18-month occurrence of severe events among early diagnosed HIV-infected children before antiretroviral therapy in Abidjan, Côte d'Ivoire: A cohort study

<p>Abstract</p> <p>Objective</p> <p>To assess the 18-month field effectiveness on severe events of a pediatric package combining early HIV-diagnosis and targeted cotrimoxazole prophylaxis in HIV-infected children from age six-week before the antiretroviral era, in Abidjan, Côte d'Ivoire.</p> <p>Methods</p> <p>Data from two consecutive prevention of HIV mother-to-child transmission programs were compared: the ANRS 1201/1202 Ditrame-Plus cohort (2001–2005) and the pooled data of the ANRS 049a Ditrame randomized trial and its following open-labeled cohort (1995–2000), used as a reference group. HIV-infected pregnant women ≥ 32–36 weeks of gestation were offered a short-course peri-partum antiretroviral prophylaxis (ZDV in Ditrame, and ZDV ± 3TC+single-dose (sd) NVP in Ditrame-Plus). Neonatal prophylaxis was provided in Ditrame-Plus only: 7-day ZDV and sdNVP 48–72 h after birth. A 6-week pediatric HIV-RNA diagnosis was provided on-line in the Ditrame-Plus while it was only oriented on clinical symptoms in Ditrame. Six-week HIV-infected children received a daily cotrimoxazole prophylaxis in Ditrame-Plus while no prophylaxis was provided in Ditrame. The determinants of severe events (death or hospitalization > 1 day) were assessed in a Cox regression model.</p> <p>Results</p> <p>Between 1995 and 2003, 98 out of the 1121 live-births were diagnosed as HIV-infected in peri-partum: 45 from Ditrame-Plus and 53 from Ditrame. The 18-month Kaplan-Meier cumulative probability of presenting a severe event was 66% in Ditrame-Plus (95% confidence interval [95%CI]: 50%–81%) and 77% in Ditrame (95%CI: 65%–89%), Log Rank test: p = 0.47. After adjustment on maternal WHO clinical stage, maternal death, 6-week pediatric viral load, birth-weight, and breastfeeding exposure, the 18-month risk of severe event was lower in Ditrame-Plus than in Ditrame (adjusted Hazard Ratio (aHR): 0.55, 95%CI: 0.3–1.1), although the difference was not statistically significant; p = 0.07). Maternal death was the only variable determinant of the occurrence of severe events in children (aHR: 3.73; CI: 2.2–11.2; p = 0.01).</p> <p>Conclusion</p> <p>Early cotrimoxazole from 6 weeks of age in HIV-infected infants seemed to reduce probability of severe events but the study lacked statistical power to prove this. Even with systematic cotrimoxazole prophylaxis, infant morbidity and mortality remained high pointing towards a need for early pediatric HIV-diagnosis and antiretroviral treatment in Africa.</p

SFP PC-83 – Inclusion dans un essai du traitement antirétroviral pédiatrique en Afrique

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Estimated cumulative transmission risk (CTR) and 95% confidence interval (CI) of HIV-1 infection diagnosis at age 18 months in live-born children.

<p>ANRS 1201/1202 Ditrame-Plus and ANRS 049a DITRAME cohorts, Abidjan, Côte d'Ivoire, 2001–2005. Turnbull estimates and Kaplan-Meier estimates.</p><p>I/n: number of children infected/number of children at risk for mother-to-child transmission.</p>*<p>ART = antiretroviral therapy if WHO clinical stage 4 or WHO clinical stage 3 and CD4<350/mm³ or WHO clinical stage 1/2 and CD4<200/mm³.</p>**<p>Two children were not classified for infant feeding modality. † Confidence interval based on Kaplan-Meier estimates.</p

Determinants of 18-month HIV-1 infection or death (Cox proportional hazard model; reference: ZDV long-term breastfed).

<p>ANRS 1201/1202 Ditrame-Plus and ANRS 049a DITRAME cohorts, Abidjan, Côte d'Ivoire.</p><p>*Variables with p<0.25 in the comparison of the three treatment groups (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001645#pone-0001645-t002" target="_blank">table 2</a>). ^§Estimated cumulative transmission risk (CTR) of HIV-1 infection at 18-month using Kaplan-Meier estimates. ^§§Log-rank test; CI: confidence interval; ^#univariate = unadjusted Cox proportional hazards model; HR: hazard ratio; HRa: adjusted Hazard Ratio; 3TC = lamivudine; sdNVP = single-dose nevirapine during labour; ZDV  = zidovudine. ART = highly active antiretroviral therapy if WHO clinical stage 4 or WHO clinical stage 3 and CD4<350 /mm³ or WHO clinical stage 1/2 and CD4<200/mm³. #in the adjusted analysis, this variable took into account both the treatment duration and the antiretroviral regimen used.</p

Determinants of 18-month HIV-1 infection or death (Multivariate Cox proportional hazard model, reference: ZDV+sdNVP).

