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1.  Breastfeeding is associated with decreased pneumonia incidence among HIV-exposed, uninfected Kenyan infants 
AIDS (London, England)  2013;27(17):2809-2815.
HIV-exposed uninfected infants (HEU) 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.
A retrospective cohort of HEU participating in a Kenyan perinatal HIV study, enrolled between 1999-2002.
Infants were followed monthly from birth to 12 months. Incidence of pneumonia diagnosed at monthly study visits, sick-child visits or by means of a verbal autopsy, was estimated with a 14-day window for new episodes. Cox proportional hazards regression was used to identify predictors of first pneumonia occurrence.
Among 388 HEU infants with 328 person-years of follow-up, the incidence of pneumonia was 900/1,000 child-years (95% CI: 800-1,000). Maternal HIV viral load at 32 weeks gestation [HR=1.2 (1.0-1.5) per log10 difference] and being underweight (weight-for-age Z-score <-2) at the previous visit [HR=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 [HR=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 (HR=0.26 (0.13-0.53)).
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.
PMCID: PMC4084504  PMID: 23921609
HIV-exposed uninfected; infants; morbidity; breastfeeding; pneumonia
2.  Toll-like Receptor (TLR) variants are associated with infant HIV-1 acquisition and peak plasma HIV-1 RNA level 
AIDS (London, England)  2013;27(15):2431-2439.
We evaluated the association of single nucleotide polymorphisms (SNPs) in TLRs with infant HIV-1 acquisition and viral control.
Infant HIV-1 outcomes were assessed in a Kenyan perinatal HIV-1 cohort.
Infants were genotyped for six candidate and 118 haplotype-tagging polymorphisms in TLRs 2, 3, 4, 7, 8, and 9, MYD88 and TIRAP. Cox proportional hazards and linear regression were performed to assess associations with time to HIV-1 acquisition, time to infant mortality, and peak viral load (VL).
Among 368 infants, 56 (15%) acquired HIV-1 by month 1 and 17 (4.6%) between 1 and 12 months. Infants with the TLR9 1635A (rs352140) variant were more likely to acquire HIV-1 by 1 month (HR=1.81, 95% confidence interval [CI] =1.05-3.14, p=0.033) and by 12 months (HR=1.62, CI=1.01-2.60, p=0.044) in dominant models adjusted for maternal plasma HIV-1 RNA level and genetic ancestry. Among 56 infants infected at ≤1 month of age, ≥1 copy of the TLR9 1635A allele was associated with a 0.58 log10 c/ml lower peak VL (p=0.002). Female infants with ≥1 copy of the TLR8 1G (rs3764880) variant had a 0.78 log10 c/ml higher peak VL (p=0.0009) and having ≥1 copy of the C allele for a haplotype tagging TLR7 variant (rs1634319) was associated with a 0.80 log10 c/ml higher peak VL in female infants (p=0.0003).
In this African perinatal cohort, we found several TLR polymorphisms associated with HIV-1 acquisition and progression. Defining mechanisms for these TLR associations may inform HIV-1 prevention strategies that leverage innate responses.
PMCID: PMC4124859  PMID: 24037211
pediatric HIV; mother-to-child transmission; genetic epidemiology; HIV genetics; innate immunity; single nucleotide polymorphisms; toll-like receptors; TLRs
3.  Prevalence, Perceptions and Correlates of Pediatric HIV Disclosure in an HIV Treatment Program in Kenya 
AIDS care  2012;25(9):1067-1076.
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 to 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 (IQR: 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 non-disclosure included age and fear of inadvertent disclosure.
Our study found that disclosure rates in this Kenyan setting are lower than observed rates in the United States 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.
PMCID: PMC3626761  PMID: 23256520
disclosure; pediatric; HIV; stigma; adherence
4.  Mode of delivery and postpartum HIV-1 disease progression and mortality in a Kenyan cohort 
There are limited data on the impact of cesarean section delivery on HIV-1 infected women in Sub-Saharan Africa. The purpose of this study was to assess the effect of mode of delivery on HIV-1 disease progression and postpartum mortality in a Kenyan cohort.
A prospective cohort study was conducted in Nairobi, Kenya from 2000–2005. We determined changes in CD4+ counts, HIV-1 RNA levels and mortality during the first year postpartum between HIV-1 infected women who underwent vaginal delivery (VD), non-scheduled cesarean section (NSCS) and scheduled cesarean section (SCS) and received short-course zidovudine. Loess curves and multivariate linear mixed effects models were used to compare longitudinal changes in maternal HIV-1 RNA and CD4+ counts by mode of delivery. Kaplan Meier curves, the log rank test, and Cox proportional hazards regression were used to assess difference in mortality.
Of 501 women, 405 delivered by VD, 74 delivered by NSCS and 22 by SCS. Baseline characteristics were similar between the VD and NSCS groups. Baseline antenatal CD4+ counts were lowest and HIV-1 RNA levels highest in the NSCS group but HIV-1 RNA levels were similar between groups at delivery. The rate of decline in CD4+ cells and rate of increase in HIV-1 RNA did not differ between groups. After adjusting for confounders, women who underwent NSCS had a 3.39-fold (95% CI 1.11, 10.35, P = 0.03) higher risk of mortality in the first year postpartum compared to women with VD.
