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1.  Genital Tract HIV RNA Levels and Their Associations with Human Papillomavirus Infection and Risk of Cervical Pre-Cancer 
Plasma HIV RNA levels have been associated with risk of human papillomavirus (HPV) and cervical neoplasia in HIV-seropositive women. However, little is known regarding local genital tract HIV RNA levels and their relation with cervical HPV and neoplasia.
In an HIV-seropositive women’s cohort with semi-annual follow-up, we conducted a nested case-control study of genital tract HIV RNA levels and their relation with incident high-grade squamous intraepithelial lesions sub-classified as severe (severe HSIL), as provided for under the Bethesda 2001 classification system. Specifically, 66 incident severe HSIL were matched to 130 controls by age, CD4+ count, HAART use, and other factors. We also studied HPV prevalence, incident detection, and persistence in a random sample of 250 subjects.
Risk of severe HSIL was associated with genital tract HIV RNA levels (odds ratio comparing HIV RNA ≥ the median among women with detectable levels versus undetectable [ORVL] 2.96; 95% CI: 0.99–8.84; Ptrend=0.03). However, this association became non-significant (Ptrend=0.51) following adjustment for plasma HIV RNA levels. There was also no association between genital tract HIV RNA levels and the prevalence of any HPV or oncogenic HPV. However, the incident detection of any HPV (Ptrend=0.02) and persistence of oncogenic HPV (Ptrend=0.04) were associated with genital tract HIV RNA levels, after controlling plasma HIV RNA levels.
These prospective data suggest that genital tract HIV RNA levels are not a significant independent risk factor for cervical pre-cancer in HIV-seropositive women, but leave open the possibility that they may modestly influence HPV infection, an early stage of cervical tumoriogenesis.
PMCID: PMC4267467  PMID: 24694931
Genital tract HIV viral load; cervical neoplasia; HPV natural history
2.  Evaluation of Immune Survival Factors in Pediatric HIV-1 Infection 
Peripheral blood CD4+ and CD8+ T cells, CD19+/20+ B cells, and serum immunoglobulins (Igs) have been implicated as survival factors for pediatric HIV-1 infection. To determine which of these immune factors might be important in predicting survival, we studied HIV-1 vertically infected (HIV-1+) children over a 5-year period. Peripheral blood lymphocytes and Igs were measured in 298 HIV-1+ children, who were classified as survivors or nonsurvivors, and in 463 HIV-1 vertically exposed and noninfected (HIV-1–) children. Measurements of other possible survival factors were included in this study: albumin, hemoglobin, lactic dehydrogenase (LDH), and HIV-1 RNA levels. Survivors had significantly higher CD4+ T-cell, CD8+ T-cell, and CD19+/CD20+ B-cell counts and serum IgG levels, but lower serum IgA and IgM levels than nonsurvivors. Serum albumin and blood hemoglobin levels were higher, but serum LDH and HIV-1 RNA levels were lower in the survivors compared to non-survivors. In univariable analysis, factors affecting survival were baseline CD4+ T-cell and CD8+ T-cell counts, IgG, albumin, hemoglobin, LDH, and HIV-1 RNA (all p < 0.001). In multivariable analysis, high baseline CD4+ T-cell count, IgG and albumin levels, and low baseline HIV-1 RNA load remained important factors for survival. Serum IgG level has been identified as an immune factor that independently predicts survival, in addition to the already established CD4+ T-cell count. The HIV-1 RNA and serum albumin levels also predicted survival.
PMCID: PMC4412260  PMID: 11144332
3.  Effect of Cytomegalovirus Co-Infection on Normalization of Selected T-Cell Subsets in Children with Perinatally Acquired HIV Infection Treated with Combination Antiretroviral Therapy 
PLoS ONE  2015;10(3):e0120474.
We examined the effect of cytomegalovirus (CMV) co-infection and viremia on reconstitution of selected CD4+ and CD8+ T-cell subsets in perinatally HIV-infected (PHIV+) children ≥ 1-year old who participated in a partially randomized, open-label, 96-week combination antiretroviral therapy (cART)-algorithm study.
Participants were categorized as CMV-naïve, CMV-positive (CMV+) viremic, and CMV+ aviremic, based on blood, urine, or throat culture, CMV IgG and DNA polymerase chain reaction measured at baseline. At weeks 0, 12, 20 and 40, T-cell subsets including naïve (CD62L+CD45RA+; CD95-CD28+), activated (CD38+HLA-DR+) and terminally differentiated (CD62L-CD45RA+; CD95+CD28-) CD4+ and CD8+ T-cells were measured by flow cytometry.
Of the 107 participants included in the analysis, 14% were CMV+ viremic; 49% CMV+ aviremic; 37% CMV-naïve. In longitudinal adjusted models, compared with CMV+ status, baseline CMV-naïve status was significantly associated with faster recovery of CD8+CD62L+CD45RA+% and CD8+CD95-CD28+% and faster decrease of CD8+CD95+CD28-%, independent of HIV VL response to treatment, cART regimen and baseline CD4%. Surprisingly, CMV status did not have a significant impact on longitudinal trends in CD8+CD38+HLA-DR+%. CMV status did not have a significant impact on any CD4+ T-cell subsets.
