Immunologic Pathways That Predict Mortality in HIV-Infected Ugandans Initiating Antiretroviral Therapy.

The plasma kynurenine/tryptophan (KT) ratio, a marker of adaptive immune defects, strongly predicts mortality during treated human immunodeficiency virus (HIV) disease in Ugandans as compared to US-based populations. Here, the KT ratio and T-cell and plasma biomarkers of immune activation were measured among 535 HIV-infected Ugandans prior to ART initiation and at month 6 of viral suppression. The month 6 KT ratio (adjusted hazard ratio [aHR], 2.74), soluble CD14 level (aHR, 2.32), interleukin 6 level (aHR, 2.34), and D-dimer level (aHR, 1.95) were associated with mortality occurring ≥6 months after ART initiation. The KT ratio remained significantly predictive of mortality even after adjustment for the additional biomarkers, suggesting an independent contribution to clinical outcomes in resource-limited settings.

Declining prevalence of probable depression among patients presenting for antiretroviral therapy in rural Uganda: the role of early treatment initiation.

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.

The kynurenine pathway of tryptophan catabolism, CD4+ T-cell recovery, and mortality among HIV-infected Ugandans initiating antiretroviral therapy.

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.

Evidence for the reliability and validity of the internalized AIDS-related stigma scale in rural Uganda.

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.

Changes in Immune Activation During Pregnancy and the Postpartum Period in Treated HIV Infection.

BACKGROUND: Pregnant women with HIV (PWWH) have high postpartum morbidity and mortality from infections like tuberculosis. Immunologic changes during pregnancy and postpartum periods may contribute to these risks, particularly the immunoregulatory kynurenine pathway of tryptophan catabolism, which contributes to both HIV and tuberculosis pathogenesis and increases in the early postpartum period. METHODS: Women with HIV initiating antiretroviral therapy (ART) in the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort who were pregnant at enrollment or became pregnant during observation were studied (n = 54). Plasma kynurenine/tryptophan (KT) ratio, soluble CD14 (sCD14), sCD163, sCD27, interferon-inducible protein 10 (IP-10), D-dimer, interleukin-6, and intestinal fatty-acid binding protein levels were assessed through the first year of ART and at 3-month intervals throughout pregnancy and 1 year postpartum. Biomarker changes were assessed with linear mixed models adjusted for ART duration. Hemoglobin concentration changes were used to estimate pregnancy-related changes in plasma volume. RESULTS: The median pre-ART CD4 count was 134. D-dimer increased through the third trimester before returning to baseline postpartum, while most other biomarkers declined significantly during pregnancy, beyond what would be expected from pregnancy-associated plasma volume expansion. IP-10 and sCD14 remained suppressed for at least 12 months postpartum. KT ratio was the only biomarker that increased above prepregnancy baseline postpartum (mean + 30%; P < .001) and remained higher than baseline for ≥9 months (P ≤ .045 for all time points). CONCLUSIONS: Several immune activation markers decline during pregnancy and remain suppressed postpartum, but the kynurenine pathway of tryptophan catabolism increases above baseline for ≥9 months postpartum. The mechanisms underlying postpartum kynurenine pathway activity are incompletely understood but may contribute to increased tuberculosis risk in this setting.

Internalized stigma, depressive symptoms, and the modifying role of antiretroviral therapy: A cohort study in rural Uganda.

