Women 's Interagency Human Immunodeficiency Virus Research Articles

Hepatitis C Seropositivity and Kidney Function Decline Among Women With HIV: Data From the Women's Interagency HIV Study

How coinfection with hepatitis C virus (HCV) impacts on the trajectory of kidney function in human immunodeficiency virus (HIV)-infected patients is unclear. This study examined the effect of HCV infection on kidney function over time in women infected with HIV. Retrospective observational cohort. Study sample included participants from the Women's Interagency HIV Study who were HIV infected and had undergone HCV antibody testing and serum creatinine measurement at baseline. HCV seropositivity. Estimated glomerular filtration rate (eGFR) calculated from semi-annual serum creatinine measurements using the 4-variable Modification of Diet in Renal Diseases (MDRD) Study equation. Linear mixed models were used to evaluate the independent effect of HCV seropositivity on eGFR over time, adjusting for demographic factors, comorbid conditions, illicit drug use, measures of HIV disease status, use of medications, and interactions with baseline low eGFR (<60 mL/min/1.73 m(2)). Of 2,684 HIV-infected women, 952 (35%) were found to be HCV seropositive. In 180 women with chronic kidney disease (CKD) at baseline (eGFR < 60 mL/min/1.73 m(2)), HCV seropositivity was independently associated with a fully adjusted net decrease in eGFR of approximately 5% per year (95% confidence interval, 3.2 to 7.2) relative to women who were seronegative. In contrast, HCV infection was not independently associated with a decrease in eGFR in women without low eGFR at baseline (P < 0.001 for interaction). The MDRD Study equation has not been validated as a measure of GFR in persons with HIV or HCV infection. Proteinuria was not included in the study analysis. Because the study is observational, effects of residual confounding cannot be excluded. In HIV-infected women with CKD, coinfection with HCV is associated with a modest, but statistically significant, decrease in eGFR over time. More careful monitoring of kidney function may be warranted for HIV-infected patients with CKD who are also coinfected with HCV.

Age and Racial/Ethnic Differences in the Prevalence of Reported Symptoms in Human Immunodeficiency Virus-Infected Persons on Antiretroviral Therapy

Few studies have evaluated age and racial/ethnic differences in the prevalence of symptoms in human immunodeficiency virus (HIV)-infected persons. Thus, the objective of this study was to compare the prevalence of gastrointestinal, metabolic, general malaise, neurologic, or other self-reported symptoms by age and race/ethnicity among 1574 HIV-infected women enrolled in the Women's Interagency HIV Study and 955 HIV-infected men who have sex with men (MSM) enrolled in the Multicenter AIDS Cohort Study. All patients had known dates of initiation of highly active antiretroviral therapy. It was observed that women aged 50 years or more were less likely to experience gastrointestinal symptoms (24% vs. 27%; multivariable P = 0.024), but more likely to experience general malaise (47% vs. 37%; multivariable P = 0.004), neurologic (44% vs. 38%; multivariable P = 0.048), or other symptoms (40% vs. 28%; multivariable P < 0.001) compared with women less than 40 years of age. Only neurologic symptoms had a higher prevalence among older MSM (52% vs. 37%; multivariable P = 0.002), largely driven by paresthesias (48% vs. 31%; multivariable P = 0.004), the most common individual symptom reported by men. Caucasian women generally had the highest prevalence of symptoms, and African American women had the lowest prevalence. Few racial/ethnic differences were noted for MSM. Depression and a prior diagnosis of acquired immunodeficiency syndrome were the strongest and most consistent predictors of clinical symptoms in both cohorts. In summary, the prevalence of reported symptoms varies with patient race/ethnicity, age, and modifiable factors, such as depression and HIV disease stage. Clinicians should consider these factors when counseling patients regarding potential adverse effects of antiretrovirals or symptoms associated with HIV disease.

Longitudinal trends in hazardous alcohol consumption among women with human immunodeficiency virus infection, 1995-2006.

