2022

21st September Patel et al., Dolutegravir in pregnancy for HIV


Dolutegravir in pregnancy as compared with current HIV regimens in the United States.  New England Journal of Medicine

Patel et al. on behalf of the Pediatric HIV/AIDS Cohort Study and the Swiss Mother and Child HIV Cohort Study aimed to evaluate viral suppression at delivery and adverse birth outcomes in persons with HIV infection whose initial regimen in pregnancy included dolutegravir as compared with those whose initial regimen included other contemporary antiretroviral therapy (ART) drugs commonly prescribed in the United States and Europe.

Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir–cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir–ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir.

In conclusion, this study contributes data on the effectiveness and safety of contemporary, commonly used integrase inhibitors, protease-inhibitors, and NNRTIs during pregnancy. The study-results provide evidence suggesting that atazanavir–ritonavir and raltegravir provide less HIV viral suppression at delivery than dolutegravir and support darunavir–ritonavir as a reasonable alternative when dolutegravir use is not feasible.

PubMed

15th September Kusejko et al., COVERALL to study Covid-19 vaccine response


Developing and testing a Corona VaccinE tRiAL pLatform (COVERALL) to study Covid-19 vaccine response in immunocompromised patients.    BMC Infectious Diseases

Kusejko et al. developed and implemented a trial platform (COVERALL) within the frameworks of the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS). The platform leverages the well-established data infrastructure of the two cohorts and allows to enroll their participants into randomized trials in a very efficient way with minimal administrative burden.

A trial data collection tool developed with REDCap was connected to the cohort databases, and pre-existing baseline information was then used for automatic patient selection based on user-provided eligibility criteria. Cohort participants were flagged within the cohort data entry tool as potentially eligible for the trial, with trial inclusion of the patient being possible with one click. After inclusion, baseline data from the cohorts were automatically used for the stratified randomization algorithm.

The implementation of the trial platform started in August 2020, and was used to compare the efficacy of the two mRNA vaccines against SARS-CoV-2 (Comirnaty and Spikevax) in individuals with HIV or solid organ transplants. Final ethics approval of the trial protocol was obtained on 15th April 2021, and the first patient was randomized on 19th April. Within four days, 40 individuals were recruited, and the full study population of 380 patients was recruited within 22 days.

Implementing randomized trials within cohorts has many advantages, which include rapid identification of individuals, collection of longitudinal data, which can complement trial analyses, and a low rate of loss to follow-up as individuals remain within the cohort. The COVERALL trial platform allowed the study team to identify and enroll cohort participants into the trial within a matter of weeks and therefore proved to be a highly valuable tool for future trials in the SHCS as well as the STCS.

PubMed

1st September Thoueille et al., Long-acting cabotegravir and rilpivirine


Real-life therapeutic concentration monitoring of long-acting cabotegravir and rilpivirine: Preliminary results of an ongoing prospective observational study in Switzerland.    Pharmaceutics

Thoueille et al. assessed cabotegravir (CAB) and rilpivirine (RPV) plasma concentrations in a preliminary analysis of individuals who receive long-acting CAB/RPV within the Swiss HIV Cohort Study.

Plasma drug concentrations were measured among individuals who received CAB/RPV either as oral lead-in or as intramuscular injection (at 4- or 8-week intervals) at unselected time-points using high-performance chromatography coupled to tandem mass spectrometry (LC-MS/MS).

Within five months after the approval of CAB/RPV in Switzerland, 46 individuals who received CAB/RPV were included in the present analysis. Study participants were predominantly male (83%) and Caucasian (63%), with 61% being less than 50 years old. Overall, 54% had a BMI above 25 kg/m2, and seven (15%) were considered to be obese. Intramuscular injections were administered without oral lead-in in 8 (17%) individuals, and 96% received injections every 8 weeks. Although observed drug concentrations were generally within the ranges reported in registration trials, the authors observed a considerable inter-individual variability of drug levels for both CAB and RPV and unexpectedly low RPV concentrations which were only two-times above the 90% inhibitory concentration (IC90). Viral blips were observed in 3 individuals overall within the study period, but no viral failures occurred.

In summary, the present study highlights the importance of monitoring CAB/RPV drug levels in a real-life cohort outside of randomized registration trials. The considerable inter-individual variability and the low RPV concentrations observed warrant further investigation. Population pharmacokinetic models may provide valuable tools to evaluate individual factors affecting drug levels and to optimize long-acting ART for our patients.

PubMed

18th August Chammartin et al., Determinants of antibody response to severe acute respiratory syndrome coronavirus 2 mRNA vaccines in PWH


Determinants of antibody response to severe acute respiratory syndrome coronavirus 2 mRNA vaccines in people with HIV.   AIDS

Chammartin et al. aimed to investigate factors that influence the antibody response to both SARS-CoV-2 mRNA vaccines in people with HIV (PWH).

The authors systematically tested the association of antibody titers to SARS-CoV-2 with routinely collected clinical, laboratory and life style factors. In particular, they looked at SARS-CoV-2 vaccine type (BNT162b2 versus mRNA-1273). Antibody reactivity was measured with the immunoassay ABCORA that assesses antibody response to SARS-CoV-2 and also allows for a reliable prediction of neutralization activity against the SARS-CoV-2 Wuhan-Hu-1 strain.

Between April 19 and June 9 2021, 352 PWH from the SHCS were enrolled in the COVERALL trial. For the current analysis, they included 333 PWH who received two doses of the vaccines and had an antibody response measured 8 ±4 weeks after the second vaccination. Antibody response was higher among PWH less than 60 years, with CD4R cell count superior to 350 cells/ml and vaccinated with mRNA-1273 by Moderna compared with BNT162b2 by Pfizer-BioNTech. Preinfection with SARS-CoV-2 boosted the antibody response and smokers had an overall lower antibody response.

In conclusion, the study results strongly encourage PWH, most importantly older patients and those with lower CD4+ cell counts, to receive mRNA vaccine boosters to improve SARS-CoV-2 neutralizing antibody titers.

