HIV-infected Participants Research Articles

Epidemiological studies of malaria parasite on HIV patients attending General Hospital Awo-Omamma, Oru East, Imo State,Nigeria

HIV and malaria are the two most prevalent and deadly diseases in the world. Malaria and HIV accounted for about 255 million cases in 2017, with malaria having 86% of this distribution and HIV having 14% of the distribution. Given the overlap of their geographic distribution and resultant rates of coinfection, interactions between the two diseases pose major public health problems. This study was aimed at investigating the epidemiology of malaria –HIV co-infection in respect to sex, age and its association with CD4+ count and viral load. 230 HIV sero-positive participants and 100 HIV sero-negative participants(control) were employed for this study. 52 (22.6%) of the HIV infected participants tested positive for malaria while only 9(9.0%) of the non-HIV participants tested positive to malaria. The prevalence of malarial infection in HIV positive individuals was higher in females (23.9%) than in males (18.5%). While in age group of 30-39 showed the highest prevalence (35.3%) of co-infection. A high prevalence of 47.7% was recorded with CD4+ below 200 cells/μl than 7.6% in participants with CD4+ greater than 200 cells/μl. A highprevalence (49.2%) was also detected in patients with viral load of above 10,000 copies/μl compared to that of those with viral load less than 10,000 copies/μl(12.6%). This study showed a high prevalence of malaria in HIV patients in Awo-Omamma,Oru East, Imo state. This should be considered a great concern to public health. Thus, more effort should be put in research to curb this health issue.

Associations Between Plasma Immunomodulatory and Inflammatory Mediators With VACS Index Scores Among Older HIV-Infected Adults on Antiretroviral Therapy.

The prevalence of age-related comorbidities is increased in people living with HIV, even in those well-controlled on combination antiretroviral therapy (ART). Persistent immune activation and inflammation may play pivotal roles in the pathogenesis; however, the burden of morbidities in the older HIV infected population may be exacerbated and driven by distinct mechanisms. In a cross sectional study of 45 HIV-infected participants 60 years or older, we examined the relationships between 14 immunomodulatory and inflammatory factors and the Veterans Aging Cohort Study (VACS) Index, a metric of multimorbidity and mortality comprised of age, CD4 count, hemoglobin, Fibrosis-4 [FIB-4], and estimated glomerular filtration rate [eGFR], by linear regression analysis. All participants were virally suppressed (<50 HIV RNA copies/mL), on ART, and primarily Caucasian (86.7%), and male (91.1%). Plasma levels of monocyte/macrophage-associated (neopterin, IP-10, sCD163, sCD14, and MCP-1) and glycan-binding immunomodulatory factors (galectin (Gal)-1, Gal-3, and Gal-9) were assessed, as well as inflammatory biomarkers previously linked to the VACS Index (i.e., CRP, cystatin C, TNF-α, TNFRI, IL-6, and D-dimer) for comparison. In regression analysis, higher VACS index scores were associated with higher levels of neopterin, cystatin C, TNFRI, and Gal-9 (all p < 0.05), potentially driven by correlations found with individual VACS components, including age, CD4 count, FIB-4, and eGFR. Gal-9, cystatin C, and TNFRI directly correlated with the extent of multimorbidity. Multiple correlations among markers were observed, suggesting an interplay of overlapping, but distinct, pathways. Collectively, in addition to cystatin C and TNFRI, both galectin-9 and neopterin, independently emerged as novel fluid markers of the VACS Index and burden of comorbidity and may further guide in understanding pathogenic mechanisms of age-related disorders in older HIV-infected individuals on suppressive ART.

Elevated liver stiffness without histological evidence of liver fibrosis in rural Ugandans.

Liver fibrosis may be assessed noninvasively with transient electrography (TE). Data on the performance of TE for detecting liver fibrosis in sub-Saharan Africa are limited. We evaluated the diagnostic accuracy of TE by performing liver biopsies on persons with liver fibrosis indicated by TE. We enrolled HIV-infected and HIV-uninfected participants with TE scores consistent with at least minimal disease (liver stiffness measurement [LSM]≥7.1kPa). Biopsies were performed and staged using the Ishak scoring system. A concordant result was defined using accepted thresholds for significant fibrosis by TE (LSM≥9.3kPa) and liver biopsy (Ishak score≥2). We used modified Poisson regression methods to quantify the univariate and adjusted prevalence risk ratios (PRR) of the association between covariates and the concordance status of TE and liver biopsy in defining the presence of liver fibrosis. Of 131 participants with valid liver biopsy and TE data, only 5 participants (3.8%) had Ishak score≥2 of whom 4 had LSM≥9.3kPa (sensitivity=80%); of the 126 (96.2%) with Ishak score<2, 76 had LSM<9.3kPa (specificity=61%). In multivariable analysis, discordance was associated with female gender (adjPRR=1.80, 95%CI 1.1-2.9; P=.019), herbal medicine use (adjPRR 1.64, 95% CI=1.0-2.5; P=.022), exposure to lake or river water (adjPRR 2.05, 95% CI=1.1-3.7; P=.016), and current smoking (adjPRR 1.72, 95%CI 1.0-2.9; P=.045). These data suggest that TE among rural Ugandans has low specificity for detection of histologically confirmed liver fibrosis. Caution should be exercised when using this tool to confirm significant liver fibrosis.

