BACKGROUND: Initiation criteria and pediatric antiretroviral treatment regimens have changed over the past few years in South Africa. We reported worse early virological outcomes associated with the use of abacavir (ABC)-based regimens at 1 large site: here, we expand this analysis to multiple sites in the IeDEA-Southern Africa collaboration.
METHODS: Data for 9543 antiretroviral treatment-naïve children <16 years at treatment initiation started on either stavudine/lamivudine (d4T/3TC) or ABC/3TC with efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r) treated at 6 clinics in Johannesburg and Cape Town, South Africa, were analyzed with χ tests and logistic regression to evaluate viral suppression at 6 and 12 months.
RESULTS: Prevalence of viral suppression at 6 months in 2174 children started on a d4T-based LPV/r regimen was greater (70%) than among 438 children started on an ABC-based LPV/r regimen (54%, P < 0.0001). Among 3189 children started on a d4T-based EFV regimen, a higher proportion (86%) achieved suppression at 6 months compared with 391 children started on ABC-containing EFV regimens (78%, P < 0.0001). Relative benefit of d4T versus ABC on 6-month suppression remained in multivariate analysis after adjustment for pretreatment characteristics, cohort and year of program [LPV/r: odds ratio = 0.57 (confidence interval: 0.46-0.72); EFV: odds ratio = 0.46 (confidence interval: 0.32-0.65)].
CONCLUSIONS: This expanded analysis is consistent with our previous report of worse virological outcomes after ABC was introduced as part of first-line antiretroviral treatment in South Africa. Whether due to the drug itself or coincident with other changes over time, continued monitoring and analyses must clarify causes and prevent suboptimal long-term outcomes.
Background: In April 2010 the South African government replaced stavudine with abacavir in first-line antiretroviral therapy (ART) for children and young adolescents 5-14 years old. It was hoped that this change would improve treatment outcomes, partly through reduced toxicity and improved adherence. We examined treatment outcomes among HIV-positive children and adolescents initiated on abacavir-based versus stavudine-based first-line regimens. Methods: Prospective cohort analysis among HIV-positive children (5-9.9 years) and adolescents (10-13.9 years) initiating lamivudine/efavirenz with either stavudine (between April 2009- March 2010) or abacavir (between April 2010- March 2011) at one of eight HIV clinics in Gauteng and Mpumalanga provinces in South Africa. Modified Poisson regression was used to evaluate the association of regimen with all-cause mortality, loss to follow-up and detectable viral load over 24-months on ART. Linear regression was used to evaluate the relationship between regimen and immunologic response. Results: 371 (56.9%) patients initiating stavudine and 240 (43.1%) initiating abacavir were included in our analysis. A total of 12 (3.8%) stavudine and 5 (2.1%) abacavir patients died, while 43 (13.6%) stavudine and 34 (14.2%) abacavir patients were lost to follow-up over the first 24-months on ART. A total of 97 (30.6%) stavudine and 72 (30.0%) abacavir had a detectable viral load at 24-months on treatment. While estimates lacked precision, our regression analysis showed that patients on stavudine may be at increased risk of death (RR 2.0; 95%CI:0.6-6.3) compared to abacavir. However, results showed that regimens were comparable in regards to loss to follow-up (RR 0.8; 95%CI:0.5-1.4), viral load status (RR 1.1; 95%CI:0.8-1.7) and mean change in CD4 count from ART initiation (-22 cells/mm3; 95%CI:-94.5-50.6 cells/mm3). Adjusted models also showed that adolescents (10-13.9 years) compared to children (5-9.9 years) and those with CD4 count < 200 vs. >200 cell/smm3 were also at increased risk of death and loss from care. Conclusions: Although comparable in regards to loss to follow-up, viral load status and immunological response by 24-months on treatment, patients initiated on stavudine may have a higher risk of death versus those initiated on abacavir. The use of abacavir could help improve long-term treatment outcomes in HIV-positive children and adolescents.
BACKGROUND: Concerns about stavudine (d4T) toxicity have led to increased use of abacavir (ABC) in first-line pediatric antiretroviral treatment (ART) regimens. Field experience with ABC in ART-naïve children is limited.
METHODS: Deidentified demographic, clinical and laboratory data on HIV-infected children initiating ART between 2004 and 2011 in a large pediatric HIV treatment program in Johannesburg, South Africa, were used to compare viral suppression at 6 and 12 months by initial treatment regimen, time to suppression (<400 copies/mL) and rebound (>1000 copies/mL after initial suppression). Adjusted logistic regression was used to investigate confounders and calendar effects.
RESULTS: Two thousand thirty-six children initiated either d4T/3TC- or ABC/3TC-based first-line regimens in combination with either boosted lopinavir (LPV/r) or efavirenz (EFV). 1634 received d4T regimens (LPV/r n = 672; EFV n = 962) and 402 ABC regimens (LPV/r n = 192; EFV n = 210). At 6 and 12 months on ART, viral suppression rate was poorer in ABC versus d4T groups within both the LPV/r and EFV groups (P < 0.0001 for all points). In ABC groups, time to suppression was significantly slower (log-rank P < 0.0001 and P = 0.0092 for LPV/r- and EFV-based, respectively) and time to rebound after suppression significantly faster (log-rank P = 0.014 and P = 0.0001 for LPV/r- and EFV-based, respectively). Logistic regression confirmed the worse outcomes in the ABC groups even after adjustment for confounders.
CONCLUSION: Data from this urban pediatric ART service program show significantly poorer virological performance of ABC compared with d4T-based regimens, a signal that urgently warrants further investigation.
