In Utero Antiretroviral Exposure and Risk of Neurodevelopmental Problems in HIV-Exposed Uninfected 5-Year-Old Children.

Studies have observed neurodevelopmental (ND) challenges among young children perinatally HIV-exposed yet uninfected (CHEU) with in utero antiretroviral (ARV) exposure, without clear linkage to specific ARVs. Atazanavir (ATV) boosted with ritonavir has been a preferred protease inhibitor recommended for pregnant women, yet associations of ATV with ND problems in CHEU have been reported. Studies among early school-age children are lacking. The pediatric HIV/AIDS cohort study (PHACS) surveillance monitoring for antiretroviral therapy (ART) toxicities (SMARTT) study evaluated 5-year-old monolingual English-speaking CHEU using the behavior assessment system for children, Wechsler preschool and primary scales of intelligence, and test of language development-primary. A score ≥1.5 standard deviations worse than population norms defined a signal within each domain. Analyses of risk for signals were stratified by timing of any ARV initiation. Associations between ARV exposure and risk of ND signals were assessed using proportional odds models, adjusting for confounders. Among 230 children exposed to ARVs at conception, 15% had single and 8% had multiple ND problems; ATV exposure was not associated with higher risk of signals [adjusted cumulative odds ratio (cOR) = 0.66, confidence interval (CI): 0.28-1.56]. However, among 461 children whose mothers initiated ARVs during pregnancy, 21% had single and 12% had multiple ND problems; ATV exposure was associated with higher risk of signals (cOR = 1.70, CI: 0.82-3.54). The specific regimen tenofovir/emtricitabine/ATV was associated with higher risk (cOR = 2.31, CI: 1.08-4.97) relative to regimens using a zidovudine/lamivudine backbone combined with non-ATV ARVs. It remains important to monitor neurodevelopment of CHEU during early childhood and investigate the impact and the role of timing of in utero exposure to specific ARVs.

Auditory Function in the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol Up Young Adults: A Pilot Study.

BACKGROUND: To collect and compare selected hearing measures in a pilot study of young adults with perinatally acquired HIV (YAPHIV) and those with perinatal HIV exposure who are uninfected young adults with PHEU (YAPHEU). SETTING: Cross-sectional hearing measures in YAPHIV and YAPHEU enrolled in the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol (AMP) for Participants 18 Years of Age and Older (AMP Up). METHODS: Pure-tone air conduction audiometry and distortion product otoacoustic emission (DPOAE) data were collected in 1 visit. A low-frequency pure-tone average (PTA) (LFPTA, at 0.25, 0.5, 1, and 2 kHz), a speech-frequency PTA (SFPTA, at 0.5, 1, 2, and 4 kHz), and a high-frequency PTA (HFPTA, at 3, 4, 6, and 8 kHz) were calculated. Hearing loss was defined as worse ear SFPTA of ≥20 dB HL. Separate linear regression models were fit for worse ear LFPTA, SFPTA, and HFPTA to assess associations with PHIV status. DPOAE signal-to-noise ratios (SNRs) were obtained at 3 frequencies in each ear. RESULTS: Forty-seven YAPHIV and 9 YAPHEU completed hearing testing. All adjusted mean PTAs were similar between YAPHIV and YAPHEU. Hearing loss occurred more in YAPHIV (7/47, 15.2%; 95% CI: 6.3%-28.9%), compared with YAPHEU (0/9, 0%). No associations were detected between HIV disease severity measures and worse ear SFPTA. DPOAE SNRs were similar between YAPHIV and YAPHEU. CONCLUSIONS: In this pilot study, peripheral hearing (ie, PTAs) and cochlear function (ie, DPOAEs) were similar between YAPHIV and YAPHEU. A larger study is warranted to confirm these findings.

Low maternal vitamin D is associated with increased risk of congenital and peri/postnatal transmission of Cytomegalovirus in women with HIV.