Elevated Plasma Levels of sCD14 and MCP-1 Are Associated With HIV Associated Neurocognitive Disorders Among Antiretroviral-Naive Individuals in Nigeria.

Mononuclear cells play key roles in the pathogenesis of HIV-associated neurocognitive disorders (HAND). Limited studies have looked at the association of markers of monocyte activation with HAND in Africa. We examined this association among HIV-1-infected patients in Nigeria. A total of 190 HIV-infected treatment-naive participants with immune marker data were included in this cross-sectional study. Plasma levels of soluble CD14 (sCD14), soluble CD163, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), and neopterin were measured. Demographically adjusted T scores obtained from a 7-domain neuropsychological test battery were generated, and functional status was assessed using activities of daily living questionnaire. Participants were classified as unimpaired, having asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD) in line with the "Frascati" criteria. Thirty-two participants (16.8%) had ANI, 14 (7.4%) had MND, whereas none had HAD. In multivariable linear regression analyses, after adjusting for age, gender, education, CD4 count, and viral load, mean levels of sCD14 were higher among those with ANI and MND as compared with the unimpaired (P = 0.033 and 0.023, respectively). Similarly, the mean level of MCP-1 was greater among those with HAND as compared with the unimpaired (P = 0.047). There were also trends for higher levels of sCD163 and TNF-α among females with MND in univariable analyses. Levels of monocyte activation markers correlate with the severity of impairment among individuals with HAND. The mechanisms that underlie these effects and the potential role of gender require further study.

4086 HIV-Associated Myocardial Diastolic Dysfunction and Soluble ST2 Concentration in Tanzanian Adults: A Cross-Sectional Study

OBJECTIVES/GOALS: To determine the prevalence of myocardial diastolic dysfunction (DD) and association of serum concentration of the cardiac biomarker serum soluble ST2 in HIV-infected as compared to uninfected Tanzanian adults at the time of HIV diagnosis. METHODS/STUDY POPULATION: In this cross-sectional study we consecutively enrolled HIV-infected participants and uninfected controls at a large, referral HIV clinic in Mwanza, Tanzania. Standardized history, physical examination, echocardiography and serum samples were obtained. The primary outcome was prevalence of myocardial diastolic dysfunction in HIV-infected as compared to uninfected adults. The secondary outcome was the association of baseline serum sST2 concentration with diastolic dysfunction prevalence. Regression models were used to quantify the associations. RESULTS/ANTICIPATED RESULTS: We enrolled 388 HIV-infected, ART naïve and 461 HIV-uninfected controls. Participants with HIV had a higher prevalence of DD (OR = 2.44, p = 0.001, controlled for age, sex, hypertension and BMI) and more severe dysfunction (66.7% vs 42.5%, p = 0.056) at an earlier age. Baseline serum sST2 concentration was significantly associated with DD in HIV-infected but not uninfected participants (p = 0.04 and 0.90, respectively). More HIV-infected adults with concurrent DD exceeded the threshold of 35ng/mL as compared to controls (15.7% vs 5.3%, p&lt;0.0001). Additionally, a significant population level shift to higher sST2 concentration was observed in HIV-infected adults with dysfunction as compared to both HIV-infected without and HIV-uninfected adults with dysfunction (Kolmogrov-Smirnov test: p = 0.02 and 0.04). DISCUSSION/SIGNIFICANCE OF IMPACT: In a large population of HIV-infected adults in sub-Saharan Africa, HIV infection is associated with myocardial diastolic dysfunction. This dysfunction is associated with higher sST2 concentrations. Therefore, we conclude that the sST2 pathway may provide insight into the pathophysiologic mechanisms of dysfunction in HIV-infected adults.

Changes in gastrointestinal microbial communities influence HIV-specific CD8+ T-cell responsiveness to immune checkpoint blockade.