OBJECTIVE: To describe the long-term efficacy over 5 years of regimens including combinations of abacavir, lamivudine and/or zidovudine in previously untreated children in the PENTA 5 trial.
DESIGN: PENTA 5 was a 48-week randomised controlled trial comparing three dual nucleoside reverse transcriptase inhibitor (NRTI) combinations as part of first triple antiretroviral therapy (ART).
METHODS: 128 ART-naïve children were randomised to zidovudine\lamivudine (n = 36), zidovudine\abacavir (45) or lamivudine\abacavir (47). Asymptomatic children (n = 55) were also randomised to nelfinavir or placebo; all other children received open-label nelfinavir. Analyses are intent-to-treat and adjusted for minor baseline imbalances and receipt of nelfinavir/placebo.
RESULTS: Median follow-up was 5.8 years. By 5 years, 17 (47%), 28 (64%) and 18 (39%) children had changed their randomised NRTIs in the zidovudine\lamivudine, zidovudine\abacavir and lamivudine\abacavir groups respectively, but 18%, 50% and 50% of these changes were either early single drug substitutions for toxicity or switches with viral suppression (HIV-1 RNA < 400 copies/ml; e.g. to simplify regimen delivery). At 5 years, 55%/32% zidovudine\lamivudine, 50%/25% zidovudine\abacavir and 79%/63% lamivudine\abacavir had HIV-1 RNA < 400/< 50 copies/ml respectively (p = 0.03/p = 0.003). Mean increase in height-for-age 0.42, 0.68, 1.05 (p = 0.02); weight-for-age 0.03, 0.13, 0.75 (p = 0.02). Reverse transcriptase resistance mutations emerging on therapy differed between the groups: zidovudine\lamivudine (M41L, D67N, K70R, M184V, L210W, T215Y); zidovudine\abacavir (M41L, D67N, K70R, L210W, T215F/Y, K219Q); lamivudine\abacavir (K65R, L74V, Y115F, M184V).
CONCLUSIONS: Five year data demonstrate that lamivudine\abacavir is more effective in terms of HIV-1 RNA suppression and growth changes, with lower rates of switching with detectable HIV-1 RNA than zidovudine\lamivudine or zidovudine\abacavir, and should be preferred as first-line NRTI backbone.
INTRODUCTION: Treatment options for children with HIV-1 are limited. We aimed to compare activity and safety of three dual-nucleoside analogue reverse-transcriptase inhibitor (NRTI) regimens with or without a protease inhibitor in previously untreated children with HIV-1.
METHODS: In our multicentre trial, we randomly assigned 36 children to zidovudine and lamivudine, 45 to zidovudine and abacavir, and 47 to lamivudine and abacavir. Children who were symptom-free (n=55) were also randomly assigned to receive nelfinavir or placebo. Children with more advanced disease received open-label nelfinavir (73). Primary endpoints were change in plasma HIV-1 RNA at 24 and 48 weeks for the NRTI comparison and occurrence of serious adverse events for both randomised comparisons. Analyses were by intention to treat.
FINDINGS: Children had a median CD4 percentage of 22% (IQR 15-29) and a mean HIV-1 RNA concentration of 5.0 log copies/mL (SD 0.8). One child was lost to follow-up and one died of sepsis. At 48 weeks, in the zidovudine/lamivudine, zidovudine/abacavir, and lamivudine/abacavir groups, mean HIV-1 RNA had decreased by 1.71, 2.19, and 2.63 log copies/mL, respectively (estimated in absence of nelfinavir) (p=0.02 after adjustment for baseline factors). One child had a hypersensitivity reaction to abacavir; and three with possible reactions stopped abacavir. There were 24 serious adverse events--six in the symptom-free children (all on nelfinavir), but none were attributed to nelfinavir.
INTERPRETATION: Regimens containing abacavir were more effective than zidovudine/lamivudine. Such regimens could be combined with protease inhibitors and non-nucleoside reverse transcriptase inhibitors for safe and effective treatment of previously untreated children with HIV-1.
Initiation criteria and pediatric antiretroviral treatment regimens have changed over the past few years in South Africa. We reported worse early virological outcomes associated with the use of abacavir (ABC)-based regimens at 1 large site: here, we expand this analysis to multiple sites in the IeDEA-Southern Africa collaboration.
METHODS:
Data for 9543 antiretroviral treatment-naïve children <16 years at treatment initiation started on either stavudine/lamivudine (d4T/3TC) or ABC/3TC with efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r) treated at 6 clinics in Johannesburg and Cape Town, South Africa, were analyzed with χ tests and logistic regression to evaluate viral suppression at 6 and 12 months.
RESULTS:
Prevalence of viral suppression at 6 months in 2174 children started on a d4T-based LPV/r regimen was greater (70%) than among 438 children started on an ABC-based LPV/r regimen (54%, P < 0.0001). Among 3189 children started on a d4T-based EFV regimen, a higher proportion (86%) achieved suppression at 6 months compared with 391 children started on ABC-containing EFV regimens (78%, P < 0.0001). Relative benefit of d4T versus ABC on 6-month suppression remained in multivariate analysis after adjustment for pretreatment characteristics, cohort and year of program [LPV/r: odds ratio = 0.57 (confidence interval: 0.46-0.72);
EFV:
odds ratio = 0.46 (confidence interval: 0.32-0.65)].
CONCLUSIONS:
This expanded analysis is consistent with our previous report of worse virological outcomes after ABC was introduced as part of first-line antiretroviral treatment in South Africa. Whether due to the drug itself or coincident with other changes over time, continued monitoring and analyses must clarify causes and prevent suboptimal long-term outcomes.
