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1.  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.
PMCID: PMC3387274  PMID: 15995964
2.  Infant feeding and prevention of mother-to-child transmission of HIV-1 
Current Opinion in HIV and AIDS  2008;3(2):173-179.
Purpose of review
To review new studies and directions regarding infant feeding and HIV-1 transmission.
Recent findings
With antiretroviral drugs and shortened breastfeeding, breast milk HIV-1 transmission risk can be decreased from 16 to less than 5%. In the context of peripartum antiretroviral drugs/short breastfeeding, replacement feeding provides negligible benefit in decreasing the risk of HIV-1/death in contrast to previous studies of no antiretroviral drugs/unlimited breastfeeding in which it offered benefit. One study noted a high risk of infant HIV-1 or death (≥17%) after 4 months, with no difference in risk in infants with shortened breastfeeding versus indefinite breastfeeding. This study suggests that shortened breastfeeding needs caution in implementation. Other African studies have noted minimal risk of HIV-1 or death (<2%) after shortened breastfeeding, underscoring the heterogeneity of infant survival in different settings and the potential to improve infant survival.
Antiretroviral drugs and shortened breastfeeding markedly decrease breastfeeding HIV-1 transmission, shifting the balance to make replacement feeding less beneficial. In some settings shortened breastfeeding poses similar risks as replacement feeding and provides no infant health benefit compared with extended breastfeeding. Programmes aimed at decreasing infant HIV-1 need to do so in the context of promoting infant survival. Strengthening systems to promote infant health is critical.
PMCID: PMC3373175  PMID: 19372962
breastfeeding; HAART; replacement feeding
3.  Acute HIV Infection among Kenyan Infants 
Clinical signs and symptoms of acute human immunodeficiency virus (HIV) infection in infants are not well characterized.
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. ≥2 months). HIV RNA was measured serially in infected infants and was compared between infants with and infants without symptoms of acute HIV infection.
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 ≥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).
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.
PMCID: PMC3310239  PMID: 18171265
4.  Consistency of Mycobacterium tuberculosis-Specific Interferon-Gamma Responses in HIV-1-Infected Women during Pregnancy and Postpartum 
Background. We determined the consistency of positive interferon-gamma (IFN-γ) release assays (IGRAs) to detect latent TB infection (LTBI) over one-year postpartum in HIV-1-infected women. Methods. Women with positive IGRAs during pregnancy had four 3-monthly postpartum IGRAs. Postpartum change in magnitude of IFN-γ response was determined using linear mixed models. Results. Among 18 women with positive pregnancy IGRA, 15 (83%) had a subsequent positive IGRA; 9 (50%) were always positive, 3 (17%) were always negative, and 6 (33%) fluctuated between positive and negative IGRAs. Women with pregnancy IGRA IFN-γ>8 spot forming cells (SFCs)/well were more likely to have consistent postpartum IGRA response (odds ratio: 10.0; 95% confidence interval (CI): 0.9–117.0). Change in IFN-γ response over postpartum was 10.2 SFCs/well (95% CI: −1.5–21.8 SFCs/well). Conclusion. Pregnancy positive IGRAs were often maintained postpartum with increased consistency in women with higher baseline responses. There were modest increases in magnitude of IGRA responses postpartum.
PMCID: PMC3312220  PMID: 22496602
5.  When Is Replacement Feeding Safe for Infants of HIV-Infected Women? 
PLoS Medicine  2007;4(1):e30.
PMCID: PMC1769417  PMID: 17227137
6.  Toll-like Receptor (TLR) variants are associated with infant HIV-1 acquisition and peak plasma HIV-1 RNA level 
AIDS (London, England)  2013;27(15):2431-2439.
We evaluated the association of single nucleotide polymorphisms (SNPs) in TLRs with infant HIV-1 acquisition and viral control.
Infant HIV-1 outcomes were assessed in a Kenyan perinatal HIV-1 cohort.
