Difficult-to-treat HIV in Sweden: a cross-sectional study.

BACKGROUND: Our aim was to examine the prevalence and characteristics of difficult-to-treat HIV in the current Swedish HIV cohort and to compare treatment outcomes between people with difficult and non-difficult-to-treat HIV. METHODS: In this cross-sectional analysis of the Swedish HIV cohort, we identified all people with HIV currently in active care in 2023 from the national register InfCareHIV. We defined five categories of difficult-to-treat HIV: 1) advanced resistance, 2) four-drug regimen, 3) salvage therapy, 4) virologic failure within the past 12 months, and 5) ≥ 2 regimen switches following virologic failure since 2008. People classified as having difficult-to-treat HIV were compared with non-difficult for background characteristics as well as treatment outcomes (viral suppression and self-reported physical and psychological health). RESULTS: Nine percent of the Swedish HIV cohort in 2023 (n = 8531) met at least one criterion for difficult-to-treat HIV. Most of them had ≥ 2 regimen switches (6%), and the other categories of difficult-to-treat HIV were rare (1-2% of the entire cohort). Compared with non-difficult, people with difficult-to-treat HIV were older, had an earlier first year of positive HIV test and lower CD4 counts, and were more often female. The viral suppression rate among people with difficult-to-treat HIV was 84% compared with 95% for non-difficult (p = 0.001). People with difficult-to-treat HIV reported worse physical (but not psychological) health, and this remained statistically significant after adjustment for age, sex, and transmission group. CONCLUSIONS: Although 9% of the HIV cohort in Sweden in 2023 were classified as having difficult-to-treat HIV, a large proportion of these were virally suppressed, and challenges such as advanced resistance and need for salvage therapy are rare in the current Swedish cohort.

The molecular epidemiology of HIV-1 in Sweden 1996 to 2022, and the influence of migration from Ukraine.

BackgroundThe global distribution of HIV-1 subtypes is evolving, which is reflected in the Swedish HIV cohort. The subtype HIV-1A6, which may be prone to developing resistance to cabotegravir, is the most common subtype in Ukraine.AimWe aimed to examine trends in HIV-1 subtype distribution in Sweden, with a special focus on HIV-1A6, and to describe the virology, demography and treatment of Ukrainian people living with HIV (PLWH) who migrated to Sweden in 2022.MethodsData about PLWH in Sweden are included in a national database (InfCareHIV). We used the online tool COMET to establish HIV-1 subtypes and the Stanford database to define drug resistance mutations. We investigated the relation between virological characteristics and demographic data.ResultsThe early epidemic was predominated by HIV-1 subtype B infections in people born in Sweden. After 1990, the majority of new PLWH in Sweden were PLWH migrating to Sweden, resulting in an increasingly diverse epidemic. In 2022, HIV-1A6 had become the sixth most common subtype in Sweden and 98 of the 431 new PLWH that were registered in Sweden came from Ukraine. We detected HIV RNA in plasma of 32 Ukrainian patients (34%), of whom 17 were previously undiagnosed, 10 had interrupted therapy and five were previously diagnosed but not treated. We found HIV-1A6 in 23 of 24 sequenced patients.ConclusionThe molecular HIV epidemiology in Sweden continues to diversify and PLWH unaware of their HIV status and predominance of HIV-1A6 should be considered when arranging care directed at PLWH from Ukraine.

Cohort profile: InfCareHIV, a prospective registry-based cohort study of people with diagnosed HIV in Sweden.