Non-scheduled cesarean section was an independent risk factor for postpartum mortality in HIV-1 positive Kenyan women. The cause of death was predominantly due to HIV-1 related infections, and not direct maternal deaths, however, this was not mirrored by differential changes in HIV-1 progression markers between the groups.
PMCID: PMC4133616  PMID: 25086834
HIV; Mode of delivery; Cesarean section; HIV-1 disease progression; Maternal mortality
5.  Performance of the Integrated Management of Childhood Illness (IMCI) Algorithm for Diagnosis of HIV-1 Infection among Kenyan Infants 
AIDS (London, England)  2012;26(15):1935-1941.
Early infant HIV-1 diagnosis and treatment substantially improve survival. Where virologic HIV-1 testing is unavailable, Integrated Management of Childhood Illness (IMCI) clinical algorithms may be used for infant HIV-1 screening. We evaluated the performance of the 2008 WHO IMCI HIV algorithm in a cohort of HIV-exposed Kenyan infants.
From 1999–2003, 444 infants had monthly clinical assessments and quarterly virologic HIV-1 testing. Using archived clinical data, IMCI sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated using virologic testing as a gold standard. Linear regression and survival analyses were used to determine the effect of age on IMCI performance and timing of diagnosis.
Overall IMCI sensitivity, specificity, PPV, and NPV value were 58%, 87%, 52%, and 90%, respectively. Sensitivity (1.4%) and PPV (14%) were lowest at 1 month of age, when 81% of HIV-infections already had occurred. Sensitivity increased with age (p<0.0001), but remained low throughout infancy (range=1.4–35%). Specificity (range=97–100%) was high at each time point and was not associated with age. Fifty-eight percent of HIV-1 infected infants (50/86) were eventually diagnosed by IMCI, and use of IMCI was estimated to delay diagnosis in HIV-infected infants by a median of 5.9 months (p<0.0001).
IMCI had low sensitivity during the first month of life, when the majority of HIV-1 infections had already occurred, and initiation of treatment is most critical. Although sensitivity increased with age, the substantial delay in HIV-1 diagnosis using IMCI limits its utility in early infant HIV-1 diagnosis.
PMCID: PMC4113472  PMID: 22824627
IMCI; HIV; infant; Africa; clinical algorithm; pediatric
6.  Lipid Changes in Kenyan HIV-1-Infected Infants Initiating Highly Active Antiretroviral Therapy by One Year of Age 
Early highly active antiretroviral therapy (HAART) is recommended for HIV-1 infected infants. There are limited data on lipid changes during infant HAART.
Non-fasting total (TC), low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol, and triglycerides (TG) were measured at 0, 6 and 12 months. Correlates of lipid levels and changes post-HAART were assessed using linear regression.
Among 115 infants, pre-HAART median age was 3.8 months, CD4% was 19%, and weight-for-age z-score (WAZ) was −2.42. Pre-HAART median lipid levels were: TC, 108.7 mg/dl, LDL, 42.5 mg/dl, HDL, 29.4 mg/dl and TG, 186.9 mg/dl. Few infants had abnormally high TC (6.2%) or LDL (5.6%), but many had low HDL (76.5%) or high TG (69.6%). Higher pre-HAART WAZ and HAZ were each associated with higher pre-HAART TC (P=0.04 and P=0.01) and LDL (P=0.02 and P=0.008). From 0–6 months post-HAART, TC (P<0.0001), LDL (P<0.0001), and HDL (P<0.0001) increased significantly, and 23.1% (P=0.002), 14.0% (P=0.2), 31.3% (P<0.0001), and 50.8% (P=0.2) of infants had abnormally high TC, high LDL, low HDL, and high TG, respectively. Changes in TC and HDL were each associated with higher gain in WAZ (P=0.03 and P=0.01) and HAZ (P=0.01 and P=0.007). Increased change in LDL was associated with higher gain in HAZ (P=0.03). Infants on protease inhibitor (PI)-HAART had smaller HDL increase (P=0.004).
Infants had substantive increases in lipids, which correlated with growth. Increases in HDL were attenuated by PI-HAART. It is important to determine clinical implications of these changes.
PMCID: PMC3737429  PMID: 23385950
lipids; pediatric HIV-1; highly active antiretroviral therapy; infants; Africa
7.  Pooled HIV-1 RNA Viral Load Testing for Detection of Antiretroviral Treatment Failure in Kenyan children 
Pooled viral load (VL) testing with two different testing strategies was evaluated as a potential cost-saving method to monitor antiretroviral therapy (ART) in HIV-infected children receiving ART in a resource-limited setting.
Archived samples collected from 250 HIV-1 infected children on first-line ART at various time-points post-ART initiation were evaluated for pooled VL testing using a minipool+algorithm strategy. Additionally, samples collected in real-time from 125 children on ART were assessed for virologic failure using a minipool strategy for pooled viral load testing. Virologic failure was determined as HIV-1 RNA viral loads >1500 copies/ml.
