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1.  Explaining the uptake of paediatric guidelines in a Kenyan tertiary hospital – mixed methods research 
Background
Evidence-based standards for management of the seriously sick child have existed for decades, yet their translation in clinical practice is a challenge. The context and organization of institutions are known determinants of successful translation, however, research using adequate methodologies to explain the dynamic nature of these determinants in the quality-of-care improvement process is rarely performed.
Methods
We conducted mixed methods research in a tertiary hospital in a low-income country to explore the uptake of locally adapted paediatric guidelines. The quantitative component was an uncontrolled before and after intervention study that included an exploration of the intervention dose-effect relationship. The qualitative component was an ethnographic research based on the theoretical perspective of participatory action research. Interpretive integration was employed to derive meta-inferences that provided a more complete picture of the overall study results that reflect the complexity and the multifaceted ontology of the phenomenon studied.
Results
The improvement in health workers’ performance in relation to the intensity of the intervention was not linear and was characterized by improved and occasionally declining performance. Possible root causes of this performance variability included challenges in keeping knowledge and clinical skills updated, inadequate commitment of the staff to continued improvement, limited exposure to positive professional role models, poor teamwork, failure to maintain professional integrity and mal-adaptation to institutional pressures.
Conclusion
Implementation of best-practices is a complex process that is largely unpredictable, attributed to the complexity of contextual factors operating predominantly at professional and organizational levels. There is no simple solution to implementation of best-practices. Tackling root causes of inadequate knowledge translation in this tertiary care setting will require long-term planning, with emphasis on promotion of professional ethics and values and establishing an organizational framework that enhances positive aspects of professionalism. This study has significant implications for the quality of training in medical institutions and the development of hospital leadership.
doi:10.1186/1472-6963-14-119
PMCID: PMC3975593  PMID: 24613001
ETAT+; Ethnographic; Guidelines; Implementation; Performance; Mixed methods research; Hospital leadership; Complex adaptive system
2.  Factors influencing performance of health workers in the management of seriously sick children at a Kenyan tertiary hospital - participatory action research 
Background
Implementation of World Health Organization case management guidelines for serious childhood illnesses remains a challenge in hospitals in low-income countries. Facilitators of and barriers to implementation of locally adapted clinical practice guidelines (CPGs) have not been explored.
Methods
This ethnographic study based on the theory of participatory action research (PAR) was conducted in Kenyatta National Hospital, Kenya’s largest teaching hospital. The primary intervention consisted of dissemination of locally adapted CPGs. The PRECEDE-PROCEED health education model was used as the conceptual framework to guide and examine further reinforcement activities to improve the uptake of the CPGs. Activities focussed on introduction of routine clinical audits and tailored educational sessions. Data were collected by a participant observer who also facilitated the PAR over an eighteen-month period. Naturalistic inquiry was utilized to obtain information from all hospital staff encountered while theoretical sampling allowed in-depth exploration of emerging issues. Data were analysed using interpretive description.
Results
Relevance of the CPGs to routine work and emergence of a champion of change facilitated uptake of best-practices. Mobilization of basic resources was relatively easily undertaken while activities that required real intellectual and professional engagement of the senior staff were a challenge. Accomplishments of the PAR were largely with the passive rather than active involvement of the hospital management. Barriers to implementation of best-practices included i) mismatch between the hospital’s vision and reality, ii) poor communication, iii) lack of objective mechanisms for monitoring and evaluating quality of clinical care, iv) limited capacity for planning strategic change, v) limited management skills to introduce and manage change, vi) hierarchical relationships, and vii) inadequate adaptation of the interventions to the local context.