PURPOSE: The Swedish InfCareHIV cohort was established in 2003 to ensure equal and effective care of people living with HIV (PLHIV) and enable long-term follow-up. InfCareHIV functions equally as a decision support system as a quality registry, ensuring up-to-date data reported in real time. PARTICIPANTS: InfCareHIV includes data on >99% of all people with diagnosed HIV in Sweden and up to now 13 029 have been included in the cohort. InfCareHIV includes data on HIV-related biomarkers and antiretroviral therapies (ART) and also on demographics, patient-reported outcome measures and patient-reported experience measures. FINDINGS TO DATE: Sweden was in 2015 the first country to reach the UNAIDS (United Nations Programme on HIV/AIDS)/WHO's 90-90-90 goals. Late diagnosis of HIV infection was identified as a key problem in the Swedish HIV-epidemic, and low-level HIV viraemia while on ART associated with all-cause mortality. Increased HIV RNA load in the cerebrospinal fluid (CSF) despite suppression of the plasma viral load was found in 5% of PLHIV, a phenomenon referred to as 'CSF viral escape'. Dolutegravir-based treatment in PLHIV with pre-existing nucleoside reverse transcriptase inhibitor-mutations was non-inferior to protease inhibitor-based regimens. An increase of transmitted drug resistance was observed in the InfCareHIV cohort. Lower efficacy for protease inhibitors was not due to lower adherence to treatment. Incidence of type 2 diabetes and insulin resistance was high in the ageing HIV population. Despite ART, the risk of infection-related cancer as well as lung cancer was increased in PLHIV compared with HIV-negative. PLHIV were less likely successfully treated for cervical precancer and more likely to have human papillomavirus types not included in current HPV vaccines. Self-reported sexual satisfaction in PLHIV is improving and is higher in women than men. FUTURE PLANS: InfCareHIV provides a unique base to study and further improve long-term treatment outcomes, comorbidity management and health-related quality of life in people with HIV in Sweden.

Inhaled ciclesonide in adults hospitalised with COVID-19: a randomised controlled open-label trial (HALT COVID-19).

OBJECTIVE: To assess the efficacy of inhaled ciclesonide in reducing the duration of oxygen therapy (an indicator of time to clinical improvement) among adults hospitalised with COVID-19. DESIGN: Multicentre, randomised, controlled, open-label trial. SETTING: 9 hospitals (3 academic hospitals and 6 non-academic hospitals) in Sweden between 1 June 2020 and 17 May 2021. PARTICIPANTS: Adults hospitalised with COVID-19 and receiving oxygen therapy. INTERVENTION: Inhaled ciclesonide 320 µg two times a day for 14 days versus standard care. MAIN OUTCOME MEASURES: Primary outcome was duration of oxygen therapy, an indicator of time to clinical improvement. Key secondary outcome was a composite of invasive mechanical ventilation/death. RESULTS: Data from 98 participants were analysed (48 receiving ciclesonide and 50 receiving standard care; median (IQR) age, 59.5 (49-67) years; 67 (68%) men). Median (IQR) duration of oxygen therapy was 5.5 (3-9) days in the ciclesonide group and 4 (2-7) days in the standard care group (HR for termination of oxygen therapy 0.73 (95% CI 0.47 to 1.11), with the upper 95% CI being compatible with a 10% relative reduction in oxygen therapy duration, corresponding to a <1 day absolute reduction in a post-hoc calculation). Three participants in each group died/received invasive mechanical ventilation (HR 0.90 (95% CI 0.15 to 5.32)). The trial was discontinued early due to slow enrolment. CONCLUSIONS: In patients hospitalised with COVID-19 receiving oxygen therapy, this trial ruled out, with 0.95 confidence, a treatment effect of ciclesonide corresponding to more than a 1 day reduction in duration of oxygen therapy. Ciclesonide is unlikely to improve this outcome meaningfully. TRIAL REGISTRATION NUMBER: NCT04381364.

Virologic Failure Following Low-level Viremia and Viral Blips During Antiretroviral Therapy: Results From a European Multicenter Cohort.

