on second-line: RT/PR (28 DTG, 39 SOC), IN (22 DTG). First line ART: No participants on first-line DTG had a major IAS drug resistance mutation post-failure (0/11 NRTI/NNRTI/PI; 0/10 INSTI). On SOC, 18/29(62%) participants had NRTI resistance post-failure (DTG vs. SOC p<0.001), 27/29(93%) NNRTI resistance (p<0.001) and 0/29 PI resistance. Of 13 with NRTI resistance post-failure and a baseline resistance test, all developed at least one new NRTI mutation; 18/19(95%) developed new NNRTI resistance. Second line ART: 20/28(71%) DTG vs. 28/39(72%) SOC had at least one NRTI mutation post-failure; 21/28(75%) vs. 35/39(90%) had NNRTI resistance; and 2/28(7%) vs. 2/39(5%) had PI resistance. Among DTG vs. SOC participants with a major resistance mutation post-failure and baseline result, 0/16 DTG vs. 3/23 SOC (p=0.26) developed new NRTI resistance, 0/18 vs. 3/26 (p=0.26) new NNRTI resistance and 1/2 vs. 1/1 new PI resistance. On DTG, 4/22(18%) on second-line developed INSTI resistance (2 Q148R/K, 1 G118R, 1 G118R+R263K); 3/4 were on ZDV/3TC.

Conclusion: ODYSSEY demonstrated that DTG has a high genetic resistance barrier in children, preventing emergent resistance to NRTIs. We identified no postfailure resistance to any drug class amongst children initiating first-line DTG, significantly less than first-line SOC. Among those on second-line DTG, there was no new NRTI resistance, however 4 children developed new INSTI resistance. These results support using DTG-containing regimens for children starting firstline or second-line ART, but ongoing adherence support is required for children on second-line.

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Authors: A Turkova, A Kekitiinwa, E White, V Mumbiro, E Khauda, A Liberty, E Dobbels, GM Ahimbisibwe, T Moloantoa, L Atwine, S Kanjanavanit, NR Mosia, T Puthanakit, T Smit, R Kobbe, C Fortuny, E Chidziva, RC Kyambadde, D Bbuye, T Sarfati, A Coelho, Y Saïdi, A Lugemwa, N Klein, M Bwakura-Dangarembizi, C Kityo, M Cotton, C Giaquinto, P Rojo, DM Gibb, D Ford, the ODYSSEY trial team

Published in: IAS 2021

Abstract

Background:  Dolutegravir is associated with neuropsychiatric adverse events (NPAEs) in adults. We present first randomised data in children and adolescents.

Methods: ODYSSEY is an open-label, multi-centre, randomised trial, comparing efficacy and safety of dolutegravir-based ART(DTG) with standard of care (SOC) in children initiating first- or second-line therapy.   We compared NPAEs, including serious adverse events (SAEs), grade ≥3 events, ART-modifying events and suicidality-related events, and patient/carer mood-and-sleep questionnaire responses in DTG versus SOC.

Results: 707 children ≥14kg were randomised (sub-Saharan Africa 88%, Thailand 9%, Europe 4%); 311 children started first-line (92% efavirenzbased in SOC); 396 second-line(98% PI-based). Median(IQR) age was 12.2 (9.1,14.9); 362 (51%) were male; median follow-up 142 (124,159) weeks. There were 31 NPAEs (in 23 children): 18 (15) in DTG vs 13 (8) in SOC (Table). Median (IQR) age and time from enrolment at first event were 15.9 (10.4,17.5) years and 72 (47,124) weeks respectively. Most NPAEs (23) were in children starting first-line; and most (22) occurred in males. Ten participants (5 DTG;5 SOC) had 13 SAEs: 7 DTG (3 epilepsy/convulsions, 1 headache/hypertension, 1 depression, 1 parasuicide, 1 psychosis) vs 6 SOC (3 epilepsy/convulsions, 1 dizziness, 2 parasuicide). 12 children (8 DTG;4 SOC) experienced 15 suicidality events: 10 suicidality ideation (6 DTG;4 SOC) and 5 parasuicide (2 DTG;3 SOC). ART-modifying NPAE(s) included 3 DTG (2 depression, 1 psychosis) and 2 SOC (1 parasuicide, 1 dizziness). Small number of participants/carers reported symptoms of self-harm (8 DTG;1 SOC, p=0.04), “life was not worth living” (17 DTG; 5 SOC, p=0.009) or suicidal thoughts (13 DTG; 0 SOC, p<0.001) in mood-and-sleep questionnaires; the reported symptoms were transient and did not lead to treatment change. There were no differences between treatment groups in low mood/feeling sad, problems concentrating, feeling worried or feeling angry/aggressive, time to fall asleep, nightmares/ vivid dreams or sleep quality.