PubMed

3rd August Kusejko et al., Differences in transmission patterns of the local HIV-1 epidemics


Similar but different: Integrated phylogenetic analysis of Austrian and Swiss HIV-1 sequences reveal differences in transmission patterns of the local HIV-1 epidemics.    JAIDS

Kusejko et al. compared HIV transmission dynamics and studied the role of international HIV transmission using phylogenetic analyses in the Swiss and the Austrian HIV Cohort Studies (SHCS and AHVICOS).

Data from the drug resistance databases of the two cohorts as well as the international Los Alamos HIV sequence database were used to create phylogenetic pairs (so-called “cherries”) which were categorized as follows: domestic cherries included 2 patients from the same cohort, international cherries included one patient from SHCS or AHVICOS and one patient from the international Los Alamos database, and SHCS/AHVICOS cherries included patients from both SHCS and AHVICOS.

The authors included 3’141 individuals from AHIVCOS and 12’902 from the SHCS. Patient characteristics from the two cohorts were very similar (73% male, 41% men who have sex with men (MSM), and 73% were sequenced prior to any antiretroviral therapy. Individuals were predominantly in domestic (SHCS 43.0%, AHIVCOS 36.5%) and international cherries (SHCS 8.2%, AHIVCOS 8.3%), and 220 patients formed SHCS/AHIVCOS cherries, reflecting 1.7% of the SHCS and 7.0% of the AHIVCOS population. The international transmissions were driven by MSM in Austria and heterosexual individuals in Switzerland, whereas transmission among intravenous drug users mainly occurred in local transmission networks.

In summary, the present study shows that international transmission plays an essential role in the HIV epidemics in Switzerland and Austria. This work highlights the importance of international collaborations to understand transmission patterns and guide HIV prevention efforts.

PubMed

20th July Speich et al., SARS-CoV-2 vaccine trial in immunocompromised patients


Antibody response in immunocompromised patients after the administration of SARS-CoV-2 vaccine BNT162b2 or mRNA-1273: A randomised controlled trial.   Clinical Infectious Diseases.

Speich et al. compared the antibody response between the two available SARS-CoV-2 mRNA vaccines BNT162b2 (by Pfizer-BioNTech) and mRNA-1273 (Spikevax, by Moderna) in people living with HIV (PLWH) and solid organ transplant (SOT) recipients.

A trial platform was implemented within the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS), and participants from the cohort centers in Bern, Basel and Zürich were randomly allocated 1:1 to 2 doses of BNT162b2 or mRNA-1273. Between April and June 2021, vaccines were administered in 2 doses on days 0 and 28 in both groups. The primary outcome in this non-inferiority trial was antibody response to SARS-CoV-2 spike protein (S1) defined as ≥ 0.8 units/mL assessed at 4 weeks after the second injection (non-inferiority margin of 10%). At the same time point, serum neutralization activity against SARS-CoV-2 was assessed using a cut-off of 17 in the ABCORA2 sum S1 algorithm.

Of the 430 randomized individuals, 142 patients were included in the intention-to-treat analysis. The median age was 53 years (IQR 43-61), 76% were men, 82% were PLWH and 18% were SOT recipients (53% lung transplants, 47% kidney transplants). Overall, antibody response was sufficient in 92.1% who received mRNA-1273, and 94.3% in those who received BNT162b2 (difference -2.2%, 95% CI -7.1 to 2.7), confirming non-inferiority of mRNA-1279 compared to BNT162b2. Neutralizing antibodies were present in 84.7% of individuals who received mRNA-1273 and in 82.4% of those who received BNT162b2. Importantly, whereas antibody response was observed in all PLWH, sufficient antibodies were detectable in only 60.6%, and neutralizing antibody activity was present in only 21.1% of SOT recipients.

In summary, the present head-to-head comparison of the two available SARS-CoV-2 mRNA vaccines among PLWH and SOT recipients demonstrated the non-inferiority of mRNA-1273 compared to BNT162b2. Whereas the two doses were followed by a good immune response among PLWH, the vaccines were less efficient among immunocompromised SOT recipients, warranting further doses in those individuals. This elegant study highlights the great potential of the collaboration between SHCS and STCS, and shows nicely how randomized controlled trials can efficiently be implemented within cohorts.

PubMed

6th July Bick et al., Prevalence of clonal hematopoiesis of indeterminate potential amongst PLWH


Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV.    Scientific Reports

Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD).

In the current study, Bick et al. aimed to assess whether people living with HIV (PLWH) have a greater prevalence of CHIP compared to other risk groups.

The authors searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n= 600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n= 8111) from blood DNA-derived exome sequences. They observed that HIV is associated with a twofold increase in CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p = 0.005). They also observed that ASXL1 is the most commonly mutated CHIP-associated gene in PLWH.

In conclusion, the study suggests that CHIP may contribute to the excess cardiovascular risk observed in PLWH. Since PLWH have accelerated biologic aging, CHIP detection may represent a new opportunity for identification of at-risk patients with particular relevance for HIV medicine. Conversely, PLWH may provide a rich source of information to understand mechanisms of clonal expansion of different CHIP-associated variants under long-term low-grade inflammation.

PubMed

23rd June Neesgard et al., Associations between INSTI and CVD in people living with HIV


Associations between integrase strand-transfer inhibitors and cardiovascular disease in people living with HIV: a multicentre prospective study from the RESPOND cohort consortium.   Lancet HIV

Neesgard et al. investigated whether integrase strand-transfer inhibitors (INSTI) are associated with an increased risk for cardiovascular disease among people living with HIV in the International Cohort Consortium of Infectious Disease (RESPOND), a large collaboration of 17 European and Australian cohorts.

All patients without exposure to INSTI at cohort registration were included and followed over time. Cardiovascular events were defined as myocardial infarction (fatal or non-fatal), stroke, or invasive cardiovascular procedure. The authors calculated incidence rates of cardiovascular disease events over time stratified by exposure to INSTI (unexposed, 0-6 months, 6-12 months, 12-24 months, 24-36 months, and >36 months). Multivariable binomial regression models were used to evaluate associations between INSTI exposure and cardiovascular disease.