BACKGROUND: It is unclear whether low-level viremia (LLV), defined as repeatedly detectable viral load (VL) of <200 copies/mL, and/or transient viremic episodes (blips) during antiretroviral therapy (ART), predict future virologic failure. We investigated the association between LLV, blips, and virologic failure (VF) in a multicenter European cohort. METHODS: People with HIV-1 who started ART in 2005 or later were identified from the EuResist Integrated Database. We analyzed the incidence of VF (≥200 copies/mL) depending on viremia exposure, starting 12 months after ART initiation (grouped as suppression [≤50 copies/mL], blips [isolated VL of 51-999 copies/mL], and LLV [repeated VLs of 51-199 copies/mL]) using Cox proportional hazard models adjusted for age, sex, injecting drug use, pre-ART VL, CD4 count, HIV-1 subtype, type of ART, and treatment experience. We queried the database for drug-resistance mutations (DRM) related to episodes of LLV and VF and compared those with baseline resistance data. RESULTS: During 81 837 person-years of follow-up, we observed 1424 events of VF in 22 523 participants. Both blips (adjusted subhazard ratio [aHR], 1.7; 95% confidence interval [CI], 1.3-2.2) and LLV (aHR, 2.2; 95% CI, 1.6-3.0) were associated with VF, compared with virologic suppression. These associations remained statistically significant in subanalyses restricted to people with VL <200 copies/mL and those starting ART 2014 or later. Among people with LLV and genotype data available within 90 days following LLV, 49/140 (35%) had at least 1 DRM. CONCLUSIONS: Both blips and LLV during ART are associated with increased risk of subsequent VF.

Associations between HIV viremia during antiretroviral therapy and cardiovascular disease.

OBJECTIVE: To investigate the association between HIV viremia exposure during antiretroviral therapy (ART) and cardiovascular disease (CVD) risk. DESIGN: Nationwide observational cohort. METHODS: Participants (age >15 years) from the Swedish nationwide InfCareHIV register initiating ART 1996-2017 were categorized in a time-updated manner into four viremia categories, starting from 12 months after ART initiation: suppression (<50 copies/ml), low-level viremia (50-199 copies/ml and 200-999 copies/ml, respectively), and high-level viremia (≥1000 copies/ml). In addition, cumulative viremia was estimated as the area under the log viral load (VL) curve. Proportional subhazard models adjusted for sex, age, pre-ART CD4 and VL, injection drug use, and country of birth were used to analyze the association between viremia exposure and CVD risk (ischemic heart disease, stroke, and heart failure; data obtained by linkage to national registers), accounting for the competing risk of non-CVD death. RESULTS: In all, 337 cases of CVD were observed during 44 937 person-years of follow-up ( n  = 6562). Higher viremia exposure was associated with CVD, both when parameterized as cumulative viremia (adjusted subhazard ratio [aSHR] per 1 log 10  copy × year/ml, 1.03; 95% confidence interval [CI], 1.01-1.05) and as viremia category (aSHR for high-level viremia versus suppression, 1.45; 95% CI, 1.03-2.05). We observed no association between CVD and low-level viremia compared with those with suppression. CONCLUSIONS: Higher exposure to HIV viremia was linked to CVD in ART recipients, whereas no increased risk was detected for people with low-level viremia compared with viral suppression. Causal inference is limited by the observational nature of this study.

Factors associated with low-level viraemia in people with HIV starting antiretroviral therapy: A Swedish observational study.

OBJECTIVE: Low-level viraemia (LLV) occurs in some people with HIV (PWH) receiving antiretroviral therapy (ART) and has been linked to inferior treatment outcomes. We investigated factors associated with LLV in a nationwide cohort of Swedish PWH starting ART. METHODS: Participants were identified from the InfCareHIV register, with the following inclusion criteria: ART initiation 2006-2017, age >15 years, ≥4 viral load (VL) results available and no documented treatment interruptions or virologic failure (≥2 consecutive VL ≥200 copies/ml) during follow-up. Starting from 6 months after ART initiation, participants were followed for 24 months and categorised as viral suppression (VS; VL <50 copies/ml) or LLV (≥2 consecutive VL 50-199 copies/ml). We analysed the association between the following factors and LLV using multivariable logistic regression: sex, age, pre-ART VL and CD4 count, ART regimen, country of birth, HIV-1 subtype and transmission category. RESULTS: Among 3383 participants, 3132 (92.6%) had VS and 251 (7.4%) had LLV. In univariable analyses, factors associated with LLV were male sex, higher age, lower pre-ART CD4 count, higher pre-ART VL and ART regimen. After adjustment, the following factors were associated with LLV (adjusted odds ratio; 95% confidence interval): male sex (1.6; 1.1-2.3), higher pre-ART VL (2.7; 2.2-3.3), pre-ART CD4 count <200 cells/µl (1.6; 1.2-2.2), protease inhibitor (PI)-based regimen (1.5; 1.1-2.1), non-standard ART (2.4; 1.0-5.5) and injecting drug use (2.0; 1.1-3.7). CONCLUSION: Among Swedish PWH, LLV during ART was associated with markers of HIV disease severity before starting ART, male sex, injecting drug use and use of PI-based or non-standard ART regimens.

