Incidence and risk factors for suicide, death due to substance use, and violent/accidental death in people with HIV.

OBJECTIVE: Deaths due to suicide, substance use and violence/accident may reflect similar risk factors and overlap in their classification. This study aimed to investigate incidence and risk factors of mortality among people with HIV (PWH) due to these three related causes. DESIGN: Prospectively collected data from PWH at least 18 years old and under active follow-up in the EuroSIDA study from 2007 to 2019 were analysed. METHODS: Cause-specific Cox regression analysis was used to assess risk factors. RESULTS: A total of 17 881 participants were included, comprising 149 327 person-years of follow-up (PYFU). Forty participants died by suicide {incidence rate [IR] [95% confidence interval (CI)]: 0.3/1000 PYFU (0.2, 0.4)} 93 from substance use [IR (95% CI): 0.6/1000 PYFU (0.5, 0.8)], and 57 by violence/accident [IR (95% CI): 0.4/1000 PYFU (0.3, 0.5)]. An AIDS diagnosis within the last 12 months was associated with nine-fold increased risk of suicide vs. no history of AIDS [adjusted hazard ratio (aHR): 9.06; 95% CI: 2.07, 39.7]. Male gender was associated with double the risk of violent/accidental death (aHR: 2.28; 95% CI: 1.09, 4.78). PWH in Eastern Europe and those who acquired HIV by injection drug use (IDU) demonstrated a greater risk of death due to substance use or violence/accident. CONCLUSIONS: The association between a recent diagnosis of AIDS and suicide highlights a critical period for intervention. HIV infection acquired through IDU demonstrated an expected relationship with death due to substance use and violent/accidental deaths. Increased risk of death due to substance use and violence/accident in Eastern Europe demands investigation into specific differences that may drive that association.

A Lower CD4 Count Predicts Most Causes of Death except Cardiovascular Deaths. The Austrian HIV Cohort Study.

(1) Objective: To investigate changes in mortality rates and predictors of all-cause mortality as well as specific causes of death over time among HIV-positive individuals in the combination antiretroviral therapy (cART) era. (2) Methods: We analyzed all-cause as well as cause-specific mortality among the Austrian HIV Cohort Study between 1997 and 2014. Observation time was divided into five periods: Period 1: 1997-2000; period 2: 2001-2004; period 3: 2005-2008; period 4: 2009-2011; and period 5: 2012-2014. Mortality rates are presented as deaths per 100 person-years (d/100py). Potential risk factors associated with all-cause mortality and specific causes of death were identified by using multivariable Cox proportional hazard models. Models were adjusted for time-updated CD4, age and cART, HIV transmission category, population size of residence area and country of birth. To assess potential nonlinear associations, we fitted all CD4 counts per patient using restricted cubic splines with truncation at 1000 cells/mm3. Vital status of patients was cross-checked with death registry data. (3) Results: Of 6848 patients (59,704 person-years of observation), 1192 died: 380 (31.9%) from AIDS-related diseases. All-cause mortality rates decreased continuously from 3.49 d/100py in period 1 to 1.40 d/100py in period 5. Death due to AIDS-related diseases, liver-related diseases and non-AIDS infections declined, whereas cardiovascular diseases as cause of death remained stable (0.27 d/100py in period 1, 0.10 d/100py in period 2, 0.16 d/100py in period 3, 0.09 d/100py in period 4 and 0.14 d/100py in period 5) and deaths due to non-AIDS-defining malignancies increased. Compared to latest CD4 counts of 500 cells/mm3, lower CD4 counts conferred a higher risk of deaths due to AIDS-related diseases, liver-related diseases, non-AIDS infections and non-AIDS-defining malignancies, whereas no significant association was observed for cardiovascular mortality. Results were similar in sensitivity analyses where observation time was divided into two periods: 1997-2004 and 2005-2014. (4) Conclusions: Since the introduction of cART, risk of death decreased and causes of death changed. We do not find evidence that HIV-positive individuals with a low CD4 count are more likely to die from cardiovascular diseases.

Hypersensitivity reactions, hepatotoxicity, and other discontinuations in persons receiving integrase strand transfer inhibitors: results from the EuroSIDA study.