In this cohort of PHIV+ children, the normalization of naïve and terminally differentiated CD8+ T-cell subsets in response to cART was detrimentally affected by the presence of CMV co-infection. These findings may have implications for adjunctive treatment strategies targeting CMV co-infection in PHIV+ children, especially those that are now adults or reaching young adulthood and may have accelerated immunologic aging, increased opportunistic infections and aging diseases of the immune system.
PMCID: PMC4368806  PMID: 25794163
4.  Prospective 5-year study of peripheral blood CD4+, CD8+, and CD19+/CD20+ lymphocytes and serum Igs in children born to HIV-1+ women 
Peripheral blood CD4+ and CD8+ T cells, CD19+/20+ B cells, and serum Igs are known to be altered by the progression of pediatric HIV-1 infection, but their evaluation as predictors of survival needs further definition.
To determine the natural history of these immune factors and their importance in predicting survival, we studied 298 HIV-1 vertically infected (HIV-1+) children over a 5-year period.
These immune factors and serum HIV-1 RNA levels were measured in two groups: (1) a birth cohort of children enrolled up to age 28 days postnatally, including 93 HIV-1+ and 463 HIV-1 uninfected infants (HIV-1−), and (2) an older cohort of 205 HIV-1+ children enrolled after the age of 28 days, who were classified as survivors or nonsurvivors.
In the birth cohort HIV-1+ children had significantly lower CD4+ T-cell counts, higher CD8+ T-cell counts, and lower CD19+/20+ B-cell counts and higher IgG, IgA, and IgM levels than HIV-1− children. In the older cohort survivors had significantly higher CD4+ and CD8+ T-cell and CD19+/CD20+ B-cell counts and higher IgG, lower IgA, and lower IgM levels than did nonsurvivors. In univariable analysis factors affecting survival in the older cohort were baseline CD4+ and CD8+ T-cell and CD19+/20+ B-cell counts and IgG and HIV-1 RNA levels (all P < .05). In multivariable analysis high baseline CD4+ T-cell count and low baseline HIV-1 RNA load remained important.
The longitudinal mean profiles of CD4 and CD8 T-cell and CD19/20 B-cell counts and serum IgG levels helped to describe the natural progression of HIV-1 disease in children. However, only baseline CD4 T-cell count independently predicted survival.
PMCID: PMC4360071  PMID: 10984378
Pediatric HIV-1 infection; survival; CD4+T cells; CD8+T cells; CD19+/20+B cells; serum Igs
5.  Alterations in Cardiac and Pulmonary Function in Pediatric Rapid Human Immunodeficiency Virus Type 1 Disease Progressors 
Pediatrics  2000;105(1):e9.
Infants with human immunodeficiency virus type 1 (HIV-1) can be divided into rapid progressors (RPs) and non-rapid progressors (non-RPs) based on symptoms and immunologic status, but detailed information about cardiac and pulmonary function in RP and non-RP children needs to be adequately described.
Cardiac, pulmonary, and immunologic data and HIV-1 RNA burden were periodically measured in 3 groups: group I, 205 vertically infected children enrolled from 1990 to 1994 and followed through 1996; group II, a prospectively studied cohort enrolled at birth that included 93 infected (group IIa); and 463 noninfected infants (group IIb).
Mean respiratory rates were generally higher in group IIa RP than non-RP children throughout the period of follow-up, achieving statistical signifance at 1 month, 12 months, 24 months, 30 months, and 48 months of follow-up. Non-RP and group IIb (HIV-uninfected children) had similar mean respiratory rates from birth to 5 years of age.
Significant differences in mean respiratory rates were found between group I RP and non-RP at 7 age intervals over the first 6 years of life. Mean respiratory rates were higher in RP than in non-RP at <1 year, 2.0 years, 2.5 years, 3.0 years, 3.5 years, 4.0 years, and 6.0 years of age.
Mean heart rates in group IIa RP, non-RP, and group IIb differed at every age. Rapid progressors had higher mean heart rates than non-RP at all ages through 24 months. Mean heart rates at 30 months through 60 months of age were similar for RP and non-RP children. Non-RP children had higher mean heart rates than did group IIb at 8 months, 24 months, 36 months, 42 months, 48 months, 54 months, and 60 months of age.
In group I, RP had higher mean heart rates than non-RP at 2.0 years, 2.5 years, 3.0 years, and 4.0 years of age. After 4 years of age, the non-RP and RP had similar mean heart rates.
Mean fractional shortening differed between the 3 group II subsets (RP, non-RP, and IIb) at 4, 8, 12, 16, and 20 months of age. Although mean fractional shortening was lower in RP than in non-RP in group II at all time points between 1 and 20 months, the mean fractional shortening was significantly lower in RP only at 8 months when restricting the statistical comparisons to the 2 HIV-infected groups (RP and non-RP). Mean fractional shortening increased in the first 8 months of life followed by a gradual decline through 5 years of age among group IIb children. No significant differences among the 3 groups in mean fractional shortening were detected after 20 months of age.
