Identifying individuals with virologic failure after initiating effective antiretroviral therapy: The surprising value of mean corpuscular hemoglobin in a cross-sectional study

<p>Abstract</p> <p>Objective</p> <p>Recent studies have shown that the current guidelines suggesting immunologic monitoring to determine response to highly active antiretroviral therapy (HAART) are inadequate. We assessed whether routinely collected clinical markers could improve prediction of concurrent HIV RNA levels.</p> <p>Methods</p> <p>We included individuals followed within the Johns Hopkins HIV Clinical Cohort who initiated antiretroviral therapy and had concurrent HIV RNA and biomarker measurements ≥4 months after HAART. A two tiered approach to determine whether clinical markers could improve prediction included: 1) identification of predictors of HIV RNA levels >500 copies/ml and 2) construction and validation of a prediction model.</p> <p>Results</p> <p>Three markers (mean corpuscular hemoglobin [MCH], CD4, and change in percent CD4 from pre-HAART levels) in addition to the change in MCH from pre-HAART levels contained the most predictive information for identifying an HIV RNA >500 copies/ml. However, MCH and change in MCH were the two most predictive followed by CD4 and change in percent CD4. The logistic prediction model in the validation data had an area under the receiver operating characteristic curve of 0.85, and a sensitivity and specificity of 0.74 (95% CI: 0.69-0.79) and 0.89 (95% CI: 0.86-0.91), respectively.</p> <p>Conclusions</p> <p>Immunologic criteria have been shown to be a poor guideline for identifying individuals with high HIV RNA levels. MCH and change in MCH were the strongest predictors of HIV RNA levels >500. When combined with CD4 and percent CD4 as covariates in a model, a high level of discrimination between those with and without HIV RNA levels >500 was obtained. These data suggest an unexplored relationship between HIV RNA and MCH.</p

Parametric mixture models to evaluate and summarize hazard ratios in the presence of competing risks with time-dependent hazards and delayed entry

In the analysis of survival data, there are often competing events that preclude an event of interest from occurring. Regression analysis with competing risks is typically undertaken using a cause-specific proportional hazards model. However, modern alternative methods exist for the analysis of the subdistribution hazard with a corresponding subdistribution proportional hazards model. In this paper, we introduce a flexible parametric mixture model as a unifying method to obtain estimates of the cause-specific and subdistribution hazards and hazard ratio functions. We describe how these estimates can be summarized over time to give a single number that is comparable to the hazard ratio that is obtained from a corresponding cause-specific or subdistribution proportional hazards model. An application to the Women’s Interagency HIV Study is provided to investigate injection drug use and the time to either the initiation of effective antiretroviral therapy, or clinical disease progression as a competing event

An Instrumental Variable Evaluation of Antidepressant Use on Employment Among HIV-Infected Women Using Highly-Active Antiretroviral Therapy in the United States: 1996-2004

This paper examines the effect of antidepressant use on the likelihood of being employed among HIV-positive women receiving highly active antiretroviral therapy (HAART) in the United States from 1994 to 2004. We use instrumental variables to predict antidepressant use independently of outcomes; thus, addressing potential sources of bias -- more depressed women are more likely to receive antidepressant treatment, but they are also more likely to be unemployed. The results show that antidepressant use has a positive effect on the employment probability of women living with HIV. The proposed instrumental variables can be used to identify antidepressant use in the WIHS population. Among women receiving HAART, and controlling for individual and local area labor market characteristics, the use of antidepressants is associated with a higher probability of being employed.