The study included 29’340 individuals (median age 44 years, 26% female, median CD4 nadir 200 cells/μL, 28% smokers). Of the 14’000 individuals (48%) who received INSTI during follow-up, most were exposed to dolutegravir (61.8%), followed by elvitegravir (23.9%), raltegravir (23.5%) and bictegravir (6%). 748 individuals (2.5%) had a cardiovascular event (4.67 per 1000 person-years, 95% CI 4.34 - 5.01). The highest incidence was observed in individuals with 0 to 6 months of INSTI exposure (8.46 events per 1000 PY, 95% CI 6.58-10.71), which then decreased gradually to 4.25 per 1000 PY (95% CI 2.89-6.04) after 24 months of INSTI use. Adjusted analyses similarly showed a higher risk for cardiovascular disease at 0-6 months compared to no INSTI exposure (adjusted incidence rate ratio 1.85, 95% CI 1.44-2.39). The results were similar for men and women and independent of the baseline cardiovascular disease risk.

In summary, the present study suggests that exposure to INSTI is associated with cardiovascular disease, irrespective of cardiovascular risk factors at INSTI start. The increased risk was observed mainly in the first 6 months but persisted until 24 months of exposure. As individuals with increased cardiovascular disease risk were more likely to receive INSTI in the present study, confounding by indication cannot be excluded despite statistical adjustment methods. With INSTI being the mainstay of antiretroviral therapy worldwide, replicating or refuting these findings and gaining insights for underlying mechanisms should be a high public health priority.

PubMed

15th June Kusejko et al., HCVree post screening


Sustained effect on hepatitis C elimination among men who have sex with men in the Swiss HIV Cohort Study: A systematic re-screening for hepatitis C RNA two years following a nation-wide elimination program.   Clinical Infectious Diseases

Kuseijo et al. aimed to explore the long-term effect of the Swiss HCVree Trial. This trial was conducted in 2015–2017 with the goal of implementing a population-based systematic hepatitis C virus (HCV) micro-elimination program among men who have sex with men (MSM) living with human immunodeficiency virus (HIV) enrolled in the Swiss HIV Cohort Study (SHCS). The trial led to a 91% and 77% decline of HCV prevalence and incidence, respectively. The crucial question after the Swiss HCVree Trial was, whether this short-term effort was enough for achieving a further decrease of HCV prevalence and incidence, or at least for maintaining the post-intervention level.

All MSM enrolled in the SHCS were screened for HCV RNA using stored plasma samples obtained in 2019, termed “Swiss HCVree Post” screen. The incidence of HCV infection over time was assessed using additional information on HCV testing routinely collected in the SHCS. Characteristics of participants with replicating HCV infection were analyzed.

The point-prevalence of “Swiss HCVree Post” (N=4641) was 0.6%, reflecting a decline of 48% compared to the end of the Swiss HCVree Trial where the prevalence was 1.2%. Further, the incidence of HCV among MSM in the SHCS declined from 0.31/100 person-years (py) (95% confidence interval [CI] [.17, .55]) in 2017 to 0.19/100 py (95% CI [.09, .39]) in 2019.

In conclusion, the systematic screening and testing in the Swiss HCVree Trial followed by continuous surveillance and direct acting agent treatment in the SHCS resulted in a sustained marked reduction in HCV incidence and prevalence. This indicates that the Swiss HCVree Trial was successful in curbing the HCV epidemic among MSM living with HIV in Switzerland.

PubMed

2nd June Branca et al., HIV-1 reservoir and dual therapy


Role of the HIV-1 reservoir to maintain viral suppression in a simplified strategy for the long-term management of HIV-1 infection (The SIMPL’HIV Trial).    Frontiers in Virology

Branca et al. assessed the association between the size of the HIV reservoir and the maintenance of HIV viral suppression among participants of the SIMPL’HIV Trial.

The SIMPL’HIV Trial was a randomized controlled trial conducted within the Swiss HIV Cohort Study that compared the efficacy of dual therapy (dolutegravir and emtricitabine) with the standard of care. In the study participants, HIV reservoir size was assessed by quantifying HIV-1 DNA in peripheral blood mononuclear cells. The authors assessed changes in reservoir size over time and evaluated if reservoir size predicts whether patients continue to have HIV viral suppression (<20 copies/mL) during the 48-week study period using multivariable logistic regression. 

In the present study, 175 patients with available HIV-1 DNA reservoir data were included. The median age was 48 years, median CD4 were 240 cells/mL (nadir) and 669 cells/mL (baseline), and patients received ART for a median of 7.8 years prior to randomization. The HIV reservoir size at baseline was similar in both the dual therapy (3.10 log10 HIV DNA copies, IQR 2.81-3.30) and the standard of care arm (3.05, 2.76-3.32), and remained unchanged at 48 weeks. Over time, 45 patients had a detectable HIV viral load on one or more occasions. After adjusting for the time since first ART start and nadir CD4, higher HIV-1 DNA levels were strongly associated with having a detectable HIV viral load during follow-up (adjusted Odds Ratio 2.67 per log10 HIV DNA copy, 95% CI 1.13-6.32).

In summary, the present study illustrates the stability of the HIV reservoir over time in individuals with a long-standing HIV infection and shows that individuals with a large HIV reservoir were more likely to have a detectable HIV viral load on antiretroviral therapy.

Frontiers in Virology

19th May Friedrich et al., Conformations of the HIV-1 V3 loop crown are targetable for broad neutralization


Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization.    Nature Communications

The V3 loop of the HIV-1 envelope (Env) protein elicits a vigorous, but largely non-neutralizing antibody response directed to the V3-crown, whereas rare broadly neutralizing antibodies (bnAbs) target the V3-base.

In this work, Friedrich et al. used the Designed Ankyrin Repeat Proteins (DARPin) technology in order to define conformational states of the V3-crown that are targetable for broad neutralization.