Minipool+algorithm strategy for pooled VL testing of archived samples had estimated viral failure of 13.6%, with a relative efficiency (RE) of 23.6% (95% CI; 18.5, 29.4), and negative predictive value (NPV) of 88%. This testing strategy would have resulted in 24% fewer assays needed, for a cost savings of $1,180 per 100 samples. The minipool strategy for pooled viral load testing of samples obtained in real-time yielded an estimated 23.2% of samples with viral failure and a RE of 8.0 % (95% CI; 3.9, 14.2); however had a minipool+algorithm pooling strategy been used the RE would increase to 20%.
The minipool+algorithm strategy for pooled VL testing to detect virologic failure in HIV-1 infected children on ART was determined to be relatively efficient in detecting virologic failure, had high NPV, with substantial cost savings. Pooling strategies may be important components of cost-effect strategies to reduce rates of viral failure and resistance, thus improving clinical outcomes.
PMCID: PMC3767042  PMID: 23542638
8.  Evaluating the level of adherence to Ministry of Health guidelines in the management of Severe Acute Malnutrition at Garissa Provincial General hospital, Garissa, Kenya 
Half of Kenya's high infant and under five mortality rates is due to malnutrition. Proper implementation of World Health Organization's (WHO) Evidence Based Guidelines (EBG) in management of severe acute malnutrition can reduce mortality rates to less than 5%. The objectives were to establish the level of adherence to WHO guideline and the proportion of children appropriately managed for severe acute malnutrition (steps 1-8) as per the WHO protocol in the management of severe acute malnutrition. This was a short longitudinal study of 96 children, aged 6-59 months admitted to the pediatric ward with diagnosis of severe acute malnutrition.
Data was extracted from patients’ medical files and recorded into an audit tool to compare care provided in this hospital with WHO guidelines.
Non-edematous malnutrition was the commonest presentation (93.8%). A higher proportion (63.5%) of patients was male. Most (85.4%) of patients were younger than 2 years. Patients with non-edematous malnutrition were younger (mean age for non-edematous malnutrition was 16 (± 10.6) months versus 25 (± 13.7) months in edematous malnutrition). The commonest co- morbid condition was diarrhea (52.1%). Overall, 13 children died giving an inpatient case fatality rate of 13.5%. Appropriate management was documented in only 14.6% for hypoglycemia (step1), 5.2% for hypothermia (step 2) and 31.3% for dehydration (step 3).
The level of adherence to MOH guidelines was documented in 5 out of the 8 steps. Appropriate management of children with severe acute malnutrition was inadequate at Garissa hospital.
PMCID: PMC4163184  PMID: 25237411
Severe malnutrition; adherence; audit; WHO guidelines
9.  Prevalence of hearing loss in children following bacterial meningitis in a tertiary referral hospital 
BMC Research Notes  2014;7:138.
This study aimed to examine hearing function in a group of children aged between the ages of six months and twelve years admitted with bacterial meningitis so as to determine the prevalence and degree of sensorineural hearing loss in them. This prospective study was conducted in the audiology unit and paediatric wards of Kenyatta National Hospital, KNH.
The study involved 83 children (49 males and 34 females) between the ages of six months and twelve years admitted with bacterial meningitis. The median age for the children examined was 14 months (range from 5 to 120 months). They were sequentially recruited and at discharge following treatment, underwent age-appropriate hearing testing to evaluate presence and degree of hearing loss which was analyzed. The study was limited by the absence of otoacoustic emission and auditory brainstem responses testing by excluding the significant numbers of children below six months of age admitted with bacterial meningitis.
Thirty six of the 83 children (44.4%) were found to have at least a unilateral mild sensorineural hearing loss during initial audiologic testing. Of the children with hearing loss, 22 (26.5%) had mild or moderate sensorineural hearing loss and 14 (16.9%) had severe or profound sensorineural hearing loss.
Sensorineural hearing loss was shown to be highly prevalent in children treated for bacterial meningitis. There is therefore a need for objective hearing assessment in infants and young children following bacterial meningitis and further studies involving larger population sizes.
PMCID: PMC3975328  PMID: 24618106
Hearing tests; Kenyatta national hospital; Sensorineural hearing loss (SNHL); Coma score; Seizures; Cranial nerve neuropathy; Positive CSF culture; Fever
10.  Long-term Virologic Response and Genotypic Resistance Mutations in HIV-1 Infected Kenyan Children on Combination Antiretroviral Therapy 
HIV-infected children may require the use of combination antiretroviral treatment (cART) into adulthood. However, regimens are limited to first- 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.
Children ages 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 based on clinical and immunologic criteria according to national guidelines. Virologic failure was determined retrospectively as defined by ≥2 viral loads >5000 copies/mL. Drug resistance was assessed during viral failure by population-based sequencing.
Among 100 children on first-line cART followed for a median 49 months, 34% experienced virologic failure. Twenty-three (68%) of the 34 children with viral failure had detectable resistance mutations, of whom 14 (61%) had multi-class 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 a median of 12 months prior to the switch 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.
