Case report: Severe central nervous system manifestations associated with aberrant efavirenz metabolism in children: the role of CYP2B6 genetic variation

BackgroundEfavirenz, widely used as part of antiretroviral drug regimens in the treatment of paediatric human immunodeficiency virus infection, has central nervous system side effects. We describe four children presenting with serious, persistent central nervous system adverse events who were found to have elevated plasma efavirenz concentrations as a result of carrying CYP2B6 single nucleotide polymorphisms, known to play a role in the metabolism of EFV. None of the children had a CYP2B6 wildtype haplotype. We believe this is the first case of cerebellar dysfunction associated with efavirenz use to be described in children.Case presentationFour black African children, between the ages of 4 and 8years presenting between 1 and 20months post-efavirenz initiation, are described. Cerebellar dysfunction, generalised seizures and absence seizures were the range of presenting abnormalities. Plasma efavirenz levels ranged from 20-60mg/L, 5–15 times the upper limit of the suggested reference range. All abnormal central nervous system manifestations abated after efavirenz discontinuation.ConclusionEfavirenz toxicity should always be considered in human immunodeficiency virus-infected children with unexplained central nervous system abnormalities. Our findings further our understanding of the impact of genetic variants on antiretroviral pharmacokinetics in children across various ethnic groups. Screening for potential EFV-toxicity based on the CYP2B6 c.516 SNP alone, may not be adequate

The art and science of preventing and treating HIV disease in children: a life cycle approach

Dr Abrams will review current scientific knowledge in the area of pediatric HIV infection from infancy through adolescence and will identify critical gaps that significantly impact successful care of children with HIV disease. She will explore three interconnected themes: evolution of physical and psychological development throughout childhood; the relationship between the child and her family; and importance of psychological, behavioral, and social issues as they affect successful treatment of the HIV infected child as well as vulnerability of the uninfected adolescent to acquisition of HIV infection. Combining experiences from HIV programs in resource rich and resource constrained settings, Dr. Abrams will highlight a number of pressing questions warranting urgent scientific inquiry

Clinical decision tools are needed to identify HIV-positive patients at high risk for poor outcomes after initiation of antiretroviral therapy

Over the past decade, the scale-up of HIV programs in resource-limited settings has been remarkable, with over 17 million persons initiating lifesaving antiretroviral therapy (ART) by the end of 2015 . However, in order to reduce HIV-related morbidity and mortality and decrease the number of new infections, it is critical to double the number of HIV-positive patients on treatment by 2020. It is equally important for health outcomes among children and adults on ART to be optimized. To achieve these two goals—i.e., a massive increase in the number of patients on ART as well as an enhancement in the quality of care—the global health community has recognized the need for tailored HIV services to meet the unique needs of different patient groups, often referred to as differentiated models of service delivery

Family-centred approaches to the prevention of mother to child transmission of HIV

Background: Prevention of mother to child transmission (PMTCT) programmes have traditionally been narrow in scope, targeting biomedical interventions during the perinatal period, rather than considering HIV as a family disease. This limited focus restricts programmes' effectiveness, and the opportunity to broaden prevention measures has largely been overlooked. Although prevention of vertical transmission is crucial, consideration of the family environment can enhance PMTCT. Family-centred approaches to HIV prevention and care present an important direction for preventing paediatric infections while improving overall family health. This paper reviews available literature on PMTCT programmatic models that have taken a broader or family-centred approach. We describe findings and barriers to the delivery of family-centred PMTCT and identify a number of promising new directions that may achieve more holistic services for children and families. Methods: Literature on the effectiveness of family-centred PMTCT interventions available via PubMed, EMBASE and PsycINFO were searched from 1990 to the present. Four hundred and three abstracts were generated. These were narrowed to those describing or evaluating PMTCT models that target broader aspects of the family system before, during and/or after delivery of an infant at risk of acquiring HIV infection (N = 14). Results: The most common aspects of family-centred care incorporated by PMTCT studies and programme models included counselling, testing, and provision of antiretroviral treatment for infected pregnant women and their partners. Antiretroviral therapy was also commonly extended to other infected family members. Efforts to involve fathers in family-based PMTCT counselling, infant feeding counselling, and general decision making were less common, though promising. Also promising, but rare, were PMTCT programmes that use interventions to enrich family capacity and functioning; these include risk assessments for intimate partner violence, attention to mental health issues, and the integration of early childhood development services. Conclusions: Despite barriers, numerous opportunities exist to expand PMTCT services to address the health needs of the entire family. Our review of models utilizing these approaches indicates that family-centred prevention measures can be effectively integrated within programmes. However, additional research is needed in order to more thoroughly evaluate their impact on PMTCT, as well as on broader family health outcomes

