2017

22nd November Beauparlant et al., Delineating CD4 dependency of HIV-1


Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality.    PLoS Pathogens

A hallmark of HIV-1 infection is the continuously declining number of the virus' predominant target cells, activated CD4+ T cells. With diminishing CD4+ T cell levels, the capacity to utilize alternate cell types and receptors, including cells that express low CD4 receptor levels such as macrophages, thus becomes crucial.

In this study, Beauparlant et al. aimed to explore evolutionary paths that allow HIV-1 to acquire a wider host cell range by infecting cells with lower CD4 levels. For that, they dissected the evolution of the envelope-CD4 interaction under in vitro culture conditions that mimicked the decline of CD4high target cells, using a prototypic subtype B, R5-tropic strain.

The authors found that adaptation to CD4low targets proved to severely alter envelope functions including trimer opening. There was a strikingly decreased infectivity on CD4high target cells, but sustained infectivity on CD4low targets, including macrophages. The adaptation to CD4low targets altered the kinetic of the entry process, leading to rapid CD4 engagement and an extended transition time between CD4 and CCR5 binding during entry. This phenotype was also observed for certain central nervous system (CNS) derived macrophage-tropic viruses, highlighting that the functional perturbation defined upon in vitro adaptation to CD4low targets also occurs in vivo.

In sum, the analysis suggests that CD4low adapted envelopes may exhibit severe deficiencies in entry fitness and shielding early in their evolution. Considering this, adaptation to CD4low targets may preferentially occur in a sheltered and immune-privileged environment such as the CNS to allow fitness restoring compensatory mutations to occur.

pdf publication

16th November Achhra et al., Impact of early versus deferred ART on eGFR rate


Impact of early versus deferred antiretroviral therapy on estimated glomerular filtration rate in HIV-positive individuals in the START trial.    International Journal of Antimicrobial Agents

The START trial is a randomised controlled clinical trial of immediate initiation of antiretroviral therapy (ART) (‘immediate’ arm) versus deferral of ART initiation until CD4+ counts decline to <350 cells/mm3 or clinical symptoms develop (‘deferred’ arm) among participants naïve to ART with CD4+ counts >500 cells/mm3.

In this study, Achhra et al. on behalf of the INSIGHT START Study Group aimed to assess the effect of early ART upon kidney function among persons with relative immune preservation and low risk for acquired immune deficiency syndrome (AIDS) complications. Serum creatinine and urine dipstick protein were longitudinally measured and the two arms were compared for changes in eGFR (mL/min/1.73m2).

Of 4’685 START participants, 4’629 (2’294 in immediate and 2’335 deferred arm) were included. Median baseline CD4+ and eGFR were 651 and 111.5, respectively. ART was initiated in 99.0% in the immediate and 48.3% in the deferred arm, accounting for >94% and >19% of follow-up time, respectively. Overall, 89% started ART using a tenofovir-based regimen. Over 2.1 years median follow-up, mean eGFR was 0.56 higher in the immediate versus deferred arm, which was more prominent after adjustment for current tenofovir or boosted protease inhibitor use (1.85) and in Black participants (3.90) versus non-Blacks (1.05). Relative risk for proteinuria in the immediate versus deferred arm was 0.74.

In summary, this study suggests modest short-term benefit on kidney function from the immediate initiation of ART in HIV-positive individuals with high CD4+ cell count. This benefit was especially prominent in individuals of Black race and in the absence of tenofovir or boosted protease inhibitor use.

PubMed

15th November Bachmann et al., Heritability of an HIV 1 trait in a realistic setup


Parent-offspring regression to estimate the heritability of an HIV-1 trait in a realistic setup.   Retrovirology

Parent-offspring (PO) regression is a central tool to determine the heritability of phenotypic traits; i.e., the relative extent to which those traits are controlled by genetic factors. The applicability of PO regression to viral traits is unclear because the direction of viral transmission - who is the donor (parent) and who is the recipient (offspring) - is typically unknown and viral phylogenies are sparsely sampled.