Conclusions:  Numbers of NPAEs and reported neuropsychiatric symptoms were low. More participants reported neuropsychiatric symptoms in the DTG arm vs SOC, however this difference should be interpreted with caution in an open-label trial.

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Authors: Violari A, Kekitiinwa A, White E, Mumbiro V, Rutebarika D, Dobbels E, Kataike H, Moloantoa T, Atwine L, Nazzinda R, Mbabazi R, Kanjanavanit S, Mosia N, Na-Rajsimax S, Techakunakorn P, Nakabuye S, Puthanakit T, Smit T, Kobbe R, Fortuny C, Chidziva E, Nansamba W, Kakayi B, Bbuye D, Sarfati T, Shakeshaft C, Coelho A, Saïdi Y, Lugemwa A, Klein N, Mujuru H, Bwakura- Dangarembizi M, Musiime V, Cotton M, Giaquinto C, Rojo P, Gibb D, Ford D, Turkova A

Published in: International workshop on HIV pediatrics 2021

Abstract

Background: Dolutegravir is associated with neuropsychiatric adverse events (NPAEs) in adults. We present first randomised data in children and adolescents.

Methods: ODYSSEY is an open-label, multi-centre, randomised trial, comparing efficacy and safety of dolutegravir-based ART (DTG) with standard of care (SOC) in children initiating first- or second-line therapy. We compared NPAEs, including serious adverse events (SAEs), grade ≥3 events, ARTmodifying events and suicidality-related events, and patient/carer mood-and-sleep questionnaire responses in DTG versus SOC.

Results: 707 children ≥14kg were randomised (subSaharan Africa 88%, Thailand 9%, Europe 4%); 311 children started first-line (92% efavirenz-based in SOC); 396 second-line (98% PI-based). Median (IQR) age was 12.2 (9.1,14.9) years; 362 (51%) were male; median follow-up 142 (124,159) weeks. There were 31 NPAEs (in 23 children): 18(15) in DTG vs 13(8) in SOC; hazard ratio for time to first NPAE (DTG vs SOC) was 1.87 (95%CI: 0.79, 4.41). 12 AEs were neurological: 6(6) in DTG vs 6(5) in SOC. 19 AEs were psychiatric: 12(10) in DTG vs 7(4) in SOC. Median(IQR) age and time from enrolment to first event were 15.9 (10.4,17.5) years and 72 (47,124) weeks respectively. Most NPAEs (23) were in children starting first-line; and most (22) occurred in males. Ten participants (5 DTG; 5 SOC) had 13 SAEs: 7 DTG (3 epilepsy/convulsions, 1 headache/hypertension, 1 depression, 1 parasuicide, 1 psychosis) vs 6 SOC (3 epilepsy/convulsions, 1 dizziness, 2 parasuicide). 12 children (8 DTG; 4 SOC) experienced 15 suicidality events: 10 suicidality ideation (6 DTG; 4 SOC) and 5 parasuicide (2 DTG; 3 SOC). ART-modifying NPAE(s) included 3 DTG (2 depression, 1 psychosis) and 2 SOC (1 parasuicide, 1 dizziness). Small numbers of participants/carers reported symptoms of self-harm (8 DTG; 1 SOC,p=0.04), “life was not worth living”(17 DTG; 5 SOC,p=0.009) or suicidal thoughts(13 DTG; 0 SOC,p<0.001) in moodand-sleep questionnaires; the reported symptoms were transient and did not lead to treatment change. There were no differences between treatment groups in low mood/feeling sad, problems concentrating, feeling worried or feeling angry/aggressive, time to fall asleep, nightmares/vivid dreams or sleep quality.

Conclusion: Numbers of NPAEs and reported neuropsychiatric symptoms were low. More participants reported neuropsychiatric symptoms in the DTG arm vs SOC, however, this difference should be interpreted with caution in an open-label trial.