Conclusions
Educational interventions, often regarded as ‘quick-fixes’ to improve care in low-income countries, may be necessary but are unlikely to be sufficient to deliver improved services. We propose that an understanding of organizational issues that influence the behaviour of individual health professionals should guide and inform the implementation of best-practices.
doi:10.1186/1472-6963-14-59
PMCID: PMC3942276  PMID: 24507629
Clinical audits; Clinical practice guidelines; Continuous medical educational sessions; ETAT+; Ethnographic study; Implementation of best-practices; Interpretive description; Participatory action research; Participant observer; Performance of health workers
3.  Correlates and outcomes of preterm birth, low birth weight, and small for gestational age in HIV-exposed uninfected infants 
Background
Preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA) contribute to neonatal mortality. Maternal HIV-1 infection has been associated with an increased risk of PTB, but mechanisms underlying this association are undefined. We describe correlates and outcomes of PTB, LBW, and SGA in HIV-exposed uninfected infants.
Methods
This was a retrospective analysis of cohort study. Between 1999–2002, pregnant, HIV-infected women were enrolled into an HIV-1 transmission study. Logistic regression was used to identify correlates of PTB, LBW and SGA in HIV-negative, spontaneous singleton deliveries. Associations between birth outcomes and mortality were measured using survival analyses.
Results
In multivariable models, maternal plasma (OR = 2.1, 95% CI = 1.1-3.8) and cervical HIV-1 RNA levels (OR = 1.6, 95% CI = 1.1-2.4), and CD4 < 15% (OR = 2.4, 95% CI = 1.0-5.6) were associated with increased odds of PTB. Abnormal vaginal discharge and cervical polymorphonuclear leukocytes were also associated with PTB. Cervical HIV-1 RNA level (OR = 2.4, 95% CI = 1.5-6.7) was associated with an increased odds of LBW, while increasing parity (OR = 0.46, 95% CI = 0.24-0.88) was associated with reduced odds. Higher maternal body mass index (OR = 0.75, 95% CI = 0.61-0.92) was associated with a reduced odds of SGA, while bacterial vaginosis was associated with >3-fold increased odds (OR = 3.2, 95% CI = 1.4-7.4). PTB, LBW, and SGA were each associated with a >6-fold increased risk of neonatal death, and a >2-fold increased rate of infant mortality within the first year.
Conclusions
Maternal plasma and cervical HIV-1 RNA load, and genital infections may be important risk factors for PTB in HIV-exposed uninfected infants. PTB, LBW, and SGA are associated with increased neonatal and infant mortality in HIV-exposed uninfected infants.
doi:10.1186/1471-2393-14-7
PMCID: PMC3897882  PMID: 24397463
Preterm birth; Low birth weight; Small for gestational age; Pediatric HIV
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.  Hospital outcomes for paediatric pneumonia and diarrhoea patients admitted in a tertiary hospital on weekdays versus weekends: a retrospective study 
BMC Pediatrics  2013;13:74.
Background
Quality of patient care in hospitals has been shown to be inconsistent during weekends and night-time hours, and is often associated with reduced patient monitoring, poor antibiotic prescription practices and poor patient outcomes. Poorer care and outcomes are commonly attributed to decreased levels of staffing, supervision and expertise and poorer access to diagnostics. However, there are few studies examining this issue in low resource settings where mortality from common childhood illnesses is high and health care systems are weak.
Methods
This study uses data from a retrospective cross-sectional study aimed at “evaluating the uptake of best practice clinical guidelines in a tertiary hospital” with a pre and post intervention approach that spanned the period 2005 to 2009. We evaluated a primary hypothesis that mortality for children with pneumonia and/or dehydration aged 2–59 months admitted on weekends differed from those admitted on weekdays. A secondary hypothesis that poor quality of care could be a mechanism for higher mortality was also explored. Logistic regression was used to examine the association between mortality and the independent predictors of mortality.
Results
Our analysis indicates that there is no difference in mortality on weekends compared to weekdays even after adjusting for the significant predictors of mortality (OR = 1.15; 95% CI 0.90 -1.45; p = 0.27). There were similarly no significant differences between weekends and weekdays for the quality of care indicators, however, there was an overall improvement in mortality and quality of care through the period of study.