Hazardous alcohol consumption among women with human immunodeficiency virus (HIV) infection is associated with several adverse health and behavioral outcomes, but the proportion of HIV-positive women who engage in hazardous drinking over time is unclear. The authors sought to determine rates of hazardous alcohol consumption among these women over time and to identify factors associated with this behavior. Subjects were 2,770 HIV-positive women recruited from 6 US cities who participated in semiannual follow-up visits in the Women's Interagency HIV Study from 1995 to 2006. Hazardous alcohol consumption was defined as exceeding daily (> or =4 drinks) or weekly (>7 drinks) consumption recommendations. Over the 11-year follow-up period, 14%-24% of the women reported past-year hazardous drinking, with a slight decrease in hazardous drinking over time. Women were significantly more likely to report hazardous drinking if they were unemployed, were not high school graduates, had been enrolled in the original cohort (1994-1995), had a CD4 cell count of 200-500 cells/mL, were hepatitis C-seropositive, or had symptoms of depression. Approximately 1 in 5 of the women met criteria for hazardous drinking. Interventions to identify and address hazardous drinking among HIV-positive women are urgently needed.

Effect of HAART on salivary gland function in the Women’s Interagency HIV Study (WIHS)

To determine the impact of highly active antiretroviral therapy (HAART) on salivary gland function in human immunodeficiency virus (HIV) positive women from the Women's Interagency HIV Study (WIHS). Longitudinal cohort study. A total of 668 HIV positive women from the WIHS cohort with an initial and at least one follow-up oral sub-study visit contributed 5358 visits. Salivary gland function was assessed based on a dry mouth questionnaire, whole unstimulated and stimulated salivary flow rates, salivary gland enlargement or tenderness and lack of saliva on palpation of the major salivary glands. Changes in unstimulated and stimulated flow rates at any given visit from that of the immediate prior visit (continuous variables). The development of self-reported dry mouth (present/absent), enlargement or tenderness of salivary glands (present/absent), and absence of secretion on palpation of the salivary glands were binary outcomes (yes/no). Protease Inhibitor (PI) based HAART was a significant risk factor for developing decreased unstimulated (P = 0.01) and stimulated (P = 0.0004) salivary flow rates as well as salivary gland enlargement (P = 0.006) as compared with non-PI based HAART. PI-based HAART therapy is a significant risk factor for developing reduced salivary flow rates and salivary gland enlargement in HIV positive patients.

Patterns, Predictors, and Consequences of Initial Regimen Type among HIV-Infected Women Receiving Highly Active Antiretroviral Therapy

It is important to elucidate differences among initial highly active antiretroviral therapy (HAART) regimen types in comparative studies of therapy effectiveness. We aimed to identify predictors of initiation with different HAART regimen types and the effect of initial regimen type on switching and immunologic response to therapy--controlling for those predictors--among human immunodeficiency virus (HIV)-infected women in the United States. Participants in the Women's Interagency HIV Study underwent semiannual interview, venipuncture, and clinical examination. Those beginning with protease inhibitor-based, nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based, or triple-nucleoside reverse-transcriptase inhibitor (NRTI)-based HAART during April 1996-March 2005 were eligible for analysis. Predictors of initial regimen type were assessed with polytomous logistic regression. Correlates of switching were assessed with discrete-time proportional hazards models, and immunologic response to therapy was assessed with linear regression. Among 1555 HAART initiators, CD4(+) lymphocyte count and HIV load were significant predictors of initial regimen type during 1996-2002; only sociodemographic predictors were significant during 2002-2005. Initial regimen type was not a significant predictor of subsequent regimen switching. Compared with those whose initial treatment was protease inhibitor-based HAART, those who began with triple-NRTI-based regimens had significantly lower CD4(+) cell counts at 1 year (P=.006) and 2 years (P=.004) after initiation; NNRTI initiators had lower CD4(+) cell counts after 2 years (P=.05). We demonstrate that predictors of initial regimen type among women in the United States have been changing over time. Protease inhibitor initiators had significantly higher CD4(+) cell counts than did NNRTI or triple-NRTI initiators up to 2 years after HAART initiation. Adjustment for biological predictors of initial regimen is important to avoid confounding in the study of treatment effectiveness.

