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1.  Safety of cotrimoxazole in pregnancy: a systematic review and meta-analysis 
Cotrimoxazole is widely prescribed to treat a range of infections and for HIV-infected individuals it is administered as prophylaxis to protect against opportunistic infections. Some reports suggest that fetuses exposed to cotrimoxazole during early pregnancy may have an increased risk of congenital anomalies. We carried out this systematic review in order to update the evidence of cotrimoxazole safety in pregnancy.
Three databases and one conference abstract site were searched in duplicate up to 31 October, 2013 for studies reporting adverse maternal and infant outcomes among women receiving cotrimoxazole during pregnancy. This search was updated in MEDLINE via PUBMED to 28 April 2014. Studies were included irrespective of HIV-infection status or the presence of other co-infections. Our primary outcome was birth defects of any kind. Secondary outcomes included spontaneous abortions, terminations of pregnancy, stillbirths, preterm deliveries, and drug-associated toxicity.
24 studies were included for review. There were 232 infants with congenital anomalies among 4196 women receiving cotrimoxazole during pregnancy, giving an overall pooled prevalence of 3.5% (95% CI 1.8–5.1%; τ2 0.03). Three studies reported 31 infants with neural tube defects, giving a crude prevalence of 0.7% (95%CI 0.5–1.0%) with most data (29 neural tube defects) coming from a single study. The majority of adverse drug reactions were mild. The quality of the evidence was very low.
The findings of this review support continued recommendations for cotrimoxazole as a priority intervention for HIV-infected pregnant women. It is critical to improve data collection on maternal and infant outcomes.
PMCID: PMC4331013  PMID: 24853309
birth defects; congenital anomalies; cotrimoxazole; HIV/AIDS; pregnancy
2.  Growth Patterns in the First Year of Life Differ in Infants Born to Perinatally vs. Non-Perinatally HIV-infected Women 
AIDS (London, England)  2015;29(1):111-116.
To compare growth patterns in the first year of life between children born to perinatally HIV-infected (PHIV) vs. non-perinatally HIV-infected (NPHIV) women in the U.S.
Retrospective cohort study of HIV-infected pregnant women who received care and delivered a liveborn at two urban tertiary centers from January 2004 - March 2012.
We collected data via chart review on demographics, behavioral risk factors, HIV clinical markers, combination antiretroviral therapy (cART), mode of HIV acquisition, pregnancy outcomes, and infant anthropometrics on study subjects. Mixed effects models were used to assess the association between maternal mode of HIV acquisition and weight-for-age (WAZ), length-for-age (LAZ), and weight-for-length (WLZ) z-scores.
Of 152 pregnancies evaluated, 32 and 120 infants were born to 25 PHIV and 99 NPHIV women respectively. Infants of PHIV women exhibited lower mean WAZ and LAZ throughout the first year of life in unadjusted analyses. After adjusting for potential confounders, the relationship between PHIV & LAZ persisted (β=−0.54, p=0.026). Small for gestational age for each birth anthropometric parameter [birth length, birth weight, and both birth length and weight] was associated with decreased LAZ (β=−0.48, p=0.007), WAZ (β=−0.99, p<0.001) and WLZ (β=−0.36, p=0.027) respectively. A delivery HIV RNA level <400 copies/mL was associated with increased WAZ & WLZ (β=0.43, p=0.015; β=0.38, p=0.021).
Infants of PHIV women may remain at persistently decreased lengths throughout the first year of life. Further studies aimed at understanding intrauterine and environmental factors in PHIV women are warranted.
PMCID: PMC4326225  PMID: 25562495
3.  Improved identification and enrolment into care of HIV-exposed and -infected infants and children following a community health worker intervention in Lilongwe, Malawi 
Early identification and entry into care is critical to reducing morbidity and mortality in children with HIV. The objective of this report is to describe the impact of the Tingathe programme, which utilizes community health workers (CHWs) to improve identification and enrolment into care of HIV-exposed and -infected infants and children.
Three programme phases are described. During the first phase, Mentorship Only (MO) (March 2007–February 2008) on-site clinical mentorship on paediatric HIV care was provided. In the second phase, Tingathe-Basic (March 2008–February 2009), CHWs provided HIV testing and counselling to improve case finding of HIV-exposed and -infected children. In the final phase, Tingathe-PMTCT (prevention of mother-to-child transmission) (March 2009–February 2011), CHWs were also assigned to HIV-positive pregnant women to improve mother-infant retention in care. We reviewed routinely collected programme data from HIV testing registers, patient mastercards and clinic attendance registers from March 2005 to March 2011.
During MO, 42 children (38 HIV-infected and 4 HIV-exposed) were active in care. During Tingathe-Basic, 238 HIV-infected children (HIC) were newly enrolled, a six-fold increase in rate of enrolment from 3.2 to 19.8 per month. The number of HIV-exposed infants (HEI) increased from 4 to 118. During Tingathe-PMTCT, 526 HIC were newly enrolled over 24 months, at a rate of 21.9 patients per month. There was also a seven-fold increase in the average number of exposed infants enrolled per month (9.5–70 patients per month), resulting in 1667 enrolled with a younger median age at enrolment (5.2 vs. 2.5 months; p<0.001).