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.
PMCID: PMC3593972  PMID: 23196827
11.  Survival Benefit of Early Infant Antiretroviral Therapy is Compromised when Diagnosis is Delayed 
Late presentation is common among African HIV-1-infected infants. Incidence and correlates of mortality were examined in 99 infants with HIV-1 diagnosis by age 5 months. Twelve-month survival was 66.8% (95% confidence interval, 55.9%, 75.6%). WHO stage 3/4, underweight, wasting, microcephaly, low hemoglobin, pneumonia, and gastroenteritis predicted mortality. Early HIV-1 diagnosis with ART before symptomatic disease is critical for infant survival.
PMCID: PMC3756892  PMID: 22544051
Pediatric; Infant; HIV-1; Antiretroviral therapy; Mortality
12.  Breast milk cellular HIV-specific interferon γ responses are associated with protection from peripartum HIV transmission 
AIDS (London, England)  2012;26(16):2007-2016.
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.
A prospective study was designed to measure associations between maternal breast milk HIV-specific interferon-γ (IFN-γ) responses and infant HIV-1 detection at 1 month of age.
In a Kenyan cohort of HIV-infected mothers, blood and breastmilk HIV-gag IFN-γ ELISpot responses were measured. Logistic regression was used to measure associations between breast milk IFN-γ responses and infant HIV infection at 1 month of age.
IFN-γ responses were detected in breast milk from 117 of 170 (69%) women. IFN-γ responses were associated with breast milk viral load, levels of macrophage inflammatory protein (MIP) 1α, MIP-1β, 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-γ response (P =0.08, P =0.04, respectively), breast milk MIP-1β 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-1β, breast milk IFN-γ 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).
These data show breast milk HIV-gag-specific IFN-γ 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.
PMCID: PMC3718292  PMID: 22948269
breastfeeding; breast milk cytotoxic T lymphocytes; cytokines; early postnatal transmission; infant; MIP-1β; pediatric; sub-Saharan Africa
13.  Risk Factors for Hearing Loss in Children following Bacterial Meningitis in a Tertiary Referral Hospital 
Objective. This study aimed to examine hearing function in children admitted with bacterial meningitis to determine the risk factors for sensorineural hearing loss. Setting. The study was conducted in the audiology unit and paediatric wards of Kenyatta National Hospital. Subjects and Methods. The study involved 83 children between the ages of six months and twelve years admitted with bacterial meningitis. The median age for the children examined was 14. On discharge they underwent hearing testing to evaluate for presence and degree of hearing loss. Results. Thirty six of the 83 children (44.4%) were found to have at least a unilateral mild sensorineural hearing loss during initial audiologic testing. Of the children with hearing loss, 22 (26.5%) had mild or moderate sensorineural hearing loss and 14 (16.9%) had severe or profound sensorineural hearing loss. Significant determinants identified for hearing loss included coma score below eight, seizures, cranial nerve neuropathy, positive CSF culture, and fever above 38.7 degrees Celsius. Conclusions. Sensorineural hearing loss was found to be highly prevalent in children treated for bacterial meningitis. There is need to educate healthcare providers on aggressive management of coma, fever, and seizures due to their poor prognostic value on hearing.
PMCID: PMC3671307  PMID: 23762065
14.  Maternal Human Leukocyte Antigen - A*2301 Is Associated with Increased Mother-to-Child HIV-1 Transmission 
The Journal of infectious diseases  2010;202(8):1273-1277.
We examined associations between maternal HLA and vertical HIV-1 transmission in a perinatal cohort of 277 HIV-infected women in Nairobi. HLA class I genes were amplified using sequence-specific oligonucleotide probes and analyses were performed using logistic regression. Maternal A*2301 was associated with increased transmission risk before and after adjusting for maternal viral load (odds ratio [OR]=3.21; 95% CI: 1.42, 7.27, p=0.005, pcorr=0.04; adjusted OR=3.07; 95% CI: 1.26, 7.51, p=0.01, pcorr=NS). That maternal HLA-A*2301 was associated with transmission independent of plasma HIV-1 RNA levels, suggests that HLA may alter infectivity through mechanisms other than influencing HIV-1 viral load.
PMCID: PMC3404885  PMID: 20812845
Human immunodeficiency virus; vertical HIV-1 transmission; human leukocyte antigen
15.  High Uptake of Postpartum Hormonal Contraception Among HIV-1-Seropositive Women in Kenya 
Sexually Transmitted Diseases  2007;34(1):25-29.
The objectives of this study were to determine patterns of contraceptive utilization among sexually active HIV-1-seropositive women postpartum and to identify correlates of hormonal contraception uptake.
The goal of this study was to improve delivery of family planning services to HIV-1-infected women in resource-limited settings.
Study Design
HIV-1-infected pregnant women were followed prospectively in a perinatal HIV-1 transmission study. Participants were referred to local clinics for contraceptive counseling and management.
