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MBORI-, PROFNGACHADOROTHYA, W. PROFNDUATIRUTH, ELIZABETH DROBIMBO.  Submitted.  HIV-1 Disease Progression in Breast-Feeding and Formula-Feeding Mothers: A Prospective 2-Year Comparison of T Cell Subsets, HIV-1 RNA Levels, and Mortality. Otieno PA, Brown ER, Mbori-Ngacha DA, Nduati RW, Farquhar C, Obimbo EM, Bosire RK, Emery S, Overba. J Infect Dis. 2007 Jan 15;195(2):220-9. Epub 2006 Dec 13.. : Earthscan, London. 978-1-84407-469-3 (*) Abstracthiv.pdf

Centre for Clinical Research, Kenya Medical Research Institute, University of Nairobi, Nairobi, Kenya. Background. There is conflicting evidence regarding the effects of breast-feeding on maternal mortality from human immunodeficiency virus type 1 (HIV-1) infection, and little is known about the effects of breast-feeding on markers of HIV-1 disease progression.Methods. HIV-1-seropositive women were enrolled during pregnancy and received short-course zidovudine. HIV-1 RNA levels and CD4 cell counts were determined at baseline and at months 1, 3, 6, 12, 18, and 24 postpartum and were compared between breast-feeding and formula-feeding mothers.Results. Of 296 women, 98 formula fed and 198 breast-fed. At baseline, formula-feeding women had a higher education level and prevalence of HIV-1-related illness than did breast-feeding women; however, the groups did not differ with respect to CD4 cell counts and HIV-1 RNA levels. Between months 1 and 24 postpartum, CD4 cell counts decreased 3.9 cells/ mu L/month (P<.001), HIV-1 RNA levels increased 0.005 log(10) copies/mL/month (P=.03), and body mass index (BMI) decreased 0.03 kg/m(2)/month (P<.001). The rate of CD4 cell count decline was higher in breast-feeding mothers (7.2 cells/ mu L/month) than in mothers who never breast-fed (4.0 cells/ mu L/month) (P=.01). BMI decreased more rapidly in breast-feeding women (P=.04), whereas HIV-1 RNA levels and mortality did not differ significantly between breast-feeding and formula-feeding women.Conclusions. Breast-feeding was associated with significant decreases in CD4 cell counts and BMI. HIV-1 RNA levels and mortality were not increased, suggesting a limited adverse impact of breast-feeding in mothers receiving extended care for HIV-1 infection.

MBORI-, PROFNGACHADOROTHYA.  Submitted.  Nduati R, and Mbori-Ngacha D. Prevention Of Breastmilk Transmission of HIV: Balancing the Benefits and the Risks In: Essex M, Mboup S, Kanki PJ, Kalengayi MR, (eds). AIDS in Africa. 2nd Ed.. Book. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
A study of malaria on the Kano Plain, Kisumu District, Western Kenya, was carried out between April and August, 1985. The study included a knowledge, attitudes and practices (K.A.P.) survey on malaria illness and the mosquito vector. Overall knowledge about malaria illness was found to be good. However, treatment and prevention practices of malaria were found to be poor. Knowledge of the mosquito and its relationship to malaria was found to be high. Knowledge of methods of prevention of mosquito bites was also found to be high but actual use of the methods was low. Knowledge of traditional methods of prevention of mosquito bites was also found to be high. Actual use was again found to be low.

2012

Slyker, JA;, Lohman-Payne B;, John-Stewart GC;, Dong T;, Mbori-Ngacha DA;, Tapia K;, Atzberger A;, Taylor S;, Rowland-Jones SL;, Blish CA.  2012.  The impact of HIV-1 infection and exposure on natural killer (NK) cell phenotype in Kenyan infants during the first year of life. Abstract

Natural killer (NK) cells play an important role in the containment of HIV replication during primary infection, though their functions are impaired during chronic HIV infection. Infants experience more rapid HIV disease progression than adults, but contributions of infant NK cells to containing HIV infection are unknown. The aim of this study was to determine the impact of HIV infection on infant NK cell phenotype by evaluating samples and data from a cohort study of women and their infants, conducted in Nairobi, Kenya between 1999 and 2003. The percentage and phenotype of NK cells was evaluated longitudinally by multi-parameter flow cytometry over the first year of life in HIV-infected (HIV+, = 16), HIV-exposed uninfected (HIV-EU, n = 6), and healthy unexposed controls (HIV-, n = 4). At birth, NK subset distributions based on expression of CD56 and CD16 did not differ between HIV+, HIV-EU, or HIV- infants. However, HIV infection was associated with a subsequent decline in NK cells as a percentage of total lymphocytes (p < 0.001), and an expanding proportion of CD56-CD16+ NK cells (p < 0.001). Activated CD38(bright)CD69+ NK cells were more frequent in the HIV+ infants, followed by HIV-EU and HIV- infants, in both CD56(dim) (p = 0.005) and CD56(bright) compartments (p = 0.03). HIV infection and exposure was also associated with a significant decline in the percentage of perforin-expressing NK cells in the CD56(dim) compartment over the first year of life, with HIV+ infants losing approximately 2.5% (p < 0.001) and HIV-EU infants losing 3.0% (p = 0.01) of perforin+ cells per month. Thus, infant HIV infection is associated with alterations in NK cell subsets, activation, and cytolytic potential that could contribute to their poor control over HIV infection. Furthermore, exposure to HIV infection in infants who escaped infection is also associated with alterations in NK cells that may contribute to the reduced ability to fight infections that is observed in HIV-EU infants

John-Stewart, GC, Wariua G, Beima-Sofie KM, Richardson BA, Farquhar C, Maleche-Obimbo E, Mbori-Ngacha DA, Wamalwa D.  2012.  Prevalence, perceptions, and correlates of pediatric HIV disclosure in an HIV treatment program in Kenya. Abstract

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.

