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1.  Prevalence of hearing loss in children following bacterial meningitis in a tertiary referral hospital 
BMC Research Notes  2014;7:138.
Background
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.
Methods
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.
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.
Conclusions
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.
doi:10.1186/1756-0500-7-138
PMCID: PMC3975328  PMID: 24618106
Hearing tests; Kenyatta national hospital; Sensorineural hearing loss (SNHL); Coma score; Seizures; Cranial nerve neuropathy; Positive CSF culture; Fever
2.  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- 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 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.
Results
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.
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.
doi:10.1097/QAI.0b013e31827b4ac8
PMCID: PMC3593972  PMID: 23196827
3.  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.
doi:10.1097/INF.0b013e3182587796
PMCID: PMC3756892  PMID: 22544051
Pediatric; Infant; HIV-1; Antiretroviral therapy; Mortality
4.  Breast milk cellular HIV-specific interferon γ responses are associated with protection from peripartum HIV transmission 
AIDS (London, England)  2012;26(16):2007-2016.
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-γ (IFN-γ) responses and infant HIV-1 detection at 1 month of age.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1097/QAD.0b013e328359b7e0
PMCID: PMC3718292  PMID: 22948269
breastfeeding; breast milk cytotoxic T lymphocytes; cytokines; early postnatal transmission; infant; MIP-1β; pediatric; sub-Saharan Africa
5.  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.
doi:10.1155/2013/354725
PMCID: PMC3671307  PMID: 23762065
6.  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.
doi:10.1086/656318
PMCID: PMC3404885  PMID: 20812845
Human immunodeficiency virus; vertical HIV-1 transmission; human leukocyte antigen
7.  High Uptake of Postpartum Hormonal Contraception Among HIV-1-Seropositive Women in Kenya 
Sexually Transmitted Diseases  2007;34(1):25-29.
Objectives
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.
Goal
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.
Results
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.
Conclusions
Using existing the healthcare infrastructure, it is possible to achieve high levels of postpartum hormonal contraceptive utilization among HIV-1-seropositive women.
doi:10.1097/01.olq.0000218880.88179.36
PMCID: PMC3387272  PMID: 16691159
8.  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.
doi:10.1089/aid.2006.0125
PMCID: PMC3382116  PMID: 17331027
9.  Early Response to Highly Active Antiretroviral Therapy in HIV-1–Infected Kenyan Children 
Objectives
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.
Design
Observational prospective cohort.
Methods
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.
Results
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.
Conclusion
Good early clinical and virologic response to NNRTI-based HAARTwas observed in HIV-1–infected Kenyan children with advanced HIV-1 disease.
doi:10.1097/QAI.0b013e318042d613
PMCID: PMC3380073  PMID: 17356470
antiretroviral; children; HIV-1; response
10.  Morbidity Among HIV-1–Infected Mothers in Kenya 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/QAI.0b013e318141fcc0
PMCID: PMC3372412  PMID: 17667334
HIV/AIDS; HIV-1 progression; maternal health; morbidity; postpartum; pregnancy; prevention of mother-to-child transmission; women
11.  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.
doi:10.1155/2012/950650
PMCID: PMC3312220  PMID: 22496602
12.  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.
Background
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.
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 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.
Results
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).
Conclusions
Positive IGRAs in HIV-1 infected pregnant women were associated with postpartum active TB and mortality in mothers and their infants.
doi:10.1086/657411
PMCID: PMC3058232  PMID: 21067370
Latent tuberculosis infection; HIV-1; women; infants; T-SPOT.TB; IGRA
13.  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.
doi:10.1086/657411
PMCID: PMC3058232  PMID: 21067370
14.  Risk factors for neonatal conjunctivitis in babies of HIV-1 infected mothers 
Ophthalmic epidemiology  2009;16(6):337-345.
Purpose
To determine the prevalence and correlates of neonatal conjunctivitis in infants born to human immunodeficiency virus type 1 (HIV-1) infected mothers.
Methods
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.
Results
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.
Conclusions
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.
doi:10.3109/09286580903144746
PMCID: PMC3223245  PMID: 19995198
Case-control; HIV; Maternal; Neonatal conjunctivitis; Risk factors
15.  Performance of Clinical Algorithms for HIV-1 Diagnosis and Antiretroviral Initiation among HIV-1-Exposed Children Aged Less Than 18 Months in Kenya 
Background
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.
Methods
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.
Findings
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.
Interpretation
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.
doi:10.1097/QAI.0b013e318198a8a4
PMCID: PMC3223246  PMID: 19225401
HIV-1; infant diagnosis; clinical algorithms
16.  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.
Background
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.
Objectives
To evaluate utility of total lymphocyte count (TLC) as surrogate marker for CD4 count in HIV-infected children.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2334-11-259
PMCID: PMC3207914  PMID: 21961890
Total Lymphocyte Count; TLC; CD4; HIV; Children; surrogate marker
17.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2431-11-18
PMCID: PMC3050718  PMID: 21332984
18.  Illness during Pregnancy and Bacterial Vaginosis are Associated with In Utero HIV-1 Transmission 
AIDS (London, England)  2010;24(1):153-155.