The aim of this study was to examine the relationship between gut microbial communities in HIV-infected individuals on suppressive antiretroviral therapy (cART), and the peripheral HIV-Gag-specific CD8 T-cell responses before and after ex-vivo immune checkpoint blockade (ICB). Thirty-four HIV-seropositive, 10 HIV-seronegative and 12 HIV-seropositive receiving faecal microbiota transplant (FMT) participants were included. Gut microbial communities, peripheral and gut associated negative checkpoint receptors (NCRs) and peripheral effector functions were assessed. Bacterial 16s rRNA sequencing for gut microbiome study and flow-based assays for peripheral and gut NCR and their cognate ligand expression, including peripheral HIV-Gag-specific CD8 T-cell responses before and after ex-vivo anti-PD-L1 and anti-TIGIT ICB were performed. Fusobacteria abundance was significantly higher in HIV-infected donors compared to uninfected controls. In HIV-infected participants receiving Fusobacteria-free FMT, Fusobacteria persisted up to 24 weeks in stool post FMT. PD-1 TIGIT and their ligands were expanded in mucosal vs. peripheral T cells and dendritic cells, respectively. PD-L1 and TIGIT blockade significantly increased the magnitude of peripheral anti-HIV-Gag-specific CD8 T-cell responses. Higher gut Fusobacteria abundance was associated with lower magnitude of peripheral IFN-γ+ HIV-Gag-specific CD8 T-cell responses following ICB. The gut colonization of Fusobacteria in HIV infection is persistent and may influence anti-HIV T-cell immunity to PD-1 or TIGIT blockade. Strategies modulating Fusobacteria colonization may elicit a favourable mucosal immune landscape to enhance the efficacy of ICB for HIV cure.

HIV infection, and overweight and hypertension: a cross-sectional study of HIV-infected adults in Western Kenya

BackgroundNon-communicable diseases (NCDs) are increasing in Kenya, where HIV/AIDS remains a leading cause of death; however, few studies have investigated obesity and hypertension among adults with HIV infection. We conducted a cross-sectional study in Homa Bay, Western Kenya, during 2015 to determine the prevalence of overweight/obesity and hypertension among HIV-infected adults and to identify their risk factors.ResultsAnthropometric measurements and a structured questionnaire were administered to adults with HIV infection receiving care at Mbita Sub-county Hospital. A total of 251 HIV-positive individuals were enrolled. More women were overweight (17.2%) and obese (3.6%) than underweight (8.3%). The prevalence of abdominal obesity was high in women (62.7%), especially those aged 30–39 years. The prevalence of hypertension was 9.8% and 11.8% in men and women, respectively. Male participants tended to develop hypertension at an early age. Multivariate analysis showed that female sex was significantly associated with abdominal obesity. Regarding clinical factors, we identified an association between overweight and a history of opportunistic infections, as well as between hypertension and World Health Organization clinical stage. Sixty percent of HIV-infected participants assumed that a very thin body size indicated HIV infection.ConclusionsThe main findings of this study include a greater prevalence of overweight than underweight as well as a high prevalence of abdominal obesity among women. Social perception toward body size among people with HIV infection might remain problematic. Individuals living with HIV in Kenya should receive preventive intervention for overweight and abdominal obesity, with consideration of relevant social and cultural aspects.

Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir

BackgroundCabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure.ObjectivesTo investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks).MethodsPlasma cabotegravir PK was assessed in 346 UGT-genotyped participants with and without UGT1A1 functional variants across six studies (four Phase I and two Phase II) of oral cabotegravir, including 215 HIV-infected participants who received oral cabotegravir followed by cabotegravir LA. Changes from baseline in total bilirubin and ALT were assessed in one study (LATTE; NCT01641809).ResultsStatistically significant (P < 0.05) associations were observed between UGT1A1 genotype and plasma cabotegravir PK parameters, with 28%–50% increases following oral cabotegravir [plasma cabotegravir concentration at the end of the dosing interval (Ctau), 1.50-fold; AUCtau, 1.41-fold; and Cmax, 1.28-fold] and 16%–24% increases following cabotegravir LA administration (48 week Ctau, 1.24-fold; AUCtau, 1.16-fold; and Cmax, 1.18-fold) among those with low-versus-normal genetically predicted UGT1A1 activity. A statistically significant (P < 10−5) association between predicted UGT1A1 activity and maximum change in total bilirubin was also observed (2.45-fold asymptomatic increase for low versus normal) without a corresponding change in ALT.ConclusionsThis modest increase in oral and parenteral cabotegravir exposure associated with a reduced function of UGT1A1 is not considered clinically relevant based on accumulated safety data; no dose adjustment is required.

Predictors and Barriers to Condom Use in the African Cohort Study.

