Comorbidities of HIV infection: role of Nef-induced impairment of cholesterol metabolism and lipid raft functionality Combination antiretroviral therapy has dramatically changed the outcome of HIV infection, turning it from a death sentence to a manageable chronic disease. However, comorbidities accompanying HIV infection, such as metabolic and cardio-vascular diseases, as well as cognitive impairment, persist despite successful virus control by combination antiretroviral therapy and pose considerable challenges to clinical management of people living with HIV. These comorbidities involve a number of pathological processes affecting a variety of different tissues and cells, making it challenging to identify a common cause(s) that would link these different diseases to HIV infection. In this article, we will present evidence that impairment of cellular cholesterol metabolism may be a common factor driving pathogenesis of HIV-associated comorbidities. Potential implications for therapeutic approaches are discussed.

T cells with high PD-1 expression are associated with lower HIV-specific immune responses despite long-term antiretroviral therapy Objective: We evaluated frequencies of T cells with high PD-1 expression (PD-1HI) before and after long-term effective antiretroviral therapy (ART), and determined if frequencies on-ART correlated positively with measures of HIV persistence and negatively with HIV-specific responses. Methods: We enrolled individuals who started ART during chronic infection and had durable suppression of viremia for at least 4 years (N = 99). We assessed PD-1HI T-cell frequencies at timepoints pre-ART and on-ART using flow cytometry, and evaluated how frequencies on-ART are associated with measures of HIV persistence, HIV-specific immune responses, and immune activation levels. Results: Pre-ART, PD-1HI CD4+ T cells correlated positively with viremia and negatively with CD4+ T-cell count. At year 1 on-ART, %PD-1HI CD4+ T cells decreased but then remained stable at 4 and 6–15 years on-ART, whereas %PD-1HI CD8+ T cells on-ART remained similar to pre-ART. PD-1HI CD4+ T cells correlated positively with HIV DNA pre-ART and on-ART, and with CD4+ T-cell activation on-ART. PD-1HI CD4+ T cells negatively correlated with HIV Gag-specific and Env-specific T-cell responses but not with CMV-specific or EBV-specific responses. PD-1HI CD8+ T cells trended towards a negative correlation with responses to Gag and Env, but not to CMV and EBV. Conclusion: PD-1HI T cells persist in blood despite prolonged suppression on ART, correlate with HIV DNA levels, and are associated with lower HIV-specific T-cell responses but not CMV-specific or EBV-specific responses, suggesting that these cells are HIV-specific. The findings support evaluating PD-1 blockade strategies for their effect on HIV persistence and HIV-specific immunity.

Association of complement C3d receptor 2 genotypes with the acquisition of HIV infection in a trial of recombinant glycoprotein 120 vaccine Objectives: Complement C3d receptor 2 (CR2) is the main receptor for complement protein C3d and plays an important role in adaptive immune responses. CR2 genetic variants are associated with susceptibility to systemic lupus erythematosus as well as to HIV-1 infection. In addition, CR2 function can be subverted by HIV-1 for an efficient entry into target cells; in a process known as antibody-dependent enhancement of viral infection. We sought to determine the association between CR2 gene variants with HIV-1 acquisition after vaccination with recombinant gp120 protein (Vax004 clinical trial). Design and methods: This is a retrospective cross-sectional study, comprising male volunteers of European ancestry including infected (n = 273) and uninfected (n = 402) vaccinees and placebo, who were genotyped for three single nucleotide polymorphisms (SNPs) in the CR2 gene region. Results: An interaction was observed between the baseline sexual behavior and the SNP rs3813946 for higher risk of infection in vacinees (interaction term P = 0.02). This SNP was associated with increased susceptibility to HIV-1 infection after vaccination in volunteers with low behavioral risk odds ratio (95% confidence interval): 5.5 (1.4–21.7) P = 0.006 but not vaccinees with high behavioral risk or volunteers given placebo (P = 0.7). Moreover, CR2 genotype was strongly associated with the rate of HIV-1 acquisition after vaccination in low-risk volunteers [hazard odds ratio (95% confidence interval): 3.3 (1.6–7.0), P = 0.001]. Conclusion: The current study suggests that CR2 may play a role in HIV-1 acquisition after vaccination with rgp120 proteins.