Live birth patterns among human immunodeficiency virus-infected women before and after the availability of highly active antiretroviral therapy

The objective of the study was to investigate the relationship between human immunodeficiency virus (HIV) infection and childbearing before and after the availability of highly active antiretroviral therapy (HAART). Enrollment in the Women's Interagency HIV study took place in 1994-1995 (pre-HAART era) and again in 2001-2002 (HAART era). Live birth rates prior to enrollment were compared between treatment era cohorts for HIV-infected and HIV-uninfected women aged 15-44 years using Poisson regression. For HIV-infected women, we included live births between HIV diagnosis date and study entry; the HAART era cohort included only women diagnosed with HIV in 1996 and afterward. Among HIV-infected women, the HAART era live birth rate was 150% higher than in the pre-HAART era (P = .001) vs a 5% increase among HIV-uninfected women. The rate of increase in live birth rate was higher for women > or = 35 years old (vs younger than 25 years, P = .02), and with more than a high school education (vs. less than high school, P = .05). The availability of effective therapeutic interventions has had a profound impact on child-bearing among HIV-infected women.

Effect of Tuberculosis on the Survival of Women Infected with Human Immunodeficiency Virus

Evidence regarding the effect of tuberculosis (TB) disease on progression of human immunodeficiency virus (HIV) disease is inconclusive. The authors estimated the effect of time-varying incident TB on time to acquired immunodeficiency syndrome (AIDS)-related mortality using a joint marginal structural Cox model. Between 1995 and 2002, 1,412 HIV type 1 (HIV-1)-infected women enrolled in the Women's Interagency HIV Study were followed for a median of 6 years. Twenty-nine women incurred incident TB, and 222 died of AIDS-related causes. Accounting for age, CD4 cell count, HIV-1 RNA level, serum albumin level, and non-TB AIDS at study entry, as well as for time-varying CD4 cell count, CD4 cell count nadir, HIV-1 RNA level, peak HIV-1 RNA level, serum albumin level, HIV-related symptoms, non-TB AIDS, anti-Pneumocystis jiroveci prophylaxis, antiretroviral therapy, and household income, the hazard ratio for AIDS-related death comparing time after incident TB with time before incident TB was 4.0 (95% confidence interval (CI): 1.2, 14). The effect of incident TB on mortality was similar among highly active antiretroviral therapy (HAART)-exposed women (hazard ratio = 4.3, 95% CI: 0.9, 22) and non-HAART-exposed women (hazard ratio = 3.9, 95% CI: 0.9, 17; interaction p = 0.91). Although results were imprecise because few women incurred TB, irrespective of HAART exposure, incident TB increases the hazard of AIDS-related death among HIV-infected women.

Mortality among Participants in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study

Many studies that have reported decreases in human immunodeficiency virus (HIV)-related mortality since the advent of highly active antiretroviral therapy (HAART) have also reported steady increases in non-HIV-related mortality over the same time periods. We examined temporal trends and risk factors for accident- and injury-related mortality among HIV-infected and -uninfected participants in the Women's Interagency HIV Study (WIHS) and the Multicenter AIDS Cohort Study (MACS). Information on causes of death was recorded for all participants in the MACS and WIHS cohort studies who died, and causes of death were categorized as accident- or injury-related deaths or not. Mortality rates were calculated by time periods, prior to the widespread use of HAART (before 1997) and after (1997-2002), and risk factors. Cause of death information was available for 619 women in the WIHS who died (during the period 1994-2002) and 1830 men in the MACS who died (during the period 1984-2002). The death rates were higher for accident- or injury-related mortality in the WIHS (2.96 deaths per 1000 person-years for the HIV-infected group and 2.96 per 1000 person-years for the HIV-uninfected group), compared with the participants in MACS (0.79 deaths per 1000 person-years for the HIV-infected group and 0.63 per 1000 person-years for the HIV-uninfected group). In the final multivariate analysis, the following factors were associated with significantly higher risk in men: higher education, depressive symptoms, and a greater number of sex partners. Among women, the significant risk factors for death were decreased CD4+ T cell count, unemployment, higher alcohol use, and injection drug use. The characteristics of the men in the MACS who died and women in the WIHS who died differ, as do the risk factors for mortality. These results characterize important target groups for interventions to reduce accident- and injury-related deaths.

