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In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis. Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case-control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0-4.1; p = 0.05), 8.3 (95% CI, 3.3-20.8; p < 0.0001), and 12.4 (95% CI, 4.2-37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case-control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1-3.1; p = 0.02) to 1.5 (95% CI, 0.8-2.8) and 1.4 (95% CI, 0.8-2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively. IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation.

Mycoplasma genitalium (MG) is a cause of urethritis. While resistance to azithromycin is increasing, routine detection of MG is not performed in Belgium, where its prevalence is unknown. The aim of this study is to determine prevalence of MG in men with urethritis. An \"in-house\" amplification assay detecting MG was performed on urine of men with complaints of urethritis who consulted the emergency unit or the Sexually Transmitted Infection clinic of our public hospital in Brussels. Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) were tested on the same sample. A total of 187 men were tested. Prevalence of MG was 9% (95% Confidence Interval: 5 to 13.2%). CT was detected in 20%, NG in 22% and 56% of samples were negative for these three pathogens. Neither age, ethnic origin, sexual orientation nor HIV infection were associated with MG urethritis. M. genitalium was identified in 9% of men with complaints of urethritis indicating that amplification assay detecting MG should be implemented in routine testing for those patients.

Treatment of Helicobacter pylori infection in people living with HIV is associated with several challenges, including those related to drug metabolism which plays a major role in treatment efficacy. In this review, we will discuss the enzymes involved in the metabolism of anti-Helicobacter pylori and anti-HIV drugs to provide a basis for understanding the potential for interactions between these drug classes. We will also provide a clinical perspective on other issues related to the treatment of Helicobacter pylori and HIV infections such as comorbidities, adherence, and peer communication. Finally, based on our understanding of the interplay between the above issues, we propose a new concept “Antimicrobial susceptibility testing-drug interaction-supports-referent physician” (AISR), to provide a framework for improving rates of H. pylori eradication in people living with HIV.

Objective: Helicobacter pylori and human immunodeficiency virus (HIV) are both pandemic infections with variable geographic prevalence rates. H. pylori–HIV co-infection at the regional and sub-regional levels with a perspective on gastric cancer incidence is discussed. Design: Based on PRISMA guidelines, national data for H. pylori, HIV, and H. pylori–HIV co-infection were collected for the general population through December 2019. Joint temporal and geographical data for H. pylori and HIV infections in 48 countries were available and used to generate H. pylori–HIV co-infection estimates by cross-sectional analysis. These data were compared with gastric carcinoma statistics for the same countries. Results: The estimated global prevalence rate of H. pylori–HIV co-infection was 1.7 per 1000 people, representing 12.6 million people. Prevalence according to region was, in decreasing order, sub-Saharan Africa 21.9‰, Eastern Europe/Central Asia 4.3‰, Latin America/Caribbean 2.0 ‰, North America/Western/Southern/Northern Europe 1.1‰, Asia/Pacific 0.8‰, and North Africa/Middle East 0.1 ‰. The incidence and mortality rates for gastric carcinoma were higher in East/Pacific Asia, Southern/Andean Latin America, and Eastern Europe regions, and the incidence appeared to be 1.8-fold greater in H. pylori–HIV-infected people in East Asia. Conclusions: The population at risk of H. pylori–HIV co-infection is estimated to be 12.6 million people (2015 reference year). The heterogeneity of H. pylori–HIV co-infection across regions and sub-regions does not show a clear association with gastric carcinoma. Other methodological approaches with analytical studies (cohort, case–control) are required to measure the potential effect of H. pylori infection and its treatment on the incidence of gastric carcinoma in the large HIV–H. pylori-positive cohort.

Background Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004–2010, and described subsequent mortality and predictors of these. Methods Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient’s last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient’s death, 1st February 2010 or 6 months after the patient’s last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression. Results Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin’s lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004–2010 in this large observational cohort. Conclusions The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC.

With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. 3909 of the 49 731 D:A:D study participants died during the 308 719 person-years of follow-up (crude incidence mortality rate, 12·7 per 1000 person-years [95% CI 12·3–13·1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17·5 in 1999–2000 to 9·1 in 2009–11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5·9 to 2·0), deaths from liver disease (2·7 to 0·9), and cardiovascular disease deaths (1·8 to 0·9). However, non-AIDS cancers increased slightly from 1·6 per 1000 person-years in 1999–2000 to 2·1 in 2009–11 (p=0·58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009–11 vs 1999–2000: 0·92 [0·70–1·22]). However, all-cause (0·72 [0·61–0·83]), liver disease (0·48 [0·32–0·74]), and cardiovascular disease (0·33 [0·20–0·53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999–2000 and 141/627 [22%] in 2009–11) and liver-related (40/256 [16%] in 1999–2000 and 64/627 [10%] in 2009–11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999–2000 to 142/627 [23%] in 2009–11). Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.