Conclusion
Mortality and the quality of care does not differ by the day of admission in a Kenyan tertiary hospital, however mortality remains high suggesting that continued efforts to improve care are warranted.
doi:10.1186/1471-2431-13-74
PMCID: PMC3655904  PMID: 23663546
Children; Pneumonia; Diarrhea; Weekend versus weekday; Quality of health care
6.  Acute Cytomegalovirus Infection Is Associated with Increased Frequencies of Activated and Apoptosis-Vulnerable T Cells in HIV-1-Infected Infants 
Journal of Virology  2012;86(20):11373-11379.
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.
doi:10.1128/JVI.00790-12
PMCID: PMC3457128  PMID: 22875969
7.  Breast Milk HIV-1 RNA Levels and Female Sex Are Associated With HIV-1–Specific CD8+ T-Cell Responses in HIV-1–Exposed, Uninfected Infants in Kenya 
The Journal of Infectious Diseases  2011;204(11):1806-1810.
Background. Although evidence supports a relationship between human immunodeficiency virus (HIV)–1 exposure and HIV-1−specific CD8+ T cell responses, studies have not demonstrated a direct association between the quantity of HIV-1 to which a person is exposed and the presence or absence of a response.
Methods. From 1999 to 2005, maternal HIV-1 RNA levels were measured in blood, cervical secretions, and breast milk at delivery and 1 month after delivery. HIV-1−specific interferon (IFN)–γ Elispot assays were conducted to determine infant CD8+ T-cell responses at 3 months of age.
Results. Among 161 infants tested with Elispot assays, 23 (14%) had positive results. Mothers whose infants had a positive assay had higher breast milk HIV-1 RNA levels at month 1 compared with mothers whose infants had negative Elispot assays (3.1 vs 2.5 log10 copies/mL; P = .017). Female infants were also more likely to have positive Elispot assays than male infants (P = .046), and in multivariate analyses, both female sex and high breast milk HIV-1 levels remained important predictors of a positive response (P = .022 and P = .015, respectively).
Conclusions. Exposure to breast milk HIV-1 and sex were associated with development of HIV-1−specific CD8+ T-cell responses in infants. These data support a role for mucosal exposure via the oral route in induction of systemic HIV-1−specific cellular immunity.
doi:10.1093/infdis/jir643
PMCID: PMC3203234  PMID: 21984736
8.  The Study of HIV and Antenatal Care Integration in Pregnancy in Kenya: Design, Methods, and Baseline Results of a Cluster-Randomized Controlled Trial 
PLoS ONE  2012;7(9):e44181.
Background
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.
Methodology/Principal Findings
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.
Conclusions/Significance
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.
Trial Registration
ClinicalTrials.gov NCT00931216 NCT00931216.
doi:10.1371/journal.pone.0044181
PMCID: PMC3435393  PMID: 22970177
9.  Performance of Health Workers in the Management of Seriously Sick Children at a Kenyan Tertiary Hospital: Before and after a Training Intervention 
PLoS ONE  2012;7(7):e39964.
Background
Implementation of WHO case management guidelines for serious common childhood illnesses remains a challenge in hospitals in low-income countries. The impact of locally adapted clinical practice guidelines (CPGs) on the quality-of-care of patients in tertiary hospitals has rarely been evaluated.
Methods and Findings
We conducted, in Kenyatta National Hospital, an uncontrolled before and after study with an attempt to explore intervention dose-effect relationships, as CPGs were disseminated and training was progressively implemented. The emergency triage, assessment and treatment plus admission care (ETAT+) training and locally adapted CPGs targeted common, serious childhood illnesses. We compared performance in the pre-intervention (2005) and post-intervention periods (2009) using quality indicators for three diseases: pneumonia, dehydration and severe malnutrition. The indicators spanned four domains in the continuum of care namely assessment, classification, treatment, and follow-up care in the initial 48 hours of admission. In the pre-intervention period patients' care was largely inconsistent with the guidelines, with nine of the 15 key indicators having performance of below 10%. The intervention produced a marked improvement in guideline adherence with an absolute effect size of over 20% observed in seven of the 15 key indicators; three of which had an effect size of over 50%. However, for all the five indicators that required sustained team effort performance continued to be poor, at less than 10%, in the post-intervention period. Data from the five-year period (2005–09) suggest some dose dependency though the adoption rate of the best-practices varied across diseases and over time.
