Higher HIV-1 evolutionary rate is associated with cytotoxic T lymphocyte escape mutations in infants.

Escape from cytotoxic T lymphocyte (CTL) responses toward HIV-1 Gag and Nef has been associated with reduced control of HIV-1 replication in adults. However, less is known about CTL-driven immune selection in infants as longitudinal studies of infants are limited. Here, 1,210 gag and 1,264 nef sequences longitudinally collected within 15 months after birth from 14 HIV-1 perinatally infected infants and their mothers were analyzed. The number of transmitted founder (T/F) viruses and associations between virus evolution, selection, CTL escape, and disease progression were determined. The analyses indicated that a paraphyletic-monophyletic relationship between the mother-infant sequences was common (80%), and that the HIV-1 infection was established by a single T/F virus in 10 of the 12 analyzed infants (83%). Furthermore, most HIV-1 CTL escape mutations among infants were transmitted from the mothers and did not revert during the first year of infection. Still, immune-driven selection was observed at approximately 3 months after HIV-1 infection in infants. Moreover, virus populations with CTL escape mutations in gag evolved faster than those without, independently of disease progression rate. These findings expand the current knowledge of HIV-1 transmission, evolution, and CTL escape in infant HIV-1 infection and are relevant for the development of immune-directed interventions in infants.IMPORTANCEDespite increased coverage in antiretroviral therapy for the prevention of perinatal transmission, paediatric HIV-1 infection remains a significant public health concern, especially in areas of high HIV-1 prevalence. Understanding HIV-1 transmission and the subsequent virus adaptation from the mother to the infant's host environment, as well as the viral factors that affect disease outcome, is important for the development of early immune-directed interventions for infants. This study advances our understanding of vertical HIV-1 transmission, and how infant immune selection pressure is shaping the intra-host evolutionary dynamics of HIV-1.

Persistent Immune Activation in Human Immunodeficiency Virus-Infected Pregnant Women Starting Combination Antiretroviral Therapy After Conception.

This study evaluated the impact of human immunodeficiency virus (HIV) and combination antiretroviral therapy (cART) on immune activation during pregnancy in a Zambian cohort of HIV-exposed but uninfected children followed up from birth. Activated CD8+ T cells (CD38+ and HLA-DR+) were compared among HIV-uninfected (n = 95), cART experienced HIV-infected (n = 111), and cART-naive HIV-infected (n = 21) pregnant women. Immune activation was highest among HIV-infected/cART-naive women but decreased during pregnancy. Immune activation HIV-infected women who started cART during pregnancy was reduced but not to levels similar to those in HIV-uninfected women. The effects of elevated maternal immune activation in pregnancy on subsequent infant health and immunity remain to be determined.

Incident HSV-2 infections are common among HIV-1-discordant couples.

BACKGROUND: The synergy between herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1) is well known, but lack of knowledge about the epidemiology of HSV-2 acquisition in HIV-1-discordant couples hampers development of HSV-2 prevention interventions that could reduce HIV-1 transmission. METHODS: HIV-1-discordant couples were enrolled in Nairobi, Kenya, and followed for up to 2 years. HSV-2 status was determined using HerpeSelect HSV-2 ELISA. Correlates of prevalence and incidence were assessed. RESULTS.: Of 469 HIV-1-discordant couples, at baseline, 353 (75.3%) were affected by HSV-2, of which 189 (53.5%) were concordantly HSV-2 seropositive and 164 (46.5%) were HSV-2-discordant. Prevalence was lowest among HIV-1-uninfected men (39.9%) compared to HIV-1-infected women (64.8%), HIV-1-infected men (66.7%), and HIV-1-uninfected women (68.5%). During follow-up, HSV-2 seroincidence was 14.9 per 100 person-years. Incidence was 1.6-fold higher among females compared to males (95% confidence interval [CI], 1.00-2.48) and 2.5-fold higher in HIV-1-infected compared to uninfected women (95% CI, 1.12-5.74). At least 30% of incident HSV-2 infections originated from an outside partner. CONCLUSIONS: The high HSV-2 prevalence and incidence in HIV-1-discordant couples in sub-Saharan Africa suggest HSV-2 treatment and prevention could be an effective targeted strategy to reduce HSV-2 and HIV-1 transmission in this high-risk population.

Acute cytomegalovirus infection is associated with increased frequencies of activated and apoptosis-vulnerable T cells in HIV-1-infected infants.

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.