Chi, BH, Adler MR, Bolu O, Mbori-Ngacha DA, Ekouevi DK, Gieselman A, Chipato T, Luo C, Phelps BR, McClure C, Mofenson LM, Stringer JS.  2012.  Progress, challenges, and new opportunities for the prevention of mother-to-child transmission of HIV under the US President's Emergency Plan for AIDS Relief. Abstract

In June 2011, the Joint United Nations Programme on HIV/AIDS, the US President's Emergency Plan for AIDS Relief (PEPFAR), and other collaborators outlined a transformative plan to virtually eliminate pediatric AIDS worldwide. The ambitious targets of this initiative included a 90% reduction in new pediatric HIV infections and a 50% reduction in HIV-related maternal mortality--all by 2015. PEPFAR has made an unprecedented commitment to the expansion and improvement of prevention of mother-to-child HIV transmission (PMTCT) services globally and is expected to play a critical role in reaching the virtual elimination target. To date, PEPFAR has been instrumental in the success of many national programs, including expanded coverage of PMTCT services, an enhanced continuum of care between PMTCT and HIV care and treatment, provision of more efficacious regimens for antiretroviral prophylaxis, design of innovative but simplified PMTCT approaches, and development of new strategies to evaluate program effectiveness. These accomplishments have been made through collaborative efforts with host governments, United Nations agencies, other donors (eg, the Global Fund for AIDS, Tuberculosis, and Malaria), nongovernmental organizations, and private sector partners. To successfully meet the ambitious global targets to prevent new infant HIV infections, PEPFAR must continue to leverage the existing PMTCT platform, while developing innovative approaches to rapidly expand quality HIV services. PEPFAR must also carefully integrate PMTCT into the broader combination prevention agenda for HIV, so that real progress can be made toward an "AIDS-free generation" worldwide.

Turan, JM, Steinfeld RL, Onono M, Bukusi EA, Woods M, Shade SB, Washington S, Marima R, Penner J, Ackers ML, Mbori-Ngacha DA, Cohen CR.  2012.  The study of HIV and antenatal care integration in pregnancy in Kenya: design, methods, and baseline results of a cluster-randomized controlled trial. Abstractpone.0044181.pdf

Despite strong evidence for the effectiveness of anti-retroviral therapy for improving the health of women living with HIV and for the prevention of mother-to-child transmission (PMTCT), HIV persists as a major maternal and child health problem in sub-Saharan Africa. In most settings antenatal care (ANC) services and HIV treatment services are offered in separate clinics. Integrating these services may result in better uptake of services, reduction of the time to treatment initiation, better adherence, and reduction of stigma.A prospective cluster randomized controlled trial design was used to evaluate the effects of integrating HIV treatment into ANC clinics at government health facilities in rural Kenya. Twelve facilities were randomized to provide either fully integrated services (ANC, PMTCT, and HIV treatment services all delivered in the ANC clinic) or non-integrated services (ANC clinics provided ANC and basic PMTCT services and referred clients to a separate HIV clinic for HIV treatment). During June 2009- March 2011, 1,172 HIV-positive pregnant women were enrolled in the study. The main study outcomes are rates of maternal enrollment in HIV care and treatment, infant HIV testing uptake, and HIV-free infant survival. Baseline results revealed that the intervention and control cohorts were similar with respect to socio-demographics, male partner HIV testing, sero-discordance of the couple, obstetric history, baseline CD4 count, and WHO Stage. Challenges faced while conducting this trial at low-resource rural health facilities included frequent staff turnover, stock-outs of essential supplies, transportation challenges, and changes in national guidelines. This is the first randomized trial of ANC and HIV service integration to be conducted in rural Africa. It is expected that the study will provide critical evidence regarding the implementation and effectiveness of this service delivery strategy, with important implications for programs striving to eliminate vertical transmission of HIV and improve maternal health.

Slyker, JA, Rowland-Jones SL, Dong T, Reilly M, Richardson B, Emery VC, Atzberger A, Mbori-Ngacha DA, Lohman-Payne BL, John-Stewart GC.  2012.  Acute cytomegalovirus infection is associated with increased frequencies of activated and apoptosis-vulnerable T cells in HIV-1-infected infants. AbstractWebsite

Cytomegalovirus (CMV) coinfection is associated with infant HIV-1 disease progression and mortality. In a cohort of Kenyan HIV-infected infants, the frequencies of activated (CD38(+) HLA-DR(+)) and apoptosis-vulnerable (CD95(+) Bcl-2(-)) CD4(+) and CD8(+) T cells increased substantially during acute CMV infection. The frequency of activated CD4(+) T cells was strongly associated with both concurrent CMV coinfection (P = 0.001) and HIV-1 viral load (P = 0.05). The frequency of apoptosis-vulnerable cells was also associated with CMV coinfection in the CD4 (P = 0.02) and CD8 (P < 0.001) T cell subsets. Similar observations were made in HIV-exposed uninfected infants. CMV-induced increases in T cell activation and apoptosis may contribute to the rapid disease progression in coinfected infants.

2011

Mbori-Ngacha, DA, Wamalwa DC, Nderitu M, Maleche-Obimbo E, Githinji N.  2011.  Utility of total lymphocyte count as a surrogate marker for CD4 counts in HIV-1 infected children in Kenya. Abstract

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 HIVinfected 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.

2010

Choi, RY; Farquhar, JM-NDA; L-PVWTBJ-SC; J; B.  2010.  http://profiles.uonbi.ac.ke/dorothymbori/publications. Abstract

The C868T single nucleotide polymorphism (SNP) in the CD4 receptor encodes an amino acid change that could alter its structure and influence human immunodeficiency virus (HIV-1) infection risk. HIV-1-infected pregnant women in Nairobi were followed with their infants for 1 year postpartum. Among 131 infants, those with the 868T allele were more likely than wild-type infants to acquire HIV-1 overall [hazard ratio (HR) = 1.92, 95% confidence interval (CI) 1.05, 3.50, P = 0.03; adjusted HR = 2.03, 95% CI 1.03, 3.98, P = 0.04], after adjusting for maternal viral load. This SNP (an allele frequency of approximately 15% in our cohort) was associated with increased susceptibility to mother-to-child HIV-1 transmission, consistent with a previous study on this polymorphism among Nairobi sex workers.

Wamalwa, DC, Obimbo EM, Farquhar C, Richardson BA, Mbori-Ngacha DA, Inwani I, Benki-Nugent S, John-Stewart G.  2010.  Predictors of mortality in HIV-1 infected children on antiretroviral therapy in Kenya. Abstract

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.

Farquhar, C;, Mbori-Ngacha DA;, Overbaugh J;, Wamalwa D;, Harris J;, Bosire R;, John-Stewart G.  2010.  Illness during pregnancy and bacterial vaginosis are associated with in-utero HIV-1 transmission. Abstract

HIV-1 transmission in utero accounts for 20-30% of vertical transmission events in breast-feeding 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% confidence interval (CI) 1.2-5.8] and bacterial vaginosis with a three-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

2009

Elizabeth Maleche Obimbo, Dalton Wamalwa, Richardson B, Mbori-Ngacha DA, Overbaugh J, Emery S, Phelgona Otieno, Grace C. John-Stewart, Farquhar C, Bosire R, Barbara Lohman Payne, John-Stewart G.  2009.  Pediatric HIV-1 in Kenya. Abstract

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

Inwani, I, Mbori-Ngacha DA, R W Nduati, Obimbo E, Dalton Wamalwa, Farquhar C, John-Stewart G.  2009.  Performance of Clinical Algorithms for HIV-1 Diagnosis and Antiretroviral Initiation among HIV-1-Exposed Children Aged Less Than 18 Months in Kenya. Abstract

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.