Infants were genotyped for six candidate and 118 haplotype-tagging polymorphisms in TLRs 2, 3, 4, 7, 8, and 9, MYD88 and TIRAP. Cox proportional hazards and linear regression were performed to assess associations with time to HIV-1 acquisition, time to infant mortality, and peak viral load (VL).
Among 368 infants, 56 (15%) acquired HIV-1 by month 1 and 17 (4.6%) between 1 and 12 months. Infants with the TLR9 1635A (rs352140) variant were more likely to acquire HIV-1 by 1 month (HR=1.81, 95% confidence interval [CI] =1.05-3.14, p=0.033) and by 12 months (HR=1.62, CI=1.01-2.60, p=0.044) in dominant models adjusted for maternal plasma HIV-1 RNA level and genetic ancestry. Among 56 infants infected at ≤1 month of age, ≥1 copy of the TLR9 1635A allele was associated with a 0.58 log10 c/ml lower peak VL (p=0.002). Female infants with ≥1 copy of the TLR8 1G (rs3764880) variant had a 0.78 log10 c/ml higher peak VL (p=0.0009) and having ≥1 copy of the C allele for a haplotype tagging TLR7 variant (rs1634319) was associated with a 0.80 log10 c/ml higher peak VL in female infants (p=0.0003).
In this African perinatal cohort, we found several TLR polymorphisms associated with HIV-1 acquisition and progression. Defining mechanisms for these TLR associations may inform HIV-1 prevention strategies that leverage innate responses.
PMCID: PMC4124859  PMID: 24037211
pediatric HIV; mother-to-child transmission; genetic epidemiology; HIV genetics; innate immunity; single nucleotide polymorphisms; toll-like receptors; TLRs
7.  Domestic violence and prevention of mother-to-child transmission of HIV-1 
AIDS (London, England)  2006;20(13):1763-1769.
To determine the prevalence of life-time domestic violence by the current partner before HIV-1 testing, its impact on the uptake of prevention of mother-to-child transmission (PMTCT) interventions and frequency after testing.
A prospective cohort.
Antenatally, women and their partners were interviewed regarding physical, financial, and psychological abuse by the male partner before HIV-1 testing and 2 weeks after receiving results.
Before testing, 804 of 2836 women (28%) reported previous domestic violence, which tended to be associated with increased odds of HIV-1 infection [univariate odds ratio (OR) 1.7, 95% confidence interval (CI) 1.3–2.2; P < 0.0001, adjusted OR 1.2, 95% CI 0.9–1.6; P = 0.1], decreased odds of coming with partners for counseling (adjusted OR 0.7, 95% CI 0.5–1.0; P = 0.04), and decreased odds of partner notification (adjusted OR 0.7, 95% CI 0.5–1.1; P = 0.09). Previous domestic violence was not associated with a reduced uptake of HIV-1 counseling, HIV-1 testing, or nevirapine. After receiving results, 15 out of 1638 women (0.9%) reported domestic violence. After notifying partners of results, the odds of HIV-1-seropositive women reporting domestic violence were 4.8 times those of HIV-1-seronegative women (95% CI 1.4–16; P = 0.01). Compared with women, men reported similar or more male-perpetrated domestic violence, suggesting a cultural acceptability of violence.
Domestic violence before testing may limit partner involvement in PMTCT. Although infrequent, immediate post-test domestic violence is more common among HIV-1-infected than uninfected women. Domestic violence prevention programmes need to be integrated into PMTCT, particularly for HIV-1-seropositive women.
PMCID: PMC3384736  PMID: 16931941
Adverse effects; Africa; domestic violence; HIV; vertical transmission; prevention of mother-to-child transmission
8.  The effect of rapid HIV-1 testing on uptake of perinatal HIV-1 interventions: a randomized clinical trial 
AIDS (London, England)  2003;17(1):113-118.