Conclusion
Active dissemination of locally adapted clinical guidelines for common serious childhood illnesses can achieve a significant impact on documented clinical practices, particularly for tasks that rely on competence of individual clinicians. However, more attention must be given to broader implementation strategies that also target institutional and organisational aspects of service delivery to further enhance quality-of-care.
doi:10.1371/journal.pone.0039964
PMCID: PMC3409218  PMID: 22859945
10.  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
11.  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 
The Journal of Infectious Diseases  2006;195(2):220-229.
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/µL/month (P< .001), HIV-1 RNA levels increased 0.005 log10 copies/mL/month (P = .03), and body mass index (BMI) decreased 0.03 kg/m2/month (P< .001). The rate of CD4 cell count decline was higher in breast-feeding mothers (7.2 cells/µL/month) than in mothers who never breast-fed (4.0 cells/µL/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.
doi:10.1086/510245
PMCID: PMC3394541  PMID: 17191167
12.  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
13.  Subtype C Is Associated with Increased Vaginal Shedding of HIV-1 
The Journal of Infectious Diseases  2005;192(3):492-496.
The prevalence of human immunodeficiency virus (HIV)–1–infected cells and HIV-1 RNA levels in genital secretions and breast milk and the risk of mother-to-child transmission of HIV-1 were compared among subtypes A, C, and D in a Kenyan cohort. Pregnant women infected with subtype C were significantly more likely to shed HIV-1-infected vaginal cells than were those infected with subtype A or D (odds ratio [OR], 3.6 [95% confidence interval {CI}, 1.4–8.8]; P = .006). This relationship held after adjusting for age, CD4 cell count, and plasma HIV-1 RNA load (OR, 3.1 [95% CI, 1.1–8.6]; P = .03). These observations suggest that HIV-1 subtype influences mucosal shedding of HIV-1.
doi:10.1086/431514
PMCID: PMC3387274  PMID: 15995964
14.  Longitudinal Analysis of Human Immunodeficiency Virus Type 1 RNA in Breast Milk and of Its Relationship to Infant Infection and Maternal Disease 
The Journal of Infectious Diseases  2003;187(5):741-747.
Transmission of human immunodeficiency virus type 1 (HIV-1) via breast-feeding can occur throughout lactation. Defining both fluctuation in breast-milk virus level over time and how breast-milk virus correlates with mother-to-child transmission is important for establishing effective interventions. We quantified breast-milk HIV-1 RNA levels in serial samples collected from 275 women for up to 2 years after delivery. Higher maternal plasma virus load, lower maternal CD4 T cell count, and detection of HIV-1 DNA in maternal genital secretions were significantly associated with elevated breast-milk HIV-1 RNA. Within women who breast-fed, median virus load in colostrum/early milk was significantly higher than that in mature breast milk collected 14 days after delivery (P ≤ .004). Breast-feeding mothers who transmitted HIV-1 to their infants had both significantly higher breast-milk viral RNA throughout lactation and more-consistent viral shedding, compared with mothers who did not transmit HIV-1. In breast-feeding women, a 2-fold-increased risk of transmission was associated with every 10-fold increase in breast-milk virus load (95% confidence interval, 1.3–3.0; P < .001). These results indicate that the risk of infant infection from breast-feeding is influenced by breast-milk virus load, which is highest early after delivery.