Brown, ER, Phelgona Otieno, Grace C. John-Stewart, Mbori-Ngacha DA, Farquhar C, Obimbo EM, R W Nduati, Overbaugh J, John-Stewart GC.  2009.  Comparison of CD4 Cell Count, Viral Load, and other markers for the prediction of mortality among HIV-1–Infected Kenyan pregnant women. AbstractWebsite

Background. There are limited data regarding the relative merits of biomarkers as predictors of mortality or time
to initiation of antiretroviral therapy (ART).
Methods. We evaluated the usefulness of the CD4 cell count, CD4 cell percentage (CD4%), human immunodeficiency
virus type 1 (HIV-1) load, total lymphocyte count (TLC), body mass index (BMI), and hemoglobin measured
at 32 weeks’ gestation as predictors of mortality in a cohort of HIV-1–infected women in Nairobi, Kenya. Sensitivity,
specificity, positive predictive value (PPV), and area under the receiver operating characteristic (ROC) curve (AUC)
were determined for each biomarker separately, as well as for the CD4 cell count and the HIV-1 load combined.
Results. Among 489 women with 10,150 person-months of follow-up, mortality rates at 1 and 2 years postpartum
were 2.1% (95% confidence interval [CI], 0.7%–3.4%) and 5.5% (95% CI, 3.0%–8.0%), respectively. CD4 cell count
and CD4% had the highest AUC value ( 0.9). BMI, TLC, and hemoglobin were each associated with but poorly
predictive of mortality (PPV, 7%). The HIV-1 load did not predict mortality beyond the CD4 cell count.
Conclusions. The CD4 cell count and CD4% measured during pregnancy were both useful predictors of mortality
among pregnant women. TLC, BMI, and hemoglobin had a limited predictive value, and the HIV-1 load did not
predict mortality any better than did the CD4 cell count alone.

Lohman-Payne, B; Slyker, RBA; FMM-OM-NDA; ORJA; C;.  2009.  Infants with late breast milk acquisition of HIV-1 generate interferon-gamma responses more rapidly than infants with early peripartum acquisition. Abstract

Infants infected with HIV-1 after the first month of life have a lower viral set-point and slower disease progression than infants infected before 1 month. We investigated the kinetics of HIV-1-specific CD8+ T lymphocyte secretion of interferon (IFN)-g in infants infected before 1 month of life compared with those infected between months 1 and 12 (late infection). HIV-1 infection was assessed at birth and at months 1, 3, 6, 9 and 12 and timing of infection was determined by HIV-1 gag DNA from dried blood spots and verified by plasma HIV-1 RNA levels. HIV-1 peptide-specific IFN-g responses were measured by enzyme-linked immunospot at months 1, 3, 6, 9 and 12. Timing of development of IFN-g responses was compared using the log–rank test and Kaplan–Meier survival curves. Infants infected late developed HIV-1-specific CD8+ T cell responses 2·8 months sooner than infants infected peripartum: 2·3 versus 5·1 months after HIV-1 infection (n = 52, P = 0·04). Late-infected infants had more focused epitope recognition than early-infected infants (median 1 versus 2 peptides, P = 0·03); however, there were no differences in the strength of IFN-g responses. In infants infected with HIV-1 after the first month of life, emergence of HIV- 1-specific CD8+ IFN-g responses is coincident with the decline in viral load, nearly identical to what is observed in adults and more rapid than in earlyinfected infants.

ohn-Stewart, G.C; Mbori-Ngacha, DA; PFREOODSBL; C;.  2009.  HV-1-specific cytotoxic T lymphocytes and breast milk HIV-1 transmission.. Abstract

Breast-feeding by infants exposed to human immunodeficiency virus type 1 (HIV-1) provides an opportunity to assess the role played by repeated HIV-1 exposure in eliciting HIV-1-specific immunity and in defining whether immune responses correlate with protection from infection. Breast-feeding infants born to HIV-1-seropositive women were assessed for HLA-selected HIV-1 peptide-specific cytotoxic T lymphocyte interferon (IFN)-gamma responses by means of enzyme-linked immunospot (ELISpot) assays at 1, 3, 6, 9, and 12 months of age. Responses were deemed to be positive when they reached > or = 50 HIV-1-specific sfu/1 x 10(6) peripheral blood mononuclear cells (PBMCs) and were at least twice those of negative controls. A total of 807 ELISpot assays were performed for 217 infants who remained uninfected with HIV-1 at approximately 12 months of age; 101 infants (47%) had at least 1 positive ELISpot result (median, 78-170 sfu/1 x 10(6) PBMCs). The prevalence and magnitude of responses increased with age (P = .01 and P = .007, respectively); the median log(10) value for HIV-1-specific IFN-gamma responses increased by 1.0 sfu/1 x 10(6) PBMCs/month (P < .001) between 1 and 12 months of age. Of 141 HIV-1-uninfected infants with 1-month ELISpot results, 10 (7%) acquired HIV-1 infection (0/16 with positive vs. 10/125 [8%] with negative ELISpot results; P = .6). Higher values for log(10) HIV-1-specific spot-forming units at 1 month of age were associated with a decreased risk of HIV-1 infection, adjusted for maternal HIV-1 RNA level (adjusted hazard ratio, 0.09 [95% confidence interval, 0.01-0.72]).. Breast-feeding HIV-1-exposed uninfected infants frequently had HIV-1-specific IFN-gamma responses. Greater early HIV-1-specific IFN-gamma responses were associated with decreased HIV-1 acquisition.

Gichuhi, S, Bosire R, Mbori-Ngacha DA, Christine Gichuhi, Dalton Wamalwa, Dalton Wamalwa, Maleche-Obimbo E, Farquhar C, Wariua G, Phelgona Otieno, Grace C. John-Stewart, John-Stewart GC.  2009.  Risk factors for neonatal conjunctivitis in babies of HIV-1 infected mothers. Abstract

o 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.