We examined whether HIV-1 testing using a rapid assay increases the proportion of pregnant women obtaining HIV-1 results and the uptake of perinatal HIV-1 interventions.
Pregnant women attending public health clinics in Nairobi were offered voluntary counselling and testing for HIV-1. Consenting women were randomly assigned to receive either rapid or conventional HIV-1 testing. Women randomly assigned to rapid testing were allowed to receive same-day results or to return later. The results for women randomly assigned to conventional enzyme-linked immunosorbent assay (ELISA) testing were available after 7 days. HIV-1-infected women were referred for antiretroviral prophylaxis to prevent mother-to-child transmission of HIV-1.
Among 1282 women offered voluntary HIV-1 testing and counselling, 1249 accepted testing, of whom 627 were randomly assigned to rapid testing and 622 to conventional testing. The median duration between testing and obtaining results was 0 days for women who received rapid testing compared with 11 days for women who received conventional testing. The percentage receiving HIV-1 results was significantly higher among women who received rapid testing compared with conventional testing. Of 161 HIV-1-seropositive women, only 24 received antiretroviral prophylaxis. The uptake of perinatal HIV-1 interventions did not differ between HIV-1-seropositive women randomly assigned to rapid testing or conventional ELISA testing.
Rapid HIV-1 testing significantly increased the proportion of women receiving HIV-1 results, which is important for sexual and perinatal HIV-1 prevention. The challenge remains to improve the uptake of perinatal HIV-1 interventions among HIV-1-seropositive women.
PMCID: PMC3380077  PMID: 12478076
Africa; perinatal HIV interventions; prevention of mother-to-child transmission of HIV; randomized clinical trial; rapid HIV testing; voluntary counselling and testing
9.  Comparing Papanicolau smear, visual inspection with acetic acid and human papillomavirus cervical cancer screening methods among HIV-positive women by immune status and antiretroviral therapy 
AIDS (London, England)  2013;27(18):2909-2919.
A rigorous comparison of cervical cancer screening methods utilizing data on immune status, antiretroviral therapy (ART) and colposcopy-directed biopsy has not been performed among HIV-positive women.
Between June and November 2009, 500 HIV-positive women were enrolled at an HIV treatment clinic in Nairobi, Kenya, and underwent Papanicolau (Pap) smear, visual inspection with acetic acid (VIA), human papillomavirus (HPV) and colposcopy-directed biopsy (gold standard). Positive Pap smear (ASCUS+, LSIL+, HSIL+), VIA, HPV and their combinations were compared with CIN2/3+. Sensitivity, specificity and AUC (sensitivity and 1–specificity) were compared using pairwise tests and multivariate logistic regression models that included age, CD4+ cell count and ART duration.
Of 500 enrolled, 498 samples were collected. On histology, there were 172 (35%) normal, 186 (37%) CIN1, 66 (13%) CIN2, 47 (9%) CIN3 and 27 (5%) indeterminate. Pap (ASCUS+) was the most sensitive screening method (92.7%), combination of both Pap (HSIL+) and VIA positive was the most specific (99.1%) and Pap (HSIL+) had the highest AUC (0.85). In multivariate analyses, CD4+ cell count of 350 cells/μl or less was associated with decreased HPV specificity (P = 0.002); ART duration of less than 2 years was associated with decreased HPV (P = 0.01) and VIA (P = 0.03) specificity; and age less than 40 years was associated with increased VIA sensitivity (P < 0.001) and decreased HPV specificity (P = 0.005).
Pap smear is a robust test among HIV-positive women regardless of immune status or ART duration. Results should be cautiously interpreted when using HPV among those younger, immunosuppressed or on ART less than 2 years, and when using VIA among those aged 40 years or more.