Relationship between Prevalent Oral and Cervical Human Papillomavirus Infections in Human Immunodeficiency Virus-Positive and -Negative Women

Human papillomavirus (HPV) is an etiologic agent for both oropharyngeal and cervical cancers, yet little is known about the interrelationship between oral and cervical HPV infections. Therefore, we compared the prevalences and type distributions of oral and cervical HPV infections and evaluated infection concordance in a cross-sectional study within the Women's Interagency HIV Study cohort. Oral rinse and cervical-vaginal lavage samples were concurrently collected from a convenience sample of 172 human immunodeficiency virus (HIV)-positive and 86 HIV-negative women. HPV genomic DNA was detected by PGMY09/11 L1 consensus primer PCR and type specified by reverse line blot hybridization for 37 HPV types and beta-globin. Only 26 of the 35 HPV types found to infect the cervix were also found within the oral cavity, and the type distribution for oral HPV infections appeared distinct from that for cervical infections (P<0.001). Oral HPV infections were less common than cervical infections for both HIV-positive (25.2% versus 76.9%, P<0.001) and HIV-negative (9.0% versus 44.9%, P<0.001) women. Oral HPV infections were more common among women with a cervical HPV infection than those without a cervical HPV infection (25.5% versus 7.9%, P=0.002). The majority of women (207; 93.7%) did not have simultaneous oral and cervical infections by the same HPV type; however, the number of women who did (14; 6.3%) was significantly greater than would be expected by chance (P=0.0002). Therefore, the oral and cervical reservoirs for HPV infection are likely not entirely independent of one another.

Longitudinal Evaluation of Loss of Attachment in HIV‐Infected Women Compared to HIV‐Uninfected Women

The Women's Interagency HIV Study (WIHS) is the largest, most detailed, controlled longitudinal collection of data to evaluate the influence of human immunodeficiency virus (HIV) disease and its therapies on the periodontium. This report evaluates periodontal probing depth (PD), attachment loss (AL), and tooth loss from 584 HIV-seropositive and 151 HIV-seronegative women, recorded at 6-month intervals from 1995 to 2002. Using the random split-mouth method, PD and AL were recorded from four sites per tooth: mesial-buccal, buccal, distal-buccal, and lingual. Influence of viral load, CD4 count, race, smoking, drug use, low income, and level of education were evaluated. At baseline, AL was 1.6 versus 1.1 mm (P = 0.003) and PD was marginally deeper (2.1 versus 2.0 mm; P = 0.02) in HIV-seropositive versus HIV-seronegative women. Adjusted longitudinal analysis showed that HIV infection did not increase the mean PD (rate ratio [RR], 1.00; 95% confidence interval [CI], 0.96 to 1.04), worst PD (RR, 1.03; 95% CI, 0.98 to 1.09), mean AL (RR, 0.97; 95% CI, 0.96 to 1.02), worst AL (RR, 1.01; 95% CI, 0.94 to 1.07), or tooth loss (RR, 1.02; 95% CI, 1.0 to 1.05). CD4 count and viral load had no consistent effects on PD or AL. Among HIV-infected women, a 10-fold increase in viral load was associated with a marginal increase in tooth loss. The progression of periodontal disease measured by PD and AL did not significantly differ between HIV-infected and HIV-uninfected women. The HIV-seropositive women lost more teeth. Race, smoking, drug use, income, and education level did not influence the results for either group.

