28th March Béguelin et al., Hepatitis delta infection among PWHIV in Europe

Hepatitis delta infection among persons living with HIV in Europe. Liver International

Béguelin et al. described the prevalence and clinical consequences of hepatitis delta (HDV) infection among individuals with HIV and hepatitis B virus (HBV) coinfection in Europe using data from the Swiss HIV Cohort Study and EuroSIDA.

All individuals with a positive HBsAg between 01/1988 and 12/2019 were considered, and if not already available from clinical specimens, HDV serology and HDV RNA were measured using stored samples. For prevalence estimates, HDV infection was defined as positive serology, and prevalence was calculated separately for the European regions (North-western Europe, Southern Europe, and Eastern Europe). Overall mortality, liver-related mortality, and incidence of hepatocellular carcinoma (HCC) were compared between individuals with HIV/HBV/HDV coinfection and those with HIV/HBV without HDV infection using multivariable Cox regression models.

Of 2’793 individuals with a positive HBs-Ag, 1’556 (56%) had results for HDV serology available. The prevalence of HDV coinfection overall was 15.2% (95% CI 13.5-17.1), and was similar across European regions. The highest prevalence was found among individuals who inject drugs, 50.5% being seropositive for HDV (95% CI 45.3-55.7). Compared to individuals with HIV/HBV coinfection, those with additional HDV coinfection were more likely to die from any cause (adjusted hazard ratio [aHR] 1.8, 95% CI 1.3-2.5) and from liver-related causes (aHR 3.1, 1.7-5.7), and were at higher risk for developing HCC (aHR 6.3, 2.5-16.0).

In summary, this large cohort collaboration found an overall prevalence of 15% of HDV infection among individuals with HIV/HBV coinfection, and of 50% among individuals who inject drugs. As individuals with additional HDV infection are at increased risk for morbidity and mortality, the present study underlines the importance of a systematic HDV screening of all individuals with HIV/HBV coinfection to provide HCC close clinical follow-up including screening for HCC.


22nd March Herderschee et al., High-dimensional immune phenotyping of blood cells by mass cytometry in patients infected with HCV

High-dimensional immune phenotyping of blood cells by mass cytometry in patients infected with HCV.   Clinical Microbiology and Infection

Herderschee et al. aimed to assess whether elimination of hepatitis C (HCV) with direct-acting antivirals (DAA) leads to a restoration of the immune system affected by HCV.

To answer this research question, the authors analyzed before and 12 weeks after sustained virological response (SVR12) to DAA therapy 22 cell populations by mass cytometry in blood collected from ten healthy control individuals and 20 HCV-infected patients with or without human immunodeficiency virus (HIV) infection.

They found that HCV infection altered the frequency of 14/22 (64%) blood cell populations. At baseline, the frequencies of intermediate monocytes, non-classical monocytes, conventional dendritic cells type 2 and CD56dim natural killer cells were reduced by 35% to 65%, particularly in HCV/HIV co-infected patients. In contrast, activated double-negative T cells activated CD4 T cells and activated CD8 T cells were increased 1.4 to 3.5 times. Upon stimulation with Toll-like receptor ligands, the expression of cytokines was up-regulated in 7/9 (78%) and 17/19 (89%) of the conditions in HCV- and HCV/HIV-infected patients, respectively. Most alterations persisted at SVR12.

In conclusion, high-dimensional immune profiling of blood cells provided a broad and in-depth picture of the systemic immune dysregulation induced by chronic HCV. A salient finding was the observation of a profound derangement of the homeostasis of the immune system triggered by HCV, characterized by a pro-inflammatory innate immune signature extending well beyond the clearance of HCV, especially in HCV/HIV-infected patients. This inflammatory phenotype may contribute to the pathogenesis of systemic complications of chronic HCV infection.


9th March Surial et al., PAGE-B score for HCC risk prediction in HIV/HBV coinfection

External validation of the PAGE-B score for HCC risk prediction in people living with HIV/HBV coinfection.    Journal of Hepatology

Surial et al. assessed the usefulness of PAGE-B to determine the risk of developing hepatocellular carcinoma (HCC) among people with HIV and hepatitis B virus (HBV) coinfection from four large European cohorts of people with HIV. PAGE-B is an easy-to-calculate score (range: 0-25) based on the covariates age, sex, and platelet count, and is widely used to determine the need for HCC screening in individuals with HBV mono-infection.