Background: Hypersensitivity reaction (HSR) and hepatotoxicity are rare, but potentially serious side-effects of antiretroviral use.Objective: To investigate discontinuations due to HSR, hepatotoxicity or other reasons among users of dolutegravir (DTG) vs. raltegravir (RAL) or elvitegravir (EVG) in the EuroSIDA cohort.Methods: We compared individuals ≥18 years and starting combination antiretroviral therapy (ART, ≥3 drugs) with DTG vs. RAL or EVG, with or without abacavir (ABC), between January 16, 2014 and January 23, 2019. Discontinuations due to serious adverse events (SAEs) were independently reviewed.Results: Altogether 4366 individuals started 5116 ART regimens including DTG, RAL, or EVG, contributing 9180 person-years of follow-up (PYFU), with median follow-up 1.6 (interquartile range 0.7-2.8) years per treatment episode. Of these, 3074 (60.1%) used DTG (1738 with ABC, 1336 without) and 2042 (39.9%) RAL or EVG (286 with ABC, 1756 without). 1261 (24.6%) INSTI episodes were discontinued, 649 of the DTG-containing regimens (discontinuation rate 115, 95% CI 106-124/1000 PYFU) and 612 RAL or EVG-containing regimens (173, CI 160-188/1000 PYFU). After independent review, there were five HSR discontinuations, two for DTG (one with and one without ABC, discontinuation rate 0.35, CI 0.04-1.28/1000 PYFU), and three for RAL or EVG without ABC (0.85, CI 0.18-2.48/1000 PYFU). There was one hepatotoxicity discontinuation on DTG with ABC (discontinuation rate 0.18, CI 0.00-0.99/1000 PYFU).Conclusion: During 5 years of observations in the EuroSIDA cohort independently reviewed discontinuations due to HSR or hepatotoxicity were very rare, indicating a low rate of SAEs.

Safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-1-infected adults with end-stage renal disease on chronic haemodialysis: an open-label, single-arm, multicentre, phase 3b trial.

BACKGROUND: Current treatment for HIV-infected individuals with renal failure on haemodialysis frequently requires complex regimens with multiple pills. A daily single-tablet regimen of coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is approved in Europe, the USA, and in other regions for use in HIV-1-infected individuals with mild-to-moderate chronic kidney disease (creatinine clearance 30-69 mL/min). We aimed to assess the safety, efficacy, and pharmacokinetics of this regimen in HIV-infected adults with end-stage renal disease on chronic haemodialysis. METHODS: We did an open-label, single-arm, multicentre, phase 3b trial at 26 outpatient clinics in Austria, France, Germany, and the USA. Participants were HIV-1-infected adults with end-stage renal disease (creatinine clearance <15 mL/min), on chronic haemodialysis for at least 6 months before screening. Virological suppression (ie, plasma HIV-1 RNA <50 copies per mL) on a stable antiretroviral regimen was required for at least 6 months before screening with a CD4 count of at least 200 cells per µL. We switched all participants to coformulated elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg once daily, taken after haemodialysis for up to 96 weeks. We did assessments at study visits at weeks 2, 4, 8, 12, 24, 36, and 48, and every 12 weeks thereafter up to 96 weeks. The primary endpoint was the incidence of treatment-emergent adverse events of grade 3 or higher up to week 48. All participants who received at least one dose of study drug were included in the primary analysis. This study is registered with ClinicalTrials.gov (NCT02600819) and is closed to new participants. FINDINGS: Between Feb 1, and Nov 3, 2016, 55 participants were enrolled and received at least one dose of study drug. Through week 48, 18 of 55 participants (33%, 95% CI 20-45) had an adverse event of grade 3 or higher on study treatment. Treatment-emergent grade 3 or higher adverse events that occurred in more than one participant included anaemia, osteomyelitis, prolonged electrocardiogram QT, fluid overload, hyperkalaemia, hypertension, and hypotension (all n=2). No adverse event of grade 3 or higher was considered by the site investigators to be treatment related. Three participants (5%, 95% CI 0-11) discontinued treatment because of adverse events; one of these (grade 1 allergic pruritus) was considered treatment related. Treatment-related adverse events were reported for six individuals (11%, 95% CI 3-19), the most common of which was nausea (in four individuals [7%]); all treatment-related adverse events were grade 1 or 2 in severity. INTERPRETATION: At 48 weeks, switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was well tolerated. This regimen might provide a tolerable and convenient option for ongoing treatment of HIV-1 infection in adults with end-stage renal disease on chronic haemodialysis. FUNDING: Gilead Sciences.

Variation in antiretroviral treatment coverage and virological suppression among three HIV key populations.