High soluble CD163 levels correlate with disease progression and inflammation in Kenyan children with perinatal HIV-infection Objectives: CD163 is a hemoglobin scavenger receptor on monocytes and macrophages, cleaved to soluble CD163 (sCD163) in the plasma following activation. In HIV+ adults, sCD163 is linked to non-AIDS morbidity and predicts mortality, but there is limited data in children. We investigated sCD163 levels in HIV+ children and their correlations with disease progression, immune activation and gut mucosal damage. Design and methods: We quantified sCD163 levels in Kenyan children aged 0–20 years with perinatal HIV infection, including 74 antiretroviral treatment (ART)-naïve (ART−) and 64 virally suppressed on ART (ART+), and 79 HIV unexposed-uninfected controls (HIV−). The cohort was divided into age groups 0–5 (younger) and 5–20 (older) years. Correlations between sCD163 and HIV viral load, %CD8+, CD4+ : CD8+ ratio, markers of T-cell activation and proliferation, and gut mucosal damage were also assessed. Results: ART− children have higher sCD163 levels compared with HIV− and ART+ children (P ≤ 0.01); ART+ have equivalent sCD163 levels to HIV− children. In a prospective analysis, sCD163 levels decreased in older ART− children after 12 months of treatment (P < 0.0001). Regardless of age, sCD163 levels correlate with clinical disease progression measured by %CD4+ T cells, CD4+ : CD8+ T-cell ratios and HIV viral load. sCD163 levels directly correlate with T-cell activation markers CD38, human leukocyte antigen-DR isotype, and Ki67 (P ≤ 0.01). Conclusion: High plasma sCD163 levels in HIV+ children correlate with advancing disease and T-cell activation. ART initiation normalizes sCD163 levels and may alleviate HIV-related morbidities and improve long-term pediatric outcomes.

Female genital tract shedding of HIV-1 is rare in women with suppressed HIV-1 in plasma Objective: Determine the frequency of genital HIV-1 shedding in a large cohort of women on long-term suppressive antiretroviral therapy (ART) and its association with mucosal inflammation. Design: We measured levels of HIV-1 RNA and inflammation biomarkers in cervicovaginal lavage (CVL) from HIV-seropositive women enrolled in the Women's Interagency HIV Study (WIHS). Methods: HIV-1 was quantified (Abbott RealTime HIV-1 assay) from CVL samples of 332 WIHS participants with and without clinical evidence of genital inflammation at the time of CVL collection; participants had suppressed plasma viral load (PVL; limit of quantitation less than 20-4000 copies/ml depending on year of collection) for a median of 7.1 years [interquartile range (IQR) 3.4–9.8, Group 1] or for a median of 1.0 years (IQR = 0.5–1.0, Group 2). Twenty-two biomarkers of inflammation were measured in CVL to compare with clinical markers. Results: HIV-1 was detected in 47% of 38 pre-ART CVL samples (median 668 copies/ml) and detection in CVL was associated with higher pre-ART PVL. HIV-1 was detected in only 1 of 38 CVL samples from these women on suppressive antiretroviral therapy for 1 year. No HIV-1 RNA was detected in 294 CVL samples from a cross-sectional set of women with suppressed PVL for a median of 7 years. Clinical inflammation markers were correlated with inflammatory biomarkers in CVL specimens, although genital inflammation was not associated with measurable genital HIV-1 shedding in these WIHS participants on ART. Conclusion: ART that suppresses HIV-1 in the plasma of women also prevents genital tract HIV-1 shedding, even in the presence of genital tract inflammation.

