Effectiveness and safety of tenofovir alafenamide in children and adolescents living with HIV: a systematic review.

INTRODUCTION: Tenofovir alafenamide (TAF) is approved for paediatric use in fixed-dose combination tablets, but efficacy and safety data in children are limited. We conducted a systematic review on the efficacy/effectiveness and safety of TAF in infants, children and adolescents living with HIV. METHODS: We searched MEDLINE, Embase, the Cochrane Library, clinical trial registries, reference lists and relevant conferences to identify literature published January 2009-March 2021. We included clinical trials and observational studies assessing the efficacy/effectiveness or safety of TAF through ≥6 months of treatment in participants aged 0-19 years. RESULTS AND DISCUSSION: Overall 3626 abstracts and 371 full papers were screened. Four single-arm, innovator-funded trials (341 participants) and a pooled analysis of those trials were identified. All four trials included treatment-experienced and virally suppressed children or adolescents. One trial also included treatment-naïve adolescents with baseline viral load >1000 copies/ml. The risk of bias was rated as low in one study and unclear in the other three owing to missing data on study design (all conference presentations). At 48 weeks, 92% (46/50) of treatment-naïve participants were virally suppressed (one trial). Among treatment-experienced participants with viral load at 48 weeks, 214 of 224 participants were virally suppressed. Across the studies, one grade 3/4 adverse event was considered drug-related (intermediate uveitis). There were three discontinuations for adverse events (grade 2 anxiety and insomnia, grade 1 iridocyclitis [drug-related] and grade 1 pulmonary tuberculosis [unrelated to treatment]). One accidental death occurred across the four studies. In the pooled analysis of 223 participants, the median change in bone mineral density z-score (height- and age-adjusted) from baseline to 48 weeks was -0.12 (interquartile range [IQR] -0.46, 0.17) to 0.05 (IQR not reported) for spine, and -0.09 (IQR -0.33, 0.07) to 0.09 (IQR not reported) for total body less head. Weight-for-age z-scores increased by 0.25 from baseline to 48 weeks. CONCLUSIONS: Four single-arm trials were identified in this systematic review, with initial evidence suggesting good viral suppression and no obvious safety concerns in children and adolescents on TAF-containing regimens over 24-48 weeks. However, further comparative and longer-term safety data are needed in children and adolescents, including on weight and metabolic changes.

Effectiveness and safety of dolutegravir and raltegravir for treating children and adolescents living with HIV: a systematic review.

INTRODUCTION: Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0-19 years. METHODS: Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009-March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post-treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted. RESULTS AND DISCUSSION: In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single-arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single-arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second- or subsequent-line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second- or subsequent-line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0-50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug. CONCLUSIONS: These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer-term outcomes, such as weight and metabolic changes.

Safety and efficacy of abacavir for treating infants, children, and adolescents living with HIV: a systematic review and meta-analysis.