PMCID: PMC4007364  PMID: 23842133
cervical cancer screening; HIV-1; human papillomavirus; Papanicolau smear; visual inspection with acetic acid
10.  Mode of delivery and postpartum HIV-1 disease progression and mortality in a Kenyan cohort 
There are limited data on the impact of cesarean section delivery on HIV-1 infected women in Sub-Saharan Africa. The purpose of this study was to assess the effect of mode of delivery on HIV-1 disease progression and postpartum mortality in a Kenyan cohort.
A prospective cohort study was conducted in Nairobi, Kenya from 2000–2005. We determined changes in CD4+ counts, HIV-1 RNA levels and mortality during the first year postpartum between HIV-1 infected women who underwent vaginal delivery (VD), non-scheduled cesarean section (NSCS) and scheduled cesarean section (SCS) and received short-course zidovudine. Loess curves and multivariate linear mixed effects models were used to compare longitudinal changes in maternal HIV-1 RNA and CD4+ counts by mode of delivery. Kaplan Meier curves, the log rank test, and Cox proportional hazards regression were used to assess difference in mortality.
Of 501 women, 405 delivered by VD, 74 delivered by NSCS and 22 by SCS. Baseline characteristics were similar between the VD and NSCS groups. Baseline antenatal CD4+ counts were lowest and HIV-1 RNA levels highest in the NSCS group but HIV-1 RNA levels were similar between groups at delivery. The rate of decline in CD4+ cells and rate of increase in HIV-1 RNA did not differ between groups. After adjusting for confounders, women who underwent NSCS had a 3.39-fold (95% CI 1.11, 10.35, P = 0.03) higher risk of mortality in the first year postpartum compared to women with VD.
Non-scheduled cesarean section was an independent risk factor for postpartum mortality in HIV-1 positive Kenyan women. The cause of death was predominantly due to HIV-1 related infections, and not direct maternal deaths, however, this was not mirrored by differential changes in HIV-1 progression markers between the groups.
PMCID: PMC4133616  PMID: 25086834
HIV; Mode of delivery; Cesarean section; HIV-1 disease progression; Maternal mortality
11.  Lipid Changes in Kenyan HIV-1-Infected Infants Initiating Highly Active Antiretroviral Therapy by One Year of Age 
Early highly active antiretroviral therapy (HAART) is recommended for HIV-1 infected infants. There are limited data on lipid changes during infant HAART.
Non-fasting total (TC), low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol, and triglycerides (TG) were measured at 0, 6 and 12 months. Correlates of lipid levels and changes post-HAART were assessed using linear regression.
Among 115 infants, pre-HAART median age was 3.8 months, CD4% was 19%, and weight-for-age z-score (WAZ) was −2.42. Pre-HAART median lipid levels were: TC, 108.7 mg/dl, LDL, 42.5 mg/dl, HDL, 29.4 mg/dl and TG, 186.9 mg/dl. Few infants had abnormally high TC (6.2%) or LDL (5.6%), but many had low HDL (76.5%) or high TG (69.6%). Higher pre-HAART WAZ and HAZ were each associated with higher pre-HAART TC (P=0.04 and P=0.01) and LDL (P=0.02 and P=0.008). From 0–6 months post-HAART, TC (P<0.0001), LDL (P<0.0001), and HDL (P<0.0001) increased significantly, and 23.1% (P=0.002), 14.0% (P=0.2), 31.3% (P<0.0001), and 50.8% (P=0.2) of infants had abnormally high TC, high LDL, low HDL, and high TG, respectively. Changes in TC and HDL were each associated with higher gain in WAZ (P=0.03 and P=0.01) and HAZ (P=0.01 and P=0.007). Increased change in LDL was associated with higher gain in HAZ (P=0.03). Infants on protease inhibitor (PI)-HAART had smaller HDL increase (P=0.004).
Infants had substantive increases in lipids, which correlated with growth. Increases in HDL were attenuated by PI-HAART. It is important to determine clinical implications of these changes.