In group I, differences between RP and non-RP in mean fractional shortening were detected at 1.5, 2.0, 2.5, and 3.0 years of age. After 3 years of age, group means for fractional shortening in RP and non-RP did not differ. Because of the limited data from the first months of the group I patients, it could not be determined whether this group experienced the gradual early rise in mean fractional shortening seen in the group II infants.
In group IIa, RP had more clinical (eg, oxygen saturation <96%) and chest radiographic abnormalities (eg, cardiomegaly) at 18 months of life. RP also had significantly higher 5-year cumulative mortality than non-RP, higher HIV-1 viral burdens than non-RP, and lower CD8+ T-cell counts.
Rapid disease progression in HIV-1-infected infants is associated with significant alterations in heart and lung function: increased respiratory rate, increased heart rate, and decreased fractional shortening. The same children exhibited the anticipated significantly increased 5-year cumulative mortality, increased serum HIV-1 RNA load, and decreased CD8+ (cytotoxic) T-cell counts. Measurements of cardiopulmonary function in HIV-1-infected children seem to be useful in the total assessment of HIV-1 disease progression.
PMCID: PMC4331103  PMID: 10617746
6.  Effect of protease inhibitors on steady state pharmacokinetics of oral norethindrone contraception in HIV infected women 
Pharmacokinetic interactions exist between combined oral contraceptives and protease inhibitors (PI). However, such information is lacking for progestin-only oral contraception. We sought to define the steady-state pharmacokinetic interaction between norethindrone (NET) and PI in HIV infected women.
Methods and design
We conducted an open-label, prospective, non-randomized trial to characterize the steady-state pharmacokinetics of serum NET in HIVinfected women receiving PI compared to a control group of HIVinfected women receiving other non interacting drugs. Following 21 days of NET 0.35 mg ingestion once daily, serial serum samples were obtained at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 hours. The area under the curve between 0 and 72 hours after ingestion was calculated by trapezoidal approximation.
Thirty-five women were enrolled, two withdrew. Sixteen women in the PI group and 17 controls completed the study. NET half life, and maximum concentration were not significantly different between the two groups. Minimum concentration of NET was significantly higher in the PI group (p=0.01). The ratio of the geometric mean NET area under the curve in the PI group compared to controls was 1.5 (90% confidence interval 1.21-1.86). NET serum concentrations are significantly higher in HIVinfected women taking a PI compared to controls (p=0.004).
Co-administration of PI inhibits NET metabolism as shown by higher serum NET area under the curve levels, a surrogate marker for therapeutic contraceptive efficacy. This study supports increased utilization of progestin only pills in HIV infected women receiving certain PI regimens.
PMCID: PMC3946363  PMID: 24025339
HIV; hormonal contraception; protease inhibitor; progestin only pills; norethindrone; pharmacokinetics; contraception; drug interaction; efficacy
Background and Methods
Cytomegalovirus (CMV) has been implicated as a cofactor in the progression of human immunodeficiency virus type 1 (HIV-1) disease. We assessed 440 infants (75 of whom were HIV-1–infected and 365 of whom were not) whose CMV status was known, who were born to HIV-1–infected women, and who were followed prospectively. HIV-1 disease progression was defined as the presence of class C symptoms (according to the criteria of the Centers for Disease Control and Prevention [CDC]) or CD4 counts of less than 750 cells per cubic millimeter by 1 year of age and less than 500 cells per cubic millimeter by 18 months of age.
At birth the frequency of CMV infection was similar in the HIV-1–infected and HIV-1–uninfected infants (4.3 percent and 4.5 percent, respectively), but the HIV-1–infected infants had a higher rate of CMV infection at six months of age (39.9 percent vs. 15.3 percent, P=0.001) and continued to have a higher rate of CMV infection through four years of age (P=0.04). By 18 months of age, the infants with both infections had higher rates of HIV-1 disease progression (70.0 percent vs. 30.4 percent, P=0.001), CDC class C symptoms or death (52.5 percent vs. 21.7 percent, P=0.008), and impaired brain growth or progressive motor deficits (35.6 percent vs. 8.7 percent, P=0.005) than infants infected only with HIV-1. In a Cox regression analysis, CMV infection was associated with an increased risk of HIV-1 disease progression (relative risk, 2.59; 95 percent confidence interval, 1.13 to 5.95). Among children infected with HIV-1 alone, but not among those infected with both viruses, children with rapid progression of HIV-1 disease had higher mean levels of HIV-1 RNA than those with slower or no progression of disease.
HIV-1–infected infants who acquire CMV infection in the first 18 months of life have a significantly higher rate of disease progression and central nervous system disease than those infected with HIV-1 alone.
PMCID: PMC4280563  PMID: 10395631
8.  Association of HIV clinical disease progression with profiles of early immune activation: results from a cluster analysis approach 
AIDS (London, England)  2013;27(9):1473-1481.
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.
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.
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.
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.
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.
PMCID: PMC3949252  PMID: 23945505
AIDS; cluster analysis; immune activation
9.  Relation of HLA Class I and II Supertypes with Spontaneous Clearance of Hepatitis C Virus 
Genes and immunity  2013;14(5):330-335.