Using simulated data on phylogenies derived from 11’442 Swiss HIV Cohort Study (SHCS) partial pol sequences and set-point viral load (SPVL) data from 3’293 patients, Bachmann et al. tested PO regression robustness against both the lack of knowledge concerning transmission directionality and sparse sampling. The authors found that the misidentification of donor and recipient plays a minor role in estimating heritability and showed that sparse sampling does not influence the mean heritability estimated by PO regression. A mixed-effect model with pairs as groups yielded heritability estimates equivalent to PO regression. Using both methods to estimate SPVL heritability in the SHCS, they employed a wide range of transmission pair criteria to measure heritability and found a strong dependence of the heritability estimates to these criteria. However, the estimates did not change substantially after adjusting for host-demographic factors in the mixed-effect model.

In conclusion, the study-results suggest that PO regression is for conservative transmission pair criteria a robust estimator of heritability in large datasets and that its conceptual problems are not quantitatively relevant in a real-life setting. Overall, the study found a strong effect of viral genetics on SPVL (32-46%) that is not confounded by host demographics.

pdf publication

9th November Chereau et al., Loss of virological control among HIV controllers


Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers.   PLoS One

Chereau et al. on behalf of the HIV Controllers Project Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCOORD aimed to identify factors associated with loss of virological control among HIV controllers (HICs). HICs were defined as ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV diagnosis.

Among the 111’073 eligible individuals, 1’067 HICs (0.96%) were identified; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds.

<p< From this internationally largest series of HIV controllers, the authors conclude that expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. The study-findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs. From a clinical perspective, careful monitoring of untreated HICs who experience decrease of CD4 and CD4/CD8 ratio during virological control, or transient viral rebounds, is needed.

pdf publication

8th November Bertels et al., Dissecting HIV virulence


Dissecting HIV virulence: heritability of setpoint viral load, CD4+ T cell decline and per-parasite pathogenicity.    Molecular Biology and Evolution

The ability of pathogens to evoke virulence by different diseases-causing mechanisms independent of their load refers to as ”per-parasite pathogenicity”. Using viral load and CD4+ T cell measures from 2’014 HIV-1 subtype B infected individuals enrolled in the Swiss HIV Cohort Study, Bertels at el. aimed to investigate if virulence - measured as the rate of decline of CD4+ T cells - and per-parasite pathogenicity are heritable from donor to recipient. They estimated heritability by donor-recipient regressions applied to 196 previously identified transmission pairs, and by phylogenetic mixed models applied to a phylogenetic tree inferred from HIV pol sequences.

They found that the CD4+ T cell declines and per-parasite pathogenicities of the transmission pairs did not yield heritability estimates significantly different from zero. With the phylogenetic mixed model, however, the best estimate for the heritability of the CD4+ T cell decline was 17% (5%–30%), and that of the per-parasite pathogenicity was 17% (4%–29%). Further, they confirmed that the set-point viral load is heritable, and estimate a heritability of 29% (12%–46%).

In conclusion, the analysis shows that the viral genotype affects virulence mainly by modulating the per-parasite pathogenicity, while the indirect effect via the set-point viral load is minor.

PubMed

2nd November enrollment of the 20'000th patient in the SHCS

Dear all,

We proudly announce the inclusion of the 20’000th patient in the Swiss HIV Cohort Study.

In the last three decades, the SHCS participants attended together almost 300’000 visits, some patients had over 70 study visits. Patients enrolled in the SHCS represent at least

  • 50% of the overall epidemic in Switzerland,
  • 75% of AIDS cases, and
  • 72% of all individuals treated with antiretrovirals in Switzerland.

The biobank contains more than 1.3 Mio samples of plasma and PBMCs.

The achievement of such incredible numbers is only possible thanks to the tireless commitment of the participants, physicians, study nurses, researchers, data managers, administrative staff and funders.

We look forward to continuing our work, as the SHCS is a fantastic tool to further address urgent research questions in order to improve quality of care, study potential long-term toxicities of antiretroviral drugs, address basic science questions in HIV-biology also using big data approaches, work towards an HIV vaccine, target elimination of HCV in HIV-infected patients and improve prevention and quality of life of HIV-infected individuals in general.

At this occasion we also want to thank the Federal Office of Public Health for an additional financial support of CHF 300’000.- for the year 2018 to further improve preventive efforts.

Kind regards,

Alexandra Scherrer
(head of data center) and

Huldrych Günthard
(president SHCS)

2nd November Bayard et al., Avascular necrosis in HIV


Associations between antiretroviral treatment and avascular bone necrosis: The Swiss HIV Cohort Study.    Open Forum Infectious Diseases.