The study included all individuals with HIV/HBV coinfection who received tenofovir-containing antiretroviral therapy from the ATHENA cohort (Netherlands), the Aquitaine cohort (France), EuroSIDA, and the Swiss HIV Cohort Study (SHCS). Hepatocellular carcinoma cases were identified using standardized case report forms in all cohorts. The prediction model was evaluated by calculating the c-index (with 1.0 indicating the highest and 0.5 indicating the lowest possible accuracy of the predictions) and negative predictive values.

The study included 2’963 individuals with HIV/HBV coinfection; the median age at tenofovir start was 41 years, 16% were female, and 18% were of African origin. PAGE-B was <10 in 26.5%, 10–17 in 57.7%, and ≥18 in 15.7% of patients. Within a median follow-up of 9.6 years, 68 HCCs occurred. The c-index was 0.77 (range 0.73-0.80 across multiple imputations), close to the one found in the original derivation study (c-index 0.80). A PAGE-B cut-off of <10 had a negative predictive value for developing an HCC within 5 years of 99.4% and would spare unnecessary HCC screening in 27% of individuals. 

Taken together, the present study shows that the PAGE-B score performs well in individuals with HIV/HBV coinfection. In addition, the high negative predictive value of 99.4% in this population indicates that the PAGE-B score is useful to determine the need for HCC screening.


1st March Zhao et al., Phylogenetic estimation of the viral fitness landscape of HIV-1 set-point viral load

Phylogenetic estimation of the viral fitness landscape of HIV-1 set-point viral load.    Virus Evolution

Set-point viral load (SPVL), a common measure of human immunodeficiency virus (HIV)-1 virulence, is partially determined by viral genotype. Epidemiological evidence suggests that this viral property has been under stabilising selection, with a typical optimum for the virus between 104 and 105 copies of viral RNA per ml.

In the current study, Zhao et al. aimed to detect transmission fitness differences between viruses from individuals with different SPVLs directly from phylogenetic trees inferred from whole-genome sequences. They used the local branching index (LBI) as a proxy for transmission fitness.

The authors found that LBI is more sensitive to differences in infectiousness than to differences in the duration of the infectious state. By analysing subtype-B samples from the Bridging the Evolution and Epidemiology of HIV in Europe project, they inferred a significant positive relationship between SPVL and LBI up to approximately 105 copies/ml, with some evidence for a peak around this value of SPVL.

In sum, the study results suggest that there is evidence of selection against low values of SPVL in HIV-1 subtype-B strains, likely related to lower infectiousness, and perhaps a peak in the transmission fitness in the expected range of SPVL. The less prominent signatures of selection against higher SPVL could be explained by an inherent limit of the method or the deployment of antiretroviral therapy. The authors propose, that the application of this phylogeny-based method should also be expanded to other viruses and other phenotypes as well, not limited to SPVL.


15th February Bosetti and Mugglin et al., Risk factors and incidence of sexually transmitted infections in the SHCS

Risk factors and incidence of sexually transmitted infections in the Swiss HIV Cohort Study.    Open Forum Infectious Diseases

Bosetti and Mugglin et al. assessed the incidence and related risk factors of sexually transmitted infections (STI) among people living with HIV in the Swiss HIV Cohort Study (SHCS).

The authors considered all sexually active cohort participants with follow-up between April 2017 and November 2019. All individuals were screened for syphilis every two years or yearly if they were men who have sex with men (MSM). Testing for chlamydia and gonorrhea was performed at the discretion of cohort physicians and included asymptomatic screening as well as targeted testing of symptomatic individuals. Risk factors for STIs were evaluated using multivariable Poisson regression.

The study included 7’667 sexually active individuals (median age 51 years, 27.2% were women, 46.7% were MSM). During 17’766 person-years (PY) of follow-up, 1’634 STIs were reported (incidence rate 91.9 per 1000 PY), with 41.1% of STIs being asymptomatic. Of those, syphilis was diagnosed in 573 episodes (35.1%), followed by gonorrhea in 497 episodes (30.4%), and 418 (25.6%) episodes were chlamydia infections. The most important risk factors for any STI were male sex (adjusted incidence rate ratio [aIRR] 2.03, 95% CI 1.36–3.02), being MSM (aIRR 3.62, 2.99–4.55), age 18-34 years (aIRR 1.78, 1.51–2.10), having occasional sexual partners (aIRR 6.87, 5.40–8.73) and injecting drug use (aIRR 2.48, 1.91–3.23).

In summary, the present study shows a high incidence of STIs in the SHCS. Together with the high proportion of asymptomatic infections, these findings underline the importance of performing regular screening of sexually active individuals with risk factors for STIs.


