There are few published examples of absolute risk estimated from epidemiologic data subject to censoring and competing risks with adjustment for multiple confounders. We present an example estimating the effect of injection drug use on 6-year risk of acquired immunodeficiency syndrome (AIDS) after initiation of combination antiretroviral therapy between 1998 and 2012 in an 8-site US cohort study with death before AIDS as a competing risk. We estimate the risk standardized to the total study sample by combining inverse probability weights with the cumulative incidence function; estimates of precision are obtained by bootstrap. In 7,182 patients (83% male, 33% African American, median age of 38 years), we observed 6-year standardized AIDS risks of 16.75% among 1,143 injection drug users and 12.08% among 6,039 nonusers, yielding a standardized risk difference of 4.68 (95% confidence interval: 1.27, 8.08) and a standardized risk ratio of 1.39 (95% confidence interval: 1.12, 1.72). Results may be sensitive to the assumptions of exposure-version irrelevance, no measurement bias, and no unmeasured confounding. These limitations suggest that results be replicated with refined measurements of injection drug use. Nevertheless, estimating the standardized risk difference and ratio is straightforward, and injection drug use appears to increase the risk of AIDS.
AIDS; cohort study; competing risks; HIV; survival function
In the last decade, timely initiation of antiretroviral therapy and resulting virologic suppression have greatly improved in North America concurrent with the development of better tolerated and more potent regimens, but significant barriers to treatment uptake remain.
Background. Since the mid-1990s, effective antiretroviral therapy (ART) regimens have improved in potency, tolerability, ease of use, and class diversity. We sought to examine trends in treatment initiation and resulting human immunodeficiency virus (HIV) virologic suppression in North America between 2001 and 2009, and demographic and geographic disparities in these outcomes.
Methods. We analyzed data on HIV-infected individuals newly clinically eligible for ART (ie, first reported CD4+ count <350 cells/µL or AIDS-defining illness, based on treatment guidelines during the study period) from 17 North American AIDS Cohort Collaboration on Research and Design cohorts. Outcomes included timely ART initiation (within 6 months of eligibility) and virologic suppression (≤500 copies/mL, within 1 year). We examined time trends and considered differences by geographic location, age, sex, transmission risk, race/ethnicity, CD4+ count, and viral load, and documented psychosocial barriers to ART initiation, including non–injection drug abuse, alcohol abuse, and mental illness.
Results. Among 10 692 HIV-infected individuals, the cumulative incidence of 6-month ART initiation increased from 51% in 2001 to 72% in 2009 (Ptrend < .001). The cumulative incidence of 1-year virologic suppression increased from 55% to 81%, and among ART initiators, from 84% to 93% (both Ptrend < .001). A greater number of psychosocial barriers were associated with decreased ART initiation, but not virologic suppression once ART was initiated. We found significant heterogeneity by state or province of residence (P < .001).
Conclusions. In the last decade, timely ART initiation and virologic suppression have greatly improved in North America concurrent with the development of better-tolerated and more potent regimens, but significant barriers to treatment uptake remain, both at the individual level and systemwide.
antiretroviral therapy; healthcare disparities; HIV; time factors; viral load
Antiretroviral therapy (ART) adherence interruptions have been associated with viral rebound; however, the true risk is unknown because HIV RNA has never been measured during ongoing interruptions.
The Uganda AIDS Rural Treatment Outcomes Study is an observational longitudinal cohort of adults taking ART. We monitored adherence with device that wirelessly transmits records of device openings, and routinely assessed HIV RNA quarterly. When 48+ hour lapses between device openings were detected, we made unannounced visits to participants to investigate the cause and assess HIV RNA. Generalized estimating equation logistic regressions were used to assess factors associated with viral rebound.
We followed 479 participants (median 25 months per participant). Most were female (72%), median age was 36 years, median pre-ART CD4 count was 198 cells/μL, median pre-ART HIV RNA level was 5.0 log10 copies/ml, and median duration of prior viral suppression was 13 months. A total of 587 adherence interruptions followed confirmed prior viral suppression, of which 13 (2%) had detectable viral rebound. Viral rebound was associated with duration of adherence interruption (OR 1.25 for each day beyond 48 hours, p=0.007) and 30-day adherence prior to the interruption (OR 0.73, p=0.02).
This paper is the first demonstration of HIV RNA rebound during adherence interruptions objectively measured in real-time. Odds of viral rebound increased by 25% with each day beyond 48 hours. Real-time adherence monitoring was feasible in a sub-Saharan African setting. Further research should assess the potential for real-time adherence interventions to sustain adherence to affordable first-line regimens.
