Apr, 2019

Long-term trends in mortality and AIDS-defining events after combination ART initiation among children and adolescents with perinatal HIV infection in 17 middle- and high-income countries in Europe and Thailand: A cohort study


Authors: Judd A, Chappell E, Turkova A; for European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) Study Group in EuroCoord.

Published in: PLoS Med. 2018;15(1): e1002491

Background Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand.

Methods and Findings Children with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (≤/>6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4–9.3) years; 35% of children aged <5 years had a CD4 lymphocyte percentage <15% in 1997–2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count <200 cells/mm3 in 1997–2003 and in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6 (2.9–8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load >400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time.

Conclusions In our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.



Apr, 2019

Severe haematologic toxicity is rare in high risk HIV-exposed infants receiving combination neonatal prophylaxis.


Authors: European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord

Published in: HIV Med. 2019;20(5):291-307

Objectives Combination neonatal prophylaxis (CNP) is recommended in high‐risk situations for the prevention of mother‐to‐child HIV transmission, although data on its safety are limited. The aim of the study was to identify whether neonatal prophylaxis (NP) type is associated with the risk of severe anaemia or neutropaenia.

Methods An individual patient data meta‐analysis was conducted within six European cohorts, in infants at high risk for acquiring HIV infection. Adjusted logistic regression models were used to assess the risk of National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) grade 3–4 anaemia/neutropaenia at ages 0–6 months. Mixture models of haemoglobin (Hb) level and log10‐transformed neutrophil count (NC) were used to explore associations with NP type at ages 0–18 months.

Results Of 1836 infants, 25% were preterm, 1149 (63%) had antenatal combination antiretroviral therapy (cART) exposure and 395 (22%) received NP (125 received CNP with three drugs). Overall, 117 (6.7%) infants had grade 3–4 anaemia at age 0–6 months and 140 (9.1%) had grade 3–4 neutropaenia. The presence of grade 3–4 anaemia or neutropaenia was not associated with NP type [adjusted odds ratio (aOR) 1.04 for one‐drug NP and 1.60 for three‐drug NP versus two‐drug NP (P = 0.879 and P = 0.277, respectively) for anaemia; aOR 1.33 for one‐drug NP and 1.98 for three‐drug NP versus two‐drug NP (=0.330 and =0.113, respectively) for neutropaenia], but was associated with preterm delivery. Overall, 7746 Hb and NC results were available for 1836 infants up to age 18 months; no significant differences in predicted Hb level or NC were apparent by NP type.

Conclusions A small proportion of infants experienced grade 3–4 haematological adverse events; risk of anaemia or netropenia was not associated with type of NP.


Apr, 2019

Prevalence and clinical outcomes of poor immune response despite virologically suppressive antiretroviral therapy among children and adolescents with HIV in Europe and Thailand: cohort study


Authors: Collins IJ; European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord

Published in: Clin Infect Dis. 2019; 28. pii: ciz253. doi: 10.1093/cid/ciz253. [Epub ahead of print]

Background In HIV-positive adults, low CD4 cell counts despite fully suppressed HIV-1 RNA on antiretroviral therapy (ART) have been associated with increased risk of morbidity and mortality. We assessed the prevalence and outcomes of poor immune response (PIR) in children on suppressive ART.

Methods Sixteen cohorts from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) contributed data. Children aged<18 years at ART initiation, with sustained viral suppression (VS) (≤400copies/mL) for ≥1 year were included. The prevalence of PIR (defined as WHO advanced/severe immunosuppression for age: CD4%<30% in children aged<12 months, CD4%<25% in 12-35 months, CD4%<20% in 36-59 months; CD4%<15%/CD4<350 cells/mm3 in ≥5-years) at 1 year of VS was described. Factors associated with PIR were assessed using logistic regression. Rates of AIDS or death on suppressive ART were calculated by PIR status.

Results Of 2318 children included, median age was 6.4 [IQR, 2.1, 10.4] years and 68% had advanced/severe immunosuppression at ART initiation. At 1 year of VS, 12% had PIR. In multivariable analysis, PIR was associated with older age and worse immunological stage at ART start, hepatitis-B coinfection and residing in Thailand (all p≤0.03). Rates of AIDS/death (95% CI) per 100,000 person-years were 1052 (547, 2022) among PIR versus 261 (166, 409) among immune responders; rate ratio of 4.04 (1.83, 8.92), p<0.001.

Conclusions One in eight children in our cohort experienced PIR despite sustained viral suppression. While the overall rate of AIDS/death was low, children with PIR had four-fold increase in risk of event as compared to immune responders.


