Objective

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.

Design

A cohort investigation.

Methods

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.

Results

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.

Conclusion

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.

Tuberculosis (TB) is the worldwide leading cause of death among HIV-infected individuals, accounting for more than half of AIDS-related deaths. A high risk of tuberculosis (TB) has been shown in early stages of the HIV disease, even in the presence of normal CD4+ cell counts. Moreover, the factors that determine protective immunity vs. susceptibility to M. tuberculosis cannot be fully explained by simple changes in IFNγ levels or a shift from Th1 to Th2 cytokines. This work investigated the relationship between cytokine expression profiles in peripheral blood mononuclear cells (PBMC) and susceptibility to M. tuberculosis in ten HIV+ women who went on to develop TB. RNA transcripts for IL-4, IL-4δ2, IL-10, IL-12(p35), IL-13, IL-17A, IFNγ and TNFα were measured by real-time quantitative PCR in unstimulated or TB peptide antigen-stimulated PBMCs from ten HIV+ women with positive tuberculin skin tests (TST) and compared with HIV-seropositive and seronegative women without previous TB and negative TST. Stimulated PBMC cultures showed significantly lower expression of IL-12p35 (p=0.004) and IL-10 (p=0.026) in the HIV+TB+ group six to twelve months before onset of TB compared to HIV+TB− women. Unstimulated PBMC from HIV+TB+ women also had lower expression of Th2 cytokines [IL-4 (p=0.056) and IL-13 (p=0.050)] compared to HIV+TB− women. These results suggest that lower IL-12 production by PBMC in response to TB antigens and lower levels of both Th1 and Th2 cytokines by PBMC correlate with future development of TB in HIV-infected women and may be responsible for their increased susceptibility.

Abstract

Objective

To estimate the association between vitamin D deficiency and bacterial vaginosis (BV) among nonpregnant HIV-infected and uninfected women.

Methods

In a substudy of the Women's Interagency HIV Study, including women from Chicago and New York, the association between BV and vitamin D deficiency, demographics, and disease characteristics was tested using generalized estimating equations. Deficiency was defined as <20 ng/mL 25 (OH) vitamin D and insufficiency as >20 and ≤30 ng/mL. BV was defined by the Amsel criteria.

Results

Among 602 observations of nonpregnant women (480 HIV infected and 122 uninfected), BV was found in 19%. Vitamin D deficiency was found in 59.4%, and insufficiency was found in 24.4%. In multivariable analysis, black race was the most significant predictor of BV (adjusted odds ratio [AOR] 5.90, (95% confidence interval [CI] 2.52-13.8). Vitamin D deficiency was independently associated with BV among HIV-infected women (AOR 3.12, 95% CI 1.16-8.38) but not among HIV-uninfected women. There was a negative linear correlation between vitamin D concentration and prevalence of BV in HIV-infected women (r=−0.15, p=0.001).

Conclusions

Vitamin D deficiency was very common in this cohort and significantly associated with BV among HIV-infected women. These preliminary findings suggest that further epidemiologic and mechanistic exploration of the relationship between vitamin D and BV in HIV-infected women is warranted.

The 2009 H1N1 pandemic was a unique opportunity to investigate differences in influenza infection using serology by HIV status. Using serial serum specimens collected from 1 April to 30 September 2009 and the prior 2 years from Women’s Interagency HIV study participants, there was no difference in serologic evidence of 2009 H1N1 infection among HIV-infected women with a CD4 cell count at least 350 cells/µl compared with HIV-uninfected women. Owing to evidence showing a greater risk of influenza-related complications, HIV-infected individuals should continue to be a priority group for vaccination.

Background

Vitamin D deficiency is of increasing concern in HIV-infected persons, because of its reported association with a number of negative health outcomes that are common in HIV. We undertook this study to determine the prevalence and predictors of vitamin D deficiency among a nationally representative cohort of middle-aged, ethnically diverse HIV-infected and uninfected women enrolled in the Women’s Interagency HIV study (WIHS).

Methods

Vitamin D testing was performed by Quest Diagnostics on frozen sera using the liquid chromatography/mass spectroscopy (LC-MS) method. Vitamin D deficiency was defined as 25 (OH) D ≤20 ng/ml. Comparisons of continuous and categorical characteristics among HIV-infected and HIV-uninfected women were made by Wilcoxon tests and Pearson chi-squared tests, respectively.