Other than Kaposi's sarcoma (KS)-associated herpesvirus and CD4+ T cell lymphopenia, the mechanisms responsible for KS in the context of HIV are poorly understood. One recently explored pathway of HIV pathogenesis involves induction of the enzyme indoleamine 2,3 dioxygenase-1 (IDO), which catabolizes tryptophan into kynurenine and several other immunologically active metabolites that suppress T cell proliferation. We investigated the role of IDO in the development of KS in HIV disease.
In a case-control study among untreated HIV-infected Ugandans, cases were adults with KS and controls were without KS. IDO activity was assessed by the ratio of plasma kynurenine to tryptophan levels (KT ratio), measured by liquid chromatography tandem mass spectrometry.
We studied 631 HIV-infected subjects: 222 KS cases and 409 controls. Non-KS controls had a higher median plasma KT ratio (130, IQR: 90 to190 nM/μM) than cases (110, IQR: 90 to 150 nM/μM) (p = 0.004). After adjustment for age, sex, CD4 count and plasma HIV RNA level, subjects with the highest (fourth quartile) plasma KT ratios had a 59% reduction (95% CI: 27% to 77%) in the odds of KS compared to those with the lowest (first quartile) levels. KS was also independently associated with lower CD4+ count, higher plasma HIV RNA, and men.
Among HIV-infected individuals, greater activity of the kynurenine pathway of tryptophan catabolism, as evidenced by higher levels of plasma KT ratio, was associated with lower occurrence of KS. Some consequences of immune activation in HIV infection might actually suppress certain cancers.
tryptophan; kynurenine; indoleamine 2,3-dioxygenase-1; HIV; Kaposi's sarcoma; plasma HIV RNA; Africa
We sought to determine whether biomarkers ST2, GDF-15, NT-proBNP, and high-sensitivity Troponin I are elevated in HIV-infected patients and associated with cardiovascular dysfunction and all-cause mortality.
HIV-infected individuals have high rates of cardiovascular disease. Markers of myocardial stress may identify at-risk patients and provide additional prognostic information.
Biomarkers and echocardiograms were assessed in 332 HIV-infected patients and 50 age- and gender-matched controls. Left ventricular systolic dysfunction (LVSD) was defined as ejection fraction <50%, diastolic dysfunction (DD) as ≥stage 1, and pulmonary hypertension as PASP ≥35mmHg. Mortality data was obtained from the National Death Index.
HIV patients were a median 49 years and 80% male. Compared with controls, HIV patients had higher percent estimates of all biomarkers except ST2 and interleukin-6. Among HIV patients, 45% had DD; only ST2 was associated with DD (RR 1.36, p=0.047). LVSD was rare in this cohort (5%). Pulmonary hypertension was present in 27% of HIV patients and associated with GDF-15 (RR 1.18, p=0.04), NT-proBNP (RR 1.18, p=0.007), and Cystatin C (RR 1.54, p=0.03). Thirty-eight deaths occurred among HIV subjects over a median 6.1 years. In adjusted analysis, all-cause mortality was independently predicted by ST2 (HR 2.04, p=0.010), GDF-15 (HR 1.42, p=0.0054), hsCRP (HR 1.25, p=0.023) and D-dimer (HR 1.49, p=0.029). Relationships were unchanged when analyses were restricted to virally-suppressed HIV-infected patients on antiretroviral therapy.
Among HIV-infected individuals, ST2 and GDF-15 are associated with both cardiovascular dysfunction and all-cause mortality and may be useful at identifying those at-risk for developing cardiovascular events and death.
HIV; death; cardiovascular dysfunction; biomarkers; mortality
To determine individual and dyadic factors associated with effective contraceptive use among HIV-infected women accessing antiretroviral therapy (ART) in rural Uganda.
HIV-infected women enrolled in the Uganda AIDS Rural Treatment Outcomes cohort completed questionnaires (detailing socio-behavioral characteristics, sexual and reproductive history, contraceptive use, fertility desires), and phlebotomy (October 2011–March 2013). We describe prevalence of effective contraceptive use (i.e., consistent condom use, and/or oral contraceptives, injectable hormonal contraception, intrauterine device, female sterilization) in the previous six months among sexually active, non-pregnant women (18–40 years). We assessed covariates of contraceptive use using multivariable logistic regression.
362 women (median values: age 30 years, CD4 count 397 cells/mm3, 4.0 years since ART initiation) were included. Among 284 sexually active women, 50% did not desire a(nother) child and 51% had a sero-concordant partner. 45% (n=127) reported effective contraceptive use of whom, 57% (n=72) used condoms, 42% (n=53) injectables, 12% (n=15) oral contraceptives, and 11% (n=14) other effective methods. Dual contraception was reported by 6% (n=8). Only ‘partnership fertility desire’ was independently associated with contraceptive use; women who reported neither partner desired a child had significantly increased odds of contraceptive use (aOR: 2.40, 95% CI: 1.07–5.35) compared with women in partnerships where at least one partner desired a child.
