2016

21st December Sauter et al., CD4/CD8 ratio and CD8 counts predict CD4 response in HIV-1-infected individuals


CD4/CD8 ratio and CD8 counts predict CD4 response in HIV-1-infected drug naive and in patients on cART.  Medicine

Higher plasma HIV RNA levels are known to correlate with CD4 decline and disease progression. The extent to which CD8 cells, in addition to RNA viral load, predict the depletion of CD4 cells is not well characterized in large and well described patient populations. Sauter et al. examined whether past CD8 cell counts contain additional information to determine future CD4 cell counts and investigated this effect separately, for treatment naive individuals and for patients receiving combination antiretroviral therapy (ART).

In both subgroups, 2’500 naive and 8’902 cART patients, past CD4 cells were positively (P<0.0001) and past viral load was negatively (P<0.0001) associated with disease progression measured here as CD4 cell count. Including additionally past CD8 cell counts improved the fit significantly (P<0.0001). The model which includes the lagged levels of CD4 and CD8 as 2 separate predictors was inferior compared to an approach which included the lagged CD4/CD8 ratio instead of the CD8 level.

In sum, the authors could confirm the findings by other studies, which attributed an important role to CD8 cells for describing the HIV-1 disease progression and could show that the CD4/CD8 ratio is an important time-dependent prognostic factor, for treatment naive and newly also for cART-treated patients. The additional information captured by the CD8 levels and even more by the CD4/CD8 ratio clearly improves prediction models for CD4 counts in addition to the viral load.

Additional comment Dr. Dominique Braun and Prof. Huldrych Günthard
With this 56th press release in 2016 we say good bye to you and wish you a merry Christmas and a happy New Year. We hope that you will read us again in 2017 and that we can continue to provide you interesting results from the SHCS research community.

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15th December May et al., Mortality according to CD4 count at start of cART


Mortality according to CD4 count at start of combination antiretroviral therapy among HIV positive patients followed for up to 15 years after start of treatment: collaborative cohort study.  Clinical Infectious Diseases

May et al. on behalf of the Antiretroviral Therapy Cohort Collaboration estimated mortality rates by time since start of combination antiretroviral treatment (cART) among patients from 18 European and North American cohorts who started ART during 1996-2001. Median follow-up time was 11.3 years. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. Overall mortality per 1000 person-years declined from 33 during the first 6 months of ART to 14 among those who survived 10 years from start of ART. After adjusting for other prognostic factors, the mortality rates ratios comparing baseline CD4 count

In conclusion, CD4 count at start of ART strongly predicts mortality rates during the first 5 years of ART. This finding reinforces the need for earlier diagnosis and treatment of people living with HIV. However, the burden of increased mortality associated with starting treatment late is alleviated for those who survive 5 years on ART.

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14th December the FOPH supports the SHCS with CHF 300'000


On 1st of December 2016, the World AIDS day, the SHCS obtained the final note that the Federal Office of Public Health (FOPH) will support the SHCS with CHF 300'000.- for the year 2016. This is the result from almost two years of negotiations between FOPH and SHCS to start a collaboration.

The FOPH has recognized that the SHCS is a major cornerstone in the effort to further improve HIV care and is crucial to reduce HIV-1 transmission and sexually transmitted infections. This common endeavor may have a significant impact in the years to come to reduce the HIV-1 epidemic and will contribute to the ultimate goal: to stop the HIV-1 epidemic in Switzerland and to finally eliminate HIV-1.

We very much want to thank the FOPH and are looking forward to further support and fruitful collaboration in the years to come!

on behalf of the SHCS
Huldrych Günthard

7th December Borges et al., Effect of timing of ART on the risk of infection-related and unrelated cancer


Immediate antiretroviral therapy reduces risk of infection-related cancer during early HIV infection. Clinical Infectious Disease

The Strategic Timing of Antiretroviral Treatment (START) trial randomized HIV-infected adults with a CD4 count >500 cells/μL to immediate combination antiretroviral therapy (cART) initiation or cART deferral until CD4 counts dropped below 350 cells/μL. In the START trial, immediate cART reduced risk of cancer by 64%. In the current study, Borges et al. aimed at determine factors associated with cancer development among START participants and to assess mediators of the benefit of immediate cART in reducing cancer risk. Of note, infection-related cancer was defined as cancer driven by the following infectious agents: human herpesvirus 8 (Kaposi sarcoma), Epstein-Barr virus (non-Hodgkin lymphoma, Hodgkin lymphoma), and human papillomavirus (anal cancer, cervical cancer). All other malignancies were classified as infection-unrelated cancer.

There were 14 malignancies among persons randomized to the immediate cART arm (6 infection-related and 8 infection-unrelated) and 39 malignancies in the deferred arm (23 infection-related and 16 infection-unrelated). Immediate cART significantly reduced the risk of infection-related cancer by 74% (hazard ratio [HR] of immediate vs deferred cART initiation, 0.26), and the risk of infection-unrelated cancer by 51% (HR, 0.49). There was no statistical significance for infection-related vs infection-unrelated cancers. Independent baseline predictors of infection-related cancer were older age (HR, 1.42), higher BMI (HR, 1.47), low- to middle-income region (HR, 3.40), baseline HIV RNA (HR, 2.01) and baseline CD8 count (HR, 1.13). Older age (HR, 2.54) and baseline CD8 count (HR, 1.12) were the only independent predictors of infection-unrelated cancer. Adjustment for latest HIV RNA level, but not for CD4 cell count or cancer risk factors, attenuated the effect of immediate cART on infection-unrelated cancer.

In sum, immediate cART initiation significantly reduced the risk of cancer. With regard to infection-related cancer, this effect was mainly driven by a reduction in cases of Kaposi sarcoma and non-Hodgkin lymphoma. Adjustment for latest HIV RNA level suggest that the benefit of immediate cART does not be solely attributable to HIV RNA suppression and may also be mediated by other mechanisms.

PubMed

30th November Béguelin et al., Hepatitis delta-associated mortality in HIV/HBV-coinfected patients


Hepatitis delta-associated mortality in HIV/HBV-coinfected patients. Journal of Hepatology

Béguelin et al. aimed to describe the main epidemiological characteristics of hepatitis delta virus (HDV) infection and to evaluate its impact on clinical outcomes in the Swiss HIV Cohort Study. The prevalence of HDV infection was 15.4% (119/771) and the proportion of HDV-positive patients with HDV replication 62.9% (73/116).

HDV-positive individuals were more likely to be people who inject drugs (60.6% vs. 9.1%) and to have a positive hepatitis C virus serology (73.1% vs. 17.8%). Of note, in HIV/HBV/HDV-coinfected patients with replicating HDV, HCV RNA was suppressed in 90% of patients.

In multivariable analyses, HDV infection was strongly associated with overall death (adjusted hazard ratio [aHR] 2.33), with liver-related mortality (aHR 7.71), and with the occurrence of hepatocellular carcinoma (aHR 9.30). In addition, HDV replication was strongly associated with overall death (aHR 7.14), liver-related mortality and the occurrence of hepatocellular carcinoma. In analyses restricted to patients who had received tenofovir (77%), the point estimate of the association between HDV infection and overall death remained similar.

In conclusion, there is a high prevalence of hepatitis delta in HIV/HBV-coinfected individuals in Switzerland. The strong association between HDV infection and mortality as well as liver-related events, including hepatocellular carcinoma, highlights the importance of HDV screening of all HIV/HBV-coinfected patients.

PubMed

23rd November Salazar-Vizcaya et al., Effect of behavioral and treatment interventions on HCV transmission among HIV-positive MSM


Hepatitis C virus transmission among human immunodeficiency virus-infected men who have sex with men: Modeling the effect of behavioral and treatment interventions. Hepatology

Salazar-Vizcaya et al. predicted the effect of behavioral and treatment interventions on hepatitis C Virus (HCV) incidence and prevalence among HIV-infected men who have sex with men (MSM) up to 2030 using a HCV transmission model parameterized with data from the Swiss HIV Cohort Study. In their model the prevention of high-risk behavior alone resulted in a considerably reduced HCV transmission. Contrary, if high-risk behavior continued and the treatment practice did not change, HCV incidence converged to 10.7/100 person-years. Stabilization of high-risk behavior combined with increased treatment uptake and the use of direct-acting antivirals reduced incidence by 77% (from 2.2 in 2015 to 0.5/100 person-years) and prevalence by 81% (from 4.8% in 2015 to 0.9%) over the next 15 years.

In conclusion, reducing high-risk behavior associated with HCV transmission would be the most effective intervention for controlling the HCV epidemic, even if this was not accompanied by an increase in treatment uptake or efficacy.

