Is there a trial effect in HIV clinical trials?: identifying who participates in clinical trials and assessing the effect of trial participation on the response to highly active antiretroviral therapy

There is a widespread belief, that participation in a clinical trial provides an additional benefit called a trial effect. In HIV infection this claim appears to have been unexamined and therefore is unsubstantiated. Evidence of a trial effect may be confounded by systematic differences between trial and non trial participants. Women, minorities and heterosexuals represent an increasing proportion of HIV infected persons but are reportedly underrepresented in clinical trials. We examined if gender/sexual orientation or race/ethnicity differed by trial participation and if there was a trial effect in HIV clinical trials. Using the UNC CFAR HIV/AIDS Clinical Cohort we conducted a cross sectional study of 738 antiretroviral treatment naïve HIV positive adults. Of these, 30% initiated highly active antiretroviral therapy (HAART) in 13 different clinical trials. Subjects were characterized as trial participants if HAART was initiated in a clinical trial. Heterosexual men and women participated in trials at the same rate as men who have sex with men (PR 0.79, 95% CI 0.57, 1.11 and PR 0.97, 95% CI 0.94, 1.66 respectively). Blacks were slightly less likely than non blacks to participate in clinical trials (PR 0.80, 95% CI 0.60, 1.06). This lack of substantial race/ethnicity and gender differences between groups supported our further investigation of a trial effect. For this analysis virologic success was assessed within strata of early (1996-1999) and current (2000-06) HAART periods and was defined as a plasma HIV RNA [less than or equal to]400 copies/ml at six months post HAART initiation. Trial participants initiating HAART in the early period were more likely to achieve virologic success than non trial participants (RR 1.33; 95% CI 1.15, 1.54), but this difference was not observed in the current period (RR 0.98; 95% CI 0.87, 1.11). We found no difference in participation rates between women contrasted with men and a small insignificant difference for blacks contrasted with non blacks. In the current HAART period, both trial and non trial participants were equally likely to achieve virologic success suggesting that there is no evidence for a trial effect. These results suggest that data from HIV clinical trials can be generalized to clinical practice

High acceptance rate of anal pap screening despite limited knowledge about anal dysplasia among HIV+ MSM

Anal cancer in the general population is more prevalent in women, but in most HIV populations, MSM have the highest risk. Data suggest that screening can prevent invasive carcinoma. Use of routine cervical pap smears resulted in an 80% reduction in cervical cancer rates. The current study examines the effectiveness of a clinical intervention designed to increase anal dysplasia education, screening, and treatment for HIV+ MSM

Increased Cortical Cerebral Blood Flow in Asymptomatic Human Immunodeficiency Virus-Infected Subjects

Human Immunodeficiency Virus (HIV) infected individuals are at high risk for ischemic stroke. To investigate the physiological basis for this risk, we used magnetic resonance imaging (MRI) to measure oxygen extraction fraction (OEF) and cerebral blood flow (CBF) in treatment naïve asymptomatic HIV-infected subjects and controls

Low Prevalence of Antiretroviral Resistance Among HIV Type 1-Positive Prisoners in the Southeast United States

