Human Papillomavirus Antibody Levels and Quadrivalent Vaccine Clinical Effectiveness in Perinatally Human Immunodeficiency Virus-infected and Exposed, Uninfected Youth.

BACKGROUND: Persons who are infected with human immunodeficiency virus (HIV) are at high risk of human papillomavirus (HPV)-associated cancers. The objectives are to compare antibody titers to HPV 6, 11, 16, and 18 and rate of abnormal cytology between perinatally HIV-infected (PHIV) and perinatally HIV-exposed, uninfected (PHEU) youth. METHODS: This is a prospective observational cohort study of HPV4 vaccinated youth performed as part of the multicenter Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol. Seroconversion and geometric mean titer (GMT) against HPV types 6, 11, 16, and 18 were calculated. Vaccine effectiveness included rates of abnormal cervical cytology and genital warts. RESULTS: Seroconversion to HPV 6, 11, 16, and 18 occurred in 83%, 84%, 90%, and 62% of 310 vaccinated PHIV youth compared to 94%, 96%, 99%, and 87% of 148 vaccinated PHEU youth, respectively (P < .05 for all comparisons). GMTs were lower in the PHIV vs PHEU within each category of HPV4 doses received. Higher GMTs were associated with younger age, lower HIV type 1 RNA viral load, and higher CD4% at first HPV4 vaccination, as well as shorter duration between last vaccine dose and antibody specimen. Abnormal cytology occurred in 33 of 56 PHIV and 1 of 7 PHEU sexually active vaccinated females, yielding incidence rates per 100 person-years of 15.0 (10.9 to 20.6) and 2.9 (0.4 to 22.3), respectively. CONCLUSION: Antibody titers to HPV4 were lower for all serotypes in PHIV compared to PHEU youth. Protection against abnormal cytology was also diminished in sexually active PHIV females.

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.

Sexually Transmitted Infections in Youth With Controlled and Uncontrolled Human Immunodeficiency Virus Infection.

BACKGROUND: Sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), disproportionately affect adolescents and young adults (AYAs) ages 13-24 years. Sexually transmitted infections likewise are a risk factor for HIV acquisition and transmission; however, there is a lack of data on STI acquisition in HIV-infected AYAs. METHODS: We determined the incidence of STIs in HIV-infected AYAs 12.5 <25 years of age in the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1074 observational cohort study. Univariate and multivariable logistic regression models were used to evaluate the association of HIV control (mean viral load <500 copies/mL and CD4+ T cells >500 cells/mm3 in the year preceding STI diagnosis) and other risk factors with STI occurrence. RESULTS: Of 1201 enrolled subjects, 1042 participants met age criteria and were included (49% male, 61% black, 88% perinatally infected; mean age 18.3 years). One hundred twenty participants had at least 1 STI on study, of whom 93 had their first lifetime STI (incidence rate = 2.8/100 person-years). For individual STI categories, 155 incident category-specific events were reported; human papillomavirus (HPV) and chlamydial infections were the most common. In the multivariable model, having an STI was associated with older age (adjusted odds ratio [aOR] = 1.13; 95% confidence interval [CI], 1.05-1.22), female sex (aOR = 2.65; 95% CI, 1.67-4.21), nonperinatal HIV acquisition (aOR = 2.33; 95% CI, 1.29-4.22), and uncontrolled HIV infection (aOR = 2.05; 95% CI, 1.29-3.25). CONCLUSIONS: Sexually transmitted infection acquisition in HIV-infected AYAs is associated with older age, female sex, nonperinatal HIV acquisition, and poorly controlled HIV infection. Substantial rates of STIs among HIV-infected AYAs support enhanced preventive interventions, including safe-sex practices and HPV vaccination, and antiretroviral adherence strategies.

Chronic kidney disease associated with perinatal HIV infection in children and adolescents.