Passively Acquired Constant Region 5-Specific Antibodies Associated With Improved Survival in Infants Who Acquire Human Immunodeficiency Virus.

Studying vertical human immunodeficiency virus (HIV) transmission enables the impact of passively transferred antibodies on HIV transmission and pathogenesis to be examined. Using phage display of HIV envelope peptides and peptide enzyme-linked immunosorbent assay (ELISA), we found that, in infants who acquired HIV, passive antibody responses to constant region 5 (C5) were associated with improved survival in 2 cohorts. In a combined analysis, C5 peptide ELISA activity was correlated directly with survival and estimated infection time and inversely with set point viral load. These results suggest that preexisting C5-specific antibodies may be correlated with the survival of infants living with HIV, motivating additional research into their protective potential.

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.

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.

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 log(10) 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.

Maternal human leukocyte antigen A*2301 is associated with increased mother-to-child HIV-1 transmission.

We examined associations between maternal human leukocyte antigen (HLA) and vertical human immunodeficiency virus type 1 (HIV-1) transmission in a perinatal cohort of 277 HIV-infected women in Nairobi. HLA class I genes were amplified by using sequence-specific oligonucleotide probes, and analyses were performed using logistic regression. Maternal HLA-A*2301 was associated with increased transmission risk before and after adjusting for maternal viral load (unadjusted: odds ratio [OR], 3.21; 95% confidence interval [CI], 1.42-7.27; P = .005; Pcorr = 0.04; adjusted: OR, 3.07; 95% CI, 1.26-7.51; P =.01; Pcorr is not significant). 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 load.

Latent tuberculosis detection by interferon γ release assay during pregnancy predicts active tuberculosis and mortality in human immunodeficiency virus type 1-infected women and their children.

BACKGROUND: We evaluated the prognostic usefulness of interferon γ release assays (IGRAs) for active tuberculosis and mortality in Kenyan human immunodeficiency virus type 1 (HIV-1)-infected women and their infants. METHODS: Prevalence and correlates of Mycobacterium tuberculosis-specific T-SPOT.TB IGRA positivity were determined during pregnancy in a historical cohort of HIV-1-infected women. Hazard ratios, adjusted for baseline maternal CD4 cell count (aHR(CD4)), were calculated for associations between IGRA positivity and risk of active tuberculosis and mortality over 2-year postpartum follow-up among women and their infants. RESULTS: Of 333 women tested, 52 (15.6%) had indeterminate IGRA results. Of the remaining 281 women, 120 (42.7%) had positive IGRA results, which were associated with a 4.5-fold increased risk of active tuberculosis (aHR(CD4), 4.5; 95% confidence interval [CI], 1.1-18.0; P = .030). For immunosuppressed women (CD4 cell count, <250 cells/µL), positive IGRA results were associated with increased risk of maternal mortality (aHR(CD4), 3.5; 95% CI, 1.02-12.1;), maternal active tuberculosis or mortality (aHR(CD4), 5.2; 95% CI, 1.7-15.6; P = .004), and infant active tuberculosis or mortality overall (aHR(CD4), 3.0; 95% CI, 1.0-8.9; P = .05) and among HIV-1-exposed uninfected infants (aHR(CD4), 7.3; 95% CI, 1.6-33.5; P = .01). CONCLUSIONS: Positive IGRA results for HIV-1-infected pregnant women were associated with postpartum active tuberculosis and mortality among mothers and their infants.

Immune responses to measles and tetanus vaccines among Kenyan human immunodeficiency virus type 1 (HIV-1)-infected children pre- and post-highly active antiretroviral therapy and revaccination.

BACKGROUND: : HIV-1-infected children have lower response rates after measles and tetanus immunization than uninfected children. We determined the extent to which highly active antiretroviral therapy (HAART) augments vaccine immunity and promotes responses to revaccination. METHODS: : Previously immunized, antiretroviral-naive HIV-1-infected children were evaluated for immunity against measles and tetanus. After 6 months on HAART, children meeting CD4% criteria (>15%) who were persistently antibody negative were revaccinated and immunity was reassessed. RESULTS: : At enrollment, among 90 children with mean age of 4.9 years, 67% had negative measles IgG and 22% negative tetanus IgG. Among 62 children completing 6 months on HAART, 17 (40%) of 43 without protective measles IgG converted and 10 (53%) of 19 positive children lost measles responses (P = 0.3). Children who lost responses had significantly lower measles antibody concentrations than those who remained measles IgG positive during follow-up (7.1 vs. 20.3 mg/mL; P = 0.003). Three (23%) of 13 children negative for tetanus IgG spontaneously seroconverted on HAART, while 15 (31%) of 49 children lost tetanus antibody (P = 0.008). There was a nonsignificant trend for an association between spontaneous measles seroconversion and lower baseline HIV-1 viral load (P = 0.06). Tetanus seroconversion was associated with older age (P = 0.03). After revaccination, positive responses were observed in 78% and 75% of children reimmunized against measles and tetanus, respectively. CONCLUSIONS: : After 6 months of HAART, more than half of previously immunized children still lacked positive measles antibody. With increased use of HAART in pediatric populations, revaccination against measles and tetanus should be considered to boost response rates and immunization coverage.