doi:10.1086/374273
PMCID: PMC3384731  PMID: 12599047
15.  Antenatal Couple Counseling Increases Uptake of Interventions to Prevent HIV-1 Transmission 
Summary
To determine effect of partner involvement and couple counseling on uptake of interventions to prevent HIV-1 transmission, women attending a Nairobi antenatal clinic were encouraged to return with partners for voluntary HIV-1 counseling and testing (VCT) and offered individual or couple posttest counseling. Nevirapine was provided to HIV-1-seropositive women and condoms distributed to all participants. Among 2104 women accepting testing, 308 (15%) had partners participate in VCT, of whom 116 (38%) were couple counseled. Thirty-two (10%) of 314 HIV-1-seropositive women came with partners for VCT; these women were 3-fold more likely to return for nevirapine (P = 0.02) and to report administering nevirapine at delivery (P = 0.009). Nevirapine use was reported by 88% of HIV-infected women who were couple counseled, 67% whose partners came but were not couple counseled, and 45% whose partners did not present for VCT (P for trend = 0.006). HIV-1-seropositive women receiving couple counseling were 5-fold more likely to avoid breast-feeding (P = 0.03) compared with those counseled individually. Partner notification of HIV-1-positive results was reported by 138 women (64%) and was associated with 4-fold greater likelihood of condom use (P = 0.004). Partner participation in VCT and couple counseling increased uptake of nevirapine and formula feeding. Antenatal couple counseling may be a useful strategy to promote HIV-1 prevention interventions.
PMCID: PMC3384734  PMID: 15577420
voluntary counseling and testing; couple counseling; mother-to-child HIV-1 transmission; breastfeeding; nevirapine; condom use; partner notification
16.  Association of Levels of HIV-1–Infected Breast Milk Cells and Risk of Mother-to-Child Transmission 
The Journal of Infectious Diseases  2004;190(10):1880-1888.
Understanding how the level of human immunodeficiency virus type 1 (HIV-1)–infected breast milk cells (BMCs) affects HIV transmission via breast-feeding can shed light on the mechanism of infection and aid in establishing effective interventions. The proportion of infected cells to total cells was measured in serial breast milk samples collected from 291 HIV-1–infected women in Nairobi, Kenya, by use of real-time DNA polymerase chain reaction amplification of BMCs. The number of infected BMCs per million cells was associated with levels of cell-free viral RNA in breast milk (R = .144; P = .032), levels of cell-free virus in blood plasma (R = .365; P < .001), and the detection of proviral DNA in cervical and vaginal secretions (P < .001 and P = .030, respectively). The number of infected BMCs per million cells was lower in colostrum or early milk than in mature milk (P < .001). Previous studies demonstrated that the concentration of BMCs varies throughout lactation, and we used these data to transform infected BMCs per million cells to infected BMCs per milliliter. The estimated concentration of infected BMCs per milliliter was higher in colostrum or early milk than in mature milk (P < .001). Each log10 increase in infected BMCs per milliliter was associated with a 3.19-fold–increased risk of transmission (P = 002), after adjustment for cell-free virus in plasma (hazard ratio [HR], 2.09; P = 03) and breast milk (HR, 1.01; P = 1.00). This suggests that infected BMCs may play a more important role in transmission of HIV via breast-feeding than does cell-free virus.
doi:10.1086/425076
PMCID: PMC3384735  PMID: 15499546
17.  Longitudinal Comparison of Chemokines in Breastmilk Early Postpartum Among HIV-1-Infected and Uninfected Kenyan Women 
Breastfeeding Medicine  2007;2(3):129-138.
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-1α, MIP-1β, RANTES, and SDF-1α. 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-1α, MIP-1β, and SDF-1α, 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-1β 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-1β 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.
doi:10.1089/bfm.2007.0009
PMCID: PMC3381953  PMID: 17903098
18.  Salivary Secretory Leukocyte Protease Inhibitor Is Associated with Reduced Transmission of Human Immunodeficiency Virus Type 1 through Breast Milk 
The Journal of Infectious Diseases  2002;186(8):1173-1176.
Secretory leukocyte protease inhibitor (SLPI), a protein found in saliva, breast milk, and genital secretions, is capable of inhibiting human immunodeficiency virus (HIV) type 1 in vitro. The aim of this study was to determine whether SLPI in infant saliva provides protection against mother-to-child HIV-1 transmission. In total, 602 saliva specimens were collected from 188 infants at birth and at ages 1, 3, and 6 months. Infants’ median salivary SLPI concentrations were higher at birth than at 6 months (341 vs. 219 ng/mL; P = .001). There was no association between SLPI concentration and HIV-1 transmission overall. However, among 122 breast-fed infants who were HIV-1 uninfected at 1 month, higher salivary SLPI levels were associated with a decreased risk of HIV-1 transmission through breast milk (hazard ratio, 0.5; 95% confidence interval, 0.3–0.9; P = .03). These results suggest that SLPI plays an important role in reducing HIV-1 transmission through breast milk.