PMCID: PMC3737429  PMID: 23385950
lipids; pediatric HIV-1; highly active antiretroviral therapy; infants; Africa
12.  Short Communication: T Cell Activation in HIV-1/Herpes Simplex Virus-2-Coinfected Kenyan Women Receiving Valacyclovir 
Herpes simplex virus-2 (HSV-2) suppression with acyclovir or valacyclovir reduces HIV-1 viral RNA levels; one hypothesis is that HSV-2 suppression reduces immune activation. We measured T cell immune activation markers among women participating in a randomized placebo-controlled trial of valacyclovir to reduce HIV-1 RNA levels among pregnant women. Although valacyclovir was associated with lower HIV-1 RNA levels, the distribution of both CD4+ and CD8+ CD38+HLA-DR+ T cells was not different among women taking valacyclovir when compared to women taking placebo. Further study is needed to understand the mechanism of HIV-1 RNA reduction following herpes suppression among those coinfected with HIV-1 and HSV-2.
PMCID: PMC3537320  PMID: 22852760
14.  Male, Mobile, and Moneyed: Loss to Follow-Up vs. Transfer of Care in an Urban African Antiretroviral Treatment Clinic 
PLoS ONE  2013;8(10):e78900.
The purpose of this study was to analyze characteristics, reasons for transferring, and reasons for discontinuing care among patients defined as lost to follow-up (LTFU) from an antiretroviral therapy (ART) clinic in Nairobi, Kenya.
The study used a prospective cohort of patients who participated in a randomized, controlled ART adherence trial between 2006 and 2008.
Participants were followed from pre-ART clinic enrollment to 18 months after ART initiation, and were defined as LTFU if they failed to return to clinic 4 weeks after their last scheduled visit. Reasons for loss were captured through phone call or home visit. Characteristics of LTFU who transferred care and LTFU who did not transfer were compared to those who remained in clinic using log-binomial regression to estimate risk ratios.
Of 393 enrolled participants, total attrition was 83 (21%), of whom 75 (90%) were successfully traced. Thirty-seven (49%) were alive at tracing and 22 (59%) of these reported having transferred their antiretroviral care. In the final model, transfers were more likely to have salaried employment [Risk Ratio (RR), 2.7; 95% confidence interval (CI), 1.2-6.1; p=0.020)] and pay a higher monthly rent (RR, 5.8; 95% CI, 1.3-25.0; p=0.018) compared to those retained in clinic. LTFU who did not transfer care were three times as likely to be men (RR, 3.1; 95% CI, 1.1-8.1; p=0.028) and nearly 4 times as likely to have a primary education or less (RR, 3.8; 95% CI, 1.3-10.6; p=0.013). Overall, the most common reason for LTFU was moving residence, predominantly due to job loss or change in employment.
A broad definition of LTFU may include those who have transferred their antiretroviral care and thereby overestimate negative effects on ART continuation. Interventions targeting men and considering mobility due to employment may improve retention in urban African ART clinics.
Clinical Trials
The study’s identifier is NCT00273780.
PMCID: PMC3812001  PMID: 24205345
15.  A Phase I Randomized Clinical Trial of Candidate Human Immunodeficiency Virus type 1 Vaccine MVA.HIVA Administered to Gambian Infants 
PLoS ONE  2013;8(10):e78289.
A vaccine to decrease transmission of human immunodeficiency virus type 1 (HIV-1) during breast-feeding would complement efforts to eliminate infant HIV-1 infection by antiretroviral therapy. Relative to adults, infants have distinct immune development, potentially high-risk of transmission when exposed to HIV-1 and rapid progression to AIDS when infected. To date, there have been only three published HIV-1 vaccine trials in infants.
Trial Design
We conducted a randomized phase I clinical trial PedVacc 001 assessing the feasibility, safety and immunogenicity of a single dose of candidate vaccine MVA.HIVA administered intramuscularly to 20-week-old infants born to HIV-1-negative mothers in The Gambia.