Consistent condom use is an inexpensive and efficacious HIV prevention strategy. Understanding factors associated with condom use and barriers to use can inform strategies to increase condom uptake. The ongoing African Cohort Study prospectively enrolls adults at 12 clinical sites in Uganda, Kenya, Tanzania, and Nigeria. At enrollment, participants are asked about condom use at last sex with a regular partner. Robust Poisson regression models were used to evaluate predictors of self-reported condom use. Participants who reported not using condoms were asked to provide reasons. From January 2013 to September 2019, 2482 participants reported having at least one regular sexual partner in the preceding 6 months. Of those, 1577 (63.5%) reported using a condom at last sex. Condom use was more common among older participants, males, HIV-infected participants, and those with an HIV-infected partner. Married participants, those with a partner of unknown HIV status, and those reporting alcohol use were less likely to report condom use at last sex. Condom use at last sex also varied significantly by clinical site. Partner disapproval or refusal to use a condom was a consistent driver of disparities in condom use among participants who were HIV infected, female, and aged 18-24 years. Effective HIV prevention programs should integrate condom education with the tools necessary to negotiate condom use with regular partners.

Diabetes prevalence by HbA1c and oral glucose tolerance test among HIV-infected and uninfected Tanzanian adults.

BackgroundThe burden of diabetes is increasing in sub-Saharan Africa, including among people living with HIV. We assessed the prevalence of diabetes and the roles of HIV, antiretroviral therapy (ART) and traditional risk factors among adults in Tanzania.MethodsWe analysed diabetes-relevant baseline data from 1,947 adult participants in the CICADA study in Mwanza, Tanzania: 655 HIV-uninfected, 956 HIV-infected ART-naïve, and 336 HIV-infected persons on ART. WHO guidelines for haemoglobin A1c (HbA1c) and oral glucose tolerance test (OGTT) were used to define diabetes and prediabetes. Risk factors were evaluated using multinomial logistic regression analysis. Relative risk ratios (RRR) were generated comparing participants with diabetes and prediabetes against the reference of those with no diabetes.ResultsMean age was 41 (SD 12) years; 59% were women. The prevalence of diabetes was 13% by HbA1c and 6% by OGTT, with partial overlap among participants identified by the two tests. Relative to HIV-uninfected, HIV-infected ART-naïve persons had increased relative risks of diabetes (HbA1c: RRR = 1.95, 95% CI 1.25–3.03; OGTT: RRR = 1.90, 95% CI 0.96–3.73) and prediabetes (HbA1c: RRR = 2.89, 95% CI 1.93–4.34; OGTT: RRR = 1.61, 95% CI 1.22–2.13). HIV-infected participants on ART showed increased risk of prediabetes (RRR 1.80, 95% CI 1.09, 2.94) by HbA1c, but not diabetes. CD4 count < 200 cell/μL at recruitment increased risk and physical activity decreased risk of diabetes by both HbA1c and OGTT.ConclusionsThe prevalence of diabetes was high, especially among HIV-infected ART-naïve adults. Being more physically active was associated with lower risk of diabetes. HbA1c and OGTT identified different participants as having diabetes or prediabetes. Overall, the finding of high burden of diabetes among HIV-infected persons suggests that health systems should consider integrating diabetes screening and treatment in HIV clinics to optimize the care of HIV patients and improve their health outcomes.

Preliminary Effects of a Mobile Interactive Supervised Therapy Intervention on People Living With HIV: Pilot Randomized Controlled Trial.

BackgroundAs people living with HIV infection require lifelong treatment, nonadherence to medication will reduce their chance of maintaining viral suppression and increase the risk of developing drug resistance and HIV transmission.ObjectiveThis study aimed to evaluate the efficacy of a mobile app, Mobile Interactive Supervised Therapy (MIST), for improving adherence to oral HIV medications among HIV-infected adults in Singapore.MethodsWe conducted a two-group pilot randomized controlled trial (RCT) with a process evaluation, in which 40 HIV-infected participants with once-daily medication regimes were recruited from a public tertiary hospital in Singapore and randomly assigned equally to either the intervention (receiving MIST and routine care) or control (receiving routine care only) groups. The intervention lasted for 2 months. The outcome of antiretroviral therapy (ART) adherence was measured by a 7-day recall self-report (SR), pill count (PC), an electronic medical device—Medication Event Monitoring System (MEMS)—and a mobile app—MIST (for the intervention group only). In total, 20 participants from the intervention group were interviewed at the end of the intervention to assess the acceptability of MIST. Data were collected at baseline and at 1-month and 2-month postintervention.ResultsAll participants had excellent medication adherence at baseline (median 100, IQR 100-100). The use of MIST did not result in a significant improvement in ART adherence when measured by the SR, PC, and MEMS, as compared with the control group at 1-month (P values >.99, .86, and .74, respectively) and 2-month (P values=.80, .84, and .82, respectively) postintervention. ART adherence also did not improve in each group over the same period. MIST was perceived to be a beneficial tool based on the process evaluation results.ConclusionsAlthough MIST did not enhance medication adherence to HIV treatments, mainly owing to the ceiling effect, it was perceived to be beneficial among the participants of this study. Our process evaluation provided useful data to further develop MIST for bigger and long-term mobile phone app–assisted intervention RCTs in the future.Trial RegistrationClinicalTrials.gov NCT03794648; https://clinicaltrials.gov/ct2/show/NCT03794648