Among 319 HIV-1-infected women, median time to sexual activity postpartum was 2 months and 231 (72%) women used hormonal contraception for at least 2 months during follow-up, initiating use at approximately 3 months postpartum (range, 1–11 months). Overall, 101 (44%) used DMPA, 71 (31%) oral contraception, and 59 (25%) switched methods during follow-up. Partner notification, infant mortality, and condom use were similar between those using and not using contraception.
Using existing the healthcare infrastructure, it is possible to achieve high levels of postpartum hormonal contraceptive utilization among HIV-1-seropositive women.
PMCID: PMC3387272  PMID: 16691159
16.  Breast Milk α-Defensins Are Associated with HIV Type 1 RNA and CC Chemokines in Breast Milk But Not Vertical HIV Type 1 Transmission 
α-Defensins are proteins exhibiting in vitro anti-HIV-1 activity that may protect against mother-to-child transmission of HIV-1 via breast milk. Correlates of α-defensins in breast milk and transmission risk were determined in a cohort of HIV-1-infected pregnant women in Nairobi followed for 12 months postpartum with their infants. Maternal blood was collected antenatally and at delivery for HIV-1 viral load and infant HIV-1 infection status was determined <48 h after birth and at months 1, 3, 6, 9, and 12. Breast milk specimens collected at month 1 were assayed for α-defensins, HIV-1 RNA, subclinical mastitis, and CC and CXC chemokines. We detected α-defensins in breast milk specimens from 108 (42%) of 260 HIV-1-infected women. Women with detectable α-defensins (≥50 pg/ml) had a median concentration of 320 pg/ml and significantly higher mean breast milk HIV-1 RNA levels than women with undetectable α-defensins (2.9 log10 copies/ml versus 2.5 log10 copies/ml, p = 0.003). Increased α-defensins concentrations in breast milk were also associated with subclinical mastitis (Na+/K+ ratio > 1) and increased breast milk chemokine levels. Overall, 40 (15%) infants were HIV-1 uninfected at birth and subsequently acquired HIV-1. There was no significant association between month 1 α-defensins and risk of HIV-1 transmission. In conclusion, α-defensins were associated with breast milk HIV-1 viral load, chemokine levels, and subclinical mastitis, all of which may alter risk of infant HIV-1 acquisition. Despite these associations there was no significant relationship between breast milk α-defensins and mother-to-child transmission, suggesting a complex interplay between breast milk HIV-1, inflammation, and antiinfective factors.
PMCID: PMC3382116  PMID: 17331027
17.  Early Response to Highly Active Antiretroviral Therapy in HIV-1–Infected Kenyan Children 
To describe the early response to World Health Organization (WHO)–recommended nonnucleoside reverse transcriptase inhibitor (NNRTI)–based first-line highly active antiretroviral therapy (HAART) in HIV-1–infected Kenyan children unexposed to nevirapine.
Observational prospective cohort.
HIV-1 RNA level, CD4 lymphocyte count, weight for age z score, and height for age z score were measured before the initiation of HAART and every 3 to 6 months thereafter. Children received no nutritional supplements.
Sixty-seven HIV-1–infected children were followed for a median of 9 months between August 2004 and November 2005. Forty-seven (70%) used zidovudine, lamivudine (3TC), and an NNRTI (nevirapine or efavirenz), whereas 25% used stavudine (d4T), 3TC, and an NNRTI. Nevirapine was used as the NNRTI by 46 (69%) children, and individual antiretroviral drug formulations were used by 63 (94%), with only 4 (6%) using a fixed-dose combination of d4T, 3TC, and nevirapine (Triomune; Cipla, Mumbai, India). In 52 children, the median height for age z score and weight for age z score rose from −2.54 to −2.17 (P < 0.001) and from −2.30 to −1.67 (P = 0.001), respectively, after 6 months of HAART. Hospitalization rates were significantly reduced after 6 months of HAART (17% vs. 58%; P < 0.001). The median absolute CD4 count increased from 326 to 536 cells/μL (P < 0.001), the median CD4 lymphocyte percentage rose from 5.8% before treatment to 15.4% (P < 0.001), and the median viral load fell from 5.9 to 2.2 log10 copies/mL after 6 months of HAART (P < 0.001). Among 43 infants, 47% and 67% achieved viral suppression to less than 100 copies/mL and 400 copies/mL, respectively, after 6 months of HAART.
Good early clinical and virologic response to NNRTI-based HAARTwas observed in HIV-1–infected Kenyan children with advanced HIV-1 disease.
PMCID: PMC3380073  PMID: 17356470
antiretroviral; children; HIV-1; response
18.  Morbidity Among HIV-1–Infected Mothers in Kenya 
Much of the burden of morbidity affecting women of childbearing age in sub-Saharan Africa occurs in the context of HIV-1 infection. Understanding patterns of illness and determinants of disease in HIV-1–infected mothers may guide effective interventions to improve maternal health in this setting.
We describe the incidence and cofactors of comorbidities affecting peripartum and postpartum HIV-1–infected women in Kenya. Women were evaluated by clinical examination and standardized questionnaires during pregnancy and for up to 2 years after delivery.