doi:10.1086/343805
PMCID: PMC3382060  PMID: 12355371
19.  High Maternal HIV-1 Viral Load During Pregnancy Is Associated With Reduced Placental Transfer of Measles IgG Antibody 
Background
Studies among HIV-1–infected women have demonstrated reduced placental transfer of IgG antibodies against measles and other pathogens. As a result, infants born to women with HIV-1 infection may not acquire adequate passive immunity in utero and this could contribute to high infant morbidity and mortality in this vulnerable population.
Methods
To determine factors associated with decreased placental transfer of measles IgG, 55 HIV-1–infected pregnant women who were enrolled in a Nairobi perinatal HIV-1 transmission study were followed. Maternal CD4 count, HIV-1 viral load, and HIV-1–specific gp41 antibody concentrations were measured antenatally and at delivery. Measles IgG concentrations were assayed in maternal blood and infant cord blood obtained during delivery to calculate placental antibody transfer.
Results
Among 40 women (73%) with positive measles titers, 30 (75%) were found to have abnormally low levels of maternofetal IgG transfer (<95%). High maternal HIV-1 viral load at 32 weeks’ gestation and at delivery was associated with reductions in placental transfer (P < 0.0001 and P = 0.0056, respectively) and infant measles IgG concentrations in cord blood (P < 0.0001 and P = 0.0073, respectively). High maternal HIV-1–specific gp41 antibody titer was also highly correlated with both decreased placental transfer (P = 0.0080) and decreased infant IgG (P < 0.0001).
Conclusions
This is the first study to evaluate the relationship between maternal HIV-1 viremia, maternal HIV-1 antibody concentrations, and passive immunity among HIV-1–exposed infants. These data support the hypothesis that high HIV-1 viral load during the last trimester may impair maternofetal transfer of IgG and increases risk of measles and other serious infections among HIV-1–exposed infants.
PMCID: PMC3382062  PMID: 16280707
placental antibody transfer; maternal HIV-1 viral load; measles IgG; HIV-1–specific gp41 antibody; mother-to-child HIV-1 transmission
20.  Modified vaccinia Ankara expressing HIVA antigen stimulates HIV-1-specific CD8 T cells in ELISpot assays of HIV-1 exposed infants☆ 
Vaccine  2005;23(38):4711-4719.
Recombinant modified vaccinia virus Ankara expressing HIV-1 antigens (MVA.HIVA) was used in ELISpot assays to monitor HIV-1-specific T cell responses in infants. Responses to MVA.HIVA and HIV-1 peptides were examined in 13 infected and 81 exposed uninfected infants in Nairobi, Kenya. Responses to MVA.HIVA (38%) and peptide stimulation (38%) were similar in frequency (p = 1.0) and magnitude (mean 176 versus 385 HIVSFU/106, p = 0.96) in HIV-1 infected infants. In exposed uninfected infants, MVA.HIVA detected more positive responses and higher magnitude responses as compared to peptide. MVA.HIVA ELISpot is a sensitive method for quantification of HIV-1-specific CD8+ T cell responses in HIV-1 exposed infants. These results demonstrate the relevance of HIV-1 clade A consensus-derived immunogen HIVA for the viruses currently circulating in Nairobi.