BACKGROUND: Abacavir is a nucleoside reverse transcriptase inhibitor recommended in paediatric HIV care. We assessed the safety and efficacy profile of abacavir used in first, second, or subsequent lines of treatment for infants, children, and adolescents living with HIV to inform 2021 WHO paediatric ART recommendations. METHODS: In this systematic review and meta-analysis, we included observational and experimental studies conducted in infants aged 0-1 year, children aged 1-10 years, and adolescents aged 10-19 years living with HIV; with data on safety or efficacy, or both, of abacavir-based antiretroviral therapy (ART); published in English or French between Jan 1, 2009, and Oct 1, 2020, plus an updated search to incorporate studies published between Oct 1, 2020, and May 15, 2022. Studies could be non-randomised or non-comparative and include patients who are treatment-naive or those who previously received abacavir (only if abacavir was combined with other ART). Case studies, studies in adults aged 18 years or older, and those assessing the effect of maternal ART exposure were excluded. We extracted data related to study identifier, study design, study period, setting, population characteristics, ART treatment, and safety (any hypersensitivity reaction, death, grade 3 or 4 adverse events, treatment discontinuation, any other morbidities, and serious adverse events), and efficacy outcomes (HIV viral load and CD4 counts reported at 6 and 12 months after ART initiation). Using random-effect models, we estimated weighted pooled incidence and relative risk (RR) of outcomes. The protocol is published in PROSPERO (CRD42022309230). FINDINGS: Of 1777 records identified, 1475 (83%) were screened after removing duplicates and a further 1421 (96%) were excluded. Of 54 full-text articles assessed for eligibility, 33 (61%) were excluded. Four records were identified from grey literature plus one duplicate from database searching, resulting in 24 studies included (two randomised controlled trials, one single-arm trial, 12 prospective cohorts, seven retrospective cohorts, and two cross-sectional studies). 19 studies described safety data and 15 described efficacy data. 18 (75%) studies were conducted in ART-naive participants. The risk of bias was considered moderate to high for most studies, and all outcomes had significant between-study heterogeneity. Data from 24 265 participants were included, of whom 7236 (30%) received abacavir. Abacavir hypersensitivity reaction was reported in nine (38%) studies, with an incidence ranging from 0·00% to 8·26% (I2=85%; p<0·0001). The incidence of death (reported in seven studies) following abacavir treatment varied from 0·00% to 5·49% (I2=58%; p=0·026). Viral suppression (<400 copies per mL) varied from 50% to 70% at 6 months (I2=92%, p<0·0001) and from 57% to 78% at 12 months (I2=88%, p<0·0001). INTERPRETATION: Toxic effects due to abacavir use remain rare and manageable. Despite scarce data on efficacy, this meta-analysis supports the use of abacavir as a preferred first-line regimen for infants and children living with HIV. FUNDING: WHO.

Advancing the prevention and treatment of HIV in children: priorities for research and development.

Safe and effective paediatric formulations of the most promising antiretroviral drugs are crucial to advance the treatment and prevention of HIV in neonates, infants, children, and adolescents. The WHO Paediatric Drug Optimization for HIV (PADO-HIV) group brings together stakeholders and experts every 2-3 years to identify priority products and define research gaps in the development of new HIV drugs and formulations for children in low-income and middle-income countries. PADO-HIV 5 met from Sept 27 to Oct 15, 2021. The group evaluated HIV agents from known and novel drug classes, oral and parenteral long-acting formulations, and developments in broadly neutralising antibodies, and included focused sessions on neonates and new delivery technologies. A list of medium-term and long-term priorities was generated, and research questions were defined. This forward-looking analysis is intended to provide guidance to funders, drug developers, and researchers, and to accelerate access for children to the best HIV drugs and formulations.

Effectiveness and Safety of Atazanavir Use for the Treatment of Children and Adolescents Living With HIV: A Systematic Review.

Background: Atazanavir/ritonavir is recommended as a preferred second-line antiretroviral regimen in children older than 3 months, alternatively to lopinavir/ritonavir. We performed a systematic review to assess safety and effectiveness of atazanavir use in children and adolescents. Methods: We searched observational studies and clinical trials on Web of Science, Embase and Cochrane CENTRAL database between 2009/01/01 and 2020/10/01; as well as grey literature. We extracted safety (adverse events, grade 3 or 4 adverse events, treatment discontinuation) and effectiveness (CD4 cell counts and HIV viral load) outcomes. We estimated weighted summary pooled incidence with corresponding 95% confidence intervals. Results: Out of the 1,085 records screened, we included five studies (one comparative cohort, three single phase 2-3 trial arms, one retrospective cohort) reporting 975 children and adolescents, of whom 56% (544) received atazanavir. Three studies reported all-cause treatment discontinuation rates, yielding a pooled incidence of 19% [15-22] at 12 months. The comparative cohort compared atazanavir to darunavir, with few grade 3-4 adverse events, except transient hyperbilirubinemia, occurring in half (92/188) of the atazanavir patients. No death occurred (two studies reporting). Four studies described increased CD4 cell counts and decreased HIV viral load at 6 or 12 months. Conclusion: Few safety and effectiveness data were available for children and adolescents exposed to atazanavir. Transient grade 3-4 hyperbilirubinemia was the main adverse outcome reported. Immune and viral responses were descriptive. The use of atazanavir/ritonavir in children and adolescents needs further investigation, but remains a suitable option for a preferred second-line antiretroviral regimen. PROSPERO number: CRD42022309230.