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16th November Wang et al., HBV/HCV infection and risk for non-Hodgkin lymphoma in HIV-infected patients


Chronic hepatitis B and C virus infection and risk for non-Hodgkin lymphoma in HIV-infected patients: A Cohort Study. Annals of Internal Medicine

Wang et al. on behalf of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord investigated whether chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are associated with increased incidence of non-Hodgkin lymphoma (NHL) in HIV-infected patients.

The median follow-up was 13 months for ART-naive patients and 50 months for treated patients. A total of 252 treatment-naive patients and 310 treated patients developed NHL, with incidence rates of 219 and 168 cases per 100 000 person-years, respectively. In ART-naive patients, the adjusted hazard ratios for NHL with chronic HBV and HCV infection were 1.33 (CI, 0.69 to 2.56) and 0.67 (CI, 0.40 to 1.12), respectively. In ART-treated patients, chronic HBV and HCV infection were both associated with increased risk for NHL, with adjusted hazard ratios of 1.74 (CI, 1.08 to 2.82) for HBV infection and 1.73 (CI, 1.21 to 2.46) for HCV infection.

In conclusion, ART-treated patients with chronic HBV and HCV co-infection are at increased risk for NHL. However, treatment-naive patients later initiated ART, which limits the study of the associations of chronic HBV and HCV infection with NHL in this patient group. Early diagnosis and treatment of HIV infection in conjunction with routine screening for chronic HBV and HCV infection is essential to further decrease NHL morbidity and mortality in HIV-infected persons.

PubMed

4th November Matthias Egger is the new president of the National Research Council of the SNSF


We are proud to inform you that Matthias Egger was elected as president of the Research Council by the Executive Committee of the Foundation Council of the SNSF for the 2017-2020 term of office.

Matthias Egger is a long-term member of the SHCS and also a long-term member of the Scientific board and has published many very important epidemiological studies based on data from the SHCS.

We wish him best success in his new challenge!

more details in Englisch  Deutsch  français

3rd November Oberle et al., Characteristics of HIV-1 transmission pairs


Tracing HIV-1 transmission: envelope traits of HIV-1 transmitter and recipient pairs. Retrovirology

Oberle et al. investigated phenotypic virus characteristics of nine HIV-1 subtype B transmission pairs to define if transmitted/founder (T/F) viruses harbor distinct features that are crucial during the earliest stages of HIV-1 infection endowing viruses with a transmission advantage.

Their analyses revealed that recipient and transmitter viruses showed no signs of selection for specific Env modifications. Recipient viruses were resistant to circulating plasma antibodies of the transmitter but there was no difference between transmitted and founder virus in neutralization sensitivity to a large panel of entry inhibitors and neutralizing antibodies, in cell-cell transmission, and in replicative capacity. However, there was a higher sensitivity of several recipient virus isolates to interferon-α.

In sum, the study-findings suggest that contrary to previous studies resistance to IFNα cannot be a general driving force in T/F establishment. The finding that none of the other phenotypic properties consistently distinguished recipient from transmitter HIV-1 subtype B viruses suggests that transmission is to a considerable extent a stochastic event.

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27th October Shepherd et al., Malignancies, infection and aging in HIV


Infection-related and -unrelated malignancies, HIV and the aging population. HIV Medicine

Shepherd et al. on behalf of EuroSIDA in EuroCOORD determined the impact of aging on future infection-related malignancies (IRM) and infection-unrelated malignancies (IURM) incidence. Out of 15’648 persons contributing to 95’033 person-years of follow-up, a total of 610 people (3.9%) developed 643 malignancies, of which 60.3% were IRMs and the remaining 39.7% were IURMs. The most common IRMs were non-Hodgkin lymphoma (n = 116), anal cancer (85), Kaposi sarcoma (62) and Hodgkin lymphoma (43). Lung (n = 55), prostate (28), colorectal (23) and breast (22) cancers were common IURMs.

A higher IRM incidence was strongly associated with traditional HIV factors such as a higher HIV-viral load and a lower CD4 cell count and, to a lesser extent, older age. The incidence of IRMs steadily increased with lower CD4 count category. For IURM, older age was the largest contributor with a twofold higher IURM incidence for a 10-years increase in age. Smoking was associated with IURMs compared with never smokers in people aged ≥ 50 years only, and not with IRMs.

In sum, these findings suggest the need for targeted preventive measures and evaluation of the cost-benefit of screening for IURMs in HIV-infected populations.

PubMed

13th October Rodger et al., Risk of HIV transmission in serodifferent couples


Sexual activity without condoms and risk of HIV transmission in serodifferent couples when the HIV-positive partner is using suppressive antiretroviral therapy.  Journal of the American Medical Association (JAMA)

Rodger et al. on behalf of the PARTNER study group followed serodifferent partnerships in which the HIV-positive partner took antiretroviral therapy (ART) with a plasma HIV-1 RNA load less than 200 copies/ml to study the risk of HIV transmission through anal and vaginal sex in the absence of condom use. Among 1’166 enrolled couples, 548 heterosexual and 340 men who have sex with men provided 1’238 eligible couple-years.

During a median follow-up of 1.3 years per couple, 11 HIV-negative partners became HIV-positive. However, there were no phylogenetically linked cases of within-couple HIV transmission, giving a rate of within-couple HIV transmission of zero, with an upper 95% confidence limit of 0.30/100 couple-years of follow-up. Of note, acquisition of a sexually transmitted infection was not associated with risk of HIV-1 transmission within the couples under study.

In conclusion, this study provides the first estimate of HIV transmission risk through condomless anal sex in which the HIV-positive partner is taking ART with suppressed plasma HIV viral load. However, 95% confidence limits suggest that with eligible couple-years accrued so far, appreciable levels of risk cannot be excluded, particularly for anal sex and when considered from the perspective of a cumulative risk over several years. Therefore, additional longer-term follow-up is needed to provide more precise estimates of risk.

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5th October Borges et al., Inflammation, Coagulation, and Clinical Outcomes


Interleukin 6 is a stronger predictor of clinical events than high-sensitivity C-reactive protein or D-dimer during HIV infection. Journal of Infectious Diseases

Borges et al. for the INSIGHT SMART Study and ESPRIT Groups investigated the associations of several inflammation and coagulation markers with different clinical endpoints. Among 4’304 participants, there were 157 all-cause deaths, 117 non–AIDS-related deaths, 101 AIDS cases, 121 cardiovascular disease (CVD) cases, and 99 non–AIDS-defining malignancies. Higher interleukin 6 (IL-6) levels at study entry were more strongly associated with subsequent risk of non–AIDS-defining end points such as CVD and non–AIDS-defining malignancies, compared with high-sensitivity C-reactive protein (hsCRP) or D-dimer levels. Furthermore, higher IL-6 level was more strongly associated with fatal events than with fatal and nonfatal CVD or non–AIDS-defining malignancies. These findings were broadly consistent after adjustment for confounders and accounting for potential reverse causality.

In conclusion, IL-6 is a stronger predictor of fatal events than of fatal and nonfatal CVD and non–AIDS-defining cancer. There is a need for clinical end point–driven trials to determine whether adjuvant anti-inflammatory and antithrombotic therapies can reduce morbidity and mortality in treated HIV infection.

PubMed

29th September The 1000th SHCS publication: Rusert, Kouyos et al., Determinants of HIV-1 broadly neutralizing antibody induction


Determinants of HIV-1 broadly neutralizing antibody induction.  Nature Medicine

Rusert, Kouyos et al. performed a systematic investigation of parameters that steer broadly neutralizing antibodies (bnAb) induction in HIV-1 infection by analyzing the plasma neutralization activity of 4’484 individuals enrolled in the Swiss HIV Cohort Study, or the Zurich Primary HIV Infection study. They found that antigen load, duration of viral exposure and viral diversity independently promote the evolution of broad neutralization responses. Interestingly, black participants showed significantly higher rates of bnAb induction than white participants. There was strong virus subtype dependency with higher frequencies of CD4-binding-site bnAbs in infection with subtype B viruses and higher frequencies of V2-glycan-specific bnAbs in infection with non–subtype B viruses.

In conclusion, the conducted population-wide survey allowed for the first time to put the increasing number of parameters considered as drivers of neutralization breadth into perspective, explore their interdependencies and define novel parameters. These will be key findings for the future development of rational bnAb-based HIV-1 vaccine design.

Additional comment Dominique Braun (MD) and Huldrych Günthard (MD)
Multiple reasons for celebration come along with this publication: the current press release summarizes the 1000th publication originating from the SHCS.

We would like to thank all participants in the SHCS, the physicians, study nurses, interdisciplinary researchers, the data managers, the data center, the administration and all the many funders.

The SHCS is true teamwork. We toast now on the first thousand publications and hope that there will be another thousand soon! It is a privilege to be part of this exciting long-term endeavor!