Human leukocyte antigen (HLA) genotype has been associated with probability of spontaneous clearance of hepatitis C virus (HCV). However, no prior studies have examined whether this relationship may be further characterized by grouping HLA alleles according to their supertypes, defined by their binding capacities. There is debate regarding the most appropriate method to define supertypes. Therefore, previously reported HLA supertypes (46 class I and 25 class II) were assessed for their relation with HCV clearance in a population of 758 HCV-seropositive women. Two HLA class II supertypes were significant in multivariable models that included: (i) supertypes with significant or borderline associations with HCV clearance after adjustment for multiple tests, and (ii) individual HLA alleles not part of these supertypes, but associated with HCV clearance in our prior study in this population. Specifically, supertype DRB3 (prevalence ratio (PR)=0.4; p=0.004) was associated with HCV persistence while DR8 (PR=1.8; p=0.01) was associated with HCV clearance. Two individual alleles (B*57:01 and C*01:02) associated with HCV clearance in our prior study became non-significant in analysis that included supertypes while B*57:03 (PR=1.9; p=0.008) and DRB1*07:01 (PR=1.7; p=0.005) retained significance. These data provide epidemiologic support for the significance of HLA supertypes in relation to HCV clearance.
PMCID: PMC3723800  PMID: 23636221
hepatitis C virus; HLA; human leukocyte antigen; supertype
10.  Effects of hepatitis C and HIV on cognition in women: Data from the Women’s Interagency HIV Study 
To compare neuropsychological scores in women infected with HIV, women infected with both HIV and hepatitis C, and uninfected subjects.
Some, but not all, studies have demonstrated that dual infection with HCV and HIV has worse effects on cognition than infection with HIV alone.
The Women’s Interagency HIV Study (WIHS) is an ongoing prospective study of the natural history of HIV in women where participants are reevaluated every 6 months. In a cross-sectional analysis, we evaluated the effects of active HIV and HCV-infections on scores on symbol-digit test (SDMT), the Stroop interference test, and trails A and B after controlling for age, ethnicity, education, depression, liver disease, and current or past substance abuse.
Data were available for 1338 women – 17.8 % had detectable hepatitis C virus and 67% were HIV-seropositive. In fully adjusted general linear models, HCV viremia was not associated with scores on any of the cognitive tests.
In this large sample of women, active HCV infection was not associated with scores on a small battery of neuropsychological tests.
PMCID: PMC3319079  PMID: 22107817
Hepatitis C; HIV; neurocognition; women
11.  The insulin-like growth factor axis and risk of liver disease in hepatitis C virus/HIV-co-infected women 
AIDS (London, England)  2008;22(4):527-531.
Insulin-like growth factor (IGF) I stimulates the proliferation of hepatic stellate cells (HSC), the primary source of extracellular matrix accumulation in liver fibrosis. In contrast, insulin-like growth factor binding protein (IGFBP) 3, the most abundant IGFBP in circulation, negatively modulates HSC mitogenesis. To investigate the role of the IGF axis in hepatitis C virus (HCV)-related liver disease among high-risk patients, we prospectively evaluated HCV-viremic/HIV-positive women.
A cohort investigation.
Total IGF-I and IGFBP-3 were measured in baseline serum specimens obtained from 472 HCV-viremic/HIV-positive subjects enrolled in the Women's Inter-agency HIV Study, a large multi-institutional cohort. The aspartate aminotransferase to platelet ratio index (APRI), a marker of liver fibrosis, was assessed annually.
Normal APRI levels (< 1.0) at baseline were detected in 374 of the 472 HCV-viremic/HIV-positive subjects tested, of whom 302 had complete liver function test data and were studied. IGF-I was positively associated [adjusted odds ratio comparing the highest and lowest quartiles (AORq4–q1), 5.83; 95% confidence interval (CI) 1.17–29.1; Ptrend = 0.03], and IGFBP-3 was inversely associated (AORq4–q1, 0.13; 95% CI 0.02–0.76; Ptrend = 0.04), with subsequent (incident) detection of an elevated APRI level(> 1.5), after adjustment for the CD4 T-cell count, alcohol consumption, and other risk factors.
High IGF-I may be associated with increased risk and high IGFBP-3 with reduced risk of liver disease among HCV-viremic/HIV-positive women.
PMCID: PMC3507535  PMID: 18301066
aspartate aminotransferase to platelet ratio index; APRI; hepatitis C virus (HCV); HIV; IGFBP-3; IGF; liver disease
12.  Hepatitis C Virus Quasispecies in HIV-Infected Women: Role of Injecting Drug Use and Highly Active Antiretroviral Therapy (HAART) 
Hepatology (Baltimore, Md.)  2007;46(2):359-370.