Less than half of sexually active HIV-infected women accessing ART used effective contraception, of which 44% (n=56) relied exclusively on male condoms, highlighting a continued need to expand access to a wider range of longer acting female-controlled contraceptive methods. Association with partnership fertility desire underscores the need to include men in reproductive health programming.
HIV; antiretroviral therapy; family planning; contraceptive use; Uganda
A dynamic visual display highlights the dramatic changes in human immunodeficiency virus type 1 (HIV-1) plasma viral load and CD4 cell count after antiretroviral therapy initiation among adults with HIV, providing insight into the heterogeneous treatment outcomes observed among these patients.
Background. Using a dynamic visual display, we examine the changes in human immunodeficiency virus type 1 (HIV-1) plasma viral load and CD4 cell count for 5 years after antiretroviral therapy initiation in a large cohort of patients with HIV.
Methods. Patients at a Centers for AIDS Research Network of Integrated Clinical Systems site who initiated combination antiretroviral therapy between 1 January 2000 and 31 December 2012 were followed for 5 years for HIV-1 plasma viral load, CD4 cell count, and mortality. The joint distribution of CD4 cell count and viral load over time was depicted in an animated display using a bivariate kernel smoother.
Results. Within days of therapy initiation, many patients had a suppressed viral load and their median CD4 cell count had increased. However, the median CD4 cell count remained below normal levels throughout follow-up period and the proportion of patients with high viral load occasionally increased, even years after therapy initiation.
Conclusions. The dramatic changes in viral load and CD4 cell count after therapy initiation highlight the overwhelming effectiveness of antiretroviral therapy in the modern era. However, this work also emphasizes the need for pharmaceutical or behavioral interventions to prevent virologic failure and to stimulate complete recovery of normal CD4 cell count.
HIV/AIDS; antiretroviral therapy
Among antiretroviral therapy initiators in the Centers for AIDS Research Network of Integrated Clinical Systems, 10-year all-cause mortality was significantly higher among black patients than among white men. White women and Hispanic patients had lower 10-year mortality than white men.
Background. Ensuring equal access to antiretroviral therapy (henceforth therapy) should alleviate disparities in health outcomes among persons infected with human immunodeficiency virus (HIV). However, evidence supporting the persistence of disparities in survival following therapy initiation is mixed.
Methods. Patients initiating therapy in eight academic medical centers in the Centers for AIDS Research Network of Integrated Clinical Systems between 1 January 1998 and 30 December 2011. Patients (n = 10 017) were followed from therapy initiation until death from any cause, administrative censoring at 10 years after therapy initiation or the end of follow-up on 31 December 2011. The 10-year risk of all-cause mortality was calculated from standardized Kaplan–Meier survival curves.
Results. Patients were followed for a median of 4.7 years (interquartile range: 2.2, 8.2). During 51 121 person-years of follow-up, 1224 of the 10 017 patients died. The overall 10-year mortality risk was 20.2% (95% confidence interval [CI], 19.2%, 21.3%). Black men and women experienced standardized 10-year all-cause mortality risks that were 7.2% (95% CI, 4.3%, 10.1%) and 7.9% (95% CI, 3.9%, 12.0%) larger (absolute difference) than white men. White women, Hispanic men, and Hispanic women all had lower 10-year mortality than white men.
Conclusions. These data serve as a call to action to identify modifiable mechanisms leading to these observed mortality disparities among HIV-infected black patients. Effective interventions are needed to ensure that the goal of the National HIV/AIDS Strategy to overcome health disparities becomes a reality.
HIV; health status disparities; cohort studies; survival analysis; antiretroviral therapy
To determine viral and immune factors involved in transmission and control of HIV-1 infection in persons without functional CCR5
Understanding transmission and control of HIV-1 in persons homozygous for CCR5Δ32 is important given efforts to develop HIV-1 curative therapies aimed at modifying or disrupting CCR5 expression.
We identified two HIV-infected CCR5Δ32/Δ32 individuals among a cohort of patients with spontaneous control of HIV-1 infection without antiretroviral therapy and determined co-receptor usage of the infecting viruses. We assessed genetic evolution of full-length HIV-1 envelope sequences by single-genome analysis from one participant and his sexual partner, and explored HIV-1 immune responses and HIV-1 mutations following virologic escape and disease progression.
Both participants experienced viremia of less than 4,000 RNA copies/ml with preserved CD4+ T cell counts off ART for at least 3.3 and 4.6 years after diagnosis, respectively. One participant had phenotypic evidence of X4 virus, had no known favorable HLA alleles, and appeared to be infected by minority X4 virus from a pool that predominately used CCR5 for entry. The second participant had virus that was unable to use CXCR4 for entry in phenotypic assay but was able to engage alternative viral coreceptors (e.g. CXCR6) in vitro.