2008

MBORI-, PROFNGACHADOROTHYA.  2008.  Acute HIV infection among Kenyan infants. Clin Infect Dis . 2008 Jan 15; 46 ( 2 ): 289-95 . PMID: 18171265 [PubMed - indexed for MEDLINE] Richardson BA, Nduati R, Mbori-Ngacha D, Overbaugh J, John-Stewart GC.. Clin Infect Dis . 2008 Jan 15; 46 ( 2 ): 289-95 .. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
Department of Biostatistics, University of Washington, Seattle, Washington, USA. BACKGROUND: Clinical signs and symptoms of acute human immunodeficiency virus (HIV) infection in infants are not well characterized. METHODS: Serial clinical assessments and HIV PCR assays were conducted in a cohort of children born to HIV-seropositive mothers from birth to 2 years of age. Acute HIV infection visits were defined as those up to 3 months prior to and including the visit at which HIV DNA was first detected. Noninfection visits included all visits at which the child had test results negative for HIV, including the last visit at which a test result negative for HIV DNA was obtained in children who later acquired HIV infection. Differences in the prevalence of symptoms at acute infection versus noninfection visits were determined overall and were stratified by age at infection (<2 months vs. >or=2 months). HIV RNA was measured serially in infected infants and was compared between infants with and infants without symptoms of acute HIV infection. RESULTS: There were 125 acute infection visits (among 56 infants) and 3491 noninfection visits (among 306 infants). Acute HIV infection was associated with rash (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.1-2.8), failure to thrive (OR, 1.9; 95% CI, 1.0-3.5), and lymphadenopathy (OR, 2.5; 95% CI, 1.4-4.8). Acute HIV infection was associated with lymphadenopathy (OR, 2.6; 95% CI, 1.3-5.0) in infants <2 months of age and with pneumonia (OR, 3.2; 95% CI, 1.1-9.3) and dehydration (OR, 6.0; 95% CI, 1.9-18.5) in infants >or=2 months of age. Infant peak viral load and mortality were not associated with symptoms of acute HIV infection. However, infants with symptoms had higher viral levels later in the course of infection than did those without symptoms (P=.05). CONCLUSIONS: Infants may manifest symptoms early during the course of HIV infection, and symptoms of acute HIV infection may correlate with poor viral control. Rash, failure to thrive, lymphadenopathy, pneumonia, and dehydration may signify acute HIV infection in infants. PMID: 18171265 [PubMed - indexed for MEDLINE]
MBORI-, PROFNGACHADOROTHYA.  2008.  Maternal HLA homozygosity and mother-child HLA concordance increase the risk of vertical transmission of HIV-1. J Infect Dis . 2008 Apr 15; 197 ( 8 ): 1156-61 . PMID: 18462163 [PubMed - indexed for MEDLINE] Mackelprang RD, John-Stewart G, Carrington M, Ri. J Infect Dis . 2008 Apr 15; 197 ( 8 ): 1156-61 .. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
Department of Epidemiology, University of Washington, Seattle 98104, USA. BACKGROUND: Mother-child human leukocyte antigen (HLA) concordance and maternal HLA homozygosity may increase the risk of vertical transmission of human immunodeficiency virus type 1 (HIV-1) risk by reducing infant immune responses. METHODS: We analyzed mother-child HLA concordance and maternal HLA homozygosity in a Kenyan perinatal cohort receiving antenatal zidovudine. HLA concordance was scored as the number of shared class I alleles, and relative risk estimates were adjusted for maternal HIV-1 load. RESULTS: Among 277 mother-infant pairs, HIV-1 transmission occurred in 58 infants (21%), with in utero transmission in 21 (36%), peripartum transmission in 26 (45%), and transmission via breast-feeding in 11 (19%). With increased concordance, we observed a significant increase in the risk of transmission overall (adjusted hazard ratio [aHR], 1.3 [95% confidence interval {CI}, 1.0-1.7]; [Formula: see text]), in utero (adjusted odds ratio, 1.72 [95% CI, 1.0-1.7]; [Formula: see text]), and via breast-feeding (aHR, 1.6 [95% CI, 1.0-2.5]; [Formula: see text]). Women with homozygosity had higher plasma HIV-1 RNA levels at 32 weeks of gestation (5.1 vs. 4.8 log(10) copies/mL; [Formula: see text]) and an increased risk of transmission overall (aHR, 1.7 [95% CI, 1.1-2.7]; [Formula: see text]) and via breast-feeding (aHR, 5.8 [95% CI, 1.9-17.7]; [Formula: see text]). CONCLUSION: The risks of overall, in utero, and breast milk HIV-1 transmission increased with HLA concordance and homozygosity. The increased risk may be due to reduced alloimmunity or less diverse protective immune responses. PMID: 18462163 [PubMed - indexed for MEDLINE]
MBORI-, PROFNGACHADOROTHYA.  2008.  Optimizing paediatric HIV care in Kenya: challenges in early infant diagnosis. Bull World Health Organ . 2008 Feb; 86 ( 2 ): 155-60 . PMID: 18297171 [PubMed - indexed for MEDLINE] Cherutich P, Inwani I, Nduati R, Mbori-Ngacha D.. Bull World Health Organ . 2008 Feb; 86 ( 2 ): 155-60 .. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
National AIDS/STD Control Programme, Ministry of Health, Nairobi, Kenya. pcheru2000@yahoo.com PROBLEM: In 2003, the goal of the Kenyan Ministry of Health was to avail antiretroviral treatment (ART) to 50% of the estimated 250 000 eligible individuals by the end of 2005. By July 2005, 45 000 adults and more than 2000 children were on treatment. A study was conducted to determine the barriers to identification of HIV-infected children. APPROACH: Existing government policies were reviewed and the ART register of the Kenya National AIDS Control Programme was used to identify facilities providing ART. This paper reports the findings around diagnosis and staging of HIV infection in children. LOCAL SETTING: At the time of the study, 58 health facilities were providing ART to children. Only one institution had achieved universal HIV testing in the antenatal clinics. Six facilities systematically followed up HIV-exposed children. HIV antibody testing was not readily available to the children. Although four research centres were capable of carrying out diagnostic HIV polymerase chain reaction (PCR), the services were restricted to research purposes. Other constraints were inadequate physical infrastructure, inadequate systems for quality control in the laboratories and shortage of staff. LESSONS LEARNT: The policy framework to support identification of HIV-infected children had been established, albeit with narrow focus on sick children. The assessment identified the weaknesses in the structures for systematic diagnosis of HIV through laboratory or clinical-based algorithms. The researchers concluded that health staff training and implementation of a systematic standard approach to identification of HIV-infected children is urgently required. PMID: 18297171 [PubMed - indexed for MEDLINE]
MBORI-, PROFNGACHADOROTHYA.  2008.  Salivary human immunodeficiency virus (HIV)-1-specific immunoglobulin A in HIV-1-exposed infants in Kenya. Clin Exp Immunol . 2008 Jul; 153 ( 1 ): 37-43 . Epub 2008 May 23. PMID: 18505437 [PubMed - in process] Farquhar C, VanCott T, Bosire R, Bermudez C, . Clin Exp Immunol . 2008 Jul; 153 ( 1 ): 37-43 . Epub 2008 May 23.. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
Department of Medicine, University of Washington, Seattle, Washington 98104-2499, USA. cfarq@u.washington.edu Humoral immunity, and specifically immunoglobulin A (IgA) that is directed against human immunodeficiency virus (HIV)-1, may contribute to protection against HIV-1 acquisition at mucosal surfaces. HIV-1-specific IgA has been detected in genital tract secretions of HIV-1-uninfected commercial sex workers with HIV-1 exposure, and may be produced in parotid saliva by infants exposed orally to HIV-1 during delivery and breastfeeding. To explore this hypothesis, we collected saliva from 145 infants aged < or = 6 months enrolled in a perinatal HIV-1 transmission study in Nairobi and from 55 control infants without HIV-1 exposure who were born to HIV-1-seronegative mothers. Among the 145 infants, 115 (79%) remained uninfected during the 12-month study period and 30 (21%) became HIV-1-infected during follow-up. Nine (8%) of the 115 HIV-1-exposed, uninfected infants had detectable levels of HIV-1 gp160-specific IgA compared with four (13%) of 30 infected infants and none of 55 control infants (P = 0.47 and P = 0.03 respectively). Among the nine HIV-1-exposed, uninfected infants with positive assays, median age was 1 month and none acquired HIV-1 during follow-up. We conclude that HIV-1-specific salivary IgA responses may be generated by very young infants exposed perinatally to maternal HIV-1. Mucosal responses would be an appropriate target for paediatric vaccines against breast milk HIV-1 transmission. PMID: 18505437 [PubMed - in process]

