Multivariable analysis to determine if HIV-1 Tat dicysteine motif is associated with neurodevelopmental delay in HIV-infected children in Malawi.

BACKGROUND: HIV-1 Tat protein is implicated in HIV-neuropathogenesis. Tat C31S polymorphism (Tat(CS)) has been associated with milder neuropathology in vitro and in animal models but this has not been addressed in a cohort of HIV-infected adults or children. METHODS: HIV viral load (VL) in plasma and cerebrospinal fluid (CSF) were determined and plasma HIV tat gene was sequenced. Neurodevelopmental assessment was performed using Bayley Scales of Infant Development III (BSID-III), with scores standardized to Malawian norms. The association between Tat(CS) and BSID-III scores was evaluated using multivariate linear regression. RESULTS: Neurodevelopmental assessment and HIV tat genotyping were available for 33 children. Mean age was 19.4 (SD 7.1) months, mean log VL was 5.9 copies/mL (SD 0.1) in plasma and 3.9 copies/mL (SD 0.9) in CSF. The prevalence of Tat(CC) was 27 %. Z-scores for BSID-III subtests ranged from -1.3 to -3.9. Tat(CC) was not associated with higher BSID-III z-scores. CONCLUSIONS: The hypothesis of milder neuropathology in individuals infected with HIV Tat(CS) was not confirmed in this small cohort of Malawian children. Future studies of tat genotype and neurocognitive disorder should be performed using larger sample sizes and investigate if this finding is due to differences in HIV neuropathogenesis between children and adults.

Impact of daily cotrimoxazole on clinical malaria and asymptomatic parasitemias in HIV-exposed, uninfected infants.

BACKGROUND: Cotrimoxazole preventive therapy (CPT) is recommended for all human immunodeficiency virus (HIV)-exposed infants to avoid opportunistic infections. Cotrimoxazole has antimalarial effects and appears to reduce clinical malaria infections, but the impact on asymptomatic malaria infections is unknown. METHODS: We conducted an observational cohort study using data and dried blood spots (DBSs) from the Breastfeeding, Antiretrovirals and Nutrition study to evaluate the impact of CPT on malaria infection during peak malaria season in Lilongwe, Malawi. We compared malaria incidence 1 year before and after CPT implementation (292 and 682 CPT-unexposed and CPT-exposed infants, respectively), including only infants who remained HIV negative by 36 weeks of age. Malaria was defined as clinical, asymptomatic (using DBSs at 12, 24, and 36 weeks), or a composite outcome of clinical or asymptomatic. Linear and binomial regression with generalized estimating equations were used to estimate the association between CPT and malaria. Differences in characteristics of parasitemias and drug resistance polymorphisms by CPT status were also assessed in the asymptomatic infections. RESULTS: CPT was associated with a 70% (95% confidence interval, 53%-81%) relative reduction in the risk of asymptomatic infection between 6 and 36 weeks of age. CPT appeared to provide temporary protection against clinical malaria and more sustained protection against asymptomatic infections, with no difference in parasitemia characteristics. CONCLUSIONS: CPT appears to reduce overall malaria infections, with more prolonged impacts on asymptomatic infections. Asymptomatic infections are potentially important reservoirs for malaria transmission. Therefore, CPT prophylaxis may have important individual and public health benefits.

Barriers to successful early infant diagnosis of HIV infection at primary care level in Malawi.

HIV-infected women seeking early infant HIV diagnosis (EID) services in Malawi were asked about factors potentially associated with returning for EID results. Many (33.3%) infants failed to complete the EID process because of time and costs required for multiple visits. Infants of mothers receiving antiretroviral treatment were less likely to drop out (adjusted risk ratio 0.51), suggesting that EID completion may improve in programs providing antiretroviral treatment to all pregnant women.

Validity of US norms for the Bayley Scales of Infant Development-III in Malawian children.

OBJECTIVE: Most psychometric tests originate from Europe and North America and have not been validated in other populations. We assessed the validity of United States (US)-based norms for the Bayley Scales of Infant and Toddler Development-III (BSID-III), a neurodevelopmental tool developed for and commonly used in the US, in Malawian children. METHODS: We constructed BSID-III norms for cognitive, fine motor (FM), gross motor (GM), expressive communication (EC) and receptive communication (RC) subtests using 5173 tests scores in 167 healthy Malawian children. Norms were generated using Generalized Additive Models for location, scale and shape, with age modeled continuously. Standard z-scores were used to classify neurodevelopmental delay. Weighted kappa statistics were used to compare the classification of neurological development using US-based and Malawian norms. RESULTS: For all subtests, the mean raw scores in Malawian children were higher than the US normative scores at younger ages (approximately <6 months) after which the mean curves crossed and the US normative mean exceeded that of the Malawian sample and the age at which the curves crossed differed by subtest. Weighted kappa statistics for agreement between US and Malawian norms were 0.45 for cognitive, 0.48 for FM, 0.57 for GM, 0.50 for EC, and 0.44 for RC. CONCLUSION: We demonstrate that population reference curves for the BSID-III differ depending on the origin of the population. Reliance on US norm-based standardized scores resulted in misclassification of the neurological development of Malawian children, with the greatest potential for bias in the measurement of cognitive and language skills.