Our study demonstrates that individuals may be infected by minority X4 viruses from a population that predominately uses CCR5 for entry, and that viruses may bypass traditional HIV-1 coreceptors (CCR5 and CXCR4) completely by engaging alternative coreceptors to establish and propagate HIV-1 infection.
HIV-1; CCR5; CCR5 Δ32 mutation; HIV tropism; HIV controller; viral coreceptor
We estimated US Department of Health and Human Services (DHHS)–approved human immunodeficiency virus (HIV) indicators. Among patients, 71% were retained in care, 82% were prescribed treatment, and 78% had HIV RNA ≤200 copies/mL; younger adults, women, blacks, and injection drug users had poorer outcomes. Interventions are needed to reduce retention- and treatment-related disparities.
HIV; quality of care; retention in care; antiretroviral therapy; HIV RNA suppression
Human immunodeficiency virus-infected individuals have benefited from improved viral suppression, but a discrepancy in end-stage renal disease risk between black and nonblack HIV-infected persons remains, in part due to continued disparities in antiretroviral use and viral suppression, and higher rates of comorbidities.
Background. Human immunodeficiency virus (HIV)-infected adults, particularly those of black race, are at high-risk for end-stage renal disease (ESRD), but contributing factors are evolving. We hypothesized that improvements in HIV treatment have led to declines in risk of ESRD, particularly among HIV-infected blacks.
Methods. Using data from the North American AIDS Cohort Collaboration for Research and Design from January 2000 to December 2009, we validated 286 incident ESRD cases using abstracted medical evidence of dialysis (lasting >6 months) or renal transplant. A total of 38 354 HIV-infected adults aged 18–80 years contributed 159 825 person-years (PYs). Age- and sex-standardized incidence ratios (SIRs) were estimated by race. Poisson regression was used to identify predictors of ESRD.
Results. HIV-infected ESRD cases were more likely to be of black race, have diabetes mellitus or hypertension, inject drugs, and/or have a prior AIDS-defining illness. The overall SIR was 3.2 (95% confidence interval [CI], 2.8–3.6) but was significantly higher among black patients (4.5 [95% CI, 3.9–5.2]). ESRD incidence declined from 532 to 303 per 100 000 PYs and 138 to 34 per 100 000 PYs over the time period for blacks and nonblacks, respectively, coincident with notable increases in both the prevalence of viral suppression and the prevalence of ESRD risk factors including diabetes mellitus, hypertension, and hepatitis C virus coinfection.
Conclusions. The risk of ESRD remains high among HIV-infected individuals in care but is declining with improvements in virologic suppression. HIV-infected black persons continue to comprise the majority of cases, as a result of higher viral loads, comorbidities, and genetic susceptibility.
end-stage renal disease (ESRD); chronic kidney disease (CKD); HIV infection/AIDS; HIV/AIDS; glomerular filtration rate (GFR)
Background: Even among HIV-infected patients who fully suppress plasma HIV RNA replication on antiretroviral therapy, genetic (e.g. CCL3L1 copy number), viral (e.g. tropism) and environmental (e.g. chronic exposure to microbial antigens) factors influence CD4 recovery. These factors differ markedly around the world and therefore the expected CD4 recovery during HIV RNA suppression may differ globally.
Methods: We evaluated HIV-infected adults from North America, West Africa, East Africa, Southern Africa and Asia starting non-nucleoside reverse transcriptase inhibitor-based regimens containing efavirenz or nevirapine, who achieved at least one HIV RNA level <500/µl in the first year of therapy and observed CD4 changes during HIV RNA suppression. We used a piecewise linear regression to estimate the influence of region of residence on CD4 recovery, adjusting for socio-demographic and clinical characteristics. We observed 28 217 patients from 105 cohorts over 37 825 person-years.
Results: After adjustment, patients from East Africa showed diminished CD4 recovery as compared with other regions. Three years after antiretroviral therapy initiation, the mean CD4 count for a prototypical patient with a pre-therapy CD4 count of 150/µl was 529/µl [95% confidence interval (CI): 517–541] in North America, 494/µl (95% CI: 429–559) in West Africa, 515/µl (95% CI: 508–522) in Southern Africa, 503/µl (95% CI: 478–528) in Asia and 437/µl (95% CI: 425–449) in East Africa.
Conclusions: CD4 recovery during HIV RNA suppression is diminished in East Africa as compared with other regions of the world, and observed differences are large enough to potentially influence clinical outcomes. Epidemiological analyses on a global scale can identify macroscopic effects unobservable at the clinical, national or individual regional level.
HIV; Africa; antiretroviral therapy; CD4 + T cell counts; immunological activation
HIV infection is an independent risk factor for PAH, but the underlying pathogenesis remains unclear. ET-1 is a robust vasoconstrictor and key mediator of pulmonary vascular homeostasis. Higher levels of ET-1 predict disease severity and mortality in other forms of PAH, and endothelin receptor antagonists are central to treatment, including in HIV-associated PAH. The direct relationship between ET-1 and PAH in HIV-infected individuals is not well described.