PubMed

Links to the press release of this publication in English and Deutsch on the webpage of the University of Zurich

22nd September Bohlius et al., Changing incidences and risk factors for Kaposi sarcoma


Changing incidence and risk factors for Kaposi sarcoma by time since starting antiretroviral therapy: Collaborative analysis of 21 European cohort studies. Clinical Infectious Diseases

Bohlius et al. on behalf of the COHERE study in EuroCoord examined incidence rates and risk factors for Kaposi sarcoma (KS) in different time periods after the start of combination antiretroviral therapy (cART) in patients from European observational HIV-cohorts. The overall KS incidence rate was 183/100’000 patient years (pys). The incidence rate of KS was around 1’500/100’000 pys in the first weeks after staring cART but declined thereafter to plateau at about 82-85/100’000 pys after two years since starting cART. The risk of KS was increased in men who have sex with men (MSM) (hazard ratio [HR] 5.87 comparing MSM with heterosexual men in period 30-90 days), in patients of African origin, and in patients with low current CD4 cell counts (HR 7.37 comparing 100’000 copies/mL with

In conclusion, this study shows that in patients early after starting cART immunodeficiency is the dominant risk factor for KS, whereas detectable HIV-1 RNA viral load becomes an increasingly important risk factor in patients who started cART several years ago, independently of immunodeficiency.

PubMed

14th September Junier et al., Genetics of low-trauma fractures in HIV


Contribution of genetic background and clinical risk factors to low-trauma fractures in HIV-positive persons: The Swiss HIV Cohort Study. Open Forum Infectious Diseases

Junier et al. aimed to quantitate the contribution of 6 common single-nucleotide polymorphisms (SNPs) to the risk of low-trauma fracture (LTF) in HIV-positive participants enrolled in the Swiss HIV Cohort Study (SHCS). In multivariable analysis, LTF risk was associated with height, corticosteroids, and smoking. Of note, weight, CD4 nadir, HCV coinfection, alcohol, injection drug use, cumulative exposure to tenofovir disoproxil fumarate, and protease inhibitors were not associated with LTF risk. In the multivariable model that included genetic background, the additive genetic score built from the 6 LTF-associated SNPs was not associated with LT.

The study-results suggest that genetic testing is presently not a useful predictor or monitoring tool for bone health in HIV.

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7th September NEAT ID Foundation Integration Grant to Dr. Gilles Wandeler


Dr. Gilles Wandeler has been awarded a NEAT ID Foundation Integration Grant of Euros 100,000 for his application titled

Multi-cohort study to inform hepatocellular carcinoma screening strategies in HIV/HBV-coinfected individuals on tenofovir-containing therapy

This project is based on data from the SHCS and other major European cohorts (Athena, ANRS, Acquitaine).

2nd September SSI / SAFE-ID prize awarded to Dr. Alexandra Scherrer


The Swiss Society for Infectious Diseases (SSI) and the Swiss Academic Foundation for Education in Infectious Diseases (SAFE-ID) awarded on 1st September 2016,

a prize in the amount of CHF 15'000 to Dr. Alexandra Scherrer for an excellent publication in the category “clinical research in infectious diseases” with the title

Emergence of acquired HIV-1 drug resistance almost stopped in Switzerland: A 15-year prospective cohort analysis

published in Clinical Infectious Diseases.

This work was primarily based on the Swiss HIV Cohort Study and the SHCS drug resistance database.

information University Hospital Zurich

information SSI / SAFE-ID

29th August Hatleberg et al., Short-term mortality after myocardial infarction


Improvements over time in short-term mortality following myocardial infarction in HIV-positive individuals AIDS

Hatleberg et al. for the D:A:D study group evaluated changes in short-term mortality after myocardial infarction (MI) in HIV-positive individual. One thousand and eight D:A:D participants experienced an MI over the period 1999–2014. The absolute number of MIs decreased from 214 (1999–2002) to 154 (2011–2014). Over a median follow-up time of 42.7 months after their MI, 117 of the 1008 HIV-positive individuals (11.6%) experienced a further MI and 339 (33.6%) died. The proportion of individuals who died in the first month after MI dropped from 26.6% in 1999–2002 to 8.4% in 2011–2014. Predictors of decreased short-term mortality were higher CD4+ cell count, family history of cardiovascular disease, later year of MI and the receipt of antiplatelets, lipid lowering drugs, and invasive cardiovascular procedures.

In conclusion, this study demonstrates improvements in short-term survival after MI in HIV-positive individuals, which appeared to be largely driven by increased use of drug interventions and invasive cardiovascular procedures.

PubMed

22nd August Gjærde et al., HCC and other liver events in HIV/HCV coinfected individuals from 2001 to 2014


Trends in incidences and risk factors for hepatocellular carcinoma and other liver events in HIV and hepatitis C Virus–coinfected individuals from 2001 to 2014: a multicohort study Clinical Infectious Diseases

Gjærde et al. aimed to study HIV/HCV–coinfected individuals in Europe and Canada and to describe the epidemiology of hepatocellular carcinoma (HCC) and other liver events in a multicohort collaboration of HIV/HCV–coinfected individuals. From 2001 to 2014, 72 cases of HCC and 375 cases of other liver events occurred, resulting in overall incidence rates of 1.6 cases of HCC per 1000 person-years of follow-up (PYFU) and 8.6 cases of other liver events per 1000 PYFU. From 2001 to 2014 HCC increased from 0.4 to 2.3 cases per 1000 PYFU, whereas other liver events decreased from 9.9 to 5.2 cases per 1000 PYFU. Older age, cirrhosis, and lower current CD4 cell count were independent risk factors for both HCC and other liver events. There was no impact of alcohol abuse, diabetes mellitus, or detectable HIV RNA on the incidence of HCC.

The authors conclude that treatment with direct-acting antivirals and earlier HIV treatment will likely reduce the rates of HCC and other liver events. However, as HCC can develop after sustained virologic response is achieved, or as a consequence of other hepatotoxic exposures, continuous surveillance of incidence trends is needed.

PubMed

10th August Scherrer et al., Successful prevention of transmission of INSTI resistance in the SHCS


Successful prevention of transmission of integrase resistance in the Swiss HIV Cohort Study. Journal of Infectious Diseases

Scherrer et al. aimed to analyze the prevalence of transmitted integrase strand transfer inhibitor (INSTI) resistance in the Swiss HIV Cohort Study (SHCS) and to identify risk factors for its occurrence. Only 1 major mutation (T66I) was found (1 of 1316 [0.1%]) in a sample retrieved in 2001. In 38 of 1316 samples (2.9%), viruses were found with minor INSTI resistance mutations. Minor mutations were significantly more common in subtype non-B infections as compared to subtype B infections. There was no evidence for an increase in prevalence of minor mutations in the years after the introduction of INSTIs. The study demonstrates on a population-level that it is possible to avoid transmitted drug resistance to a new drug class for years.

Commentary Dominique Braun (MD) and Huldrych Günthard (MD)
The Swiss setting cannot be compared to other settings with limited access to viral load monitoring or no available second-line and third-line therapies. In these settings, patients may continue to receive failing regimens and may accumulate more drug resistance mutations. Of particular importance will be to investigate the effect of decreasing monitoring frequency that is proposed and performed in some countries. This may lead to delayed detection of treatment failures with subsequent emergence of resistance and a higher population viral load of nonresponding patients.

PubMed

3rd August Stucki et al., Tuberculosis transmission among immigrants


Standard genotyping overestimates transmission of Mycobacterium tuberculosis among immigrants in a low-incidence country. Journal of Clinical Microbiology

Stucki et al. for the Swiss HIV Cohort and Molecular Epidemiology of Tuberculosis Study Groups reanalyzed transmission clusters previously defined by mycobacterial interspersed repetitive-unit–variable-number tandem-repeat (MIRU-VNTR) typing by using whole-genome sequencing (WGS) to assess the transmission of M. tuberculosis among Swiss and foreign-born tuberculosis (TB) patients. Of 520 TB patients, 18 of 35 transmission clusters identified by standard molecular genotyping (spoligotyping and MIRU-VNTR typing) were refuted by WGS. There was a striking difference between transmission clusters involving Swiss-born patients and clusters involving foreign-born patients.

The study-results suggest that transmission of M. tuberculosis is generally overestimated in countries with a low incidence of TB such as Switzerland. The authors recommend the use of WGS for more accurate identification of recent transmission of M. tuberculosis among immigrants.

pdf publication

27th July Ryom et al., End-stage liver disease, hepatocellular carcinoma and antiretroviral treatment


Use of antiretroviral therapy and risk of end-stage liver disease and hepatocellular carcinoma in HIV-positive persons. AIDS

Ryom et al. on behalf of the D:A:D Study Group aimed to describe incidence rates, predictors and survival after end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) with focus on the potential association with cumulative use of individual antiretrovirals. During a median follow-up of 8.4 years, a total of 319 ESLD/HCC events occurred (incidence rate 1.01/1000 person-years of follow-up) of which 209 were ESLD and 110 HCC events. Eighty-three percent of all events occurred in individuals coinfected with viral hepatitis. The median survival after an ESLD/HCC diagnosis was 0.27 years. After adjustment, cumulative (per 5 years) exposure to stavudine (relative rate 1.46), didanosine (1.32), tenofovir (1.46) and (fos)amprenavir (1.47) was associated with increased ESLD/HCC rates.

