Elizabeth Maleche-Obimbo

Acute cytomegalovirus infection in Kenyan HIV-infected infants.

Objective:Cytomegalovirus (CMV) coinfection may influence HIV-1 disease progression during infancy. Our aim was to describe the incidence of CMV infection and the kinetics of viral replication in Kenyan HIV-infected and HIV-exposed uninfected infants. Methods:HIV-1 and CMV plasma viral loads were serially measured in 20 HIV-exposed uninfected and 44 HIV-infected infants born to HIV-infected mothers. HIV-infected children were studied for the first 2 years of life, and HIV-exposed uninfected infants were studied for 1 year. Results:CMV DNA was detected frequently during the first months of life; by 3 months of age, CMV DNA was detected in 90% of HIV-exposed uninfected infants and 93% of infants who had acquired HIV-1 in utero. CMV viral loads were highest in the 1–3 months following the first detection of virus and declined rapidly thereafter. CMV peak viral loads were significantly higher in the HIV-infected infants compared with the HIV-exposed uninfected infants (mean 3.2 versus 2.7 log10 CMV DNA copies/ml, respectively, P = 0.03). The detection of CMV DNA persisted to 7–9 months post-CMV infection in both the HIV-exposed uninfected (8/17, 47%) and HIV-infected (13/18, 72%, P = 0.2) children. Among HIV-infected children, CMV DNA was detected in three of the seven (43%) surviving infants tested between 19 and 21 months post-CMV infection. Finally, a strong correlation was found between peak CMV and HIV-1 viral loads (ρ = 0.40, P = 0.008). Conclusion:Acute CMV coinfection is common in HIV-infected Kenyan infants. HIV-1 infection was associated with impaired containment of CMV replication.

Prevalence, perceptions, and correlates of pediatric HIV disclosure in an HIV treatment program in Kenya.

Disclosure to HIV-infected children regarding their diagnosis is important as expanding numbers of HIV-infected children attain adolescence and may become sexually active. In order to define correlates of pediatric disclosure and facilitate development of models for disclosure, we conducted a cross-sectional survey of primary caregivers of HIV-1 infected children aged 6–16 years attending a pediatric HIV treatment program in Nairobi, Kenya. We conducted focus group discussions with a subset of caregivers to further refine perceptions of disclosure. Among 271 caregiver/child dyads in the cross-sectional survey, median child age was 9 years (interquartile range: 7–12 years). Although 79% of caregivers believed children should know their HIV status, the prevalence of disclosure to the child was only 19%. Disclosure had been done primarily by health workers (52%) and caregivers (33%). Caregivers reported that 5 of the 52 (10%) who knew their status were accidentally disclosed to. Caregivers of older children (13 vs. 8 years; p<0.001), who were HIV-infected and had disclosed their own HIV status to the child (36% vs. 4%; p=0.003), or who traveled frequently (29% vs. 16%, p=0.03) were more likely to have disclosed. Children who had been recently hospitalized (25% vs. 44%, p=0.03) were less likely to know their status, and caregivers with HIV were less likely to have disclosed (p=0.03). Reasons for disclosure included medication adherence, curiosity or illness while reasons for nondisclosure included age and fear of inadvertent disclosure. Our study found that disclosure rates in this Kenyan setting are lower than observed rates in the USA and Europe but consistent with rates from other resource-limited settings. Given these low rates of disclosure and the potential benefits of disclosure, strategies promoting health worker trainings and caregiver support systems for disclosure may benefit children with HIV.

