2017

9th February Kovari et al., HCV and non-liver-related morbidity


Hepatitis C infection and the risk of non-liver-related morbidity and mortality in HIV-positive persons in the Swiss HIV Cohort Study. Clinical Infectious Diseases

Kovari et al. aimed to explore the contribution of hepatitis C virus (HCV) exposure to non-liver-related morbidity and mortality, and to investigate whether successful HCV treatment reduces the risk of non-liver-related events and death by comparing HCV-viremic with successfully treated non-viremic persons, within the Swiss HIV Cohort Study (SHCS).

For the analysis, 2’503 HCV-seropositive cases and 2’503 matched HCV-seronegative controls were included. HCV treatment consisted in 90.1% of pegylated interferon plus ribavirin, and in 9.9% of a regimen containing direct acting agents DAAs (87% interferon based).

HCV-seropositive persons had an increased risk of liver disease (adjusted incidence rate ratio [IRR], 6.29), liver-related death (IRR, 8.24), kidney disease (IRR, 2.43), and osteoporosis/fracture (IRR, 1.43), compared with HCV-seronegative controls. No evidence for an increased risk in HCV-seropositive persons was found for diabetes mellitus, cardiovascular disease, non-AIDS malignancy, and non-liver-related death. Treated patients with non-SVR vs those with SVR had a higher risk of liver events and diabetes mellitus. The increased risk for liver-related deaths disappeared after adjustment for advanced fibrosis. HCV-viremic patients compared to those with SVR had a trend for an elevated incidence of kidney disease, cardiovascular events, and non-AIDS malignancies, but this was statistically not significant.

In conclusion, HCV-exposed, HIV-infected individuals have an increased risk of kidney disease and bone-related events that does not seem to be related to persistent viral replication. In addition to a significant decrease of liver-related disease and death, therapeutic viral eradication leads to a reduction of diabetes mellitus. Prospective large-scale cohort collaborations are needed to further describe the impact of HCV eradication with direct acting agents on non-liver-related morbidity and mortality.

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editorial commentary

2nd February Combes et al., Human papillomavirus antibody response following HAART in MSM


Human papillomavirus antibody response following HAART initiation among MSM.   AIDS

Antibodies to high-risk human papilloma virus (HPV) L1 protein are considered as markers of cumulative HPV exposure, whereas antibodies against HPV E6 protein have been shown to be highly specific markers for HPV-related cancer. In this study, Combes et al. aimed to describe pre and post-highly active antiretroviral therapy (HAART) HPV-L1 and HPV-E6 antibody response in HIV-positive MSM, and the meaning of this response for subsequent HPV-related cancer risk.

Antibodies were tested using a multiplex HPV-serology assay. For each individual, two serum samples, one at HAART initiation (pre-HAART) and another 24 months later (post-HAART), were tested. Identification of HPV-related cancer included data linkage with Swiss cancer registries.

Pre-HAART, 127 (45.2%) participants were seropositive for any high-risk HPV-L1, and 91 (32.4%) were HPV16-L1-seropositive. Only one participant was positive for HPV16-E6. Post-HAART, seropositivity for any high-risk HPV-L1 increased to 170 (60.5%), and HPV16-L1-seropositivity to 135 (48%). Two more individuals seroconverted to HPV16-E6 positivity. Factors associated with seroconversion were low CD4+ cell count [OR 5.28] and low CD4+/CD8+ ratio [OR 6.56] at HAART initiation. Anal cancer incidence was 63/100’000 person-years for post-HAART HPV16-E6 seronegatives versus 3’956/100’000 person-years in seropositives, corresponding to a statistically significant incidence rate ratio of 63.1.

In conclusion, the authors described for the first time, that HAART is associated with seroconversion and increasing titers of HPV-antibodies. Although numbers of cancer cases were small, HAART-related seroconversion seemed to improve the ability of HPV16-L1 and E6 antibody status to discriminate future anal cancer risk.