In conclusion, the viral hepatitis independent, tenofovir association calls for further investigations, whereas use of stavudine and didanosine should be avoided, where there are alternatives available.

PubMed

21st July Caniglia et al., Monitoring CD4 cell count and HIV RNA in virologically suppressed HIV-positive persons


When to monitor CD4 cell count and HIV RNA to reduce mortality and AIDS-defining illness in virologically suppressed HIV-positive persons on antiretroviral therapy in high-income countries: A prospective observational study. Journal of Acquired Immune Deficiency Syndromes

Caniglia et al. on behalf of the Center for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration estimated the effect of CD4 cell count and HIV RNA monitoring strategies on clinical, virologic, and immunologic outcomes in virologically suppressed HIV-positive patients.

Compared with monitoring every 3 months, the overall mortality hazard ratio was 0.86 for 6 months and 0.82 for 9–12 months. The corresponding hazard ratios for the combined endpoint of AIDS-defining illness or death were 0.76 and 1.06. Compared with monitoring every 3 months, the overall risk ratio for virologic failure (HIV RNA ≥50 copies/mL) was 0.64 for six months and 1.18 for 9–12 months.

In conclusion, the study shows little evidence for an effect of monitoring frequency on death or AIDS-defining illness or death in the short term among individuals who achieve virologic suppression within 12 months of cART initiation. The findings suggest that monitoring every 9–12 months increases the risk of virologic failure compared with monitoring every 3 months.

Commentary Dominique Braun (MD) and Huldrych Günthard (MD)
The authors conclude that there is no evidence for an effect of reducing the monitoring frequency on death or AIDS-defining illnesses. However, one has to realize that the risk for a treatment failure was significantly higher in the 9-12 month monitoring group when compared to the 3 and 6 month groups. For this reason, we strongly suggest to maintain a 3 or at the most a 6 months monitoring interval.

pdf publication

20th July Sabin et al., Abacavir and the risk of myocardial infarction


Is there continued evidence for an association between abacavir usage and myocardial infarction risk in individuals with HIV? A cohort collaboration. BMC Medicine

Sabin et al. for the D:A:D Study Group investigated whether the association between abacavir (ABC) and myocardial infarction (MI) remained present in data collected after 2008, when ABC was less likely to be prescribed to those at high cardiovascular disease (CVD) risk than before 2008. Overall, the rate of MI was 0.47/100 person-years (PYRS) among those currently receiving ABC and 0.21/100 PYRS among those not currently receiving ABC. After adjustment for potential confounders, current ABC use was associated with a 98 % increase in MI rate (adjusted rate ratio 1.98), with no difference in the pre- (1.97) and post- (1.97) March 2008 periods. Results were unchanged after stratifying by Framingham risk group, or after further adjusting for factors potentially on the causal pathway.

The study-results strongly suggest that the finding of a raised risk of MI for people on ABC is not explained by channelling of people with high CVD risk onto the drug.

pdf publication

6th July Shilaih et al., HBV prophylaxis using HIV/HBV active ART


Dually active HIV/HBV antiretrovirals as protection against incident hepatitis B infections: potential for prophylaxis. Journal of Infectious Diseases

Shilaih et al. examined the effect of dually active antiretroviral therapy (DAART) containing regimens (TDF, 3TC, and FTC) in protecting against incident hepatitis B virus (HBV) infections in HIV-infected individuals. The overall incidence rate per 1000 person-years was 16. DAART had a protective effect against HBV acquisition, with a hazard ratio (HR) of 0.4 (95% CI, .2–.6), whereas other ART regimens had none. Self-reported risky sexual behavior, a history of condomless sex, being a man who has sex with men and intravenous drug use was associated with higher risk of acquiring HBV. DAART had a higher protective effect in patients with a better long-term immunological status (i.e., CD4 cell count ≥200×10h6/mL).

In conclusion, the study-results suggest that early ART initiation, regardless of CD4 cell counts, has a strong beneficial public health impact, including preexposure prophylaxis of HBV coinfections.

PubMed

30th June Calmy et al., HIV+ to HIV+ liver transplantation


HIV-positive-to-HIV-positive liver transplantation.  American Journal of Transplantation

Calmy et al. report on the successful liver transplantation from an HIV-positive donor to an HIV-positive recipient. Both, donor and recipient had been treated for many years with antiretroviral therapy and harbored multidrug-resistant viruses. To decrease the risk that the transplanted liver would transmit a viral strain with distinct mutations, the physicians adapted the recipient’s pretransplant suppressive ART to the donor’s HIV genotype by adding an integrase inhibitor and a short course of enfuvirtide. A donor peroperative liver biopsy identified no HIV-RNA by polymerase chain reaction performed on cells extracted from formalin-fixed paraffin-embedded liver tissue. Five months after transplantation, HIV viremia remains undetectable.

In conclusion, treating physicians of HIV-infected individuals should inform their patients if the option exists for organ donation, and encourage policymakers to consider lifting restrictions on organ donation from HIV-positive individuals for HIV-positive recipients.

PubMed

23rd June Zahnd et al., Impact of deferring HCV treatment


Modelling the impact of deferring HCV treatment on liver-related complications in HIV coinfected men who have sex with men. Journal of Hepatology

Zahnd et al. aimed to estimate the long term impact of deferring hepatitis C virus (HCV) treatment for men who have sex with men who are coinfected with HIV for liver disease progression. The percentage of simulated individuals who died of liver-related complications was 2% if treatment was initiated in F0 or in F1. It rose to 3% if treatment was deferred until F2, 7% if deferred until F3, and 22% if deferred until F4. The median time individuals spent with replicating HCV increased from 5 years if treatment was initiated in F2 to almost 15 years if it was deferred until F4. The cost calculations suggest that early treatment might be cost-effective since the increase in treatment cost is balanced by the savings in health care costs. In conclusion, the study-findings support arguments that HCV therapy should be accessible to everyone at an early stage. To make this affordable for health insurances and governments, the costs for new direct acting antivirals need to be lowered substantially.

pdf publication

8th June Clifford et al., Cervical cancer and neoplasia in SHCS


Immunodeficiency and the risk of cervical intraepithelial neoplasia 2/3 and cervical cancer: A nested case-control study in the Swiss HIV cohort study. International Journal of Cancer

Clifford et al. Clifford et al. aimed to characterize the influence of immunodeficiency and combination antiretroviral therapy (cART) use on the development of cervical intraepithelial neoplasia grade 2/3 (CIN2/3) and invasive cervical cancer (ICC) among women infected with HIV. They found that CIN2/3 risk was significantly associated with low CD4+ cell counts, measured as nadir or at CIN 2/3 diagnosis. An increased risk for CIN 2/3 and ICC was also evident even at moderate levels of immunosuppression (200–349 cells/lL). Similar associations were seen for ICC, notably with nadir CD4+. A protective effect of >2-year cART use was seen against CIN2/3.

The findings emphasize a key role for early HIV detection and cART initiation in cervical cancer prevention for HIV-infected women.

PubMed

2nd June Pantazis et al., Reinitiation of combination anti-HIV treatment


The impact of transient cART in early HIV infection on viral suppression and immunologic response in later treatment. AIDS

Pantazis et al. on behalf of CASCADE in EuroCoord assessed if transient combination antiretroviral therapy (cART) administered during early HIV infection (EHI) has any effect on response to cART reinitiated during chronic HIV infection (CHI). Of 4465 individuals, 202 received transient cART during EHI and restarted cART in CHI, and 4263 started cART during CHI, respectively. Both groups had similar virologic response and relapse rates but pretreated individuals restarted treatment with higher baseline CD4+ cell count (~80 cells/ml). Duration of transient cART in EHI and its timing relative to estimated seroconversion did not appear to have any significant effect on virologic or immunologic outcome of long-term cART in CHI.