Drug-resistant HIV complicates management of HIV infection. Although an estimated 14% of all HIV-positive persons pass through a prison or jail in the United States each year, little is known about the overall prevalence of antiretroviral (ARV) resistance in incarcerated persons. All genotypic sequence data on HIV-positive prisoners in the North Carolina (NC) Department of Corrections (DOC) were obtained from LabCorp. Screening for major resistance mutations in protease (PI) and reverse transcriptase (NRTI and NNRTI) was done using Genosure and the Stanford HIV Database. For subjects with multiple genotype reports, each mutation was counted only once and considered present on all subsequent genotypes. Between October 2006 and February 2010, the NC DOC incarcerated 1,911 HIV+ individuals of whom 19.2% (n=367) had at least one genotype performed. The overall prevalence of a major resistance mutation was 28.3% (95% CI 23.7, 33.0). Among prisoners ever exposed to an ARV during incarceration (n=329) prevalence of a major resistance mutation was 29.8% (95% CI 24.9, 34.7); resistance by class was 20.4% (95% CI 16.0, 24.7) for NRTIs, 19.8% (95% CI 15.5, 24.1) for NNRTIs, and 8.8% (95% CI 5.8,11.9) for PIs. Single class drug resistance was most prevalent at 14.2% (10.2,17.7) followed by dual 12.5% (I8.9,16.0) and triple class 3.3% (1.4,5.3) resistance. The three most prevalent mutations were K103N 15.8% (12.0, 20.2), M184V 14.3% (10.7,18.5), and M41L 4.9% (2.8,7.8). In the NC DOC ARV resistance prevalence, dual and triple class drug resistance was moderate over the study period. Resistance to PIs was lower than NNRTIs and NRTIs, likely reflecting higher usage of these two classes or a lower barrier to resistance

Expression of p16INK4a as a biomarker of T-cell aging in HIV-infected patients prior to and during antiretroviral therapy

The p16INK4a tumor suppressor gene is a mediator of cellular senescence and has been suggested to be a biomarker of ‘molecular’ age in several tissues including T-cells. To determine the association of both active and suppressed HIV infection with T-cell aging, T-cell p16INK4a expression was compared between 60 HIV+ suppressed subjects, 23 HIV+ untreated subjects, and 18 contemporaneously collected HIV-negative controls, as well as 148 HIV-negative historical samples. Expression did not correlate with chronologic age in untreated HIV+ patients, consistent with an effect of active HIV replication on p16INK4a expression. In patients on cART with suppressed viral loads, however, p16INK4a levels were similar to uninfected controls and correlated with chronologic age, with a trend toward an inverse correlation with CD4 count. These data show that p16INK4a is a reliable biomarker of T cell aging in HIV+ patients with suppressed viral loads and suggest that poor CD4 cell recovery on cART may be associated with increased T-cell expression of p16INK4a, a marker of cellular senescence

Good Performance of Rapid Prostate-Specific Antigen Test for Detection of Semen Exposure in Women: Implications for Qualitative Research

Prostate-specific antigen (PSA) is a valid biomarker of semen exposure in women and has been used to assess reliability of self-reported sexual behavior as well as serve as a proxy measure for condom efficacy. Quantitative PSA tests are expensive and require specialized equipment. A simple, rapid, and inexpensive test for PSA would facilitate semen biomarker evaluation in a variety of research settings. This study evaluated the performance of a rapid PSA test compared with a quantitative assay to identify semen in vaginal swab specimens

Hepatitis C Virus (HCV) NS3 Sequence Diversity and Antiviral Resistance-Associated Variant Frequency in HCV/HIV Coinfection

ABSTRACT HIV coinfection accelerates disease progression in chronic hepatitis C and reduces sustained antiviral responses (SVR) to interferon-based therapy. New direct-acting antivirals (DAAs) promise higher SVR rates, but the selection of preexisting resistance-associated variants (RAVs) may lead to virologic breakthrough or relapse. Thus, pretreatment frequencies of RAVs are likely determinants of treatment outcome but typically are below levels at which the viral sequence can be accurately resolved. Moreover, it is not known how HIV coinfection influences RAV frequency. We adopted an accurate high-throughput sequencing strategy to compare nucleotide diversity in HCV NS3 protease-coding sequences in 20 monoinfected and 20 coinfected subjects with well-controlled HIV infection. Differences in mean pairwise nucleotide diversity (π), Tajima's D statistic, and Shannon entropy index suggested that the genetic diversity of HCV is reduced in coinfection. Among coinfected subjects, diversity correlated positively with increases in CD4 + T cells on antiretroviral therapy, suggesting T cell responses are important determinants of diversity. At a median sequencing depth of 0.084%, preexisting RAVs were readily identified. Q80K, which negatively impacts clinical responses to simeprevir, was encoded by more than 99% of viral RNAs in 17 of the 40 subjects. RAVs other than Q80K were identified in 39 of 40 subjects, mostly at frequencies near 0.1%. RAV frequency did not differ significantly between monoinfected and coinfected subjects. We conclude that HCV genetic diversity is reduced in patients with well-controlled HIV infection, likely reflecting impaired T cell immunity. However, RAV frequency is not increased and should not adversely influence the outcome of DAA therapy