9th February Hamusonde et al., Triggers of change in sexual behavior among people with HIV

Triggers of change in sexual behavior among people with HIV: The Swiss U = U statement and Covid-19 compared.    Journal of Infectious Diseases

Hamusonde et al. aimed to investigate the impact of 2 external factors (termed “triggers” herein) which might influence sexual behavior: (1) the Swiss U = U statement (“trigger of relief”), and (2) the COVID-19 social distancing (“trigger of restriction”). For this purpose, they investigated over 20 years of long-term trajectories in condom use and occasional partnership among people with HIV in the Swiss HIV Cohort Study (SHCS).

Trajectories of condom use were assessed among 2’212 men who have sex with men (MSM) and 2’417 heterosexuals (HET). Trajectories of occasional partnership were assessed among 5’617 MSM and 6’356 HET.

Since the publication of the Swiss Statement in 2008, consistent condom use with an HIV-negative stable partner declined from over 90% to around 30% in 2021. Consistent condom use with an HIV-positive stable partner declined from over 50% to around 10%. The long-term trajectories in condom use were remarkably similar between MSM and HET.

Consistent condom use with occasional partners declined following the Swiss Statement with a more pronounced decrease among MSM. Occasional partnership frequencies were consistently higher among MSM than HET with stable levels until the COVID-19 pandemic. Shortly after the onset of the COVID-19 pandemic, there was a marked decline in the frequency of occasional partnership among MSM.

In sum, this study shows that overall external triggers of relief and restriction had a marked impact on sexual behavior among people with HIV.


1st February Jaschinski et al., Recent abacavir use and incident CVD in contemporary treated people living with HIV

Recent abacavir use and incident cardiovascular disease in contemporary treated people living with HIV.   AIDS

Jaschinski et al. analyzed the relationship between abacavir (ABC) use and the development of cardiovascular disease (CVD) events among participants of RESPOND, a large collaboration of HIV cohorts from Europe and Australia.

All individuals with follow-up after 2012 were included. CVD events included a composite of myocardial infarction, stroke, or invasive cardiovascular procedures. The association between recent ABC use (within the last 6 months) and CVD events were evaluated using negative binomial regression models, adjusted for clinical and HIV-specific confounders.

The study included 29’340 individuals, of whom 74% were men, 43% were of Western European origin, 45% were MSM, and the median age was 44 years (interquartile range 36-51). Within 6.2 years of follow-up (3.9-7.5), 748 CVD events occurred: 299 myocardial infarctions, 228 strokes, and 221 invasive cardiovascular procedures. After adjusting for confounders, the incidence rate ratio (IRR) for developing CVD events was higher for individuals with recent ABC use compared to those who did not receive ABC (adjusted IRR 1.40, 95% CI 1.20-1.64).

In summary, the present study found a 40% CVD risk increase for individuals who receive ABC as part of their antiretroviral therapy. These results confirm previous findings from the D:A:D cohort, and add to the body of evidence of CVD-related adverse effects of ABC.


25th January Chaudron et al., HIV-1 superinfection screen in the SHCS

A systematic molecular epidemiology screen reveals numerous HIV-1 superinfections in the Swiss HIV Cohort Study.    Journal of Infectious Diseases

Chaudron et al. aimed to study immunodeficiency virus type 1 (HIV-1) superinfection in the Swiss HIV Cohort Study (SHCS). Superinfection is the acquisition of another HIV-1 strain among individuals with an already established HIV-1 infection.

The authors used a phylogeny built from 22’243 HIV-1 partial polymerase sequences to identify potential superinfections among 4’575 SHCS participants with longitudinal sequences. A subset of potential superinfections was tested by near-full-length viral genome sequencing (NFVGS) of biobanked plasma samples.

Based on phylogenetic and distance criteria, 325 potential HIV-1 superinfections were identified and categorized by their likelihood of being detected as superinfections due to sample misidentification. NFVGS was performed for 128 potential superinfections; of these, 52 were confirmed by NFVGS, 15 were not confirmed, and for 61 sampling did not allow confirming or rejecting superinfection because the sequenced samples did not include the relevant time points causing the superinfection signal in the original screen. Thus, NFVGS could support 52 of 67 adequately sampled potential superinfections.

In conclusion, the study confirms that superinfections are rare but not negligible events, with an estimated prevalence of 1% to 7%, most likely an underestimation since detection is challenging. Nevertheless, this work paves the way for follow-up studies to benefit from the sample size and the NGS data generated to molecularly characterize HIV-1 superinfection and investigate other risk factors associated. Better molecular characterization and risk factors understanding could provide further insights into HIV transmission and pathogenesis, benefit HIV vaccine research, and enable preventive measures to raise awareness on HIV-1 superinfection in the community.