DCas9 Targeted Chromatin and Histone Enrichment for Mass Spectrometry (Catchet-MS) Identifies IKZF1 as a Novel Drug-Able Target for HIV-1 Latency Reversal

A major pharmacological strategy for HIV cure aims to reverse latency in infected cells to promote reservoir eradication. While the unbiased identification of putative molecular targets physically associated with the latent HIV-1 promoter would be crucial for the development of latency reversal drugs, due to technical limitations, this has not been possible. Here we use dCas9 targeted chromatin and histone enrichment strategy coupled to mass spectrometry (Catchet-MS) to isolate and identify the locus-bound protein complexes on the latent and activated HIV-1 promoter. Catchet-MS identified both known and novel host factors distinctly associated with the latent HIV-1 5’LTR. Among these, IKZF1 is a novel transcriptional repressor of HIV-1 required for latency. We find the drug iberdomide, which targets IKZF1 for degradation, to be a clinically advanced novel LRA that reverses latency in latent ex vivo HIV-1 infected primary CD4+ T cells and in cells isolated from virally suppressed HIV-1 infected participants.

N-Acetyltransferase 2 Genotypes among Zulu-Speaking South Africans and Isoniazid and N-Acetyl-Isoniazid Pharmacokinetics during Antituberculosis Treatment.

The distribution of N-acetyltransferase 2 gene (NAT2) polymorphisms varies considerably among different ethnic groups. Information on NAT2 single-nucleotide polymorphisms in the South African population is limited. We investigated NAT2 polymorphisms and their effect on isoniazid pharmacokinetics (PK) in Zulu black HIV-infected South Africans in Durban, South Africa. HIV-infected participants with culture-confirmed pulmonary tuberculosis (TB) were enrolled from two unrelated studies. Participants with culture-confirmed pulmonary TB were genotyped for the NAT2 polymorphisms 282C>T, 341T>C, 481C>T, 857G>A, 590G>A, and 803A>G using Life Technologies prevalidated TaqMan assays (Life Technologies, Paisley, UK). Participants underwent sampling for determination of plasma isoniazid and N-acetyl-isoniazid concentrations. Among the 120 patients, 63/120 (52.5%) were slow metabolizers (NAT2*5/*5), 43/120 (35.8%) had an intermediate metabolism genotype (NAT2*5/12), and 12/120 (11.7%) had a rapid metabolism genotype (NAT2*4/*11, NAT2*11/12, and NAT2*12/12). The NAT2 alleles evaluated in this study were *4, *5C, *5D, *5E, *5J, *5K, *5KA, *5T, *11A, *12A/12C, and *12M. NAT2*5 was the most frequent allele (70.4%), followed by NAT2*12 (27.9%). Fifty-eight of 60 participants in study 1 had PK results. The median area under the concentration-time curve from 0 to infinity (AUC0-∞) was 5.53 (interquartile range [IQR], 3.63 to 9.12 μg h/ml), and the maximum concentration (Cmax) was 1.47 μg/ml (IQR, 1.14 to 1.89 μg/ml). Thirty-four of 40 participants in study 2 had both PK results and NAT2 genotyping results. The median AUC0-∞ was 10.76 μg·h/ml (IQR, 8.24 to 28.96 μg·h/ml), and the Cmax was 3.14 μg/ml (IQR, 2.39 to 4.34 μg/ml). Individual polymorphisms were not equally distributed, with some being represented in small numbers. The genotype did not correlate with the phenotype, with those with a rapid acetylator genotype showing higher AUC0-∞ values than those with a slow acetylator genotype, but the difference was not significant (P = 0.43). There was a high prevalence of slow acetylator genotypes, followed by intermediate and then rapid acetylator genotypes. The poor concordance between genotype and phenotype suggests that other factors or genetic loci influence isoniazid metabolism, and these warrant further investigation in this population.