Serological Detection of Human Papillomavirus Type 16 Infection in Human Immunodeficiency Virus (HIV)-Positive and High-Risk HIV-Negative Women

Serial measurement of antibodies has not been used to provide evidence of active viral replication of human papillomavirus (HPV). Serum specimens from sequential study visits contributed by 642 human immunodeficiency virus (HIV)-positive and 116 HIV-negative participants enrolled in the Women's Interagency HIV Study were used to detect significant rises in HPV type 16 (HPV-16) antibody levels. Factors associated with a significant rise were identified using multivariable logistic regression models with generalized estimating equations. Among HIV-positive women, 8.3% of 1,997 pairs showed antibody rises, compared to 6.1% of 361 pairs among HIV-negative women (P = 0.191). For HIV-positive women, rises were associated with current (odds ratio [OR], 23.4; P < 0.001) or past (OR, 8.9; P < 0.001) HPV-16 infection relative to never being HPV-16 infected and with CD4+ cell counts (OR per 100-cell increase, 0.8; P < 0.001) but not with sexual behavior. For HIV-negative women, rises were associated with past (OR, 10.9; P = 0.033) HPV-16 infection relative to no HPV-16, current cigarette smoking (OR, 5.0; P = 0.029) relative to no smoking history, and having 6 to 10 lifetime sexual partners compared to 0 to 5 partners (OR, 9.9; P = 0.036). Serial measurement of HPV-16 serum antibodies is a useful tool for identifying active HPV-16 viral replication. Rises among HIV-positive women may more often result from reactivation of a latent HPV infection in the context of HIV-induced immunosuppression, while rises among HIV-negative women may more often result from reinfection with HPV.

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

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 Women's Interagency HIV Study. 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. 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.

Neutropenia in Human Immunodeficiency Virus Infection

Neutropenia is well described in individuals infected with human immunodeficiency virus (HIV) and occurs in approximately 10% to 50% of cases. Neither the effect of highly active antiretroviral therapy (HAART) on neutrophil counts nor the significance of neutropenia in terms of survival has previously been evaluated. The prevalence of neutropenia among 1729 HIV-infected women, followed up as part of the Women's Interagency HIV Study, was evaluated. The CD4 lymphocyte counts, HIV-1 RNA levels, and complete blood cell counts, including absolute neutrophil counts, were obtained at 6-month intervals. Neutropenia was common among HIV-infected women; at baseline, 44% had neutrophil counts less than 2000/microL, whereas 7% had counts less than 1000/microL. During 7.5 years of follow-up, neutrophil counts less than 2000/microL occurred on at least 1 occasion in 79%, whereas absolute neutrophil counts less than 1000/microL were documented in 31%. Worsening HIV disease parameters, such as lower CD4 cell counts (P<.001) and higher HIV-1 RNA levels (P<.001), were associated with development of neutropenia. Resolution of neutropenia was associated with higher CD4 cell counts (P<.001) and use of HAART (P=.007). We found that HAART, without zidovudine, was associated with protection against development of neutropenia. On multivariate analysis, neutropenia was not found to be associated with decreased survival among HIV-infected women. Worsening HIV disease parameters are associated with neutropenia in HIV-infected women. Treatment with HAART, without zidovudine in the regimen, protects against development of neutropenia, whereas HAART use and higher CD4 cell counts are associated with resolution of neutropenia. Neutropenia is not associated with decreased survival in HIV-infected women.

Variants of human papillomaviruses 16 and 18 and their natural history in human immunodeficiency virus-positive women