During the Tingathe-Basic and Tingathe-PMTCT periods, CHWs conducted 44,388 rapid HIV tests, 7658 (17.3%) in children aged 18 months to 15 years; 351 (4.6%) tested HIV-positive. Over this time, 1781 HEI were enrolled, with 102 (5.7%) found HIV-infected by positive PCR. Additional HIC entered care through various mechanisms (including positive linkage by CHWs and transfer-ins) such that by February 2011, a total of 866 HIC were receiving care, a 23-fold increase from 2008.
A multipronged approach utilizing CHWs to conduct HIV testing, link HIC into care and provide support to PMTCT mothers can dramatically improve the identification and enrolment into care of HIV-exposed and -infected children.
PMCID: PMC4287633  PMID: 25571857
case finding; linkage to care; children; HIV; paediatrics; Africa; community health workers; HIV-exposed infants
4.  The VUKA Family Program: Piloting a family-based psychosocial intervention to promote health and mental health among HIV infected early adolescents in South Africa 
AIDS care  2013;26(1):10.1080/09540121.2013.806770.
An increasing number of adolescents born with HIV in South Africa are on antiretroviral treatment and have to confront complex issues related to coping with a chronic, stigmatizing and transmittable illness. Very few evidence-based mental health and health promotion programs for this population exist in South Africa. This study builds on a previous collaboratively designed and developmentally-timed family-based intervention for early adolescents (CHAMP). The study uses community-based participatory approach as part of formative research to evaluate a pilot randomized control trial at two hospitals. The paper reports on the development, feasibility and acceptability of the VUKA family-based program and its short-term impact on a range of psychosocial variables for HIV+ pre-adolescents and their caregivers. A ten session intervention of approximately 3 months duration was delivered to 65 pre-adolescents aged 10-13 years and their families. VUKA participants were noted to improve on all dimensions, including mental health, youth behaviour, HIV treatment knowledge, stigma, communication and adherence to medication. VUKA shows promise as a family-based mental and HIV prevention program for HIV+ pre-adolescents and which could be delivered by trained lay staff.
PMCID: PMC3838445  PMID: 23767772
Family-based; Psychosocial intervention; Mental health; HIV+ adolescents
5.  CD4/CD8 T-cell ratio predicts HIV infection in infants: The National Heart, Lung, and Blood Institute P2C2 Study 
In resource-poor regions of the world, HIV virologic testing is not available.
We sought to evaluate the diagnostic usefulness of the CD4/CD8 T-cell ratio in predicting HIV infection in infants.
Data from the 3- and 9-month visits for non–breastfed infants born to HIV-infected mothers enrolled (1990–1994) in the Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study (mother-to-child transmission of HIV, 17%) were analyzed. Data from the 3-month visit for infants enrolled (1985–1996) in the Perinatal AIDS Collaborative Transmission Study (mother-to-child transmission of HIV, 18%) were used for validation.
At 3 months of age, data were available on 79 HIV-infected and 409 uninfected non–breast-fed infants in the Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study. The area under the curve (AUC) of the receiver operating characteristic curve at 3 months was higher for the CD4/CD8 ratio compared with the CD4+ T-cell count (AUC, 0.83 and 0.75; P = .03). The mean CD4/CD8 ratio at the 3-month visit was 1.7 for HIV-infected infants and 3.0 for uninfected infants. A CD4/CD8 ratio of 2.4 at 3 months of age was almost 2.5 times more likely to occur in an HIV-infected infant compared with an uninfected infant (test sensitivity, 81%; posttest probability of HIV, 33%). Model performance in the Centers for Disease Control and Prevention Perinatal AIDS Collaborative Transmission Study validation test (224 HIV-infected and 1015 uninfected 3-month-old infants) was equally good (AUC, 0.78 for CD4/CD8 ratio).
The CD4/CD8 T-cell ratio is a more sensitive predictor of HIV infection in infants than the CD4+ T-cell count.
Clinical implications
The CD4/CD8 T-cell ratio can be used with caution to predict HIV infection in children.
PMCID: PMC4271194  PMID: 17920669
CD4/CD8 T-cell ratio; mother-to-child transmission of HIV; HIV infection
6.  Plasma lopinavir concentrations predict virological failure in a cohort of South African children initiating a protease-inhibitor-based regimen 
Antiviral therapy  2014;19(4):399-406.
Poor adherence to antiretroviral therapy contributes to pharmacokinetic variability and is the major determinant of virological failure. However, measuring treatment adherence is difficult, especially in children. We investigated the relationship between plasma lopinavir concentrations, pretreatment characteristics and viral load >400 copies/ml.
A total of 237 HIV-infected children aged 4–42 months on lopinavir/ritonavir oral solution were studied prospectively and followed for up to 52 weeks. Viral load and lopinavir concentration were measured at clinic visits 12, 24, 36 and 52 weeks after starting treatment. Cox multiple failure events models were used to estimate the crude and adjusted effect of lopinavir concentrations on the hazard of viral load >400 copies/ml.
The median (IQR) pretreatment CD4+ T-lymphocyte percentage was 18.80% (12.70–25.35) and 53% of children had a pretreatment viral load >750,000 copies/ml. The median (IQR) weight-for-age and height-for-age z-scores were −2.17 (−3.35–−2.84) and −3.34 (−4.57–−3.41), respectively. Median (IQR) lopinavir concentrations were 8.00 mg/l (4.11–12.42) at median (IQR) 3.50 h (2.67–4.25) after the dose. The hazard of viral load >400 copies/ml was increased with lopinavir concentrations <1 mg/l versus ≥1 mg/l (adjusted hazard ratio 2.3 [95% CI 1.63, 3.26]) and lower height-for-age z-scores.