2007

C., DRWAMALWADALTON, MBORI- PROFNGACHADOROTHYA.  2007.  Herpes simplex virus type 2 and risk of intrapartum human immunodeficiency virus transmission. Obstet Gynecol . 2007 Feb; 109 ( 2 Pt 1 ): 403-9 . Erratum in: Obstet Gynecol. 2007 Apr;109(4):1002-3. PMID: 17267842 [PubMed - indexed for MEDLINE] Drake AL, J. Obstet Gynecol . 2007 Feb; 109 ( 2 Pt 1 ): 403-9 . Erratum in: Obstet Gynecol. 2007 Apr;109(4):1002-3.. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
Departments of Epidemiology and Medicine, University of Washington, Seattle, WA 98195, USA. adrake2@u.washington.edu OBJECTIVE: To determine whether herpes simplex virus type 2 (HSV-2) infection was associated with risk of intrapartum human immunodeficiency virus type 1 (HIV-1) transmission and to define correlates of HSV-2 infection among HIV-1-seropositive pregnant women. METHODS: We performed a nested case control study within a perinatal cohort in Nairobi, Kenya. Herpes simplex virus type 2 serostatus and the presence of genital ulcers were ascertained at 32 weeks of gestation. Maternal cervical and plasma HIV-1 RNA and cervical HSV DNA were measured at delivery. RESULTS: One hundred fifty-two (87%) of 175 HIV-1-infected mothers were HSV-2-seropositive. Among the 152 HSV-2-seropositive women, nine (6%) had genital ulcers at 32 weeks of gestation, and 13 (9%) were shedding HSV in cervical secretions. Genital ulcers were associated with increased plasma HIV-1 RNA levels (P=.02) and an increased risk of intrapartum HIV-1 transmission (16% of transmitters versus 3% of nontransmitters had ulcers; P = .003), an association which was maintained in multivariable analysis adjusting for plasma HIV-1 RNA levels (P=.04). We found a borderline association for higher plasma HIV-1 RNA among women shedding HSV (P=.07) and no association between cervical HSV shedding and either cervical HIV-1 RNA levels or intrapartum HIV-1 transmission (P=.4 and P=.5, [corrected] respectively). CONCLUSION: Herpes simplex virus type 2 is the leading cause of genital ulcers among women in sub-Saharan Africa and was highly prevalent in this cohort of pregnant women receiving prophylactic zidovudine. After adjusting for plasma HIV-1 RNA levels, genital ulcers were associated with increased risk of intrapartum HIV-1 transmission. These data suggest that management of HSV-2 during pregnancy may enhance mother-to-child HIV-1 prevention efforts. LEVEL OF EVIDENCE: II. PMID: 17267842 [PubMed - indexed for MEDLINE]
C., DRWAMALWADALTON, MBORI- PROFNGACHADOROTHYA, ELIZABETH DROBIMBO.  2007.  High uptake of postpartum hormonal contraception among HIV-1-seropositive women in Kenya. Sex Transm Dis . 2007 Jan; 34 ( 1 ): 25-9 . PMID: 16691159 [PubMed - indexed for MEDLINE] Balkus J, Bosire R, John-Stewart G, Mbori-Ngacha D, Schiff MA, Wamalwa D, G. Sex Transm Dis . 2007 Jan; 34 ( 1 ): 25-9 .. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
Department of Epidemiology, University of Washington, Seattle, Washington 98104, USA. jbalkus@u.washington.edu 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. PMID: 16691159 [PubMed - indexed for MEDLINE]
C., DRWAMALWADALTON, MBORI- PROFNGACHADOROTHYA.  2007.  Breast milk alpha-defensins are associated with HIV type 1 RNA and CC chemokines in breast milk but not vertical HIV type 1 transmission. AIDS Res Hum Retroviruses . 2007 Feb; 23 ( 2 ): 198-203 . PMID: 17331027 [PubMed - indexed for MEDLINE] Bosire R, Joh. AIDS Res Hum Retroviruses . 2007 Feb; 23 ( 2 ): 198-203 .. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
{ Department of Pediatrics, University of Nairobi, Nairobi, Kenya. Alpha-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 alpha-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 alpha-defensins, HIV-1 RNA, subclinical mastitis, and CC and CXC chemokines. We detected alpha-defensins in breast milk specimens from 108 (42%) of 260 HIV-1-infected women. Women with detectable alpha-defensins (> or =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 alpha-defensins (2.9 log(10) copies/ml versus 2.5 log(10) copies/ml
MBORI-, PROFNGACHADOROTHYA.  2007.  Cloning and characterization of functional subtype A HIV-1 envelope variants transmitted through breastfeeding. Curr HIV Res . 2007 Mar; 5 ( 2 ): 189-97 . PMID: 17346133 [PubMed - indexed for MEDLINE] Rainwater SM, Wu X, Nduati R, Nedellec R, Mosier D, Jo. Curr HIV Res . 2007 Mar; 5 ( 2 ): 189-97 .. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-0124, USA. Previous studies of HIV-1 variants transmitted from mother-to-infant have focused primarily on computational analyses of partial envelope gene sequences, rather than analyses of functional envelope variants. There are very few examples of well-characterized functional envelope clones from mother-infant pairs, especially from envelope variants representing the most prevalent subtypes worldwide. To address this, we amplified the envelope variants present in 4 mother-infant transmission pairs, all of whom were infected with subtype A and three of whom presumably transmitted HIV-1 during the breastfeeding period. Functional envelope clones were constructed, either encoding full-length envelope sequences from the mother and baby or by making chimeric envelope clones in a common backbone sequence. The infant envelope sequences were genetically homogeneous compared to the maternal viruses, and pseudoviruses bearing these envelopes all used CCR5 as a coreceptor. The infant viruses were generally resistant to neutralization by maternal antibodies present near the time of transmission. There were no notable differences in sensitivity of the mother and infant envelope variants to neutralization by heterologous plasma or monoclonal antibodies 2G12 and b12, or to inhibition by sCD4, PSC-RANTES or TAK779. This collection of viral envelopes, which can be used for making pseudotyped viruses, may be useful for examining the efficacy of interventions to block mother-infant transmission, including sera from vaccine candidates, purified antibodies under consideration for passive immunization and viral entry inhibitors. PMID: 17346133 [PubMed - indexed for MEDLINE]