Prioritising the most needed paediatric antiretroviral formulations: the PADO4 list.

Despite considerable progress in paediatric HIV treatment and timely revision of global policies recommending the use of more effective and tolerable antiretroviral regimens, optimal antiretroviral formulations for infants, children, and adolescents remain limited. The Paediatric Antiretroviral Drug Optimization group reviews medium-term and long-term priorities for antiretroviral drug development to guide industry and other stakeholders on formulations most needed for low-income and middle-income countries. The group convened in December, 2018, to assess progress since the previous meeting and update the list of priority formulations. Issues relating to drug optimisation for neonatal prophylaxis and paediatric treatment, and those relating to the investigation of novel antiretrovirals in adolescents and pregnant and lactating women were also discussed. Continued focus on identifying, prioritising, and providing access to optimal antiretroviral formulations suitable for infants, children, and adolescents is key to ensuring that global HIV treatment targets can be met.

Long-acting or extended-release antiretroviral products for HIV treatment and prevention in infants, children, adolescents, and pregnant and breastfeeding women: knowledge gaps and research priorities.

Antiretroviral agents with long-acting properties have potential to improve treatment outcomes substantially for people living with HIV. In November 2017, the Long acting/Extended Release Antiretroviral Resource Program (LEAP) convened a workshop with the aim of shaping the research agenda and promoting early development of long-acting or extended release products for key populations: pregnant and lactating women, children aged up to 10 years, and adolescents aged 10-19 years. Goals included strategies and principles to ensure that the needs of children, adolescents, and pregnant and lactating women are considered when developing long-acting formulations. Research should focus not only on how best to transition long-acting products to these populations, but also on early engagement across sectors and among stakeholders. A parallel rather than sequential approach is needed when establishing adult, adolescent, and paediatric clinical trials and seeking regulatory approval. Pregnant and lactating women should be included in adult clinical trials. Adolescent-friendly trial design is needed to improve recruitment and retention of young people.

Stillbirth in Women Living With HIV Delivering in the United Kingdom and Ireland: 2007-2015.

BACKGROUND: Women living with HIV have a higher risk of adverse birth outcomes, but questions remain regarding their specific risk factors for stillbirth and the extent to which maternal HIV is associated with stillbirth. METHODS: Using data on pregnant women with HIV reported within population-based surveillance in the United Kingdom/Ireland, we described stillbirth rates in 2007-2015 stratified by type of antiretroviral therapy (ART) and evaluated risk factors using Poisson regression. General population stillbirth rates by maternal world region of origin were derived from national annual birth statistics, and compared with rates in women with HIV, using standardized stillbirth ratios with the general population as the reference. RESULTS: Between 2007 and 2015, there were 10,434 singleton deliveries in 8090 women with HIV; 75% of pregnancies were in women of African origin; and 49% were conceived on ART. The stillbirth rate was 8.5 (95% confidence interval: 6.9 to 10.5) per 1000 births. Risk factors for stillbirth included pre-eclampsia, diabetes, Asian maternal origin (versus United Kingdom/Ireland), CD4 count <350 cells/mm, older maternal age, and primiparity. Conceiving on ART did not increase the risk. The stillbirth rates (per 1000 births) by type of ART were 14.3, 11.7, 8.3, and 6.0, respectively for NVP + XTC/TDF-, LPV/r + 3TC/ZDV-, NVP + XTC/ABC-, and NVP + XTC/ZDV-exposed pregnancies (P value = 0.40). The standardized stillbirth ratio was 129 (95% confidence interval: 101 to 165) in women with HIV compared with the general population. CONCLUSION: After adjusting for maternal origin, the stillbirth rate remained higher in women with HIV than the general population. We recommend further studies to understand and prevent this excess.