Cardiovascular Profile of South African Adults with Low-Level Viremia during Antiretroviral Therapy.

Chronic inflammation is an HIV infection feature, contributing to elevated risk of cardiovascular disease among people with HIV, which can be induced by viral replication. A proportion of antiretroviral therapy (ART) recipients fail to achieve viral suppression, despite not meeting criteria for treatment failure, so-called low-level viremia (LLV). We investigated the relationship between LLV and an array of cardiovascular measures and biomarkers. South Africans with LLV (viral load = 50−999 copies/mL) and virological suppression (viral load <50 copies/mL) were selected from the EndoAfrica study (all receiving efavirenz-based ART) for cross-sectional comparison of vascular structure and function measures, as well as 21 plasma biomarkers related to cardiovascular risk and inflammation. Associations were investigated with univariate, multivariate, and binomial logistic regression analyses (having outcome measures above (cases) or below (controls) the 75th percentile). Among 208 participants, 95 (46%) had LLV, and 113 (54%) had viral suppression. The median age was 44 years, 73% were women, and the median ART duration was 4.5 years. Cardiovascular measures and biomarker levels were similar between these two categories. Cardiovascular function and structure measures were not associated with viremia status and having LLV did not increase the odds of having outcome measures above the 75th percentile. In this study among South African ART recipients, LLV did not associate with cardiovascular risk.

Associations Between Plasma Human Immunodeficiency Virus (HIV) Ribonucleic Acid Levels and Incidence of Invasive Cancer in People With HIV After Initiation of Combination Antiretroviral Therapy.

BACKGROUND: Human immunodeficiency virus (HIV) viremia could be involved in the increased risk of cancer in people with HIV (PWH) receiving combination antiretroviral therapy (cART). We analyzed the association between plasma HIV ribonucleic acid levels in PWH starting cART and incident invasive cancer using the Swedish cohort InfCare HIV linked with national registers. METHODS: Adults starting cART in 1996-2017 were included if they had ≥1 viral load (VL) measurement before receiving any antiretroviral agent (pre-ART VL) and ≥2 VLs ≥6 months after start of cART. Viremia during cART was analyzed both as viremia-copy-years and categorized as suppression (<50 copies/mL), low-level viremia ([LLV] 50-999 copies/mL), and nonsuppression (≥1000 copies/mL). The main outcome was a composite of invasive malignancies with increased incidence among PWH. We fitted proportional subhazard models (including sex, age, pre-ART CD4 count, and injection drug use) for both pre-ART VL and viremia during cART. RESULTS: After 32 105 person-years, 3254 of 4931 participants (66%) were classified as suppressed, 438 (9%) were classified as LLV, and 1221 (25%) were classified as nonsuppressed. Neither viremia category nor cumulative viremia during cART had a statistically significant association with cancer. Higher pre-ART VL was associated with cancer (adjusted subhazard ratio, 1.4; 95% confidence interval, 1.0-1.8); this remained statistically significant with viremia during cART in the model. In subanalysis, the association with pre-ART VL was statistically significant for acquired immune deficiency syndrome (AIDS)-defining and infection-related non-AIDS-defining cancer, but not for other malignancies. CONCLUSIONS: In this nationwide cohort, pre-ART VL was an independent predictor of invasive cancer, whereas viremia profile during cART was not associated with cancer incidence.