The detection of cytomegalovirus DNA in maternal plasma is associated with mortality in HIV-1 infected women and their infants

Objective:Cytomegalovirus (CMV) is an important pathogen in healthy neonates and individuals with human immunodeficiency virus (HIV-1). The objective of this study was to determine whether the detection of CMV DNA (CMV DNAemia) in maternal plasma was associated with mortality in HIV-1-infected women or their infants. Methods:A longitudinal study was designed to examine the relationship between maternal CMV DNAemia and maternal-infant mortality during 2 years postpartum. Sixty-four HIV-1-infected women and their infants were studied. CMV DNA loads were quantified in plasma from the mothers near the time of delivery. Baseline maternal CD4 cell counts, CD4%, HIV-1 RNA, and CMV DNAemia were evaluated as covariates of subsequent maternal or infant mortality in univariate and multivariate Cox regression. Results:CMV DNA was detected in 11/64 (17%) of the HIV-1-infected women. HIV-1 and CMV viral load were strongly correlated in CMV DNAemic women (ρ = 0.84, P = 0.001). Detection of CMV DNAemia was associated with decreased maternal survival at 24 months postpartum (log-rank P = 0.006). Additionally, HIV-1-infected infants born to CMV DNAemic women had a four-fold increased risk of mortality during 24 months of follow-up. Maternal CMV DNAemia remained a significant risk factor for mortality in HIV-1-infected infants after adjusting for maternal CD4 cells/μl [adjusted hazard ratio (HR) = 4.3, confidence interval (CI) = 1.4–13], CD4% (HR = 3.2, CI = 1.0–10), HIV-1 viral load (HR = 4.1, CI = 1.4–12) or maternal death (HR = 3.7, CI = 1.0–13). Conclusion:Maternal plasma CMV DNAemia identified a subgroup of Kenyan women and infants at high risk for death in the 2 years following delivery.

Correlates and outcomes of preterm birth, low birth weight, and small for gestational age in HIV-exposed uninfected infants

BackgroundPreterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA) contribute to neonatal mortality. Maternal HIV-1 infection has been associated with an increased risk of PTB, but mechanisms underlying this association are undefined. We describe correlates and outcomes of PTB, LBW, and SGA in HIV-exposed uninfected infants.MethodsThis was a retrospective analysis of cohort study. Between 1999–2002, pregnant, HIV-infected women were enrolled into an HIV-1 transmission study. Logistic regression was used to identify correlates of PTB, LBW and SGA in HIV-negative, spontaneous singleton deliveries. Associations between birth outcomes and mortality were measured using survival analyses.ResultsIn multivariable models, maternal plasma (OR = 2.1, 95% CI = 1.1-3.8) and cervical HIV-1 RNA levels (OR = 1.6, 95% CI = 1.1-2.4), and CD4 < 15% (OR = 2.4, 95% CI = 1.0-5.6) were associated with increased odds of PTB. Abnormal vaginal discharge and cervical polymorphonuclear leukocytes were also associated with PTB. Cervical HIV-1 RNA level (OR = 2.4, 95% CI = 1.5-6.7) was associated with an increased odds of LBW, while increasing parity (OR = 0.46, 95% CI = 0.24-0.88) was associated with reduced odds. Higher maternal body mass index (OR = 0.75, 95% CI = 0.61-0.92) was associated with a reduced odds of SGA, while bacterial vaginosis was associated with >3-fold increased odds (OR = 3.2, 95% CI = 1.4-7.4). PTB, LBW, and SGA were each associated with a >6-fold increased risk of neonatal death, and a >2-fold increased rate of infant mortality within the first year.ConclusionsMaternal plasma and cervical HIV-1 RNA load, and genital infections may be important risk factors for PTB in HIV-exposed uninfected infants. PTB, LBW, and SGA are associated with increased neonatal and infant mortality in HIV-exposed uninfected infants.

Clinical and Virologic Manifestations of Primary Epstein-Barr Virus (EBV) Infection in Kenyan Infants Born to HIV-Infected Women