BACKGROUND: CMV infection of the fetus or neonate can lead to devastating disease, and there are no effective prevention strategies to date. Vitamin D is a potent immunomodulator, supports antiviral immune responses, and plays an important role in placental immunity. METHODS: Retrospective cohort study to evaluate the impact of low maternal vitamin D on congenital and early postnatal transmission of CMV among HIV-infected, non-breastfeeding women and their HIV exposed but negative infants from an urban HIV clinic. Vitamin D panel was performed on stored maternal plasma obtained near time of delivery. Infant CMV testing at 0-6 months included urine and oral cultures, and/or serum polymerase chain reaction testing. RESULTS: Cohort included 340 mother-infant pairs (births 1991-2014). Among 38 infants (11%) with a CMV+ test between 0-6 months, 4.7% (14/300) had congenital CMV transmission (CMV+ test 0-3 weeks), and 7.6% (24/315) had peri/postnatal CMV (CMV+ test >3 weeks-6 months). Women with lower calcitriol (1,25-dihydroxyvitamin D), the active form of vitamin D, were more likely to have an infant with congenital (OR 12.2 [95% CI 1.61-92.2] P = 0.02) and peri/postnatal (OR 9.84 [95% CI 2.63-36.8] P = 0.0007) infections in multivariate analyses, independent of maternal HIV viral load and CD4 count. CONCLUSION: This study demonstrates an association between inadequate maternal calcitriol during pregnancy and increased congenital and early postnatal acquisition of CMV among non-breastfeeding women with HIV and their HIV negative infants.

Low Bioactive Vitamin D Is Associated with Pregnancy-Induced Hypertension in a Cohort of Pregnant HIV-Infected Women Sampled Over a 23-Year Period.

OBJECTIVE: To examine the association of vitamin D insufficiency and risk of pregnancy-induced hypertension (PIH) among human immunodeficiency virus (HIV)-infected pregnant women. STUDY DESIGN: This is a retrospective cohort study evaluating the impact of low maternal vitamin D levels on PIH and perinatal outcomes among HIV-infected pregnant women receiving care at an urban HIV center from 1991 to 2014. RESULTS: A total of 366 pregnant women were included, of which 11% developed PIH. Lower levels of 25-hydroxyvitamin D (25(OH)D) and bioactive 1,25-dihydroxyvitamin D (1,25(OH)2D) were associated with increased HIV disease activity. 25(OH)D levels were not significantly associated with the incidence of PIH. Higher 1,25(OH)2D levels were associated with reduced incidence of PIH in univariate (odds ratio, OR: 0.87 [95% confidence interval, CI: 0.79-0.95], p = 0.004) and multivariate (OR: 0.88 [95% CI: 0.80-0.97], p = 0.010) analyses. No association was found between 25(OH)D levels and other obstetric outcomes. Lower 1,25(OH)2D levels were associated with group B Streptococcus colonization (OR: 0.92 [95% CI: 0.86-0.99]) and low birth weight (LBW) (OR: 0.90 [95% CI: 0.83-0.98]) on multivariate analysis. Mean 1,25(OH)2D levels were significantly lower in women with preterm delivery and LBW infants. CONCLUSION: Lower bioactive vitamin D levels are related to PIH in HIV-infected women. This association may be related to the coexistence of abnormal placental vitamin D metabolism and abnormal placental implantation.

Association of HLA Genotype With T-Cell Activation in Human Immunodeficiency Virus (HIV) and HIV/Hepatitis C Virus-Coinfected Women.

BACKGROUND: Global immune activation and HLA alleles are each associated with the pathogenesis of human immunodeficiency virus (HIV) and hepatitis C virus . METHODS: We evaluated the relationship between 44 HLA class I and 28 class II alleles and percentages of activated CD8 (CD8+CD38+DR+) and CD4 (CD4+CD38+DR+) T cells in 586 women who were naive to highly active antiretroviral therapy. We used linear generalized estimating equation regression models, adjusting for race/ethnicity, age, HIV load, and hepatitis C virus infection and controlling for multiplicity using a false discovery rate threshold of 0.10. RESULTS: Ten HLA alleles were associated with CD8 and/or CD4 T-cell activation. Lower percentages of activated CD8 and/or CD4 T cells were associated with protective alleles B*57:03 (CD8 T cells, -6.6% [P = .002]; CD4 T cells, -2.7% [P = .007]), C*18:01 (CD8 T cells, -6.6%; P < .0008) and DRB1*13:01 (CD4 T cells, -2.7%; P < .0004), and higher percentages were found with B*18:01 (CD8 T cells, 6.2%; P < .0003), a detrimental allele. Other alleles/allele groups associated with activation included C*12:03, group DQA1*01:00, DQB1*03:01, DQB1*03:02, DQB1*06:02, and DQB1*06:03. CONCLUSION: These findings suggest that a person's HLA type may play a role in modulating T-cell activation independent of viral load and sheds light on the relationship between HLA, T-cell activation, immune control, and HIV pathogenesis.