While most bnAbs target prefusion Env, V3-crown bnDs binded open Env conformations triggered by CD4 engagement. BnDs achieved breadth by focusing on highly conserved residues that are accessible in two distinct V3 conformations, one of which resembles CCR5-bound V3.

The authors showed that these V3-crown conformations can, in principle, be attacked by antibodies. Supporting this conclusion, analysis of antibody binding activity in the Swiss 4.5 K HIV-1 cohort (n = 4,281) revealed a co-evolution of V3-crown reactivities and neutralization breadth.

In sum, these findings strongly suggest that directing antibody responses to distinct V3-crown conformations accessible after CD4 attachment should be feasible, thus opening roads for developing vaccine strategies to elicit bnD-like V3-crown bnAbs.

Exploiting this knowledge will likely require the design of appropriate epitope scaffolds to be used as immunogens in order to channel the polyclonal V3-crown response to the desired specificity. These responses will likely not be potent, but due to their high breadth and capacity to recognize an entry state in which bnAbs targeting prefusion Env have less activity, may add important functionality to multivalent vaccines.

PubMed

12th May Salazar-Vizcaya et al., Interaction between behavioral and transmission clusters


An approach to quantifying the interaction between behavioral and transmission clusters.   Viruses

Groups of individuals with similar sexual risk behavior have been identified previously in people living with HIV and incident hepatitis C virus (HCV) infection. In addition, phylogenetic analyses have confirmed the presence of HCV transmission networks. However, little is known about the interplay of sexual risk behavior and the conformation of transmission networks.

In this proof-of-concept study, Salazar-Vizcaya et al. aimed to quantify the relationship between behavioral and transmission clusters in people living with HIV and incident HCV infection in the Swiss HIV Cohort Study. The authors used hierarchical clustering algorithms to identify individuals with similar condom use for anal intercourse with unsteady partners (behavioral cluster), and used maximum-likelihood phylogenetic trees of the HCV virus to identify transmission networks (transmission cluster). Membership of behavioral and transmission clusters for were then combined for each patient, and Monte Carlo simulation was used to quantify the strength of the interaction between them.

The study included 36 men who have sex with men and were part of an HCV transmission cluster. Five distinct behavioral clusters were identified and subsequently combined with the information on the HCV transmission cluster. The authors identified interactions between behavioral and transmission groups that were non-random, suggesting some influence of risk behavior on the conformation of transmission clusters. However, the study was not powered to confirm statistical significance.

In summary, the present study outlines a useful approach to characterize associations between clusters of behavior and clusters of transmission. Such analyses could be applied to other infections including HIV or COVID-19 with large transmission networks and increased power. Future studies using this approach may prove useful to complement and guide public health interventions to limit transmission.

PubMed

4th May Seifert et al., Detecting selection in the HIV-1 genome during sexual transmission events


Detecting selection in the HIV-1 genome during sexual transmission events.   Viruses

Little is known about whether and how variation in the HIV-1 genome affects its transmissibility. Assessing which genomic features of HIV-1 are under positive or negative selection during transmission is challenging, because very few virus particles are typically transmitted, and random genetic drift can dilute genetic signals in the recipient virus population

In the current work, Seifert et al. developed a new statistical test to detect selection during transmission, called Selection Test in Transmission (SeTesT), based on comparing the transmitter and recipient virus population and accounting for the transmission bottleneck. They analyzed 30 transmitter-recipient pairs from the Zurich Primary HIV Infection Study and the Swiss HIV Cohort Study using near full-length HIV-1 genomes.

The authors performed extensive simulations and found that sensitivity of detecting selection during transmission is limited by the strong population bottleneck of few transmitted virions. When pooling individual test results across patients, they found two candidate HIV-1 genomic features for affecting transmission, namely amino acid positions 3 and 18 of Vpu, which were significant before but not after correction for multiple testing.

In summary, SeTesT provides a general framework for detecting selection based on genomic sequencing data of transmitted viruses. The authors found new potential candidates for selection in Vpu. However, the results suggest that a higher number of transmitter–recipient pairs is required to improve sensitivity of detecting selection. Besides HIV transmission events, SeTesT could be used in other settings and for different viruses. For instance, it could also be used for estimating selection on the genome of the Hepatitis C virus, given that the genetic bottleneck for an intravenous transmission mode could be estimated.

PubMed

20th April Fursa et al., Hepatitis C virus cascade of care in Europe


The hepatitis C cascade of care in HIV/hepatitis C virus coinfected individuals in Europe: regional and intra-regional differences.   AIDS

Fursa et al. aimed to identify gaps in the care for individuals with HIV and hepatitis C virus (HCV) infection in the EuroSIDA cohort. Using the cascade of care method, the authors monitored the progress towards the WHO target of diagnosing 90% of all individuals with HCV coinfection, and treating 80% of those diagnosed.

The cascade of care described (1) the number of anti-HCV antibody positive individuals, (2) the proportion of individuals who ever had an HCV-RNA test, and (3) the proportion of individuals currently HCV-RNA positive. In addition, authors assessed the proportion of chronically infected individuals who ever started and completed anti-HCV treatment, respectively. The cascade of care was assessed separately for five European regions: South (e.g. Greece, Italy), Central-West (e.g. Switzerland, France), North (e.g. Denmark, Finland), Central-East (e.g. Poland, Romania), and East (e.g. Ukraine, Belarus).

Of 22’356 EuroSIDA participants, 20’437 (91.4%) ever had an anti-HCV antibody test, and 40.7% were anti-HCV positive. For this study, 4773 anti-HCV positive individuals under active follow-up were included (median age 42, IQR 38-46; 70% men; HIV transmission with injection drug use in 57% of cases). Of those, 4446 (93.1%) ever had HCV-RNA measured, of which 19% were HCV-RNA positive at the last visit closest to October 2019. HCV-RNA positivity ranged from 10% in Central-West to 33% in East Europe. Overall, 72.5% of all individuals estimated to have had chronic HCV infection ever started HCV treatment, with 98% of them having completed the treatment. The proportion of individuals who received treatment was highest in Central-Western Europe (85.1%), and lowest in Eastern Europe (46.7%). With a proportion of just below 80%, Switzerland had the lowest HCV treatment rate of the Central-Western region, thereby missing the WHO targets.