We measured ET-1 and estimated pulmonary artery systolic pressure (PASP) with transthoracic echocardiography (TTE) in 106 HIV-infected individuals. Participants with a PASP ≥ 30 mmHg (n = 65) underwent right heart catheterization (RHC) to definitively diagnose PAH. We conducted multivariable analysis to identify factors associated with PAH.
Among 106 HIV-infected participants, 80% were male, the median age was 52 years and 77% were on antiretroviral therapy. ET-1 was significantly associated with higher values of PASP [14% per 0.1 pg/mL increase in ET-1, p = 0.05] and PASP ≥ 30 mmHg [PR (prevalence ratio) = 1.24, p = 0.012] on TTE after multivariable adjustment for PAH risk factors. Similarly, among the 65 individuals who underwent RHC, ET-1 was significantly associated with higher values of mean pulmonary artery pressure and PAH (34%, p = 0.003 and PR = 2.43, p = 0.032, respectively) in the multivariable analyses.
Higher levels of ET-1 are independently associated with HIV-associated PAH as hemodynamically assessed by RHC. Our findings suggest that excessive ET-1 production in the setting of HIV infection impairs pulmonary endothelial function and contributes to the development of PAH.
Program implementers have argued that the increasing availability of anti-retroviral therapy (ART) will reduce the stigma of HIV. We analyzed data from Uganda to assess how HIV-related stigma has changed during a period of ART expansion.
Serial cross-sectional surveys.
We analyzed data from the Uganda AIDS Rural Treatment Outcomes (UARTO) study during 2007-2012 to estimate trends in internalized stigma among people living with HIV (PLHIV) at the time of treatment initiation. We analyzed data from the Uganda Demographic and Health Surveys (DHS) from 2006 and 2011 to estimate trends in stigmatizing attitudes and anticipated stigma in the general population. We fitted regression models adjusted for socio-demographic characteristics, with year of data collection as the primary explanatory variable.
We estimated an upward trend in internalized stigma among PLHIV presenting for treatment initiation (adjusted b=0.18; 95% CI, 0.06 to 0.30). In the general population, the odds of reporting anticipated stigma were greater in 2011 compared to 2006 (adjusted OR=1.80; 95% CI, 1.51 to 2.13), despite an apparent decline in stigmatizing attitudes (adjusted OR=0.62; 95% CI, 0.52 to 0.74).
Internalized stigma has increased over time among PLHIV in the setting of worsening anticipated stigma in the general population. Further study is needed to better understand the reasons for increasing HIV-related stigma in Uganda and its impact on HIV prevention efforts.
Stigma; trends; incidence; HIV; Uganda
Microbial translocation and innate immune action characterize HIV infection. Continued gut mucosal dysfunction during treatment and its relationship to CD4+ T cell recovery has not been well described.
A cross-sectional study was performed of ART-suppressed (immunologic responders with CD4 >500 and immunologic non-responders with CD4 <350), untreated HIV-infected, and seronegative participants consenting to gut biopsies and a blood draw.
Neutrophil infiltration as a surrogate response to epithelial breach, colorectal epithelial proliferation as a measure of repair, and mucosal apoptosis by immunohistochemistry was determined in gut biopsies. Plasma markers of monocyte activation (sCD14), immune activation (IL-6), and indoleamine 2,3-dioxygenase-1 activity (plasma kynurenine/tryptophan (KT) ratio) were concurrently measured.
Each HIV-infected group had greater neutrophil infiltration than controls. Similarly, untreated HIV-infected participants and ART-suppressed immunologic responders had increased epithelial proliferation compared with controls, but immunologic non-responders had no appreciable increase in epithelial proliferation despite elevated neutrophil infiltration. The CD4+ T cell count was positively correlated with epithelial proliferation and was modestly negatively correlated with neutrophil infiltration in ART-suppressed patients. Epithelial proliferation was inversely correlated with mucosal apoptosis, and apoptosis was linked to plasma sCD14 and modestly to KT ratio.
Neutrophil infiltration and mucosal apoptosis remain abnormally high despite ART. Epithelial proliferation increases in HIV, but may be impaired in immunologic non-responders. Whether mucosal apoptosis is a cause or consequence of epithelial proliferative defects is unclear, but appears to be associated with systemic inflammation. The impact of ART and interventions targeting the gut epithelial barrier in treated HIV infection warrant further investigation.