Mar, 2019

Nucleoside reverse transcriptase inhibitor backbones and pregnancy outcomes


Authors: European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) Study Group

Published in: Aids. 2019;33(2):295-304.

Objectives The aim of this study was to investigate whether specific nucleoside reverse transcriptase inhibitor (NRTI) backbones are associated with risk of adverse pregnancy outcomes among pregnant women starting antiretroviral therapy (ART).

Design Seven observational studies across eight European countries of pregnancies in HIV-positive women.

Methods Individual-level data were pooled on singleton pregnancies conceived off-ART in which a single combination ART regimen was initiated at least 2 weeks before delivery, and ending in a live birth in 2008-2014. Preterm delivery (PTD) was defined as less than 37 gestational weeks and small-for-gestational-age (SGA) as less than 10th percentile according to INTERGROWTH standards. Poisson regression models were fitted to investigate associations between NRTI backbones and PTD/SGA.

Results Out of 7193 pregnancies, 45% (3207) were in UK/Ireland, 44% (3134) in Ukraine. 10% (722/7193) of deliveries were preterm and 11.1% (785/7089) of newborns SGA. The most common NRTI backbones were zidovudine (ZDV)-lamivudine (3TC) (71%), tenofovir (TDF)-XTC (16%) and abacavir (ABC)-3TC (10%) with TDF-containing backbone use increasing over time. Overall, 77% of regimens contained ritonavir-boosted lopinavir (LPV/r). There was no association between NRTI backbone and PTD in main adjusted analyses [adjusted prevalence ratios (aPRs) 0.97 (95% confidence interval, 95% CI 0.73-1.28] for ABC-3TC and aPR 1.06 (95% CI 0.83-1.35) for TDF-XTC, both vs. ZDV-3TC) or in 4720 pregnancies on LPV/r [aPR 1.03 (95% CI 0.74-1.43) for ABC-3TC and aPR 1.16 [0.85-1.57] for TDF-XTC, both vs. ZDV-3TC]. Infants exposed to ABC-3TC or TDF-XTC in utero were less likely to be SGA than those exposed to ZDV-3TC [aPR 0.72 (95% CI 0.53-0.97) and aPR 0.70 (95% CI 0.53-0.93), respectively].

Conclusion Results support the safety of TDF-XTC backbones initiated in pregnancy with respect to gestation length and birthweight.


Mar, 2019

Birth Defects After Exposure to Efavirenz-Based Antiretroviral Therapy at Conception/First Trimester of Pregnancy A Multicohort Analysis


Authors: Martinez de Tejada B; European Pregnancy and Paediatric HIV Cohort Collaboration Study Group.

Published in: J Acquir Immune Defic Syndr. 2019;80(3):316-324


Background To investigate the association between efavirenz (EFV) use during conception or first trimester (T1) of pregnancy and the occurrence of birth defects.

Setting Seven observational studies of pregnant HIV-positive women across 13 European countries and Thailand.

Methods Individual-level data were pooled on singleton pregnancies included in participating cohorts in 2002-2015. Birth defects were coded according to ICD-10 and the EUROCAT classification. We performed mixed-effects logistic regression models to assess the association between EFV exposure in utero and likelihood of birth defects.

Results We included 24,963 live births from 21,093 women. At conception, 30.2% (7537) women were on a non-EFV-based regimen, 4.8% (1200) on EFV, and 65% (16,226) were unexposed to antiretroviral therapy (ART). There were 412 infants with ≥1 birth defect, a prevalence of 1.65% (95% confidence interval: 1.50 to 1.82). Limb/musculoskeletal and congenital heart defects were the most common defects reported. Birth defects were present in 2.4%, 1.6%, and 1.3% of infants exposed to non-EFV, EFV, and unexposed to ART during conception/T1 (P = 0.135), respectively. The association between exposure to ART during conception/T1 and birth defects remained nonsignificant in adjusted analyses, as did exposure to EFV versus non-EFV (adjusted odds ratio 0.61; 95% confidence interval: 0.36 to 1.03, P = 0.067). Among the 21 birth defects in 19 infants on EFV, no neural tube defects were reported.

Conclusions Prevalence of birth defects after exposure to EFV-based compared with non-EFV-based ART in conception/T1 was not statistically different in this multicohort study, and even lower. EFV is at least as safe as other ART drugs currently recommended for antenatal use.