Does HAART Efficacy Translate to Effectiveness? Evidence for a Trial Effect

Background: Patients who participate in clinical trials may experience better clinical outcomes than patients who initiate similar therapy within clinical care (trial effect), but no published studies have evaluated a trial effect in HIV clinical trials. Methods: To examine a trial effect we compared virologic suppression (VS) among patients who initiated HAART in a clinical trial versus in routine clinical care. VS was defined as a plasma HIV RNA #400 copies/ml at six months after HAART initiation and was assessed within strata of early (1996–99) or current (2000–06) HAART periods. Risk ratios (RR) were estimated using binomial models. Results: Of 738 persons initiating HAART, 30.6 % were women, 61.7 % were black, 30 % initiated therapy in a clinical trial and 67 % (n = 496) had an evaluable six month HIV RNA result. HAART regimens differed between the early and current periods (p,0.001); unboosted PI regimens (55.6%) were more common in the early and NNRTI regimens (46.4%) were more common in the current period. Overall, 78 % (95%CI 74, 82%) of patients achieved VS and trial participants were 16 % more likely to achieve VS (unadjusted RR 1.16, 95%CI 1.06, 1.27). Comparing trial to non-trial participants, VS differed by study period. In the early period, trial participants initiating HAART were significantly more likely to achieve VS than non-trial participants (adjusted RR 1.33; 95%CI 1.15, 1.54), but not in the current period (adjusted RR 0.98; 95%CI 0.87, 1.11). Conclusions: A clear clinical trial effect on suppression of HIV replication was observed in the early HAART period but not i

Microalbuminuria predicts overt proteinuria among patients with HIV infection

BACKGROUND: This study examines the association between microalbuminuria and the development of proteinuria among HIV-infected persons. METHODS: 948 subjects provided urine samples for albumin, protein, and creatinine measurements semiannually. Microalbuminuria was an albumin-to-creatinine ratio of >30 mg/gm. Proteinuria was a protein-to-creatinine ratio of ≥0.350 mg/mg. The progression from microalbuminuria to proteinuria was described. RESULTS: At baseline, 69.4% had no detectable proteinuria, 20.2% had microalbuminuria, and 10.4% had proteinuria. Subjects with microalbuminuria and proteinuria were more likely to be black (p=0.03), have lower CD4+ counts (p=0.02,0.0001 compared to subjects without abnormal proteinuria, respectively), and have a higher HIV RNA level (p=0.08,0.04). Among 658 subjects with normal urine protein, 82.7% continued to have no abnormality, 14.3% developed microalbuminuria, and 3.0% developed proteinuria. Subjects without baseline proteinuria (i.e. either normal protein excretion or microalbuminuria) who developed proteinuria were more likely to have microalbuminuria (p=0.001), a lower CD4+ count (p=0.06), and a higher plasma HIV RNA (p=0.03) than those who did not progress to proteinuria. In multivariate analysis, only microalbuminuria remained associated with the development of proteinuria (OR=2.9; 95% CI 1.5, 5.5; p=0.001). CONCLUSION: Microalbuminuria predicts the development of proteinuria among HIV-infected persons. Because proteinuria has been linked to poorer outcomes, strategies to affect microalbuminuria should be tested

Sensitivity Analyis: Risk Ratios for viral suppression following different adjustment schema for missing data.

<p>Sensitivity Analyis: Risk Ratios for viral suppression following different adjustment schema for missing data.</p