Postpartum depression and HIV infection among women in Malawi.

BACKGROUND: HIV-infected women face several risk factors related to postpartum depression (PPD). We aimed to describe the prevalence and cumulative incidence of PPD in the low-income setting of Malawi and to determine the association between maternal and infant HIV and PPD. METHODS: This longitudinal cohort study included 156 HIV-uninfected and 373 HIV-infected Malawian women enrolled 10-14 weeks after delivery who returned at 6, 9, 12, 15, and 18 months for follow-up visits. PPD was assessed at all visits. The prevalence of PPD at all visits was estimated using the Edinburgh Postnatal Depression Scale (EPDS). Association between PPD at 10-14 weeks and maternal and infant HIV status was assessed using log binomial regression. Cumulative incidence of PPD was assessed using Kaplan-Meier curves. RESULTS: Prevalence of PPD was highest (11%) at 10-14 weeks postpartum and decreased to 2.9% at 18 months. There was no association between maternal HIV status and PPD (prevalence ratio, 1.18; 95% confidence interval: 0.68 to 2.08). Among HIV-infected women, prevalence of PPD was higher among women whose infants had acquired HIV (prevalence ratio, 2.0; 95% confidence interval: 1.1 to 3.6). The cumulative probability of experiencing PPD over the first 12 months postpartum was estimated to be 33.5% for HIV-infected mothers with HIV-infected infants vs. 22.5% for HIV-infected mothers with uninfected infants and 23.2% for HIV-uninfected mothers. CONCLUSIONS: PPD prevalence did not differ between HIV-infected and -uninfected mothers but increased among women with an HIV-infected infant. Our findings suggest that it may be important to monitor PPD among women with HIV-infected infants.

The effect of cotrimoxazole prophylactic treatment on malaria, birth outcomes, and postpartum CD4 count in HIV-infected women.

BACKGROUND: Limited data exist on cotrimoxazole prophylactic treatment (CPT) in pregnant women, including protection against malaria versus standard intermittent preventive therapy with sulfadoxine-pyrimethamine (IPTp). METHODS: Using observational data we examined the effect of CPT in HIV-infected pregnant women on malaria during pregnancy, low birth weight and preterm birth using proportional hazards, logistic, and log binomial regression, respectively. We used linear regression to assess effect of CPT on CD4 count. RESULTS: Data from 468 CPT-exposed and 768 CPT-unexposed women were analyzed. CPT was associated with protection against malaria versus IPTp (hazard ratio: 0.35, 95% Confidence Interval (CI): 0.20, 0.60). After adjustment for time period this effect was not statistically significant (adjusted hazard ratio: 0.66, 95% CI: 0.28, 1.52). Among women receiving and not receiving CPT, rates of low birth weight (7.1% versus 7.6%) and preterm birth (23.5% versus 23.6%) were similar. CPT was associated with lower CD4 counts 24 weeks postpartum in women receiving (-77.6 cells/ µ L, 95% CI: -125.2, -30.1) and not receiving antiretrovirals (-33.7 cells/ µ L, 95% CI: -58.6, -8.8). CONCLUSIONS: Compared to IPTp, CPT provided comparable protection against malaria in HIV-infected pregnant women and against preterm birth or low birth weight. Possible implications of CPT-associated lower CD4 postpartum warrant further examination.

Implementing early infant diagnosis of HIV infection at the primary care level: experiences and challenges in Malawi.

PROBLEM: Malawi's national guidelines recommend that infants exposed to the human immunodeficiency virus (HIV) be tested at 6 weeks of age. Rollout of services for early infant diagnosis has been limited and has resulted in the initiation of antiretroviral therapy (ART) in very few infants. APPROACH: An early infant diagnosis programme was launched. It included education of pregnant women on infant testing, community sensitization, free infant testing at 6 weeks of age, active tracing of HIV-positive infants and referral for treatment and care. LOCAL SETTING: The programme was established in two primary care facilities in Blantyre, Malawi. RELEVANT CHANGES: Of 1214 HIV-exposed infants, 71.6% presented for early diagnosis, and 14.5% of those who presented tested positive for HIV. Further testing of 103 of these 126 apparently HIV-positive infants confirmed infection in 88; the other 15 results were false positives. The initial polymerase chain reaction testing of dried blood spots had a positive predictive value (PPV) of 85.4%. Despite active tracing, only 87.3% (110/126) of the mothers of infants who initially tested positive were told their infants' test results. ART was initiated in 58% of the infants with confirmed HIV infection. LESSONS LEARNT: Early infant diagnosis of HIV infection at the primary care level in a resource-poor setting is challenging. Many children in the HIV diagnosis and treatment programme were lost to follow-up at various stages. Diagnostic tools with higher PPV and point-of-care capacity and better infrastructures for administering ART are needed to improve the management of HIV-exposed and HIV-infected infants.