Infants were followed to 9 months of age with assessment of safety, immunogenicity and interference with Expanded Program on Immunization (EPI) vaccines. The trial is the first stage of developing more complex prime-boost vaccination strategies against breast milk transmission of HIV-1.
From March to October 2010, 48 infants (24 vaccine and 24 no-treatment) were enrolled with 100% retention. The MVA.HIVA vaccine was safe with no difference in adverse events between vaccinees and untreated infants. Two vaccine recipients (9%) and no controls had positive ex vivo interferon-γ ELISPOT assay responses. Antibody levels elicited to the EPI vaccines, which included diphtheria, tetanus, whole-cell pertussis, hepatitis B virus, Haemophilus influenzae type b and oral poliovirus, reached protective levels for the vast majority and were similar between the two arms.
A single low-dose of MVA.HIVA administered to 20-week-old infants in The Gambia was found to be safe and without interference with the induction of protective antibody levels by EPI vaccines, but did not alone induce sufficient HIV-1-specific responses. These data support the use of MVA carrying other transgenes as a boosting vector within more complex prime-boost vaccine strategies against transmission of HIV-1 and/or other infections in this age group.
Trial Registration NCT00982579
The Pan African Clinical Trials Registry PACTR2008120000904116
PMCID: PMC3813444  PMID: 24205185
16.  Survival Benefit of Early Infant Antiretroviral Therapy is Compromised when Diagnosis is Delayed 
Late presentation is common among African HIV-1-infected infants. Incidence and correlates of mortality were examined in 99 infants with HIV-1 diagnosis by age 5 months. Twelve-month survival was 66.8% (95% confidence interval, 55.9%, 75.6%). WHO stage 3/4, underweight, wasting, microcephaly, low hemoglobin, pneumonia, and gastroenteritis predicted mortality. Early HIV-1 diagnosis with ART before symptomatic disease is critical for infant survival.
PMCID: PMC3756892  PMID: 22544051
Pediatric; Infant; HIV-1; Antiretroviral therapy; Mortality
17.  Increased incidence of symptomatic peripheral neuropathy among adults receiving stavudine- versus zidovudine-based antiretroviral regimens in Kenya 
Journal of neurovirology  2012;18(3):200-204.
The incidence of peripheral neuropathy (PN) among adults initiating antiretroviral therapy (ART) containing stavudine (d4T) versus zidovudine (ZDV) is not well described. We compared 1-year incidence between d4T- and ZDV-based regimens in adults initiating ART in a programmatic setting in Kenya. Of 1,848 adults on ART, 1,579 (85 %) initiated d4T-based and 269 (15 %) initiated ZDV-based regimens. One-year incidence of symptomatic PN per 100 person-years was 21.9 (n=236) among d4T users and 6.9 (n=7) among ZDV users (P=0.0002). D4T was associated with 2.7 greater risk of PN than ZDV (adjusted hazard ratio, 2.7, P=0.009). In settings with continued d4T use, such as Africa, the effects of d4T on PN compared to ZDV should be considered when choosing ART regimens.
PMCID: PMC3726537  PMID: 22528481
Peripheral neuropathy; Africa; Antiretroviral therapy; Toxicity; HIV
18.  Low-frequency nevirapine resistance at multiple sites may predict treatment failure in infants on nevirapine-based treatment 
Resistance commonly arises in infants exposed to single-dose nevirapine (sdNVP) for prevention of mother to child transmission (PMTCT). While K103N and Y181C are common following sdNVP, multiple other mutations also confer NVP-resistance. It remains unclear whether specific NVP-resistance mutations or combinations of mutations predict virologic failure in infants when present at low frequencies prior to NVP-based treatment.