Highly oncogenic human papillomavirus (HPV) 16 and 18 variants might be expected to be particularly aggressive in HIV-positive women. The association of HPV16 and 18 variant lineages with race, human immunodeficiency virus (HIV) coinfection, CD4+ T-cell count, HIV-RNA level, time-to-clearance of HPV infection and presence of squamous intraepithelial lesions (SIL) among women in the Women's Interagency HIV Study was studied. Subjects were followed semi-annually with Pap smear and cervicovaginal lavage (CVL). HPV DNA was detected in CVLs using MY09/11 L1 PCR assay. Specimens positive for HPV16/18 underwent E6 PCR and sequencing to determine the variant present. Specimens from 195 HPV16- and 162 HPV18-positive women were classified into variant lineages based on sequencing results. African variants of HPV16 and HPV18 were significantly more prevalent among African-Americans than among Caucasians [42 versus 14 % (P=0.001) and 60 versus 13 % (P<0.001), respectively]. However, it was not possible to detect associations between the HPV16 or 18 variant lineages and other factors studied. African variants of HPV16/18 were more common in women of African descent living outside Africa, which could reflect mixing behaviours and/or immunogenetic factors. However, in a large population of HIV-infected women, the variant of HPV16 or 18 was unrelated to persistence of infection or presence of SIL. If non-European variants are more oncogenic, the effect may involve a late stage in cervical tumorigenesis.

The Women's Interagency HIV Study: an Observational Cohort Brings Clinical Sciences to the Bench

The Women's Interagency HIV Study (WIHS) is an ongoing long-term observational study of 3,772 women who are either infected with human immunodeficiency virus (HIV) or considered to be at risk for acquiring HIV. Since 1994, the WIHS (pronounced like “wise”) has developed a large database and specimen repository that serve as resources for WIHS investigators as well as for nonaffiliated researchers working on HIV-related or HIV coinfection issues. The purpose of this report is to update researchers on the progress of the WIHS and to provide information on WIHS resources, the methods by which they were obtained, and background for any new potential researchers interested in conducting collaborative research through shared use of these resources.

Utility of Amsel Criteria, Nugent Score, and Quantitative PCR for Gardnerella vaginalis , Mycoplasma hominis , and Lactobacillus spp. for Diagnosis of Bacterial Vaginosis in Human Immunodeficiency Virus-Infected Women

Bacterial vaginosis (BV) is a clinical syndrome presenting with a malodorous vaginal discharge and increased vaginal pH. Diagnosis has been based on clinical Amsel criteria and direct Gram stain of vaginal secretions. Human immunodeficiency virus (HIV)-infected participants in the Women's Interagency HIV Study contributed cervicovaginal lavage (CVL) samples. Lactobacilli, Gardnerella vaginalis, and Mycoplasma hominis in cervicovaginal lavage samples were quantified by PCR. Gynecologic evaluation included Nugent score and Amsel criterion assessment. We compared the gold standard Nugent score to Amsel criteria and quantitative bacterial PCR for diagnosing BV in 203 CVL samples from women with Nugent scores of 7 to 10 (BV group) and 203 samples from women with BV Nugent scores of 0 to 3 ("No-BV" group). Only 75 of the 203 CVL samples from women with Nugent scores of 7 to 10 met positive Amsel criteria. Increasing levels of G. vaginalis and M. hominis and decreasing levels of lactobacilli were significantly associated with BV by Nugent score. Of the group with Nugent scores of 7 to 10, 83% and 81% had log(10) G. vaginalis counts and log(10) M. hominis counts greater than 6.81 and 4.82, respectively, while only 30% and 31% of the group with Nugent scores of 0 to 3 were above these thresholds, respectively. There was significant overlap in the log(10) lactobacillus counts between the two groups. Utilizing all three log(10) bacterial counts (G. vaginalis, M. hominis, and lactobacilli) in our model improved the sensitivity and specificity to 83% and 78%, respectively, in comparison with Nugent score. In this cohort, Amsel criteria were poorly predictive of BV. PCR quantification of G. vaginalis and M. hominis from CVL is significantly more sensitive than Amsel criteria for diagnosing BV.