PubMed

26th January Cecchinato et al., Migration of CCR6+ and CXCR3+ Th cells in HIV


Impairment of CCR6+ and CXCR3+ Th cell migration in HIV-1 infection is rescued by modulating actin polymerization. Journal of Immunology

Cecchinato et al. investigated the mechanisms that might be responsible for a poor repopulation of Th cells in the gut of HIV-1–infected patients, despite successful treatment with antiretroviral therapy (ART).

For this study, 63 adult rhesus monkeys experimentally infected with simian immunodeficiency virus (SIV), 110 mice, and 58 HIV-1–infected patients who were followed in the SHCS, were studied. Patients were divided into three groups according to their CD4 nadir count and the use of ART in the last 3 years.

In both, humans and in the pathogenic model of SIV, Th cells showed an impaired response to chemotactic stimuli, thus preventing their trafficking to peripheral organs. This mechanism was characterized by an inefficient actin polymerization and the hyperactivation of cofilin, an actin-severing protein. The authors showed that impaired response to chemotactic stimuli resulted in accumulation of CCR6+ and CXCR3+ Th cells in the blood of ART-treated HIV-1–infected patients, and their frequencies correlated with a status of chronic immune activation. Although the impaired migration of Th cells is a common feature of both SIV and HIV-1 infection, their accumulation in the blood became evident only in patients successfully treated by ART. Using their mice-model, the authors demonstrated that cytoskeleton remodeling, induced by application of okadaic acid, reverted the impaired response of Th cells to chemotactic stimuli, both in vitro and in vivo.

In conclusion, the authors demonstrated as a proof-of-concept, that efficient T cell migration can be restored by okadaic acid-induced remodeling of the cytoskeleton. Since the use of okadaic acid in vivo is limited due to its high toxicity, this model could be used for testing new compounds, with lower systemic toxicity, with the aim of targeting the cytoskeleton machinery in a number of diseases where chronic immune activation is part of the pathogenic features. The study-findings presented here, imply a novel role for chronic immune activation during HIV-1 infection, which dampens the ability of leukocytes to respond to chemotactic stimuli, thus preventing a complete tissue reconstitution.

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18th January Schäfer et al., Physical activity in the SHCS


High prevalence of physical inactivity among patients from the Swiss HIV Cohort Study.    AIDS CARE

Schäfer et al. assessed levels of self-reported physical activity (PA) over time in 10’540 patients enrolled in the Swiss HIV Cohort Study (SHCS). The SHCS data were compared with data collected in the ’Sport Switzerland’ 2014 survey of the general Swiss population.

During 2009-2014, the percentage of patients reporting no free-time PA declined from 49% to 44%. In contrast, in the two ’Sport Switzerland’ surveys of the general population in 2008 and 2014, the percentage of individuals reporting no sports activities was lower and relatively stable over time with 27% and 26%, respectively. Patients with CDC category C infection and reduced CD4 cell count were less likely to be physically active than those in an early stage of infection and with higher CD4 cell counts. Compared with the general population, data patterns of PA were similar in HIV-infected individuals: Men were more physically active than women, with continuously decreasing levels of free-time PA after the age of 25. Patients with higher completed education reported more free-time PA than those with lower completed education; and residents in the German-speaking regions of Switzerland showed a trend towards higher levels of free-time PA than those in the French- and Italian speaking regions.

In conclusion, integrating PA counselling into the routine care of HIV-infected patients and promoting PA among this population has the potential to improve patients’ general state of health and to reduce their risk of cardiovascular disease.

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12th January Shilaih et al., Role of marginalized populations in HIV-1 transmission in Switzerland


Genotypic resistance tests sequences reveal the role of marginalized populations in HIV-1 transmission in Switzerland.    Scientific Reports

Shilaih et al. aimed to investigate the utility of HIV-1 sequence data from the Swiss HIV Cohort Study (SHCS) and non-cohort sequences to assess the proportion of marginalized/underrepresented populations (e.g., patients facing barriers for enrolment) which might be missed by the SHCS.