Effects of cotrimoxazole prophylactic treatment on adverse health outcomes among HIV-exposed, uninfected infants.

BACKGROUND: The World Health Organization guidelines recommend cotrimoxazole prophylactic treatment (CPT) for all HIV-exposed infants from age 6 weeks to the cessation of breastfeeding and the exclusion of HIV infection. There are limited data on the effects of CPT among this population of infants. We examined the effects of CPT on adverse health outcomes among HIV-exposed infants during the first 36 weeks of life using data from the Breastfeeding, Antiretrovirals and Nutrition study, a large clinical trial of antiretroviral drugs given to the mother or infant for the prevention of HIV transmission during breastfeeding. METHODS: For the analysis, we assigned a status of CPT-exposed to infants who were participating in the study after the CPT program started. We estimated unadjusted and adjusted hazard ratios for the effect of CPT status on time to incident malaria, severe illness or death, anemia, and weight-for-age Z score < -2.0. Participation in the study was limited to focus exclusively on HIV-exposed, uninfected infants. RESULTS: The hazard ratio for the effect of CPT on incident malaria was 0.35 (95% confidence interval: 0.21, 0.57) during the first 10 weeks of CPT exposure and 0.93 (95% confidence interval: 0.67, 1.29) for the remaining 20 weeks. CPT was not associated with the other outcomes examined. CONCLUSIONS: CPT offered temporary protection against malaria among HIV-exposed, uninfected infants. However, CPT offered no protection against anemia, low weight for age or the collapsed outcome of severe illness or death.

"They have already thrown away their chicken": barriers affecting participation by HIV-infected women in care and treatment programs for their infants in Blantyre, Malawi.

HIV-infected infants and young children are at high risk of serious illness and death. Morbidity and mortality can be greatly reduced through early infant diagnosis (EID) of HIV and timely initiation of antiretroviral therapy (ART). Despite global efforts to scale-up of EID and infant ART, uptake of these services in resource poor, high HIV burden countries remain low. We conducted a qualitative study of 59 HIV-infected women to identify and explore barriers women face in accessing HIV testing and care for their infants. To capture different perspectives, we included mothers whose infants were known positive (n=9) or known negative (n=14), mothers of infants with unknown HIV status (n=13), and pregnant HIV-infected women (n=20). Five important themes emerged: lack of knowledge regarding EID and infant ART, the perception of health care workers as authority figures, fear of disclosure of own and/or child's HIV status, lack of psychosocial support, and intent to shorten the life of the child. A complex array of cultural, economic, and psychosocial factors creates barriers for HIV-infected women to participate in early infant HIV testing and care programs. For optimal impact of EID and infant ART, reasons for poor uptake should be better understood and addressed in a culturally sensitive manner.

Central nervous system compartmentalization of HIV-1 subtype C variants early and late in infection in young children.

HIV-1 subtype B replication in the CNS can occur in CD4+ T cells or macrophages/microglia in adults. However, little is known about CNS infection in children or the ability of subtype C HIV-1 to evolve macrophage-tropic variants. In this study, we examined HIV-1 variants in ART-naïve children aged three years or younger to determine viral genotypes and phenotypes associated with HIV-1 subtype C pediatric CNS infection. We examined HIV-1 subtype C populations in blood and CSF of 43 Malawian children with neurodevelopmental delay or acute neurological symptoms. Using single genome amplification (SGA) and phylogenetic analysis of the full-length env gene, we defined four states: equilibrated virus in blood and CSF (n = 20, 47%), intermediate compartmentalization (n = 11, 25%), and two distinct types of compartmentalized CSF virus (n = 12, 28%). Older age and a higher CSF/blood viral load ratio were associated with compartmentalization, consistent with independent replication in the CNS. Cell tropism was assessed using pseudotyped reporter viruses to enter a cell line on which CD4 and CCR5 receptor expression can be differentially induced. In a subset of compartmentalized cases (n = 2, 17%), the CNS virus was able to infect cells with low CD4 surface expression, a hallmark of macrophage-tropic viruses, and intermediate compartmentalization early was associated with an intermediate CD4 entry phenotype. Transmission of multiple variants was observed for 5 children; in several cases, one variant was sequestered within the CNS, consistent with early stochastic colonization of the CNS by virus. Thus we hypothesize two pathways to compartmentalization: early stochastic sequestration in the CNS of one of multiple variants transmitted from mother to child, and emergence of compartmentalized variants later in infection, on average at age 13.5 months, and becoming fully apparent in the CSF by age 18 months. Overall, compartmentalized viral replication in the CNS occurred in half of children by year three.