Birth Prevalence of Congenital Cytomegalovirus Infection in HIV-Exposed Uninfected Children in the Era of Combination Antiretroviral Therapy.

OBJECTIVES: To estimate birth prevalence of congenital cytomegalovirus (cCMV) in HIV-exposed uninfected children born in the current era of combination antiretroviral therapy and describe cCMV-related neurodevelopmental and hearing outcomes. STUDY DESIGN: The Surveillance Monitoring for ART Toxicities cohort study follows HIV-exposed uninfected children at 22 sites in the US and Puerto Rico. Birth cCMV prevalence was estimated in a subset of participants who had blood pellets collected within three weeks of birth and underwent ≥1 of 6 assessments evaluating cognitive and language development including an audiologic examination between 1 and 5 years of age. Detection of CMV DNA by polymerase chain reaction testing of peripheral blood mononuclear cells was used to diagnose cCMV. Proportions of suboptimal assessment scores were compared by cCMV status using Fisher exact test. RESULTS: Mothers of 895 eligible HIV-exposed uninfected children delivered between 2007 and 2015. Most (90%) were on combination antiretroviral therapy, 88% had an HIV viral load of ≤400 copies/mL, and 93% had CD4 cell counts of ≥200 cells/µL. Eight infants were diagnosed with cCMV, yielding an estimated prevalence of 0.89% (95% CI, 0.39%-1.75%). After adjusting for a sensitivity of 70%-75% for the testing method, projected prevalence was 1.2%-1.3%. No differences were observed in cognitive, language and hearing assessments by cCMV status. CONCLUSIONS: Although birth cCMV prevalence in HIV-exposed uninfected children born to women with well-controlled HIV is trending down compared with earlier combination antiretroviral therapy-era estimates, it is above the 0.4% reported for the general US population. HIV-exposed uninfected children remain at increased risk for cCMV.

Risk for Speech and Language Impairments in Preschool Age HIV-exposed Uninfected Children With In Utero Combination Antiretroviral Exposure.

BACKGROUND: Perinatally HIV-exposed but uninfected (HEU) children have elevated risk of late language emergence at 1 year of age, with possible links to in utero antiretroviral (ARV) exposure. We investigated possible risks for speech impairments (SIs) and language impairments (LI) in preschool monolingual HEU children in the United States. METHODS: Speech and language assessments were conducted as part of the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART Toxicities study at ages 3 (N = 208) and 5 (N = 429) years. Domains of speech, overall language, vocabulary and grammar were assessed. SI and LI were defined by standardized scores <15th percentile and categorized as primary (normal nonverbal IQ ≥ 85 without hearing loss) and concomitant (low nonverbal IQ and/or presence of hearing loss). Logistic regression models were used to estimate odds of SI and LI for different ARV exposures, adjusted for confounding variables. RESULTS: The risk for language impairments in HEU children was higher than population norms; risk for SIs was not elevated. Risk factors for impairments included male sex, black race and other socioeconomic measures, although these varied by age, primary (P) versus concomitant (C) impairment and by speech or language measure. Adjusted logistic regression models revealed lower and increased risk for specific ARVs. Tenofovir exposure was associated with increased risk for SI at 3 years of age but was associated with decreased risk for concomitant language impairment at 5 years of age. CONCLUSIONS: Further investigation of combination ARV exposure and speech/language impairment among preschool children is needed to confirm associations.

Perinatal HIV Exposure Surveillance and Reporting in the United States, 2014.

OBJECTIVE: We sought to describe the current status of perinatal HIV exposure surveillance (PHES) activities and regulations in the United States and to make recommendations to strengthen PHES. METHODS: In 2014, we sent an online survey to health departments in the 50 states, District of Columbia, Puerto Rico, Virgin Islands, and 6 cities and counties (Chicago, Illinois; Houston, Texas; Los Angeles, California; New York, New York; Philadelphia, Pennsylvania; and San Francisco, California). We analyzed responses from 56 of the 59 (95%) jurisdictions. RESULTS: Thirty-three of 56 jurisdictions (59%) reported conducting PHES and following infants to determine their infection status. Of the 33 jurisdictions performing PHES, 28 (85%) linked maternal and infant data, but only 12 (36%) determined the HIV care status of postpartum women. Themes of respondents' recommendations for strengthening PHES centered on updating laws and regulations to support PHES, reporting all HIV test results and linking vital records with PHES data to identify and follow HIV-exposed infants, communicating with health care providers to improve reporting, training staff, and getting help from experienced jurisdictions to implement PHES. CONCLUSIONS: Our findings indicate that data on perinatal exposure collected through the current system are inadequate to comprehensively monitor and prevent perinatal HIV exposure and transmission. Comprehensive PHES data collection and reporting are needed to sustain the progress that has been made toward lowering perinatal HIV transmission rates. We propose that minimum standards be established for perinatal HIV exposure reporting to improve the completeness, quality, and efficiency of PHES in the United States.