Injection drug use and patterns of highly active antiretroviral therapy use: an analysis of ALIVE, WIHS, and MACS cohorts

<p>Abstract</p> <p>Background</p> <p>Sustained use of antiretroviral therapy has been consistently shown to be one of the primary predictors of long-term effectiveness. Switching and discontinuation reflect patient and provider decisions that may limit future treatment options. In this study, we utilize data reported at semi-annual study visits from three prospective cohort studies, the AIDS Link to IntraVenous Exposure (ALIVE), the Women's Interagency HIV Study (WIHS), and the Multicenter AIDS Cohort Study (MACS), to investigate determinants of HAART modification with a particular focus on reported injection drug use (IDU).</p> <p>Methods</p> <p>Longitudinal data collected between 1996 and 2004 contributed from 2,266 participants (37% with a reported history of IDU) who reported initiating their first HAART regimen during follow-up were utilized. Separate proportional-hazards models were used to identify factors measured prior to HAART-initiation associated with the time to first HAART discontinuation and first switch of components of HAART among continuous HAART users.</p> <p>Results</p> <p>The use of PI- vs. NNRTI-based regimens among HAART users with and without any history of IDU was similar over follow-up. The median time to a first report of discontinuation of HAART was 1.1 years for individuals with a history of IDU but 2.5 years for those without a history of IDU and multivariate analyses confirmed overall that individuals with a history of IDU were at greater risk for HAART discontinuation (adj RH = 1.24, 95% CI: 1.03–1.48). However, when restricting to data contributed after 1999, there was no longer any significant increased risk (adj RH = 1.05, 95% CI: 0.81–1.36). After adjusting for pre-HAART health status and prior ARV exposure, individuals who were ethnic/racial minorities, reported an annual income < $10,000/year, and were not employed were at significantly greater risk for HAART discontinuation. The median time to a first change in HAART regimen was approximately 1.5 years after first HAART report and was not elevated among those with a history of IDU (adj RH = 1.09, 95% CI: 0.89–1.34).</p> <p>Conclusion</p> <p>Our analyses demonstrate that injection drug use by itself does not appear to be an independent risk factor for HAART switching or discontinuation in more recent years. However, as continued HAART use is of paramount importance for long-term control of HIV infection, efforts to improve maintenance to therapy among disadvantaged and minority populations remain greatly needed.</p

CD4 Count At Presentation For HIV Care In The United States And Canada: Are Those Over 50 Years More Likely To Have A Delayed Presentation?

We assessed CD4 count at initial presentation for HIV care among [greater than or equal to]50-year-olds from 1997-2007 in 13 US and Canadian clinical cohorts and compared to &lt;50-year-olds. 44,491 HIV-infected individuals in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were included in our study. Trends in mean CD4 count (measured as cells/mm3) and 95% confidence intervals ([,]) were determined using linear regression stratified by age category and adjusted for gender, race/ethnicity, HIV transmission risk and cohort. From 1997-2007, the proportion of individuals presenting for HIV care who were [greater than or equal to]50-years-old increased from 17% to 27% (p-value &lt; 0.01). The median CD4 count among [greater than or equal to]50 year-olds was consistently lower than younger adults. The interaction of age group and calendar year was significant (p-value &lt;0.01) with both age groups experiencing modest annual improvements over time (&lt; 50-year-olds: 5 [4 , 6] cells/mm3; [greater than or equal to]50-year-olds: 7 [5 , 9] cells/mm3), after adjusting for sex, race/ethnicity, HIV transmission risk group and cohort; however, increases in the two groups were similar after 2000. A greater proportion of older individuals had an AIDS-defining diagnosis at, or within three months prior to, first presentation for HIV care compared to younger individuals (13% vs. 10%, respectively). Due to the increasing proportion, consistently lower CD4 counts, and more advanced HIV disease in adults [greater than or equal to]50-year-old at first presentation for HIV care, renewed HIV testing efforts are needed. &nbsp

Serum lipid profiles among patients initiating ritonavir-boosted atazanavir versus efavirenz-based regimens