Early diagnosis and risk factors of acute hepatitis C in high-risk MSM on preexposure prophylaxis Background: A high incidence of acute hepatitis C virus (HCV) (AHCV) infection has been reported among at-risk HIV-negative MSM. The optimal strategy for early diagnosis of AHCV in this population is not clearly defined. Methods: In the ANRS IPERGAY PrEP trial, among high-risk HIV-negative MSM, HCV serology and serum alanine aminotransferase (ALT) were used for screening at enrollment and during follow-up. Behavioral risk factors were compared at baseline between participants who were diagnosed with AHCV during the study compared with those who did not. In participants with a positive HCV serology, we used stored sera to perform the following tests at diagnosis and on previous visits: HCV-antibodies rapid tests, plasma HCV viral load and HCV antigen immunoassay. We evaluated the sensitivity of each test for AHCV diagnosis. Results: Among 429 enrolled participants, 14 were diagnosed with AHCV infection, with a median follow-up of 2.1 (interquartile range, 1.5–2.8) years. AHCV incidence was 1.40 per 100 person-years (95% confidence interval, 0.74–2.39). Patients with AHCV reported a significantly higher number of sexual acts and/or partners, and more frequent recreational drug use at baseline. At the prior visit before AHCV diagnosis (median of 2 months earlier), sensitivities of HCV RNA and HCV antigen tests were, respectively, 100 and 89%, whereas none of the patients had a positive serology, and only 25% had elevated ALT. Conclusion: HCV antigen and RNA tests were positive within a median of 2 months before the detection of antibodies and ALT elevation. These tests could be considered for HCV screening in high-risk MSM.

Switching from efavirenz to rilpivirine improves sleep quality and self-perceived cognition but has no impact on neurocognitive performances Background: Efavirenz (EFV) association with neurocognitive impairment is debated. Whether switching away from EFV improves neurocognitive performances is still controversial. Methods: In a randomized open-label controlled trial, patients under effective treatment with tenofovir disoproxil-fumarate (TDF), emtricitabine (FTC) and EFV, who had altered neurocognitive assessment (z-transformed score below −1 in at least one cognitive domain), depression, anxiety or low sleep-quality, were randomized 1 : 1 to immediate or delayed (24-weeks) switch to TDF/FTC/rilpivirine (RPV). Treatment efficacy, neurocognitive function, symptoms and quality of life were evaluated 12, 24 and 48 weeks after randomization. Findings: Seventy-four patients were randomized to immediate (36 patients) or delayed switch (38 patients). At baseline, 63 and 25% of patients had z-scores below −1 in at least one or two neurocognitive domains, 31.1, 17.6 and 44.6% had significant depression or anxiety symptoms or low sleep quality. At week 24 (primary end-point), overall neurocognitive improvement was observed, with no statistically significant differences between arms, neither considering the global z score (between arms difference +0.1; P = 0.458), nor domain-specific z scores. Patients switching away from EFV had significant greater improvement of sleep quality index (between-arm difference −1.5; P = 0.011), self-reported cognitive failures (−6.2; P = 0.001) and CNS symptoms score (−5; P = 0.002), but not of anxiety or depression. No protocol defined virological failure, grade at least 3 lab abnormalities or drug-related serious adverse events were reported. Conclusion: Our results do not support the hypothesis that switching to RPV improves cognitive function in patient under stable treatment with EFV. Nonetheless, improvements in neuropsychiatric symptoms, sleep quality and self-perceived cognition were observed.

Adherence to tuberculosis preventive therapy measured by urine metabolite testing among people with HIV Objectives: Tuberculosis preventive therapy for people living with HIV is effective, widely recommended, and increasingly prescribed, but completion rates are less than ideal, and adherence is not typically monitored. We sought to quantify adherence to isoniazid preventive therapy using a urine metabolite assay. Design: Two cross-sectional surveys. Setting: Rio de Janeiro, Brazil, 2008–2009; and Northwest Province, South Africa, 2018–2019. Participants: Two hundred and three Brazilian and 93 South African patients attending HIV clinics with active prescriptions for isoniazid preventive therapy Main outcome measures: Self-reported isoniazid adherence, paired with semiquantitative measurement of urine isoniazid metabolites. Results: By self-report, 90% of patients [95% confidence interval (CI) 86–93%] reported having taken a dose of isoniazid on the day of enrollment or the preceding day, and 91% (95% CI 87–94%) reported missing an average of one dose or fewer per week. By urine testing, only 65% (95% CI 59–70%) of all patients, and 69% (95% CI 63–74%) of those who reported having taken isoniazid on the current or preceding day, had detectable urine metabolites (expected in 95% of patients at 24 h). Longer time since starting preventive therapy was independently associated with a negative urine test for isoniazid metabolites (adjusted prevalence ratio 1.11 per month of isoniazid, 95% CI 1.05–1.18). Conclusion: Adherence to isoniazid preventive therapy among patients with HIV in Brazil and South Africa is inadequate, is overestimated by self-report, and declines with time on treatment. Shorter regimens for TB preventive therapy may improve adherence and completion, but adherence support for all patients may be necessary.