Longitudinal Evaluation of Language Impairment in Youth With Perinatally Acquired Human Immunodeficiency Virus (HIV) and Youth With Perinatal HIV Exposure.

BACKGROUND: Language impairment (LI) risk is increased for perinatally acquired human immunodeficiency virus-infected (PHIV) and perinatally exposed to HIV but uninfected (PHEU) youth. This study evaluates the persistence of LI in these groups. METHODS: The Clinical Evaluation of Language Fundamentals was repeated on participants of the Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol 18 months postbaseline. Regression models identified factors associated with change in standardized score (SC) and the resolution or development of LI. RESULTS: Of 319 participants, 112 had LI at baseline. Upon re-evaluation, SCs were highly stable and changes were similar in PHIV (n = 212) and PHEU (n = 107) participants. Those with family history of language delays had a 2.39 point lower mean increase in SCs than those without, after controlling for demographic and socioeconomic factors and baseline LI status. Among PHIV participants, CD4 count <350 cells/mm3 was associated with lower mean SC change (4.32 points), and exposure to combination antiretroviral therapy (cART) or protease inhibitors (PIs) was associated with a higher mean SC change (5.93 and 4.19 points, respectively). Initial LI was persistent in most cases (78%); 20 new cases occurred (10%). Female sex was associated with higher odds of LI resolution. Among PHIV, duration and baseline cART and history of PI use were associated with LI resolution; higher percentage of detectable viral loads before baseline was associated with lower odds of resolution. CONCLUSIONS: The PHIV and PHEU youth are at risk for persistent LI, and family history of language delays was a risk factor for persistence of problems. Measures of successful HIV treatment predicted more favorable outcomes among PHIV youth.

Women of Color Reflect on HIV-Related Stigma through PhotoVoice.

HIV-related stigma affects people living with HIV (PLWH), especially in communities of color. In our study, African American and Latina/Hispanic women living with HIV (WLWH) described experiences of stigma through PhotoVoice, a community-based participatory method of documentary photography. Ten WLWH from Los Angeles documented stigma experiences through photographs for up to 5 weeks and discussed their images during a focus group or semi-structured individual interview. Qualitative interpretive phenomenological analysis of participant narratives and photographs revealed lack of education and cultural myths as the main triggers of the stigma our participants faced. Stigma was experienced in health care settings, and participants identified depression, fear of intimate relationships, and nondisclosure of HIV status as its consequences. Social support and faith were noted as key coping mechanisms. WLWH recommended involving PLWH and public health officials in stigma reduction campaigns and youth education. PhotoVoice was perceived as a useful tool for education and self-improvement.

Impact of Hepatitis C Virus on the Circulating Levels of IL-7 in HIV-1 Coinfected Women.

OBJECTIVES: Hepatitis C virus (HCV) infection causes an alteration in T-cell maturation and activation in patients coinfected with human immunodeficiency virus (HIV). Because interleukin 7 (IL-7) is a major cytokine controlling T-cell homeostasis, we analyzed the potential influence of HCV coinfection on circulating IL-7 levels in HIV-infected women before and after highly active antiretroviral therapy (HAART). DESIGN AND METHODS: This prospective study included 56 HIV monoinfected, 55 HIV/HCV coinfected without HCV viremia, 132 HIV/HCV coinfected with HCV viremia, and 61 HIV/HCV-uninfected women for whom plasma levels of IL-7 were determined by enzyme-linked immunosorbent assay at 1 or more follow-up visits before and after HAART. Cross-sectional analyses of the associations between plasma IL-7 levels and HCV infection, demographic, clinical, and immunologic characteristics were evaluated using univariate and multivariate linear regression models before and after HAART. RESULTS: In multivariate models, IL-7 levels were significantly higher in coinfected HCV viremic women than in HIV monoinfected women (multiplicative effect = 1.48; 95% confidence interval: 1.01 to 2.16; P = 0.04) before HAART, but were similar between these two groups among women after HAART. In addition to HCV viremia, higher IL-7 levels were associated with older age (P = 0.02), lower CD4(+) T-cell count (P = 0.0007), and higher natural killer T-cell count (P = 0.02) in women before HAART. Among HAART-treated women, only lower CD4(+) T-cell count was significantly associated with IL-7 level (P = 0.006). CONCLUSIONS: Our data demonstrate that in HIV-infected women, circulating levels of IL-7 are strongly associated with CD4 T-cell depletion both before and after HAART. Our data also demonstrate that HCV viremia increases circulating IL-7 levels before HAART but not after HAART in coinfected women. This suggests that the effect of HCV on lymphopenia is abrogated by HAART.