Taken together, the present study performed in the era of highly effective direct-acting antivirals revealed regional differences in the HCV cascade of care, with the largest gaps in HCV-RNA testing and treatment coverage detected in Eastern Europe. The detailed analysis in this pan-European cohort identified distinct regional and country level gaps, allowing stakeholders to take targeted actions to reach the WHO hepatitis C elimination targets.

PubMed

4th April Congratulation to Roger Kouyos !

It is with great pleasure that we inform you that the Swiss National Science Foundation (SNF) will support the following project of Roger Kouyos

The Evolutionary Epidemiology of HIV Elimination

The awarded amount is CHF 698’541 for a 4 years period starting May 2022 until April 2026.

partners: Andri Rauch, Huldrych Günthard, Mary-Ann Davies, Niko Beerenwinkel

We wish Roger Kouyos and his partners all the best for this project!

Kind regards,
Huldrych Günthard
President of the SHCS

1st April Tepekule et al., Impact of latent tuberculosis on diabetes


Impact of latent tuberculosis infection on the incidence of type 2 diabetes mellitus in HIV-infected participants in the Swiss HIV Cohort Study.   Journal of Infectious Diseases

Tepekule et al. assessed whether latent tuberculosis infection (LTBI) is a risk factor for diabetes among people living with HIV in the Swiss HIV Cohort Study.

The authors compared the risk of developing diabetes in patients with LTBI (defined as having a positive tuberculin skin test or interferon-γ release assay) and in those without LTBI. They used time-dependent Cox proportional hazards regression models adjusted for sex, ethnicity, and time-varying calendar year, age, BMI, ART treatment status, CD4 cell counts, and smoking status. The adjustment was performed using multivariable regression and inverse probability weighting, the latter allowing an estimation of the average causal effect

The study included 10’841 individuals with an LTBI test available (70% male, 14.2% of African origin, 37% were overweight or obese). Overall, 974 individuals had LTBI (69% by means of tuberculin skin testing, and 25% by interferon-γ release assay). Within the first 10 years after LTBI testing, 5.5% of patients with a positive test developed diabetes (60 cases), compared to 3.8% of individuals without LTBI (433 cases, log-rank test p = 0.006). The hazard ratios were 1.44 (95% CI 1.09-1.90) using multivariable Cox regression, and 1.47 (95% CI 1.06-2.03) after adjustment with inverse probability weighting, indicating a 47% risk increase for diabetes with LTBI. These findings were robust across several sensitivity analyses.

In summary, the study shows that LTBI may be a risk factor for diabetes mellitus. In people living with HIV, LTBI has previously been associated with lower HIV viral loads and a lower risk for opportunistic infections. However, the present findings indicate that this state of chronic low-grade inflammation may lead to increases in individuals' risk for metabolic diseases.

PubMed

24th March Wymant et al., A highly virulent variant of HIV-1 circulating in the NL


A highly virulent variant of HIV-1 circulating in the Netherlands.   Science

Wymant et al. on behalf of the ATHENA HIV Observational Cohort and the BEEHIVE Collaboration report on the discovery of a highly virulent variant of subtype-B HIV-1 in the Netherlands.

In this study, 109 individuals with this variant had a 0.54 to 0.74 log10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6’604 individuals with other subtype-B strains. Without treatment, advanced HIV-CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences—is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant.

Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence.

In conclusion, this study shows that widespread treatment is helpful to prevent new virulent variants, not harmful. The absolute fitness of viral variants must be considered in addition to their relative fitness, and treatment reduces the total onward transmission over the course of one infection, regardless of virulence. Early treatment also prevents CD4 cell decline from leading to later morbidity and mortality; thus clinical, epidemiological, and evolutionary considerations are aligned. The discovery of a highly virulent and transmissible viral variant therefore emphasizes the importance of access to frequent testing for at-risk individuals and of adherence to recommendations for immediate treatment initiation for every person living with HIV.

PubMed

16th March VITA Label for the SHCS Biobank


We are happy to announce that our SHCS Biobank has been awarded with the VITA Label by the Swiss Biobanking Platform (SBP).

This label demonstrates compliance with the applicable legal and ethical framework. This labelling approach is part of our long-term strategy to strengthen biobanking practices and provide high-quality samples to the research community.

https://www.biobanksqan.ch/#/biobanks/4346 

 

10th March Greenberg et al., INSTI use and cancer incidence


Integrase strand transfer inhibitor use and cancer incidence in a large cohort setting.   Open Forum Infectious Diseases

Greenberg et al. on behalf of the RESPOND Study Group aimed to assess whether there is an association between integrase strand transfer inhibitors (INSTI) use and the incidence of cancer, among people with HIV (PWH) in real-life settings in the International Cohort Consortium of Infectious Diseases (RESPOND).

Participants were followed from baseline (latest of local cohort enrollment or January 1, 2012) until the earliest of first cancer, final follow-up, or December 31, 2019.

Of 29’340 individuals, 74% were male, 24% were antiretroviral treatment (ART)-naive, and median baseline age was 44 years (interquartile range [IQR], 36–51). Overall, 13’950 (48%) individuals started an INSTI during follow-up. During 160’657 person-years of follow-up ([PYFU] median 6.2; IQR, 3.9–7.5), there were 1’078 cancers (incidence rate [IR] 6.7/1000 PYFU; 95% confidence interval [CI], 6.3–7.1). The commonest cancers were non-Hodgkin lymphoma (n = 113), lung cancer (112), Kaposi’s sarcoma (106), and anal cancer (103). After adjusting for potential confounders, there was no association between cancer risk and INSTI exposure (≤6 months vs no exposure IR ratio: 1.15 [95% CI, 0.89–1.49], >6–12 months; 0.97 [95% CI, 0.71–1.32], >12–24 months; 0.84 [95% CI, 0.64– 1.11], >24–36 months; 1.10 [95% CI, 0.82–1.47], >36 months; 0.90 [95% CI, 0.65–1.26] [P= .60]). In ART-naive participants, cancer incidence decreased with increasing INSTI exposure, mainly driven by a decreasing incidence of acquired immune deficiency syndrome cancers; however, there was no association between INSTI exposure and cancer for those ART-experienced (interaction P <.0001).