Tuberculosis in HIV-Associated Cryptococcal Meningitis is Associated with an Increased Risk of Death.

Tuberculosis (TB) and cryptococcal meningitis are leading causes of morbidity and mortality in advanced HIV disease. Data are limited on TB co-infection among individuals with cryptococcal meningitis. We performed a retrospective analysis of HIV-infected participants with cryptococcal meningitis from 2010–2017. Baseline demographics were compared between three groups: ‘prevalent TB’ if TB treated >14 days prior to cryptococcal meningitis diagnosis, ‘concurrent TB’ if TB treated ± 14 days from diagnosis, or ‘No TB at baseline’. We used time-updated proportional-hazards regression models to assess TB diagnosis as a risk for death. Of 870 participants with cryptococcal meningitis, 50 (6%) had prevalent TB, 67 (8%) had concurrent TB, and 753 (86%) had no baseline TB. Among participants without baseline TB, 67 (9%) were diagnosed with incident TB (after >14 days), with a median time to TB incidence of 41 days (IQR, 22–69). The 18-week mortality was 50% (25/50) in prevalent TB, 46% (31/67) in concurrent TB, and 45% (341/753) in the no TB group (p = 0.81). However, TB co-infection was associated with an increased hazard of death (HR = 1.75; 95% CI, 1.33–2.32; p < 0.001) in a time-updated model. TB is commonly diagnosed in cryptococcal meningitis, and the increased mortality associated with co-infection is a public health concern.

Assessing the Suitability of Next-Generation Viral Outgrowth Assays to Measure Human Immunodeficiency Virus 1 Latent Reservoir Size.

BackgroundEvaluations of human immunodeficiency virus (HIV) curative interventions require reliable and efficient quantification of replication-competent latent reservoirs. The “classic” quantitative viral outgrowth assay (QVOA) has been regarded as the reference standard, although prohibitively resource and labor intensive. We compared 6 “next-generation” viral outgrowth assays, using polymerase chain reaction or ultrasensitive p24 to assess their suitability as scalable proxies for QVOA.MethodsNext-generation QVOAs were compared with classic QVOA using single leukapheresis-derived samples from 5 antiretroviral therapy–suppressed HIV-infected participants and 1 HIV-uninfected control; each laboratory tested blinded batches of 3 frozen and 1 fresh sample. Markov chain Monte Carlo methods estimated extra-Poisson variation at aliquot, batch, and laboratory levels. Models also estimated the effect of testing frozen versus fresh samples.ResultsNext-generation QVOAs had similar estimates of variation to QVOA. Assays with ultrasensitive readout reported higher infectious units per million values than classic QVOA. Within-batch testing had 2.5-fold extra-Poisson variation (95% credible interval [CI], 2.1–3.5-fold) for next-generation assays. Between-laboratory variation increased extra-Poisson variation to 3.4-fold (95% CI, 2.6–5.4-fold). Frozen storage did not substantially alter infectious units per million values (−18%; 95% CI, −52% to 39%).ConclusionsThe data offer cautious support for use of next-generation QVOAs as proxies for more laborious QVOA, while providing greater sensitivities and dynamic ranges. Measurement of latent reservoirs in eradication strategies would benefit from high throughput and scalable assays.

Detection of &lt;i&gt;M. tuberculosis&lt;/i&gt; DNA in CD34-Positive Peripheral Blood Mononuclear Cells of Asymptomatic TB Contacts