Low lopinavir concentrations (<1 mg/l) are associated with viraemia in children. This measure could be used as a proxy for adherence and to determine which children are more likely to fail.
PMCID: PMC4229495  PMID: 24518130
7.  Disengagement of HIV-positive pregnant and postpartum women from antiretroviral therapy services: a cohort study 
Recent international guidelines call for expanded access to triple-drug antiretroviral therapy (ART) in HIV-positive women during pregnancy and postpartum. However, high levels of non-adherence and/or disengagement from care may attenuate the benefits of ART for HIV transmission and maternal health. We examined the frequency and predictors of disengagement from care among women initiating ART during pregnancy in Cape Town, South Africa.
We used routine medical records to follow-up pregnant women initiating ART within prevention of mother-to-child transmission of HIV services in Cape Town, South Africa. Outcomes assessed through six months postpartum were (1) disengagement (no attendance within 56 days of a scheduled visit) and (2) missed visits (returning to care 14–56 days late for a scheduled visit).
A total of 358 women (median age, 28 years; median gestational age, 26 weeks) initiated ART during pregnancy. By six months postpartum, 24% of women (n=86) had missed at least one visit and an additional 32% (n=115) had disengaged from care; together, 49% of women had either missed a visit or had disengaged by six months postpartum. Disengagement was more than twice as frequent postpartum compared to in the antenatal period (6.2 vs. 2.4 per 100 woman-months, respectively; p<0.0001). In a proportional hazards model, later gestational age at initiation (HR: 1.04; 95% CI: 1.00–1.07; p=0.030) and being newly diagnosed with HIV (HR: 1.57; 95% CI: 1.07–2.33; p=0.022) were significant predictors of disengagement after adjusting for patient age, starting CD4 cell count and site of ART initiation.
These results demonstrate that missed visits and disengagement from care occur frequently, particularly post-delivery, among HIV-positive women initiating ART during pregnancy. Women who are newly diagnosed with HIV may be particularly vulnerable and there is an urgent need for interventions both to promote retention overall, as well as targeting women newly diagnosed with HIV during pregnancy.
PMCID: PMC4192834  PMID: 25301494
antiretroviral therapy; pregnancy; postpartum; retention; prevention of mother-to-child transmission (PMTCT); HIV/AIDS; South Africa
10.  Masivukeni: Development of a Multimedia Based Antiretroviral Therapy Adherence Intervention for Counselors and Patients in South Africa 
AIDS and behavior  2013;17(6):1979-1991.
Effective medical treatment for HIV/AIDS requires patients’ optimal adherence to antiretroviral therapy (ART). In resource-constrained settings, lack of adequate standardized counseling for patients on ART remains a significant barrier to adherence. Masivukeni (“Lets Wake Up” in Xhosa) is an innovative multimedia-based intervention designed to help people living with HIV in resource-limited settings achieve and maintain high levels of ART adherence. Adapted from a couples-based intervention tested in the United States (US), Masivukeni was developed through community-based participatory research with US and South African partners and informed by Ewart’s Social Action Theory. Innovative computer-based multimedia strategies were used to translate a labor- and training-intensive intervention into one that could be readily and widely used by lay counselors with relatively little training with low-literacy patients. In this paper, we describe the foundations of this new intervention, the process of its development, and the evidence of its high acceptability and feasibility.
PMCID: PMC3674110  PMID: 23468079
HIV; ART adherence; intervention; multimedia; task-shifting
11.  Impact of Antiretroviral Drugs in Pregnant Women and Their Children in Africa: HIV Resistance and Treatment Outcomes 
The Journal of Infectious Diseases  2013;207(Suppl 2):S93-S100.
The global community has committed itself to eliminating new pediatric HIV infections by 2015 and improving maternal, newborn, and child health and survival in the context of HIV. Such objectives require regimens to prevent mother-to-child transmission (pMTCT) which, while being highly efficacious, protect the efficacy of future first-line antiretroviral therapy (ART). Major obstacles to eliminating vertical transmissions globally include low rates of adherence to ART and non-completion of the ‘pMTCT cascade’ due to programmatic and structural challenges faced by healthcare systems in low-income countries. Providing all pregnant women with lifelong ART regardless of CD4 count/disease stage (Option B+) could be the most effective option to prevent both HIV transmission and resistance, assuming adherence is successfully maintained. This strategy is more likely to achieve sustained undetectable HIV viremia, does not involve ART interruptions, is simpler to implement, and is cost-effective. Where Option B+ is not available, options A (short course zidovudine with single-dose nevirapine and an ARV “tail”) and B (combination ART during pregnancy and breastfeeding, with ART cessation after weaning in women not qualifying for ART for their own health) are also efficacious, highly cost-effective and associated with infrequent resistance selection if taken properly.
PMCID: PMC3657116  PMID: 23687295
mother-to-child transmission; HIV; prophylaxis; antiretroviral therapy; resistance
12.  Initiation of Antiretroviral Therapy Before 6 Months of Age is Associated with Faster Growth Recovery in South African Children Perinatally infected with HIV 
The Journal of pediatrics  2013;162(6):1138-1145.e2.
To describe the effects of age at ART initiation on growth outcomes among children infected with HIV followed for 48 months after treatment initiation.