Depression affects over 40% of people with HIV (PHIV) in low- and middle-income countries, and over half of PHIV report HIV-related internalized stigma. However, few longitudinal studies of PHIV have examined the relationship between HIV-related stigma and depression. Data were analyzed from the 2007-15 Uganda AIDS Rural Treatment Outcomes (UARTO) Study, a cohort of 454 antiretroviral therapy (ART)-naïve PHIV (68% women) starting ART. Our primary outcome was depression symptom severity over the first two years of ART, measured using a locally adapted version of the Hopkins Symptom Checklist; our primary exposure was the 6-item Internalized AIDS-Related Stigma Scale. Both scores were measured at enrollment and at quarterly follow-up visits. We fit linear generalized estimating equations (GEE) regression models to estimate the association between stigma and depression symptom severity, adjusting for potential confounders. We included a stigma×time product term to assess the modifying effect of ART on the association between internalized stigma and depression symptom severity. UARTO participants had a median age of 32 years and median enrollment CD4 count of 217 cells/mm3. Both depression symptom severity and internalized stigma declined on ART, particularly during the first treatment year. In multivariable regression models, depression symptom severity was positively associated with internalized stigma (b=0.03; 95% confidence interval [CI], 0.02 to 0.04) and negatively associated with ART duration >6 months (b =- 0.16; 95% CI,- 0.19 to -0.13). The estimated product term coefficient was negative and statistically significant (P = 0.004), suggesting that the association between internalized stigma and depression symptom severity weakened over time on ART. Thus, in this large cohort of PHIV initiating ART in rural Uganda, depression symptom severity was associated with internalized stigma but the association declined with time on ART. These findings underscore the potential value of ART as a stigma reduction intervention for PHIV, particularly during early treatment.

High Incidence of Intended Partner Pregnancy Among Men Living With HIV in Rural Uganda: Implications for Safer Conception Services.

BACKGROUND: Many men with HIV express fertility intentions and nearly half have HIV-uninfected sexual partners. We measured partner pregnancy among a cohort of men accessing antiretroviral therapy in Uganda. METHODS: Self-reported partner pregnancy incidence and bloodwork (CD4, HIV-RNA) were collected quarterly. Interviewer-administered questionnaires assessed men's sexual and reproductive health annually and repeated at time of reported pregnancy (2011-2015). We measured partner pregnancy incidence overall, by pregnancy intention and by reported partner HIV serostatus. We assessed viral suppression (≤400 copies/mL) during the periconception period. Cox proportional hazard regression with repeated events identified predictors of partner pregnancy. RESULTS: Among 189 men, the baseline median age was 39.9 years (interquartile range: 34.7-47.0), years on antiretroviral therapy was 3.9 (interquartile range: 0.0-5.1), and 51% were virally suppressed. Over 530.2 person-years of follow-up, 63 men reported 85 partner pregnancies (incidence = 16.0/100 person-years); 45% with HIV-serodifferent partners. By 3 years of follow-up, 30% of men reported a partner pregnancy, with no difference by partner HIV serostatus (P = 0.75). Sixty-nine percent of pregnancies were intended, 18% wanted but mistimed, and 8% unwanted. Seventy-eight percent of men were virally suppressed before pregnancy report. Men who were younger [adjusted hazard ratio (aHR): 0.94/yr; 95% confidence interval (CI): 0.89 to 0.99], had incomplete primary education (aHR: 2.95; 95% CI: 1.36 to 6.40), and reported fertility desires (aHR: 2.25; 95% CI: 1.04 to 4.85) had higher probability of partner pregnancy. CONCLUSIONS: A high incidence of intended partner pregnancy highlights the need to address men's reproductive goals within HIV care. Nearly half of pregnancy partners were at-risk for HIV, and one-quarter of men were not virally suppressed during periconception. Safer conception care provides opportunity to support men's health and reproductive goals, while preventing HIV transmission to women and infants.

ART adherence and viral suppression are high among most non-pregnant individuals with early-stage, asymptomatic HIV infection: an observational study from Uganda and South Africa.

