The impact of human pulmonary tuberculosis (TB) on the bioenergetic metabolism of circulating immune cells remains elusive, as does the resolution of these effects with TB treatment. In this study, the rates of oxidative phosphorylation (OXPHOS) and glycolysis in circulating lymphocytes and monocytes of patients with drug-susceptible TB at diagnosis, 2 months, and 6 months during treatment, and 12 months after diagnosis were investigated using extracellular flux analysis. At diagnosis, the bioenergetic parameters of both blood lymphocytes and monocytes of TB patients were severely impaired in comparison to non-TB and non-HIV-infected controls. However, most bioenergetic parameters were not affected by HIV status or glycemic index. Treatment of TB patients restored the % spare respiratory capacity (%SRC) of the circulating lymphocytes to that observed in non-TB and non-HIV infected controls by 12 months. Treatment also improved the maximal respiration of circulating lymphocytes and the %SRC of circulating monocytes of the TB patients. Notably, the differential correlation of the clinical and bioenergetic parameters of the monocytes and lymphocytes from the controls and TB patients at baseline and month 12 was consistent with improved metabolic health and resolution of inflammation following successful TB treatment. Network analysis of the bioenergetic parameters of circulating immune cells with serum cytokine levels indicated a highly coordinated immune response at month 6. These findings underscore the importance of metabolic health in combating TB, supporting the need for further investigation of the bioenergetic immunometabolism associated with TB infection for novel therapeutic approaches aimed at bolstering cellular energetics to enhance immune responses and expedite recovery in TB patients.
The diagnostic gold standard for active tuberculosis (TB) is the detection of Mycobacterium tuberculosis (MTB) by culture or molecular methods. However, despite its limited sensitivity, sputum smear microscopy is still the mainstay of TB diagnosis in resource-limited settings. Consequently, diagnosis of smear-negative pulmonary and extrapulmonary TB remains challenging in such settings. A number of novel or alternative techniques could provide adjunctive diagnostic use in the context of difficult-to-diagnose TB. These may be especially useful in certain patient groups such as persons infected with human immunodeficiency virus (HIV) and children, who are disproportionably affected by smear-negative and extrapulmonary disease and who are also most adversely affected by delays in TB diagnosis and treatment. We review a selection of these methods that are independent of nucleic acid amplification techniques and could largely be implemented in resource-limited settings in current or adapted versions. Specifically, we discuss the diagnostic use and potential of serologic tests based on detection of antibodies to MTB antigens; interferon gamma release assays using site-specific lymphocytes; detection of lipoarabinomannan, a glycolipid of MTB, in urine; the string test, a novel technique to retrieve lower respiratory tract samples; and fine needle aspiration biopsy of lymph nodes.
Emergence of resistance to antifungal drugs during therapy for invasive aspergillosis has received scant attention. We recovered Aspergillus isolates from six patients with invasive aspergillosis, who were receiving amphotericin B before fungal isolation. Although isolates were susceptible to amphotericin B in vitro, none of the patients survived. The MIC of amphotericin B for isolates was similar to that for isolates from 35 patients with no prior exposure to amphotericin B. Laboratory attempts to produce amphotericin B resistance in Aspergillus were unsuccessful. These data indicate that emergence of resistance to amphotericin B is uncommon during therapy for invasive aspergillosis.
Abstract Purpose Elevated levels of inflammation associated with human immunodeficiency virus (HIV) infection are one of the primary causes for the burden of age‐related diseases among people with HIV (PWH). Circulating proteins can be used to investigate pathways to inflammation among PWH. Experimental design We profiled 73 inflammation‐related protein markers and assessed their associations with chronological age, sex, and CD4 + cell count among 87 black South African PWH before antiretroviral therapy (ART). Results We identified 1, 1, and 14 inflammatory proteins significantly associated with sex, CD4 + cell count, and age respectively. Twelve out of 14 age‐associated proteins have been reported to be associated with age in the general population, and 4 have previously shown significant associations with age for PWH. Furthermore, many of the age‐associated proteins such as CST5, CCL23, SLAMF1, MMP‐1, MCP‐1, and CDCP1 have been linked to chronic diseases such as cardiovascular disease and neurocognitive decline in the general population. We also found a synergistic interaction between male and older age accounting for excessive expression of CST5. Conclusions and clinical relevance We found that advanced age may lead to the elevation of multiple inflammatory proteins among PWH. We also demonstrated the potential utility of proteomics for evaluating and characterizing the inflammatory status of PWH.
Abstract Objectives Viral suppression (VS) is the hallmark of successful antiretroviral therapy (ART) programmes. We sought to compare clinic retention, virological outcomes, drug resistance and mortality between peri‐urban and rural settings in South Africa after first‐line ART. Methods Beginning in July 2014, 1000 (500 peri‐urban and 500 rural) ART‐naïve patients with HIV were enrolled and managed according to local standard of care. Clinic retention, virological suppression, virological failure (VF), genotypic drug resistance and mortality were assessed. The definition of VS was a viral load ≤1000 copies/ml. Time to event analyses were stratified by site, median age and gender. Kaplan–Meier curves were calculated and graphed with log‐rank modelling to compare curves. Results Based on 2741 patient‐years of follow‐up, retention and mortality did not differ between sites. Among all 1000 participants, 47%, 84% and 91% had achieved VS by 6, 12 and 24 months, respectively, which was observed earlier in the peri‐urban site. At both sites, men aged < 32 years had the highest proportion of VF (15.5%), while women aged > 32 years had the lowest, at 7.1% ( p = 0.018). Among 55 genotypes, 42 (76.4%) had at one or more resistance mutations, which did not differ by site. K103N (59%) and M184V (52%) were the most common mutations, followed by V106M and K65R (31% each). Overall, death was infrequent (< 4%). Conclusions No significant differences in treatment outcomes between peri‐urban and rural clinics were observed. In both settings, young men were especially susceptible to clinic attrition and VF. More effective adherence support for this important demographic group is needed to achieve UNAIDS targets.