Analysis of the TCR Repertoire in HIV-Exposed but Uninfected Infants.

Maternal human immunodeficiency virus (HIV) infection has been shown to leave profound and lasting impacts on the HIV-exposed uninfected (HEU) infant, including increased mortality and morbidity, immunological changes, and developmental delays compared to their HIV-unexposed (HU) counterparts. Exposure to HIV or antiretroviral therapy may influence immune development, which could increase morbidity and mortality. However, a direct link between the increased mortality and morbidity and the infant's immune system has not been identified. To provide a global picture of the neonatal T cell repertoire in HEU versus HU infants, the diversity of the T cell receptor beta chain (TRB) expressed in cord blood samples from HEU infants was determined using next-generation sequencing and compared to healthy (HU) infants collected from the same community. While the TRB repertoire of HU infants was broadly diverse, in line with the expected idea of a naïve T cell repertoire, samples of HEU infants showed a significantly reduced TRB diversity. This study is the first to demonstrate differences in TRB diversity between HEU and HU cord blood samples and provides evidence that maternal HIV, in the absence of transmission, influences the adaptive immune system of the unborn child.

High background in ELISpot assays is associated with elevated levels of immune activation in HIV-1-seronegative individuals in Nairobi.

INTRODUCTION: Spontaneous interferon-γ (IFNγ) released detected by enzyme-linked immunospot (ELISpot) assays may be a biological phenomenon. Markers of immune activation levels were assessed as correlates of high background among individuals in Kenya. METHODS: Couples concordantly seronegative for HIV-1 were enrolled. IFN-γ ELISpot assays were conducted and negative control wells were categorized as having either high or low background (≥50 and <50 SFU/106 peripheral blood mononuclear cells [PBMC], respectively). PBMC were stained for CD4, CD8, and immune activation markers (CD38 and HLA-DR) and analyzed using flow cytometry. Proportions of activated T-cells were compared between those with low and high background by Mann-Whitney U test. Correlates of background SFU and immune activation were assessed using regression models. RESULTS: Among 58 individuals, 14 (24%) had high background. Frequencies of CD4+ CD38+ HLA-DR+ and CD8+ CD38+ HLA-DR+ cells were higher in individuals with high background compared to those with low background (P = 0.02). Higher background SFU was associated with history of sexually transmitted infections (P = 0.03), and illness in the past 3 months (P = 0.005), in addition to increased levels of activated CD4+ and CD8+ cells (P range = 0.008-0.03). Female gender and male circumcision decreased levels of CD4+ and CD8+ immune activation (P range = 0.002-0.03). Additionally, higher background SFU and activated CD4+ and CD8+ cells were individually associated with positive ELISpot responses to HIV-1 peptide pools (P range = 0.01-0.03). CONCLUSIONS: These findings suggest that increased basal immune responses may be a biological mechanism contributing to higher background ELISpot SFU. Systematic exclusion of data from individuals with increased background in IFN-γ release assays may bias results in population-based studies.

HIV-exposed uninfected infants: elevated cord blood Interleukin 8 (IL-8) is significantly associated with maternal HIV infection and systemic IL-8 in a Kenyan cohort.