Bayard et al. aimed to study the associations of antiretroviral therapy (ART) with the occurrence of avascular bone necrosis (AVN) among Swiss HIV Cohort Study participants. For each case with confirmed AVN, they randomly selected SHCS participants without any signs of AVN and matched these controls for gender, SHCS registration date, and last follow-up date.

The authors analyzed 219 SHCS participants, 74 with AVN and 145 controls. AVN was located in the femoral head in 59 (80%) participants. In the adjusted models, associations with AVN were shown for heterosexual HIV acquisition (odds ratio [OR], 3.4), alcohol consumption (OR, 2.7), and hyperlipidemia (OR, 3.6). After adding ART substances to the multivariable base model, there was evidence of an association for treatment with tenofovir (TDF) >1 year (OR, 4.4) with AVN. Neither exposure to specific frequently prescribed ART combinations or ART drug classes nor cumulative ART exposure showed any associations with AVN.

In conclusion, the study-results confirm previously recorded AVN risk factors such as heterosexual HIV acquisition, moderate/severe alcohol consumption, hyperlipidemia, and corticosteroid use >3 months (trend). The finding of an increased risk for AVN in heterosexual HIV acquisition is probably mediated by advanced immunosuppression, considering the fact that heterosexual participants in the study were more likely to be late presenters compared with other transmission groups. The observation that TDF contributes to AVN needs to be confirmed in other patient populations. However, a recent study in a large international HIV cohort did not find any association of antiretrovirals with osteonecrosis.

pdf publication

25th October Salazar-Vizcaya et al., Potential of short-term intensive intervention to interrupt HCV transmission in MSM


On the potential of a short-term intensive intervention to interrupt HCV transmission in HIV-positive men who have sex with men: a mathematical modelling study.    Journal of Viral Hepatitis

Salazar-Vizcaya et al. assessed the potential to interrupt hepatitis C virus (HCV) transmission among HCV-positive men who have sex with men (MSM) of the Swiss-HCVree-trial and a similar intensive intervention where all HCV genotypes could be treated. To capture potential changes outside intensive interventions, the authors varied time from HCV infection to treatment in clinical routine and overall high-risk behaviour among HIV-positive MSM.

In their model, the simulated prevalence dropped from 5.5% in 2016 to ≤2.0% over the intervention period (June/2016-May/2017) with the pangenotypic intervention, and to ≤3.6% with the Swiss-HCVree-trial. Assuming time to treatment in clinical routine reflected reimbursement restrictions at the time of the model simulation (METAVIR ≥F2, 16.9 years) and stable high-risk behaviour in the overall MSM population, prevalence in 2025 reached 13.1% without intensive intervention, 11.1% with the pangenotypic intervention and 11.8% with the Swiss-HCVree-trial. If time to treatment in clinical routine was 2 years, prevalence in 2025 declined to 4.8% without intensive intervention, to 2.8% with the pangenotypic intervention, and to 3.5% with the Swiss-HCVree-trial. In this scenario, the pangenotypic intervention and the Swiss-HCVree-trial reduced cumulative (2016-2025) treatment episodes by 36% and 24%, respectively.

In conclusion, the model projections suggest that a 1-year intensive intervention could save HCV treatment costs while boosting the benefits of long-term efforts to prevent high-risk behaviour and to increase treatment rate in clinical routine. In the scenario where treatment reimbursement restrictions were not relieved and the level of high-risk behaviour in the overall HIV-positive MSM population did not decrease, HCV prevalence doubled by 2025 despite intensive interventions. The study-results underscore the importance of the achievement of universal access to treatment with newest HCV direct acting agents for all HCV positive individuals with regard to HCV elimination in Switzerland.

PubMed

19th October Cozzi-Lepri et al., Raltegravir and the risk of malignancies and mortality


Incidence of cancer and overall risk of mortality in individuals treated with raltegravir-based and non-raltegravir-based cART regimens.   HIV Medicine

Cozzi-Lepri et al. on behalf of the EuroSIDA Study Group aimed to compare the incidences of malignancies and other comorbidities as well as survival rates in cohorts of individuals initiating raltegravir (RAL-) based and non-RAL-based combination antiretroviral therapy (cART) regimens in a large European cohort of HIV-infected patients. The cohort was divided into three groups: those starting RAL-based cART on or after 21 December 2007 (RAL); a historical cohort (HIST) of individuals adding a new antiretroviral (ARV) drug (not RAL) to their cART between 1 January 2005 and 20 December 2007, and a concurrent cohort (CONC) of individuals adding a new ARV drug (not RAL) to their cART on or after 21 December 2007.