All-Cause Mortality and Serious Non-AIDS Events in Adults With Low-level Human Immunodeficiency Virus Viremia During Combination Antiretroviral Therapy: Results From a Swedish Nationwide Observational Study.

BACKGROUND: The impact of low levels of human immunodeficiency virus (HIV) RNA (low-level viremia [LLV]) during combination antiretroviral therapy (cART) on clinical outcomes is unclear. We explored the associations between LLV and all-cause mortality, AIDS, and serious non-AIDS events (SNAEs). METHODS: We grouped individuals starting cART 1996-2017 (identified from the Swedish InfCare HIV register) as virologic suppression (VS; <50 copies/mL), LLV (repeated viral load, 50-999 copies/mL), and nonsuppressed viremia (NSV; ≥1000 copies/mL). Separately, LLV was subdivided into 50-199 and 200-999 copies/mL (reflecting different definitions of virologic failure). Proportional-hazard models (including sex, age, pre-ART CD4 count and viral load, country of birth, injection drug use, treatment experience and interruptions, and an interaction term between viremia and time) were fitted for the study outcomes. RESULTS: A total of 6956 participants were followed for a median of 5.7 years. At the end of follow-up, 60% were categorized as VS, 9% as LLV, and 31% as NSV. Compared with VS, LLV was associated with increased mortality (adjusted hazard ratio [aHR], 2.2; 95% confidence interval [CI], 1.3-3.6). This association was also observed for LLV 50-199 copies/mL (aHR, 2.2; 95% CI, 1.3-3.8), but was not statistically significant for LLV 200-999 copies/mL (aHR, 2.1; 95% CI, .96-4.7). LLV 50-999 copies/mL was not linked to increased risk of AIDS or SNAEs, but in subanalysis, LLV 200-999 copies/mL was associated with SNAEs (aHR, 2.0; 95% CI, 1.2-3.6). CONCLUSIONS: In this population-based cohort, LLV during cART was associated with adverse clinical outcomes.

Virological failure and all-cause mortality in HIV-positive adults with low-level viremia during antiretroviral treatment.

OBJECTIVE: Although most HIV-infected individuals achieve undetectable viremia during antiretroviral therapy (ART), a subset have low-level viremia (LLV) of varying duration and magnitude. The impact of LLV on treatment outcomes is unclear. We investigated the association between LLV and virological failure and/or all-cause mortality among Swedish patients receiving ART. METHODS: HIV-infected patients from two Swedish HIV centers were identified from the nationwide register InfCare HIV. Subjects aged ≥15 years with triple agent ART were included at 12 months after treatment initiation if ≥2 following viral load measurements were available. Patients with 2 consecutive HIV RNA values ≥1000 copies/mL at this time point were excluded. Participants were stratified into four categories depending on viremia profiles: permanently suppressed viremia (<50 copies/mL), LLV 50-199 copies/mL, LLV 200-999 copies/mL and viremia ≥1000 copies/mL. Association between all four viremia categories and all-cause death was calculated using survival analysis with viremia as a time-varying covariate, so that patients could change viremia category during follow-up. Association between the three lower categories and virological failure (≥2 consecutive measurements ≥1000 copies/mL) was calculated in a similar manner. RESULTS: LLV 50-199 copies/mL was recorded in 70/1015 patients (6.9%) and LLV 200-999 copies/mL in 89 (8.8%) during 7812 person-years of follow-up (median 6.5 years). LLV 200-999 copies/mL was associated with virological failure (adjusted hazard ratio 3.14 [95% confidence interval 1.41-7.03, p<0.01]), whereas LLV 50-199 copies/mL was not (1.01 [0.34-4.31, p = 0.99]; median follow-up 4.5 years). LLV 200-999 copies/mL had an adjusted mortality hazard ratio of 2.29 (0.98-5.32, p = 0.05) and LLV 50-199 copies/mL of 2.19 (0.90-5.37, p = 0.09). CONCLUSIONS: In this Swedish cohort followed during ART for a median of 4.5 years, LLV 200-999 copies/mL was independently associated with virological failure. Patients with LLV had higher rates of all-cause mortality, although not statistically significant in multivariate analysis.