In conclusion, although treatment interruptions are not recommended, stopping cART initiated in EHI does not seem to reduce the chance of a successful outcome of treatment in CHI.

pdf publication

26th May Bader et al., HIV tropism and immunological response


Correlating HIV tropism with immunological response under cART. HIV Medicine

Bader et al. assessed whether a HIV tropism determination prior to combination antiretroviral therapy (cART) initiation would be able to predict a later poorer immune response. Of the 88 baseline profiles available for comparison of immunological responses, 82.1% carried an R5-tropic virus and 17.9% an X4-tropic virus. Sixty percent of all patients with X4-tropic viruses at therapy initiation experienced only partial immune recovery during the following 5 years (ΔCD4

PubMed

25th May a webpage for 'SHCS participants and community'


Dear members and friends of the SHCS,

For a long time it has been a goal to also directly inform participants of the cohort, their friends and families and other interested people about news of interest for them. Now, we have created the SHCS participants and community webpage in Italian, French and German with a special entry on the homepage (direct links deutsch, français, italiano).

Interested people can subscribe for the newsletter that we will send out also in the three languages sporadically. Of course, we will not report on every paper but pick the ones that will be of interest to the community. The idea is also to comment on important topics in HIV in general, or maybe sometimes to put something into context that was not correctly reported by the media. Anyway, we will see how this will evolve.

We have also added the links to the respective centers, to the site of the Positivrat and to the BAG and a contact form if patients have specific questions or comments concerning the cohort. The overall aim of this site is to more directly involve interested people and to create an interactive platform.

Please inform your patients about this possibility.

With this step we also fulfil a point raised by the reviewers of the last SNF evaluation to more directly involve HIV-infected individuals.

At this point, I would like to very much thank Danièle Perraudin and Lukas Humbel for continuously improving our webpage, and Dominique Braun for writing all the short summaries on the SHCS publications.

Kind regards,
Huldrych Günthard

 

19th May An et al., APOBEC3F and HIV-1


Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia. PLoS Genetics

The human APOBEC3 (A3) proteins are cellular cytidine deaminases that serve as intrinsic resistance factors to retroviruses and therefore defend against HIV-1. However, HIV-1 encodes a viral infectivity factor that degrades APOBEC3 proteins. To assess the effect of A3F for their influence on HIV- acquisition and HIV disease progression An et al. performed a genetic association study of genetic variants in vivo in six well-characterized HIV-1 natural cohorts. They found that a common A3F haplotype was associated with a 30% reduced rate of AIDS disease progression, lower set-point viral load and delayed development of pneumocystis pneumonia in European Americans.

In conclusion this study provides the first epidemiological evidence that A3F might modify HIV-1/AIDS pathogenesis.

pdf publication

12th May Barceló et al., Pharmakokinetic analysis of elvitegravir and cobicistat


Population pharmacokinetic analysis of elvitegravir and cobicistat in HIV-1-infected individuals. Journal of Antimicrobial Chemotherapy

Barceló et al. aimed to develop a population pharmacokinetic model for elvitegravir and cobicistat in a cohort of HIV-1-infected individuals. Concomitant administration of non-ritonavir-boosted atazanavir decreased elvitegravir clearance by 35%. Concomitant administration of non-ritonavir-boosted atazanavir and ritonavir-boosted darunavir decreased cobicistat clearance by 47% and 27%, respectively. A reduced elvitegravir dose of 85 mg co-administered with cobicistat and atazanavir produced a concentration-time course comparable to the standard regimen without atazanavir. None of the demographic and clinical covariates tested appeared to have a significant impact on elvitegravir and cobicistat elimination.

In conclusion, Elvitegravir and cobicistat pharmacokinetic variability appears to be mainly explained by drug-drug interactions that may be encountered in routine clinical practice.

PubMed

11th May news from the SHCS


Dear members, friends and supporters of the SHCS,

I would like to inform you about some changes that have occurred recently in the SHCS.

Leadership datacenter
As many of you probably already know, Franziska Schoeni-Affolter took a new job at the Federal Office of Public Health (FOPH), starting May 2016. For this reason, the datacenter needed a new leader. Very luckily we found a highly qualified person for this very important job: Alexandra Scherrer, PhD. She officially started on May 1st. For this reason, please direct all data-queries etc. directly to her: alexandra.scherrer@usz.ch. We wish Alexandra a very good start!

In the name of the SHCS, I would like to thank Franziska Schoeni-Affolter for all the work she did for the SHCS since she joined the datacenter in 2008. I would also like to thank her for the work she did as the leader of the datacenter after Martin Rickenbach’s retirement. She was instrumental for planning and implementing the WebMED for the SHCS. We wish her a very good start at the FOPH!

Transition datacenter from Lausanne to Zurich
For various reasons, we decided to move the datacenter now from Lausanne to Zurich. The reason is not that the datacenter was not working well but rather that after Martin and now Franziska left, it is harder to coordinate administrative issues etc. at the CHUV from the outside. In addition, we also need to make technical changes regarding the database and this is easier in an administration  we are directly part of. For those who don’t know: the opposite (from Zurich to Lausanne) happened in 1995. Thus, the SHCS remains a flexible undertaking.

We are very close to get office space from the University of Zurich. We also do have  informatics support from the UZH and should be able to keep our costs at reasonable levels. We are trying to make the transition process as smooth as possible but, of course, it is a major undertaking. Thus, if problems arise we hope that you will understand.

Financial situation
The financial situation has not improved yet in the SHCS. Together with the FOPH we worked very hard to join forces and we hope to be able to start cooperation with the FOPH mid of 2016. We really hope that this cooperation will start soon. Combining data from the FOPH and the SHCS in an anonymized way will considerably improve the data quality in Switzerland regarding HIV and other STIs and will form a very good base for future combined prevention efforts. Such a cooperation would also improve the financial situation of the SHCS.

After  having started to distribute the new SHCS brochure, some donations from patients came in. This shows us that patients appreciate the work we do. Please keep informing interested people about the SHCS. Donations from all sides are always welcome!

Changes on the webpage

  • Soon we will start a window for ‘SHCS participants and community’. The idea is to explain interesting research from the SHCS also to non-professionals.

  • We have added links of relevant websites for patient management (drug-drug interactions, resistance, prediction scores of vascular risks etc.) on our website. This might make it easier for new residents etc. to find the relevant links. This will regularly  be updated. You find the link under: http://www.shcs.ch/190-clinicians-and-study-nurses.

  • Link to the SHCS research foundation (http://shcsfoundation.ch/): as many of you know, the SHCS research foundation is instrumental for the SHCS. It helps us to cover in part the substantial deficit of the SHCS and  renders three major long-term projects of the SHCS possible:
    the genetic-core, the resistance-core and the metabolic and aging core projects.
    We also want to thank the pharmaceutical companies, who support the SHCS by unrestricted research grants. Many of them already for many years. On the SHCS research foundation website, those donations are transparently listed.

Thanks again for your continuing interest and support for the SHCS.

Best wishes,

Huldrych Günthard
President of the SHCS

4th May Nakagawa et al., Method to estimate HIV-positive populations


A method to estimate the size and characteristics of HIV-positive populations using an individual-based stochastic simulation model Epidemiology

Nakagawa et al. on behalf of EuroCoord developed an individual-based simulation model to estimate the size and characteristics of HIV-positive populations. The method was applied to data on men who have sex with men (MSM) in the UK and to pseudo data to assess the impact of different levels of availability of data. By 2013, an estimated 48,310 MSM were living with HIV in the UK, of them 22% MSM were undiagnosed and 23% were not in care. Of all MSM living with HIV, 66% were receiving antiretroviral therapy (ART) and more than half of them (62%) were thought to have suppressed viral load. Of the 40,530 MSM in need of treatment (defined as people on ART and people ART-naïve with CD4 count

pdf publication

28th April Monge et al., Mortality in migrants living with HIV


Mortality in migrants living with HIV in Western Europe (1997-2013): a collaborative cohort study. Lancet HIV

Monge et al. on behalf of the COHERE collaboration in EuroCoord aimed to assess the differences in overall mortality by geographical origin in HIV-positive men and women. Overall, crude mortality was significantly lower in women than in men (risk ratio 0.73), and significantly higher in injecting drug users (3.19) and with heterosexual transmission (1.36) compared with transmission by men who have sex with men. Migrants had a mortality rate 17% lower than native populations (0.83) in adjusted analyses, however, high mortality was identified in heterosexual men from Latin America (1.46) and heterosexual women from the Caribbean (1.48). No significant difference in mortality was identified by geographical origin in men who have sex with men. For populations with heterosexual transmission, however, the pattern differed for men and women.

In conclusion, the characteristics and risks of migrant populations differ for men and women and for populations infected heterosexually, by sex between men, or by injecting drug use. Although mortality in most groups is similar to or lower than that in native populations, some groups are at increased risk of death.