Study design
This secondary analysis describes anthropometric changes in children infected with HIV in Johannesburg, South Africa who initiated ritonavir-boosted lopinavir (LPV/r)-based ART before 24 months of age and were randomized to continue LPV/r or to receive nevirapine after achieving and maintaining virologic suppression. Weight, height, and head circumference were measured at visits over 48 months post-ART initiation. Growth patterns including z-scores for weight for age (WAZ), height for age (HAZ), BMI for age, and head circumference for age (HCAZ) were compared between children initiating ART <6 months, 6–12 months, and 12–24 months of age.
195 children (mean±SD age 10.7±5.9 months), including 54(27.7%) <6 months, 69(35.4%) 6–12 months, and 72(36.9%) 12–24 months of age at ART initiation, were evaluated. In the first 12 months on treatment, children <6 months of age at ART initiation experienced more rapid improvement in WAZ (1.98 vs. 1.44, p=0.084) and HCAZ (1.24 vs. 0.45, p=0.004) than children who initiated ART between 12–24 months of age. By 48 months on ART, growth outcomes were similar, regardless of age at ART initiation. WAZ approached population norms by 12 months on ART. Although improving, HAZ remained on average 1.0 z-score below population norms at 48 months of therapy.
Initiation of ART before 6 months of age results in more rapid growth recovery in children infected with HIV. These data provide further evidence for the importance of prompt diagnosis and early initiation of ART for infants infected with HIV.
PMCID: PMC3640753  PMID: 23312691
height; weight; BMI; head circumference
13.  Adherence and Viral Suppression among Infants and Young Children Initiating Protease Inhibitor-Based Antiretroviral Therapy 
High levels of adherence to antiretroviral therapy (ART) are considered necessary to achieve viral suppression. We analyzed data from a cohort of HIV-infected children who were less than 2 years of age receiving protease inhibitor (PI)-based ART to investigate associations between viral suppression and adherence ascertained using different methods.
Data were from the pre-randomization phase of a clinical trial in South Africa of HIV-infected children initiating either ritonavir-boosted lopinavir (LPV/r)- or ritonavir-based ART. At scheduled visits during the first 24 weeks of enrollment, study pharmacists measured quantities of medications returned (MR) to the clinic. Caregivers answered questionnaires on missed doses and adherence barriers. Associations between adherence and viral suppression (HIV-1 RNA <400 copies/mL) were investigated by regimen.
By 24 weeks, 197/269 (73%) children achieved viral suppression. There was no association between viral suppression and caregiver reported missed doses or adherence barriers. For children receiving the LPV/r-based regimen, MR adherence to each of the three drugs in the regimen (LPV/r, lamivudine or stavudine) individually or together was associated with viral suppression at different adherence thresholds. For example, <85% adherence to any of the three medications significantly increased odds of lack of viral suppression (Odds Ratio [OR] 2.30 [95% CI: 1.30–4.07], p=.004). In contrast, for children receiving the ritonavir-based regimen, there was no consistent pattern of association between MR and viral suppression.
Caregiver reports of missed doses did not predict virologic response to treatment. Pharmacist medication reconciliation correlated strongly with virologic response for children taking a LPV/r-based regimen and appears to be a valid method for measuring pediatric adherence.
PMCID: PMC3624073  PMID: 23249913
adherence; pediatric ART; HIV; measurement
14.  Sex differences in responses to antiretroviral treatment in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-based treatment 
BMC Pediatrics  2014;14:39.
While studies of HIV-infected adults on antiretroviral treatment (ART) report no sex differences in immune recovery and virologic response but more ART-associated complications in women, sex differences in disease progression and response to ART among children have not been well assessed. The objective of this study was to evaluate for sex differences in response to ART in South African HIV-infected children who were randomized to continue ritonavir-boosted lopinavir (LPV/r)-based ART or switch to nevirapine-based ART.
ART outcomes in HIV-infected boys and girls in Johannesburg, South Africa from 2005–2010 were compared. Children initiated ritonavir-boosted lopinavir (LPV/r)-based ART before 24 months of age and were randomized to remain on LPV/r or switch to nevirapine-based ART after achieving viral suppression. Children were followed for 76 weeks post-randomization and then long-term follow up continued for a minimum of 99 weeks and maximum of 245 weeks after randomization. Viral load, CD4 count, lipids, anthropometrics, drug concentrations, and adherence were measured at regular intervals. Outcomes were compared between sexes within treatment strata.
A total of 323 children (median age 8.8 months, IQR 5.1-13.5), including 168 boys and 155 girls, initiated LPV/r-based ART and 195 children were randomized. No sex differences in risk of virological failure (confirmed viral load >1000 copies/mL) by 156 weeks post-randomization were observed within either treatment group. Girls switched to nevirapine had more robust CD4 count improvement relative to boys in this group through 112 weeks post-randomization. In addition, girls remaining on LPV/r had higher plasma concentrations of ritonavir than boys during post-randomization visits. After a mean of 3.4 years post-randomization, girls remaining on LPV/r also had a higher total cholesterol:HDL ratio and lower mean HDL than boys on LPV/r.
Sex differences are noted in treated HIV-infected children even at a young age, and appear to depend on treatment regimen. Future studies are warranted to determine biological mechanisms and clinical significance of these differences.
Trial registration Identifier: NCT00117728
PMCID: PMC3927631  PMID: 24521425
HIV; Children; Sex differences; Antiretroviral treatment outcomes; Pharmacokinetics
16.  Determinants of Mortality and Loss to Follow-Up among Adults Enrolled in HIV Care Services in Rwanda 
PLoS ONE  2014;9(1):e85774.