BACKGROUND Human immunodeficiency virus (HIV) infection is a risk factor for Epstein-Barr virus (EBV)-associated lymphomas. Characterizing primary infection may elucidate risk factors for malignancy. METHODS To describe clinical and virologic manifestations of primary EBV infection among infants born to HIV-infected women, specimens were utilized from a cohort study conducted in Nairobi, Kenya. HIV and EBV viral loads were measured serially in plasma. EBV serology was performed on EBV DNA-negative infants. Monthly clinical examinations were performed by pediatricians. RESULTS The probability of EBV infection by 1 year of age was .78 (95% CI, .67-.88) in HIV-infected and .49 (95% CI, .35-.65) in HIV-uninfected infants (P < .0001). At 2 years, probability of EBV infection was .96 (95% CI, .89-.99) in HIV-infected infants. Peak EBV loads were higher in HIV-infected versus HIV-uninfected infants (median 2.6 vs 2.1 log10 copies/mL; P < .0001). The majority of HIV-infected infants had detectable EBV DNA for >3 months (79%). Primary EBV infection was associated with cough, fever, otitis media, pneumonia, hepatomegaly, splenomegaly, and hospitalization in HIV-infected infants; conjunctivitis and rhinorrhea in HIV-uninfected infants. CONCLUSIONS EBV infection occurs early in infants born to HIV-infected women. HIV infection was associated with more frequent and higher quantity EBV DNA detection.

Long-term virologic response and genotypic resistance mutations in HIV-1 infected Kenyan children on combination antiretroviral therapy.

Background:HIV-infected children may require the use of combination antiretroviral treatment (cART) into adulthood. However, regimens are limited to first line and second line in many African settings. Therefore, understanding the long-term rate of virologic failure and drug resistance during prolonged antiretroviral treatment is important for establishing treatment strategies in African pediatric cohorts. Methods:Children aged 18 months to 12 years initiated first-line cART and were followed every 1–3 months, for up to 5.5 years. Treatment was switched to second-line cART based on clinical and immunologic criteria according to national guidelines. Virologic failure was determined retrospectively as defined by ≥2 viral loads >5000 copies per milliliter. Drug resistance was assessed during viral failure by population-based sequencing. Results:Among 100 children on first-line cART followed for a median of 49 months, 34% children experienced virologic failure. Twenty-three (68%) of the 34 children with viral failure had detectable resistance mutations, of whom 14 (61%) had multiclass resistance. Fourteen (14%) children were switched to second-line regimens and followed for a median of 28 months. Retrospective analysis revealed that virologic failure had occurred at a median of 12 months before switching to second line. During prolonged first-line treatment in the presence of viral failure, additional resistance mutations accumulated; however, only 1 (7%) of 14 children had persistent viremia during second-line treatment. Discussion:Virologic suppression was maintained on first-line cART in two-thirds of HIV-infected children for up to 5 years. Switch to second line based on clinical/immunologic criteria occurred ∼1 year after viral failure, but the delay did not consistently compromise second-line treatment.

Using health provider insights to inform pediatric HIV disclosure: a qualitative study and practice framework from Kenya

Optimal pediatric HIV disclosure impacts illness and developmental experiences while improving access to timely treatment. However, disclosure rates in high HIV prevalence countries remain low and there are limited data on best practices. We conducted a qualitative study of disclosure practices and interviewed healthcare providers from five pediatric HIV clinics in Kenya. We identified themes central to disclosure practices, rationale for approaches, barriers to implementing disclosure, and creative strategies to overcome challenges. We used these insights to develop a practice-based framework for disclosure that is sensitive to practical challenges. Overall, providers had limited training but extensive experience in disclosure, endorsed individualized disclosure practices, invested substantial time on disclosure despite clinical burden, and noted adverse outcomes associated with unplanned or abrupt disclosure. Providers advocated for an approach to disclosure that is child-centered but respects caregiver fears and values. Caregiver support was provided to enable caregivers to be the person who ultimately disclosed HIV status to children. Unplanned or abrupt disclosure to children was reported to have severe and persistent adverse impact and was a stimulus to accelerate disclosure in scenarios when providers believed children may be suspecting their diagnosis. Based on these expert insights, the framework we developed incorporates concurrent evaluation of child and caregiver readiness, identifies cues to prompt disclosure discussions, includes caregiver education and support, and utilizes a gradual approach of unveiling HIV diagnosis to the child.