Despite the high frequency of HCV and HIV coinfection, little is known about HCV quasispecies in HIV-positive patients. The current analysis included 236 HIV+/anti-HCV+ women enrolled in the Women’s Interagency HIV Study (WIHS). Hypervariable region 1 of the second envelope gene was analyzed by single-strand conformation polymorphism (SSCP). The relationship between the HCV quasispecies and clinical and demographic features were analyzed in multivariate models. Age over 40 years and high HCV RNA load were the only factors significantly associated with quasispecies complexity, assessed as the number of SSCP bands. High HIV and HCV plasma loads were associated with quasispecies stability over time, as reflected by stable SSCP band patterns. However, women who were actively injecting drugs were 3 times more likely to experience quasispecies changes than their noninjecting counterparts. No affect on HCV quasi-species dynamics was noted in relation to CD4 count or highly active antiretroviral therapy (HAART). Conclusion: among HIV/HCV coinfected patients, HCV quasispecies complexity and dynamics correlate more closely with HIV and HCV plasma loads than with CD4+ cell counts. Active drug use is associated with quasispecies changes probably due to repeated superinfections with new HCV strains. This needs to be considered when planning treatment and prevention strategies for HCV in coinfected individuals.
PMCID: PMC3508063  PMID: 17659581
13.  Factors associated with hepatitis C viremia in a large cohort of HIV-infected and - uninfected women 
Coinfection with hepatitis C virus (HCV) is common among HIV-infected women.
To further our understanding of the risk factors for HCV viremia and the predictors of HCV viral load among women.
Study design
We investigated sociodemographic, immunologic, and virologic factors associated with presence and level of HCV viremia among 882 HIV-infected and 167 HIV-uninfected HCV-seropositive women at entry into the Women's Interagency HIV Study.
Plasma HCV RNA was detected in 852 (81%) of these 1,049 women (range: 1.2–7.8 log10 copies/ml). HCV-viremic women were more likely to have an HIV RNA level >100,000 copies/ml (P =0.0004), have reported smoking (P =0.01), or to be Black (P =0.005). They were less likely to have current or resolved hepatitis B infection. HCV RNA levels were higher in women who were >35 years old, or HIV-infected. Current smoking and history of drug use (crack/freebase cocaine, marijuana, amphetamines, or heroin) were each associated with both presence and level of viremia.
Substance abuse counseling aimed at eliminating ongoing use of illicit drugs and tobacco may reduce clinical progression, improve response to treatment, and decrease HCV transmission by lowering levels of HCV viremia in women.
PMCID: PMC3493623  PMID: 18243785
Hepatitis C; Hepatitis C RNA levels; Hepatitis C viremia; HIV/hepatitis C virus coinfection
14.  T-cell activation and neurodevelopmental outcomes in perinatally HIV-infected children 
AIDS (London, England)  2012;26(8):959-969.
To evaluate baseline T-cell activation and neurodevelopmental outcomes over time in a cohort of perinatally HIV-infected (PHIV-infected) children with severe disease.
Pediatric AIDS Clinical Trials Group protocol 366 (PACTG 366) was a partially randomized, open-label, multicenter 96-week antiretroviral treatment-algorithm study. Neurodevelopmental status, measured by age-dependent evaluations (Bayley scales of infant development-II; Wechsler preschool and primary scale of intelligence-revised; Wechsler intelligence scale for children-III), was a secondary outcome.
Linear mixed models were used to assess the baseline and follow-up neurodevelopmental outcomes in relation to immune activation, measured by CD38 and human leukocyte antigen (HLA) DR expression on peripheral CD4+ and CD8+ T cells at study baseline. Models were adjusted for age, sex, race/ethnicity, baseline viral load, baseline CD4%, cytomegalovirus (CMV) infection status at entry, study treatment arms, central nervous system penetrance score of antiretroviral regimen at entry, and viral load response 16 weeks postentry.
Among 126 PACTG 366 enrollees who were at least 1 year old and had both immune activation and age-appropriate neurodevelopmental assessments at baseline, 80 (63%) were black non-Hispanic, 71 (56%) males, 122 (97%) were on antiretrovirals, and 45 (36%) were in Centers for Disease Control and Prevention (CDC) disease category C at entry. CD4+CD38+HLADR+%, CD4+CD38−HLADR+%, and CD8+CD38+HLADR+% were positively associated with full-scale Intelligence Quotient scores (FSIQ) (slope =0.18, 0.70, and 0.15, respectively; P =0.02, 0.03, and 0.04, respectively). CD4+CD38+HLADR−% was negatively associated with FSIQ (slope =−0.16, P =0.01).
Contrary to HIV-infected adults, in PHIV-infected children higher CD4+CD38+HLADR+% may be associated with a neuroprotective effect and higher percentage of CD4+CD38+ but HLADR− T cells may be deleterious.
PMCID: PMC3437925  PMID: 22382148
HIV-associated central nervous system disease; immune activation; neurodevelopmental outcomes; pediatric neuro-AIDS; perinatally HIV-infected children
15.  The Relation of HLA Genotype to Hepatitis C Viral Load and Markers of Liver Fibrosis in HIV-Infected and HIV-Uninfected Women 
The Journal of Infectious Diseases  2011;203(12):1807-1814.
Background. Human leukocyte antigen (HLA) class I and II genotype is associated with clearance of hepatitis C virus (HCV) infection, but little is known regarding its relation with HCV viral load or risk of liver disease in patients with persistent HCV infection.