Five hundred thirty-five women were enrolled in the cohort (median CD4 count of 433 cells/mm3) and accrued 7736 person-months of follow-up. During 1-year follow-up, the incidence of upper respiratory tract infections was 161 per 100 person-years, incidence of pneumonia was 33 per 100 person-years, incidence of tuberculosis (TB) was 11 per 100 person-years, and incidence of diarrhea was 63 per 100 person-years. Immunosuppression and HIV-1 RNA levels were predictive for pneumonia, oral thrush, and TB but not for diarrhea; CD4 counts <200 cells/mm3 were associated with pneumonia (relative risk [RR] = 2.87, 95% confidence interval [CI]: 1.71 to 4.83), TB (RR = 7.14, 95% CI: 2.93 to 17.40) and thrush. The risk of diarrhea was significantly associated with crowding (RR = 1.86, 95% CI: 1.19 to 2.92) and breast-feeding (RR = 1.71, 95% CI: 1.19 to 2.44). Less than 10% of women reported hospitalization during 2-year follow-up; mortality risk in the cohort was 1.9% and 4.8% for 1 and 2 years, respectively.
Mothers with HIV-1, although generally healthy, have substantial morbidity as a result of common infections, some of which are predicted by immune status or by socioeconomic factors. Enhanced attention to maternal health is increasingly important as HIV-1–infected mothers transition from programs targeting the prevention of mother-to-child transmission to HIV care clinics.
PMCID: PMC3372412  PMID: 17667334
HIV/AIDS; HIV-1 progression; maternal health; morbidity; postpartum; pregnancy; prevention of mother-to-child transmission; women
19.  Consistency of Mycobacterium tuberculosis-Specific Interferon-Gamma Responses in HIV-1-Infected Women during Pregnancy and Postpartum 
Background. We determined the consistency of positive interferon-gamma (IFN-γ) release assays (IGRAs) to detect latent TB infection (LTBI) over one-year postpartum in HIV-1-infected women. Methods. Women with positive IGRAs during pregnancy had four 3-monthly postpartum IGRAs. Postpartum change in magnitude of IFN-γ response was determined using linear mixed models. Results. Among 18 women with positive pregnancy IGRA, 15 (83%) had a subsequent positive IGRA; 9 (50%) were always positive, 3 (17%) were always negative, and 6 (33%) fluctuated between positive and negative IGRAs. Women with pregnancy IGRA IFN-γ>8 spot forming cells (SFCs)/well were more likely to have consistent postpartum IGRA response (odds ratio: 10.0; 95% confidence interval (CI): 0.9–117.0). Change in IFN-γ response over postpartum was 10.2 SFCs/well (95% CI: −1.5–21.8 SFCs/well). Conclusion. Pregnancy positive IGRAs were often maintained postpartum with increased consistency in women with higher baseline responses. There were modest increases in magnitude of IGRA responses postpartum.
PMCID: PMC3312220  PMID: 22496602
20.  Latent TB detection by interferon gamma release assay (IGRA) in pregnancy predicts active TB and mortality in HIV-1 infected women and their children 
The Journal of infectious diseases  2010;202(12):1826-1835.
We evaluated the prognostic utility of interferon-gamma release assays (IGRAs) for active tuberculosis (TB) and mortality in Kenyan HIV-1 infected women and their infants.
Prevalence and correlates of Mycobacterium tuberculosis-specific T-SPOT.TB IGRA positivity were determined during pregnancy in a historical cohort of HIV-1 infected women. Hazard ratios, adjusted for baseline maternal CD4 count (aHRCD4) were calculated for associations between IGRA positivity and risk of active TB and mortality over 2-year postpartum follow-up in women and their infants.
Of 333 women tested, 52 (15.6%) had indeterminate IGRAs. Of the remaining 281 women, 120 (42.7%) had positive IGRAs, which were associated with a 4.5-fold increased risk of active TB [aHRCD4: 4.5; 95% confidence interval (CI): 1.1–18.0; p=0.03]. Among immunosuppresed women (CD4<250 cell/mm3), positive IGRAs were associated with increased risk of maternal mortality (aHRCD4: 3.5; 95% CI: 1.02–12.1; p=0.045), maternal active TB or mortality (aHRCD4: 5.2; 95% CI: 1.7–15.6; p=0.004) and infant active TB or mortality, overall (aHRCD4: 3.0; 95% CI: 1.0–8.9; p= 0.05) and in HIV-1 exposed uninfected infants (aHRCD4: 7.3; 95% CI: 1.6–33.5; p =0.01).
Positive IGRAs in HIV-1 infected pregnant women were associated with postpartum active TB and mortality in mothers and their infants.
PMCID: PMC3058232  PMID: 21067370
Latent tuberculosis infection; HIV-1; women; infants; T-SPOT.TB; IGRA
21.  Latent Tuberculosis Detection by Interferon γ Release Assay during Pregnancy Predicts Active Tuberculosis and Mortality in Human Immunodeficiency Virus Type 1-Infected Women and Their Children 
The Journal of Infectious Diseases  2010;202(12):1826-1835.