Breastfeeding is associated with decreased pneumonia incidence among HIV-exposed, uninfected Kenyan infants

Objective:HIV-exposed uninfected (HEU) infants have higher infectious disease morbidity and mortality than unexposed infants. We determined the incidence and risk factors for pneumonia, a leading cause of infant mortality worldwide, in a cohort of HEU infants. Identifying predictors of pneumonia among HEU infants may enable early identification of those at highest risk. Design:A retrospective cohort of HEU infants participating in a Kenyan perinatal HIV study, enrolled between 1999 and 2002. Methods:Infants were followed monthly from birth to 12 months. Incidence of pneumonia diagnosed at monthly study visits, sick-child visits or by means of averbal autopsy was estimated with a 14-day window for new episodes. Cox proportional hazards regression was used to identify predictors of first pneumonia occurrence. Results:Among 388 HEU infants with 328 person-years of follow-up, the incidence of pneumonia was 900/1000 child-years [95% confidence interval (CI) 800–1000]. Maternal HIV viral load at 32 weeks’ gestation [hazard ratio 1.2 (1.0–1.5) per log10 difference] and being underweight (weight-for-age Z-score <−2) at the previous visit [hazard ratio 1.8 (1.1–2.8)] were associated with increased risk of pneumonia. Breastfed infants had a 47% lower risk of pneumonia than those never breastfed [hazard ratio 0.53 (0.39–0.73)], independent of infant growth, maternal viral load and maternal CD4%. Breastfeeding was also associated with a 74% lower risk of pneumonia-related hospitalization [hazard ratio 0.26 (0.13–0.53)]. Conclusions:The incidence of pneumonia in this cohort of HEU infants was high. Our observations suggest that maternal viral suppression and breastfeeding may reduce the burden of pneumonia among HEU infants.

Oral Amoxicillin Versus Benzyl Penicillin for Severe Pneumonia Among Kenyan Children: A Pragmatic Randomized Controlled Noninferiority Trial

Evidence demonstrating noninferiority of oral amoxicillin vs benzyl penicillin for severe childhood pneumonia is largely drawn from Asian populations where mortality is low. This study confirms noninferiority and is expected to inform policy on treatment of pneumonia in sub-Saharan Africa.

Breast milk cellular HIV-specific interferon γ responses are associated with protection from peripartum HIV transmission.

Objective:Breast milk is a major route of infant HIV infection, yet the majority of breast-fed, HIV-exposed infants escape infection by unknown mechanisms. This study aimed to investigate the role of HIV-specific breast milk cells in preventing infant HIV infection. Design:A prospective study was designed to measure associations between maternal breast milk HIV-specific interferon-&ggr; (IFN-&ggr;) responses and infant HIV-1 detection at 1 month of age. Methods:In a Kenyan cohort of HIV-infected mothers, blood and breast milk HIV-gag IFN-&ggr; ELISpot responses were measured. Logistic regression was used to measure associations between breast milk IFN-&ggr; responses and infant HIV infection at 1 month of age. Results:IFN-&ggr; responses were detected in breast milk from 117 of 170 (69%) women. IFN-&ggr; responses were associated with breast milk viral load, levels of macrophage inflammatory protein (MIP) 1&agr;, MIP-1&bgr;, regulated upon activation, normal T-cell expressed, and secreted and stromal-cell derived factor 1 and subclinical mastitis. Univariate factors associated with infant HIV infection at 1 month postpartum included both detection and breadth of breast milk IFN-&ggr; response (P = 0.08, P = 0.04, respectively), breast milk MIP-1&bgr; detection (P = 0.05), and plasma (P = 0.004) and breast milk (P = 0.004) viral load. In multivariate analyses adjusting for breast milk viral load and MIP-1&bgr;, breast milk IFN-&ggr; responses were associated with an approximately 70% reduction in infant HIV infection [adjusted odds ratio (aOR) 0.29, 95% confidence interval (CI) 0.092–0.91], and each additional peptide pool targeted was associated with an approximately 35% reduction in infant HIV (aOR 0.65, 95% CI 0.44–0.97). Conclusion:These data show breast milk HIV-gag-specific IFN-&ggr; cellular immune responses are prevalent and may contribute to protection from early HIV transmission. More broadly, these data suggest breast milk cellular responses are potentially influential in decreasing mother-to-child transmission of viruses.