Methods. High-resolution HLA class I and II genotyping was conducted in a prospective cohort of 519 human immunodeficiency virus (HIV)–seropositive and 100 HIV-seronegative women with persistent HCV infection. The end points were baseline HCV viral load and 2 noninvasive indexes of liver disease, fibrosis-4 (FIB-4), and the aspartate aminotransferase to platelet ratio index (APRI), measured at baseline and prospectively.
Results. DQB1*0301 was associated with low baseline HCV load (β = −.4; 95% confidence interval [CI], −.6 to −.3; P < .00001), as well as with low odds of FIB-4–defined (odds ratio [OR], .5; 95% CI, .2–.9; P = .02) and APRI-defined liver fibrosis (OR, .5; 95% CI, .3–1.0; P = .06) at baseline and/or during follow-up. Most additional associations with HCV viral load also involved HLA class II alleles. Additional associations with FIB-4 and APRI primarily involved class I alleles, for example, the relation of B*1503 with APRI-defined fibrosis had an OR of 2.0 (95% CI, 1.0–3.7; P = .04).
Conclusions. HLA genotype may influence HCV viral load and risk of liver disease, including DQB1*0301, which was associated with HCV clearance in prior studies.
PMCID: PMC3100515  PMID: 21606539
16.  Systemic and Mucosal Differences in HIV Burden, Immune and Therapeutic Responses 
Mucosal tissues represent major targets for HIV transmission, but differ in susceptibility and reservoir function by unknown mechanisms.
In a cross-sectional study, HIV RNA and infectious virus were compared between oral and genital compartments and blood in HIV-infected women, in association with clinical parameters, co-pathogens and putative innate and adaptive HIV inhibitors.
HIV RNA was detectable in 24.5% of women from all 3 compartments, whereas 45% had RNA in only one or two sites. By comparison, infectious HIV, present in blood of the majority, was rare in mucosal sites. Innate mediators, SLPI and TSP, were highest in mucosae. Highly active antiretroviral therapy (HAART) was associated with an 80% decreased probability of shedding. Multivariate logistic regression models revealed that mucosal HIV RNA was associated with higher plasma RNA, infectious virus, and total mucosal IgA, but not IgG. There was a 37-fold increased probability of detecting RNA in both genital and oral specimens (P=0.008;P=0.02, respectively) among women in highest vs lowest IgA tertiles.
Mucosal sites exhibit distinct characteristics of infectious HIV, viral shedding and responses to therapy, dependent upon both systemic and local factors. Of the putative innate and adaptive mucosal defense factors examined, only IgA was associated with HIV RNA shedding. However, rather than being protective, there was a striking increase in probability of detectable HIV RNA shedding in women with highest total IgA.
PMCID: PMC3164950  PMID: 21239996
HIV-1; mucosa; innate immunity; adaptive immunity; IgA; SLPI
17.  Negative-Strand Hepatitis C Virus (HCV) RNA in Peripheral Blood Mononuclear Cells from Anti-HCV–Positive/HIV-Infected Women 
The Journal of Infectious Diseases  2006;195(1):124-133.
Hepatitis C virus (HCV) has been reported to replicate in peripheral blood mononuclear cells (PBMCs), particularly in patients coinfected with HCV and human immunodeficiency virus (HIV). However, there are limited data regarding the prevalence of and the factors associated with extrahepatic replication.
The presence of negative-strand HCV RNA in PBMCs was evaluated by a strand-specific assay for 144 anti-HCV–positive/HIV-infected women enrolled in the Women’s Interagency HIV Study. One to 5 PBMC samples obtained from each woman were tested. Multivariate analyses were used to assess for associations with the clinical and demographic characteristics of the women.
Negative-strand HCV RNA was detected in 78 (25%) of 315 specimens, and, for 61 women (42%), ≥1 specimen was found to have positive results. The presence of negative-strand HCV RNA in PBMCs was significantly positively associated with an HCV RNA plasma level of ≥6.75 log copies/mL (P =.04) and consumption of ≥7 alcoholic drinks per week (P =.02). It was also negatively associated with injection drug use occurring in the past 6 months (P =.03). A negative association with a CD4+CD38+DR+ cell percentage of >10% and a positive association with acquired immunodeficiency syndrome were borderline significant (P =.05).
HCV replication in PBMCs is common among HIV-coinfected women and appears to be a dynamic process related to lifestyle, virologic, and immunologic factors.
PMCID: PMC3319123  PMID: 17152016
18.  CC Chemokine Receptor 5 Genotype and Susceptibility to Transmission of Human Immunodeficiency Virus Type 1 in Women 
The Journal of Infectious Diseases  2003;187(4):569-575.