PubMed

27th April Scherrer et al., Acquired HIV-1 drug resistance in Switzerland


Emergence of acquired HIV-1 drug resistance has almost been stopped in Switzerland - a 15 year prospective cohort analysis. Clinical Infectious Diseases

Scherrer et al. aimed to study the trends of HIV-1 drug resistance prevalence in the Swiss HIV Cohort Study during 15 years in antiretroviral treatment (ART)-experienced individuals. Overall, 28.9% of ART-experienced patients were ever detected with a drug resistance mutation. This proportion was highest in patients who started ART before 1999 (56.2%) and declined to 19.7% and 9.7% among patients who started ART in 1999-2006 or 2007–2013, respectively. The prevalence of 3-class resistance decreased from 9.0% to 4.4% and was always <0.4% for patients who initiated ART after 2006. Most patients actively participating in the SHCS in 2013 with drug-resistant viruses initiated ART before 1999 (59.8%).

In conclusion, the study demonstrates that the emergence of HIV-1 drug resistance has been dramatically reduced with the introduction of new drugs and modern treatment strategies, particularly in the period after 2007. New emergence of 3-class resistance on ART is almost nonexistent.

pdf publication
pdf of editorial to publication

21st April Mocroft et al., Nephrotoxic antiretrovirals and development of chronic kidney disease


Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate: a prospective international cohort study. The Lancet HIV

Mocroft et al. on behalf of the D:A:D study aimed to investigate the association between duration of exposure to antiretrovirals and the development of chronic kidney disease in people with initially normal renal function. Out of 23’905 study-participants, 285 (1%) developed chronic kidney disease during a median follow-up of 7.2 years, giving an incidence of chronic kidney disease of 1.76 per 1’000 person-years of follow-up. After adjustment for potential confounding variables, there was a 14%, 20%, and 11% increase in chronic kidney disease associated with each additional year of exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, and ritonavir-boosted lopinavir, respectively. There was no increased incidence of chronic kidney disease with either abacavir or other ritonavir-boosted inhibitors.

In conclusion, the incidence of chronic kidney disease in HIV-positive individuals increases continuously with duration of exposure to specific antiretrovirals, with no evidence that the development of chronic kidney disease is limited to the first few months of starting antiretrovirals and no plateau in the increasing incidence after a median follow-up of more than 6 years.

PubMed

20th April Rotzinger et al., TDF/FTC/EFV single pill switch


Switching from a two-tablet regimen of tenofovir/emtricitabine and efavirenz to a one-tablet regimen may affect patients’ perceptions and drug management. HIV Medicine

Rotzinger et al. aimed to study the switch from a two-tablet tenofovir/emtricitabine/efavirenz regimen to a one-tablet regimen by comparing daily medication management, medication adherence, tolerance and satisfaction of subjects during the switch. Among the 88 subjects, six (7%) switched back to their previous two-tablet regimen because of adverse drug reactions. Of note, the efavirenz blood level increased significantly after the switch. Subjects who did not back-switch preferred the one-tablet regimen. However, the Beliefs about Medicines Questionnaire showed a significant decrease in the necessity score. The number of subjects self-reporting at least one missed dose during the last 4 weeks was similar at the study-visits.

In conclusion, professionals should pay particular attention to treatment management during switching to prevent patients becoming discouraged and experiencing treatment interruptions because of emerging side effects.

PubMed

13th April Boulle et al., Mortality by viral subtypes


Mortality of treated HIV-1 positive individuals according to viral subtype in Europe and Canada: collaborative cohort analysis. AIDS

Boulle et al. on behalf of eight European and three Canadian cohorts, aimed at estimating the prognosis by viral subtype in HIV-1-infected individuals from start of antiretroviral therapy (ART) and after viral failure. The authors analyzed 20’784 patients who experienced 1’172 deaths during 104’649 person-years of follow-up for an overall mortality rate of 11.2 per 1000 person-years. Subtype B was most frequent (74%), followed by C (10%), CRF02AG (5%), A (4%), CRF01AE (2.4%), G (1.7%), and D (1.1%). Subtype C was predominant in those from sub-Saharan Africa (SSA) (63%), whereas subtype CRF02_AG was common in those from SSA, and CRF01_AE was predominant in Asian patients. Subtype B included the highest proportion of MSM (67%) and IDU (10%), whereas more than 50% of those with subtypes A, C, D, G and CRF02_AG were female. Crude mortality was greatest for subtype B but after stratification by cohort, region of origin and transmission group the highest mortality hazard ratio (MHR) was for subtype A. There was little difference in adjusted MHR between the other subtypes and in survival after viral failure between subtypes A, B, and C.

In conclusion, patients infected with subtype A may be at a survival disadvantage compared with other subtypes although this may be due to other epidemiological factors rather than subtype per se.

pdf publication

7th April Efsen et al., TB/HIV patients in Eastern Europe


Major challenges in clinical management of TB/HIV coinfected patients in Eastern Europe compared with Western Europe and Latin America. PLoS ONE

Efsen et al. on behalf of the TB:HIV study group in EuroCoord aimed to study clinical characteristics, factors associated with multi-drug resistant tuberculosis (MDR-TB) and predicted activity of empiric anti-TB treatment at time of TB diagnosis among TB/HIV coinfected patients in Eastern Europe (EE), Western Europe (WE) and Latin America (LA). In both EE and LA, fewer patients had a definite TB diagnosis (47% and 40%, respectively, vs. 71% and 72% in WE and SE, respectively). The prevalence of MDR-TB in EE ranged from 11–56% between countries. Injecting drug use (adjusted odds ratio (aOR) = 2.03), prior anti-TB treatment (3.42), and living in EE (7.19) were associated with MDR-TB. The proportion of participants who received treatment with at least three active drugs ranged from 66% in EE to 90–96% in the other regions (p<0.0001).

The study-findings demonstrate a clear need for improving and implementing more accurate and rapidly available diagnostics and for providing better empiric anti-TB treatment, particularly in EE.

pdf publication

6th April Villandre et al., Phylogenetic transmission clusters and communities in sexual contact networks


Assessment of overlap of phylogenetic transmission clusters and communities in simple sexual contact networks: Applications to HIV-1. PLoS ONE

Villandre et al. explored through simulations the association between communities and the epidemic spread of sexually-transmitted infections (STIs). The analyses revealed modest mean correspondence between communities in graphs and phylogenetic transmission clusters as the currently widely-used phylogenetic clustering methods often fail to recover sexual contact network communities reliably. The main drawback of these common methods is that the requirement that network communities correspond to clades in the phylogeny is rarely-fulfilled.

The authors conclude that community structure cannot be inferred reliably using the existing phylogenetic clustering tools. This work stresses the need for new clustering algorithms that focus on community recovery.

pdf publication

31st March SNSF grant to Prof. Manuel Battegay and PD Catia Marzolini

The SNSF granted Prof. Manuel Battegay and PD Dr. Catia Marzolini a financial support of CHF 360’000.- for the research project

“Use of physiologically based pharmacokinetic modeling to simulate drug-drug interactions between antiretroviral drugs and commonly prescribed co-medications in the aging HIV population”.

This project is mainly based on the SHCS.

30th March Kovari et al., ART and risk of chronic ALT elevation


Antiretroviral drugs and risk of chronic alanine aminotransferase elevation in HIV-monoinfected persons: The D:A:D Study. Open Forum Infectious Diseases

Kovari et al. on behalf of the D:A:D Study Group aimed to identify risk factors associated with chronic liver enzyme elevation (cLEE) among HIV-positive individuals without viral hepatitis and to evaluate the outcome of liver enzyme elevation with regard to liver-related and all-cause mortality. Among 21’485 participants observed for 105 413 person-years (PY), 6’368 (29.6%) participants experienced episodes of cLEE, resulting in an incidence of 6.04 per 100 person years of follow-up (PYFU). There was an association of cLEE with short- and long-term exposure to tenofovir disoproxil fumarate, didanosine and stavudine, but only with short-term exposure to emtricitabine, nevirapine, efavirenz, and atazanavir. Exposure to lamivudine was inversely correlated with cLEE. All-cause mortality was slightly higher in those who ever had an episode of cLEE compared with participants without cLEE (0.66/100 PYFU versus 0.60/100 PYFU), but this was not significant.

In conclusion, the novel tenofovir-cLEE signal should be further investigated to understand the pathophysiological mechanisms and its clinical implications.

pdf publication

30th March SNSF grant to Prof. Laurent Decosterd

The SNSF granted Prof. Laurent Decosterd a financial support of CHF 430’500.- for the research project

“Modélisation, simulation et validation clinique des interactions médicamenteuses dans la Swiss HIV Cohort Study”.

23rd March De Luca et al., Improved HIV darunavir resistance score


Improved darunavir genotypic mutation score predicting treatment response for patients infected with HIV-1 subtype B and non-subtype B receiving a salvage regimen. Journal of Antimicrobial Chemotherapy

De Luca et al. on behalf of EuroCoord aimed to derive a refined genotypic interpretation score (GIS) for darunavir based on virological response in patients harbouring subtype B HIV-1, and to validate its performance for non-B HIV-1 subtypes. The main finding was that a model including the new weighted score was more accurate in predicting the virological response at 8 weeks compared with three popular existing GISs for darunavir. Surprisingly, the model also outperformed GIS prediction of virological outcome in an independent validation set of non-B subtypes.