OBJECTIVES: We assessed differences in antiretroviral treatment (ART) coverage and virological suppression across three HIV key populations, as defined by self-reported HIV transmission category: sex between men, injection drug use (IDU) and heterosexual transmission. DESIGN: A multinational cohort study. METHODS: Within the EuroSIDA study, we assessed region-specific percentages of ART-coverage among those in care and virological suppression (<500 copies/ml) among those on ART, and analysed differences between transmission categories using logistic regression. RESULTS: Among 12 872 participants followed from 1 July 2014 to 30 June 2016, the percentages of ART-coverage and virological suppression varied between transmission categories, depending on geographical region (global P for interaction: P = 0.0148 for ART-coverage, P = 0.0006 for virological suppression). In Western [adjusted odds ratio (aOR) 1.41 (95% confidence interval 1.14-1.75)] and Northern Europe [aOR 1.68 (95% confidence interval 1.25-2.26)], heterosexuals were more likely to receive ART than MSM, while in Eastern Europe, there was some evidence that infection through IDU [aOR 0.60 (95% confidence interval 0.31-1.14)] or heterosexual contact [aOR 0.58 (95% confidence interval 0.30-1.10)] was associated with lower odds of receiving ART. In terms of virological suppression, people infected through IDU or heterosexual contact in East Central and Eastern Europe were around half as likely as MSM to have a suppressed viral load on ART, while we observed no differences in virological suppression across transmission categories in Western and Northern Europe. CONCLUSION: In our cohort, patterns of ART-coverage and virological suppression among key populations varied by geographical region, emphasizing the importance of tailoring HIV programmes to the local epidemic.

A prospective evaluation of pulmonary, systemic and hepatic haemodynamics in HIV-HCV-coinfected patients before and after antiviral therapy with pegylated interferon and ribavirin.

BACKGROUND: Patients coinfected with HIV and HCV are at risk for developing portal hypertension (PHT), hyperdynamic circulation and pulmonary arterial hypertension (PAH). Data on the influence of antiviral therapy with pegylated interferon-α (PEG-IFN-α) and ribavirin (RBV) are limited. METHODS: Haemodynamic parameters, including hepatic venous pressure gradient (HVPG), pulmonary arterial pressure (PAP(mean)), cardiac output (CO) and systemic vascular resistance (SysVR), were prospectively evaluated before and after PEG-IFN-α+RBV therapy in 80 HIV-HCV-coinfected patients. RESULTS: Baseline evaluation showed a mean HVPG of 4.7 mmHg, CO of 6.15 l/min and PAP(mean) of 14.8 mmHg. PHT was present in 26% of patients, hyperdynamic circulation in 5% and PAH in 4%. Patients with advanced fibrosis (METAVIR stage F3/F4; n=32) had significantly higher CO (P=0.008), lower SysVR (P=0.035), higher PAP(mean) (P=0.018) and higher pulmonary vascular resistance (P=0.022) than patients with stage F0-F2 fibrosis (n=48). Both hyperdynamic circulation and PAH were significantly associated with liver stiffness, fibrosis stage and portal pressure; a non-significant trend was found for CD4(+) T-cell counts and HIV RNA levels. No significant changes in PAP(mean), CO and SysVR were observed after PEG-IFN-α+RBV treatment, although a significant decrease in HVPG was noted in patients with HCV eradication (P=0.013). CONCLUSIONS: The overall prevalence of hyperdynamic circulation and PAH in HIV-HCV coinfection is low. Advanced fibrosis, increased liver stiffness, elevated portal pressure and probably CD4(+) T-cell count and HIV viraemia represent risk factors for hyperdynamic circulation and PAH. PHT is present in 26% of HIV-HCV-coinfected patients evaluated for antiviral therapy. Successful HCV eradication significantly decreases HVPG.

HIV coreceptor tropism in antiretroviral treatment-naive patients newly diagnosed at a late stage of HIV infection.

OBJECTIVE: A substantial number of HIV infections worldwide are diagnosed at a late stage of disease. Mortality in late presenters is high, and their treatment is a specific challenge. We have determined the relative proportions of HIV-1 strains of different coreceptor tropism (CRT) in this group of patients and investigated the impact of CRT on progression markers such as CD4 cell counts and viral load, and on the clinical presentation of the patients. DESIGN AND METHODS: Plasma samples from 50 treatment-naive patients with a late HIV diagnosis (CD4 cell counts of <200 cells/microl at the time of diagnosis) were analyzed. HIV strains were sequenced, and for CRT determination, the internet tool geno2pheno[coreceptor] was used, with a 20% false-positive rate as the cutoff. Differences in progression markers, patient characteristics and HIV subtype distribution between the R5-infected and X4/DM-infected patient groups were evaluated statistically. RESULTS: CRT predictions indicated that 62% of the patients had only R5-tropic strains. CRT was not associated with CD4 cell counts or viral load at the time of diagnosis. Only in very late presenters (CD4 cell counts <50 cells/microl) was there a significant difference in disease stage at the time of presentation, showing that patients with R5 more often were at Centers for Disease Control and Prevention stage C3 compared with those with X4/DM strains (P = 0.04). CONCLUSION: A substantial number of patients diagnosed at a late stage of HIV-1 infection may be infected exclusively with R5-tropic virus strains, making this specific patient group a possible candidate for coreceptor antagonist treatment.