Antiretroviral therapy (ART) improves morbidity and mortality in patients with HIV, however high rates of loss to follow-up (LTF) and mortality have been documented in HIV care and treatment programs.
We analyzed routinely-collected data on HIV-infected patients ≥15 years enrolled at 41 healthcare facilities in Rwanda from 2005 to 2010. LTF was defined as not attending clinic in the last 12 months for pre-ART patients and 6 months for ART patients. For the pre-ART period, sub-distribution hazards models were constructed to estimate LTF and death to account for competing risks. Kaplan-Meier (KM) and Cox proportional hazards models were used for patients on ART.
31,033 ART-naïve adults were included, 64% were female and 75% were WHO stage I or II at enrollment. 17,569 (56%) patients initiated ART. Pre-ART competing risk estimates of LTF at 2 years was 11.2% (95%CI, 10.9–11.6%) and 2.9% for death (95%CI 2.7–3.1%). Among pre-ART patients, male gender was associated with higher LTF (adjusted sub-hazard ratio (aSHR) 1.3, 95%CI 1.1–1.5) and death (aSHR 1.7, 95%CI 1.4–2.1). Low CD4 count (CD4<100 vs. ≥350 aSHR 0.2, 95%CI 0.1–0.3) and higher WHO stage (WHO stage IV vs. stage I aSHR 0.4, 95%CI 0.2–0.6) were protective against pre-ART LTF. KM estimates for LTF and death in ART patients at 2 years were 4.4% (95%CI 4.4–4.5%) and 6.3% (95%CI 6.2–6.4%). In patients on ART, male gender was associated with LTF (adjusted hazard ratio (AHR) 1.4, 95%CI 1.2–1.7) and death (AHR1.3, 95%CI 1.2–1.5). Mortality was higher for ART patients ≥40 years and in those with lower CD4 count at ART initiation.
Low rates of LTF and death were founds among pre-ART and ART patients in Rwanda but greater efforts are needed to retain patients in care prior to ART initiation, particularly among those who are healthy at enrollment.
PMCID: PMC3893284  PMID: 24454931
17.  Reviewing progress: 7 year trends in characteristics of adults and children enrolled at HIV care and treatment clinics in the United Republic of Tanzania 
BMC Public Health  2013;13:1016.
To evaluate the on-going scale-up of HIV programs, we assessed trends in patient characteristics at enrolment and ART initiation over 7 years of implementation.
Data were from Optimal Models, a prospective open cohort study of HIV-infected (HIV+) adults (≥15 years) and children (<15 years) enrolled from January 2005 to December 2011 at 44 HIV clinics in 3 regions of mainland Tanzania (Kagera, Kigoma, Pwani) and Zanzibar. Comparative statistics for trends in characteristics of patients enrolled in 2005–2007, 2008–2009 and 2010–2011 were examined.
Overall 62,801 HIV + patients were enrolled: 58,102(92.5%) adults, (66.5% female); 4,699(7.5%) children.
Among adults, pregnant women enrolment increased: 6.8%, 2005–2007; 12.1%, 2008–2009; 17.2%, 2010–2011; as did entry into care from prevention of mother-to-child HIV transmission (PMTCT) programs: 6.6%, 2005–2007; 9.5%, 2008–2009; 12.6%, 2010–2011
. WHO stage IV at enrolment declined: 27.1%, 2005–2007; 20.2%, 2008–2009; 11.1% 2010–2011. Of the 42.5% and 29.5% with CD4+ data at enrolment and ART initiation respectively, median CD4+ count increased: 210 cells/μL, 2005–2007; 262 cells/μL, 2008–2009; 266 cells/μL 2010–2011; but median CD4+ at ART initiation did not change (148 cells/μL overall). Stavudine initiation declined: 84.9%, 2005–2007; 43.1%, 2008–2009; 19.7%, 2010–2011.
Among children, median age (years) at enrolment decreased from 6.1(IQR:2.7-10.0) in 2005–2007 to 4.8(IQR:1.9-8.6) in 2008–2009, and 4.1(IQR:1.5-8.1) in 2010–2011 and children <24 months increased from 18.5% to 26.1% and 31.5% respectively. Entry from PMTCT was 7.0%, 2005–2007; 10.7%, 2008–2009; 15.0%, 2010–2011. WHO stage IV at enrolment declined from 22.9%, 2005–2007, to 18.3%, 2008–2009 to 13.9%, 2010–2011. Proportion initiating stavudine was 39.8% 2005–2007; 39.5%, 2008–2009; 26.1%, 2010–2011. Median age at ART initiation also declined significantly.
Over time, the proportion of pregnant women and of adults and children enrolled from PMTCT programs increased. There was a decline in adults and children with advanced HIV disease at enrolment and initiation of stavudine. Pediatric age at enrolment and ART initiation declined. Results suggest HIV program maturation from an emergency response.
PMCID: PMC3937235  PMID: 24160907
ART program; HIV-infected adults; HIV-infected children; Trends at enrolment; Trends at ART initiation; Tanzania
18.  Lipid Profiles in Young HIV-infected Children Initiating and Changing Antiretroviral Therapy 
Both HIV infection and antiretroviral therapy are associated with dyslipidemias in adults but there are fewer data on outcomes in young children. Here we examined lipid profile changes in a cohort of young children before and after suppression on an initial ritonavir-boosted lopinavir (LPV/r)-based regimen and after switch to a nevirapine (NVP)-based regimen.