In conclusion, this score may be used for predicting response to darunavir in individuals failing previous protease inhibitors with different subtypes and thus be of help in designing the most appropriate salvage regimens.

PubMed

17th March Gregson et al., Drug resistance after failure of WHO recommended first-line regimens


Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study. Lancet Infectious Diseases

Gregson et al. on behalf of the TenoRes Study Group did a global assessment of drug resistance after virological failure with first-line tenofovir-containing antiretroviral therapy (ART) including 1’926 individuals from 36 countries. They found that levels of tenofovir resistance in individuals with viral failure ranged from 20% in Europe to more than 50% in sub-Saharan Africa. A CD4 cell count of less than 100 cells per μL, treatment with nevirapine rather than efavirenz, and treatment with lamivudine rather than emtricitabine, were consistently associated with a 50% higher odds of tenofovir resistance in those with viral failure.

In conclusion, optimization of treatment programs and effective surveillance for transmission of drug resistance is crucial in low-income and middle-income regions.

pdf publication

16th March Elzi et al., HIV/AIDS and ability to work


Ability to work and employment rates in HIV-1-infected individuals receiving combination antiretroviral therapy: the Swiss HIV Cohort Study. Open Forum Infectious Diseases

Elzi et al. aimed to investigate the ability to work in 5’800 HIV-1-infected adults receiving combination antiretroviral therapy (cART). At baseline, 8.1% were only able to work part time, and 16.3% were unable to work at all. Of the individuals unable to work at baseline, 53.6% were still unable to work at 1 year after starting cART. Predictors of recovering full ability to work at 1 year were non-white ethnicity (odds ratio [OR], 2.04), higher level of education (4.03), cell counts at 1 year of at least 500 cells/μL (2.53), suppressed viral load at 1 year (2.06), and having started cART later in the study period (2.11). In contrast, older age (0.55), a psychiatric disorder (0.24) and participating in an opiate substitution program (0.41) were associated with lower odds of ability to work at 1 year. Recovering full ability to work at 1 year increased from 24.0% in 1998–2001 to 41.2% in 2009–2012, but the employment rates did not increase.

In conclusion, the study reflects a better prognosis for individuals with HIV infection who are treated with cART and with beneficial psychosocial factors.

pdf publication

9th March Wandeler et al., Alcohol J-Curve in HIV infection


The J-curve in HIV: Low and moderate alcohol intake predicts mortality but not the occurrence of major cardiovascular events. Journal of Acquired Immune Deficiency Syndrome

Wandeler et al. performed an analysis of the association between different levels of alcohol consumption and cardiovascular disease events (CADE) free survival and overall mortality. Among 9’741 SHCS participants included, there were 788 events of CADE or deaths during the follow-up period, corresponding to an incidence of 1.69 events/100 person-years. Compared with no or very low alcohol intake, low [hazard ratio (HR) 0.79] and moderate alcohol intake (0.78) were associated with a lower incidence of the endpoint, whereas no association was detected for high intake. In addition, a significant association was observed between education level and CADE or death (high vs. low: HR 0.7) and between cumulative treatment with abacavir or protease inhibitors and CADE or death.

The study-results underline the protective effect of low and moderate alcohol consumption on CADE-free survival and overall survival. However, the specific impact of drinking patterns and type of alcoholic beverage on this outcome remains to be determined.

pdf publication

2nd March Cain et al., Using observational data to emulate different treatment-switching strategies


Using observational data to emulate a randomized trial of dynamic treatment-switching strategies: an application to antiretroviral therapy. International Journal of Epidemiology

Cain et al. reviewed a framework for the comparison of dynamic switching strategies using observational data from 43’803 HIV-infected individuals. In this hypothetical randomized trial, individuals were randomized to either switch antiretroviral therapy (ART) within 90 days of HIV-1 RNA crossing above 400 copies/ml (tight-control group) compared to a switch within 90 days of HIV-1 RNA crossing above 1000 copies/ml (loose-control group). There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the fully adjusted hazard ratios for loose control were 1.10 for death and 1.04 for AIDS or death.

In conclusion, this approach detected little or no differences between switching at HIV-1 RNA thresholds of 400 and 1000 copies/ml in preventing death and AIDS-defining illness.

PubMed

24th February Jarrin et al., Sex differences in mortality from cART in Europe and North America


Sex differences in overall and cause-specific mortality among HIV-infected adults on antiretroviral therapy in Europe, Canada and the US. Antiviral Therapy

Jarrin et al. on behalf of the Antiretroviral Therapy Cohort Collaboration, examined differences in rates among men and women infected through heterosexual intercourse or injecting drug use treated with combination antiretroviral therapy in Europe and North America. Comparing women and men in Europe, all-cause mortality hazard ratio (HR) was 0.76 after adjustment for prognostic factors at baseline. The HR was similar for AIDS-related mortality but significantly lower for non-AIDS related mortality in European women compared to European men. By contrast, there was little evidence of between-sex differences in all-cause or cause-specific mortality in North America.

In conclusion, patterns of non-AIDS mortality (e.g. malignancies, cardiovascular diseases) in HIV-infected cohort members in Europe are coming to resemble those of the general population, and sex mortality ratios in treated HIV-positive people may increasingly resemble those in the general population.

pdf publication

18th February Smit et al., Effect of abacavir on HCV treatment


Effect of abacavir on sustained virologic response to HCV treatment in HIV/HCV co-infected patients, COHERE in Eurocoord. BMC Infectious Diseases

Smit et al. on behalf of COHERE in Eurocoord aimed to examine the influence of abacavir (ABC) on the response to pegylated interferon and ribavirin (RBV) containing hepatitis C virus (HCV) treatment in HIV/HCV co-infected patients. In the multivariate analyses there was no association between ABC-containing regimens and a higher or lower likelihood of achieving a sustained virological response rate (SVR). A boosted protease inhibitor (PI) regimen was significantly associated with a lower probability of achieving a SVR compared to NNRTI-based regimens (29% versus 37%). Overall, the different backbones were not associated with a low SVR with the exception of the zidovudine + lamivudine and stavudine + lamivudine combinations.

In conclusion, a potential negative impact of a boosted PI regimen may warrant further evaluation but the authors found no evidence of a harmful effect of ABC-containing regimens in future direct acting antivirals (DAA) and RBV combinations.

pdf publication

11th February Cummins et al., Efavirenz discontinuation by genetic analysis


Investigation of efavirenz discontinuation in multi-ethnic populations of HIV-positive individuals by genetic analysis. EBioMedicine

Cummins et al. aimed to determine if pharmacogenetic testing of select single nucleotide polymorphisms (SNPs) in genes which encode enzymes principally involved in efavirenz (EFV) metabolism would be associated with premature treatment discontinuation of virologically suppressive, EFV-containing ART regimens. Participants with a high genetic risk score had a significantly increased risk of discontinuing effective ART regimens containing EFV compared to participants with lower risk scores. Black participants had a higher prevalence (14.1%) of high genetic risk compared to other races (2.4%) and were only slightly more likely to discontinue EFV than non-blacks (hazard ratio 1.4).

The study results indicate that genetic risk score is superior to race in associating which patients discontinue EFV. Pharmacogenetic testing should be considered in patients who initiate EFV-based ART.

pdf publication

10th February McLaren et al., Encrypted clinical genetic testing


Privacy-preserving genomic testing in the clinic: a model using HIV treatment. Genetics in Medicine

McLaren et al. used DNA-based prediction of HIV-related outcomes to test the applicability of privacy-preserving techniques for genetic testing with ancestry inference and delivery of interpreted information to clinicians. The authors tested 17 phenotypes relevant for patients with HIV in 230 patients. The proportion of positive results ranged from 0 to 54%, and 98% of patients had at least 1 positive result. The majority (53%) of physicians reported that the test results were useful or potentially useful but only a minority (42%) reported that they would discuss these results with the patients. Only 10% of physicians reported that they would have prescribed a different first-line regimen if given the genetic results in advance.

In conclusion, the strategy successfully implemented in this pilot study allows the secure storage and analysis of large-scale genetic data, as well as the targeted delivery of specific subsets of test results to the clinic.

pdf publication

10th February A leaflet presenting the SHCS
 

please find here the leaflet presenting the SHCS in the different languages

English

deutsch

français

italiano

4th February Bartha et al., Heterozygous protein truncating variants in the human genome


The characteristics of heterozygous protein truncating variants in the human genome. PLoS Computational Biology

Genome sequencing provides evidence for large numbers of putative protein truncating variants in humans. Bartha et al. characterized genes showing fewer de novo truncations in the general population than expected under a neutral model in order to quantify the importance of heterozygous protein truncating variation. The authors identified 10% of genes that do not tolerate loss of one of the two gene copies, and of the coding genome. They showed that an additional 10 to 15% of truncated genes may be rescued by incomplete penetrance or compensatory mutations, or because the truncating variants are of limited functional impact.