Twenty sdNVP-exposed infants who were subsequently treated with NVP-based highly active antiretroviral therapy (HAART) were examined. Pre-treatment plasma samples were tested for the presence of NVP-resistance mutations by allele-specific PCR (ASPCR) for K103N and Y181C and ultra-deep pyrosequencing (UDPS) for all primary NVP mutations. Viral levels were determined every 3 months for up to 24months on NVP-HAART. Cox proportional hazard models were used to determine correlates of viral failure.
The NVP resistance mutations K103N or Y181C were detected in pre-treatment plasma samples in 6 infants by ASPCR. NVP resistance at these or other sites was detectable by UDPS in 10 out of 20 infants tested. Virologic failure occurred in 50% of infants with any NVP resistance mutations detected, while only 20% of infants without resistance experienced viral failure, but the difference was not significant (p=0.19). An increase in the number of NVP resistance mutations detectable by UDPS in an infant was significantly associated with an increased risk of virologic failure (HR=1.79 (95%CI: 1.07, 2.99), p=0.027).
Low frequencies of multiple NVP resistance mutations, in addition to K103N and Y181C, present in infants before NVP-based treatment may predict treatment outcome.
PMCID: PMC3383885  PMID: 22395670
HIV; infants; nevirapine; resistance; HAART; treatment failure
19.  HIV-1-Specific Enzyme-Linked Immunosorbent Spot Assay Responses in HIV-1-Exposed Uninfected Partners in Discordant Relationships Compared to Those in Low-Risk Controls 
Clinical and Vaccine Immunology : CVI  2012;19(11):1798-1805.
A number of studies of highly exposed HIV-1-seronegative individuals (HESN) have found HIV-1-specific cellular responses. However, there is limited evidence that responses prevent infection or are linked to HIV-1 exposure. Peripheral blood mononuclear cells (PBMC) were isolated from HESN in HIV-1-discordant relationships and low-risk controls in Nairobi, Kenya. HIV-1-specific responses were detected using gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assays stimulated by peptide pools spanning the subtype A HIV-1 genome. The HIV-1 incidence in this HESN cohort was 1.5 per 100 person years. Positive ELISpot responses were found in 34 (10%) of 331 HESN and 14 (13%) of 107 low-risk controls (odds ratio [OR] = 0.76; P = 0.476). The median immunodominant response was 18.9 spot-forming units (SFU)/106 peripheral blood mononuclear cells (PBMC). Among HESN, increasing age (OR = 1.24 per 5 years; P = 0.026) and longer cohabitation with the HIV-1-infected partner (OR = 5.88 per 5 years; P = 0.003) were associated with responses. These factors were not associated with responses in controls. Other exposure indicators, including the partner's HIV-1 load (OR = 0.99 per log10 copy/ml; P = 0.974) and CD4 count (OR = 1.09 per 100 cells/μl; P = 0.238), were not associated with responses in HESN. HIV-1-specific cellular responses may be less relevant to resistance to infection among HESN who are using risk reduction strategies that decrease their direct viral exposure.
PMCID: PMC3491560  PMID: 22971780
20.  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.
PMCID: PMC3457128  PMID: 22875969
21.  Knowing a Sexual Partner Is HIV-1-Uninfected Is Associated With Higher Condom Use Among HIV-1-Infected Adults in Kenya 
Sexually Transmitted Diseases  2011;38(9):808-810.
The relation between awareness of sexual partner’s HIV serostatus and unprotected sex was examined in HIV clinic enrollees. Increased condom use was associated with knowing that a partner was HIV-negative (adjusted odds ratio = 5.99; P < 0.001) versus not knowing partner’s status. Partner testing may increase condom use in discordant couples.
PMCID: PMC3404889  PMID: 21844734
22.  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.
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.
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.
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.
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.
PMCID: PMC3394541  PMID: 17191167
23.  Compliance with antiretroviral regimens to prevent perinatal HIV-1 transmission in Kenya 
AIDS (London, England)  2003;17(1):65-71.
To compare compliance and infant HIV-1 infection risk at 6 weeks with the Thai-CDC and HIVNET-012 antiretroviral regimens in a field setting.