Neurodevelopmental trajectory of HIV-infected children accessing care in Kinshasa, Democratic Republic of Congo.

OBJECTIVE: To assess the effect of HIV care (including highly active antiretroviral therapy if eligible) on neurodevelopment. DESIGN: Prospective cohort study. METHODS: Motor and mental development of 35 HIV-infected children (aged 18-71 months) was assessed at entry into care and after 6 and 12 months using age-appropriate tools. Developmental trajectory was compared with 35 HIV-uninfected, affected, and 90 control children using linear mixed-effects models. Effects of age (29 months) and timing of entry into care (before or after highly active antiretroviral therapy eligibility) were explored in secondary analyses. RESULTS: At baseline, HIV-infected children had the lowest, control children the highest, and HIV-uninfected affected children intermediate mean developmental scores. After 1 year of care, HIV-infected children achieved mean motor and cognitive scores that were similar to HIV uninfected, affected children although lower compared with control children. Overall, HIV-infected children experienced accelerated motor development but similar gains in cognitive development compared with control children. Exploratory analyses suggest that younger children and those presenting early may experience accelerated greater gains in development. CONCLUSIONS: HIV-infected children accessing care experience improved motor development, and may, if care is initiated at a young age or an early stage of the disease, also experience gains in cognitive development.

Impact of the HIV/AIDS epidemic on the neurodevelopment of preschool-aged children in Kinshasa, Democratic Republic of the Congo.

OBJECTIVES: Pediatric HIV infection is a growing problem in most regions of the world. Data on the effects of HIV on the neurodevelopment of children in resource-poor settings are scarce but necessary to guide interventions. The purpose of this study was to compare the neurodevelopment of preschool-aged HIV-infected, HIV-affected (HIV-uninfected AIDS orphans and HIV-uninfected children whose mother had symptomatic AIDS), and healthy control children in Kinshasa, Democratic Republic of Congo. METHODS: Thirty-five HIV-infected, 35 HIV-affected, and 90 control children aged 18 to 72 months were assessed by using the Bayley Scales of Infant Development II, Peabody Developmental Motor Scales, Snijders-Oomen Nonverbal Intelligence Test, and Rossetti Infant-Toddler Language Scale, as appropriate for age. RESULTS: Overall, 60% of HIV-infected children had severe delay in cognitive function, 29% had severe delay in motor skills, 85% had delays in language expression, and 77% had delays in language comprehension, all significantly higher rates as compared with control children. Young HIV-infected children (aged 18-29 months) performed worse, with 91% and 82% demonstrating severe mental and motor delay, respectively, compared with 46% and 4% in older HIV-infected children (aged 30-72 months). HIV-affected children had significantly more motor and language expression delay than control children. CONCLUSIONS: The impact of the HIV pandemic on children's neurodevelopment extends beyond the direct effect of the HIV virus on the central nervous system. AIDS orphans and HIV-negative children whose mothers had AIDS demonstrated significant delays in their neurodevelopment, although to a lesser degree and in fewer developmental domains than HIV-infected children. Young HIV-infected children were the most severely afflicted group, indicating the need for early interventions. Older children performed better as a result of a "survival effect," with only those children with less aggressive disease surviving.

Neurologic and neurodevelopmental manifestations of pediatric HIV/AIDS: a global perspective.

Neurodevelopmental abnormalities associated with HIV infection have been described since the first reports of pediatric AIDS in the 1980s. Before antiretroviral therapy (ART) became widely available, progressive HIV-1 encephalopathy (PHE) was reported in the US in 13-35% of children with HIV-1 infection and in 35-50% of children with AIDS. Introduction of ART can prevent PHE and reverse PHE present at ART initiation, but a high prevalence of residual problems has been described. Even though 90% of HIV-infected children live in the developing world, few children have access to ART and little is known regarding the neurological manifestations of perinatal HIV infection in those regions. Mechanisms of pediatric HIV-1 neuropathogenesis and factors associated with neurodevelopmental abnormalities in perinatally infected children are not yet fully understood. Studies have demonstrated that HIV-1 enters the CNS soon after infection and may persist in this compartment over the entire course of HIV-1 infection. The CNS is a distinct viral reservoir, differing from peripheral compartments in target cells and antiretroviral penetration. Neurotropic HIV-1 likely develops distinct genotypic characteristics in response to this unique environment. We reviewed the literature on pediatric neuroAIDS and identified gaps in the current knowledge.