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Authors: L. Barlow-Mosha, G. Ahimbisibwe, E. Chappell, P.M. Amuge, A. Nanduudu, E. Kaudha, T. Amukele, D. Balamusani, B. Kafufu, A. Nimwesiga, C. Kityo, A.R Kekitiinwa, R. Namwanje, G. Kasangaki, A. Mulindwa, G.A. Muzorah, D. Bbuye, M. Nolan, C. Giaquinto, D.M Gibb, D. Ford, P. Musoke, A. Turkova, The ODYSSEY Trial Team

Published in: IAS 2021

Abstract

Background: Neural tube defects (NTDs) are known to be associated with maternal folate and vitamin B12 deficiency, and initial surveillance studies suggested an increased risk of NTDs among infants conceived by women taking dolutegravir (DTG). We, therefore, compared folate and vitamin B12 levels among HIV-infected children aged 6-<18 years starting first- or second-line DTG-based antiretroviral treatment (ART) versus Standard of Care (SOC) at 3 Ugandan sites in the ODYSSEY trial.

Methods: Plasma folate was measured on stored samples at baseline and 4 weeks. Red blood cell (RBC) folate and vitamin B12 levels were measured using samples collected prospectively at ≥96 weeks. Samples were analysed in one laboratory using Elecys assays. Normal regression was used to compare change in plasma folate from baseline to 4 weeks (adjusted for baseline) and cross-sectional RBC folate and vitamin B12 between randomised arms, adjusting for site, sample date, first-/ second-line ART and randomisation stratification factors

Results: 229 children ≥6 years were randomised; 51% female, median(IQR) age was 12.3 years (9.0,14.7), CD4  501cells/mm3  (228,795); 67% started second-line ART; 114 started DTG, 115 started SOC (40% lopinavir/ritonavir-, 37% efavarinez-, 23% atazanavir/ritonavir-based ART). By 4 weeks, mean plasma folate was higher in DTG arm versus SOC (difference (DTG-SOC) 1.6 ng/mL; 95%CI 0.8, 2.3; p<0.01). At week ≥96, mean RBC folate was higher in the DTG arm vs SOC (difference 73 ng/mL; 95%CI 3, 143; p=0.04). Plasma and RBC folate levels varied by site, but there was no evidence for heterogeneity of treatment effects (Table). Vitamin B12 levels were similar between arms (p=0.42). 

Conclusions: We found no evidence that DTG-based ART was associated with decreased levels of plasma folate or RBC folate; levels were higher than on NNRTI-/PI-based ART though the mechanism is unclear. Vitamin B12 levels were similar in both arms. These results suggest any increased risk of NTDs in infants conceived on DTG is unlikely to be due to DTG causing decreased folate and vitamin B12 levels.   

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Authors: P Amuge on behalf of the ODYSSEY trial team

Published in: International workshop on HIV pediatrics 2021

Abstract

Background: ODYSSEY, a multi-country randomised trial, demonstrated superior treatment efficacy for dolutegravir (DTG) plus two NRTIs versus standard-ofcare (SOC) in 707 children ≥14kg (median age 12 years) starting first- or second-line ART. We report results for an additional cohort of 85 children <14kg, who completed 96 weeks follow-up on 28th June 2021. 

Methods: The primary outcome is a Kaplan-Meier (KM) estimated proportion of treatment failure defined as confirmed viral load (VL) ≥400c/mL after week 36, lack of virological response by 24 weeks with ART switch for failure, death, or new/recurrent WHO 4 or severe WHO 3 event by 96 weeks. Bayesian estimation was pre-specified as the primary analysis of participants <14kg, incorporating evidence obtained from the ≥14kg participants as a prior distribution, with relative weight 78%, based on clinical opinion elicited before availability of results for children ≥14kg. Results: 85 children <14kg were randomised (Uganda 43, Zimbabwe 22, South Africa 20); 42 to DTG and 43 to SOC. Median (range) age was 1.4 years (0.1-5.9); 23 were 3-<6kg, 40 were 6-<10kg and 22 were 10-<14kg. 72 children started first-line (29/37 PI-based among SOC); 13 second-line (3/6 PI-, 2 raltegravir- and 1 nevirapine-based among SOC). Median (IQR) followup was 120 (97-132) weeks; 5 (6%) children were lost to follow-up. 11 children in the DTG arm had treatment failure by 96 weeks (K-M estimated proportion 28%) vs 21 (48%) SOC; 8 vs. 16 failures were virological. 8 (25%) DTG vs 17 (46%) SOC failed on first line; 3 (48%) vs 4 (60%) failed on second-line. The Bayesian estimated difference in treatment failure (DTG-SOC) in participants <14kg was -11% (95% CI -19%, -2%; P=0.02). A standalone analysis of the <14kg cohort provided an estimated difference in treatment failure of -20% (95% CI -38%, -1%; P=0.04). At 96 weeks, 77% of children in the DTG arm had VL<50c/mL compared with 50% in SOC (P=0.02); corresponding proportions with VL<400c/mL were 91% vs. 71% (P=0.03). There were 15 SAEs (11 children) in the DTG arm versus 19 (11 children) in SOC (P=0.92, comparing children), including 2 versus 4 deaths; 36 (19 children) had grade ≥3 adverse events in DTG vs 34 (21 children) in SOC (p=0.79). In the DTG arm, 41/42 children remained on DTG at last visit, with no changes to NRTI backbone; 1 child in DTG stopped ART 3 weeks post enrolment and withdrew 2 weeks later. In the SOC arm, 37/43 children remained on their initial treatment regimen at last visit; changes included 4 children who switched ART due to treatment failure.