A total of 1’470 patients were included in the RAL cohort, 3’787 patients were included in the HIST comparison cohort and 4’467 patients were included in the CONC cohort. The prevalence of non-AIDS-related malignancies prior to baseline tended to be higher in the RAL cohort vs. the HIST cohort [adjusted odds ratio (aOR) 1.31; and vs. the CONC cohort (aOR 1.89). In intention-to-treat (ITT) analysis the incidence of all new malignancies was 1.10 per 100 PYFU in the RAL cohort vs. 1.20 and 0.83 in the HIST and CONC cohorts, respectively. After adjustment, there was no evidence for a difference in the risk of malignancies or mortality.

In conclusion, the study-findings show that use of RAL does not seem to be associated with an increased risk of cancer or reduced survival when compared with the cancer and survival rates seen in people treated with alternative regimens in routine clinical care.

PubMed

12th October Peters et al., Mortality in hepatitis C virus–treated HIV patients


Is response to anti-hepatitis C virus treatment predictive of mortality in hepatitis C virus/HIV-positive patients?    AIDS

Peters et al. The Hepatitis C Working Group for the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord aimed to compare the long-term risk of all-cause mortality and liver-related death according to response to pegylated interferon + ribavirin in HIV/HCV coinfected people enrolled in the large prospective multicohort study Collaboration of COHERE. Patients were categorized into “responders” (last HCV-RNA measured between 24 and 72 weeks after baseline negative), “nonresponders” (HCV-RNA positive between 24 and 72 weeks after baseline) and “unknown response” (HCV-RNA unknown).

Overall, 3’755 patients were included: 1’031 (27.5%) responders, 1’639 (43.6%) nonresponders and 1’085 (28.9%) with unknown response. Rates (per 1’000 person-years of follow-up) of all-cause death were 17.59 for nonresponders, 10.43 for responders, and 11.00 for unknown responders, respectively. After adjustment, the relative hazard (nonresponders vs. responders) for all-cause death, liver-related death and nonliver-related death was 1.53, 3.39, and 1.22, respectively.

In conclusion, the study-results show that among HIV/HCV coinfected patients a favourable virological response to HCV treatment is associated with reduced risk of both liver-related death and improved overall survival in the interferon era. There was no difference in risk of nonliver-related death when comparing responders and nonresponders. However, as interferon is contraindicated in patients with advanced cirrhosis due to the risk of liver decompensation, it is likely that patients with more advanced liver disease were excluded in this study. It is therefore conceivable that with the new tolerable and effective interferon-free direct-acting antivirals, one will be able to prevent more liver-related and, possibly, nonliver-related complications.

pdf publication

4th October Kamal et al., HIV-infected patients’ beliefs about co-treatments compared with cART


HIV-infected patients' beliefs about their chronic co-treatments in comparison with their combined antiretroviral therapy.    HIV Medicine

Kamal et al. tested the hypothesis that patients’ perceptions of and attitudes towards their combination antiretroviral therapy (cART), which is perceived as crucial to their survival, differ from their beliefs about their co-treatments, and this may have an impact on their medication adherence. Beliefs about cART were assessed using the validated French version of the Beliefs about Medicine Questionnaire for Highly Active Antiretroviral Therapy (BMQ-HAART). For co-medications, the French version of the generic Beliefs about Medicine Questionnaire (BMQ-f) was used.

Out of 150 administered questionnaires, 109 patients returned their questionnaires (72.6%). Most participants were male (74%) and the median age was 56 years. Eighty-seven percent of patients reported being adherent to cART and 75% of them reported being adherent to their co-treatment (P=0.0001). Respondents had higher Necessity and lower Concerns scores for their cART in comparison with their co-treatments. Women had higher cART Necessity scores than men. Respondents with an education level less than a bachelor’s degree had higher Necessity scores for their co-treatments than those with an education level higher than a bachelor’s degree. Respondents also had higher Necessity scores for their co-treatments the higher their CD4 count was.