doi:10.1016/j.vaccine.2005.01.145
PMCID: PMC3382083  PMID: 16043269
Enzyme-linked immunospot assay; Exposed seronegatives; Mother to child transmission
21.  Breast-feeding and Transmission of HIV-1 
Breast-feeding substantially increases the risk of HIV-1 transmission from mother to child, and although peripartum antiretroviral therapy prophylaxis significantly decreases the risk of mother-to-child transmission around the time of delivery, this approach does not affect breast-feeding transmission. Increased maternal RNA viral load in plasma and breast milk is strongly associated with increased risk of transmission through breast-feeding, as is breast health, and it has been suggested that exclusive breast-feeding could be associated with lower rates of breast-feeding transmission than mixed feeding of both breast- and other milk or feeds. Transmission through breast-feeding can take place at any point during lactation, and the cumulative probability of acquisition of infection increases with duration of breast-feeding. HIV-1 has been detected in breast milk in cell-free and cellular compartments; infant gut mucosal surfaces are the most likely site at which transmission occurs. Innate and acquired immune factors may act most effectively in combination to prevent primary HIV-1 infection by breast milk.
PMCID: PMC3382106  PMID: 14722454
breastfeeding; mother-to-child transmission; postnatal transmission; risk factors; mechanisms
22.  Breast-Milk Infectivity in Human Immunodeficiency Virus Type 1–Infected Mothers 
The Journal of Infectious Diseases  2003;187(5):736-740.
Human immunodeficiency virus type 1 (HIV-1) is transmitted through blood, genital secretions, and breast milk. The probability of heterosexual transmission of HIV-1 per sex act is .0003–0015, but little is known regarding the risk of transmission per breast-milk exposure. We evaluated the probability of breast-milk transmission of HIV-1 per liter of breast milk ingested and per day of breast-feeding in a study of children born to HIV-1–infected mothers. The probability of breast-milk transmission of HIV-1 was .00064 per liter ingested and .00028 per day of breast-feeding. Breast-milk infectivity was significantly higher for mothers with more-advanced disease, as measured by prenatal HIV-1 RNA plasma levels and CD4 cell counts. The probability of HIV-1 infection per liter of breast milk ingested by an infant is similar in magnitude to the probability of heterosexual transmission of HIV-1 per unprotected sex act in adults.
doi:10.1086/374272
PMCID: PMC3382109  PMID: 12599046
23.  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
24.  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
25.  Predictors of Early Mortality in a Cohort of Human Immunodeficiency Virus Type 1-Infected African Children 
Background
Pediatric human immunodeficiency virus type 1 (HIV-1) infection follows a bimodal clinical course with rapid progression in 10 – 45% of children before the age of 2 years and slower progression in the remainder. A prospective observational study was undertaken to determine predictors of mortality in HIV-1-infected African infants during the first 2 years of life.
Methods
Infants in a perinatal cohort identified to be HIV-1-infected by DNA PCR were followed monthly to 1 year, then quarterly to 2 years or death.
Results
Among 62 HIV-1-infected infants, infection occurred by the age of 1 month in 56 (90%) infants, and 32 (52%) died at median age of 6.2 months. All infant deaths were caused by infectious diseases, most frequently pneumonia (75%) and diarrhea (41%). Univariate predictors of infant mortality included maternal CD4 count <200 cells/μl [hazard ratio (HR), 3.4; P = 0.008], maternal anemia (HR = 3.7; P = 0.005), delivery complications (HR = 2.7; P = 0.01), low birth weight (HR = 4.1; P = 0.001), weight, length and head circumference ≤5th percentile at age 1 month (HR = 3.7, P = 0.003; HR = 5.8, P < 0.001; and HR = 10.4, P < 0.001, respectively), formula-feeding (HR = 4.0; P = 0.01), infant CD4% ≤15% (HR = 5.5; P = 0.01), infant CD4 count <750 (HR = 9.7; P = 0.006) and maternal death (HR = 2.9, P = 0.05). In multivariate analysis, maternal CD4 count <200 (HR = 2.7; P = 0.03) and delivery complications (HR = 3.4; P = 0.005) were independently associated with infant mortality.
Conclusions
Advanced maternal HIV disease, maternal anemia, delivery complications, early growth faltering, formula-feeding and low infant CD4 were predictors of early mortality in African HIV-1-infected infants. In resource-poor settings, these predictors may be useful for early identification and treatment of high risk infants.
PMCID: PMC3380074  PMID: 15194835
Human immunodeficiency virus type 1; disease progression; mortality; predictors

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