German-Austrian recommendations for HIV1-therapy in pregnancy and in HIV1-exposed newborn, update 2008.

In Germany during the last years about 200-250 HIV1-infected pregnant women delivered a baby each year, a number that is currently increasing. To determine the HIV-status early in pregnancy voluntary HIV-testing of all pregnant women is recommended in Germany and Austria as part of prenatal care. In those cases, where HIV1-infection was known during pregnancy, since 1995 the rate of vertical transmission of HIV1 was reduced to 1-2%. - This low transmission rate has been achieved by the combination of anti-retroviral therapy of pregnant women, caesarean section scheduled before onset of labour, anti-retroviral post exposition prophylaxis in the newborn and refraining from breast-feeding by the HIV1-infected mother. To keep pace with new results in research, approval of new anti-retroviral drugs and changes in the general treatment recommendations for HIV1-infected adults, in 1998, 2001, 2003 and 2005 an interdisciplinary consensus meeting was held. Gynaecologists, infectious disease specialists, paediatricians, pharmacologists, virologists and members of the German AIDS Hilfe (NGO) were participating in this conference to update the prevention strategies. A fifth update became necessary in 2008. The updating process was started in January 2008 and was terminated in September 2008. The guidelines provide new recommendations on the indication and the starting point for HIV-therapy in pregnancies without complications, drugs and drug combinations to be used preferably in these pregnancies and updated information on adverse effects of anti-retroviral drugs. Also the procedures for different scenarios and risk constellations in pregnancy have been specified again. - With these current guidelines in Germany and Austria the low rate of vertical HIV1-transmission should be further maintained.

Cytomegalovirus genotypes present in cerebrospinal fluid of HIV-infected patients.

OBJECTIVE: To compare cytomegalovirus (CMV) strains found in cerebrospinal fluid (CSF) of patients with HIV infection and CMV encephalitis with those present in the general population with respect to genetic variation in the N terminus of the glycoprotein B (gBn)-gene. DESIGN AND METHODS: We sequenced gBn, which is a major target of the antiviral immune response, of CMV strains present in CSF of nine HIV-infected patients with acute encephalitis, in serum of 18 immunocompetent patients with primary CMV infection, and in serum of nine HIV-infected patients without neurological illness. Sequences were compared to prototype strains and analysed by use of phylogeny. RESULTS: Fourty-four percent (4/9) of gBn-sequences present in CSF did not cluster with any of the four gBn-prototype strains. Phylogenetic analysis revealed that these sequences represented two further, distinct genotypes and comparison of sequences was highly suggestive for intragenic recombination. In immunocompetent patients and HIV-infected patients without neurological illness, genotype gBn1 was the predominant strain (4/9, 44% and 8/18, 42%, respectively). Genotypes distinct from prototype strains were found in none of the immunocompetent patients and 22% (2/9) of HIV- infected patients without neurological illness. CONCLUSIONS: CMV strains present in CSF of HIV-infected patients with encephalitis differ significantly from those present in the general population. Intragenic recombination of CMV may be common in patients with advanced HIV infection and a source of new CMV strains with altered biological properties.

Low proportion of recent human immunodeficiency virus (HIV) infections among newly diagnosed cases of HIV infection as shown by the presence of HIV-specific antibodies of low avidity.

The time between human immunodeficiency virus (HIV) infection and diagnosis is mostly unknown. Two hundred five newly diagnosed patients were investigated for the duration of their HIV infection by avidity testing. Recent HIV infection was identified in 27.3% of the cases. Early diagnosis was achieved significantly less frequently in heterosexually infected persons than in other patients.

Absence of human immunodeficiency virus infection after intentional injection of infected blood.

We report the case of a young man who injected himself intravenously with 2 mL of human immunodeficiency virus (HIV)-infected blood and failed to develop HIV infection.