19th January Hofmann et al., HBV replication during tenofovir therapy

Hepatitis B virus replication during tenofovir therapy is frequent in HIV/HBV coinfection.    Clinical Infectious Diseases

Hofmann et al. analyzed rates of hepatitis B virus (HBV) suppression with tenofovir-containing antiretroviral therapy (ART), and assessed determinants for ongoing HBV replication despite treatment among people living with HIV and HBV in the Swiss HIV Cohort Study (SHCS).

The present study included all cohort participants with chronic HBV infection. The authors evaluated HBV replication at 2 years and at the latest available follow-up (categorized as suppression if HBV DNA was <20 IU/mL, low-level viremia if HBV DNA was 20-2000 IU/mL, and high-level viremia if HBV DNA was >2000 IU/mL). Risk factors for persistent viral replication (HBV DNA >20 IU/mL) were assessed using multivariable logistic regression.

The study population consisted of 222 individuals with HIV/HBV coinfection on tenofovir-containing ART. The median age was 41 years (IQR 36-47), 19% were female, 21% were of African origin, and 59% had been previously treated with lamivudine- or emtricitabine-containing ART. After 2 years of tenofovir, 61/222 (27%) had persistent HBV replication. Persistent HBV replication was more common among individuals with high HBV-DNA at tenofovir start (adjusted odds ratio [aOR] 1.38, 95% CI 1.20-1.57), and less likely among patients with a CD4 cell count >350cells/μL (aOR 0.41, 0.19-0.90), among people with hepatitis D coinfection (aOR 0.07, 0.01-0.59) and those with good self-reported ART adherence (aOR 0.04, 0.01-0.33). Of the 61 individuals with a replicating HBV infection at 2 years, 14 (23%) had persistent replication at the latest follow-up visit (median 8.4 years after starting tenofovir).

In summary, this work shows that ongoing HBV replication is frequent after 2 years of tenofovir-containing ART, especially in individuals with a high HBV viral load at tenofovir start and suboptimal ART adherence. In contrast, HDV coinfection was associated with higher rates of HBV suppression. As 77% of individuals eventually achieved HBV viral suppression during follow-up, replication after 2 years does not necessarily imply treatment failure. As ongoing viral replication contributes to liver fibrosis and to the development of hepatocellular carcinoma, these findings highlight the importance of continued follow-up of individuals with HIV/HBV coinfection.


11th January Isfordink et al., DAAs in people with HIV/HCV from sub-Saharan Africa or Southeastern Asia

Low risk of failing direct-acting antivirals in people with HIV/HCV from Sub-Saharan Africa or Southeastern Asia: a European cross-sectional study.    Open Forum Infectious Diseases

Isfordink et al. for EuroSIDA, the Swiss HIV Cohort Study, and the ATHENA Observational Cohort aimed to investigate the real-world efficacy of direct-acting antivirals (DAA) treatment in individuals with HIV/hepatitis C virus (HCV) originating from low- and middle-income countries (LMICs), namely for sub-Saharan Africa (SSA) and Southeastern Asia (SEA) in multiple European cohorts of people with HIV (PWH).

The author group retrospectively analyzed data from the above-mentioned cohorts of PWH. The primary outcome was HCV cure defined as sustained virological response at least 12 weeks after the end of treatment (SVR12).

Of the 3’293 individuals with HIV/HCV treated with DAA and with available SVR12 data, 142 were from SSA (n=64) and SEA (n=78). SVR12 was achieved by 60 (94% [95% confidence interval {CI}, 86%–98%]) individuals from SSA and 76 (97% [95% CI, 92%–99%]) from SEA. The genotypes of the 6 individuals failing DAA treatment were 2, 3a, 3h, 4a, 4c, and 6j. For 2 of the 4 unsuccessfully treated individuals with available sequence data at treatment failure, NS5A resistance-associated substitutions were present (30R/93S in an individual with genotype 4c and 31M in an individual with genotype 6j).

In conclusion, the study shows that DAA efficacy in people with HIV/HCV originating from SSA or SEA and living in Europe is high. Although the limited number of participants with genotypes of concern and the lack of data on location of HCV acquisition limit conclusions on DAA efficacy for individuals with HIV/HCV residing in SSA or SEA, it seems unlikely that suboptimal response to DAAs specific to these individuals could become a complicating factor for overall HCV elimination in Europe in the near future.