<p>Abstract</p> <p>Background</p> <p>Antiretrovirals used to treat HIV-infected patients have the potential to adversely affect serum lipid profiles and increase the risk of cardiovascular disease which is an emerging concern among HIV-infected patients. Since boosted atazanavir and efavirenz are both considered preferred antiretrovirals a head to head comparison of their effects on serum lipids is needed.</p> <p>Aim</p> <p>The primary objective of the study was to compare the effects of atazanavir (boosted and unboosted) and efavirenz based regimens on serum lipid profiles.</p> <p>Study Design</p> <p>Prospective cohort study nested within three ongoing cohorts of HIV-infected individuals.</p> <p>Study Population and Methods</p> <p>Participants initiating either atazanavir or efavirenz based regimens with documented pre- and post-initiation lipid values. Multivariate linear regression was conducted to estimate adjusted mean differences between treatment groups for high density lipoprotein cholesterol (HDL-c), non-HDL-c, and log total cholesterol (TC) to HDL-c ratio outcomes; log-linear regression models were used to estimate differences in prevalence of low HDL-c and desirable TC.</p> <p>Results</p> <p>The final study population was comprised of 380 efavirenz and 281 atazanavir initiators. Both atazanavir and efavirenz users had increases in serum HDL-c and decreases in TC/HDL ratio. In comparison to individuals initiating efavirenz, boosted atazanavir users on average had lower HDL-c (-4.12 mg/dl, p < 0.001) and non HDL-c (-5.75 mg/dl, p < 0.01), but similar declines in TC/HDL ratio.</p> <p>Conclusion</p> <p>Both efavirenz and atazanavir-based regimens (boosted and unboosted) resulted in similar beneficial declines in the TC/HDL ratio.</p

Clinical Reactivations of Herpes Simplex Virus Type 2 Infection and Human Immunodeficiency Virus Disease Progression Markers

BACKGROUND: The natural history of HSV-2 infection and role of HSV-2 reactivations in HIV disease progression are unclear. METHODS: Clinical symptoms of active HSV-2 infection were used to classify 1,938 HIV/HSV-2 co-infected participants of the Women's Interagency HIV Study (WIHS) into groups of varying degree of HSV-2 clinical activity. Differences in plasma HIV RNA and CD4+ T cell counts between groups were explored longitudinally across three study visits and cross-sectionally at the last study visit. RESULTS: A dose dependent association between markers of HIV disease progression and degree of HSV-2 clinical activity was observed. In multivariate analyses after adjusting for baseline CD4+ T cell levels, active HSV-2 infection with frequent symptomatic reactivations was associated with 21% to 32% increase in the probability of detectable plasma HIV RNA (trend p = 0.004), an average of 0.27 to 0.29 log10 copies/ml higher plasma HIV RNA on a continuous scale (trend p<0.001) and 51 to 101 reduced CD4+ T cells/mm(3) over time compared to asymptomatic HSV-2 infection (trend p<0.001). CONCLUSIONS: HIV induced CD4+ T cell loss was associated with frequent symptomatic HSV-2 reactivations. However, effect of HSV-2 reactivations on HIV disease progression markers in this population was modest and appears to be dependent on the frequency and severity of reactivations. Further studies will be necessary to determine whether HSV-2 reactivations contribute to acceleration of HIV disease progression

Hepatic fibrosis and immune phenotype vary by HCV viremia in HCV/HIV co-infected subjects: A Women\u27s interagency HIV study.

HCV and HIV independently lead to immune dysregulation. The mechanisms leading to advanced liver disease progression in HCV/HIV coinfected subjects remain unclear. In this cross-sectional study, we assessed the association of HCV viremia, liver fibrosis, and immune response patterns in well-characterized HIV phenotypes: Elite controllers (Elites), HIV controlled (ARTc), and HIV uncontrolled (ARTuc) matched by age and race. Groups were stratified by HCV RNA status. Regulatory T-cell frequencies, T-cell activation (HLADR+CD38+), apoptosis (Caspase-3+), and intracellular cytokines (interferon-γ, IL-2, IL-17) were assessed using multiparametric flow-cytometry. Liver fibrosis was scored by AST to platelet ratio index (APRI). We found liver fibrosis (APRI) was 50% lower in Elites and ARTc compared to ARTuc. Higher liver fibrosis was associated with significantly low CD4+ T cell counts (P \u3c 0.001, coefficient r = −0.463). Immune activation varied by HIV phenotype but was not modified by HCV viremia. HCV viremia was associated with elevated CD8 T-cell Caspase-3 in Elites, ARTuc, and HIV− except ARTc. CD8 T-cell Caspase-3 levels were significantly higher in HCV RNA+ Elites (P = 0.04) and ARTuc (P = 0.001) and HIV− groups (P = 0.02) than ARTc. Importantly, ARTuc HCV RNA+ had significantly higher CD4 T-cell interleukin-17 levels than ARTuc HCV RNA− (P = 0.005). HIV control was associated with lower liver fibrosis in HCV/HIV co-infected women. HCV viremia is associated with an inflammatory CD4 TH-17 phenotype in absence of HIV control and higher frequency of pro-apoptosis CD8 T-cells critical to avert progression of HIV and HCV disease that is attenuated in ART controllers. Elite controllers with HCV viremia are more prone to CD8 T-cell apoptosis than ART controllers, which could have negative consequences over time, highlighting the importance of ART control in HCV/HIV coinfected individuals