BACKGROUND: This study describes the incidence, clinical and demographic characteristics, and spectrum of chronic kidney disease (CKD) in youths with perinatal HIV-1 infection. METHODS: Retrospective analysis between May 1993 and December 2006 of subjects with renal disease followed in the Pediatric AIDS Clinical Trials Group 219/219C multicenter study examining the long-term consequences of perinatal HIV infection. Diagnosis confirmation was made utilizing a questionnaire mailed to research sites. Participants with CKD of other etiology than HIV were excluded. Outcome measures were biopsy-diagnosed CKD and, in the absence of biopsy, HIV-associated nephropathy (HIVAN) using established clinical criteria. RESULTS: Questionnaires on 191 out of 2,102 participants identified 27 cases of CKD: 14 biopsy-diagnosed and 6 clinical cases of HIVAN, and 7 biopsy-diagnosed cases of immune complex-mediated kidney disease (lupus-like nephritis, 3; IgA nephropathy, 2; membranous nephropathy, 2). Incidence rates for CKD associated with HIV in pre-highly active antiretroviral therapy (HAART) (1993-1997) and HAART (1998-2002, 2003-2006) eras were 0.43, 2.84, and 2.79 events per 1,000 person years respectively. In multivariate analysis, black race and viral load ≥100,000 copies/mL (rate ratios 3.28 and 5.05, p ≤ 0.02) were associated with CKD. CONCLUSIONS: A variety of immune complex-mediated glomerulonephritides and HIVAN occurs in this population. Black race and uncontrolled viral replication are risk factors for CKD associated with HIV.

Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children.

OBJECTIVES: HIV-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction in HIV-infected children (with and without hyperlipidaemia) with those in HIV-exposed, uninfected (HEU) children enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers. METHODS: A prospective cohort study was carried out. Biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP1)], coagulant dysfunction (fibrinogen and P-selectin), endothelial dysfunction [soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM) and E-selectin], and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded. RESULTS: The median ages of the children were 12.3 years in the HIV-infected group and 10.1 years in the HEU group. Body mass index (BMI) z-scores, waist and hip circumferences, and percentage body fat were lower in the HIV-infected children. Total and non-high-density lipoprotein (HDL) cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children also had higher MCP-1, fibrinogen, sICAM and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavourable lipid profiles were positively associated with IL-6, MCP-1, fibrinogen, and P- and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP-1 and CRP) and endothelial dysfunction (sICAM and sVCAM). CONCLUSIONS: HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavourable lipid levels and active HIV replication.

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.

Effect of ciprofloxacin on lethal and sublethal challenge with endotoxin and on early cytokine responses in a murine in vivo model.

The influence of ciprofloxacin on immune responses has been suggested by results of in vitro and in vivo studies. This effect was studied using a murine model that measured mortality and early cytokine responses after challenge with endotoxin. C57/BL6 mice weighing between 18 and 21 g were given a single intraperitoneal dose of lipopolysaccharide (LPS), ranging from 200 to 1000 microg. Mice were pre-treated with an intraperitoneal injection of 5% dextrose in sterile water containing 0.0-6.0 mg of ciprofloxacin 1 h before LPS challenge. Cytokine responses were assessed by measuring concentrations in serum separated from blood obtained by cardiac puncture of anaesthetized mice at 0, 1, 3, 6 and 24 h following LPS administration. Mice were observed for 72 h following administration of LPS and serum cytokines were measured using ELISA. More than 4.5 mg of ciprofloxacin (675-900 mg/m(2) or 225-300 mg/kg) given 1 h before LPS challenge consistently protected mice from a lethal dose of LPS (14/14 versus 0/7, P < 0.00001). Ciprofloxacin significantly attenuated the production of tumour necrosis factor-alpha and interleukin-12 response after LPS challenge. In addition, ciprofloxacin significantly increased serum interleukin-10 concentrations but had little or no effect on interleukin-6 or interleukin-1beta serum concentrations. Similar effects were evident with sublethal doses of LPS and were most pronounced at the lowest dose of LPS studied. These observations indicate that ciprofloxacin can prevent endotoxin-mediated death and alter early host cytokine responses. This effect may influence the course of infection in a manner that is independent of the drug's antimicrobial activity.