HIV-1 transmission in utero accounts for 20–30% of vertical transmission events in breastfeeding populations. In a prospective study of 463 HIV-1-infected mothers and infants, illness during pregnancy was associated with 2.6-fold increased risk of in utero HIV-1 transmission (95% CI 1.2, 5.8) and bacterial vaginosis with a 3-fold increase (95% CI 1.0–7.0) after adjusting for maternal HIV-1 viral load. Interventions targeting these novel risk factors could lead to more effective prevention of transmission during pregnancy.
doi:10.1097/QAD.0b013e32832326d8
PMCID: PMC2788745  PMID: 19952542
19.  Pediatric HIV-1 in Kenya: Pattern and Correlates of Viral Load and Association With Mortality 
Background
There is limited information regarding the pattern and correlates of viral replication in vertically HIV-1–infected children and its role on their outcomes in resource-limited settings.
Methods
HIV-1–infected infants were followed from birth to 24 months. Serial HIV-1 RNA levels were compared in infants infected in utero (<48 hours), peripartum (48 hours–1 month), and late postnatal (after 1 month). Cofactors for viral peak [highest viral load (VL) within 6 months of infection] and set point and mortality were determined.
Results
Among 85 HIV-1–infected infants, 24 were infected in utero, 41 peripartum, 13 late postnatal; 7 had no 48-hour assay. HIV-1 VL set point was significantly lower in infants infected >1 month vs. ≤1 month (5.59 vs. 6.24 log10 copies per milliliter, P = 0.01). Maternal VL correlated with peak infant VL (P < 0.001). Univariately, infant peak and set point VL and 6-month CD4% <15% predicted mortality; and 6-month CD4% <15% remained independently predictive in multivariate analyses (hazard ratio = 4.85, 95% confidence interval: 1.90 to 12.36).
Conclusions
Infants infected after the age of 1 month contained virus better than infants infected before 1 month of age. Maternal VL predicted infant VL, which, in turn was associated with early mortality.
PMCID: PMC2758913  PMID: 19504753
HIV-1; mortality; pathogenesis; pediatric; timing of HIV-1 infection; viral load
20.  Predictors of mortality in HIV-1 infected children on antiretroviral therapy in Kenya: a prospective cohort 
BMC Pediatrics  2010;10:33.
Background
Among children, early mortality following highly active antiretroviral therapy (HAART) remains high. It is important to define correlates of mortality in order to improve outcome.
Methods
HIV-1-infected children aged 18 months-12 years were followed up at Kenyatta National Hospital, Nairobi after initiating NNRTI-based HAART. Cofactors for mortality were determined using multivariate Cox regression models.
Results
Between August 2004 and November 2008, 149 children were initiated on HAART of whom 135 were followed for a total of 238 child-years (median 21 months) after HAART initiation. Baseline median CD4% was 6.8% and median HIV-1-RNA was 5.98-log10 copies/ml. Twenty children (13.4%) died at a median of 35 days post-HAART initiation. Mortality during the entire follow-up period was 8.4 deaths per 100 child-years (46 deaths/100 child-years in first 4 months and 1.0 deaths/100 child-years after 4 months post-HAART initiation). On univariate Cox regression, baseline hemoglobin (Hb) <9 g/dl, weight-for-height z-score (WHZ) < -2, and WHO clinical stage 4 were associated with increased risk of death (Hb <9 g/dl HR 3.00 [95% C.I. 1.21-7.39], p = 0.02, WHZ < -2 HR 3.41 [95% C.I. 1.28-9.08], p = 0.01, and WHO clinical stage 4, HR 3.08 [1.17-8.12], p = 0.02). On multivariate analysis Hb < 9 g/dl remained predictive of mortality after controlling for age, baseline CD4%, WHO clinical stage and weight-for-height z-score (HR 2.95 (95% C.I. 1.04-8.35) p = 0.04).
Conclusion
High early mortality was observed in this cohort of Kenyan children receiving HAART, and low baseline hemoglobin was an independent risk factor for death.
doi:10.1186/1471-2431-10-33
PMCID: PMC2887829  PMID: 20482796
22.  Medication diaries do not improve outcomes with highly active antiretroviral therapy in Kenyan children: a randomized clinical trial 
Background
As highly active antiretroviral therapy (HAART) becomes increasingly available to African children, it is important to evaluate simple and feasible methods of improving adherence in order to maximize benefits of therapy.
Methods
HIV-1-infected children initiating World Health Organization non-nucleoside reverse transcriptase-inhibitor-containing first-line HAART regimens were randomized to use medication diaries plus counselling, or counselling only (the control arm of the study). The diaries were completed daily by caregivers of children randomized to the diary and counselling arm for nine months. HIV-1 RNA, CD4+ T cell count, and z-scores for weight-for-age, height-for-age and weight-for-height were measured at a baseline and every three to six months. Self-reported adherence was assessed by questionnaires for nine months.
Results
Ninety HIV-1-infected children initiated HAART, and were followed for a median of 15 months (interquartile range: 2–21). Mean CD4 percentage was 17.2% in the diary arm versus 16.3% in the control arm at six months (p = 0.92), and 17.6% versus 18.9% at 15 months (p = 0.36). Virologic response with HIV-1 RNA of <100 copies/ml at nine months was similar between the two arms (50% for the diary arm and 36% for the control, p = 0.83). The weight-for-age, height-for-age and weight-for-height at three, nine and 15 months after HAART initiation were similar between arms. A trend towards lower self-reported adherence was observed in the diary versus the control arm (85% versus 92%, p = 0.08).
Conclusion
Medication diaries did not improve clinical and virologic response to HAART over a 15-month period. Children had good adherence and clinical response without additional interventions. This suggests that paediatric HAART with conventional counselling can be a successful approach. Further studies on targeted approaches for non-adherent children will be important.
doi:10.1186/1758-2652-12-8
PMCID: PMC2708138  PMID: 19549342

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