Mar, 2019

Migrant women living with HIV in Europe: are they facing inequalities in the prevention of mother-to-child-transmission of HIV?: The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord


Authors: Favarato G, Bailey H, Burns F, et al.

Published in: Eur J Public Health. 2018;28(1):55-60

Background In pregnancy early interventions are recommended for prevention of mother-to-child-transmission (PMTCT) of HIV. We examined whether pregnant women who live with HIV in Europe and are migrants encounter barriers in accessing HIV testing and care.
Methods Four cohorts within the European Pregnancy and Paediatric HIV Cohort Collaboration provided data for pooled analysis of 11 795 pregnant women who delivered in 2002–12 across ten European countries. We defined a migrant as a woman delivering in a country different from her country of birth and grouped the countries into seven world regions. We compared three suboptimal PMTCT interventions (HIV diagnosis in late pregnancy in women undiagnosed at conception, late anti-retroviral therapy (ART) start in women diagnosed but untreated at conception and detectable viral load (VL) at delivery in women on antenatal ART) in native and migrant women using multivariable logistic regression models.
Results Data included 9421 (79.9%) migrant women, mainly from sub-Saharan Africa (SSA); 4134 migrant women were diagnosed in the current pregnancy, often (48.6%) presenting with CD4 count <350 cells/µl. Being a migrant was associated with HIV diagnosis in late pregnancy [OR for SSA vs. native women, 2.12 (95% CI 1.67, 2.69)] but not with late ART start if diagnosed but not on ART at conception, or with detectable VL at delivery once on ART.
Conclusions Migrant women were more likely to be diagnosed in late pregnancy but once on ART virological response was good. Good access to antenatal care enables the implementation of PMTCT protocols and optimises both maternal and children health outcomes generally.




Mar, 2019

Predictors of faster virological suppression in early treated infants with perinatal HIV from Europe and Thailand


Authors: Chan MK, Goodall R, Judd A, et al.

Published in: Aids. 2019; 33(7):1155-1165

Objective To identify predictors of faster time to virological suppression among infants starting combination antiretroviral therapy (cART) early in infancy.

Design Cohort study of infants from Europe and Thailand included in studies participating in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC).

Methods Infants with perinatal HIV starting cART aged <6 months with ≥1 viral load (VL) measurement within 15 months of cART initiation were included. Multivariable interval-censored flexible parametric proportional hazards models were used to assess predictors of faster virological suppression, with timing of suppression assumed to lie in the interval between last VL≥400 and first VL<400copies/ml.

Results Of 420 infants, 59% were female and 56% from Central/Western Europe, 26% UK/Ireland, 15% Eastern Europe and 3% Thailand; 46% and 54% started a boosted protease inhibitor- or non-nucleoside reverse transcriptase inhibitor- based regimen, respectively. At cART initiation, the median age, CD4% and VL were 2.9 (IQR:1.4-4.1) months, 34 (IQR:24-45)% and 5.5 (IQR:4.5-6.0) log10copies/ml, respectively. Overall, an estimated 89% (95%CI:86-92%) achieved virological suppression within 12 months of cART start. In multivariable analysis, younger age (aHR:0.84 per month older; P < 0.001), higher CD4% (aHR:1.11 per 10% higher; P = 0.010) and lower log10 VL (aHR:0.85 per log10 higher; P < 0.001) at cART initiation independently predicted faster virological suppression.

Conclusion We observed a significant independent effect of age at cART initiation, even within a narrow 6 months window from birth. These findings support the earliest feasible cART initiation in infants and suggest that early therapy influences key virological and immunological parameters that could have important consequences for long term health.


Mar, 2019

Time to switch to second-line antiretroviral therapy in children with HIV in Europe and Thailand


Authors: European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) Study Group in EuroCoord.

Published in: Clin Infect Dis. 2018;66(4):594-603.

Background Global data on durability of first-line antiretroviral therapy (ART) in children with HIV is limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand.

Methods Children <18-years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitor (NRTI) plus non-NRTI (NNRTI) or boosted-protease inhibitor (PI)) were included. Switch to second-line was defined as: (i) change across drug class (PI to NNRTI or vice versa) or within PI-class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss-to-follow-up as competing risks.

Results Of 3,668 children included, median [IQR] age at ART initiation was 6.1 [1.7,10.5] years. Initial regimens were 32% PI, 34% nevirapine (NVP), 33% efavirenz-based. Median duration of follow-up from ART start was 5.4 [2.9,8.3] years. Cumulative incidence of switch at 5 years was 21% (95% CI 20, 23), with lowest incidence in Russia/Ukraine and highest in UK/Ireland. Median time to switch was 30 [15, 58] months, two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load at ART start, and NVP-based initial regimens were associated with increased risk of switch. Among those switched, 65% had viral load <400c/mL at 12-months after start of second-line ART.