Background: The fixed-dose combination of tenofovir (TDF), lamivudine (3TC), and dolutegravir (TLD) is now preferred first-line antiretroviral therapy (ART) for most adults with HIV in Sub-Saharan Africa. Yet, concerns remain about durability of TLD with high circulating resistance to 3TC and TDF and metabolic abnormalities observed in clinical trials. Limited programmatic data are available to describe the success of the TLD transition in the region. Methods: We established the DISCO cohort to quantify viral suppression and regimen tolerability during the TLD transition. We prospectively enrolled adults from public clinics in Uganda and South Africa who had been on non-nucleoside reverse transcriptase inhibitor-based ART for ≥6 months and were programmatically switched to TLD. We obtained demographics, medical history data, and plasma specimens at enrollment and week 24. We conducted retrospective HIV-1 RNA viral load (VL) testing using the Cepheid GeneXpert platform. Though both sites were interrupted by COVID-19, here we report complete week 24 results for the Uganda cohort. Results: We enrolled 500 participants (41% female) in Uganda. Median age was 47 years (IQR 40-53). Median ART duration was 8.8 years (IQR 5.7-12.2). The most common regimens prior to TLD switch were 3TC/TDF/efavirenz (44%) and 3TC/zidovudine/nevirapine (39%). Retrospective VL testing demonstrated that 95% (475/499) had VL 1,000 copies/mL at enrollment. 90% (448/500) completed week 24 visits, with 50 additional visits delayed during COVID-19, 1 disenrollment, and 1 death. By week 24, 1% (6/448) discontinued TLD due to side effects or clinician discretion. At week 24, 96% (432/448) had VL 1,000 copies/mL. Of those with week 24 VL >50 copies/mL, 31% (5/16) had detectable VL >50 copies/mL at enrollment, versus 3% (15/431) in those with suppressed VL at week 24 (χ2 p-value<0.001). Conclusion: The great majority of participants transitioned to TLD with an undetectable VL. Overall, we documented 86% suppression at week 24 after TLD switch in the midst of the COVID-19 pandemic and 96% suppression in those completing a week 24 visit. These data support early tolerability and efficacy of TLD transition in the public sector. However, detectable VL at switch predicted detectable VL at 24 weeks. Vigilance and programmatic monitoring are needed to ensure long-term durability of TLD.
Abstract Background The KwaZulu-Natal (KZN) province of South Africa has the highest prevalence of HIV infection in the world. Viral load (VL) testing is a crucial tool for clinical and programmatic monitoring. Within uMkhanyakude district, VL suppression rates were 91% among patients with VL data; however, VL performance rates averaged only 38·7%. The objective of this study was to determine if enhanced clinic processes and community outreach could improve VL monitoring within this district. Methods A packaged intervention was implemented at three rural clinics in the setting of the KZN HIV AIDS Drug Resistance Surveillance Study. This included file hygiene, outreach, a VL register and documentation revisions. Chart audits were used to assess fidelity. Outcome measures included percentage VL performed and suppressed. Each rural clinic was matched with a peri-urban clinic for comparison before and after the start of each phase of the intervention. Monthly sample proportions were modelled using quasi-likelihood regression methods for over-dispersed binomial data. Results Mkuze and Jozini clinics increased VL performance overall from 33·9% and 35·3% to 75·8% and 72·4%, respectively which was significantly greater than the increases in the comparison clinics (RR 1·86 and 1·68, p < 0·01). VL suppression rates similarly increased overall by 39·3% and 36·2% (RR 1·84 and 1·70, p < 0·01). The Chart Intervention phase showed significant increases in fidelity 16 months after implementation. Conclusions The packaged intervention improved VL performance and suppression rates overall but was significant in Mkuze and Jozini. Larger sustained efforts will be needed to have a similar impact throughout the province.
Genome-wide association studies (GWAS) of circulating metabolites have revealed the role of genetic regulation on the human metabolome. Most previous investigations focused on European ancestry, and few studies have been conducted among populations of African descent living in Africa, where the infectious disease burden is high (e.g., human immunodeficiency virus (HIV)). It is important to understand the genetic associations of the metabolome in diverse at-risk populations including people with HIV (PWH) living in Africa. After a thorough literature review, the reported significant gene−metabolite associations were tested among 490 PWH in South Africa. Linear regression was used to test associations between the candidate metabolites and genetic variants. GWAS of 154 plasma metabolites were performed to identify novel genetic associations. Among the 29 gene−metabolite associations identified in the literature, we replicated 10 in South Africans with HIV. The UGT1A cluster was associated with plasma levels of biliverdin and bilirubin; SLC16A9 and CPS1 were associated with carnitine and creatine, respectively. We also identified 22 genetic associations with metabolites using a genome-wide significance threshold (p-value < 5 × 10−8). In a GWAS of plasma metabolites in South African PWH, we replicated reported genetic associations across ancestries, and identified novel genetic associations using a metabolomics approach.
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