Toni Frederick

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 Womens 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.

Correlates of perinatal depression in HIV-infected women.

Maternal perinatal depression (PND) may interfere with effective perinatal HIV care. In order to begin examining the prevalence and characteristics of PND in HIV-infected women, we analyzed data from the medical records of all HIV-infected women who had received perinatal care in the Maternal-Child and Adolescent Center for Infectious Diseases and Virology at LAC/USC Medical Center from 1997 through 2006. Data from 273 individual women (328 live births) were analyzed. Demographic, medical history, psychosocial, pregnancy related, and HIV-related factors measured during the perinatal period were examined for an association with PND using multivariate logistic regression with generalized estimating equations to account for the within subject correlation due to multiple births per mother. The overall prevalence of PND was 30.8%. Multivariate analysis showed that PND was significantly associated with substance abuse during pregnancy (odds ratio [OR] = 2.81, 95% confidence interval [CI]: 1.35-5.82) and past history of psychiatric illness (OR = 3.72, 95% CI: 2.06-6.71). Compared to mothers with CD4 nadir greater than 500 cells/mm3, mothers with a CD4 nadir during pregnancy #200 cells=mm3 were 3.1 times more likely to experience PND (OR = 3.01, 95% CI: 1.32-6.88). Women who had antiretroviral (ARV) medications adherence problems during pregnancy were more likely to experience PND than women who were adherent (OR = 2.14, 95% CI: 1.08-4.23). These preliminary results suggest that rates of PND among HIV-infected women are substantial. We conclude that pregnant HIV-infected women should be routinely screened for PND. Prospective studies examining the bio-psycho-social markers of PND in HIV-infected women are indicated.

Evaluating the impact of hepatitis C virus (HCV) on highly active antiretroviral therapy-mediated immune responses in HCV/HIV-coinfected women : Role of HCV on expression of primed/ memory T cells

OBJECTIVE To evaluate the impact of hepatitis C virus (HCV) on the immune system before receipt of highly active antiretroviral therapy (HAART) and on immune recovery after receipt of HAART among human immunodeficiency virus (HIV)/HCV-coinfected women enrolled in the Womens Interagency HIV Study. METHODS The study included 294 HIV-infected women who initiated HAART and attended 2 follow-up visits. The women were grouped on the basis of positive HCV antibody and HCV RNA tests. There were 148 women who were HCV antibody negative, 34 who were HCV antibody positive but RNA negative, and 112 who were HCV antibody and RNA positive. Immune recovery was measured by flow-cytometric assessment for markers of activation and maturation on CD4+ and CD8+ T cells. Data analysis used repeated measures of variance.Results. HIV/HCV coinfection is associated with an increased number of CD4+ and CD8+ primed/memory T cells. HIV/HCV coinfection, however, did not affect any further decreases in CD4+ or CD4+ and CD8+ naive/memory T cell counts or enhanced T cell activation. HIV/HCV coinfection also did not affect HAART responses in the CD4+ and CD8+ T cell compartment. CONCLUSIONS HCV does not affect immune responses to HAART in HIV/HCV-coinfected individuals but is associated with an expansion of CD4+ and CD8+ memory T cell subsets. Functional impairment in the CD4+ and CD8+ T cell compartments still needs to be assessed in coinfected patients.

Progression of human immunodeficiency virus disease among infants and children infected perinatally with human immunodeficiency virus or through neonatal blood transfusion. Los Angeles County Pediatric AIDS Consortium and the Los Angeles County-University of Southern California Medical Center and the University of Southern California School of Medicine.

Using community-based surveillance data for pediatric human immunodeficiency virus (HIV) infection, we examined disease progression using survival analysis among perinatally HIV-infected children and children HIV-infected through a neonatal blood transfusion. As of December 31, 1991, 238 HIV-infected children (classified P-1 or P-2 according to the Centers for Disease Control and Prevention classification system) were identified. Median symptom-free survival time from birth to symptomatic infection (P-2) was different for perinatally acquired (n = 166) and neonatal transfusion-acquired (n = 72) infection (6.4 months vs. 17.8 months, respectively; P < 0.001). Survival after development of symptomatic infection (P-2) did not differ by transmission mode. Survival differences from birth to death were significant at P < 0.05 (75% of perinatally HIV-infected children survived 44 months vs. 71 months for transfusion-associated children). Although survival estimates improved for those receiving antiretroviral treatment, differences by mode were still observed. For perinatally HIV-infected children, mortality was highest in the first year of life (12%). Those remaining symptom-free beyond their first year demonstrated survival experiences similar to those for children with transfusion-associated infection.

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.

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 Womens 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.

Epidemiology of Pneumocystis Colonization in Families

Whether Pneumocystis colonization is transmitted in families with human immunodeficiency virus (HIV)-infected members is unknown. Using nested polymerase chain reaction of oropharyngeal or nasopharyngeal samples, we detected colonization in 11.4% of HIV-infected adults and in 3.3% of their children, but there was no evidence of clustering.