The effect of HIV infection and HCV viremia on Inflammatory Mediators and Hepatic Injury-The Women\u27s Interagency HIV Study.

Hepatitis C virus infection induces inflammation and while it is believed that HIV co-infection enhances this response, HIV control may reduce inflammation and liver fibrosis in resolved or viremic HCV infection. Measurement of systemic biomarkers in co-infection could help define the mechanism of inflammation on fibrosis and determine if HIV control reduces liver pathology. A nested case-control study was performed to explore the relationship of systemic biomarkers of inflammation with liver fibrosis in HCV viremic and/or seropositive women with and without HIV infection. Serum cytokines, chemokines, growth factors and cell adhesion molecules were measured in HIV uninfected (HIV-, n = 18), ART-treated HIV-controlled (ARTc, n = 20), uncontrolled on anti-retroviral therapy (ARTuc, n = 21) and elite HIV controllers (Elite, n = 20). All were HCV seroreactive and had either resolved (HCV RNA-; \u3c50IU/mL) or had chronic HCV infection (HCV RNA+). In HCV and HIV groups, aspartate aminotransferase to platelet ratio (APRI) was measured and compared to serum cytokines, chemokines, growth factors and cell adhesion molecules. APRI correlated with sVCAM, sICAM, IL-10, and IP-10 levels and inversely correlated with EGF, IL-17, TGF-α and MMP-9 levels. Collectively, all HCV RNA+ subjects had higher sVCAM, sICAM and IP-10 compared to HCV RNA-. In the ART-treated HCV RNA+ groups, TNF-α, GRO, IP-10, MCP-1 and MDC were higher than HIV-, Elite or both. In ARTuc, FGF-2, MPO, soluble E-selectin, MMP-9, IL-17, GM-CSF and TGF-α are lower than HIV-, Elite or both. Differential expression of soluble markers may reveal mechanisms of pathogenesis or possibly reduction of fibrosis in HCV/HIV co-infection

Effects of Antiretroviral Therapy and Depressive Symptoms on All-Cause Mortality Among HIV-Infected Women

Abstract Depression affects up to 30% of human immunodeficiency virus (HIV)-infected individuals. We estimated joint effects of antiretroviral therapy (ART) initiation and depressive symptoms on time to death using a joint marginal structural model and data from a cohort of HIV-infected women from the Women's Interagency HIV Study (conducted in the United States) from 1998–2011. Among 848 women contributing 6,721 years of follow-up, 194 participants died during follow-up, resulting in a crude mortality rate of 2.9 per 100 women-years. Cumulative mortality curves indicated greatest mortality for women who reported depressive symptoms and had not initiated ART. The hazard ratio for depressive symptoms was 3.38 (95% confidence interval (CI): 2.15, 5.33) and for ART was 0.47 (95% CI: 0.31, 0.70). Using a reference category of women without depressive symptoms who had initiated ART, the hazard ratio for women with depressive symptoms who had initiated ART was 3.60 (95% CI: 2.02, 6.43). For women without depressive symptoms who had not started ART, the hazard ratio was 2.36 (95% CI: 1.16, 4.81). Among women reporting depressive symptoms who had not started ART, the hazard ratio was 7.47 (95% CI: 3.91, 14.3). We found a protective effect of ART initiation on mortality, as well as a harmful effect of depressive symptoms, in a cohort of HIV-infected women