Despite efficient combination of the antiretroviral therapy (cART), which significantly decreased mortality and morbidity of HIV-1 infection, a definitive HIV cure has not been achieved. Hidden HIV-1 in cellular and anatomic reservoirs is the major hurdle toward a functional cure. Microglial cells, the Central Nervous system (CNS) resident macrophages, are one of the major cellular reservoirs of latent HIV-1. These cells are believed to be involved in the emergence of drugs resistance and reseeding peripheral tissues. Moreover, these long-life reservoirs are also involved in the development of HIV-1-associated neurocognitive diseases (HAND). Clearing these infected cells from the brain is therefore crucial to achieve a cure. However, many characteristics of microglial cells and the CNS hinder the eradication of these brain reservoirs. Better understandings of the specific molecular mechanisms of HIV-1 latency in microglial cells should help to design new molecules and new strategies preventing HAND and achieving HIV cure. Moreover, new strategies are needed to circumvent the limitations associated to anatomical sanctuaries with barriers such as the blood brain barrier (BBB) that reduce the access of drugs.

The persistence of latently infected cells in patients under combinatory antiretroviral therapy (cART) is a major hurdle to HIV-1 eradication. Strategies to purge these reservoirs are needed and activation of viral gene expression in latently infected cells is one promising strategy. Bromodomain and Extraterminal (BET) bromodomain inhibitors (BETi) are compounds able to reactivate latent proviruses in a positive transcription elongation factor b (P-TEFb)-dependent manner. In this study, we tested the reactivation potential of protein kinase C (PKC) agonists (prostratin, bryostatin-1 and ingenol-B), which are known to activate NF-κB signaling pathway as well as P-TEFb, used alone or in combination with P-TEFb-releasing agents (HMBA and BETi (JQ1, I-BET, I-BET151)). Using in vitro HIV-1 post-integration latency model cell lines of T-lymphoid and myeloid lineages, we demonstrated that PKC agonists and P-TEFb-releasing agents alone acted as potent latency-reversing agents (LRAs) and that their combinations led to synergistic activation of HIV-1 expression at the viral mRNA and protein levels. Mechanistically, combined treatments led to higher activations of P-TEFb and NF-κB than the corresponding individual drug treatments. Importantly, we observed in ex vivo cultures of CD8+-depleted PBMCs from 35 cART-treated HIV-1+ aviremic patients that the percentage of reactivated cultures following combinatory bryostatin-1+JQ1 treatment was identical to the percentage observed with anti-CD3+anti-CD28 antibodies positive control stimulation. Remarkably, in ex vivo cultures of resting CD4+ T cells isolated from 15 HIV-1+ cART-treated aviremic patients, the combinations bryostatin-1+JQ1 and ingenol-B+JQ1 released infectious viruses to levels similar to that obtained with the positive control stimulation. The potent effects of these two combination treatments were already detected 24 hours post-stimulation. These results constitute the first demonstration of LRA combinations exhibiting such a potent effect and represent a proof-of-concept for the co-administration of two different types of LRAs as a potential strategy to reduce the size of the latent HIV-1 reservoirs.

Abstract Background Data on seroconversion rates following yellow fever (YF) vaccine and effect of revaccination in people living with HIV (PLWH) are scarce. We aimed at determining key factors for seroconversion after YF vaccine in PLWH and the role of preexisting neutralizing antibodies (NAbs) at vaccination. Methods A retrospective cross-sectional study at several timepoints in two Belgian AIDS Reference Center. For each individual, plasma samples from three timepoints were selected: Timepoint 0 (TP0) in the year before administration of the YF vaccine, Timepoint 1 (TP1) in the year following the YF vaccine, Timepoint 2 (TP2) >1 year after the YF vaccine. Plasma samples were analysed for YF NAbs by plaque reduction neutralization test. The primary endpoint was the number of patients with protective levels of NAbs ≥ 1/10. A boosted immune response was defined as a 4-fold increase in serologic titres following revaccination. Results Of the 160 PLWH included, protective levels of NAbs were present in 36%, 87% and 72% of subjects at baseline, at a median of 12 months and a median of 96 months after YF vaccination, respectively. Among vaccine recipients negative for YF NAbs at baseline (n = 102), 83% seroconverted. PLWH with undetectable HIV viral load (VL) at baseline were more likely to seroconvert (P < 0·01). A booster response was observed in only 17% of subjects with baseline seropositivity (n = 10 out of 58). In multivariate analysis, undetectable HIV VL at vaccination and baseline YF seropositivity were associated with persistent levels of protective NAbs at a median of 8 years after YF vaccination. Conclusion Undetectable HIV VL at baseline is associated with high rates of seroconversion. YF seropositivity before revaccination is associated with low rates of booster effect but a higher chance of long term persistent NAbs response, suggesting a benefit of revaccination in PLWH.