INTRODUCTION: The success of universal antiretroviral therapy (ART) access and aspirations for an AIDS-free generation depend on high adherence in individuals initiating ART during early-stage HIV infection; however, adherence may be difficult in the absence of illness and associated support. METHODS: From March 2015 to October 2017, we prospectively observed three groups initiating ART in routine care in Uganda and South Africa: men and non-pregnant women with early-stage HIV infection (CD4 > 350 cells/µL), pregnant women with early-stage HIV infection and men and non-pregnant women with late-stage HIV infection (CD4 < 200 cells/µL). Socio-behavioural questionnaires were administered and viral loads were performed at 0, 6 and 12 months. Adherence was monitored electronically. RESULTS: Adherence data were available for 869 participants: 322 (37%) early/non-pregnant, 199 (23%) early/pregnant and 348 (40%) late/non-pregnant participants. In Uganda, median adherence was 89% (interquartile range 74 to 96) and viral suppression was 90% at 12 months; neither differed among groups (p > 0.72). In South Africa, median adherence was higher in early/non-pregnant versus early/pregnant or late/non-pregnant participants (76%, 37%, 52%; p < 0.001), with similar trends in viral suppression (86%, 51%, 79%; p < 0.001). Among early/non-pregnant individuals in Uganda, adherence was higher with increasing age and lower with structural barriers; whereas in South Africa, adherence was higher with regular income, higher perceived stigma and use of other medications, but lower with maladaptive coping and cigarette smoking. DISCUSSION: ART adherence among non-pregnant individuals with early-stage infection is as high or higher than with late-stage initiation, supporting universal access to ART. Challenges remain for some pregnant women and individuals with late-stage infection in South Africa and highlight the need for differentiated care delivery.

Contraceptive use following unintended pregnancy among Ugandan women living with HIV.

BACKGROUND: Preventing unintended pregnancy is critical for women living with HIV (WLWH) to safely achieve their reproductive goals. Family planning services should support WLWH at risk of repeat unintended pregnancies. We examined the relationship between unintended pregnancy and subsequent contraception use among WLWH in Uganda. STUDY DESIGN: This was a retrospective analysis of data from a longitudinal cohort of individuals initiating antiretroviral therapy (ART), restricted to women with pregnancy (confirmed via urine ß-hcg testing) between 2011-2013. The exposure of interest was intended vs unintended pregnancy, and the outcome was self-report of modern contraceptive use (hormonal methods, intrauterine device, sterilization, and/or consistent condom use) at 12 (range 6-18) months post-partum. A log-binomial model was used to estimate relative risks of modern contraceptive use post-partum based on intent of the index pregnancy, adjusted for age, socioeconomic status, education, relationship and HIV status of pregnancy partner, contraceptive use prior to pregnancy, years since HIV diagnosis, ART regimen, and CD4 cell count. RESULTS: Among 455 women, 110 women reported 110 incident pregnancies with report on intent. Women had a baseline median age of 29 years, baseline CD4 count 403 cells/mm3, and were living with HIV for 3.8 years. Fifty pregnancies (45%) were reported as unintended and 60 (55%) as intended. Postpartum, 64% of women with unintended and 51% with intended pregnancy reported modern contraception (p = 0.24). In adjusted models, there was no association between pregnancy intent and post-partum contraception. However, contraceptive use prior to the referent pregnancy was positively associated with post-partum contraceptive use (aRR 1.97 (95% CI 1.12-3.48, p = 0.02), while higher baseline CD4 cell count was associated with lower post-partum contraceptive use (aRR 0.95, 95% CI 0.90-0.99, p = 0.02). CONCLUSIONS: Almost half of incident pregnancies among WLWH in this cohort were unintended. Experiencing an unintended pregnancy was not associated with post-partum contraceptive use. Creative strategies to support contraceptive uptake for birth spacing and prevention of unintended pregnancies in the post-partum period are needed.

Increasing Prevalence of HIV Pretreatment Drug Resistance in Women But Not Men in Rural Uganda During 2005-2013.