The study results indicate that the burden of rare human heterozygous variation is an unexplored source of diversity of phenotypic traits and diseases.

pdf publication

3rd February Hachfeld et al., Late presentation to HIV care in Switzerland


Reasons for late presentation to HIV care in Switzerland. Journal of the International AIDS Society

Hachfeld et al. aimed to assess the prevalence of late presentation to HIV care in Switzerland, and to identify related risk factors. Of 1366 patients enrolled in the SHCS, 680 (49.8%) were late presenters (LPs) and 347 (25.4%) had a CD4 count below 200 cells/µl. Compared to non-LPs, LPs were more likely to be male and heterosexual or female and to originate from sub-Saharan Africa or Asia. Late presentation was driven mainly by late HIV testing due to low risk perception and lack of awareness of HIV transmission, symptoms and treatment.

The study results underscore that primary care and specialist physicians need to increase HIV testing among their patients if earlier diagnosis and linkage to care are to be achieved.

PubMed

28th January Aouri et al., Known and new in vivo phase I and II efavirenz metabolites


In vivo profiling and distribution of known and novel phase I and phase II metabolites of efavirenz in plasma, urine, and cerebrospinal fluid. Drug Metabolism and Disposition

Aouri et al. performed a quantitative metabolite profile analysis of efavirenz (EFV) comprising both phase I and phase II metabolites in plasma, cerebrospinal fluid (CSF), and urine samples in 71 human immunodeficiency virus patients taking EFV. They examined their relationships with the presence of certain genetic variants in different enzymes involved and with treatment discontinuation because of CNS toxicity. They identified the new metabolite 8OH-EFV-sulfate, which was present at high concentrations in all body compartments and demonstrated that the dominant circulating metabolites of EFV are not EFV primary oxidized products, but rather the downstream phase II EFV metabolites.

They conclude that the clinical importance of these previously unreported EFV metabolites in CSF and their potential contribution to the neuropsychological effects of EFV need to be examined in larger cohort studies.

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27th January May et al., Intravenous drug use, hepatitis C virus, and mortality


Injection drug use and Hepatitis C as risk factors for mortality in HIV-infected individuals: The Antiretroviral Therapy Cohort Collaboration. JAIDS

May et al. on behalf of the Antiretroviral Therapy Cohort Collaboration aimed to determine whether the association between intravenous drug use (IDU) and mortality is explained by differential rates of hepatitis C virus (HCV) infection. The prevalence of HCV among IDU was 85%. Mortality hazard ratio (HR) for both IDU and HCV were similar and substantially elevated. For most causes of death, mortality was higher in IDU compared with non-IDU and in HCV+ compared with HCV-. The association of transmission through IDU with all-cause mortality was attenuated after adjustment for HCV coinfection, but mortality remained more than 50% higher in IDU than in non-IDU.

In conclusion, a substantial proportion of the excess mortality in HIV-infected IDU is explained by HCV coinfection. The analyses underscore the importance of treating HCV coinfection among those living with HIV, many of whom no longer use injection drugs but are continuing to suffer consequences of past use.

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21st January McLaren et al., Host genetic contribution to variation of HIV-1 virus load


Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load. PNAS

McLaren et al. combined the majority of available genome-wide genotyping data in HIV-infected populations to test for association between ∼8 million variants and set point HIV viral load (spVL) in 6’315 individuals of European ancestry. They observed strong associations between spVL and multiple alleles at HLA-A, -B, and -C over a broad range of effect sizes. A second genome-wide significant association signal was observed in the chemokine receptor gene cluster on chromosome 3. Heritability analysis demonstrated that common human genetic variation explains 25% of the variability in viral load.

In conclusion, the study results indicate that common variants of large effect explain the majority of the host genetic component of HIV viral load.

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20th January Grint at al., Liver-related death among HIV/HCV-co-infected individuals


Liver-related death among HIV/hepatitis C virus-co-infected individuals: implications for the era of directly acting antivirals. AIDS

Grint et al. on behalf of EuroSIDA aimed to describe causes of death among HIV/HCV-co-infected individuals to identify factors associated with liver-related death (LRD) and to provide guidance on who should be prioritized for treatment of HCV infection with directly acting antivirals (DAAs). One hundred forty-five out of 670 deaths (21.6%) were classified as liver-related, equating to an overall incidence of LRD of 9.0. LRD rates were 35-fold higher among those with F4 fibrosis compared with those having F0/F1 fibrosis, and 8-fold higher than those with F2/F3 fibrosis. Factors associated with LRD were HBsAg-positivity, CD4+ cell count per doubling, and age between 35 and 45 years.

In conclusion, those with significant liver fibrosis (≥F2) should be prioritized for treatment with DAAs and early initiation of cART should be considered essential to decrease the risk of LRD.

PubMed

14th January Boesecke et al., Acute hepatitis C incidence in Europe


Hepatitis C seroconversions in HIV infection across Europe: which regions and patient groups are affected? Liver International

Boesecke et al. aimed to determine whether there has been an increase in the number of acute hepatitis C virus (HCV) infections in different parts of Europe. The overall odds of seroconversion per test for HCV were 1.38% between 2002 and 2013. There was a 4% increase in HCV seroconversion per calendar year with borderline statistical significance. The highest overall number of HCV seroconversions was found in men who have sex with men (MSM) (63.2%). Patients who acquired HIV via heterosexual intercourse had 59% lower odds of HCV seroconversion than MSM, while people who inject drugs (PWID) was associated with fivefold increased odds of HCV seroconversion compared with MSM.

The study-results underscore the need for increased HCV prevention efforts with special attention to populations at high risk such as MSM and PWID.

PubMed

13th January Turkova et al., HCV treatment in HIV/HCV co-infected children and young adults


HCV treatment in children and young adults with HIV/HCV co-infection in Europe. Journal of Viral Eradication

Turkova et al. aimed to describe use of treatment for chronic hepatitis C virus (HCV) infection in HIV/HCV co-infected children and young people living in Europe and to evaluate treatment outcomes. Among the countries where patients received pegylated interferon alpha and ribavirin (peg-IFN/RBV), treatment rates were between 9% and 61% with an overall treatment rate of 24%. Factors associated with increased probability of HCV treatment were older age, advanced fibrosis and easier-to-treat genotypes (GTs). Twenty-fife patients out of fifty patients (50%) treated with peg-INF/RBV achieved sustained virological response (SVR) 24 with rates of 29% in GT 1,4 and of 80% in GT 2,3.

The study-results indicate that HCV treatment success appears to be lower in HIV/HCV co-infection and underscore the need to speed up approvals of new direct-acting antiviral combinations in children.

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7th January Jarrin et al., Rapid progression, optimal CD4+ recovery


Does rapid HIV disease progression prior to combination antiretroviral therapy hinder optimal CD4+ T-cell recovery once HIV-1 suppression is achieved? AIDS

Jarrin et al. on behalf of CASCADE compared trends in CD4+ T-cell recovery and the proportion achieving optimal restoration counts between rapid and nonrapid progressors after viral suppression following combination antiretroviral therapy (cART) initiation. They found that rapid progressors experienced a faster CD4+ T-cell increase in first month compared to nonrapid progressors. In contrast, rapid progressors less likely achieved counts of at least 500 cells/µl at months 12 and 36 but not at month 60. These differences disappeared after adjusting for baseline CD4+ T-cell count.

The study-findings underscore the current recommendation that cART should be started as soon as possible after HIV-1 diagnosis regardless of the CD4+ T-cell count.

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6th January Stucki et al., Genomic epidemiology of a tuberculosis outbreak


Tracking a tuberculosis outbreak over 21 years: strain-specific single-nucleotide polymorphism typing combined with targeted whole-genome sequencing. The Journal of Infectious Diseases

Stucki et al. combined strain-specific single-nucleotide polymorphism (SNP) typing and targeted whole-genome sequencing (WGS) to investigate a tuberculosis cluster spanning 21 years in Bern, Switzerland. The authors screened 1’642 M. tuberculosis single patient isolates for the Bernese cluster–specific SNP and identified 71 isolates (4.3%) as belonging to this cluster. Most received a tuberculosis diagnosis in 1991–1995 and two thirds were homeless and/or substance abusers. The strain-specific SNP assay was approximately 15 times less expensive than the current gold standard.

In conclusion, a combined approach using strain-specific SNP genotyping with subsequent targeted WGS could be applied to track bacterial pathogens in real time and at high resolution.

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