Randomized clinical trial.
Tertiary hospital antenatal clinic in Nairobi, Kenya.
HIV-1 infected women referred from primary care clinics.
Thai-CDC zidovudine regimen or HIVNET-012 nevirapine regimen.
Main outcome measures
Women were considered compliant if they used ≥ 80% of the doses. Infants were tested for HIV-1 at 6 weeks.
Seventy women were randomized to Thai-CDC and 69 to HIVNET-012 regimens. More women were compliant with the antenatal (86%) than the intrapartum (44%) Thai-CDC regimen doses (P = 0.001). Ninety-seven per cent took the maternal and 91% gave the infant dose of the HIVNET-012 regimen (P = 0.2). Overall, 41% were compliant with the Thai-CDC regimen and 87% with the HIVNET-012 regimen (P < 0.001). Compliance with the Thai-CDC regimen was associated with partner support of antiretroviral use [odds ratio (OR), 3.0;, 95% confidence interval (CI), 1.0–9.1] and knowledge at recruitment that antiretroviral drugs could prevent infant HIV-1 (OR, 2.9; 95% CI, 1.0–8.1). Compliance with the HIVNET-012 regimen was associated with partner notification (OR, 8.0; 95% CI, 1.5–50) and partner willingness to have HIV-1 testing (OR, 7.5; 95% CI, 1.4–40). There was a trend for a higher risk of transmission with the HIVNET-012 regimen than with the Thai-CDC regimen (22% versus 9%; P = 0.07).
Compliance with the Thai-CDC and HIVNET-012 regimens was comparable to that in efficacy trials. Partner involvement, support and education on perinatal HIV-1 prevention may improve compliance and increase the number of infants protected from HIV-1 infection.
PMCID: PMC3387271  PMID: 12478070
antiretroviral therapy; vertical transmission; compliance; prevention of perinatal transmission
24.  Implementation of free cotrimoxazole prophylaxis improves clinic retention among antiretroviral therapy-ineligible clients in Kenya 
AIDS (London, England)  2011;25(13):1657-1661.
To determine whether implementation of free cotrimoxazole (CTX) provision was associated with improved retention among clients ineligible for antiretroviral therapy (ART) enrolled in an HIV treatment program in Kenya.
Data were obtained from a clinical cohort for program evaluation purposes. Twelve-month clinic retention was compared among ART-ineligible clients enrolled in the time period before free CTX versus the time period after.
Statistical comparisons were made using Kaplan–Meier survival curves, log-rank tests, and multivariate Cox proportional hazards models. To exclude potential temporal program changes that may have influenced retention, ART clients before and after the same cut-off date were compared.
Among adult clients enrolled between 2005 and 2007, 3234 began ART within 1 year of enrollment, and 1024 of those who did not start treatment were defined as ART-ineligible. ART-ineligible clients enrolled in the period following free CTX provision had higher 12-month retention (84%) than those who enrolled prior to free CTX (63%; P < 0.001). Retention did not change significantly during these periods among ART clients (P = 0.55). In multivariate analysis, ART-ineligible clients enrolled prior to free CTX were more than twice as likely to be lost to follow-up compared to those following free CTX [adjusted hazard ratio (aHR) = 2.64, 95% confidence interval 1.95–3.57, P < 0.001].
Provision of free CTX was associated with significantly improved retention among ART-ineligible clients. Retention and CD4-monitoring of ART-ineligible clients are essential to promptly identify ART eligibility and provide treatment. Implementation of free CTX may improve retention in sub-Saharan Africa and, via increasing timely ART initiation, provide survival benefit.
PMCID: PMC3383052  PMID: 21673562
antibiotic; HIV; lost to follow-up; prophylaxis; trimethoprim–sulfamethoxazole combination
25.  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.
PMCID: PMC3384731  PMID: 12599047

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