The prevalence of HIV pretreatment drug resistance (PDR) is increasing in sub-Saharan Africa. We sought to describe correlates of PDR and evaluate effects of PDR on clinical outcomes in rural Uganda. We analyzed data from the Uganda AIDS Rural Treatment Outcomes study, a cohort of antiretroviral therapy (ART)-naive adults with HIV (2005-2015). We performed resistance testing on pre-ART specimens. We defined PDR as any World Health Organization (WHO) 2009 surveillance drug resistance mutation and classified PDR level using the Stanford algorithm. We fit unadjusted and sex-stratified log binomial regression and Cox proportional hazard models to identify correlates of PDR and the impact of PDR on viral suppression, loss to follow-up (LTFU), and death. We analyzed data from 738 participants (median age 33 years, 69% female). Overall, prevalence of PDR was 3.5% (n = 26), owing mostly to resistance to non-nucleoside reverse transcriptase inhibitors. PDR increased over time in women (1.8% in those enrolling in clinic in 2001-2006, vs. 7.0% in 2007-2013; p = 0.006), but not in men (1.15% vs. 0.72%, p = 0.737). Lower pre-ART log10 HIV RNA was also associated with higher prevalence of PDR. We identified longer time to viral suppression among those with PDR compared with without PDR (0.5 and 0.3 years, respectively, p = 0.023), but there was no significant relationship with mortality or LTFU (p = 0.139). We observed increasing rates of PDR in women in southwestern Uganda. Implications of this trend, particularly to prevention of mother-to-child transmission programs in the region, require attention due to delayed viral suppression among those with PDR.

Implementing a Global Health Qualitative Research Study: Experiences of a Project Coordinator in Uganda.

Qualitative research in global health requires substantial operational and logistical support during both the implementation phase and day-to-day operations. However, little to no published work shares the experiences of international qualitative research teams. Yet, without a strong project foundation and attention to everyday details, studies can begin without appropriate guidance and, as a result, poor quality data may be generated. This paper presents a detailed account of a project coordinator's experience implementing 4 qualitative HIV and reproductive health studies in Uganda between 2012 and 2014, reflecting on our research team's practices and lessons learnt, and provides recommendations for successful project implementation. The aim of this paper is to help new global health qualitative project coordinators, and international teams more generally, by detailing 6 coordination tasks: hiring, training, team communication, organization of study documents, data collection and storage, and research ethics. To avoid repeat learning of basic, yet important, logistical steps by each new qualitative research project coordinator, this paper can help coordinators think about how to organize their work in order to prepare for both planned and unplanned challenges that have been encountered by others. Sharing operational and logistical experiences and expertise can benefit the global health community and help future studies run more efficiently.

Beyond HIV-serodiscordance: Partnership communication dynamics that affect engagement in safer conception care.

INTRODUCTION: We explored acceptability and feasibility of safer conception methods among HIV-affected couples in Uganda. METHODS: We recruited HIV-positive men and women on antiretroviral therapy (ART) ('index') from the Uganda Antiretroviral Rural Treatment Outcomes cohort who reported an HIV-negative or unknown-serostatus partner ('partner'), HIV-serostatus disclosure to partner, and personal or partner desire for a child within two years. We conducted in-depth interviews with 40 individuals from 20 couples, using a narrative approach with tailored images to assess acceptability of five safer conception strategies: ART for the infected partner, pre-exposure prophylaxis (PrEP) for the uninfected partner, condomless sex timed to peak fertility, manual insemination, and male circumcision. Translated and transcribed data were analyzed using thematic analysis. RESULTS: 11/20 index participants were women, median age of 32.5 years, median of 2 living children, and 80% had HIV-RNA <400 copies/mL. Awareness of HIV prevention strategies beyond condoms and abstinence was limited and precluded opportunity to explore or validly assess acceptability or feasibility of safer conception methods. Four key partnership communication challenges emerged as primary barriers to engagement in safer conception care, including: (1) HIV-serostatus disclosure: Although disclosure was an inclusion criterion, partners commonly reported not knowing the index partner's HIV status. Similarly, the partner's HIV-serostatus, as reported by the index, was frequently inaccurate. (2) Childbearing intention: Many couples had divergent childbearing intentions and made incorrect assumptions about their partner's desires. (3) HIV risk perception: Participants had disparate understandings of HIV transmission and disagreed on the acceptable level of HIV risk to meet reproductive goals. (4) Partnership commitment: Participants revealed significant discord in perceptions of partnership commitment. All four types of partnership miscommunication introduced constraints to autonomous reproductive decision-making, particularly for women. Such miscommunication was common, as only 2 of 20 partnerships in our sample were mutually-disclosed with agreement across all four communication themes. CONCLUSIONS: Enthusiasm for safer conception programming is growing. Our findings highlight the importance of addressing gendered partnership communication regarding HIV disclosure, reproductive goals, acceptable HIV risk, and commitment, alongside technical safer conception advice. Failing to consider partnership dynamics across these domains risks limiting reach, uptake, adherence to, and retention in safer conception programming.