HIV; immune activation; microbial translocation; epithelial proliferation; inflammation
Little is known about trends in depression at antiretroviral therapy (ART) initiation among people living with HIV (PLHIV) in low- and middle-income countries. We used data from an ongoing cohort of treatment-naïve PLHIV in rural Uganda to estimate secular trends in depression among PLHIV at ART initiation. We fitted linear regression models with depression symptom severity as the outcome variable and year of cohort entry (2005–2012) as the explanatory variable, adjusting for socio-demographic variables and assessing physical health score, body mass index (BMI), and CD4 count as potential mediators of a secular trend in depression symptom severity. There was a statistically significant negative association between year of entry and depression symptom severity, suggesting a 3.1% relative decline in the mean depression symptom severity score at ART initiation in each year of study recruitment after the first year. This trend remained statistically significant after inclusion of baseline socio-demographic characteristics to the model and appeared to be driven by improved physical health scores, but not CD4 count or BMI.
Depression; trends; physical health; antiretroviral therapy; HIV; Uganda
Depression is one of the most prevalent psychiatric comorbidities of HIV and one of the greatest barriers to HIV self-care and adherence. Despite this, little consensus exists on how to best measure depression among people living with HIV/AIDS (PLWHA) in African settings. Measurement of depression among PLWHA may be confounded by somatic symptoms. Some research recommends excluding these items to enhance measurement validity; sensitivity may be lost with this approach. We sought to characterize depression among a cohort (N = 453) of PLWHA initiating antiretroviral therapy in Uganda via factor analysis of a widely used measure of depression, the Hopkins Symptom Checklist (HSCLD). Common factor analysis was performed, associations between HSCLD and the Mental Health subscale of the Medical Outcomes Study HIV (MOS-HIV) estimated, and a Cronbach’s alpha calculated to examine validity. Factor analysis yielded two factors: (1) somatic-cognitive symptoms and (2) behavioral disengagement. Persons with more versus less advanced disease (CD4 cell count of ≤200 cells/mm3) showed no statistically significant differences in depression scores (1.7 vs. 1.7, P ≥ 0.5). Both factors were significantly associated with the MOS-HIV (P <.01). Factor one was highly reliable (α = .81); factor two had only modest reliability (α = .65). Somatic-cognitive symptoms of depression and disengagement from life’s activities appear to be distinct components of depression in this sample. Consideration of somatic items may be valuable in identifying depression in this setting.
HIV/AIDS; Depression; Assessment; Validity
Delays and failures in initiation of antiretroviral therapy (ART) among treatment eligible patients may compromise the effectiveness of HIV care in Africa. An accurate understanding, however, of the pace and completeness of ART initiation and mortality during the waiting period is obscured by frequent losses to follow-up.
We evaluated newly ART-eligible HIV-infected adults from 2007 to 2011 in a prototypical clinic in Mbarara, Uganda. A random sample of patients lost to follow-up was tracked in the community to determine vital status and ART initiation after leaving the original clinic. Outcomes among the tracked patients were incorporated using probability weights, and a competing risks approach was used in analyses.
Among 2,633 ART-eligible patients, 490 were lost to follow-up, of whom a random sample of 132 was tracked and 111 (84.0%) had outcomes ascertained. After incorporating the outcomes among the lost, the cumulative incidence of ART initiation at 30, 90 and 365 days after eligibility was 16.0% (95% CI: 14.2–17.7), 64.5% (95% CI: 60.9–68.1), and 81.7% (95% CI: 77.7–85.6). Death prior to ART was 7.7% at one year. Male sex, higher CD4 count, and no education were associated with delayed ART initiation. Lower CD4 level, malnourishment and travel time to clinic were associated with mortality.
Using a sampling-based approach to account for losses to follow-up revealed that both the speed and completeness of ART initiation were sub-optimal in a prototypical large clinic in Uganda. Improving the kinetics of ART initiation in Africa is needed to make ART optimally effective.
Antiretroviral therapy; Africa; loss to follow-up; mortality
Background. While inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains unclear.
Methods. We assessed immunologic predictors of mortality in a case-control study within the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), using conditional logistic regression. Sixty-four case patients who died within 12 months of treatment-mediated viral suppression were each matched to 2 control individuals (total number of controls, 128) by duration of antiretroviral therapy–mediated viral suppression, nadir CD4+ T-cell count, age, sex, and prior cytomegalovirus (CMV) retinitis. A similar secondary analysis was conducted in the SCOPE cohort, which had participants with less advanced immunodeficiency.
Results. Plasma gut epithelial barrier integrity markers (intestinal fatty acid binding protein and zonulin-1 levels), soluble CD14 level, kynurenine/tryptophan ratio, soluble tumor necrosis factor receptor 1 level, high-sensitivity C-reactive protein level, and D-dimer level all strongly predicted mortality, even after adjustment for proximal CD4+ T-cell count (all P ≤ .001). A higher percentage of CD38+HLA-DR+ cells in the CD8+ T-cell population was a predictor of mortality before (P = .031) but not after (P = .10) adjustment for proximal CD4+ T-cell count. Frequencies of senescent (defined as CD28−CD57+ cells), exhausted (defined as PD1+ cells), naive, and CMV-specific T cells did not predict mortality.