Protease inhibitors and preterm delivery: another piece in the puzzle.

BACKGROUND: Questions remain regarding preterm delivery (PTD) risk in HIV-infected women on antiretroviral therapy (ART), including the role of ritonavir (RTV)-boosted protease inhibitors, timing of ART initiation and immune status. METHODS: We examined data from the UK/Ireland National Study of HIV in Pregnancy and Childhood on women with HIV delivering a singleton live infant in 2007-2015, including those pregnancies receiving RTV-boosted protease inhibitor-based (n = 4184) or nonnucleoside reverse transcriptase inhibitors-based regimens (n = 1889). We conducted logistic regression analysis adjusted for risk factors associated with PTD and stratified by ART at conception and CD4 cell count to minimize bias by indication for treatment and to assess whether PTD risk differs by ART class and specific drug combinations. RESULTS: Among women conceiving on ART, lopinavir/RTV was associated with increased PTD risk in those with CD4 cell count 350 cells/µl or less [odds ratio 1.99 (1.02, 3.85)] and with CD4 cell count more than 350 cells/µl [odds ratio 1.61 (1.07, 2.43)] vs. women on nonnucleoside reverse transcriptase inhibitors-based (mainly efavirenz and nevirapine) regimens in the same CD4 subgroup. Associations between other protease inhibitor-based regimens (mainly atazanavir and darunavir) and PTD risk were complex. Overall, PTD risk was higher in women who conceived on ART, had low CD4 cell count and were older. No trend of association of PTD with tenofovir or any specific drug combinations was observed. CONCLUSION: Our data support a link between the initiation of RTV-boosted/lopinavir-based ART preconception and PTD in subsequent pregnancies, with implications for treatment guidelines. Continued monitoring of PTD risk is needed as increasing numbers of pregnancies are conceived on new drugs.

Prevalence of depressive symptoms in pregnant and postnatal HIV-positive women in Ukraine: a cross-sectional survey.

BACKGROUND: Perinatal depression among HIV-positive women has negative implications for HIV-related and other maternal and infant outcomes. The aim of this study was to investigate the burden and correlates of perinatal depression among HIV-positive women in Ukraine, a lower middle income country with one of the largest HIV-positive populations in Europe. METHODS: Cross-sectional surveys nested within the Ukraine European Collaborative Study were conducted of HIV-positive women at delivery and between 1 and 12 months postpartum. Depressive symptoms in the previous month were assessed using a self-report screening tool. Other data collected included demographics, antiretroviral therapy (ART)-related self-efficacy, and perceptions of risks/benefits of interventions to prevent mother-to-child transmission (PMTCT). Characteristics of women with and without a positive depression screening test result were compared using Fisher's exact test and χ2 test for categorical variables. RESULTS: A quarter (27% (49/180) antenatally and 25% (57/228) postnatally) of participants screened positive for depressive symptoms. Antenatal risk factors were living alone (58% (7/12) vs. 25% (42/167) p = 0.02), being somewhat/terribly bothered by ART side effects (40% (17/43) vs. 23% (30/129) not /only slightly bothered, p = 0.05) and having lower ART-related self-efficacy (43% (12/28) vs. 23% (25/110) with higher self-efficacy, p = 0.05). Postnatally, single mothers were more likely to screen positive (44% (20/45) vs. 21% (18/84) of cohabiting and 19% (19/99) of married women, p < 0.01) as were those unsure of the effectiveness of neonatal prophylaxis (40% (20/45) vs. 18% (28/154) sure of effectiveness, p < 0.01), those worried that neonatal prophylaxis could harm the baby (30% (44/146) vs. 14% (10/73) not worried p < 0.01) and those not confident to ask for help with taking ART (48% (11/23) vs. 27% (10/37) fairly confident and 15 % (4/26) confident that they could do this). Of women who reported wanting help for their depressive symptoms, 82% (37/45) postnatally but only 31% (12/39) antenatally were already accessing peer counselling, treatment adherence programmes, support groups or social services. CONCLUSIONS: A quarter of women screened positive for depression. Results highlight the need for proactive strategies to identify depressive symptoms, and an unmet need for provision of mental health support in the perinatal period for HIV-positive women in Ukraine.