In conclusion, there was no association between the risk of cancer and cumulative exposure to INSTIs among ART-experienced PWH. The risk of cancer decreased with increasing exposure to INSTIs among ART-naive individuals, which was mainly driven by a decreasing incidence of AIDS-defining cancers.

PubMed

1st March Hachfeld and Atkinson et al., Women with HIV transitioning through menopause


Women with HIV transitioning through menopause: Insights from the Swiss HIV Cohort Study.   HIV Medicine

Hachfeld and Atkinson et al. determined the prevalence of menopause, the age of its onset, and risk factors for early menopause among women in the Swiss HIV Cohort Study (SHCS).

All women who reported menopause (defined as the absence of menstrual bleeding for at least 12 months) were included in the study. Onset before the age of 45 years was considered as early menopause, and before 40 years as premature ovarian insufficiency. The authors assessed the proportion of women in the SHCS with menopause over time and used multivariable logistic regression to explore risk factors for its early onset.

Reflecting the aging of the SHCS, the proportion of women in menopause rose from 11.5% in 2010 to 36% in 2018. For the present study, 1’130 women without menstrual bleeding for at least 12 months were included. Sixty-seven percent were Caucasian and 25% were of African origin, the median age at menopause was 50 years (range 32 - 55), 115 women (10%) were classified as having an early menopause, and 23 (2%) had premature ovarian insufficiency. Importantly, 27% of the study participants were diagnosed with depression or currently received psychiatric care. In multivariable analyses, women of African origin were most likely to have early menopause (adjusted odds ratio 4.2, 95% CI 2.5 - 7.2), whereas no other covariates (including HIV-associated factors such as CD4 cell count, viral suppression, or hepatitis coinfection) were significantly associated with the age of menopause onset. The authors also noted that within the 36 months after documentation of menopause, 11% of women received hormone replacement therapy, and 27% had a bone mineral density measurement to evaluate the risk for osteoporosis.

In summary, the present study highlights the importance of addressing menopause in the clinical care of people living with HIV. The high proportion of psychiatric conditions is concerning and warrants special attention in the care of menopausal women living with HIV. Although menopause onset occurred 2 years earlier in women living with HIV compared with HIV-negative women in Switzerland, these findings were mainly driven by the high proportion of women of African origin, whereas HIV-related factors seemed to play a lesser role. Finally, access to hormone replacement therapy and screening for osteoporosis should be improved for optimal treatment of women living with HIV.

PubMed

23rd February Delabays et al., CVR assessment in PLWH compared to the general population


Cardiovascular risk assessment in people living with HIV compared to the general population.   European Journal of Preventive Cardiology

Delabays et al. aimed to assess and to compare the accuracy of cardiovascular risk scores in people living with HIV (PLWH) and individuals from the general population using the CoLaus/PsyCoLaus cohort. The CoLaus/PsyCoLaus study is a Swiss population-based prospective cohort investigating clinical, psychological, genetic, and social determinants of cardiovascular diseases.

The authors used three validated prediction scores: i) the Data-Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) risk score, ii) the Systematic COronary Risk Evaluation 2 score (SCORE2) and iii) the Pooled Cohort Equations (PCE) score. All scores were calculated in participants free from atherosclerotic cardiovascular disease (ASCVD) between 2003 and 2009. They tested discrimination and calibration, and the value of adding HIV-specific factors to scores using the net reclassification improvement (NRI).

In total, 6’373 [mean age, 40.6 years (SD, 9.9)] PLWH from the Swiss HIV Cohort Study (SHCS) and 5’403 [52.8 years (SD, 10.7)] individuals from the CoLaus/PsyCoLaus study were eligible for analysis. During mean follow-ups of 13.5 (SD, 4.1) in SHCS and 9.9 (SD, 2.3) years in CoLaus/PsyCoLaus study, 533 (8.4%) and 374 (6.9%) people developed an incident ASCVD, respectively. This translated into age-adjusted incidence rates of 12.9 and 7.5 per 1000 person-year, respectively. In SHCS, SCORE2, PCE, and D:A:D presented comparable discriminative capacities [area under the receiver operating characteristic curve of 0.745 (95% confidence interval, CI, 0.723–0.767), 0.757 (95% CI, 0.736–0.777), and 0.763 (95% CI, 0.743–0.783)]. Adding HIV-specific variables (CD4 nadir and abacavir exposure) to SCORE2 and PCE resulted in an NRI of -0.1% (95% CI, -1.24to 1, P = 0.83) and of 2.7% (95% CI, 0.3–5.1, P = 0.03), respectively.

In conclusion, the study shows that PLWH are still presenting a two-fold higher incidence rate of ASCVD compared to individuals from the general population, making the implementation and validation of prevention tools an urgent need. In people taking lipid-lowering treatments, PLWH less often reached LDL-C targets compared to individuals from the general population in the same category of risk. Using either SCORE2 or PCE in PLWH is valid to predict ASCVD, notably due to their set of variables that are easier to use compared to more complex scores integrating HIV-specific data. Adding HIV-specific factors to scores developed for the general population did not result in a clinically significant improvement.

PubMed

15th February Congratulations to Katharina Kusejko


Dear members and friends of the SHCS,

We are very pleased to announce that Katharina Kusejko has won the Pfizer prize in the field of infectiology with the publication

Diagnosis of latent tuberculosis infection is associated with reduced HIV viral load and lower risk for opportunistic infections in people living with HIV

Congratulations to Katharina Kusejko!

We wish her all the best for further research projects.