Background: Haematopoietic stem cells expressing the CD34 surface marker have been posited as a niche for M. tuberculosis complex (MTBC) bacilli during latent tuberculosis infection (LTBI). Methods: We conducted a cross-sectional study in Ethiopia to determine whether MTBC DNA was detectable in peripheral blood mononuclear cells (PBMC) isolated from 100 ml blood taken from 197 asymptomatic adults with a history of recent household TB contact and/or HIV infection, using digital polymerase chain reaction (dPCR). A nested prospective study was conducted in a sub-set of 43 HIV-infected individuals to evaluate whether administration of isoniazid preventive therapy (IPT) was effective in clearing MTBC DNA from PBMC. Results: MTBC DNA was detected in PBMC of 156/197 participants (79.2%; 95% CI 73.5% to 84.9%). Where present, it was found more frequently in CD34-positive vs. CD34-negative PBMC (154/155 [99.4%] vs. 46/155 [29.7%], P<0.001). Prevalence of dPCR-detected MTBC DNA did not differ between QuantiFERON-negative vs. QuantiFERON-positive participants (77/99 [77.8%] vs. 79/98 [80.6%], P=0.73), but it was higher in HIV-infected vs. HIV-uninfected participants (67/75 [89.3%] vs. 89/122 [73.0%], P=0.006). By contrast, the proportion of QuantiFERON-positive participants was lower in HIV-infected vs. HIV-uninfected participants (25/75 [33.3%] vs. 73/122 [59.8%], P<0.001). Administration of IPT reduced prevalence of dPCR-detected MTBC DNA from 41/43 (95.3%) at baseline to 23/43 (53.5%) post-treatment (P<0.001), but it did not influence prevalence of QuantiFERON-positivity (17/43 [39.5%] at baseline vs. 13/43 [30.2%] post-treatment; P=0.13). Conclusions: We report a novel molecular microbiological biomarker of LTBI with properties that are distinct from those of a commercial interferon-gamma release assay. Our findings implicate the bone marrow as a niche for M. tuberculosis in latently infected individuals. Detection of MTBC DNA in PBMC has potential applications in the diagnosis of LTBI, in monitoring response to chemoprophylaxis and as an outcome measure in clinical trials of interventions to prevent or treat LTBI. Funding Statement: This work was supported by a grant from the United Kingdom Medical Research Council (Reference Number MR/P024548/1, to ARM). SF and STR acknowledge support from the Cambridge NIMR BRC antibiotic resistance theme. JM acknowledges support from the DELTAS Africa Initiative (ref DEL-15-011, via THRiVE-2). JFH, GJ and DMO’S acknowledge support from the UK government Department for Business, Energy & Industrial Strategy (BEIS). Declaration of Interests: STR has a pending patent that is relevant to the work. All other authors have no competing interests to declare. Ethics Approval Statement: The study was approved by the Ethiopian National Research Ethics Review Committee, Addis Ababa, Ethiopia (ref 310/253/2017). Written informed consent was obtained from all participants.

Age-related visual dynamics in HIV-infected adults with cognitive impairment.

ObjectiveTo investigate whether aging differentially affects neural activity serving visuospatial processing in a large functional neuroimaging study of HIV-infected participants and to determine whether such aging effects are attributable to differences in the duration of HIV infection.MethodsA total of 170 participants, including 93 uninfected controls and 77 HIV-infected participants, underwent neuropsychological assessment followed by neuroimaging with magnetoencephalography (MEG). Time-frequency analysis of the MEG data followed by advanced image reconstruction of neural oscillatory activity and whole-brain statistical analyses were used to examine interactions between age, HIV infection, and cognitive status. Post hoc testing for a mediation effect of HIV infection duration on the relationship between age and neural activity was performed using a quasi-Bayesian approximation for significance testing.ResultsCognitively impaired HIV-infected participants were distinguished from unimpaired HIV-infected and control participants by their unique association between age and gamma oscillations in the parieto-occipital cortex. This relationship between age and gamma was fully mediated by the duration of HIV infection in cognitively impaired participants. Impaired HIV-infected participants were also distinguished by their atypical relationship between alpha oscillations and age in the superior parietal cortex.ConclusionsImpaired HIV-infected participants exhibited markedly different relationships between age and neural responses in the parieto-occipital cortices relative to their peers. This suggests a differential effect of chronological aging on the neural bases of visuospatial processing in a cognitively impaired subset of HIV-infected adults. Some of these relationships were fully accounted for by differences in HIV infection duration, whereas others were more readily associated with aging.

HIV Prevalence and Factors Influencing the Uptake of Voluntary HIV Counseling and Testing among Older Clients of Female Sex Workers in Liuzhou and Fuyang Cities, China, 2016-2017: A Cross-Sectional Study.

Objective To compare the prevalence of HIV and associated factors for participating HIV voluntary counseling and testing (VCT) among older clients of female sex workers (CFSWs) in Liuzhou City and Fuyang City in China. Methods A cross-sectional study was conducted and the study employed 978 male CFSWs, aged 50 years and above from October 2016 to December 2017. All participants were required to complete a questionnaire and provide blood samples for HIV testing. Multivariate logistic regression analysis was used to analyze the influential factors of using VCT program and tested for HIV. Results The HIV infection prevalence rate was 1.2% and 0.5%, while 52.3% and 54.6% participants had ever utilized VCT service and tested for HIV in Liuzhou City and Fuyang City, respectively. The older CFSWs who ever heard of VCT program were more likely to uptake VCT program in both cities (ORLiuzhou = 2.224, ORFuyang = 2.421). Participants, whose marital status was married or cohabiting (ORLiuzhou = 0.548, ORFuyang = 0.495), who have stigma against individuals who are living with HIV/AIDS (ORLiuzhou = 0.273, ORFuyang = 0.371), whose monthly income is more than 500 yuan (ORLiuzhou = 0.622, ORFuyang = 0.600), and whose age is more than 60 years old (ORLiuzhou = 0.639, ORFuyang = 0.554), were less likely to visit VCT clinics. Those who are worried about HIV-infected participants were more likely to utilize VCT services in Fuyang City (AOR = 1.838, 95%CI : 1.146‐2.948). Conclusion Combine strategy will be needed to promote the utilization of VCT service, based on the socioeconomic characteristics of older male CFSWs in different cities of China.