Systemic Immune Activation and HIV Shedding in the Female Genital Tract.

BACKGROUND: Plasma HIV RNA is the most significant determinant of cervical HIV shedding. However, shedding is also associated with sexually transmitted infections (STIs) and cervical inflammation. The mechanism by which this occurs is poorly understood. There is evidence that systemic immune activation promotes viral entry, replication, and HIV disease progression. We hypothesized that systemic immune activation would be associated with an increase in HIV genital shedding. METHODS: Clinical assessments, HIV RNA in plasma and genital secretions, and markers of immune activation (CD38(+)DR(+) and CD38(-)DR(-)) on CD4(+) and CD8(+) T cells in blood were evaluated in 226 HIV+ women enrolled in the Women's Interagency HIV Study. There were 569 genital evaluations of which 159 (28%) exhibited HIV RNA shedding, defined as HIV viral load >80 copies per milliliter. We tested associations between immune activation and shedding using generalized estimating equations with logit link function. RESULTS: In the univariate model, higher levels of CD4(+) and CD8(+) T-cell activation in blood were significantly associated with genital tract shedding. However, in the multivariate model adjusting for plasma HIV RNA, STIs, and genital tract infections, only higher levels of resting CD8(+) T cells (CD38(-)DR(-)) were significantly inversely associated with HIV shedding in the genital tract (odds ratios = 0.44, 95% confidence interval: 0.21 to 0.9, P = 0.02). CONCLUSIONS: The association of systemic immune activation with genital HIV shedding is multifactorial. Systemic T-cell activation is associated with genital tract shedding in univariate analysis but not when adjusting for plasma HIV RNA, STIs, and genital tract infections. In addition, women with high percentage of resting T cells are less likely to have HIV shedding compared with those with lower percentages. These findings suggest that a higher percentage of resting cells, as a result of maximal viral suppression with treatment, may decrease local genital activation, HIV shedding, and transmission.

Meconium Atazanavir Concentrations and Early Language Outcomes in HIV-Exposed Uninfected Infants With Prenatal Atazanavir Exposure.

OBJECTIVE: To investigate whether prenatal atazanavir (ATV) exposure, assessed by meconium antiretroviral (ARV) quantification, predicts early child language outcomes. Prenatal ATV exposure previously was associated with poorer language development in 1-year olds. METHODS: Pregnant women with HIV and their uninfected infants enrolled in the Surveillance Monitoring of Antiretroviral Therapy Toxicities study. Meconium ARV concentrations were quantified by liquid chromatography-tandem mass spectrometry. Language development at 1 year was assessed with MacArthur-Bates Communicative Development Inventory (CDI) and Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). Late language emergence was defined as ≥ 1 of 4 CDI scores ≤ 10th percentile for age. Associations between fetal ATV exposure timing and duration, meconium ATV concentration, and language outcomes were evaluated, adjusting for potential confounders. RESULTS: Through 2013, meconium samples were available from 175 of 432 infants with prenatal ATV exposure. Valid Bayley-III (n = 93) and CDI (n = 106) assessments also were available. After adjustment for potential confounders, higher ATV meconium concentrations were associated with lower late language emergence risk (P = 0.04) and cumulative ATV exposure duration also was associated with higher Bayley-III Language scores (P = 0.03). Maternal ATV duration and initiation week correlated with ATV meconium concentrations (positively and negatively, respectively). CONCLUSIONS: Higher meconium ATV concentrations were protective against developmental language delays at 1 year, suggesting the importance of fetal ATV detoxification into meconium. This information supports ATV exposure safety for infant language development. ATV is a preferred ARV for pregnant women with HIV, suggesting the importance of ATV safety investigations. Additionally, further pursuit of the influences on language development in HIV-exposed uninfected infants is required.