Kind regards,

Huldrych Günthard
President of the SHCS

 

9th February Schoepf et al., Telomere length and HIV


Telomere length declines in persons living with HIV before antiretroviral therapy start but not after viral suppression: A longitudinal study over >17 years.   Journal of Infectious Diseases

Telomere length (TL) shortens with age, and short TL is associated with coronary artery disease (CAD) and all-cause mortality in the general population. In people with HIV (PWH), associations of short TL with CAD events, metabolic syndrome, and neurocognitive impairment are reported. PWH have shorter TL and may have accelerated or accentuated aging and an increased risk of age-associated diseases compared with HIV-negative persons.

The aim of this study was to measure the rate of TL change during >3 years of untreated chronic HIV infection in participants of the Swiss HIV Cohort Study (SHCS) and to assess in these same PWH whether the rate of TL change continues to be affected during >3 years of suppressive ART.

The author team measured TL change in peripheral blood mononuclear cells by quantitative polymerase chain reaction in 107 Swiss HIV Cohort Study participants with longitudinal samples available both before and during suppressive ART. They obtained uni-/multivariable estimates for longitudinal TL dynamics including age, sex, and CD4/ CD8 ratio. Further, they assessed the effect of (1) individual antiretrovirals and (2) an individual TL-polygenic risk score (TL-PRS) based on 239 single-nucleotide polymorphisms on TL in 798 additional participants from our previous longitudinal studies.

During untreated HIV infection (median observation, 7.7; interquartile range [IQR], 4.7–11] years), TL declined significantly (median −2.12%/year; IQR, −3.48% to −0.76%/year; P = .002). During suppressive ART (median observation, 9.8; IQR, 7.1–11.1 years), there was no evidence of TL decline or increase (median+ 0.54%/year; IQR, −0.55% to + 1.63%/year; P = .329). The TL-PRS contributed to TL change (global P= .019) but particular antiretrovirals did not (all P > .15).

In conclusion, the study shows that TL declines significantly during almost 8 years of untreated HIV infection, with a significant association with an individual TL-PRS. Telomere length is stable during suppressive ART when measured longitudinally in the same participants, with no evidence of further TL decline or increase during almost 10 years after viral suppression. The effects of untreated HIV and suppressive ART on TL change appear large and thus clinically relevant. By contributing to TL preservation, suppressive ART may have a favorable effect on biological aging and the risk of aging-associated comorbidities in PWH.

PubMed

2nd February Rüeger et al., The influence of human genetic variation on Epstein-Barr virus sequence diversity


The influence of human genetic variation on Epstein-Barr virus sequence diversity.  Scientific Reports

Rüeger, Hammer, and Loetscher et al. looked for associations between the human genome and genetic variants of Epstein-Barr virus (EBV) among individuals living with HIV in the Swiss HIV Cohort Study.

The authors hypothesized that EBV viremia is most prevalent in immunosuppressed individuals, and therefore identified treatment-naïve patients living with HIV with a CD4+ cell count below 200 cells/μL. Human genotyping, as well as EBV genome sequencing, was performed, and joint analyses for associations (so-called genome-to-genome analyses) were done using mixed models.

The study included 206 men and 62 women with a median age of 40 years (range 20-78). Of those, 57.1% of EBV sequences comprised predominantly EBNA T1, 5.7% predominantly EBNA T2, and 37.2% included multiple haplotypes. Genome-wide association studies (GWAS) were performed for 535 EBV amino acids and 52 EBV genes. Significant associations were identified between 25 human SNPs and viral variants mapping to 2 EBV genes and one EBV amino acid: the gene BALF5 which is involved in viral DNA replication, the gene BBRF1 which is involved in viral DNA translocation during packaging, and the amino acid BRLF1:p.Lys316Glu which plays a role in reactivation from latency and regulation of viral transcription. Strong associations were observed between the BALF5 gene and 17 SNPs in the human UNC5D gene, which is involved in the regulation of apoptosis.

To summarise, the present study is the first to identify genomic interactions between the human host and EBV. If confirmed in similar studies in HIV uninfected patients with EBV viremia, these findings may contribute to understanding the pathogenic processes and the very diverse clinical consequences of EBV infection.

PubMed

26th January Amele et al., HCV reinfection after HCV therapy among HIV/HCV-coinfected individuals in Europe


HCV reinfection after HCV therapy among HIV/HCV co-infected individuals in Europe.    HIV Medicine

Amele et al. on behalf of the EuroSIDA study group aimed to evaluate the 2-year prevalence of HCV reinfection after Interferon (IFN-) based or IFN-free direct acting agents (DAA) HCV therapy among HIV/HCV-coinfected individuals from the pan- European EuroSIDA cohort study.

The authors assessed factors associated with odds of reinfection by 2 years after sustained virological response (SVR) in EuroSIDA participants with one or more HCV- RNA test and 2 years follow-up.

Overall, 1’022 individuals were included. The median age was 50 (interquartile range: 43–54 years), and most were male (78%), injection drug users (52%), and received IFN-free DAAs (62%). By 24 months, 75 [7.3%, 95% confidence interval (CI): 5.7–8.9%] individuals were reinfected. Among individuals treated prior to 2014, 16.1% were reinfected compared with 4.2% and 8.3%, respectively, among those treated during or after 2014 with IFN-free and IFN-based therapy. After adjustment, individuals who had started treatment during or after 2014 with IFN-free or IFN-based therapy had significantly lower odds of reinfection (adjusted odds ratio = 0.21, 95% CI: 0.11–0.38; 0.43, 95% CI: 0.22–0.83) compared with those who had received therapy before 2014. There were no significant differences in odds of reinfection according to age, gender, European region, HIV transmission risk group or liver fibrosis.

In conclusion, this study of 1’022 HIV/HCV-coinfected people from all regions of Europe found that the HCV reinfection rate in the first 2 years after SVR was 7.3%, but with lower odds of reinfection among those treated in recent years or using IFN-free DAA therapy. Lower odds of reinfection among those treated in recent years can possibly be explained by a lower prevalence of HCV infection in the population due to the scale-up of DAA since 2014. The study found no differences in odds of reinfection when comparing IFN-treated (±DAAs) in 2014 or later with those who had received IFN-free DAA therapy in the same period. Hence, this data do not indicate that the ease of short, well-tolerated and effective DAA therapy compared with IFN-based therapy leads to increased risk of disinhibition and high rates of HCV reinfection after DAA therapy in this population.