Prevalence and clinical impacts of HIV-1 intersubtype recombinants in Uganda revealed by near-full-genome population and deep sequencing approaches.

OBJECTIVES: HIV-1 subtypes A1 and D cocirculate in a rural community in Mbarara, Uganda. This study examines HIV-1 intersubtype recombination in this community under a full-genome sequencing context. We aim to estimate prevalence, examine time trends, and test for clinical correlates and outcomes associated with intersubtype recombinants. METHODS: Near-full-genome HIV-1 Sanger sequence data were collected from plasma samples of 504 treatment-naïve individuals, who then received protease inhibitor or nonnucleoside reverse transcriptase inhibitor-containing regimens and were monitored for up to 7.5 years. Subtypes were inferred by Los Alamos Recombinant Identification Program (RIP) 3.0 and compared with Sanger/REGA and MiSeq/RIP. 'Nonrecombinants' and 'recombinants' infections were compared in terms of pretherapy viral load, CD4 cell count, posttherapy time to virologic suppression, virologic rebound, first CD4 rise above baseline and sustained CD4 recovery. RESULTS: Prevalence of intersubtype recombinants varied depending on the genomic region examined: gag (15%), prrt (11%), int (8%), vif (10%), vpr (2%), vpu (9%), GP120 (8%), GP41 (18%), and nef (4%). Of the 200 patients with near-full-genome data, prevalence of intersubtype recombination was 46%; the most frequently observed recombinant was A1-D (25%). Sanger/REGA and MiSeq/RIP yielded generally consistent results. Phylogenetic tree revealed most recombinants did not share common ancestors. No temporal trend was observed (all P > 0.1). Subsequent subtype switches were detected in 27 of 143 (19%) study participants with follow-up sequences. Nonrecombinant versus recombinants infections were not significantly different in any pre nor posttherapy clinical correlates examined (all P > 0.2). CONCLUSION: Intersubtype recombination was highly prevalent (46%) in Uganda if the entire HIV genome was considered, but was neither associated with clinical correlates nor therapy outcomes.

Treatment as long-term prevention: sustained reduction in HIV sexual transmission risk with use of antiretroviral therapy in rural Uganda.

OBJECTIVES: Suppressive antiretroviral therapy (ART) substantially decreases HIV transmission in clinical research settings. We sought to measure the frequency and correlates of periods of transmission risk among individuals taking ART during multiple years of observation in rural, southwestern Uganda. DESIGN: Observational cohort study. METHODS: We collected sexual behavior and viral load data in a Ugandan cohort of people living with HIV/AIDS from the time of ART initiation. We defined each 90-day visit as a potential transmission period if HIV-1 RNA was more than 400 copies/ml and the participant reported sexual transmission risk behavior, defined as unprotected sexual contact with at least 1 HIV-uninfected partners or partners of unknown serostatus in the prior 90 days. RESULTS: We evaluated data from 463 individuals on ART over a median 3.5 years of observation and 5293 total study visits. During that time, over half (259, 56%) had detectable viremia or reported sexual transmission risk behavior at least once. However, only 23 (5%) had both simultaneously, at 28 (<1%) of all visits. Transmission sexual behavior was reported at 6% of visits with detectable viremia. In multivariable regression modeling, correlates of transmission risk periods included younger age, lower CD4 cell count, low household asset ownership and increased internalized stigma. CONCLUSION: Although detectable viremia and/or sexual transmission risk behavior occurred in over half of individuals, ART reduced periods of HIV transmission risk by over 90% during up to 6 years of observation time. These findings provide further support for provision of ART, along with interventions to promote long-term adherence, to reduce HIV transmission in HIV-endemic settings.