Conclusions. Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation—but not T-cell activation, senescence, and exhaustion—independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.
HIV; gut epithelial cell barrier; intestinal fatty acid binding protein (I-FABP); zonulin-1; sCD14; IL-6; D-dimer; hsCRP; cytomegalovirus; CD57; CD28; CD38; HLA-DR; T-cell activation; mortality; antiretroviral therapy; immune activation
Few reports have examined the impact of HIV-1 transmitted drug resistance (TDR) in resource-limited settings where there are fewer regimen choices and limited pretherapy/posttherapy resistance testing. In this study, we examined TDR prevalence in Kampala and Mbarara, Uganda and assessed its virologic consequences after antiretroviral therapy initiation. We sequenced the HIV-1 protease/reverse transcriptase from n=81 and n=491 treatment-naive participants of the Uganda AIDS Rural Treatment Outcomes (UARTO) pilot study in Kampala (AMU 2002–2004) and main cohort in Mbarara (MBA 2005–2010). TDR-associated mutations were defined by the WHO 2009 surveillance mutation list. Posttreatment viral load data were available for both populations. Overall TDR prevalence was 7% (Kampala) and 3% (Mbarara) with no significant time trend. There was a slight but statistically nonsignificant trend indicating that the presence of TDR was associated with a worse treatment outcome. Virologic suppression (≤400 copies/ml within 6 months posttherapy initiation) was achieved in 87% and 96% of participants with wildtype viruses versus 67% and 83% of participants with TDR (AMU, MBA p=0.2 and 0.1); time to suppression (log-rank p=0.3 and p=0.05). Overall, 85% and 96% of study participants achieved suppression regardless of TDR status. Surprisingly, among the TDR cases, approximately half still achieved suppression; the presence of pretherapy K103N while on nevirapine and fewer active drugs in the first regimen were most often observed with failures. The majority of patients benefited from the local HIV care system even without resistance monitoring. Overall, TDR prevalence was relatively low and its presence did not always imply treatment failure.
Background. Human immunodeficiency virus (HIV) infection–induced indoleamine 2,3-dioxygenase-1 (IDO) expression in activated monocytes and dendritic cells catabolizes tryptophan to kynurenine and other downstream catabolites that inhibit T-cell proliferation and interleukin 17 (IL-17) production. The prognostic significance of this pathway in treated HIV disease is unknown.
Methods. We measured systemic IDO activity (calculated as the ratio of plasma levels of kynurenine to tryptophan; hereafter, the “KT ratio”) in HIV-infected Ugandans before and during antiretroviral therapy (ART)–mediated viral suppression and its association with the rate of subsequent CD4+ T-cell count recovery and mortality.
Results. Among 435 participants, a higher pre-ART KT ratio was associated with a higher plasma virus load (P < .001) and lipopolysaccharide level (P = .018), a lower CD4+ T-cell count (P < .001), and female sex (P = .047). Through month 12 of ART-mediated viral suppression, the plasma KT ratio decreased by approximately 50% (P < .001). After adjustment for pre-ART CD4+ T-cell count, virus load, age, and sex, a higher month 12 KT ratio predicted a slower rate of subsequent CD4+ T-cell count recovery (P = .001). Thirty-nine participants died. After adjustment for pre-ART CD4+ T-cell count, virus load, body mass index, sex, and age, a higher pre-ART and month 6 KT ratio predicted increased mortality (P ≤ .016).
Conclusions. The kynurenine pathway of tryptophan catabolism independently predicts poor CD4+ T-cell count recovery and increased mortality among HIV-infected Ugandans initiating ART and may be an important target for interventions.
Tryptophan; kynurenine; indoleamine 2,3-dioxygenase-1; HIV; mortality; antiretroviral therapy; Uganda
Background. Unlike cytomegalovirus (CMV) infection and aging, human immunodeficiency virus (HIV) decreases the proportion of CD28−CD8+ T cells expressing CD57. Whether this abnormality predicts mortality in treated HIV infection and can be reversed by early antiretroviral therapy (ART) remains unknown.
Methods. We sampled recently HIV-infected individuals (<6 months) and HIV-uninfected controls and compared longitudinal changes in the proportion of CD28−CD8+ T cells expressing CD57 between those who initiated ART early (<6 months) vs later (≥2 years). We also assessed the relationship between this phenotype and mortality in a nested case-control study of ART-suppressed chronically infected individuals.