195 HIV-infected children who initiated LPV/r-based therapy when <24 months of age at one site in Johannesburg, South Africa, and who achieved viral suppression (<400copies/ml sustained for ≥ 3 months) were randomised to either continue on the LPV/r-based regimen (n=99) or to switch to a NVP-based regimen (n=96). Non-fasting concentrations of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides (TG) were measured pre-treatment, at randomization when suppressed, and at 9, 20 and 31 months post-randomization.
Median age at treatment initiation was 9 months and the initial regimen was maintained for an average of 9 months before randomization. TC, LDL and HDL increased from pre-treatment to randomization (p<0.0001) and TC/HDL ratio and TG decreased (p<0.0001). After switching to NVP, HDL was significantly higher (p<0.02) and TC/HDL and TG significantly lower (p<0.0001) through 31 months post-switch relative to remaining on the LPV/r-based regimen.
Initiating antiretroviral therapy was associated with changes to a more favorable lipid profile in young children. Switching from a LPV/r-based regimen to a NVP-based regimen accentuated and continued these improvements. Investigation of safe and effective methods for managing dyslipidemias in children of different ages in resource-limited settings is warranted.
PMCID: PMC3341506  PMID: 22134152
perinatal HIV infection; dyslipidaemia; nevirapine; ritonavir boosted lopinavir
19.  Prevalence and Change in Psychiatric Disorders Among Perinatally HIV-Infected and HIV-Exposed Youth 
AIDS care  2012;24(8):953-962.
As the pediatric HIV epidemic in resource-rich countries evolves into an adolescent epidemic, there is a substantive need for studies elucidating mental health needs of perinatally HIV-infected (PHIV+) youth as they transition through adolescence. This article examines the role of perinatal HIV infection in influencing mental health by comparing changes in psychiatric disorders and substance use disorders (SUD) in perinatally HIV-infected (PHIV+) and perinatally HIV-exposed, but uninfected (PHIV−) youth over time. Participants were recruited from four medical centers in New York City. Individual interviews were administered at baseline and 18-month follow-up to 166 PHIV+ and 114 PHIV-youth (49% male, age 9–16 at baseline). Youth psychiatric disorder was assessed using the caregiver and youth versions of the Diagnostic Interview Schedule for Children (DISC-IV). Over two-thirds of participants met criteria for at least one psychiatric disorder at either baseline or follow-up, with few group differences. Among PHIV+ youth, there was a significant decrease in the prevalence of any psychiatric disorder, as well as anxiety disorders specifically over time, while prevalence of any psychiatric disorder among PHIV− youth remained the same and mood disorders increased. Rates of SUD were low in both groups, increasing slightly by follow-up. PHIV+ youth reported more use of mental health services at follow-up. CD4 count and HIV RNA Viral Load were not associated with presence or absence of disorder at either time point. In conclusion, among PHIV+ and PHIV− youth, rates of psychiatric disorder were high, even compared to other vulnerable populations, suggesting that factors other than perinatal HIV infection may be important determinants of mental health. PHIV+ youth were more likely to improve over the observation period. The data underscore the critical need for mental health interventions for both PHIV+ and PHIV− youth.
PMCID: PMC3416047  PMID: 22519762
pediatric HIV; adolescence; psychiatric disorder; substance use disorder
20.  Individual and Contextual Factors of Sexual Risk Behavior in Youth Perinatally Infected with HIV 
AIDS Patient Care and STDs  2012;26(7):411-422.
This study prospectively examines the effects of maternal and child HIV infection on youth penetrative and unprotected penetrative sex, as well as the role of internal contextual, external contextual, social and self-regulatory factors in influencing the sexual behaviors of HIV−infected (PHIV+), HIV−affected (uninfected with an HIV+ caregiver), and HIV unaffected (uninfected with an HIV− caregiver) youth over time. Data (N=420) were drawn from two longitudinal studies focused on the effects of pediatric or maternal HIV on youth (51% female; 39% PHIV+) and their caregivers (92% female; 46% HIV+). PHIV+ youth were significantly less likely to engage in penetrative sex than HIV− youth at follow-up, after adjusting for contextual, social, and self-regulatory factors. Other individual- and contextual-level factors such as youth alcohol and marijuana use, residing with a biological parent, caregiver employment, caregiver marijuana use, and youth self-concept were also associated with penetrative sex. Youth who used alcohol were significantly more likely to engage in unprotected penetrative sex. Data suggest that, despite contextual, social, and self-regulatory risk factors, PHIV+ youth are less likely to engage in sexual behavior compared to HIV− youth from similar environments. Further research is required to understand delays in sexual activity in PHIV+ youth and also to understand potential factors that promote resiliency, particularly as they age into older adolescence and young adulthood.
PMCID: PMC3432574  PMID: 22694193
21.  Low Rates of Mother-to-Child HIV Transmission in a Routine Programmatic Setting in Lilongwe, Malawi 
PLoS ONE  2013;8(5):e64979.
The Tingathe program utilizes community health workers to improve prevention of mother-to-child transmission (PMTCT) service delivery. We evaluated the impact of antiretroviral (ARV) regimen and maternal CD4+ count on HIV transmission within the Tingathe program in Lilongwe, Malawi.