Results

1778 women (1268 HIV+) were studied. 63% had vitamin D deficiency (60% HIV +vs. 72% HIV−; p<0.001). Multivariable predictors of Vitamin D Deficiency were being African American (AOR 3.02), Hispanic (AOR 1.40), Body mass index (AOR 1.43), Age (AOR 0.84), HIV+ (AOR 0.76), Glomerular filtration rate <90/ml/min (AOR 0.94) and WIHS site; Los Angeles (AOR 0.66), Chicago (AOR 0.63). In the HIV+ women multivariate predictors were; undetectable HIVRNA (AOR 0.69), CD4 50–200 cells/mm3 (AOR 1.60), CD4 <50 cells/mm3 (AOR 1.94) and recent Protease Inhibitor use (AOR 0.67).

Conclusions

In this study of over 1700 women in the US, most women with or without HIV infection had low vitamin D levels and African American women had the highest rates of Vitamin D deficiency. An understanding of the role that vitamin D deficiency plays in non-AIDS related morbidities is planned for investigation in WIHS.

Objective

To estimate whether HIV-infected pregnant women were at increased risk of hepatotoxicity when taking nevirapine (NVP) containing regimens compared to HIV-infected pregnant women taking antiretroviral therapy (ART) not containing NVP.

Methods

This analysis included HIV-infected pregnant women on ART from two multicenter, prospective cohorts: The Women and Infants Transmission Study (WITS) and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) protocol P1025. Multivariate Cox proportional hazards regression models were used to investigate the association between NVP use and hepatotoxicity. NVP use was dichotomized as use or no use and further categorized according to ART exposure history. We investigated two outcomes: any liver enzyme elevation (LEE) (grade 1-4) and severe LEE (grade 3-4).

Results

A total of 1229 women with ART use during pregnancy were studied, 218 (17.7%) of whom received NVP. Among the women receiving NVP, 137 (62.8%) were NVP naïve. Twenty-nine women (13.3%) who received NVP developed any LEE and one (0.5%) developed severe LEE. Of the 1011 women on non-NVP regimens, 145 (14.3%) developed any LEE and 14 (1.4%) developed severe LEE. There were no maternal deaths. In univariate models, LEE was not significantly associated with CD4+ count > 250 cells/μL or NVP use. In adjusted multivariate models, no significant increased risk of LEE (any or severe) in women taking NVP was detected as compared to those taking other ART regardless of prior exposure history.

Conclusions

We did not observe an increased risk of hepatotoxicity among HIV-infected pregnant women on NVP versus other ART, including women who were ART naïve.

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.

The species of vaginal lactobacilli in HIV-seropositive and -seronegative women were determined by 16S gene pyrosequencing. Lactobacillus iners sequences were the predominant lactobacillus sequences in 66% of HIV+ women and 90% of HIV− women. This has implications for resistance of HIV+ and HIV− women to genital colonization by pathogenic organisms.

PURPOSE

To examine changes in the causes of death and mortality in women with human immunodeficiency virus (HIV) infection in the era of combination antiretroviral therapy.

METHODS

Among women with, or at risk of, HIV infection, who were enrolled in a national study from 1994 to 1995, we used an algorithm that classified cause of death as due to acquired immunodeficiency syndrome (AIDS) or non-AIDS causes based on data from death certificates and the CD4 count. Poisson regression models were used to estimate death rates and to determine the risk factors for AIDS and non-AIDS deaths.

RESULTS

Of 2059 HIV-infected women and 569 who were at risk of HIV infection, 468 (18%) had died by April 2000 (451 HIV-infected and 17 not infected). Causes of death were available for 428 participants (414 HIV-infected and 14 not infected). Among HIV-infected women, deaths were classified as AIDS (n = 294), non-AIDS (n = 91), or indeterminate (n = 29). The non-AIDS causes included liver failure (n = 19), drug overdose (n = 16), non-AIDS malignancies (n = 12), cardiac disease (n = 10), and murder, suicide, or accident (n = 10). All-cause mortality declined an average of 26% per year (P = 0.03) and AIDS-related mortality declined by 39% per year (P = 0.01), whereas non-AIDS-related mortality remained stable (10% average annual decrease, P = 0.73). Factors that were independently associated with non-AIDS-related mortality included depression, history of injection drug use with hepatitis C infection, cigarette smoking, and age.

CONCLUSION

A substantial minority (20%) of deaths among women with HIV was due to causes other than AIDS. Our data suggest that to decrease mortality further among HIV-infected women, attention must be paid to treatable conditions, such as hepatitis C, depression, and drug and tobacco use.