C., DRWAMALWADALTON, MBORI- PROFNGACHADOROTHYA, ELIZABETH DROBIMBO.  2007.  Early response to highly active antiretroviral therapy in HIV-1-infected Kenyan children. J Acquir Immune Defic Syndr . 2007 Jul 1; 45 ( 3 ): 311-7 . PMID: 17356470 [PubMed - indexed for MEDLINE] Wamalwa DC, Farquhar C, Obimbo EM, Selig S, Mbori-Ngacha DA. J Acquir Immune Defic Syndr . 2007 Jul 1; 45 ( 3 ): 311-7 .. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
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/microL (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 HAART was observed in HIV-1-infected Kenyan children with advanced HIV-1 disease. PMID: 17356470 [PubMed - indexed for MEDLINE]
MBORI-, PROFNGACHADOROTHYA.  2007.  Hormonal contraception and HIV-1 disease progression among postpartum Kenyan women. AIDS . 2007 Mar 30; 21 ( 6 ): 749-53 . PMID: 17413696 [PubMed - indexed for MEDLINE] Richardson BA, Otieno PA, Mbori-Ngacha D, Overbaugh J, Farquhar C, John-Stewart GC.. AIDS . 2007 Mar 30; 21 ( 6 ): 749-53 .. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
Department of Biostatistics, University of Washington, Seattle, WA 98194-2499, USA. barbrar@u.washington.edu OBJECTIVE: To assess the immediate and longer-term effects of the use of hormonal contraception on the progression of HIV-1 disease in postpartum women. DESIGN: A prospective cohort study. METHODS: Information on contraceptive use, breastfeeding and intercurrent illnesses was obtained from HIV-infected postpartum Kenyan women monthly in the first year postpartum and quarterly in the second year. Blood was collected for T-cell subset analyses and HIV-1-RNA levels at months 1, 3, 6, 9, 12, 18, and 24 postpartum. The immediate effect of the initiation of oral contraceptive pills (OCP) and depot medroxyprogesterone acetate (DMPA) was assessed by comparing the change in the HIV-1-RNA plasma viral load and CD4 T-cell counts among women remaining off these contraceptive methods with those initiating them. The longer-term effects of OCP and DMPA on disease progression were assessed using Loess curves and linear mixed effects models to compare changes over the first 24 months postpartum in these same disease progression markers. RESULTS: There were no significant immediate or longer-term effects of the use of OCP or DMPA on HIV-1-RNA plasma viral loads and CD4 T-cell counts in this cohort of HIV-infected postpartum Kenyan women. CONCLUSION: Comprehensive contraceptive counselling for HIV-1-infected women requires an understanding of the effects of various contraceptive methods on HIV-1 disease progression. In this study, hormonal contraception reassuringly had no immediate or longer-term effects on the rate of disease progression in chronically HIV-1-infected postpartum women. This highly effective family planning method may provide a useful and safe option for the prevention of mother-to-child transmission of HIV-1. PMID: 17413696 [PubMed - indexed for MEDLINE]
C., DRWAMALWADALTON, MBORI- PROFNGACHADOROTHYA, ELIZABETH DROBIMBO.  2007.  Morbidity among HIV-1-infected mothers in Kenya: prevalence and correlates of illness during 2-year postpartum follow-up. J Acquir Immune Defic Syndr . 2007 Oct 1; 46 ( 2 ): 208-15 . PMID: 17667334 [PubMed - indexed for MEDLINE] Walson JL, Brown ER, Otien. J Acquir Immune Defic Syndr . 2007 Oct 1; 46 ( 2 ): 208-15 .. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya. walson@u.washington.edu 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/mm) 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/mm(3) 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. PMID: 17667334 [PubMed - indexed for MEDLINE]
MBORI-, PROFNGACHADOROTHYA.  2007.  Longitudinal comparison of chemokines in breastmilk early postpartum among HIV-1-infected and uninfected Kenyan women. Breastfeed Med . 2007 Sep; 2 ( 3 ): 129-38 . PMID: 17903098 [PubMed - indexed for MEDLINE] Bosire R, Guthrie BL, Lohman-Payne B, Mabuka . Breastfeed Med . 2007 Sep; 2 ( 3 ): 129-38 .. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
Center for Public Health Research, Kenya Medical Research Institute, Nairobi, Kenya. Breastmilk chemokines have been associated with increased HIV-1 RNA levels in breastmilk and altered risk of mother-to-child HIV-1 transmission. To characterize CC and CXC chemokines in breastmilk postpartum, we collected breastmilk specimens at regular intervals for 6 months after delivery from women with and without HIV-1 infection and used commercial ELISA kits to measure breastmilk concentrations of MIP-1alpha, MIP-1beta, RANTES, and SDF-1alpha. Among 54 HIV-1-infected and 26 uninfected women, mean chemokine levels were compared cross-sectionally and longitudinally at days 5 and 10, and months 1 and 3 postpartum. For both HIV-1-infected and uninfected women, breastmilk chemokine levels were highest at day 5 for MIP-1alpha, MIP-1beta, and SDF-1alpha, and subsequently decreased. RANTES levels remained constant over the follow-up period among HIV-1-uninfected women, and increased moderately among HIV-1-infected women. For MIP-1beta and RANTES, breastmilk levels were significantly higher among HIV-1-infected women compared to uninfected women early postpartum. In addition, HIV-1-infected women transmitting HIV-1 to their infant had consistently higher breastmilk RANTES levels than those who did not transmit, with the greatest difference observed at 1 month (2.68 vs. 2.21 log10 pg/mL, respectively; p = 0.007). In summary, all four chemokines were most elevated within the first month postpartum, a period of high transmission risk via breastmilk. MIP-1beta and RANTES levels in breastmilk were higher among HIV-1-infected women than among uninfected women, and breastmilk RANTES was positively associated with vertical transmission in this study, consistent with results from our earlier cohort. PMID: 17903098 [PubMed - indexed for MEDLINE]