BACKGROUND: In low and middle income countries, human immunodeficiency virus (HIV) exposed, uninfected (HEU) infants demonstrate higher morbidity and mortality than their unexposed counterparts. To determine possible immune correlates of this effect, we investigated the impact of in utero HIV exposure on the uninfected neonatal immune milieu and maternal factors mediating these abnormalities in a cohort of vaginally delivered mother-infants. Samples of delivery and cord blood plasma were selected from 22 Kenyan HIV-infected women and their HIV exposed uninfected (HEU) infants drawn from the pre-ARV era, while 19 Kenyan HIV-uninfected (HU) women and their infants were selected from a control cohort. RESULTS: Compared to HU cord plasma, HEU cord plasma contained significantly higher levels of pro-inflammatory cytokines interleukins (IL)-6 and -8 (both p < 0.001) and significantly lower levels of CXC motif chemokine 11 (CXC11) (p < 0.001). Mediation analysis demonstrated that maternal HIV infection status was a significant determinant of infant IL-8 responses: HEU status was associated with a ninefold higher infant:mother (cord:delivery) plasma levels of IL-8 (p < 0.005), whereas maternal viral load was negatively associated with HEU IL-8 levels (p = 0.04) and not associated with HEU IL-6 levels. CONCLUSIONS: Exposure to maternal HIV infection drives an increase in prenatal IL-8 that is partially mediated by maternal cytokine levels. Differences between maternal and infant cytokine levels strongly suggest independent modulation in utero, consistent with prenatal immune activation. Elevated pro-inflammatory signals at birth may interfere with T cell responses at birth and subsequently influence immune maturation and the risk of morbidity and mortality in HEU infants.

Higher Transplacental Pathogen-Specific Antibody Transfer Among Pregnant Women Randomized to Triple Antiretroviral Treatment Versus Short Course Zidovudine.

BACKGROUND: HIV-1 infection may impair transplacental antibody transfer to infants. The impact of highly active antiretroviral treatment (ART) given during pregnancy on transplacental antibody transport is unknown. METHODS: HIV-1 infected pregnant women with CD4 counts between 200 - 500 were randomized to short-course zidovudine (ZDV) or triple ART at 32 weeks gestation for prevention of mother-to-child HIV-1 transmission. Levels of maternal antibody against measles, pneumococcus and rotavirus at delivery, and antibody transfer to the baby through cord blood, were compared between trial arms. RESULTS: Overall, 141 and 148 women were randomized to triple ART and ZDV, respectively; cord blood was available for a subset (n = 20 in triple ART and n = 22 in ZDV). Maternal antibody levels to all pathogens during pregnancy and at delivery were not significantly different between arms. Within each arm, antibody levels at delivery were lower than at enrolment. For all antibodies, a woman's levels before delivery were an important predictor of amount transferred to her infant. Women on triple ART transferred higher levels of pathogen-specific antibodies when compared with women on short course ZDV. CONCLUSIONS: Women on triple ART transferred higher levels of pathogen-specific antibodies compared with women on ZDV alone.

Herpes simplex virus type 2 and risk of intrapartum human immunodeficiency virus transmission.

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.

High Rates of Exclusive Breastfeeding in Both Arms of a Peer Counseling Study Promoting EBF Among HIV-Infected Kenyan Women.

BACKGROUND: Exclusive breastfeeding (EBF) is recommended for 6 months after delivery as the optimal infant feeding method and is especially important for prevention of mother-to-child HIV transmission (PMTCT). However, EBF promotion efforts among HIV-infected mothers in sub-Saharan Africa have achieved mixed success and require context-specific interventions. METHODS: HIV-positive, pregnant women from six clinics in Nairobi were enrolled into a clinic-level, before-after counseling intervention study. All women received standard perinatal and HIV care. Women in the intervention arm were offered three counseling sessions that promoted EBF, described its benefits, and explained breastfeeding techniques. Mother-infant pairs were followed until 14 weeks postpartum, with infant HIV testing at 6 weeks. EBF prevalence at 14 weeks postpartum was compared between study arms using log-binomial regression. Proportions of 6-week HIV-free survival and 14-week infant survival were assessed using Cox regression. Risk estimates were adjusted for clinic, relationship status, and antiretroviral therapy. RESULTS: Between 2009 and 2013, 833 women were enrolled of whom 94% planned to practice EBF for 6 months and 95% were taking therapeutic or prophylactic antiretrovirals. Median age was 27 years; median CD4 count was 403 cells/µL. EBF prevalence at 14 weeks postpartum was 86% in the control and 81% in the intervention group (p = 0.19). No differences were observed between groups for 6-week HIV-free survival and 14-week infant survival. CONCLUSION: Women who received breastfeeding counseling were not more likely to breastfeed exclusively, in part due to high overall EBF prevalence in this study population. The high EBF prevalence is an important finding, given recent efforts to promote EBF in Kenya.