Rosuvastatin Treatment Affects Both Basal and Glucose-Induced Insulin Secretion in INS-1 832/13 Cells.

Rosuvastatin is a member of the statin family. Like the other statins it is prescribed to lower cholesterol levels and thereby reduce the risk of cardiovascular events. Rosuvastatin lowers the cholesterol levels by inhibiting the key enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) in the cholesterol producing mevalonate pathway. It has been recognized that apart from their beneficial lipid lowering effects, statins also exhibit diabetogenic properties. The molecular mechanisms behind these remain unresolved. To investigate the effects of rosuvastatin on insulin secretion, we treated INS-1 832/13 cells with varying doses (20 nM to 20 µM) of rosuvastatin for 48 h. At concentrations of 2 µM and above basal insulin secretion was significantly increased. Using diazoxide we could determine that rosuvastatin did not increase basal insulin secretion by corrupting the KATP channels. Glucose-induced insulin secretion on the other hand seemed to be affected differently at different rosuvastatin concentrations. Rosuvastatin treatment (20 µM) for 24-48 h inhibited voltage-gated Ca(2+) channels, which lead to reduced depolarization-induced exocytosis of insulin-containing granules. At lower concentrations of rosuvastatin (≤ 2 µM) the stimulus-secretion coupling pathway was intact downstream of the KATP channels as assessed by the patch clamp technique. However, a reduction in glucose-induced insulin secretion could be observed with rosuvastatin concentrations as low as 200 nM. The inhibitory effects of rosuvastatin on glucose-induced insulin secretion could be reversed with mevalonate, but not squalene, indicating that rosuvastatin affects insulin secretion through its effects on the mevalonate pathway, but not through the reduction of cholesterol biosynthesis. Taken together, these data suggest that rosuvastatin has the potential to increase basal insulin secretion and reduce glucose-induced insulin secretion. The latter is possibly an unavoidable side effect of rosuvastatin treatment as it occurs through the same mechanisms as the lipid-lowering effects of the drug.

ROTEM monitoring of activated and non-activated prothrombin complex concentrate correction of dilutional coagulopathy.

OBJECTIVES: Prothrombin complex concentrates have been used to correct dilutional coagulopathy, but many preparations contain anticoagulants, such as heparin, to counteract their prothrombotic effects. These anticoagulants can interfere with haemostatic assays. The aim of this study was to monitor two different prothrombin complex concentrates for the treatment of albumin dilution in vitro, using rotational thromboelastometry with or without the heparin-antagonising agent protamine. METHODS: Citrated blood from 10 healthy volunteers was, in vitro, diluted 1:1 with 5% albumin and then corrected with a four-factor prothrombin complex concentrate with heparin anticoagulant (Confidex®) corresponding to a clinical dose of 43 IU/kg. Blood samples were tested with or without protamine. An activated prothrombin complex concentrate (APCC) (FEIBA®) without heparin in doses of 50 IU/kg and 100 IU/kg was also tested. Thromboelastometry was performed after recalcification. RESULTS: Albumin dilution significantly affected all thromboelastometry parameters. The four-factor PCC had an additional anticoagulant effect when added to the albumin-diluted blood; it was partially corrected by protamine for all parameters except maximum clot firmness. The APCC significantly improved all parameters, with over-correction of clotting time but only partial correction of maximum clot firmness. CONCLUSIONS: The anticoagulant content of many prothrombin complex concentrates needs to be considered when performing in vitro testing. A heparin-free APCC better corrected an in vitro albumin-induced dilutional coagulopathy than a four-factor PCC, despite of blocking heparin with protamine.