Pregnancy outcomes in HIV-positive women in Ukraine, 2000-12 (European Collaborative Study in EuroCoord): an observational cohort study.

BACKGROUND: Women living with HIV are potentially at increased risk of adverse pregnancy outcomes, due to a range of factors, including immunosuppression, use of combination antiretroviral therapy (ART), and injecting drug use. Rates of mother-to-child transmission of HIV in Ukraine have declined to around 2-4%, but little is known about other pregnancy outcomes in this setting. We used data from an observational prospective cohort study to assess pregnancy outcomes among HIV-positive women in Ukraine. METHODS: The European Collaborative Study (ECS) in EuroCoord is a continuing cohort study, established in Ukraine in 2000. Eligible women are those with a diagnosis of HIV infection before or during pregnancy (including intrapartum) who deliver liveborn babies at seven sites. Maternal sociodemographic, HIV-related, and delivery (mother and infant) data were collected with study-specific questionnaires. We used Poisson regression models to identify factors associated with preterm delivery (before 37 weeks' gestation) and small weight for gestational age (less than the tenth percentile of weight for gestational age), based on complete cases. FINDINGS: Between January, 2000, and July, 2012, data were collected on 8884 HIV-positive mother and liveborn infant pairs. Median maternal age was 26·5 years (IQR 23·1-30·3). 832 (11%) women had WHO stage 3 or 4 HIV and 1474 (17%) had a history of injecting drug use. 7348 (83%) had received antenatal ART. Among 7435 for whom ART type was available, 4396 (50%) had received zidovudine monotherapy and 2949 (33%) combination ART. Preterm delivery was seen in 780 (9%, 95% CI 8-9) of 8860 births overall and in 77 (9%, 7-11) of 889 babies with small size for gestational age. Factors associated with preterm delivery were history of injecting drug use (adjusted risk ratio 1·64, 95% CI 1·38-1·95), no ART (2·94, 2·43-3·57 vs zidovudine monotherapy), antenatal combination ART (1·40, 1·14-1·73 vs zidovudine monotherapy), WHO stage 4 HIV (2·42, 1·71-3·41 vs WHO stage 1), and being in the most socially deprived group (1·38, 1·11-1·71). Small size for gestational age was associated with history of injecting drug use (adjusted RR 1·39, 95% CI 1·16-1·65), most socially deprived (1·32, 1·09-1·61), no ART (1·60, 1·32-1·94 vs zidovudine monotherapy), and antenatal combination ART (1·33, 1·12-1·60 vs zidovudine monotherapy). INTERPRETATION: Some risk factors for adverse pregnancy outcomes were directly associated with HIV and treatment and others were shared with the general antenatal population. Monitoring of pregnancy outcomes in Ukraine will be important as use of antenatal combination ART increases. FUNDING: European Union Seventh Framework Programme, Wellcome Trust.

Adherence to antiretroviral therapy during pregnancy and the first year postpartum among HIV-positive women in Ukraine.