We reviewed clinical records of 1088 mother-infant pairs enrolled from March 2009 to March 2011 who completed follow-up to first DNA PCR. Eligibility for antiretroviral treatment (ART) was determined by CD4+ cell count (CD4+) for women not yet on ART. ART-eligible women initiated stavudine-lamivudine-nevirapine. Early ART was defined as ART for ≥14 weeks prior to delivery. For women ineligible for ART, optimal ARV prophylaxis was maternal AZT ≥6 weeks+sdNVP, and infant sdNVP+AZT for 1 week. HIV transmission rates were determined for ARV regimens, and factors associated with vertical transmission were identified using bivariate logistic regression.
Transmission rate at first PCR was 4.1%. Pairs receiving suboptimal ARV prophylaxis were more likely to transmit HIV (10.3%, 95% CI, 5.5–18.1%). ART was associated with reduced transmission (1.4%, 95% CI, 0.6–3.0%), with early ART associated with decreased transmission (no transmission), compared to all other treatment groups (p = 0.001). No association was detected between transmission and CD4+ categories (p = 0.337), trimester of pregnancy at enrollment (p = 0.100), or maternal age (p = 0.164).
Low rates of MTCT of HIV are possible in resource-constrained settings under routine programmatic conditions. No transmissions were observed among women on ART for more than 14 weeks prior to delivery.
PMCID: PMC3669205  PMID: 23741437
Journal of community psychology  2011;39(8):956-971.
Children living with perinatal HIV illness (PHIV+) disproportionately reside in disadvantaged neighborhoods and contend with persistent mental health challenges. This study examined the influences of disadvantaged residential neighborhood on anxiety and depression, and potential resources that buffer against internalizing problems when youths were exposed to neighborhood stressors. Multilevel analysis of 196 PHIV+ and 129 perinatally HIV-exposed but uninfected youth (PHIV−) in New York City found that higher exposure to neighborhood disorder was associated with higher levels of depression and anxiety for PHIV+ and PHIV− youths. Stressful events unrelated to residential neighborhoods significantly mediated the relationship between neighborhood disorder and anxiety and depression. Social problem solving and religiosity did not moderate the relationship between neighborhood disorder and internalizing problems. Our findings highlighted that interventions that attenuate the negative effects of stressful life events were equally critical in addressing the broader impact of disadvantaged neighborhoods on the mental health of youth affected by HIV.
PMCID: PMC3587679  PMID: 23472046
23.  HIV: prevention of mother-to-child transmission  
Clinical Evidence  2011;2011:0909.
Over 2 million children are thought to be living with HIV/AIDS worldwide, of whom over 80% live in sub-Saharan Africa. Without antiretroviral treatment, the risk of HIV transmission from infected mothers to their children is 15% to 30% during gestation or labour, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding. HIV-1 infection accounts for most infections; HIV-2 is rarely transmitted from mother to child. Transmission is more likely in mothers with high viral loads, advanced disease, or both, in the presence of other sexually transmitted diseases, and with increased exposure to maternal blood. Mixed feeding practices (breast milk plus other liquids or solids) and prolonged breastfeeding are also associated with increased risk of mother-to-child transmission of HIV.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of measures to reduce mother-to-child transmission of HIV? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed a GRADE evaluation of the quality of evidence for interventions.
We found 53 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiretroviral drugs, different methods of infant feeding, elective caesarean section, immunotherapy, micronutrient supplements, vaginal microbicides, and vitamin supplements.
Key Points
Without active intervention, the risk of mother-to-child transmission (MTCT) of HIV-1 is high, especially in populations where prolonged breastfeeding is the norm. Without antiviral treatment, the risk of transmission of HIV from infected mothers to their children is approximately 15% to 30% during pregnancy and labour, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding.HIV-2 is rarely transmitted from mother to child.Transmission is more likely in mothers with high viral loads, advanced HIV disease, or both.Without antiretroviral treatment (ART), 15% to 35% of vertically infected infants die within the first year of life.The long-term treatment of children with ART is complicated by multiple concerns regarding the complications associated with life-long treatment, including adverse effects of antiretroviral drugs, difficulties of adherence across the developmental trajectory of childhood and adolescence, and the development of resistance.From a paediatric perspective, successful prevention of MTCT and HIV-free survival for infants remain the most important focus.
Antiretroviral drugs given to the mother during pregnancy or labour, to the baby immediately after birth, or to the mother and baby reduce the risk of intrauterine and intrapartum MTCT of HIV-1 and when given to the infant after birth and to the mother or infant during breastfeeding reduce the risk of postpartum MTCT of HIV-1.
Reductions in MTCT are possible using multidrug ART regimens. Longer courses of ART are more effective, but the greatest benefit is derived from treatment during late pregnancy, labour, and early infancy.Suppression of the maternal viral load to undetectable levels (below 50 copies/mL) using highly active antiretroviral therapy (HAART) offers the greatest risk reduction, and is currently the standard of care offered in most resource-rich countries, where MTCT rates have been reduced to 1% to 2%. Alternative short-course regimens have been tested in resource-limited settings where HAART is not yet widely available. There is evidence that short courses of antiretroviral drugs have confirmed efficacy for reducing MTCT. Identifying optimal short-course regimens (drug combination, timing, and cost effectiveness) for various settings remains a focus for ongoing research.The development of viral resistance in mothers and infants after single-dose nevirapine and other short-course regimens that include single-dose nevirapine is of concern. An additional short-course of antiretrovirals with a different regimen during labour and early postpartum, and the use of HAART, may decrease the risk of viral resistance in mothers, and in infants who become HIV-infected despite prophylaxis.World Health Organization guidelines recommend starting prophylaxis with antiretroviral drugs from as early as 14 weeks' gestation, or as soon as possible if women present late in pregnancy, in labour, or at delivery.