In conclusion, patients had higher Necessity and lower Concerns scores for their cART in comparison with their co-treatments. Patients also had a higher adherence to cART in comparison to the co-treatments they reported as being most likely to miss. The study-results suggests that it could be important to focus on patient beliefs to improve adherence to co-treatments.

pdf publication

28th September Bohlius et al., Regional Kaposi sarcoma risk in HIV-positive adults


Comparison of Kaposi sarcoma risk in HIV-positive adults across five continents: a multiregional multicohort study.     Clinical Infectious Diseases

Bohlius et al. on behalf of the AIDS-defining Cancer Project Working Group in EuroCoord aimed to compare Kaposi sarcoma (KS) incidence rates in HIV-positive adults who started antiretroviral therapy (ART) across different continents, and to assess factors associated with regional differences in KS risk.

The authors included data on 208’140 patients from 42 cohorts in 57 countries across the Asia-Pacific, South Africa, Europe, Latin, and North America. Over the course of 1’066’572 person-years, 2’046 KS cases were diagnosed. The raw KS incidence rate per 100’000 person-years was highest in South Africa (280), followed by Latin America (244), North America (237), Europe (180), and the Asia-Pacific (52). After adjustment for current CD4 cell count, age at ART initiation, first-line regimen, and calendar year of ART initiation, risk was 5 times higher in South African women (adjusted HR [aHR] 4.56) than in their European counterparts, and 2 times higher in South African men. In Europe, Latin, and North America KS risk was 53% higher in heterosexual men than women (aHR 1.53), and 6 times higher in men who have sex with men (MSM) (aHR 5.95). Comparing patients with current CD4 cell counts ≥700 cells/μL with those whose counts were ≥700 cells/μL with those whose counts were <50 cells/μL, the KS risk was halved in South Africa (aHR, 0.53) but reduced by ≥95% in other regions.

In conclusion, despite ART-related declines in KS incidence, men and women in South Africa and MSM remain at higher risk of KS than other HIV-positive persons, probably owing to higher human herpesvirus 8 (HHV-8) coinfection rates. While a vaccine against HHV-8 remains unavailable, early ART initiation and maintenance of high CD4 cell counts are essential to reducing the incidence of KS in populations at high risk for HHV-8 coinfection.

pdf publication

20th September Sculier et al., Rilpivirine use in the Swiss HIV Cohort Study


Rilpivirine use in the Swiss HIV Cohort Study: a prospective cohort study.     BMC Infectious Diseases

Sculier et al. aimed to determine the reasons for prescribing the rilpivirine (RPV)/tenofovir disoproxil (TDF)/emtricitabine (FTC) co-formulation within the Swiss HIV Cohort Study (SHCS) and to assess its effectiveness and safety over a 24 months period. All individuals enrolled in the SHCS who initiated a RPV/TDF/FTC co-formulation between April 2013 and March 2014 were included.

Among the 644 patients who started the RPV/TDF/FTC co-formulation, 48 (7.5%) were cART-naïve, representing only 10.5% of the total number of HIV-naïve patients enrolled in the SHCS and initiated cART during the same time period. At 24 months, viral suppression (HIV-RNA

In conclusion, the study demonstrates that rilpivirine, tenofovir disoproxil and emtricitabine in a fixed dose combination is an effective cART regimen in both treatment-experienced and -naïve patients under routine clinical conditions, although RPV was rarely used in naïve patients. RPV demonstrates a favourable neurological toxicity profile with most patients experiencing CNS side effects on efavirenz improving after a switch to RPV and very low discontinuation rate for CNS events when compared to efavirenz or integrase inhibitor.

pdf publication

14th September Béguelin et al., HCV treatment uptake, efficacy and impact on liver fibrosis in the SHCS


Trends in HCV treatment uptake, efficacy and impact on liver fibrosis in the Swiss HIV Cohort Study.    Liver International

Béguelin et al. aimed to assess the impact of new hepatitis C virus (HCV) direct acting agents (DAAs) on treatment uptake and efficacy as well as its repercussion on liver disease burden in the Swiss HIV Cohort Study (SHCS).