Background

The extended use of antiretroviral drugs among human immunodeficiency virus (HIV)–seropositive individuals underscores the need for a comprehensive evaluation of therapy-associated clinical symptoms.

Methods

Beginning in April 2000, 364 HIV-seronegative and 1256 HIV-seropositive women enrolled in a multicenter cohort study reported clinical symptoms that included abdominal pain, diarrhea, anorexia, nausea and/or vomiting, myalgias, fatigue, fever, body fat redistribution, dizziness, headaches, paresthesias, xerostomia, nephrolithiasis, and rash. We examined the prevalence of symptoms with respect to HIV infection and the use of highly active antiretroviral therapy (HAART), using data-correlation models.

Results

In the 6 months before a study visit, 49% of HIV-seronegative women, 67% of HIV-seropositive women not receiving therapy, and 69% of HIV-seropositive women receiving HAART reported any clinical symptom. The odds ratios (ORs) for reporting any symptom were 1.4 (95% confidence interval [CI], 1.1–1.8) for women who changed HAART regimens and 0.9 (95% CI, 0.7–1.1) for women reporting stable HAART use, compared with those reporting no therapy use. Significant findings (P < .05) for particular symptoms were an increased odds of diarrhea, nausea and/or vomiting, body fat redistribution, myalgias, and paresthesias, when data for women who changed HAART regimens were compared with those for women not receiving therapy. The OR for reporting any symptom was 1.5 (95% CI, 1.2–1.9) for women who switched HAART regimens and 1.6 (95% CI, 1.3–1.9) for women who discontinued HAART, compared with those reporting stable HAART use.

Conclusions

Our findings confirm the high prevalence of clinical symptoms among HIV-seropositive women who changed HAART regimens. The high prevalence of symptoms among HIV-seronegative women and HIV-seropositive women not receiving therapy demonstrates that caution should be used when attributing the occurrence of symptoms entirely to HAART.

Background

Liver disease is a leading cause of death in human immunodeficiency virus (HIV)–infected women; however, risk factors for hepatitis B virus (HBV) infection in this population have not been well studied.

Methods

We describe the seroprevalence and predictors of HBV infection in a cross-sectional analysis of 2132 women with and at risk for HIV infection enrolled in the Women’s Interagency HIV Study during the periods 1994–95 and 2001–02. Any test result positive for antibody to hepatitis B core antigen defined infection; those women with serological evidence of vaccine immunity were excluded from analysis. Women were stratified into those with a history of injection drug use (IDU), those with a history of noninjection drug use (non-IDU), and those with no history of illicit drug use.

Results

Of 1606 HIV-infected and 526 HIV-uninfected women, 7% and 12%, respectively, appeared to be vaccine immune. After exclusion of these women, 43% of 1500 HIV-infected and 22% of 461 HIV-uninfected women had HBV infection. HBV infection prevalence differed among the IDU, non-IDU, and no illicit drug use groups (76%, 30%, and 17%, respectively; P < .0001). HBV infection was strongly associated with herpes simplex virus 2 (HSV-2) seropositivity in the IDU group (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.6–5.4) and with a history of syphilis in the non-IDU group (OR, 2.7; 95% CI, 1.4–5.0).

Discussion

We found a high prevalence of HBV infection in our cohort of women with and at risk for HIV infection. HSV-2 seropositivity and a history of syphilis appeared to be important correlates of HBV infection. Sexual transmission of HBV, particularly in those with a history of genital ulcer disease, should be a major focus of education in all high-risk groups.

Summary

Sex-based differences in CD4 T-cell (CD4) counts are well recognized, but the basis for these differences has not been identified. Conceivably, homeostatic factors may play a role in this process by regulating T-cell maintenance and repletion. Interleukin (IL)-7 is essential for normal T-cell production and homeostasis. We hypothesized that differences in IL-7 might contribute to sex-based differences in CD4 counts. Circulating IL-7 levels were analyzed in 299 HIV-1–infected women and men. Regression analysis estimated that IL-7 levels were 40% higher in women than in men (P = 0.0032) after controlling for CD4 count, age, and race. Given the important role of IL-7 in T-cell development and homeostasis, these findings suggest that higher IL-7 levels may contribute to higher CD4 counts in women.

We assessed the prevalence and predictors of latent Toxoplasma infection in a large group of human immunodeficiency virus (HIV)–infected and HIV-uninfected at-risk US women. The prevalence of latent Toxoplasma infection was 15% (380 of 2525 persons) and did not differ by HIV infection status. HIV-infected women aged ≥50 years and those born outside of the United States were more likely to have latent Toxoplasma infection, with prevalences of 32% and 41%, respectively.