Elective caesarean section at 38 weeks may reduce vertical transmission rates (apart from breast-milk transmission). The potential benefits of this intervention need to be balanced against the increased risk of surgery-associated complications, high cost, and feasibility issues. These reservations are particularly relevant in resource-limited settings.
Immunotherapy with HIV hyperimmune globulin seems no more effective than immunoglobulin without HIV antibody at reducing HIV-1 MTCT risk.
Vaginal microbicides have not been demonstrated to reduce HIV-1 MTCT risk.
There is no evidence that supplementation with vitamin A reduces the risk of HIV-1 MTCT, and there is concern that postnatal vitamin A supplementation for mother and infant may be associated with increased risk of mortality.
We don't know whether micronutrients are effective in prevention of MTCT of HIV as we found no RCT evidence on this outcome.
Avoidance of breastfeeding prevents postpartum transmission of HIV, but formula feeding requires access to clean water and health education. The risk of breastfeeding-related HIV transmission needs to be balanced against the multiple benefits that breastfeeding offers. In resource-poor countries, breastfeeding is strongly associated with reduced infant morbidity and improved child survival. Exclusive breastfeeding during the first 6 months may reduce the risk of HIV transmission compared with mixed feeding, while retaining most of its associated benefits.In a population where prolonged breastfeeding is usual, early, abrupt weaning may not reduce MTCT or HIV-free survival at 2 years compared with prolonged breastfeeding, and may be associated with a higher rate of infant mortality for those infants diagnosed as HIV-infected at <4 months of age. Antiretrovirals given to the mother or the infant during breastfeeding can reduce the risk of HIV transmission in the postpartum period. World Health Organization guidelines recommend that HIV-positive mothers should exclusively breastfeed for the first 6 months, after which time appropriate complementary foods can be introduced. Breastfeeding should be continued for the first 12 months of the infant's life, and stopped only when an adequate diet without breast milk can be provided. Heat- or microbicidal-treated expressed breast milk may offer value in particular settings.
PMCID: PMC3217724  PMID: 21477392
24.  Nevirapine versus Ritonavir-Boosted Lopinavir for HIV-Infected Children 
The New England journal of medicine  2012;366(25):2380-2389.
Nevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established.
In a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24.
A total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log10 copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P = 0.04), as was the time to death (P = 0.06).
Outcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the sub-optimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 number, NCT00307151.)
PMCID: PMC3443859  PMID: 22716976
25.  Mortality Trends in the US Perinatal AIDS Collaborative Transmission Study (1986–2004) 
A significant highly active antiretroviral therapy-associated decrease in annual mortality and a prolongation in survival were seen in this US perinatal cohort of human immunodeficiency virus-infected children. Temporal reductions in opportunistic infection (OI)-associated mortality were replaced by non-OI-associated deaths.
(See the Editorial Commentary by Nachman, on pages 1035–6.)
Background. Highly active antiretroviral therapy (HAART) has improved human immunodeficiency virus (HIV)–associated morbidity and mortality. The bimodal mortality distribution in HIV-infected children makes it important to evaluate temporal effects of HAART among a birth cohort with long-term, prospective follow-up.
Methods. Perinatal AIDS Collaborative Transmission Study (PACTS)/PACTS–HIV Follow-up of Perinatally Exposed Children (HOPE) study was a Centers for Disease Control and Prevention–sponsored multicenter, prospective birth cohort study of HIV-exposed uninfected and infected infants from 1985 until 2004. Mortality was evaluated for the no/monotherapy, mono-/dual-therapy, and HAART eras, that is, 1 January 1986 through 31 December 1990, from 1 January 1991 through 31 December 1996, and 1 January 1997 through 31 December 2004.
Results. Among 364 HIV-infected children, 56% were female and 69% black non-Hispanic. Of 98 deaths, 79 (81%) and 61 (62%) occurred in children ≤3 and ≤2 years old, respectively. The median age at death increased significantly across the eras (P < .0001). The average annual mortality rates were 18 (95% confidence interval [CI], 11.6–26.8), 6.9 (95% CI, 5.4–8.8), and 0.8 (95% CI, 0.4–1.5) events per 100 person-years for the no/monotherapy, mono-/dual-therapy and HAART eras, respectively. The corresponding 6-year survival rates for children born in these eras were 57%, 76%, and 91%, respectively (P < .0001). Among children who received HAART in the first 6 months of age, the probability of 6-year survival was 94%. Ten-year survival rates for HAART and non-HAART recipients were 94% and 45% (P < .05). HAART-associated reductions in mortality remained significant after adjustment for confounders (hazard ratio, 0.3; 95% CI, .08–.76). Opportunistic infections (OIs) caused 31.8%, 16.9%, and 9.1% of deaths across the respective eras (P = .051).
Conclusions. A significant decrease in annual mortality and a prolongation in survival were seen in this US perinatal cohort of HIV-infected children. Temporal decreases in OI-associated mortality resulted in relative proportional increases of non–OI-associated deaths.
PMCID: PMC3202314  PMID: 22002982

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