Evaluation of risk for late language emergence after in utero antiretroviral drug exposure in HIV-exposed uninfected infants.

BACKGROUND: Combination antiretroviral (cARV) regimens are recommended for pregnant women with HIV to prevent perinatal HIV transmission. Safety is a concern for infants who were HIV-exposed but uninfected, particularly for neurodevelopmental problems, such as language delays. METHODS: We studied late language emergence (LLE) in HIV-exposed but uninfected children enrolled in a US-based prospective cohort study. LLE was defined as a caregiver-reported score ≤10th percentile in any of 4 domains of the MacArthur-Bates Communicative Development Inventory for 1-year olds and as ≥1 standard deviation below age-specific norms for the Ages and Stages Questionnaire for 2-year olds. Logistic regression models were used to evaluate associations of in utero cARV exposure with LLE, adjusting for infant, maternal and environmental characteristics. RESULTS: 1129 language assessments were conducted among 792 1- and 2-year-old children (50% male, 62% black and 37% Hispanic). Overall, 86% had in utero exposure to cARV and 83% to protease inhibitors. LLE was identified in 26% of 1-year olds and 23% of 2-year olds, with higher rates among boys. In adjusted models, LLE was not associated with maternal cARV or ARV drug classes in either age group. Among cARV-exposed 1-year olds, increased odds of LLE was observed for those exposed to atazanavir (adjusted odds ratio = 1.83, 95% confidence interval: 1.10-3.04), particularly after the first trimester (adjusted odds ratio = 3.56, P = 0.001), compared with atazanavir-unexposed infants. No associations of individual ARV drugs with LLE were observed among 2-year olds. CONCLUSIONS: In utero cARV exposure showed little association with LLE, except for a higher risk of language delay observed in 1-year-old infants with atazanavir exposure.

Association of HIV clinical disease progression with profiles of early immune activation: results from a cluster analysis approach.

OBJECTIVE: CD4 and CD8 T-cell activation are independent predictors of AIDS. The complete activation profile of both T-cell subtypes and their predictive value for AIDS risk is largely unknown. DESIGN: A total of 564 AIDS-free women in the Women's Interagency HIV Study were followed over 6.1 years (median) after T-cell activation assessment. A cluster analysis approach was used to evaluate the concurrent activation patterns of CD4 and CD8 T cells at the beginning of follow-up in relation to AIDS progression. METHODS: Percentages of CD4 and CD8 T cells with HLA-DR± and CD38± were assessed by flowcytometry. Eight immunologic variables (four on each CD4+ and CD8+: DR± and CD38±) were assessed to yield a 4-cluster solution on samples obtained before clinical endpoints. Proportional hazards survival regression estimated relative risks for AIDS progression by cluster membership. RESULTS: Compared with the other three clusters, outstanding activation features of each distinct cluster of women were: Cluster 1: higher CD8(+)CD38(-)DR(-) (average=41% of total CD8 T-cell pool), CD4(+)CD38(-)DR(-) (average=53% of total CD4 T-cell pool), and CD8(+)CD38(-)DR(+) (28%); Cluster 2: higher CD8(+)CD38(+)DR(-) (44%) and CD4(+)CD38(+)DR(-) (58%); Cluster 3: higher CD8(+)CD38(+)DR(+) (49%) and CD4(+)CD38(+)DR(-) (48%); Cluster 4: higher CD8(+)CD38(+)DR(+) (49%), CD4(+)CD38(+)DR(+) (36%) and CD4(+)CD38(-)DR(+) (19%). Compared with cluster 1, women in cluster 4 had two-fold increased risk of AIDS progression (Hazard ratio=2.13; 95% confidence interval=1.30-3.50) adjusted for CD4 cell count, HIV RNA, and other confounders. CONCLUSION: A profile including CD4 and CD8 T-cell activation provided insight into HIV pathogenesis indicating concurrent hyperactivation of CD4 and CD8 T cells is associated with AIDS progression.

Methicillin-Resistant Staphylococcus aureus Infections in Human Immunodeficiency Virus-Infected Children and Adolescents.