Objective

To estimate the cumulative incidence of self-reported influenza vaccination (“vaccination coverage”) and investigate predictors in HIV-infected women.

Methods

In an ongoing cohort study of HIV-infected women in five US cities, data from two influenza seasons (2006-07 n=1,209 and 2007-08 n=1,161) were used to estimate crude and adjusted prevalence ratios (aPR) and 95% confidence intervals ([,]) from Poisson regression with robust variance models using generalized estimating equations (GEE).

Results

In our study, 55% and 57% of HIV-infected women reported vaccination during the 2006-07 and 2007-08 seasons, respectively. Using data from both seasons, older age, non-smoking status, CD4 T-lymphocyte (CD4) count ≥200 cells/mm3, and reporting at least one recent healthcare visit was associated with increased vaccination coverage. In the 2007-08 season, a belief in the protection of the vaccine (aPR=1.38 [1.18, 1.61]) and influenza vaccination in the previous season (aPR=1.66 [1.44, 1.91]) most strongly predicted vaccination status.

Conclusion

Interventions to reach unvaccinated HIV-infected women should focus on changing beliefs about the effectiveness of influenza vaccination and target younger women, current smokers, those without recent healthcare visits, or a CD4 count <200 cells/mm3.

Objective

To estimate whether the association between nevirapine (NVP) and hepatotoxicity differs according to pregnancy status in HIV-infected women.

Methods

This analysis included HIV-infected pregnant women on ART from two multicenter, prospective cohorts: The Women and Infants Transmission Study (WITS) and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) protocol P1025 and HIV-infected non-pregnant women from one multicenter, prospective cohort: The Women’s Interagency HIV Study (WIHS). Using multivariate Cox proportional hazards regression, the interaction between NVP and pregnancy status in terms of hepatotoxicity was investigated. NVP use was dichotomized as use or no use and was further categorized according to ART exposure history. We investigated two outcomes: any liver enzyme elevation (LEE) (grade 1-4) and severe LEE (grade 3-4).

Results

Data on 2050 HIV-infected women taking ART were included, 1229 (60.0%) pregnant and 821 (40.0%) non-pregnant. Among the pregnant women, 174 (14.2%) developed any LEE and 15 (1.2%) developed severe LEE as compared to 75 (9.1%) and 5 (0.6%) respectively of the non-pregnant women. In multivariate adjusted models, NVP was not significantly associated with risk of LEE regardless of pregnancy status; however, pregnancy was associated with an increased risk of any LEE (RR 4.7, CI 3.4 – 6.5) and severe LEE (RR 3.8, CI 1.3 – 11.1). The association of pregnancy and LEE was seen regardless of prior ART and NVP exposure history.

Conclusions

No significant association between NVP and LEE was observed regardless of pregnancy status, but pregnancy was significantly associated with increased hepatotoxocity in HIV-infected women.

Background

To assess trends in mortality and cause of death for women with HIV, we studied deaths over a 10 year period among participants in the Women’s Interagency HIV Study (WIHS), a representative US cohort.

Methods

Deaths were ascertained by National Death Index-Plus match and causes of death determined by death certificate.

Results

From 1995 through 2004, 710 of 2792 HIV-infected participants died. During this interval the standardized mortality ratio (SMR) fell from a high of 24.7 in 1996 to a plateau with a mean of 10.3 from 2001–2004. Over the decade, deaths from non-AIDs causes increased and accounted for the majority of deaths by 2001–2004. The most common non-AIDS causes of death were trauma or overdose, liver disease, cardiovascular disease and malignancy. Independent predictors of mortality besides HIV-associated variables were depressive symptoms, and active hepatitis B or C. Women who were overweight or obese were significantly less likely to die of AIDS than women of normal weight.

Conclusion

In the WIHS, the death rate has plateaued in recent years. While HIV-associated factors predicted AIDS and non-AIDS deaths, other treatable conditions predicted mortality. Further gains in reducing mortality among HIV-infected women may require broader access to therapies for depression, viral hepatitis and HIV itself.

Background

Isolated antibody to hepatitis B core antigen (anti-HBc) is a common serologic finding in persons infected with human immunodeficiency virus (HIV), but the outcome and clinical significance are uncertain.

