Publications

OBJECTIVE

Some antiretroviral treated HIV-infected patients develop Kaposi's sarcoma despite long-term suppression of HIV replication. These Kaposi's sarcoma lesions are consistent with Kaposi's sarcoma observed in the elderly uninfected population ('classical Kaposi's sarcoma'). We investigated potential mechanisms for this phenomenon, focusing on measures of immune activation and T-cell senescence.

DESIGN

We compared markers of immunosenescence, naive T cells, activation, and inflammation in CD4+ and CD8+ T cells from antiretroviral-treated participants with new-onset Kaposi's sarcoma (cases, n =  19) and from treated individuals without Kaposi's sarcoma (controls, n  = 47).

RESULTS

There was increased frequency of CD4+ and CD8+ T cells with an immunosenescence phenotype (CD57+ and CD28-) in cases vs. controls (CD4+ T cells: CD57+ 7.4 vs. 3.7%, P = 0.025; CD28- 9.1 vs. 4.8%, P  = 0.025; CD8+ T cells: CD57+ 41.5 vs. 27.7%, P  =  0.003; CD28- 60.5 vs. 51.3%, P  = 0.041). Cases had lower proportions of naïve T cells (CD27+ CD28+ CD45RA+) in CD4+ (23.0 vs. 32.2%, P = 0.023) and CD8+ (11.3 vs. 20.7%, P  <  0.001) T-cell compartments. CCR5 was more highly expressed in CD4+ (16.3 vs. 11.0%, P  = 0.025), and CD8+ (43.1 vs. 28.3%, P < 0.001) T-cell compartments in cases vs. controls. There was no difference in telomere length or telomerase activity in peripheral blood mononuclear cells, or in T-cell expression of activation markers (HLADRCD38).

CONCLUSION

Among antiretroviral-treated patients, increased frequencies of T cells with an immunosenescence phenotype and lower frequencies of naive T cells were associated with presence of Kaposi's sarcoma among effectively treated patients. These data suggest that certain immunologic perturbations--including those associated with aging--might be causally associated with development of Kaposi's sarcoma.

Background. CD4(+)/CD8(+) T-cell activation levels often remain elevated in chronic human immunodeficiency virus (HIV) infection despite initiation of antiretroviral therapy (ART). T-cell activation predicts early death and blunted CD4+ T-cell recovery during ART and may affect persistent HIV reservoir size. We investigated whether very early ART initiation is associated with lower on-therapy immune activation and HIV persistence. Methods. From a cohort of patients with early HIV infection (<6 months duration since infection) we identified persons who started ART early (<6 months after infection) or later (≥2 years after infection) and maintained ≥2 years of virologic suppression; at-risk HIV-negative persons were controls. We measured CD4(+)/CD8(+) T-cell activation (percent CD38(+)/HLA-DR(+)) and HIV reservoir size (based on HIV DNA and cell-associated RNA levels). Results. In unadjusted analyses, early ART predicted lower on-therapy CD8(+) T-cell activation (n = 34; mean, 22.1%) than achieved with later ART (n = 32; mean, 28.8%; P = .009), although levels in early ART remained elevated relative to HIV-negative controls (P = .02). Early ART also predicted lower CD4+ T-cell activation than with later ART (5.3% vs 7.5%; P = .06). Early ART predicted 4.8-fold lower DNA levels than achieved with later ART (P = .005), and lower cell-associated RNA levels (difference in signal-to-cutoff ratio (S/Co), 3.2; P = .035). Conclusions. ART initiation <6 months after infection is associated with lower levels of T-cell activation and smaller HIV DNA and RNA reservoir size during long-term therapy.