Growth and CD4 patterns of adolescents living with perinatally acquired HIV worldwide, a CIPHER cohort collaboration analysis

HIV; Adolescent; Perinatally acquiredVIH; Adolescent; Adquirit perinatalmentVIH; Adolescente; Adquirida perinatalmenteIntroduction Adolescents living with HIV are subject to multiple co-morbidities, including growth retardation and immunodeficiency. We describe growth and CD4 evolution during adolescence using data from the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) global project. Methods Data were collected between 1994 and 2015 from 11 CIPHER networks worldwide. Adolescents with perinatally acquired HIV infection (APH) who initiated antiretroviral therapy (ART) before age 10 years, with at least one height or CD4 count measurement while aged 10–17 years, were included. Growth was measured using height-for-age Z-scores (HAZ, stunting if <-2 SD, WHO growth charts). Linear mixed-effects models were used to study the evolution of each outcome between ages 10 and 17. For growth, sex-specific models with fractional polynomials were used to model non-linear relationships for age at ART initiation, HAZ at age 10 and time, defined as current age from 10 to 17 years of age. Results A total of 20,939 and 19,557 APH were included for the growth and CD4 analyses, respectively. Half were females, two-thirds lived in East and Southern Africa, and median age at ART initiation ranged from 7 years in sub-Saharan African regions. At age 10, stunting ranged from 6% in North America and Europe to 39% in the Asia-Pacific; 19% overall had CD4 counts <500 cells/mm3. Across adolescence, higher HAZ was observed in females and among those in high-income countries. APH with stunting at age 10 and those with late ART initiation (after age 5) had the largest HAZ gains during adolescence, but these gains were insufficient to catch-up with non-stunted, early ART-treated adolescents. From age 10 to 16 years, mean CD4 counts declined from 768 to 607 cells/mm3. This decline was observed across all regions, in males and females. Conclusions Growth patterns during adolescence differed substantially by sex and region, while CD4 patterns were similar, with an observed CD4 decline that needs further investigation. Early diagnosis and timely initiation of treatment in early childhood to prevent growth retardation and immunodeficiency are critical to improving APH growth and CD4 outcomes by the time they reach adulthood.This work was supported by the International AIDS Society – Collaborative Initiative for Paediatric HIV Education & Research (IAS-CIPHER, http://www.iasociety.org/CIPHER), which is made possible through funding from CIPHER Founding Sponsor ViiV Healthcare (https://www.viivhealthcare.com) and Janssen (http://www.janssen.com)

Incidence of sexually transmitted infections during pregnancy

Prevalence of sexually transmitted infections (STI) is high among pregnant women in certain settings. We estimated STI incidence and compared STI risk in pregnant and non-pregnant women. Data came from the Methods for Improving Reproductive Health in Africa (MIRA) study conducted in South Africa and Zimbabwe 2003–2006. Women aged 18–50 years with at least one follow-up visit within 6 months of enrollment were included. Follow-up visits included laboratory testing for pregnancy, chlamydia, gonorrhea, trichomoniasis, and HIV, as well as self-report of hormonal contraceptive (HC) use, sexual behaviors and intravaginal practices. All visits were classified according to pregnancy status. Incidence of each STI was calculated using follow-up time. Cox proportional hazards models were fitted using pregnancy as a time-varying exposure and sexual behaviors and intravaginal practices as time-varying covariates. Among 4,549 women, 766 (16.8%) had a positive pregnancy test. Median follow-up time was 18 months [IQR: 12–24]. The overall incidence rate of chlamydia was 6.7 per 100 person years (py) and 9.9/100py during pregnancy; gonorrhea incidence was 2.7/100py and 4.9/100py during pregnancy; trichomoniasis incidence was 7.1/100py overall and 9.2/100py during pregnancy. Overall HIV incidence was 3.9/100py and 3.8/100py during pregnancy. In crude models, pregnancy increased risk for chlamydia (hazard ratio (HR) 1.5, 95%CI: 1.1–1.2), however there was no increased risk of any measured STI in adjusted models. STI Incidence was high during pregnancy however pregnancy did not increase STI risk after adjustment for sexual behaviors. Greater efforts are needed to help pregnant women avoid STIs