The authors defined three analysis periods based on the availability of HCV treatments in Switzerland: first period 01/2009-08/2011 (prior to the availability of DAAs), second period 09/2011-03/2014 (1° generation DAAs), third period 04/2014-12/2015 (2° generation DAAs).

At the beginning of the third period, 876 SHCS participants had a chronic HCV infection of whom 180 (20%) started treatment with a 2° generation DAA. Three quarters of them had advanced liver fibrosis, of whom 80% where cirrhotics. SV12 was achieved in 173/180 (96%) patients. Three patients died and four experienced virological failure. Over the three periods, treatment uptake (4.5/100py, 5.7/100py, 22.4/100py) and efficacy (54%, 70%, 96%) continuously increased. The proportion of cirrhotic patients with replicating HCV infection in the SHCS declined from 25% at the beginning to 12% at the end of the last period.

In conclusion, there was a substantial increase in treatment uptake and efficacy after the approval of interferon-free second-generation DAA treatments. DAAs were well tolerated and highly efficacious, even among HIV/HCV-coinfected patients with advanced liver fibrosis or cirrhosis in the SHCS. The treatment of this population with advanced liver disease was driven by treatment priorities but also by limitations in reimbursement, and resulted in a significant reduction in the number of cirrhotic patients with replicating HCV.

Comment Dr. Dominique Braun and Prof. Huldrych Günthard, SHCS
By 1st October 2017, the Federal Office of Public Health (FOPH) will annul the three years ago fixed limitations in reimbursement of hepatitis C drugs in Switzerland. With it, for the first time all patients can be treated with newest DAAs, regardless of the genotype and the liver fibrosis stage. These are fantastic news and the result of longstanding joint efforts among the community, the Swiss hepatitis strategy, the industry, and the FOPH. We are grateful to all parties who were involved in this process and who made that achievement possible.

PubMed

28th August Blaser et al., Impact of screening and ART on anal cancer incidence


Impact of screening and antiretroviral therapy on anal cancer incidence in HIV-positive MSM.     AIDS

Blaser et al. aimed to model the impact of screening strategies and combination antiretroviral therapy (cART) coverage on anal cancer incidence in Switzerland. The authors developed an individual-based mathematical simulation model to predict anal cancer incidence in HIV-positive men-who-have-sex-with-men (MSM) in Switzerland, 1980-2030. In the CD4 count dependent strategy, only those MSM were screened who had had a CD4 nadir below 200 cells/μl.

Modeled anal cancer incidence peaked at 81.7/100,000 in 2009, plateaued 2010-2015 and decreased to 58.7 by 2030 with stable cART coverage, and to 52.0 with 100% cART coverage. With yearly cytology, incidence declined to 38.2/100,000 by 2030, with yearly anoscopy to 32.8 and with CD4 count guided anoscopy to 51.3. The numbers needed to screen over 15 years to prevent one anal cancer case were 384 for yearly cytology, 313 for yearly anoscopy and 242 for CD4 count dependent screening.

In conclusion, the modelling study predicts substantial reductions in anal cancer incidence in MSM in the next 15 years, even in the absence of screening and without further increases in cART coverage. The introduction of yearly anal Pap screening or anoscopy screening, or CD4 cell count guided anoscopy screening would reduce anal cancer incidence further. Notably, the numbers needed to screen to prevent one invasive anal cancer in MSM appear to be lower than the numbers needed to screen to prevent one invasive cervical cancer in HIV-negative women.

pdf publication

16th August O'Connor et al., Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections


Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL: secondary outcome results from a randomised controlled trial.    Lancet HIV

O’Connor et al. for the INSIGHT START study group aimed to quantify the effects of immediate versus deferred antiretroviral therapy (ART) on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial. The START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per μL assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per μL.

Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferred initiation group n=86). Of the 120 people with a severe bacterial infection, 50 had a bacterial infectious disorder (e.g. pyelonephritis, cellulitis, syphilis), 48 developed bacterial pneumonia, and 26 developed tuberculosis. Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0·39, p<0·0001). In the immediate-initiation group, average neutrophil count over follow-up was 321 cells per μL higher, and average CD4 cell count 194 cells per μL higher than the deferred-initiation group (p<0·0001). In univariable analysis, higher time updated CD4 cell count was associated with reduced risk of severe bacterial infection. Time-updated neutrophil count was not associated with severe bacterial infection.