Factors associated with high-risk low-level viremia leading to virologic failure: 16-year retrospective study of a Chinese antiretroviral therapy cohort

BackgroundLow level viremia (LLV) often occurs during antiretroviral therapy (ART) against HIV-1. However, whether LLV increases the risk of virologic failure (VF) is controversial because of the non-uniform definitions of LLV and VF.MethodsA long-term first line regimen ART cohort from 2002 to 2018 from Shenyang, northeast China, was retrospectively studied. All participants were followed up every 3 to 6 months to evaluate the treatment effect. The high-risk LLV subgroups leading to VF (with strict standards) were explored with Cox proportional hazards model and linear mixed-effect model. The association factors of high-risk LLV were further explored using multivariate logistic regression analyses.ResultsA total of 2155 HIV-1 infected participants were included; of these, 38.7% showed LLV. Both high level LLV (HLLV) and any other level LLV coupled with high level blip (HLB) showed higher risk of VF (hazards ratios, HRHLLV = 5.93, and HRHLB = 2.84, p < 0.05 respectively). Moreover, HR increased with prolonged duration of LLV. Independent factors associated with high-risk LLV included the zenith baseline viral load (VL) above 6 log copies/ml (aOR = 3.49, p = 0.002), nadir baseline CD4 + T cell counts below 200 cells/mm3 (aOR = 1.78, p = 0.011), Manchu (aOR = 2.03, p = 0.003), ART over 60 months (aOR = 1.81, p = 0.004), AZT + 3TC + NVP (aOR = 2.26, p < 0.001) or DDI-based regimen (aOR = 9.96, p = 0.002), and subtype B′ infection (aOR = 8.22, p = 0.001).ConclusionsIn case of VF with strict standards, high-risk LLV leading to VF includes VL above 400 copies/ml, occurring at least once. Serious laboratory indicators or advanced stage of infection, long term ART and subtype B′ infection might also predict the occurrence of high-risk LLV.

Heart Rate Variability, HIV and the Risk of Cardiovascular Diseases in Rural South Africa

Background:Antiretroviral therapy (ART) transformed human immunodeficiency virus (HIV) infection into a chronic disease. Possible HIV-associated complications have emerged including cardiovascular diseases (CVD).Objectives:This study aims to determine the heart rate variability (HRV) distribution and association between HRV and HIV treated with ART in a rural African population.Methods:This cross-sectional study included 325 participants of the Ndlovu Cohort Study, South Africa. HRV was measured using a standardized five-minute resting ECG and assessed by the standard deviation of normal RR intervals (SDNN), root of mean squares of successive RR differences (RMSSD), percentage of RR intervals greater than 50 milliseconds different from its predecessor (pNN50), total-, low- and high-frequency power. CVD risk factors were assessed using measurements (blood pressure, anthropometry, cholesterol) and questionnaires (e.g. socio-demographics, alcohol, smoking, physical activity, age, diabetes). We used a Wilcoxon rank test to assess differences in medians between HIV-infected and HIV-uninfected participants and multivariable linear regression to investigate associations between HRV and HIV treated with ART.Conclusions:Of the participants, 196 (61.4%) were HIV-infected treated with ART and 123 (38.6%) were HIV-uninfected. HIV-infected consumed less alcohol, 52% versus 35%, smoked less, were less physically active, more often attained lower education, 26% versus 14%, and had lower systolic blood pressure, 134 mmHg versus 140 mmHg, compared to HIV-uninfected. Medians of all HRV parameters were lower for HIV-infected participants. The model fully adjusted for CVD risk factors showed a significant inverse association between HIV treated with ART and log RMSSD (–0.16) and log pnn50 (–0.61). Although HIV-infected participants treated with ART presented with less CVD risk factors they had a lower HRV indicating an increased risk of CVD.Highlights– African HIV-infected participants on ART had less conventional CVD risk factors than HIV-uninfected.– However, HIV-infected participants had lower HRV than HIV-uninfected participants.– Lower HRV of the HIV-infected participants indicates that they are at a higher risk for CVD.