Conclusions One in five children switched to second-line by 5 years of ART, with two-thirds failure related. Advanced HIV, older age and NVP-based regimens were associated with increased risk of switch.




Dec, 2016

Safety of zidovudine/lamivudine scored tablets in children with HIV infection in Europe and Thailand.


Authors: European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord.

Published inEur J Clin Pharmacol. 2017;73(4):463-468

Background Zidovudine (ZDV) has been associated with risk of haematological toxicity. Safety data from clinical trials is generally limited to 48 weeks. We assessed the short- and mid-term toxicity of ZDV/lamivudine (3TC) fixed-dose combination scored tablets in HIV-infected children followed in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) network.

Methods Fourteen cohorts provided data on patients <18 years of age taking ZDV/3TC scored tablets between 2008 and 2012. Rates of Division of AIDS (DAIDS) grade ≥3 laboratory adverse events (AEs) for hepatobiliary and haematological disorders were estimated by duration on drug (<12, 12–24, >24 months). Clinical adverse events and reasons for tablet discontinuation were described.

Results Of 541 patients on ZDV/3TC, 388 (72%) had weight and dose data available, of whom 350 (90%) weighed ≥14 kg and were eligible for tablet use; 161 (41%) were aged <10 years on an approved dose, 189 (49%) aged ≥10 years on an approved dose, and 30 (8%) were on an unapproved dose. Median age at ZDV/3TC start was 10 years, and 79% had taken ART previously (60% had prior exposure to ZDV/3TC). Overall rates of grade ≥3 AEs for absolute neutrophil counts, bilirubin, haemoglobin, platelet counts, white blood cell counts (WBC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were ≤2/100 person years (PY) for patients taking approved doses. Two hundred thirty-three (43%) patients were not on ZDV/3TC tablets at most recent follow-up; a small number (17 (7%)) discontinued due to AEs (17 (7%)), and the most common reason for discontinuation was treatment simplification (73 (31%)).

Conclusions Scored ZDV/3TC tablets, both approved and taken off-label, appear to be well tolerated with few side effects. Few patients discontinued treatment due to toxicity. As ZDV/3TC tablets are taken with other antiretrovirals, it is difficult to infer association between toxicities and specific agents, highlighting the importance of widening long-term pharmacovigilance to a broader spectrum of drug combinations.



Nov, 2016

Tuberculosis in HIV-infected children in Europe, Thailand and Brazil: paediatric TB-HIV EuroCoord study


Authors: Turkova A, Chappell E, Chalermpantmetagul S, et al.

Published in: Int J Tuberc Lung Dis 2016;20(11):1448-1456.

Setting Centres participating in the Paediatric European Network for Treatment of AIDS (PENTA), including Thailand and Brazil.

Objective To describe the incidence, presentation, treatment and treatment outcomes of tuberculosis (TB) in human immunodeficiency virus (HIV) infected children.

Design Observational study of TB diagnosed in HIV-infected children in 2011–2013.

Results Of 4265 children aged <16 years, 127 (3%) were diagnosed with TB: 6 (5%) in Western Europe, 80 (63%) in Eastern Europe, 27 (21%) in Thailand and 14 (11%) in Brazil, with estimated TB incidence rates of respectively 239, 982, 1633 and 2551 per 100 000 person-years (py). The majority (94%) had acquired HIV perinatally. The median age at TB diagnosis was 6.8 years (interquartile range 3.0–11.5). Over half (52%) had advanced/severe World Health Organization stage immunodeficiency; 67 (53%) were not on antiretroviral therapy (ART) at TB diagnosis. Preventive anti-tuberculosis treatment was given to 23% (n = 23) of 102 children diagnosed with HIV before TB. Eleven children had unfavourable TB outcomes: 4 died, 5 did not complete treatment, 1 had recurrent TB and 1 had an unknown outcome. In univariable analysis, previous diagnosis of acquired immune-deficiency syndrome, not being virologically suppressed on ART at TB diagnosis and region (Brazil) were significantly associated with unfavourable TB outcomes.

Conclusion Most TB cases were from countries with high TB prevalence. The majority (91%) had favourable outcomes. Universal ART and TB prophylaxis may reduce missed opportunities for TB prevention.