BACKGROUND: Poor adherence to antiretroviral therapy (ART) is associated with HIV disease progression and, during pregnancy, increased mother-to-child transmission risk. In Ukraine, access to combination ART is expanding but data on adherence are scarce. METHODS: Cross-sectional surveys of HIV-positive women were conducted i) at delivery (on antenatal ART adherence) and ii) during the first year postpartum (on ART adherence in the preceding four weeks). Factors associated with a score ≤ 11 on the self-report Case Adherence Support Evaluation (CASE) index or ≥ 1 self-reported missed dose were assessed using Fisher's exact test. RESULTS: Of 185 antenatal participants and 102 postnatal participants, median ages were 27.5 and 29.5 years respectively: 28% (50/180) and 27% (26/98) reported an unplanned pregnancy, and 13% (24/179) and 17% (17/98) an illicit drug-use history (excluding marijuana). One quarter (49/180 antenatally, 27/101 postnatally) screened positive for depression. The proportion reporting 'low' ART-related self-efficacy (i.e. unable to do ≥ 1/5 ART-taking activities) was 20% (28/141) antenatally and 17% (11/66) postnatally. Antenatally, 14% (95% CI 10-21%) had a CASE score ≤ 11 and 35% (95% CI 28-42%) reported missing ≥ 1 dose. Factors associated with a CASE score ≤ 11 were unplanned pregnancy (25% (12/48) vs. 11% (13/120) where planned, p = 0.03) and living with extended family (23% (13/57) vs. 10% (12/125) living with partner/alone, p = 0.04). Self-report of ≥ 1 missed dose antenatally was additionally associated with younger age (p = 0.03) and lower self-efficacy (50% (14/28) reported ≥ 1 missed dose vs. 28% (30/108) of those with high self-efficacy, p = 0.04). Of 102 postnatal participants, 8% (95% CI 4-15%) had a CASE score ≤ 11 and 31% (95% CI 22-41%) reported ≥ 1 missed dose. Of 11 women with low self-efficacy, 3 (27%) had a CASE score ≤ 11 compared with 3/55 (5%) of those with high self-efficacy (p = 0.05). Current smokers more commonly reported ≥ 1 missed dose postnatally (50% (13/26) vs. 25% (18/72) of non-smokers, p = 0.03). CONCLUSIONS: Our results highlight unmet needs for counselling and support. We identify some groups at risk of poor ART adherence, including women with markers of social vulnerability and those with low ART-related self-efficacy, who may benefit from targeted interventions.

Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000-2011.

OBJECTIVES: To analyze mother-to-child HIV transmission (MTCT) rates over time in light of changes in management, demographic, and pregnancy characteristics. DESIGN: Population-based surveillance data on diagnosed HIV-positive women and their infants are routinely collected in the UK and Ireland. METHODS: A total of 12486 singleton pregnancies delivered in 2000-2011 were analyzed. HIV infection status was available for 11515 infants (92.2%). RESULTS: The rate of MTCT declined from 2.1% (17/816) in 2000-2001 to 0.46% (nine of 1975, 95% confidence interval: 0.21-0.86%) in 2010-2011 (trend, P=0.01), because of a combination of factors including earlier initiation of antenatal combination antiretroviral therapy (cART). Excluding 63 infants who were breastfed or acquired HIV postnatally, MTCT risk was significantly higher for all modes of delivery in women with viral load of 50-399  copies/ml (1.0%, 14/1349), compared with viral load of less than 50 copies/ml (0.09%, six of 6347, P<0.001). Among the former (viral load 50-399 copies/ml), the risk of MTCT was 0.26% (two of 777) following elective cesarean section and 1.1% (two of 188) following planned vaginal delivery (P=0.17), excluding in-utero transmissions. MTCT probability declined rapidly with each additional week of treatment initially, followed by a slower decline up to about 15 weeks of cART, with substantial differences by baseline viral load. CONCLUSION: MTCT rates in the UK and Ireland have continued to decline since 2006, reaching an all-time low of 5 per 1000 in 2010-2011. This was primarily because of a reduction in transmissions associated with late initiation or nonreceipt of antenatal cART, and an increase in the proportion of women on cART at conception.

Impact of expanded access to combination antiretroviral therapy in pregnancy: results from a cohort study in Ukraine.

