Immunometabolic Reprogramming in Response to HIV Infection Is Not Fully Normalized by Suppressive Antiretroviral Therapy

Background: HIV infection results in immunometabolic reprogramming. While we are beginning to understand how this metabolic reprogramming regulates the immune response to HIV infection, we do not currently understand the impact of ART on immunometabolism in people with HIV (PWH). Methods: Serum obtained from HIV-infected (n = 278) and geographically matched HIV seronegative control subjects (n = 300) from Rakai Uganda were used in this study. Serum was obtained before and ~2 years following the initiation of ART from HIV-infected individuals. We conducted metabolomics profiling of the serum and focused our analysis on metabolic substrates and pathways assocaited with immunometabolism. Results: HIV infection was associated with metabolic adaptations that implicated hyperactive glycolysis, enhanced formation of lactate, increased activity of the pentose phosphate pathway (PPP), decreased β-oxidation of long-chain fatty acids, increased utilization of medium-chain fatty acids, and enhanced amino acid catabolism. Following ART, serum levels of ketone bodies, carnitine, and amino acid metabolism were normalized, however glycolysis, PPP, lactate production, and β-oxidation of long-chain fatty acids remained abnormal. Conclusion: Our findings suggest that HIV infection is associated with an increased immunometabolic demand that is satisfied through the utilization of alternative energetic substrates, including fatty acids and amino acids. ART alone was insufficient to completely restore this metabolic reprogramming to HIV infection, suggesting that a sustained impairment of immunometabolism may contribute to chronic immune activation and comorbid conditions in virally suppressed PWH.     

Assessment,prevalence, and correlates of frailty among middle-aged adults with HIV in rural Uganda

Journal of NeuroVirology - We investigated the prevalence and risk factors for frailty among people with HIV (PWH) in rural Uganda (n = 55, 47% male, mean age 44 years)....     

Phosphatidylethanol (PEth) as a biomarker of alcohol consumption in HIV-positive patients in sub-Saharan Africa

Background: Alcohol is heavily consumed in sub‐Saharan Africa and affects HIV transmission and treatment and is difficult to measure. Our goal was to examine the test characteristics of a direct metabolite of alcohol consumption, phosphatidylethanol (PEth). Methods: Persons infected with HIV were recruited from a large HIV clinic in southwestern Uganda. We conducted surveys and breath alcohol concentration (BRAC) testing at 21 daily home or drinking establishment visits, and blood was collected on day 21 (n = 77). PEth in whole blood was compared with prior 7‐, 14‐, and 21‐day alcohol consumption. Results: (i) The receiver operator characteristic area under the curve (ROC‐AUC) was highest for PEth versus any consumption over the prior 21 days (0.92; 95% confidence interval [CI]: 0.86 to 0.97). The sensitivity for any detectable PEth was 88.0% (95% CI: 76.0 to 95.6) and the specificity was 88.5% (95% CI: 69.8 to 97.6). (ii) The ROC‐AUC of PEth versus any 21‐day alcohol consumption did not vary with age, body mass index, CD4 cell count, hepatitis B virus infection, and antiretroviral therapy status, but was higher for men compared with women (p = 0.03). (iii) PEth measurements were correlated with several measures of alcohol consumption, including number of drinking days in the prior 21 days (Spearman r = 0.74, p < 0.001) and BRAC (r = 0.75, p < 0.001). Conclusions: The data add support to the body of evidence for PEth as a useful marker of alcohol consumption with high ROC‐AUC, sensitivity, and specificity. Future studies should further address the period and level of alcohol consumption for which PEth is detectable.     

Innate and adaptive immune responses during acute M. tuberculosis infection in adult household contacts in Kampala, Uganda

Contacts of active pulmonary tuberculosis (TB) patients are at risk for Mycobacterium tuberculosis (MTB) infection. Because most infections are controlled, studies during MTB infection provide insight into protective immunity. We compared immune responses of adult household contacts that did and did not convert the tuberculin skin test (TST). Innate and adaptive immune responses were measured by whole blood assay. Responses of TST converters (TSTC) were compared with persistently TST negative contacts (PTST-) and contacts who were TST+ at baseline (TST+). TLR-2, TLR-4, and IFN-γR responses to IFN-γ did not differ between the groups, nor did γδ T cell responses. T cell responses to MTB antigens differed markedly among TSTC, PTST-, and TST+ contacts. Thus, no differences in innate responses were found among the three household contact groups. However, adaptive T cell responses to MTB antigens did differ before and during MTB infection among PTST-, TSTC, and TST+ contacts.     

Personal barriers to antiretroviral therapy adherence: case studies from a rural Uganda prospective clinical cohort

Background

Although good adherence to antiretroviral therapy (ART) is essential for successful treatment outcomes, some patients may have specific personal barriers to ART adherence.