Conclusions: DTG-based ART was superior to SOC (predominantly PI-based) in young children starting first or second-line, judged on treatment failure by 96 weeks. The treatment benefit for DTG in the <14kg cohort was consistent with that observed in children enrolled ≥14kg. There were no safety concerns on DTG. These results strongly support WHO guidelines recommending DTG-based regimens for young children and provide impetus for rapid procurement of dispersible dolutegravir.

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Authors: Mujuru H , Lugemwa A, Puthanakit T, Amuge P, Kityo C, Compagnucci A, Variava E, Kekitiinwa A, Musiime V, BarlowMosha L, Ngampiyaskul C, Zuidewind P, Tumusiime J, Mngqbisa R, Kaudha E, Behuhuma N, Kataike H, Musoro G, Nandudu A, Bwakura M, Ahimbisibwe G, Ounchanum P, Mulindwa A, Nazzinda R, Ssenyonga M, Kanjanavanit S, Nathoo K, Makumbi S, Danaviah S, Nakabuye S, Chalermpantmetagul S, Rutebarika D, Nalusiba S, Srirompotong U, Ali S, Wynne B, Riault Y, Welch S, Cressey T, Violari A, Giaquinto C, Rojo P, Gibb D, Ford D, Turkova A

Published in: IAS 2021 and International Workshop on HIV Pediatrics 2021

Abstract:

Background: Dolutegravir is associated with excessive weight gain in adults. We present the first randomised data in children and adolescents.

Methods: ODYSSEY is a randomised multi-country trial evaluating dolutegravir (DTG) + 2NRTIs versus standard-of-care (SOC) in children starting first or second-line ART. We compared weight, height and BMI-for-age Z-scores (BAZ) between treatment arms using normal regression models adjusting for first- /second-line, randomisation stratification factors and baseline measurements. Proportions becoming newly overweight (BAZ>1-≤2) or newly obese (BAZ>2) are described. 

Results: 707 children were randomised (sub-Saharan Africa 88%, Thailand 9%, Europe 4%); 311 started first-line (80% ABC/3TC, 19% TDF/3TC(FTC); 92% efavirenz-based in SOC); 396 second-line (54% ABC/3TC, 26% TDF/3TC(FTC); 72% lopinavir/ritonavir in SOC); 49% were female. At baseline, median age (IQR; range) was 12.2 (9.1, 14.9; 2.9-18.0) years; weight (IQR) 31(23, 43)kg, height 138(125, 153)cm, BMI 16.3(14.9, 18.5)kg/m2, BAZ -0.6(-1.4, 0.1); 11% had WHO-defined severe thinness/thinness, 5% were overweight, 1% obese; 50% were pubertal/postpubertal. Median follow-up was 142(124, 159) weeks. Weight, height and BAZ increased more in DTG than SOC with adjusted difference in means (DTG-SOC) at 96 weeks of 1kg (95%CI 0.3, 1.7; p=0.004), 0.8cm (95%CI 0.2, 1.4; p=0.007) and 0.14 Z-score (95%CI 0.02, 0.26; p=0.018) respectively. Early differences between groups stabilised. Treatment differences at 96 weeks in BAZ were similar in males and females (heterogeneity p=0.42), children aged <12 and ≥12 years (p=0.95), prepubertal and pubertal/postpubertal participants (p=0.54), participants starting first- and second-line ART (p=0.746), and those starting TDF vs other (p=0.61). Findings were similar for weight and height. Overall, 14(4%) children/adolescents in DTG and 9(3%) in SOC were newly overweight or obese at 96 weeks (p=0.29). 

Conclusions: Children grew better after starting DTG. Small differences between arms in weight, height and BMI stabilized before 2 years, with few becoming newly overweight/ obese in either arm. DTG-based ART was not associated with excessive weight gain in children and adolescents.

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