Background. We evaluated the prognostic usefulness of interferon γ release assays (IGRAs) for active tuberculosis and mortality in Kenyan human immunodeficiency virus type 1 (HIV-1)-infected women and their infants.
Methods. Prevalence and correlates of Mycobacterium tuberculosis-specific T-SPOT.TB IGRA positivity were determined during pregnancy in a historical cohort of HIV-1-infected women. Hazard ratios, adjusted for baseline maternal CD4 cell count (aHRCD4), were calculated for associations between IGRA positivity and risk of active tuberculosis and mortality over 2-year postpartum follow-up among women and their infants.
Results. Of 333 women tested, 52 (15.6%) had indeterminate IGRA results. Of the remaining 281 women, 120 (42.7%) had positive IGRA results, which were associated with a 4.5-fold increased risk of active tuberculosis (aHRCD4, 4.5; 95% confidence interval [CI], 1.1–18.0; P = .030). For immunosuppressed women (CD4 cell count, <250 cells/µL), positive IGRA results were associated with increased risk of maternal mortality (aHRCD4, 3.5; 95% CI, 1.02–12.1; ), maternal active tuberculosis or mortality (aHRCD4 P = .045 , 5.2; 95% CI, 1.7–15.6; P = .004), and infant active tuberculosis or mortality overall (aHRCD4, 3.0; 95% CI, 1.0–8.9; P = .05) and among HIV-1-exposed uninfected infants (aHRCD4, 7.3; 95% CI, 1.6–33.5; P = .01).
Conclusions. Positive IGRA results for HIV-1-infected pregnant women were associated with postpartum active tuberculosis and mortality among mothers and their infants.
PMCID: PMC3058232  PMID: 21067370
22.  Risk factors for neonatal conjunctivitis in babies of HIV-1 infected mothers 
Ophthalmic epidemiology  2009;16(6):337-345.
To determine the prevalence and correlates of neonatal conjunctivitis in infants born to human immunodeficiency virus type 1 (HIV-1) infected mothers.
This was a nested case-control study within a perinatal HIV-1 cohort. HIV-1 seropositive mothers were enrolled during pregnancy and mother-infant pairs followed after delivery with assessment for neonatal conjunctivitis at 48 hours and up to 4 weeks after birth. Genital infections (chlamydia, gonorrhea, syphilis, trichomonas, bacterial vaginosis, and candida) were screened for at 32 weeks gestation. Mothers received treatment for genital infections diagnosed during pregnancy and short-course zidovudine. Newborns did not receive ocular prophylaxis at hospital deliveries. Multivariate logistic regression models were used to determine cofactors for neonatal conjunctivitis overall and stratified for infant HIV-1 status.
Four hundred and fifty-two infants were assessed and 101 (22.3%) had neonatal conjunctivitis during the first month postpartum. In multivariate analyses using odds ratios (OR) and confidence intervals (CI), neonatal conjunctivitis was associated with neonatal sepsis (adjusted OR 21.95, 95% CI 1.76, 274.61), birth before arrival to hospital (adjusted OR 13.91, 95% CI 1.39, 138.78) and birth weight (median 3.4 versus 3.3 kilograms, p=0.016, OR 1.79, 95% CI 1.01, 3.15). Infant HIV-1 infection was not associated with conjunctivitis.
Despite detection and treatment of genital infections during pregnancy, neonatal conjunctivitis was frequently diagnosed in infants born to HIV-1 infected mothers suggesting a need for increased vigilance and prophylaxis for conjunctivitis in these infants. Neonatal sepsis, birth before arrival to hospital, and higher birthweight are factors that may predict higher risk of neonatal conjunctivitis in this population.
PMCID: PMC3223245  PMID: 19995198
Case-control; HIV; Maternal; Neonatal conjunctivitis; Risk factors
23.  Performance of Clinical Algorithms for HIV-1 Diagnosis and Antiretroviral Initiation among HIV-1-Exposed Children Aged Less Than 18 Months in Kenya 
Ninety percent of HIV-1-infected children live in sub-Saharan Africa. In the absence of diagnosis and antiretroviral therapy (ART), approximately 50% die before 2 years.
We evaluated sensitivity and specificity of clinical algorithms for diagnosis of HIV-1 infection and ART initiation among HIV-1-exposed children aged less than 18 months. Children were identified with routine HIV-1 testing and assessed using 3 sets of criteria: 1) Integrated Management of Childhood Illnesses (IMCI), 2) World Health Organization Presumptive Diagnosis (WHO-PD) for HIV-1 infection, and 3) CD4 T-lymphocyte cell subsets. HIV-1 infection status was determined using DNA PCR testing.
A total of 1,418 children (median age 5.4 months) were screened for HIV-1 antibodies, of whom 144 (10.2%) were seropositive. Of these, 134 (93%) underwent HIV-1 DNA testing and 80 (60%) were found to be HIV-1-infected. Compared to HIV-1 DNA testing, sensitivity and specificity of the IMCI were 19% and 96% and for WHO-PD criteria 43% and 88%, respectively. Inclusion of severe immune deficiency determined by CD4 percent improved sensitivity of IMCI and WHO-PD to 74% and 84% respectively, however, specificity declined to 43% and 41%, respectively.