Longitudinal assessment of abnormal Papanicolaou test rates among women with HIV Objective: To describe longitudinal changes in the prevalence of abnormal Papanicolau testing among women living with HIV. Design: Prospective cohort study with sequential enrollment subcohorts. Methods: Four waves of enrollment occurred in the Women's Interagency HIV Study, the US women's HIV cohort (1994–1995, 2001–2002, 2011–2012, 2013–2015). Pap testing was done at intake, with colposcopy prescribed for any abnormality. Rates of abnormal Pap test results (atypical squamous cells of uncertain significance or worse) and cervical intraepithelial neoplasia grade 2 (CIN2) or worse were calculated. Logistic regression models assessed changes in prevalence across cohorts after controlling for severity of HIV disease and other risk factors for abnormal Pap tests. Results: The unadjusted prevalence of any Pap abnormality was 679/1769 (38%) in the original cohort, 195/684 (29%) in the 2001–2002 cohort, 46/231 (20%) in the 2011–2012 cohort, and 71/449 (16%) in the 2013–2015 cohort. In multivariable analysis, compared with risk in the 1994–1995 cohort, the adjusted risk in the 2001–2002 cohort was 0.79 (95% CI 0.59–1.05), in the 2011–2012 cohort was 0.67 (95% CI 0.43–1.04), and in the 2013–2015 cohort was 0.41 (95% CI 0.27–0.62) with P for trend less than 0.0001. Conclusion: Rates of abnormal cytology among women with HIV have fallen during the past two decades.

Clinical and procedural characteristics of persons living with HIV presenting with acute coronary syndrome Objectives: Persons living with HIV (PLWH) are at greater risk for acute coronary syndrome (ACS). Practice patterns of ACS management by HIV serostatus are unknown. We examined the presentation and management of ACS in PLWH. Design: Retrospective case–control study. Methods: We included 86 PLWH and 263 sex-matched and race-matched HIV-negative controls hospitalized with ACS between 2004 and 2013. We performed multivariable conditional logistic regression to determine the associations between HIV serostatus and ACS type and management. Results: Both groups were predominantly of black race and male sex. PLWH were significantly younger (53 vs. 60 years) and more likely to smoke (48 vs. 31%). Among PLWH, 30% had CD4+ cell count less than 200 cells/μl and 58% had undetectable HIV RNA. PLWH had more single-vessel disease and a higher median Gensini score among those with single-vessel disease (32 vs. 4.25) than controls. HIV serostatus was positively associated with ST-elevation myocardial infarction (STEMI) [adjusted odds ratio (aOR) (95% confidence interval (CI)):5.05 (1.82–14.02)], and any revascularization procedure after ACS [aOR (95% CI): 2.90 (1.01–8.39)] and negatively associated with non-STEMI [aOR (95% CI): 0.33 (0.14–0.79)] presentation. PLWH who underwent stent placement had a higher likelihood of bare metal stent placement compared with controls [70 vs. 15%, aOR (95% CI): 5.94 (1.33–26.55)]. Among PLWH, ACS characteristics were not significantly associated with CD4+ cell count, HIV RNA, or antiretroviral therapy. Conclusion: PLWH hospitalized with ACS were more likely to have severe single-vessel disease, present with STEMI rather than non-STEMI, and undergo revascularization, and less likely to have a drug-eluting stent placed than matched HIV-negative controls, suggesting that coronary plaque morphology and/or distribution is different with HIV infection and warrants further investigation.