OBJECTIVE: To investigate the scale-up of antenatal combination antiretroviral therapy (cART) in Ukraine since this became part of the national policy for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV). METHODS: Data on 3535 HIV-positive pregnant women who were enrolled into the Ukraine European Collaborative Study in 2008-2010 were analysed. Factors associated with receipt of zidovudine monotherapy (AZTm) - rather than cART - and rates of mother-to-child transmission (MTCT) of HIV were investigated. FINDINGS: cART coverage increased significantly, from 22% of deliveries in 2008 to 61% of those in 2010. After adjusting for possible confounders, initiation of antenatal AZTm - rather than cART - was associated with cohabiting (versus being married; adjusted prevalence ratio, aPR: 1.09; 95% confidence interval, CI: 1.02-1.16), at least two previous live births (versus none; aPR: 1.22; 95% CI: 1.11-1.35) and a diagnosis of HIV infection during the first or second trimester (versus before pregnancy; aPR: 1.11; 95% CI: 1.03-1.20). The overall MTCT rate was 4.1% (95% CI: 3.4-4.9); 42% (49/116) of the transmissions were from the 8% (n = 238) of women without antenatal ART. Compared with AZTm, cART was associated with a 70% greater reduction in the risk of MTCT (adjusted odds ratio: 0.30; 95% CI: 0.16-0.56). CONCLUSION: Between 2008 and 2010, access to antenatal cART improved substantially in Ukraine, but implementation of the World Health Organization's Option-B policy was slow. For MTCT to be eliminated in Ukraine, improvements in the retention of women in HIV care and further roll-out of Option B are urgently needed.

Improvements in virological control among women conceiving on combination antiretroviral therapy in Western Europe.

Among 396 HIV-infected women conceiving on combination antiretroviral therapy and enrolled in the European Collaborative Study in 2000-2011, the proportion with virological failure (>200 copies/ml after ≥24 weeks of treatment) declined substantially from 34% in 2000-2001 to 3% in 2010-2011. In adjusted analyses, younger women and those with at least two children were at increased risk of virological failure, highlighting the importance of close monitoring and adherence support.

Influence of short-course antenatal antiretroviral therapy on viral load and mother-to-child transmission in subsequent pregnancies among HIV-infected women.

BACKGROUND: HIV-infected women not requiring treatment for their own health usually receive short-course antiretroviral therapy (ART) during pregnancy. Little is known about the effect of this on response to HAART in subsequent pregnancies. METHODS: We analysed data from the UK and Ireland's National Study of HIV in Pregnancy and Childhood for 2000-2010. Analyses were restricted to live births among women not on ART at conception but receiving antenatal HAART. We compared risk of detectable viral load at delivery and mother-to-child transmission in two pregnancy groups: 'ART-naive' and 'HAART-experienced' (≥7 days of HAART during previous pregnancy). Multivariable analyses were conducted using logistic regression. RESULTS: There were 5,372 pregnancies in the ART-naive group and 605 in the HAART-experienced group. Overall, there was weak evidence of an increased risk of detectable viral load in the HAART-experienced group (adjusted odds ratio [aOR] 1.27; 95% CI 1.01, 1.60); however, the increased risk was apparent only among women who previously received non-nucleoside reverse transcriptase inhibitor-based HAART (aOR 1.81; 95% CI 1.25, 2.63), and not among those with previous protease-inhibitor-based HAART exposure (aOR 1.08; 95% CI 0.81, 1.45). There was no difference in mother-to-child transmission risk between the ART-naive and HAART-experienced groups (aOR 0.42; 95% CI 0.10, 1.78), although the number of transmissions was small. CONCLUSIONS: We found no increased risk of detectable viral load at delivery among women exposed to short-course, protease-inhibitor-based HAART during a previous pregnancy. However, women with prior exposure to non-nucleoside reverse transcriptase inhibitor-based HAART appeared to be at increased risk of not adequately suppressing the virus. These findings highlight the need for careful management of HIV-infected women presenting with repeat pregnancies.