CD4+ cell count at antiretroviral therapy initiation and economic restoration in rural Uganda.

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.

Reversal of the Kynurenine pathway of tryptophan catabolism may improve depression in ART-treated HIV-infected Ugandans.

BACKGROUND: Major depressive disorder is highly prevalent among HIV-infected persons, and depression symptom severity improves during the course of HIV antiretroviral therapy (ART). The potential biologic pathways explaining these phenomena remain unclear. We investigated the extent to which ART-mediated suppression of the kynurenine pathway of tryptophan catabolism (via indoleamine 2,3-dioxygenase-1 and potentially other sources) may correlate with improvements in depression symptom severity in this setting. METHOD: We used the first year of data from the Uganda AIDS Rural Treatment Outcomes Study, a prospective cohort of 504 HIV-infected individuals initiating their first ART regimen in rural Uganda. We fitted random-effects regression models to estimate the associations between plasma tryptophan, plasma kynurenine, dietary diversity, and self-reported depression symptom severity. RESULTS: Greater depressive symptoms were associated with both lower plasma tryptophan and higher plasma kynurenine/tryptophan (KT) ratio over 12-month follow-up. In multivariable-adjusted models, declines in KT ratio and increases in plasma tryptophan levels partially explained ART-mediated improvements in depressive symptom severity. The association between KT ratio and depression symptom severity was stronger among persons with protein-deficient diets than among those with protein-rich diets. CONCLUSIONS: Indoleamine 2,3-dioxygenase-1-mediated tryptophan catabolism may contribute to depression symptom severity among HIV-infected individuals, particularly among those with poor dietary protein intake. ART-mediated improvements in depressive symptom severity may also be at least partially mediated by immunologic mechanisms. Interventions to reduce immune activation, and dietary protein supplementation, may be promising strategies to further reduce depression in this setting.

Disinhibition in risky sexual behavior in men, but not women, during four years of antiretroviral therapy in rural, southwestern Uganda.

BACKGROUND: In resource-rich areas, risky sexual behavior (RSB) largely diminishes after initiation of anti-retroviral therapy, with notable exceptions among some populations who perceive a protected benefit from anti-retroviral therapy (ART). Yet, there is limited data about long-term trends in risky sexual behavior among HIV-infected people in sub-Saharan Africa after initiation of anti-retroviral therapy. METHODS: We administered questionnaires every three months to collect sexual behavior data among patients taking ART in southwestern Uganda over four years of follow-up time. We defined RSB as having unprotected sex with an HIV-negative or unknown status partner, or unprotected sex with a casual partner. We fit logistic regression models to estimate changes in RSB by time on ART, with and without adjustment for calendar year and CD4 count. RESULTS: 506 participants were enrolled between 2005 and 2011 and contributed a median of 13 visits and 3.5 years of observation time. The majority were female (70%) and median age was 34 years (interquartile range 29-39). There was a decrease in the proportion of men reporting RSB from the pre-ART visit to the first post-ART visit (16.2 to 4.3%, p<0.01) but not women (14.1 to 13.3%, p = 0.80). With each year of ART, women reported decreasing RSB (OR 0.85 per year, 95%CI 0.74-0.98, p = 0.03). In contrast, men had increasing odds of reporting RSB with each year of ART to near pre-treatment rates (OR 1.41, 95%CI 1.14-1.74, p = 0.001), which was partially confounded by changes in calendar time and CD4 count (AOR = 1.24, 95%CI 0.92-1.67, p = 0.16). CONCLUSIONS: Men in southwestern Uganda reported increasing RSB over four years on ART, to levels approaching pre-treatment rates. Strategies to promote long-term safe sex practices targeted to HIV-infected men on ART might have a significant impact on preventing HIV transmission in this setting.