Background. Methicillin-resistant Staphylococcus aureus (MRSA) infection incidence has increased in healthy US children. Our objective was to evaluate MRSA incidence and correlates in HIV-infected youth. Methods. The CDC-sponsored LEGACY study is a US multicenter chart abstraction study of HIV-infected youth. We identified MRSA infections among participants with ≥1 visit during 2006. We used bivariate and multivariable analyses to compare sociodemographic and HIV clinical factors between MRSA cases and noncases. Results. Fourteen MRSA infections (1 invasive, 12 soft tissue, 1 indeterminate) occurred among 1,813 subjects (11.1 infections/1,000 patient-years (PY), 95% CI: 11.06-11.14). Most (86%) isolates were clindamycin susceptible. Compared with noncases, MRSA cases were more likely older (17 versus 14 years), black (100% versus 69%), behaviorally HIV infected (43% versus 17%), and in Maryland (43% versus 7%) and had viral loads (VL) >1000 copies/mL (86% versus 51%) and lower mean CD4% (18% versus 27%) (all P < 0.05). In multivariate analysis, independent risk factors were Maryland care site (adjusted odds ratio (aOR) = 9.0), VL >1000 copies/mL (aOR = 5.9), and black race (aOR undefined). Conclusions. MRSA occurred at a rate of 11.1 infections/1,000 PY in HIV-infected youth but invasive disease was uncommon. Geographic location, black race, and increased VL, but not immunosuppression, were independently associated with MRSA risk.

The effect of prenatal highly active antiretroviral therapy on the transmission of congenital and perinatal/early postnatal cytomegalovirus among HIV-infected and HIV-exposed infants.

BACKGROUND: Before highly active antiretroviral therapy (HAART), congenital cytomegalovirus (CMV) rates were higher among human immunodeficiency virus (HIV)-exposed infants than unexposed infants. This study examines congenital and perinatal/early postnatal (P/EP) CMV among HIV-exposed infants pre- and post- HAART. METHODS: Infants born to HIV-infected women were evaluated for congenital CMV (CMV-positive culture in first 3 weeks of life) and P/EP CMV (positive culture in first 6 months of life). Prenatal maternal HAART was defined as triple antiretroviral therapy (ART) with at least 1 nonnucleoside reverse-transcriptase inhibitor or protease inhibitor. RESULTS: Among 414 infants evaluated, 1678 CMV assessment days were completed (mean = 3 assessment days per infant). Congenital CMV rates did not differ by time period, HAART use, or infant HIV infection status. P/EP CMV rates were greater for the 1988-1996 birth cohort (17.9%) compared with the 1997-2002 birth cohort (8.9%) (P < .01), HIV-infected versus uninfected infants (P < .01), and infants with no maternal ART versus those with ART (P < .01). Controlling for potential confounders, P/EP CMV was associated with no maternal ART (odds ratio = 4.7; P < .01), and among those with no maternal ART, P/EP CMV was associated with maternal CD4 count ≤200 cells/µL (P < .01). For HIV-uninfected infants with P/EP CMV, symptoms including splenomegaly, lymphadenopathy, and hepatomegaly were associated with no maternal HAART versus those with HAART (41% vs 6%; P < .05). CONCLUSIONS: Although congenital CMV rates did not change, the post-HAART era showed reduced P/EP CMV and occurrence of related clinical symptoms. These findings underscore the importance of prenatal HAART for all HIV-infected pregnant women.

Language impairment in children perinatally infected with HIV compared to children who were HIV-exposed and uninfected.

OBJECTIVE: To investigate the risk for language impairment (LI) in children perinatally infected or exposed to HIV. METHODS: We evaluated the prevalence of LI in 7- to 16-year-old children with perinatal HIV infection (HIV+) compared with HIV-exposed and uninfected children, using a comprehensive standardized language test (Clinical Evaluation of Language Functioning-Fourth Edition [CELF-4]). LI was classified as primary LI (Pri-LI) (monolingual English exposure and no cognitive or hearing impairment), concurrent LI (Con-LI) (cognitive or hearing impairment), or no LI. Associations of demographic, caregiver, HIV disease, and antiretroviral treatment factors with LI category were evaluated using univariate and multivariable logistic regression models. RESULTS: Of the 468 children with language assessments, 184 (39%) had LI. No difference was observed by HIV infection status for overall LI or for Pri-LI or Con-LI; mean (SD) CELF-4 scores were 88.5 (18.4) for HIV+ versus 87.5 (17.9) for HIV-exposed and uninfected children. After adjustment, black children had higher odds of Pri-LI versus no LI (adjusted odds ratio [aOR] = 2.43, p = .03). Children who were black, Hispanic, had a caregiver with low education or low intelligence quotient, or a nonbiological parent as caregiver had higher odds of Con-LI versus no LI. Among HIV+ children, viral load >400 copies/mL (aOR = 3.04, p < .001), Centers for Disease Control and Prevention Class C (aOR = 2.19, p = .02), and antiretroviral treatment initiation <6 months of age (aOR = 2.12, p = .02) were associated with higher odds of Con-LI versus no LI. CONCLUSIONS: Children perinatally exposed to HIV are at high risk for LI, but such risk was not increased for youth with HIV. Risk factors differed for Pri-LI and Con-LI.