Methods

We performed repeated hepatitis B virus (HBV) serologic tests on women who participated in the Women’s Interagency HIV Study and who had isolated anti-HBc at study entry.

Results

Repeated serologic tests were performed for 322 women (282 HIV-infected and 40 HIV-uninfected) at a median of 7.5 years after study entry. Seventy-one percent of women retained isolated anti-HBc serologic status, 20% acquired antibody to hepatitis B surface antigen (anti-HBs), and 2% acquired hepatitis B surface antigen (HBsAg). In unadjusted analysis, increasing age, injection drug use, and hepatitis C viremia were negatively associated with acquisition of anti-HBs. For HIV-infected women, predictors of acquisition of anti-HBs were an increase in CD4 cell count and the use of highly active antiretroviral therapy (HAART). Receipt of drugs with activity against HBV and self-reported HBV vaccination did not predict anti-HBs acquisition. In the multivariable regression model, HAART use remained a significant predictor of anti-HBs acquisition, whereas women with hepatitis C viremia were more likely to retain isolated anti-HBc serologic status.

Conclusions

Isolated anti-HBc status remained stable over time for the majority of women, especially women with chronic hepatitis C virus infection. Development of anti-HBs was predicted by HAART use and an increase in CD4 cell count. We conclude that a proportion of HIV-infected women with isolated anti-HBc have prior natural HBV infection with anti-HBs that is at an undetectable level because of immune dysfunction. Isolated anti-HBc in the presence of chronic hepatitis C virus infection may be attributable to a different phenomenon, such as dysfunctional antibody production.

Background

This study investigated whether HIV-infection is associated with a change in diversity of genital microbiota in women.

Methods

Amplicon length heterogeneity PCR (LH-PCR) and pyrosequencing of the 16S rRNA gene were used to analyze diversity of the microbiota from HIV-positive (HIV+) and HIV-negative (HIV-) women with or without bacterial vaginosis (BV).

Results

LH-PCR analysis showed significantly more diversity in BV-positive (BV+) women than in BV-negative (BV-) women, but no significant difference between HIV+ women and HIV- women. Pyrosequencing revealed that Lactobacillus constituted a median of 96% of the bacteria in BV- women. BV+ women had a significantly higher number of taxa found at ≥ 1% of the microbiota (median of 11). Common taxa in BV were Prevotella, Megasphaera, Gardnerella, Coriobacterineae, Lachnospira, and Sneathia. There was a trend (p=0.07) toward a higher number of taxa in HIV+BV+ compared to HIV-BV+ women. Propionibacterineae, Citrobacter and Anaerococcus were found only in HIV+ women (p<0.05).

Conclusions

This study showed that both LH-PCR and pyrosequencing differentiated BV+ from BV- microbiota and that pyrosequencing indicated a trend toward increased diversity in BV+HIV+ suggesting that HIV-infection is associated with changes in diversity of genital microbiota.

Infections and inflammation in the genital tract can influence HIV expression or HIV susceptibility. The goal of this study was to determine if significant relationships exist between cytokines and HIV in genital tract secretions from 57 HIV-seropositive Rwandan women. Genital tract secretions were obtained by cervicovaginal lavage (CVL). Ten different cytokines in CVL were measured by multiplex Cytometric Bead Arrays. HIV RNA in CVL and plasma were measured by quantitative PCR. In univariate analysis, genital tract HIV RNA was significantly associated with plasma HIV RNA and several of the cytokines, while in multivariate analysis, genital tract HIV RNA was only significantly associated with plasma HIV RNA and IL-6. This association of IL-6 with HIV RNA levels suggests that IL-6 is an indicator for conditions that induce HIV expression and that IL-6 may contribute to induction of HIV expression in the genital tract.

Abstract

Infections and inflammation in the genital tract can influence HIV expression or HIV susceptibility. The goal of this study was to determine if significant relationships exist between cytokines and HIV in genital tract secretions from 57 HIV-seropositive Rwandan women. Genital tract secretions were obtained by cervicovaginal lavage (CVL). Ten different cytokines in CVL were measured by multiplex cytometric bead arrays. HIV RNA in CVL and plasma were measured by quantitative PCR. In univariate analysis, genital tract HIV RNA was significantly associated with plasma HIV RNA and several of the cytokines, while in multivariate analysis, genital tract HIV RNA was significantly associated only with plasma HIV RNA and IL-6. This association of IL-6 with HIV RNA levels suggests that IL-6 is an indicator for conditions that induce HIV expression and that IL-6 may contribute to induction of HIV expression in the genital tract.