Diagnosis of HIV-1 infection among exposed children less than 18 months in a high prevalence, resource-limited setting remains a challenge and current recommended algorithms have low sensitivity. This underscores the need for rapid scale-up of viral assays for early infant diagnosis.
PMCID: PMC3223246  PMID: 19225401
HIV-1; infant diagnosis; clinical algorithms
24.  Utility of total lymphocyte count as a surrogate marker for CD4 counts in HIV-1 infected children in Kenya 
BMC Infectious Diseases  2011;11:259.
In resource-limited settings, such as Kenya, access to CD4 testing is limited. Therefore, evaluation of less expensive laboratory diagnostics is urgently needed to diagnose immuno-suppression in children.
To evaluate utility of total lymphocyte count (TLC) as surrogate marker for CD4 count in HIV-infected children.
This was a hospital based retrospective study conducted in three HIV clinics in Kisumu and Nairobi in Kenya. TLC, CD4 count and CD4 percent data were abstracted from hospital records of 487 antiretroviral-naïve HIV-infected children aged 1 month - 12 years.
TLC and CD4 count were positively correlated (r = 0.66, p < 0.001) with highest correlation seen in children with severe immuno-suppression (r = 0.72, p < 0.001) and children >59 months of age (r = 0.68, p < 0.001). Children were considered to have severe immuno-suppression if they met the following WHO set CD4 count thresholds: age below 12 months (CD4 counts < 1500 cells/mm3), age 12-35 months (CD4 count < 750 cells/mm3), age 36-59 months (CD4 count < 350 cells/mm3, and age above 59 months (CD4 count < 200 cells/mm3). WHO recommended TLC threshold values for severe immuno-suppression of 4000, 3000, 2500 and 2000 cells/mm3 for age categories <12, 12-35, 36-59 and >59 months had low sensitivity of 25%, 23%, 33% and 62% respectively in predicting severe immuno-suppression using CD4 count as gold standard. Raising TLC thresholds to 7000, 6000, 4500 and 3000 cells/mm3 for each of the stated age categories increased sensitivity to 71%, 64%, 56% and 86%, with positive predictive values of 85%, 61%, 37%, 68% respectively but reduced specificity to 73%, 62%, 54% and 68% with negative predictive values of 54%, 65%, 71% and 87% respectively.
TLC is positively correlated with absolute CD4 count in children but current WHO age-specific thresholds had low sensitivity to identify severely immunosuppressed Kenyan children. Sensitivity and therefore utility of TLC to identify immuno-suppressed children may be improved by raising the TLC cut off levels across the various age categories.
PMCID: PMC3207914  PMID: 21961890
Total Lymphocyte Count; TLC; CD4; HIV; Children; surrogate marker
25.  Evaluation of a single round polymerase chain reaction assay using dried blood spots for diagnosis of HIV-1 infection in infants in an African setting 
BMC Pediatrics  2011;11:18.
The aim of this study was to develop an economical 'in-house' single round polymerase chain reaction (PCR) assay using filter paper-dried blood spots (FP-DBS) for early infant HIV-1 diagnosis and to evaluate its performance in an African setting.
An 'in-house' single round PCR assay that targets conserved regions in the HIV-1 polymerase (pol) gene was validated for use with FP-DBS; first we validated this assay using FP-DBS spiked with cell standards of known HIV-1 copy numbers. Next, we validated the assay by testing the archived FP-DBS (N = 115) from infants of known HIV-1 infection status. Subsequently this 'in-house' HIV-1 pol PCR FP-DBS assay was then established in Nairobi, Kenya for further evaluation on freshly collected FP-DBS (N = 186) from infants, and compared with findings from a reference laboratory using the Roche Amplicor® HIV-1 DNA Test, version 1.5 assay.
The HIV-1 pol PCR FP-DBS assay could detect one HIV-1 proviral copy in 38.7% of tests, 2 copies in 46.9% of tests, 5 copies in 72.5% of tests and 10 copies in 98.1% of tests performed with spiked samples. Using the archived FP-DBS samples from infants of known infection status, this assay was 92.8% sensitive and 98.3% specific for HIV-1 infant diagnosis. Using 186 FP-DBS collected from infants recently defined as HIV-1 positive using the commercially available Roche Amplicor v1.5 assay, 178 FP-DBS tested positive by this 'in-house' single-round HIV-1 pol PCR FP-DBS PCR assay. Upon subsequent retesting, the 8 infant FP-DBS samples that were discordant were confirmed as HIV-1 negative by both assays using a second blood sample.
HIV-1 was detected with high sensitivity and specificity using both archived and more recently collected samples. This suggests that this 'in-house' HIV-1 pol FP-DBS PCR assay can provide an alternative cost-effective, reliable and rapid method for early detection of HIV-1 infection in infants.
PMCID: PMC3050718  PMID: 21332984

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