The human gene for CC chemokine receptor 5, a coreceptor for human immunodeficiency virus type 1 (HIV-1), affects susceptibility to infection. Most studies of predominantly male cohorts found that individuals carrying a homozygous deleted form of the gene, Δ32, were protected against transmission, but protection did not extend to Δ32 heterozygotes. The role played by this mutation in HIV-1 transmission to women was studied in 2605 participants in the Women's Interagency HIV Study. The Δ32 gene frequency was 0.026 for HIV-1–seropositive women and 0.040 for HIV-1–seronegative women, and statistical analyses showed that Δ32 heterozygotes were significantly less likely to be infected (odds ratio, 0.63 [95% confidence interval, 0.44–0.90]). The CCR5 Δ32 heterozygous genotype may confer partial protection against HIV-1 infection in women. Because Δ32 is rare in Africans and Asians, it seems plausible that differential genetic susceptibility, in addition to social and behavioral factors, may contribute to the rapid heterosexual spread of HIV-1 in Africa and Asia.
PMCID: PMC3319124  PMID: 12599073
19.  Human Leukocyte Antigen Genotype and Risk of HIV Disease Progression before and after Initiation of Antiretroviral Therapy▿‡ 
Journal of Virology  2011;85(20):10826-10833.
While the human leukocyte antigen (HLA) genotype has been associated with the rate of HIV disease progression in untreated patients, little is known regarding these relationships in patients using highly active antiretroviral therapy (HAART). The limited data reported to date identified few HLA-HIV disease associations in patients using HAART and even occasional associations that were opposite of those found in untreated patients. We conducted high-resolution HLA class I and II genotyping in a random sample (n = 860) of HIV-seropositive women enrolled in a long-term cohort initiated in 1994. HLA-HIV disease associations before and after initiation of HAART were examined using multivariate analyses. In untreated HIV-seropositive patients, we observed many of the predicted associations, consistent with prior studies. For example, HLA-B*57 (β = −0.7; 95% confidence interval [CI] = −0.9 to −0.5; P = 5 × 10−11) and Bw4 (β = −0.2; 95% CI = −0.4 to −0.1; P = 0.009) were inversely associated with baseline HIV viral load, and B*57 was associated with a low risk of rapid CD4+ decline (odds ratio [OR] = 0.2; 95% CI = 0.1 to 0.6; P = 0.002). Conversely, in treated patients, the odds of a virological response to HAART were lower for B*57:01 (OR = 0.2; 95% CI = 0.0 to 0.9; P = 0.03), and Bw4 (OR = 0.4; 95% CI = 0.1 to 1.0; P = 0.04) was associated with low odds of an immunological response. The associations of HLA genotype with HIV disease are different and sometimes even opposite in treated and untreated patients.
PMCID: PMC3187522  PMID: 21849458
20.  Correlates of Immune Activation Marker Changes in Human Immunodeficiency Virus (HIV)–Seropositive and High-Risk HIV-Seronegative Women Who Use Illicit Drugs 
The Journal of infectious diseases  2003;188(2):209-218.
The majority of natural history studies of human immunodeficiency virus (HIV) infection have immune and viral parameters in men. Data demonstrating that women have lower HIV-1 RNA levels than men at the same CD4 cell counts have raised the question of immunologic differences in HIV-seropositive women. This study describes levels and changes in phenotypic markers of immune maturity, function, and activation in the CD4 and CD8 cell subsets in HIV-seropositive and high-risk HIV-seronegative women. Our primary hypothesis was that activation levels would be significantly higher among illicit drug users. However, results showed that HIV-1 RNA level was the strongest predictor of marker level and that both HIV-1 RNA level and CD4 cell count were independently associated with CD4 activation, but illicit drug use was not. In summary, this study demonstrated that immune activation was a significant pathogenic feature in women and that activation was driven by HIV infection and not illicit drug use.
PMCID: PMC3164115  PMID: 12854075
21.  CCR2 Genotype and Disease Progression in a Treated Population of HIV Type 1–Infected Women 
Both antiretroviral therapy and the human coreceptor polymorphism CCR2-V64I slow progression of human immunodeficiency virus type 1 (HIV-1) disease. To examine the effect of V64I on disease progression in patients receiving therapy, we determined CCR2 genotypes in the Women’s Interagency HIV Study cohort. We studied 2047 HIV-1–infected women, most of whom initiated treatment during the study. No association was seen between CCR2 genotype and either disease progression or therapeutic response, suggesting that the benefits of treatment most likely overshadow the salutary effects of the V64I polymorphism.
PMCID: PMC3164116  PMID: 15472820
22.  Presence of Hepatitis C Virus (HCV) RNA in the Genital Tracts of HCV/HIV-1–Coinfected Women 
The Journal of infectious diseases  2005;192(9):1557-1565.
Hepatitis C virus (HCV)–infected women—in particular, those coinfected with human immunodeficiency virus type 1 (HIV-1)—can transmit infection to their children and sex partners.
The present study was conducted to analyze the presence of HCV RNA in cervicovaginal lavage (CVL) fluid from 71 women (58 HCV/HIV-1–coinfected women and 13 HCV-infected, HIV-1–uninfected women) enrolled in the Women’s Interagency HIV Study.