Objectives

To study specific personal barriers to ART adherence.

Methods

Quantitative data on patients'' health status, ART adherence, CD4 cell counts and viral loads were collected, and qualitative data on life experiences of five patients with poor ART outcomes and adherence were also collected.

Results

Out of 35 patients with poor immunological and virological ART outcomes, 17 (49%) also had poor ART adherence. Patient 1 had no living child and did not disclose her HIV serostatus to her spouse because she wanted to have a child. Patient 2 was an orphan with neither social nor family support. Patient 3 stopped ART when she conceived, returned to the study clinic when pregnant again and was sickly. She was switched to second-line ART with satisfactory outcomes. Patient 4, a 14 year old orphan had missed ART for 2 months when his treatment supporter was away. Patient 5 aged 66 years stopped ART which he blamed for his erectile dysfunction.

Conclusion

ART adherence counselling should target specific personal barriers to ART adherence like: lack of family support, health and sexual life concerns, desire to have children and family instability.     

Effect of pregnancy on immunological and virological outcomes of women on ART: a prospective cohort study in rural Uganda, 2004-2009

Objectives Before antiretroviral therapy (ART) introduction, pregnancy was associated with a sustained drop in CD4 cell count in HIV‐infected women. We examined the effects of pregnancy on immunological and virological ART outcomes. Methods Between January 2004 and March 2009, we studied HIV‐infected women receiving ART in a prospective open cohort study in rural Uganda. We used random effects regression models to compare the CD4 counts of women who became pregnant and those who did not, and among the pregnant women before and after pregnancy. CD4 count and proportions with detectable viral load (≥400 copies/ml) were compared between the two groups using the Mann–Whitney rank sum test and logistic regression respectively. Results Of 88 women aged 20–40 years receiving ART, 23 became pregnant. At ART initiation, there were no significant differences between those who became pregnant and those who did not in clinical, immunological and virological parameters. Among women who became pregnant, CD4 cell count increased before pregnancy (average 75.9 cells/mm³ per year), declined during pregnancy (average 106.0) but rose again in the first year after delivery (average 88.6). Among women who did not become pregnant, the average CD4 cell count rise per year for the first 3 years was 88.5. There was no significant difference in the proportions of women with detectable viral load at last clinic visit among those who became pregnant (8.7%) and those who did not (16.1%), P = 0.499. Conclusion Pregnancy had no lasting effect on the immunological and virological outcomes of HIV‐infected women on ART.     

The Veterans Aging Cohort Study Index is not associated with HIV-associated neurocognitive disorders in Uganda

Journal of NeuroVirology - The Veterans Aging Cohort Study (VACS) Index has been associated with HIV-associated neurocognitive disorder (HAND) in some populations but has not been studied in...     

Detection of multiple strains of <Emphasis Type="Italic">Mycobacterium tuberculosis</Emphasis> using MIRU-VNTR in patients with pulmonary tuberculosis in Kampala,Uganda

Background  

Many studies using DNA fingerprinting to differentiate Mycobacterium tuberculosis (MTB) strains reveal single strains in cultures, suggesting that most disease is caused by infection with a single strain. However, recent studies using molecular epidemiological tools that amplify multiple targets have demonstrated simultaneous infection with multiple strains of MTB. We aimed to determine the prevalence of MTB multiple strain infections in Kampala, and the impact of these infections on clinical presentation of tuberculosis (TB) and response to treatment.     

Effect of pregnancy on HIV disease progression and survival among women in rural Uganda

OBJECTIVE: To investigate the effect of pregnancy on HIV disease progression and survival among HIV-infected women in rural Uganda, prior to the introduction of anti-retroviral therapy (ART). METHODS: From a clinical cohort established in 1990, we selected records from HIV-infected women of reproductive age. We conducted two analyses: (1) all HIV-infected cases contributing to analysis of CD4 decline, using a linear regression model with random intercepts and slopes; (b) incident cases with known date of seroconversion contributed to analyses of median time to CD4 <200 cells/microl, AIDS and death. RESULTS: A total of 139 women were included in the analysis of CD4 decline. Women who subsequently became pregnant had higher CD4 counts at enrolment and had a slower CD4 decline than those who did not become pregnant. In women who became pregnant, CD4 decline was faster after pregnancy than before (P < 0.0001). The survival analyses showed no significant differences between women who became pregnant and those who did not with respect to median time to CD4 count <200, AIDS or death. CONCLUSIONS: The initial comparative immunological advantage possessed by fertile women before they become pregnant is subsequently lost as a result of their pregnancy. Women should be informed about the potential negative effect of pregnancy on their immunological status and should be offered contraception. In resource-limited settings, women determined to become pregnant should be given priority for ART if eligible.