A phylogenetic tree was built using 11’127 SHCS and 2’875 Swiss non-SHCS sequences. The non-SHCS sequences were obtained from the database of the ’Bundesamt für Sozialversicherungen’, into which mandatory all genotypic resistance tests in Switzerland have to be entered. Overall, 79% of all patients who ever had a genotypic resistance test performed in Switzerland were enrolled in the SHCS. Non-B subtype (odds-ratio [OR]: 1.9), female gender (OR 1.7), black ethnicity (OR 1.9) and heterosexual transmission group (OR 1.8), were all associated with underrepresentation in the SHCS. There were 344 transmission clusters consisting only of non-SHCS patients. These clusters occurred frequently but were limited in size with a median size of 2 patients and a maximum cluster size of seven patients. Thus, outbreaks outside the SHCS were rather small in numbers. In general, there was a strong overlap between transmission chains among SHCS and non-SHCS populations. 65% of the sequences of the non-SHCS individuals were part of SHCS clusters of > 50 individuals. In addition, the authors were capable to infer based on the sequences the transmission group of considerable numbers of non-SHCS sequences for which no epidemiological data is available, thus allowing to obtain an overall picture of the epidemic also for non-SHCS enrolled HIV infected individuals.

In conclusion, this work highlights the utility of molecular epidemiology in extending and testing the scope of classical epidemiological data. The data suggests that marginalized populations are underrepresented in the SHCS. However, there was no evidence that the SHCS misses larger outbreaks consisting of purely non-cohort patients.

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5th January Gueler et al., Life expectancy among HIV-infected people


Life expectancy in HIV-positive persons in Switzerland: matched comparison with general population.  AIDS

Gueler et al. analyzed life expectancy in the Swiss HIV Cohort Study 1988–2013 and compared life expectancy across levels of education with life expectancy in the general Swiss population, using matched controls from the Swiss National Cohort. 16’532 HIV-positive patients from the Swiss HIV Cohort Study and 927’583 residents from the Swiss National Cohort were included.

The proportion of patients who died during follow-up declined from 65.1% among patients enrolled in the monotherapy era to 2.4% among those enrolled in the most recent combination antiretroviral therapy (cART) era. In the most recent cART era, life expectancy at age 20 years was 52.7 years among participants with compulsory education, compared to 60.0 years among those with higher education. Only slight increases were observed in the general population, from 62.3 to 63.0 years overall, and from 61.1 to 61.5 years in people with compulsory education, and from 65.4 to 65.6 years in people with higher education.

In the most recent cART period, HIV-positive people continued to have an estimated life expectancy that was lower than their peers from the general population. Life expectancy in highly educated HIV-positive patients was similar to the life expectancy of individuals from the general population with compulsory education only. Male sex, smoking, injection drug use, and low CD4+cell counts at enrolment were independently associated with mortality.

In conclusion, the study-results suggest that life expectancy among HIV-positive persons could be further improved and educational inequalities reduced by earlier start of cART and effective smoking-cessation programs tailored to the HIV-positive population.

PubMed

4th January successful migration of the SHCS database from Lausanne to Zurich!

Dear members and friends of the SHCS,

The very important and almost last step of the transfer of the SHCS datacenter from Lausanne to Zurich has happened at the end of the year: the migration of the database was successful! This was a difficult undertaking and only possible by the help of many highly motivated and skilled people!

For this I want to thank the key players involved in this endeavor:

  • Alexandra Scherrer, USZ, head of the datacenter, who planned and coordinated this endeavor and showed great leadership
  • Yannick Vallet from the CHUV, who prepared the database at the CHUV for migration
  • Daniel Förderer from the University of Zurich, Zentrale Informatikdienste, who helped us a lot with all the technicalities in a very unbureaucratic manner
  • Our very motivated and skilled ‘Zivis’  Marc Stefani, Rafael Fuchs, Daniel Lichtenstern, Johannes Abegglen and Rafael Häuselmann who did or are still doing their civilian service in the SHCS datacenter.
  • Bruno Ledergerber, USZ, for his support during the last year

With this, I wish you a happy new year and I am sure that with all your help the SHCS will continue to produce important scientific output at all levels. The database and the datacenter are ready!

Kind regards,

Huldrych Günthard
President SHCS