Publications

BACKGROUND

While persistent T-cell activation has been cross-sectionally associated with poor CD4+ T-cell restoration in HIV-infected individuals maintaining antiretroviral treatment (ART)-mediated viral suppression, it remains unclear whether CD8+ T-cell activation is of predictive effect on CD4+ T-cell recovery.

OBJECTIVE

We assessed whether the extent of persistent CD8+ T-cell activation (% CD38+/HLA-DR+) in the first few years of ART-mediated viral suppression predicted subsequent CD4+ T-cell recovery in 95 subjects with up to 15 years of observation on suppressive ART.

RESULTS

Lower CD8+ T-cell activation and higher naïve CD4+ T-cell frequencies (CD45RA+/CD62L+) measured at year 3 to 5 after starting ART independently predicted greater subsequent CD4+ T-cell increases. The mean CD4 count increase from year 0 to year 5 and the increase to the average of year 10 to 15 in the low CD8 activation group (≤18.5%; mean = 13%) were 342 and 458 cells/mm,3 and the increases were 248 and 349 cells/mm3 for the high CD8 activation group (≯18.5%; mean = 29%) (P = .002 and P = .016, respectively, comparing groups). At years 10 to 15, the mean CD4 counts in the groups were 579 and 484 cells/mm3, respectively (P = .026).

CONCLUSION

These findings support the need to identify approaches to reduce immune activation in treated HIV disease.

We examined the association between CD4 cell count and adherence in a cohort of Ugandans initiating antiretrovirals (ARVs). Outcomes were (a) adherence <90%; (b) any treatment interruptions > 72 hours; (c) number of treatment interruptions; and (d) HIV-RNA >400 copies/mL. We fit regression models to estimate associations with our exposure of interest, baseline CD4 cell count ≥ 250 cells/μL (n = 60) vs <250 cells/μL (n = 413). CD4 cell count ≥250 cells/μL was independently associated with increased odds and number of treatment interruptions and increased odds of persistent viremia. Interventions to support adherence in patients with higher CD4 cell counts should be considered as drug availability to this population increases.

HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting memory CD4(+) T cells carrying latent but replication-competent viral genomes. Because strategies targeting this latent reservoir are now being tested in clinical trials, well-validated high-throughput assays that quantify this reservoir are urgently needed. Here we compare eleven different approaches for quantitating persistent HIV-1 in 30 patients on HAART, using the original viral outgrowth assay for resting CD4(+) T cells carrying inducible, replication-competent viral genomes as a standard for comparison. PCR-based assays for cells containing HIV-1 DNA gave infected cell frequencies at least 2 logs higher than the viral outgrowth assay, even in subjects who started HAART during acute/early infection. This difference may reflect defective viral genomes. The ratio of infected cell frequencies determined by viral outgrowth and PCR-based assays varied dramatically between patients. Although strong correlations with the viral outgrowth assay could not be formally excluded for most assays, correlations achieved statistical significance only for integrated HIV-1 DNA in peripheral blood mononuclear cells and HIV-1 RNA/DNA ratio in rectal CD4(+) T cells. Residual viremia was below the limit of detection in many subjects and did not correlate with the viral outgrowth assays. The dramatic differences in infected cell frequencies and the lack of a precise correlation between culture and PCR-based assays raise the possibility that the successful clearance of latently infected cells may be masked by a larger and variable pool of cells with defective proviruses. These defective proviruses are detected by PCR but may not be affected by reactivation strategies and may not require eradication to accomplish an effective cure. A molecular understanding of the discrepancy between infected cell frequencies measured by viral outgrowth versus PCR assays is an urgent priority in HIV-1 cure research.

BACKGROUND

Excessive inflammation persists despite antiretroviral treatment. Statins decrease cardiovascular (CV) disease risk by reducing low-density lipoprotein cholesterol and inflammation. We performed an exploratory analysis to evaluate whether statin therapy decreased risk of non-AIDS-defining events and nonaccidental death.

METHODS

A total of 3601 subjects not on a statin from the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort were included. Outcome was time to first clinical event (CV event, renal or hepatic disease, incident diabetes, thrombotic/embolic event, nontraumatic fracture, non-AIDS-defining malignancy, serious bacterial infection, or nonaccidental death); event categories were also analyzed separately. Inverse probability of treatment and censoring weighted Cox proportional hazard models were used to assess the causal statin effect. Differential statin effects by baseline covariates were evaluated.

RESULTS

Over 15 135 person-years (PY) of follow-up, 484 subjects initiated statins; 616 experienced an event (crude event rate, 4.4/100 PY on a statin and 4.1/100 PY not on a statin); the unadjusted hazard ratio (HR) was 1.17 (95% confidence interval [CI], .91-1.50). In a final weighted model, the adjusted HR (AHR) was 0.81 (95% CI, .53- 1.24). Results for other clinical events were similar, except for malignancies (AHR, 0.43 [95% CI, .19-.94]) and bacterial infections (AHR, 1.30 [95% CI, .64-2.65]). No differential statin effects by baseline covariates were detected.

CONCLUSIONS

Although statin therapy was not associated with a reduction in time to all non-AIDS-defining event or nonaccidental death, it was associated with a statistically significant 57% reduction in non-AIDS-defining malignancies. Confirmatory studies are needed to evaluate statin-associated reduction in risk of cancer and non-AIDS-associated morbidities.

HIV infection remains highly stigmatized throughout sub-Saharan Africa despite the increasing availability of treatment. HIV-related stigma is commonly described to be highly prevalent in East Africa, but none of these studies have employed validated scales for measurement. We used data from 456 people living with HIV/AIDS in rural Uganda to validate the six-item Internalized AIDS-Related Stigma Scale. The scale demonstrated acceptable internal consistency (Cronbach's alpha = 0.73) and time stability. Exploratory factor analysis indicated the presence of a single factor. Construct validity was supported by observations that the scale was correlated with related constructs such as depression and mental health-related quality of life. The scale was able to discriminate between groups of persons who were different in terms of treatment status and their experience of HIV-related self-blame. Taken together, these findings suggest that the Internalized AIDS-Related Stigma Scale may be a useful tool for socio-behavioral HIV research.