Activation of CD8 T cells predicts progression of HIV infection in women coinfected with hepatitis C virus.

BACKGROUND: Because activation of T cells is associated with human immunodeficiency virus (HIV) pathogenesis, CD4 and CD8 activation levels in patients coinfected with HIV and hepatitis C virus (HCV) may explain conflicting reports regarding effects of HCV on HIV disease progression. METHODS: Kaplan-Meier and multivariate Cox regression models were used to study the risk of incident clinical AIDS and AIDS-related deaths among 813 HCV-negative women with HIV infection, 87 HCV-positive nonviremic women with HIV coinfection, and 407 HCV-positive viremic women with HIV coinfection (median follow-up time, 5.2 years). For 592 women, the percentages of activated CD4 and CD8 T cells expressing HLA-DR (DR) and/or CD38 were evaluated. RESULTS: HCV-positive viremic women had a statistically significantly higher percentage of activated CD8 T cells (P < .001) and a statistically significantly higher incidence of AIDS compared with HCV-negative women (P < .001 [log-rank test]). The AIDS risk was greater among HCV-positive viremic women in the highest tertile compared with the lowest tertile (>43% vs <26%) of CD8(+)CD38(+)DR(+) T cells (hazard ratio, 2.94 [95% confidence interval, 1.50-5.77]; P = .001). This difference was not observed in the HCV-negative women (hazard ratio, 1.87 [95% confidence interval, 0.80-4.35]; P = .16). In contrast, CD4 activation predicted AIDS in both groups similarly. Increased percentages of CD8(+)CD38(-)DR(+), CD4(+)CD38(-)DR(-), and CD8(+)CD38(-)DR(-) T cells were associated with a >60% decreased risk of AIDS for HCV-positive viremic women and HCV-negative women. CONCLUSION: HCV-positive viremic women with HIV coinfection who have high levels of T cell activation may have increased risk of AIDS. Earlier treatment of HIV and HCV infection may be beneficial.

Factors associated with prevalent hepatitis C infection among HIV-infected women with no reported history of injection drug use: the Women's Interagency HIV Study (WIHS).

Although the primary mode of hepatitis C virus (HCV) transmission is exposure to blood products or injection drug use (IDU), studies have found varying independent risk factors for HCV infection among persons with no history of IDU or exposure to blood products. For HIV-infected women, sexual transmission may be another potential source of HCV infection. HIV-infected and HIV-negative women at risk for HIV enrolled in the Women's Interagency HIV Study (WIHS) during October 1994 to November 1995 and again between October 2001 and November 2002 were studied. Clinical and demographic factors associated with HCV seroprevalence were assessed in multivariate logistic regression models controlling for history of blood transfusion and IDU. Among 3636 women with HCV results, 31.5% were HCV antibody positive (HCV+) including 13.5% with no reported history of IDU or blood transfusions. Multivariate logistic regression analyses stratified on IDU showed that among women with no history of IDU, sex with an IDU male was independently associated with HCV positivity (odds ratio [OR] = 2.8, 95% confidence [CI] = 2.1, 3.8, p < 0.0001) after controlling for blood transfusion, age, HIV infection, unemployment, birth in the United States, history of hepatitis B infection, and current smoking status. Further stratification on HIV status showed that the association was significant only for the HIV+ (OR = 1.9, 95% CI = 1.3, 2.7, p = 0.0007) compared to the HIV- women (OR = 1.1, 95% CI = 0.4, 2.7) although these odds ratios were not significantly different (p = 0.25). For HIV-positive women with no reported history of IDU, sex with an IDU male was independently associated with HCV suggesting that sexual transmission may be an important mode of HCV transmission for these high-risk women.