2006

MBORI-, PROFNGACHADOROTHYA.  2006.  Contextualising the paediatric HIV epidemic: a review. East Afr Med J . 2006 Dec; 83 ( 12 ): 684-8 . Review. PMID: 17685215 [PubMed - indexed for MEDLINE] Eley BS, Tindyebwa D, Kayita J, Kieffer MP, Nduati R, Mwansambo C, Musoke P, Ntumwesigye N, Kinkasa . East Afr Med J . 2006 Dec; 83 ( 12 ): 684-8 . Review. PMID: 17685215 [PubMed - indexed for MEDLINE]. : Earthscan, London. 978-1-84407-469-3 (*) Abstract

Red Cross Children's Hospital, Rondebosch, 7701, Cape Town, South Africa.

OBJECTIVE: To draw attention to the sub-optimal care that HIV-infected children are receiving in Africa. DATA SOURCES: Relevant published literature. DATA SYNTHESIS: Sub-optimal response to paediatric HIV infection has aggravated the negative impact that the epidemic has had on child health in Africa. Recently the African Network for the Care of Children Affected by HIV/AIDS (ANNECA) released an advocacy statement that called for the optimisation of prevention, diagnosis, treatment and care for children affected by the AIDS pandemic. Effective prevention strategies if comprehensively implemented, could prevent more than 500 000 paediatric infections per annum at current antenatal HIV prevalence rates. Improved care that includes universal utilisation of early diagnostic testing systems, cotrimoxazole prophylaxis, nutritional support and the timely introduction of antiretroviral therapy could improve the quality of life and lifespan of most infected children. CONCLUSION: Political leaders, public health officials and fellow child health professionals are urged to redouble their efforts to reverse the magnitude of the paediatric epidemic in Africa.

PMID: 17685215 [PubMed - indexed for MEDLINE]

MBORI-, PROFNGACHADOROTHYA.  2006.  Neutralization Escape Variants of Human Immunodeficiency Virus Type 1 Are Transmitted from Mother to Infant Xueling Wu, Adam B. Parast, Barbra A. Richardson, Ruth Nduati, Grace John-Stewart, Dorothy Mbori-Ngacha, Stephanie M. J. Rainwater, and Julie Overb. J Virol.. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
Maternal passive immunity typically plays a critical role in protecting infants from new infections; however, the specific contribution of neutralizing antibodies in limiting mother-to-child transmission of human immunodeficiency virus type 1 is unclear. By examining cloned envelope variants from 12 transmission pairs, we found that vertically transmitted variants were more resistant to neutralization by maternal plasma than were maternal viral variants near the time of transmission. The vertically transmitted envelope variants were poorly neutralized by monoclonal antibodies biz, 2G12 , 2F5, and 4E10 individually or in combination. Despite the fact that the infant viruses were among the most neutralization resistant in the mother, they had relatively few glycosylation sites. Moreover, the transmitted variants elicited de novo neutralizing antibodies in the infants, indicating that they were not inherently difficult to neutralize. The neutralization resistance of vertically transmitted viruses is in contrast to the relative neutralization sensitivity of viruses sexually transmitted within discordant couples, suggesting that the antigenic properties of viruses that are favored for transmission may differ depending upon mode of transmission.