Adherence and virologic suppression during the first 24 weeks on antiretroviral therapy among women in Johannesburg, South Africa - a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Adherence is a necessary part of successful antiretroviral treatment (ART). We assessed risk factors for incomplete adherence among a cohort of HIV-infected women initiating ART and examined associations between adherence and virologic response to ART.</p> <p>Methods</p> <p>A secondary data analysis was conducted on a cohort of 154 women initiating non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART at a single site in Johannesburg, South Africa. Ninety women had been enrolled in a prevention of mother-to-child transmission (pMTCT) program and were exposed to single-dose nevirapine (sdNVP) >18 months earlier. Women were interviewed pre-treatment and clinical, virologic and adherence data were collected during follow-up to 24 weeks. Incomplete adherence to ART was defined as returning >5% of medications, estimated by pill counts at scheduled visits. Multivariable logistic regression analysis and unadjusted odds ratio (95%CI) were performed, using STATA/SE (ver 10.1).</p> <p>Results</p> <p>About half of the women (53%) were <30 years of age, 63% had <11 years of schooling, 69% were unemployed and 37% lived in a shack. Seven percent of women had a viral load >400 copies/ml at 24 weeks and 37% had incomplete adherence at one or more visits. Incomplete adherence was associated with less education (p = 0.01) and lack of financial support from a partner (p = 0.02) after adjustment for confounders. Only when adherence levels dropped below 80% was there a significant association with viremia in the group overall (p = 0.02) although adherence <95% was associated with viremia in the sdNVP-exposed group (p = 0.03). The main reasons for incomplete adherence were being away from home, busy with other things and forgetting to take their medication.</p> <p>Conclusion</p> <p>Virologic response to NNRTI-treatment in the cohort was excellent. However, women who received sdNVP were at greater risk of virologic failure when adherence was <95%. Women exposed to sdNVP, and those with less education and less social support may benefit from additional adherence counseling to ensure the long-term success of ART. More than 80% adherence may be sufficient to maintain virologic suppression on NNRTI-based regimens in the short-term, however complete adherence should be encouraged.</p

Pregnant and breastfeeding women: A priority population for HIV viral load monitoring

With more than 18 million HIV-infected individuals having initiated antiretroviral therapy (ART) in low- and middle-income countries (LMICs) by the end of 2016, ensuring effective HIV care and treatment services is a global public health priority [1]. Viral load (VL) quantification provides a direct measure of the effectiveness of ART, with a consistently elevated VL suggesting poor adherence or treatment failure and the need for intervention. In turn, HIV VL monitoring is now recognised as a key component of ART services in LMICs in World Health Organization (WHO) guidelines, with an emphasis on scaling up access to VL testing for ART programmes [2]. Pregnant and postpartum women are an important population within ART programmes. In many countries, the majority of identified HIV-infected adults are women, and many women of reproductive age are diagnosed with HIV infection during pregnancy through prevention of mother-to-child transmission of HIV (PMTCT) services in antenatal care (ANC) [3]. With universal eligibility for ART for all HIV-infected pregnant and postpartum women (based on the WHO’s 2013 ‘Option B+’ policy [4]), many women of reproductive age initiating ART do so during pregnancy. PMTCT services extend through early infant diagnosis around 6–10 weeks postpartum until the cessation of breastfeeding and documentation of the infant’s final HIV testing status, which may extend well beyond 1 year postpartum based on the recently updated infant feeding recommendations [5]. With ongoing risk of HIV transmission throughout breastfeeding, maintaining ART adherence and viral suppression is especially crucial during this period. Although the importance of routine VL monitoring for HIV-infected individuals on ART is widely recognised [6], there has been minimal attention to VL monitoring in pregnancy and the postpartum period. Here we discuss key considerations for VL monitoring in pregnant and breastfeeding women in the context of expanding access to VL monitoring (summarised in Box 1)

Self-reported side effects and adherence to antiretroviral therapy in HIV-infected pregnant women under option B+: a prospective study

BACKGROUND: Antiretroviral therapy (ART) regimens containing efavirenz (EFV) are recommended as part of universal ART for pregnant and breastfeeding women. EFV may have appreciable side effects (SE), and ART adherence in pregnancy is a major concern, but little is known about ART SE and associations with adherence in pregnancy. METHODS: We investigated the distribution of patient-reported SE (based on Division of AIDS categories) and the association of SE with missed ART doses in a cohort of 517 women starting EFV+3TC/FTC+TDF during pregnancy. In analysis, SE were considered in terms of their overall frequency, by systems category, and by latent classes. RESULTS: Overall 97% of women reported experiencing at least one SE after ART initiation, with 48% experiencing more than five SE. Gastrointestinal, central nervous system, systemic and skin SE were reported by 81%, 85%, 79% and 31% of women, respectively, with considerable overlap across groups. At least one missed dose was reported by 32% of women. In multivariable models, ART non-adherence was associated with systemic SE compared to other systems categories, and measures of the overall burden of SE experienced were most strongly associated with missed ART doses. CONCLUSION: These data demonstrate very high levels of SE in pregnant women initiating EFV-based ART and a strong association between SE burden and ART adherence. ART regimens with reduced SE profiles may enhance adherence, and as countries expand universal ART for all adult patients, counseling must include preparation for ART SE