<p>ANRS 1201/1202 Ditrame-Plus, 2001–2005, Abidjan, Côte d'Ivoire.</p><p>*Variables with p<0.25 in the comparison of the three treatment groups (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001645#pone-0001645-t002" target="_blank">table 2</a>). ^§Estimated cumulative transmission risk (CTR) of HIV or death at 18 months using Kaplan-Meier estimates (%). ^§§logrank test; ^#univariate analysis = unadjusted Cox proportional hazards model; CI confidence interval; HR hazard ratio; HRa adjusted Hazard Ratio; 3TC = lamivudine; NVPsd = single-dose nevirapine during labour; ZDV  = zidovudine. HAART = highly active antiretroviral therapy if WHO clinical stage 4 or WHO clinical stage 3 and CD4<350/mm³ or WHO clinical stage 1/2 and CD4<200/mm³. #in the adjusted analysis, this variable took into account both the treatment duration and the antiretroviral regimen used.</p

Number of women and children by peri-partum short-course (sc) antiretroviral regimen and infant-feeding modality for prevention of Mother-To-Child transmission (PMTCT) of HIV.

<p>ANRS 1201/1202 Ditrame-Plus and ANRS 049a DITRAME cohorts, Abidjan, Côte d'Ivoire.</p><p>ZDV = short-course zidovudine; sdNVP = single-dose nevirapine during labour; 3TC = lamivudine.</p>*<p>Eight formula-fed children were excluded.</p>**<p>Two children were not classified for infant feeding modality.</p

Efavirenz-based simplification after successful early lopinavir-boosted-ritonavir-based therapy in HIV-infected children in Burkina Faso and Côte d’Ivoire: the MONOD ANRS 12206 non-inferiority randomised trial

International audienceAbstractBackgroundThe 2016 World Health Organization guidelines recommend all children <3 years start antiretroviral therapy (ART) on protease inhibitor-based regimens. But lopinavir/ritonavir (LPV/r) syrup has many challenges in low-income countries, including limited availability, requires refrigeration, interactions with anti-tuberculous drugs, twice-daily dosing, poor palatability in young children, and higher cost than non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. Successfully initiating LPV/r-based ART in HIV-infected children aged <2 years raises operational challenges that could be simplified by switching to a protease inhibitor-sparing therapy based on efavirenz (EFV), although, to date, EFV is not recommended in children <3 years.MethodsThe MONOD ANRS 12026 study is a phase 3 non-inferiority open-label randomised clinical trial conducted in Abidjan, Côte d’Ivoire, and Ouagadougou, Burkina Faso (ClinicalTrial.gov registry: NCT01127204). HIV-1-infected children who were tuberculosis-free and treated before the age of 2 years with 12–15 months of suppressive twice-daily LPV/r-based ART (HIV-1 RNA viral load (VL) <500 copies/mL, confirmed) were randomised to two arms: once-daily combination of abacavir (ABC) + lamivudine (3TC) + EFV (referred to as EFV) versus continuation of the twice-daily combination zidovudine (ZDV) or ABC + 3TC + LPV/r (referred to as LPV). The primary endpoint was the difference in the proportion of children with virological suppression by 12 months post-randomisation between arms (14% non-inferiority bound, Chi-squared test).ResultsBetween May 2011 and January 2013, 156 children (median age 13.7 months) were initiated on ART. After 12–15 months on ART, 106 (68%) were randomised to one of the two treatment arms (54 LPV, 52 EFV); 97 (91%) were aged <3 years. At 12 months post-randomisation, 46 children (85.2%) from LPV versus 43 (82.7%) from EFV showed virological suppression (defined as a VL <500 copies/mL; difference, 2.5%; 95% confidence interval (CI), −11.5 to 16.5), whereas seven (13%) in LPV and seven (13.5%) in EFV were classed as having virological failure (secondary outcome, defined as a VL ≥1000 copies/mL; difference, 0.5%; 95% CI, −13.4 to 12.4). No significant differences in adverse events were observed, with two adverse events in LPV (3.7%) versus four (7.7%) in EFV (p = 0.43). On genotyping, 13 out of 14 children with virological failure (six out of seven EFV, seven out of seven LPV) had a drug-resistance mutation: nine (five out of six EFV, four out of seven LPV) had one or more major NNRTI-resistance mutations whereas none had an LPV/r-resistance mutation.ConclusionsAt the VL threshold of 500 copies/mL, we could not conclusively demonstrate the non-inferiority of EFV on viral suppression compared to LPV because of low statistical power. However, non-inferiority was confirmed for a VL threshold of <1000 copies/mL. Resistance analyses highlighted a high frequency of NNRTI-resistance mutations. A switch to an EFV-based regimen as a simplification strategy around the age of 3 years needs to be closely monitored.Trial registrationClinicalTrial.gov registry n°NCT01127204, 19 May 2010