Individual Variation in CD4 Cell Count Trajectory among Human Immunodeficiency Virus-infected Men and Women on Long-term Highly Active Antiretroviral Therapy: An Application using a Bayesian Random Change-Point Model

The authors evaluated population- and individual-level CD4-positive T-lymphocyte (CD4 cell) count trajectories over a 7-year period (July 1995-March 2004) following initiation of highly active antiretroviral therapy (HAART) in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study. The study population included 404 human immunodeficiency virus (HIV)-infected men and 609 HIV-infected women who 1) had a CD4 cell count measurement available from their last pre-HAART study visit, 2) provided at least four post-HAART CD4 cell count measurements, and 3) reported HAART usage for at least 80% of the post-HAART visits. The CD4 cell count trajectory was analyzed by means of a Bayesian random change-point model. The results indicated that CD4 cell count trajectories for long-term frequent HAART users can be well modeled with change points at both the population and individual levels. At the population level, regardless of CD4 cell count before HAART initiation, the gains in CD4 cell count ended approximately 2 years after HAART initiation in both men and women. At the individual level, 35% of men in the Multicenter AIDS Cohort Study versus 25% of women in the Women's Interagency HIV Study had a statistically significant change in CD4 cell count trajectory within 7 years after HAART initiation.

Structural accelerated failure time models for survival analysis in studies with time-varying treatments

In the absence of unmeasured confounding factors and model misspecification, standard methods for estimating the causal effect of time-varying treatments on survival are biased when (i) there exists a time-dependent risk factor for survival that also predicts subsequent treatment and (ii) past treatment history predicts subsequent risk factor level. In contrast, structural models provide consistent estimates of causal effects when unmeasured confounding and model misspecification are absent. The parameters of nested structural models are estimated by g-estimation and those of marginal structural models by inverse probability weighting. We describe a nested structural accelerated failure time model and use it to estimate the total causal effect of highly active antiretroviral therapy (HAART) on the time to AIDS or death among human immunodeficiency virus (HIV)-infected participants of the Multicenter AIDS Cohort and Women's Interagency HIV Studies. The Appendix describes g-estimation and methods to deal with censoring. Comparing the regime 'always treated' to 'never treated,' the AIDS-free survival time ratio was 2.5 (95% confidence interval [CI]: 1.7, 3.3). Our finding of a strongly beneficial effect is consistent with results from randomized trials and from a previous analysis of the same data using a marginal structural Cox model. In contrast, a previous analysis using a standard (non-structural) model did not find an effect of treatment on survival.

Association between Syphilis, Antibodies to Herpes Simplex Virus Type 2, and Recreational Drug Use and Hepatitis B Virus Infection in the Women's Interagency HIV Study

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. 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. 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). 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.

Association between renal disease and outcomes among HIV-infected women receiving or not receiving antiretroviral therapy.

The associations of proteinuria and an elevated creatinine level with progression to acquired immunodeficiency syndrome (AIDS) and death in the era of highly antiretroviral therapy (HAART) have not been fully described. This analysis includes 2038 human immunodeficiency virus (HIV)-infected women from the Women's Interagency HIV Study. Time to the development of a new AIDS-defining illness (ADI) and death was modeled using proportional hazards regression before the widespread availability of HAART and after initiation of HAART. Of the 2038 subjects, the 14.1% of women with proteinuria had lower CD4 lymphocyte counts and higher viral loads (P<.0001 for all) at baseline and before initiation of HAART. Before the widespread availability of HAART, proteinuria was associated with an increased risk for development of ADI (hazard ratio [HR], 1.37; P=.005), and proteinuria and an elevated creatinine level were both associated with an increased risk of death (for proteinuria: HR, 1.35 [P=.04]; for creatinine: HR, 1.72 per decrease in the inverse unit [P=.02]). Among women initiating HAART, an elevated creatinine level remained associated with an increased risk of development of ADI (HR, 1.54 per decrease in the inverse unit; P=.03), and proteinuria and an elevated creatinine level were associated with an increased risk of death (for proteinuria: HR, 2.07 [P=.005]; for creatinine: HR, 1.96 per decrease in the inverse unit [P=.04]). Proteinuria and an elevated creatinine level were associated with an increased risk of death and development of ADI. These associations may reflect the direct role of the kidney in modulating HIV disease, or they may act as markers of greater comorbidity.