HIV-infected women on antiretroviral treatment have increased mortality during pregnant and postpartum periods.

OBJECTIVE: To assess the impact of pregnancy on mortality among HIV-infected Ugandan women initiating ART. DESIGN: Prospective cohort study. METHODS: HIV-infected women initiating ART in the Uganda AIDS Rural Treatment Outcomes study were assessed quarterly for self-reported pregnancy. The association between pregnancy and postpartum ('pregnancy-related') follow-up periods and mortality was assessed with Cox proportional hazards models adjusted for age, CD4 cell count, plasma HIV-1 RNA levels, and ART duration. RESULTS: Three hundred and fifty-four women with median age 33 years (IQR: 27-37) and CD4 142 cells/µl (IQR: 82-213) were followed for a median of 4.0 years (IQR: 2.5-4.8) after ART initiation, with 3 and 7% loss-to-follow-up at years 1 and 5. One hundred and nine women experienced pregnancy. Five deaths occurred during pregnancy-related follow-up and 16 during nonpregnancy-related follow-up, for crude mortality rates during the first year after ART initiation of 12.57/100 PYs and 3.53/100 PYs (rate ratio 3.56, 95% CI: 0.97-11.07). In adjusted models, the impact of pregnancy-related follow-up on mortality was highest at ART initiation (aHR: 21.48, 95% CI: 3.73-123.51), decreasing to 13.44 (95% CI 3.28-55.11) after 4 months, 8.28 (95% CI 2.38-28.88) after 8 months, 5.18 (95% CI: 1.36-19.71) after 1 year, and 1.25 (95% CI: 0.10-15.58) after 2 years on ART. Four of five maternal deaths occurred postpartum. CONCLUSION: Pregnancy and the postpartum period were associated with increased mortality in HIV-infected women initiating ART, particularly during early ART. Contraception proximate to ART initiation, earlier ART initiation, and careful monitoring during the postpartum period may reduce maternal mortality in this setting.

Rethinking the "pre" in pre-therapy counseling: no benefit of additional visits prior to therapy on adherence or viremia in Ugandans initiating ARVs.

BACKGROUND: Many guidelines recommend adherence counseling prior to initiating antiretrovirals (ARVs), however the additional benefit of pre-therapy counseling visits on early adherence is not known. We sought to assess for a benefit of adherence counseling visits prior to ARV initiation versus adherence counseling during the early treatment period. METHODS: We performed a secondary analysis of data from a prospective cohort of HIV-infected patients in Mbarara, Uganda. Adults were enrolled upon initiation of ARVs. Our primary exposure of interest was ARV adherence counseling prior to initiating therapy (versus concurrent with initiation of therapy). Our outcomes of interest were: 1) average adherence >90% in first three months; 2) absence of treatment interruptions >72 hours in first three months; and 3) Viral load >400 copies/ml at the three month visit. We fit univariable and multivariable regression models, adjusted for predictors of ARV adherence, to estimate the association between additional pre-therapy counseling visits and our outcomes. RESULTS: 300 participants had records of counseling, of whom 231 (77%) completed visits prior to initiation of ARVs and 69 (23%) on or shortly after initiation. Median age was 33, 71% were female, and median CD4 was 133 cell/ml. Median 90-day adherence was 95%. Participants who completed pre-therapy counseling visits had longer delays from ARV eligibility to initiation (median 49 vs 14 days, p<0.01). In multivariable analyses, completing adherence counseling prior to ARV initiation was not associated with average adherence >90% (AOR 0.8, 95%CI 0.4-1.5), absence of treatment gaps (AOR 0.7, 95%CI 0.2-1.9), or HIV viremia (AOR 1.1, 95%CI 0.4-3.1). CONCLUSIONS: Completion of adherence counseling visits prior to ARV therapy was not associated with higher adherence in this cohort of HIV-infected patients in Uganda. Because mortality and loss-to-follow-up remain high in the pre-ARV period, policy makers should reconsider whether counseling can be delivered with ARV initiation, especially in patients with advanced disease.