Depot Medroxyprogesterone Acetate Use Is Associated With Elevated Innate Immune Effector Molecules in Cervicovaginal Secretions of HIV-1-Uninfected Women.

OBJECTIVE: The effects of sex hormones on the immune defenses of the female genital mucosa and its susceptibility to infections are poorly understood. The injectable hormonal contraceptive depot medroxyprogesterone acetate (DMPA) may increase the risk for HIV-1 acquisition. We assessed the local concentration in the female genital mucosa of cationic polypeptides with reported antiviral activity in relation to DMPA use. METHODS: HIV-1-uninfected women were recruited from among couples testing for HIV in Nairobi, Kenya. Cervicovaginal secretion samples were collected, and the concentrations of HNP1-3, LL-37, lactoferrin, HBD-2, and SLPI were measured by enzyme-linked immunosorbent assays. Levels of cationic polypeptides in cervicovaginal secretions were compared between women who were not using hormonal contraception and those using DMPA, oral, or implantable contraception. RESULTS: Among 228 women, 165 (72%) reported not using hormonal contraception at enrollment, 41 (18%) used DMPA, 16 (7%) used an oral contraceptive, and 6 (3%) used a contraceptive implant. Compared with nonusers of hormonal contraception, DMPA users had significantly higher mean levels of HNP1-3 (2.38 vs. 2.04 log10 ng/mL; P = 0.024), LL-37 (0.81 vs. 0.40 log10 ng/mL; P = 0.027), and lactoferrin (3.03 vs. 2.60 log10 ng/mL; P = 0.002), whereas SLPI and HBD-2 were similar. CONCLUSIONS: Although all analyzed cationic polypeptides have intrinsic antiviral capacity, their interaction and cumulative effect on female genital mucosa susceptibility to infections in vivo has yet to be unraveled. This study suggests a potential mechanism underlying the effect of DMPA on the innate immune defenses, providing a rationale to investigate its effect on HIV-1 acquisition risk.

Infant Neutropenia Associated with Breastfeeding During Maternal Antiretroviral Treatment for Prevention of Mother-to-Child Transmission of HIV.

Maternal antiretroviral treatment (ART) is recommended for prevention of mother-to-child HIV-1 transmission (PMTCT), including in women with high CD4+ cell counts. Within a pediatric HIV-1 vaccine trial PedVacc 002, we assessed hematologic profiles of infants born to mothers receiving ART. All mothers had CD4+ cell counts of >350 mm-3; 93% received zidovudine-containing ART; infants received nevirapine up to 6 weeks and cotrimoxazole after 6 weeks. Among 84 infants at 19 weeks, 58% had hematologic toxicity; 44% had neutropenia and 23% had anemia. Breastfeeding was associated with 3.8-fold higher risk of neutropenia (RR 3.8, 95% CI 1.03-14.1, p = 0.008). Hematologic monitoring and PMTCT regimen selection are important for optimizing infant outcomes.

High prevalence of tuberculosis infection in HIV-1 exposed Kenyan infants.

BACKGROUND: Infants born to HIV-1 infected mothers may have increased risk for tuberculosis (TB), but the prevalence of TB infection in this population is undefined. In contrast to tuberculin skin tests that are confounded by recent bacille Calmette-Guérin (BCG) vaccination, TB interferon gamma release assays (IGRAs) do not cross-react with BCG and enable detection of TB infection in infancy. METHODS: In a nested observational cohort of HIV-1 infected Kenyan mothers and their infants, we conducted T-SPOT.TB assays on cryopreserved peripheral blood mononuclear cells from 6-month-old infants without prior active TB. Maternal and infant correlates of infant TB infection were assessed. RESULTS: One hundred and eight-two infants were tested with T-SPOT.TB. Of 128 infants with determinate T-SPOT.TB results, the prevalence of a positive T-SPOT.TB was 10.9% [95% confidence interval (CI): 6.1-17.7%]. All infants were BCG-vaccinated and 7.0% were HIV-1 infected. Positive infant T-SPOT.TB was associated with maternal active TB (odds ratio: 15.5, 95% CI: 1.3-184; P = 0.04) and prolonged infant fever (>1 month) (odds ratio: 18.8, 95% CI: 1.6-223; P = 0.03). CONCLUSIONS: We observed a high prevalence of TB infection in 6-month-old HIV-1 exposed infants. Improved TB detection and prevention are warranted in HIV-1 exposed infants at high risk for active TB disease.