HCV RNA was detected (by a commercial polymerase chain reaction assay) in CVL fluid from 18 (29%) of the HIV-1–infected women and from none of the HIV-1–uninfected women (P < .05). Multivariate analysis revealed that risk factors for the presence of HCV RNA in CVL fluid were HCV viremia (odds ratio [OR], 16.81; P = .02) and HIV-1 RNA in CVL fluid (OR, 19.87; P = .02). This observation suggests local interactions between HIV-1 and HCV in the genital tract compartment. There was no correlation between HCV RNA in CVL fluid and CD4, CD8, or CD3 cell counts, HIV-1 RNA viremia, the number of leukocytes in CVL fluid, or HIV-1 therapy. Furthermore, in 3 of 5 analyzed patients who had a detectable CVL HCV RNA load, we found viral variants differing in the 5′ untranslated region that were present neither in plasma nor in peripheral-blood mononuclear cells.
Our observations point to the importance of the genital tract compartment, in which local HCV replication could be facilitated by local HIV-1 replication.
PMCID: PMC3164119  PMID: 16206070
23.  Antiretroviral Therapies Associated with Lipoatrophy in HIV-Infected Women 
AIDS patient care and STDs  2007;21(5):297-305.
We previously demonstrated that HIV infection is associated with peripheral and central lipoatrophy in women. We now describe the association of specific antiretroviral drugs (ARV) with body fat changes over a four-year period from 1999 to 2003. 775 HIV-positive and 205 HIV-negative women in the Women’s Interagency HIV Study with anthropometric measurements, weight, bioelectric impedance analysis and ARV collected semiannually were included in analysis. Exposure to ARV was defined as report of use for 3 consecutive semiannual study visits. The average 6–month change in weight, percent total body fat, and circumference measurements (i.e., hip, waist, chest, arm, and thigh) was compared between those exposed and those unexposed to the specific ARV for any of the same three consecutive visits. Weight, percent total body fat, and hip, waist, thigh, chest, and arm circumferences decreased in HIV-positive women, but increased in HIV-negative women on average for every six-month interval over the 4-year study period. Among the HIV-positive women, didanosine was the only ARV associated with decreases in circumference measures in the hip (−0.65 cm, 95% confidence interval [CI]: −1.18, −0.12), waist (−0.71 cm, 95% CI: −1.37, −0.04), chest (−0.71 cm, 95% CI: −1.17, −0.26), and arm (−0.23 cm, 95% CI: −0.48, 0.03; p = 0.08). These prospective data suggest that fat loss continues to predominate in HIV-positive women and exposure to didanosine for at least 12 months may further worsen fat loss.
PMCID: PMC3133726  PMID: 17518522
24.  Isolated Hepatitis B Core Antibody Is Associated with HIV and Ongoing but Not Resolved Hepatitis C Virus Infection in a Cohort of US Women 
The Journal of infectious diseases  2007;195(10):1437-1442.
To characterize predictors of isolated hepatitis B core antibody (anti-HBc) among human immunodeficiency virus (HIV)–infected and HIV-uninfected women, we compared 702 women with anti-HBc and hepatitis B surface antibody (anti-HBs) with 490 women with isolated anti-HBc (1.8% of whom had detectable hepatitis B virus [HBV] DNA). Factors independently associated with isolated anti-HBc without viremia were detectable hepatitis C virus (HCV) RNA, HIV positivity, history of injection drug use, >10 lifetime sex partners, and HIV RNA level >100,000 copies/mL. Anti-HBs levels were lower among anti-HCV–positive women. Isolated anti-HBc was rarely explained by occult HBV in this cohort but may be explained by the influence of viral coinfections on anti-HBs level or durability.
PMCID: PMC3133731  PMID: 17436223
25.  CYP2C19 Genetic Variants Affect Nelfinavir Pharmacokinetics and Virologic Response in HIV-1–Infected Children Receiving Highly Active Antiretroviral Therapy 
The objective of this research was to identify the impact of genetic variants of P-glycoprotein (ABCB1) and cytochrome P450 (CYP) on nelfinavir pharmacokinetics and response to highly active antiretroviral therapy (HAART) in HIV-1–infected children.
HIV-1–infected children (n = 152) from Pediatric AIDS Clinical Trial Group 366 or 377 receiving nelfinavir as a component of HAART were evaluated. Genomic DNA was assayed for ABCB1 and CYP genetic variants using real-time polymerase chain reaction Nelfinavir oral clearance (CL/F), M8 to nelfinavir ratios, CD4+ T cells, and HIV-1-RNA were measured during HAART.
Nelfinavir CL/F and M8 to nelfinavir ratios were significantly associated with the CYP2C19-G681A genotypes (P < 0.001). Furthermore, the CYP2C19-G681A genotype was related to virologic responses at week 24 (P = 0.01). A multivariate analysis demonstrated that age (P = 0.03), concomitant protease inhibitor use (P < 0.001), and the CYP2C19-G681A genotype (P < 0.001) remained significant covariates associated with nelfinavir CL/F.
CYP2C19 genotypes altered nelfinavir pharmacokinetics and the virologic response to HAART in HIV-1–infected children. These findings suggest that CYP2C19 genotypes are important determinants of nelfinavir pharmacokinetics and virologic response in HIV-1-infected children.
PMCID: PMC3119357  PMID: 19890215
ABCB1; CYP2C19; children; nelfinavir; virologic response

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