PubMed

20th January Mocroft et al., Hepatitis B virus infection and nonliver malignancies


The association between hepatitis B virus infection and nonliver malignancies in persons living with HIV: results from the EuroSIDA study.    HIV Medicine

Mocroft and Miró et al. aimed to determine whether people living with HIV (PLWH) and hepatitis B virus (HBV) in the EuroSIDA study are at increased risk for nonliver cancer compared to PLWH without HBV.

All participants from the EuroSIDA study with known HBV status were included. HBV coinfection was defined as positive HBsAg, and the main outcome was the occurrence of any nonliver malignancy, including anal cancer, lung cancer, non-Hodgkin’s lymphoma and other cancers. Multivariable Poisson regression was used to compare incidence rates between individuals with and without HBV coinfection. The roles of HBV treatment and detectable HBV DNA were explored in additional models.

The study included 17’485 individuals, contributing 151’766 person-years of follow-up (PYFU). The median age was 41 years (IQR 35-49), median CD4 count 440 cells/μL (IQR 284-634), and 4’601 (26.3%) were women. HBV coinfection was present in 1’269 (7.2%) cohort participants. A total of 1’360 nonliver cancers occurred in 1’298 individuals (incidence rate [IR] 8.55 per 1’000 PYFU, 95% CI 8.09-9.92). The most common cancers were anal cancer (188 events), lung cancer (147 events) and non-Hodgkin’s lymphoma (131 events). In a multivariable analysis adjusted for age, CD4 cell count, HIV viral load, liver fibrosis and smoking status, individuals with HBV coinfection were at increased risk for the development of any nonliver malignancy compared to those without HBV (incidence rate ratio [IRR] 1.23, 1.00-1.51). The increased risk for HBV infected vs. HBV uninfected PLWH was most pronounced in individuals who did not receive tenofovir, emtricitabine or lamivudine during follow-up (IRR 1.45, 1.04-2.01), and in persons with detectable HBV DNA (IRR 1.37, 1.00-1.89 compared to HBV negative individuals).

In summary, the present study indicates that people living with HIV and HBV may be at increased risk for nonliver cancer. The association was strongest for individuals without HBV-active treatment and detectable HBV DNA, suggesting a role of HBV replication as a possible risk factor for the development of nonliver malignancies.

PubMed

12th January Balakrishna et al. Bacterial pneumonia in the SHCS


Decreasing incidence and determinants of bacterial pneumonia in people with HIV: The Swiss HIV Cohort Study.    Journal of Infectious Diseases

Balakrishna et al. aimed to estimate the incidence rate of bacterial pneumonia in the Swiss HIV Cohort Study (SHCS) and to assess the risk factors associated with incidence of bacterial pneumonia.

The authors included 12’927 people with HIV (PWH) with follow-ups between 2008 and 2018. These patients had 985 bacterial pneumonia events during a follow-up of 100’779 person-years. Bacterial pneumonia incidence significantly decreased from 13.2 cases/1000 person-years in 2008 to 6.8 cases/1000 person-years in 2018. Older age, lower education level, intravenous drug use, smoking, lower CD4-cell count, higher HIV load, and prior pneumonia were significantly associated with higher bacterial pneumonia incidence. Notably, CD4 cell counts 350–499 cells/μL were significantly associated with an increased risk compared to CD4 ≥ 500 cells/μL (adjusted hazard ratio, 1.39; 95% confidence interval, 1.01–1.89).

In conclusion, decreasing incidence over the last decade can be explained by increased CD4-cell counts and viral suppression and decreased smoking frequency. Hence, improvements in the cascade of care of HIV and decrease in smoking may have mediated a substantial decrease in bacterial pneumonia incidence.

PubMed

6th January Kowalska et al., Prevalence and outcomes of pregnancies in women with HIV


Prevalence and outcomes of pregnancies in women with HIV over a 20-year period.    AIDS

Kowalska et al. evaluated time trends and outcomes of pregnancies among European women with HIV between 1996 and 2015 in the EuroSIDA cohort.

Audits were performed annually to collect information on pregnancies in female cohort participants aged between 16 and 50 years. Outcomes were categorized as birth of a HIV negative child, HIV positive child or child with unknown HIV status, stillbirth, spontaneous abortion, medical abortion, still pregnant or unknown. Pregnancy trends were analysed in three distinct periods: 1996-2002, 2003-2009 and 2010-2015, and logistic regression with generalized estimating equations was performed to assess factors associated with pregnancy.

The study included 5’535 women of reproductive age, median age of 33 years (IQR 29-39 years), most were of white ethnicity, and 62% acquired HIV heterosexually. Of those women, 4’217 (76.2%) had pregnancy information available. Between 1996 and 2015, 912 women reported a total of 1’315 pregnancies. The proportion of women who reported at least one pregnancy was 15.3% between 1996 and 2002, 17.3% between 2003 and 2009, and 12.6% between 2010 and 2015. In multivariable analyses, younger women, women with previous pregnancies and participants from Western/Central and Northern Europe were most likely to report a pregnancy, whereas women from South, Central East and Eastern Europe and individuals with previous AIDS-defining illnesses were less likely to report a pregnancy. Out of 690 live births (69.1%), 23 children were HIV-positive (3.3%), 342 were HIV-negative (49.6%), and the HIV status was unknown in 325 (47.1%). Spontaneous abortions occurred in 103 pregnancies, and 199 women had medical abortions.

In summary, the present study shows that around 22% of women in the EuroSIDA cohort reported one or more pregnancies. The highest proportion of pregnancies occurred between 2003 and 2009, and declined in recent years - reflecting trends in the general population. Women reported a high rate of medical abortions, highlighting the importance of integrating family planning and ensuring access to sexual health counselling for women with HIV.

PubMed