2005

MBORI-, PROFNGACHADOROTHYA, ELIZABETH DROBIMBO.  2005.  Longitudinal assessment of human immunodeficiency virus type 1 (HIV-1)-specific gamma interferon responses during the first year of life in HIV-1-infected infants. J Virol . 2005 Jul; 79 ( 13 ): 8121-30 . PMID: 15956557 [PubMed - indexed for MEDLINE] Lohm. J Virol . 2005 Jul; 79 ( 13 ): 8121-30 .. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
Department of Paediatrics, University of Nairobi, Kenya. bllohman@iconnect.co.ke Human immunodeficiency virus type 1 (HIV-1) infection results in different patterns of viral replication in pediatric compared to adult populations. The role of early HIV-1-specific responses in viral control has not been well defined, because most studies of HIV-1-infected infants have been retrospective or cross-sectional. We evaluated the association between HIV-1-specific gamma interferon (IFN-gamma) release from the cells of infants of 1 to 3 months of age and peak viral loads and mortality in the first year of life among 61 Kenyan HIV-1-infected infants. At 1 month, responses were detected in 7/12 (58%) and 6/21 (29%) of infants infected in utero and peripartum, respectively (P = 0.09), and in approximately 50% of infants thereafter. Peaks of HIV-specific spot-forming units (SFU) increased significantly with age in all infants, from 251/10(6) peripheral blood mononuclear cells (PBMC) at 1 month of age to 501/10(6) PBMC at 12 months of age (P = 0.03), although when limited to infants who survived to 1 year, the increase in peak HIV-specific SFU was no longer significant (P = 0.18). Over the first year of life, infants with IFN-gamma responses at 1 month had peak plasma viral loads, rates of decline of viral load, and mortality risk similar to those of infants who lacked responses at 1 month. The strength and breadth of IFN-gamma responses at 1 month were not significantly associated with viral containment or mortality. These results suggest that, in contrast to HIV-1-infected adults, in whom strong cytotoxic T lymphocyte responses in primary infection are associated with reductions in viremia, HIV-1-infected neonates generate HIV-1-specific CD8+-T-cell responses early in life that are not clearly associated with improved clinical outcomes. PMID: 15956557 [PubMed - indexed for MEDLINE] PMCID: PMC1143755
C., DRWAMALWADALTON, MBORI- PROFNGACHADOROTHYA, ELIZABETH DROBIMBO.  2005.  Predictors of mortality in HIV-1 exposed uninfected post-neonatal infants at the Kenyatta National Hospital, Nairobi. East Afr Med J . 2005 Sep; 82 ( 9 ): 447-51 . PMID: 16619717 [PubMed - indexed for MEDLINE] Gichuhi C, Obimbo E, Mbori-Ngacha D, Mwatha A. East Afr Med J . 2005 Sep; 82 ( 9 ): 447-51 .. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
{ Department of Clinical Pharmacology and Therapeutics, College of Health Sciences, University of Nairobi, P.O. Box 19676, Nairobi, Kenya. OBJECTIVES: To identify potential predictors of mortality, to determine mortality rate and to identify prevalent causes of death in a cohort of HIV-1 exposed uninfected infants. DESIGN: Prospective cohort study. SETTING: Kenyatta National Hospital, Nairobi, Kenya. SUBJECTS: Three hundred and fifty one HIV-1 exposed uninfected post-neonatal infants who survived to one year of age. RESULTS: Sixteen infants died (post-neonatal mortality rate of 47/1000 live births), 14 (88%) before six months of age. The most frequently identified medical conditions at death included bronchopneumonia, diarrhoea and failure to thrive. In multivariate analysis, prematurity (RR=10.5, 95%CI 3.8-29.1, p<0.001), teenage motherhood (RR=3.6, Cl 1.0-13.2
MBORI-, PROFNGACHADOROTHYA, W. PROFNDUATIRUTH.  2005.  John-Stewart GC, Nduati RW, Rousseau CM, Mbori-Ngacha DA, Richardson BA, Rainwater S, Pantaleef DD, Overbaugh J. ubtype C is associated with increased vaginal shedding of HIV-1 J Infect. Dis Di 2005;192:492-6.. Dis Di 2005;192:492-6.. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
1. Centre for Virus Research, Kenya Medical Research Institute, Nairobi, Kenya; Department of Biochemistry, University of Nairobi, Kenya. Background: There are limited reports on HIV-1 RNA load, CD4+ T-lymphocytes and antibody responses in relation to disease progression in HIV-1 infected untreated children in Africa. Methods: To describe the relationships between these parameters, we conducted a longitudinal cohort study involving 51 perinatally HIV-1 infected children aged between 1 and 13 years. HIV status was determined by ELISA and confirmed by western blot and PCR. Antibodies were quantified by limiting dilution ELISA, plasma HIV-1 RNA load by RT-PCR and CD4+ T-lymphocytes by FACSCount. Results: Asymptomatic and symptomatic disease had, respectively, a rise in median HIV-1 RNA load from 1,195 to 132,543 and from 42,962 to 1,109,281 copies/ml in children below 6 years. The increase in viral load was 10-fold higher for asymptomatic compared to other categories and 2-fold faster for children less than 6 years than those above. Similarly, symptomatic children below 6 years had initial median CD4+ T-lymphocyte counts of 647 (22%) cells/muL, declining to 378 (20%) while those above 6 years had initial values of below 335 (15%) but which increased to 428 (17%). Median viral load correlated significantly with median CD4+ T-lymphocyte percentage in children above 6 years (p=0.026) but not below. Conclusions: Viral load is lower in older than younger children and correlates significantly with percentage CD4+ T-lymphocytes. Survival by HIV-1 infected children requires a competent immune response early in infection to counter the rapidly replicating virus. Interventions aimed at boosting the naive immune system may prolong survival in these children.
MBORI-, PROFNGACHADOROTHYA.  2005.  High maternal HIV-1 viral load during pregnancy is associated with reduced placental transfer of Measles IgG antibody. J Acquir Immune Defic Syndr 2005;40:494-497. Farquhar C, Nduati R, Haigwood N, Sutton W, Mbori-Ngacha D. Afr Health Sci. 2006 Mar;6(1):3-13.. : Earthscan, London. 978-1-84407-469-3 (*) Abstract
1. Centre for Virus Research, Kenya Medical Research Institute, Nairobi, Kenya; Department of Biochemistry, University of Nairobi, Kenya. Background: There are limited reports on HIV-1 RNA load, CD4+ T-lymphocytes and antibody responses in relation to disease progression in HIV-1 infected untreated children in Africa. Methods: To describe the relationships between these parameters, we conducted a longitudinal cohort study involving 51 perinatally HIV-1 infected children aged between 1 and 13 years. HIV status was determined by ELISA and confirmed by western blot and PCR. Antibodies were quantified by limiting dilution ELISA, plasma HIV-1 RNA load by RT-PCR and CD4+ T-lymphocytes by FACSCount. Results: Asymptomatic and symptomatic disease had, respectively, a rise in median HIV-1 RNA load from 1,195 to 132,543 and from 42,962 to 1,109,281 copies/ml in children below 6 years. The increase in viral load was 10-fold higher for asymptomatic compared to other categories and 2-fold faster for children less than 6 years than those above. Similarly, symptomatic children below 6 years had initial median CD4+ T-lymphocyte counts of 647 (22%) cells/muL, declining to 378 (20%) while those above 6 years had initial values of below 335 (15%) but which increased to 428 (17%). Median viral load correlated significantly with median CD4+ T-lymphocyte percentage in children above 6 years (p=0.026) but not below. Conclusions: Viral load is lower in older than younger children and correlates significantly with percentage CD4+ T-lymphocytes. Survival by HIV-1 infected children requires a competent immune response early in infection to counter the rapidly replicating virus. Interventions aimed at boosting the naive immune system may prolong survival in these children.
MBORI-, PROFNGACHADOROTHYA, W. PROFNDUATIRUTH.  2005.  Subtype C Is associated with increased vaginal shedding of HIV-1. J Infect Dis. 2005 Aug 1;192(3):492-6. Epub 2005 Jun 23. PMID: 15995964 [PubMed - indexed for MEDLINE] John-Stewart GC, Nduati RW, Rousseau CM, Mbori-Ngacha DA, Richardson BA, Rainwater S, . J Infect Dis. 2005 Aug 1;192(3):492-6. Epub 2005 Jun 23. PMID: 15995964 [PubMed - indexed for MEDLINE]. : Earthscan, London. 978-1-84407-469-3 (*) Abstract

Red Cross Children's Hospital, Rondebosch, 7701, Cape Town, South Africa.

OBJECTIVE: To draw attention to the sub-optimal care that HIV-infected children are receiving in Africa. DATA SOURCES: Relevant published literature. DATA SYNTHESIS: Sub-optimal response to paediatric HIV infection has aggravated the negative impact that the epidemic has had on child health in Africa. Recently the African Network for the Care of Children Affected by HIV/AIDS (ANNECA) released an advocacy statement that called for the optimisation of prevention, diagnosis, treatment and care for children affected by the AIDS pandemic. Effective prevention strategies if comprehensively implemented, could prevent more than 500 000 paediatric infections per annum at current antenatal HIV prevalence rates. Improved care that includes universal utilisation of early diagnostic testing systems, cotrimoxazole prophylaxis, nutritional support and the timely introduction of antiretroviral therapy could improve the quality of life and lifespan of most infected children. CONCLUSION: Political leaders, public health officials and fellow child health professionals are urged to redouble their efforts to reverse the magnitude of the paediatric epidemic in Africa.

PMID: 17685215 [PubMed - indexed for MEDLINE]

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