Publications

OBJECTIVE

To determine whether earlier initiation of antiretroviral therapy (ART) is associated with better economic outcomes.

DESIGN

Prospective cohort study of HIV-positive patients on ART in rural Uganda.

METHODS

Patients initiating ART at a regional referral clinic in Uganda were enrolled in the Uganda AIDS Rural Treatment Outcomes study starting in 2005. Data on labor force participation and asset ownership were collected on a yearly basis, and CD4 cell counts were collected at pre-ART baseline. We fitted multivariable regression models to assess whether economic outcomes at baseline and in the 6 years following ART initiation varied by baseline CD4 cell count.

RESULTS

Five hundred and five individuals, followed up to 6 years, formed the estimation sample. Participants initiating ART at CD4 cell count at least 200 cells/μl were 13 percentage points more likely to be working at baseline (P < 0.01, 95% confidence interval 0.06-0.21) than those initiating below this threshold. Those in the latter group achieved similar labor force participation rates within 1 year of initiating ART (P < 0.01 on the time indicators). Both groups had similar asset scores at baseline and demonstrated similar increases in asset scores over the 6 years of follow-up.

CONCLUSION

ART helps participants initiating therapy at CD4 cell count below 200 cells/μl rejoin the labor force, though the findings for participants initiating with higher CD4 cell counts suggests that pretreatment declines in labor supply may be prevented altogether with earlier therapy. Baseline similarities in asset scores for those with early and advanced disease suggest that mechanisms other than morbidity may help drive the relationship between HIV infection and economic outcomes.

A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naïve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28- and CD57+CD28-), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions.

BACKGROUND

Defining the association of non-AIDS-defining events with inflammation and immune activation among human immunodeficiency virus (HIV)-infected persons with antiretroviral therapy (ART)-associated virological suppression is critical to identifying interventions to decrease the occurrence of these events.

METHODS

We conducted a case-control study of HIV-infected subjects who had achieved virological suppression within 1 year after ART initiation. Cases were patients who experienced non-AIDS-defining events, defined as myocardial infarction, stroke, non-AIDS-defining cancer, non-AIDS-defining serious bacterial infection, or death. Controls were matched to cases on the basis of age, sex, pre-ART CD4(+) T-cell count, and ART regimen. Peripheral blood mononuclear cells and plasma specimens obtained at the visit before ART initiation (hereafter, baseline), the visit approximately 1 year after ART initiation (hereafter, year 1), and the visit immediately preceding the non-AIDS-defining event (hereafter, pre-event) were analyzed for activated CD4(+) and CD8(+) T cells, plasma interleukin 6 (IL-6) level, soluble tumor necrosis factor receptor I (sTNFR-I) level, sTNFR-II level, soluble CD14 level, kynurenine-to-tryptophan (KT) ratio, and D-dimer level. Conditional logistic regression analysis was used to study the association between biomarkers and outcomes, with adjustment for potential confounders.

RESULTS

Higher IL-6 level, sTNFR-I level, sTNFR-II level, KT ratio, and D-dimer level at year 1 were associated with the occurrence of a non-AIDS-defining event. Significant associations were also seen between non-AIDS-defining events and values of these biomarkers in specimens obtained at baseline and the pre-event time points. Effects remained significant after control for confounders. T-cell activation was not significantly related to outcomes.

CONCLUSIONS

Interventional trials to decrease the incidence of non-AIDS-defining events among HIV-infected persons with virological suppression should consider targeting the pathways represented by these soluble markers. Clinical Trials Registration. NCT00001137.

OBJECTIVE

To estimate the association between immunologic response to antiretroviral therapy (ART) and non-AIDS defining cancer (NADC) incidence in HIV-infected patients.

DESIGN

A prospective cohort including patients with at least 1 cell/μl CD4 cell count and HIV-1 RNA measure after ART initiation between 1996 and 2011 in the Centers for AIDS Research Network of Integrated Clinical Systems, a collaboration of eight HIV clinics at major academic medical centres in the United States.

METHODS

Measures of immunologic response were 6-month CD4 post-ART, latest CD4 and CD4 count-years, a cumulative measure of CD4 lymphopenia. Cox regression with inverse probability-of-exposure weights was used to calculate adjusted hazard ratios of virus-related and virus-unrelated NADC incidence.

RESULTS

Among 9389 patients at ART initiation, median CD4 cell count was 200 cells/μl [interquartile range (IQR) 60-332)], and median HIV-1 RNA was 4.8 log10 copies/ml (IQR 4.3-5.4). Median follow-up was 3.3 years (IQR 1.5-6.5). After 6 months of ART, median CD4 cell count was 304 cells/μl (IQR 163-469). One hundred and sixty-four NADCs were diagnosed during study follow-up, 65 (40%) considered virus-related. Virus-related NADCs were inversely associated with 6-month CD4 cell count (hazard ratio per 100 cells/μl increase=0.71), latest CD4 cell count (hazard ratio per 100 cells/μl increase=0.70) and CD4 cell count-years (hazard ratio per 200 cell-years/μl increase=0.91) independent of CD4 cell count at ART initiation, age and HIV-1 RNA response. No associations were found with virus-unrelated NADCs.

CONCLUSION

Poor CD4 cell count response was strongly associated with virus-related NADC incidence, suggesting an important role for T-cell mediated immunity in pathogenesis. Lower CD4 cell count proximal to cancer diagnosis may be a result of subclinical cancer. Intensified cancer screening should be considered for patients on ART with low CD4 cell counts.