Long-term outcomes of congenital cytomegalovirus infection in Sweden and the United Kingdom.

BACKGROUND: Congenital cytomegalovirus (CMV) is an important cause of neurological problems, particularly sensorineural hearing loss, but data on long-term sequelae and the impact of nonprimary maternal infection are limited. We report updated findings on childhood outcomes from 2 large prospective studies. METHODS: Pregnant women in Malmö, Sweden, and London, United Kingdom, were included between 1977 and 1986, and newborns were screened for CMV (virus culture of urine or saliva). Cases and matched controls underwent regular, detailed developmental assessments up to at least age 5 years. RESULTS: One hundred seventy-six congenitally infected infants were identified among >50 000 screened (Malmö: 76 [4.6/1000 births]; London: 100 [3.2/1000 births]); 214 controls were selected. Symptoms were recorded in 11% of CMV-infected neonates (19/176) and were mostly mild; only 1 neonate had neurological symptoms. At follow-up, 7% of infants (11/154) were classified as having mild, 5% (7/154) moderate, and 6% (9/154) severe neurological sequelae. Four of 161 controls (2%) had mild impairment. Among children symptomatic at birth, 42% (8/19) had sequelae, versus 14% (19/135) of the asymptomatic infants (P = .006). All moderate/severe outcomes were identified by age 1; mild sequelae were first identified at age 2-5 years in 6 children, and age 6-7 years in 3. Among the 16 children with moderate/severe outcomes, 2 had mothers with confirmed and 7 with presumed nonprimary infection. CONCLUSIONS: Moderate or severe outcomes were reported in 11% of children with congenital CMV identified through population screening, all by 1 year; all impairment detected after this age was mild. Nonprimary infections contributed substantially to the burden of childhood congenital CMV disease.

Cervical screening within HIV care: findings from an HIV-positive cohort in Ukraine.

INTRODUCTION: HIV-positive women have an increased risk of invasive cervical cancer but cytologic screening is effective in reducing incidence. Little is known about cervical screening coverage or the prevalence of abnormal cytology among HIV-positive women in Ukraine, which has the most severe HIV epidemic in Europe. METHODS: Poisson regression models were fitted to data from 1120 women enrolled at three sites of the Ukraine Cohort Study of HIV-infected Childbearing Women to investigate factors associated with receiving cervical screening as part of HIV care. All women had been diagnosed as HIV-positive before or during their most recent pregnancy. Prevalence of cervical abnormalities (high/low grade squamous intraepithelial lesions) among women who had been screened was estimated, and associated factors explored. RESULTS: Overall, 30% (337/1120) of women had received a cervical screening test as part of HIV care at study enrolment (median 10 months postpartum), a third (115/334) of whom had been tested >12 months previously. In adjusted analyses, women diagnosed as HIV-positive during (vs before) their most recent pregnancy were significantly less likely to have a screening test reported, on adjusting for other potential risk factors (adjusted prevalence ratio (APR) 0.62, 95% CI 0.51-0.75 p<0.01 for 1(st)/2(nd) trimester diagnosis and APR 0.42, 95% CI 0.28-0.63 p<0.01 for 3(rd) trimester/intrapartum diagnosis). Among those with a cervical screening result reported at any time (including follow-up), 21% (68/325) had a finding of cervical abnormality. In adjusted analyses, Herpes simplex virus 2 seropositivity and a recent diagnosis of bacterial vaginosis were associated with an increased risk of abnormal cervical cytology (APR 1.83 95% CI 1.07-3.11 and APR 3.49 95% CI 2.11-5.76 respectively). CONCLUSIONS: In this high risk population, cervical screening coverage as part of HIV care was low and could be improved by an organised cervical screening programme for HIV-positive women. Bacterial vaginosis testing and treatment may reduce vulnerability to cervical abnormalities.