Results. Compared to HIV-uninfected controls (n = 15), individuals who were recently infected with HIV had lower proportions of CD28−CD8+ T cells expressing CD57 (P < .001), and these proportions increased during ART. The early ART group (n = 33) achieved normal levels, whereas the later ART group (n = 30) continued to have lower levels than HIV-uninfected controls (P = .02). Among 141 ART-suppressed participants in the SOCA study, those in the lowest quartile of CD28−CD8+ T cells expressing CD57 had 5-fold higher odds of mortality than those in the highest quartile (95% CI, 1.6–15.9, P = .007).
Conclusions. Abnormally low proportions of CD28−CD8+ T cells expressing CD57 predict increased mortality during treated HIV infection and may be reversed with early ART initiation.
HIV; CD57; CD28; Immunosenescence; aging; mortality; antiretroviral therapy; immune activation
Cross-sectional studies show that human immunodeficiency virus (HIV) stigma is negatively correlated with social support.
The purpose of this study is to examine the bidirectional relationship between social support and HIV stigma.
We collected quarterly data from a cohort of 422 people living with HIV in Uganda, followed for a median of 2.1 years. We used multilevel regression to model the contemporaneous and 3-month-lagged associations between social support and both enacted and internalized stigma.
Lagged enacted stigma was negatively correlated with emotional and instrumental social support, and lagged instrumental social support was negatively correlated with enacted stigma. Internalized stigma and emotional social support had reciprocal lagged associations.
Interventions to reduce enacted stigma may strengthen social support for people living with HIV. Improved social support may in turn have a protective influence against future enacted and internalized stigma.
HIV/AIDS; Stigma; Social support; Uganda
Identifying the mechanisms of natural control of HIV-1 infection could lead to novel approaches to prevent or cure HIV infection. Several studies have associated natural control of HIV-1 infection with IgG antibodies against HIV-1 Gag proteins (e.g. p24) and/or production of IgG2 antibodies against HIV-1 proteins. These antibodies likely exert their effect by activating anti-viral effector cell responses rather than virus neutralization. We hypothesized that an opsonophagocytic IgG antibody response against HIV-1 p24 that activates plasmacytoid dendritic cells (pDCs) through FcγRIIa would be associated with control of HIV and that this would be enhanced by antibody isotype diversification. Using the Gen2.2 pDC cell line, we demonstrated that pDC-reactive opsonophagocytic IgG antibody responses against HIV-1 p24 were higher in HIV controllers (HIV RNA <2000 copies/mL) than non-controllers (HIV RNA >10,000 copies/mL) particularly in controllers with low but detectable viremia (HIV RNA 75–2000 copies/mL). Opsonophagocytic antibody responses correlated with plasma levels of IgG1 and IgG2 anti-HIV-1 p24 and notably, correlated inversely with plasma HIV RNA levels in viremic HIV patients. Phagocytosis of these antibodies was mediated via FcγRIIa. Isotype diversification (towards IgG2) was greatest in HIV controllers and depletion of IgG2 from immunoglobulin preparations indicated that IgG2 antibodies to HIV-1 p24 do not enhance phagocytosis, suggesting that they enhance other aspects of antibody function, such as antigen opsonization. Our findings emulate those for pDC-reactive opsonophagocytic antibody responses against coxsackie, picorna and influenza viruses and demonstrate a previously undefined immune correlate of HIV-1 control that may be relevant to HIV vaccine development.
Galectin-9 (Gal-9) is a β-galactosidase-binding lectin that promotes apoptosis, tissue inflammation, and T cell immune exhaustion, and alters HIV infection in part through engagement with the T cell immunoglobulin mucin domain-3 (Tim-3) receptor and protein disulfide isomerases (PDI). Gal-9 was initially thought to be an eosinophil attractant, but is now known to mediate multiple complex signaling events that affect T cells in both an immunosuppressive and inflammatory manner. To understand the kinetics of circulating Gal-9 levels during HIV infection we measured Gal-9 in plasma during HIV acquisition, in subjects with chronic HIV infection with differing virus control, and in uninfected individuals. During acute HIV infection, circulating Gal-9 was detected as early as 5 days after quantifiable HIV RNA and tracked plasma levels of interleukin (IL)-10, tumor necrosis factor (TNF)-α, and IL-1β. In chronic HIV infection, Gal-9 levels positively correlated with plasma HIV RNA levels (r=0.29; p=0.023), and remained significantly elevated during suppressive antiretroviral therapy (median: 225.3 pg/ml) and in elite controllers (263.3 pg/ml) compared to age-matched HIV-uninfected controls (54 pg/ml). Our findings identify Gal-9 as a novel component of the first wave of the cytokine storm in acute HIV infection that is sustained at elevated levels in virally suppressed subjects and suggest that Gal-9:Tim-3 crosstalk remains active in elite controllers and antiretroviral (ARV)-suppressed subjects, potentially contributing to ongoing inflammation and persistent T cell dysfunction.