Progressive HIV infection is characterized by dysregulation of the intestinal immune barrier, translocation of immunostimulatory microbial products, and chronic systemic inflammation that is thought to drive progression of disease to AIDS. Elements of this pathologic process persist despite viral suppression during highly active antiretroviral therapy (HAART), and drivers of these phenomena remain poorly understood. Disrupted intestinal immunity can precipitate dysbiosis that induces chronic inflammation in the mucosa and periphery of mice. However, putative microbial drivers of HIV-associated immunopathology versus recovery have not been identified in humans. Using high-resolution bacterial community profiling, we identified a dysbiotic mucosal-adherent community enriched in Proteobacteria and depleted of Bacteroidia members that was associated with markers of mucosal immune disruption, T cell activation, and chronic inflammation in HIV-infected subjects. Furthermore, this dysbiosis was evident among HIV-infected subjects undergoing HAART, and the extent of dysbiosis correlated with activity of the kynurenine pathway of tryptophan catabolism and plasma concentrations of the inflammatory cytokine interleukin-6 (IL-6), two established markers of disease progression. Gut-resident bacteria with capacity to catabolize tryptophan through the kynurenine pathway were found to be enriched in HIV-infected subjects, strongly correlated with kynurenine levels in HIV-infected subjects, and capable of kynurenine production in vitro. These observations demonstrate a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection that is apparent even in the setting of viral suppression during HAART. This link suggests that gut-resident microbial populations may influence intestinal homeostasis during HIV disease.

BACKGROUND

Cancer is an important cause of morbidity and mortality in individuals infected with human immunodeficiency virus (HIV), but patterns of cancer incidence after combination antiretroviral therapy (ART) initiation remain poorly characterized.

METHODS

We evaluated the incidence and timing of cancer diagnoses among patients initiating ART between 1996 and 2011 in a collaboration of 8 US clinical HIV cohorts. Poisson regression was used to estimate incidence rates. Cox regression was used to identify demographic and clinical characteristics associated with cancer incidence after ART initiation.

RESULTS

At initiation of first combination ART among 11 485 patients, median year was 2004 (interquartile range [IQR], 2000-2007) and median CD4 count was 202 cells/mm(3) (IQR, 61-338). Incidence rates for Kaposi sarcoma (KS) and lymphomas were highest in the first 6 months after ART initiation (P < .001) and plateaued thereafter, while incidence rates for all other cancers combined increased from 416 to 615 cases per 100 000 person-years from 1 to 10 years after ART initiation (average 7% increase per year; 95% confidence interval, 2%-13%). Lower CD4 count at ART initiation was associated with greater risk of KS, lymphoma, and human papillomavirus-related cancer. Calendar year of ART initiation was not associated with cancer incidence.

CONCLUSIONS

KS and lymphoma rates were highest immediately following ART initiation, particularly among patients with low CD4 cell counts, whereas other cancers increased with time on ART, likely reflecting increased cancer risk with aging. Our results underscore recommendations for earlier HIV diagnosis followed by prompt ART initiation along with ongoing aggressive cancer screening and prevention efforts throughout the course of HIV care.

OBJECTIVE

Studies of the association between transportation barriers and HIV-related health outcomes have shown both positive and negative effects, possibly because a reliable, validated measure of transportation barriers has not been identified.

DESIGN

Prospective cohort study of HIV-infected patients in rural Uganda.

METHODS

Participants were enrolled from the HIV clinic at the regional referral hospital in Mbarara, Uganda as part of the Uganda AIDS Rural Treatment Outcomes (UARTO) Study. We collected the following measures of transportation barriers to HIV clinic: global positioning systems (GPS)-tracked distance measured by driving participants to their homes along their typical route; straight-line GPS distance from clinic to home, calculated with the Great Circle Formula; self-reported travel time; and self-reported travel cost. We assessed inter-measure agreement using linear regression, correlation coefficients and κ statistics (by measure quartile) and validated measures by fitting linear regression models to estimate associations with days late for clinic visits.

RESULTS

One hundred and eighty-eight participants were tracked with GPS. Seventy-six percent were women, with a median age of 40 years and median CD4 cell count of 193 cells/μl. We found a high correlation between GPS-based distance measures (β=0.74, P<0.001, R²=0.92, κ=0.73), but little correlation between GPS-based and self-reported measures (all R²≤0.4). GPS-based measures were associated with days late to clinic (P<0.001); but neither self-reported measure was associated (P>0.85).

CONCLUSION

GPS-measured distance to clinic is associated with HIV clinic absenteeism and should be prioritized over self-reported measures to optimally risk-stratify patients accessing care in rural, resource-limited settings.