In summary, the results of the study show the protective effect of immediate ART in reducing the risk of a broad spectrum of severe bacterial infections in HIV-positive people. The effect of immediate ART appears to be mediated in part by ART-induced increases in CD4 cell count, but not by the ART-induced increases in neutrophil count.

pdf publication

10th August Elzi et al., Adverse events of raltegravir and dolutegravir


Adverse events of raltegravir and dolutegravir.     AIDS

Elzi et al. aimed to compare the frequency and risk factors of toxicity-related treatment discontinuations between raltegravir and dolutegravir.

From 1 April 2006 to 31 December 2015, 4’041 HIV-infected individuals participating in the SHCS started an antiretroviral regimen containing either raltegravir (n=2’091) or dolutegravir (n=1’950). Of them, 568 (14.1%) had modification of their antiretroviral therapy (ART) because of any reason during the first year of treatment, corresponding to 15.5 discontinuations per 100 patient-years. The main reason for treatment modification was convenience (n=302), followed by toxicity or intolerance (n=181). Only 10 patients under raltegravir (0.48%) and two patients under dolutegravir (0.10%) demonstrated virological failure.

Adverse events leading to ART modification within the first year occurred in 4.5% of the patients, corresponding to a discontinuation rate of 4.4 per 100 patient-years for dolutegravir and 5.7 per 100 patient-years for raltegravir, although not reaching statistical significance. Neuropsychiatric complaints, occurring in overall less than 2% of the patients, were the most commonly reported adverse events and more frequently in the dolutegravir group (discontinuation rate of 1.83 per 100 patient-years) compared with the raltegravir group (discontinuation rate of 0.70 per 100 patient-years, P=0.002). In multivariable analysis of the subgroup with neurotoxicity, there was a significantly lower risk of discontinuation for raltegravir compared with dolutegravir.

In conclusion, the study confirms the excellent tolerability of the raltegravir and dolutegravir in the treatment of HIV-infected individuals. Raltegravir or dolutegravir drug toxicity is an infrequent reason for treatment modification. Although neuropsychiatric complaints are indeed observed more frequently in patients on dolutegravir compared with raltegravir, in overall these adverse events remain relatively rare.

PubMed

9th August a deputy for the head of the SHCS data centre

Dear all,

It is a great pleasure to announce that

Armelle Forrer, PhD in Epidemiology

has started to work in August as a postdoctoral researcher in my research group. She is paid by my own research funds and will primarily work on some of my/our research projects. However, she will work at the SHCS data centre closely with Alexandra Scherrer. She will become Alexandra’s deputy as the head of the data centre and takes over some of Alexandra’s responsibilities. This will allow Alexandra to do more research again besides all the work she does for the data centre.

In addition, it is very important to have a deputy for the head of the data centre and that the two of them work together as a real team. The reason we came up with this solution is that the budget of the SHCS does not allow to hire a deputy of Alexandra. Given the current financial situation, I think this is a win – win situation for all of us.  

best wishes,
Huldrych Günthard

3rd August Kamal et al., HIV adherence and HAND


The presence of human immunodeficiency virus-associated neurocognitive disorders is associated with a lower adherence to combined antiretroviral treatment.     Open Forum Infectious Diseases

Kamal et al. investigated whether there is an association between a HIV-associated neurocognitive disorders (HAND) diagnosis and medication adherence. All patients included had a state-of-the-art neurocognitive assessment performed between January 2011 and June 2015.

Fifty-nine patients were included, with a median CD4 cell count of 603 cell/µl, a median age of 53 years, and 66% were male. Twenty-two patients (35%) had no neurocognitive deficits, 16 (27%) patients had HAND, and 21 (35%) patients had non-HAND (mostly depression). Implementation over 3 years showed a significant decline (50%) in medication adherence among patients diagnosed with HAND in comparison with patients who had a normal neuropsychological status or a non-HIV-related cognitive deficit. In addition, patients with HAND showed an increased probability of detectable HIV-RNA relative to patients without HAND.

In conclusion, the study-results indicate that the detection of neuro-cognitive disorders should raise concern that the patient may be at higher risk of viral load detection and virologic failure. For patients presenting with an increase in viral load, assessing their cognitive function should be considered. To date, the most successful interventions for preventing, delaying, or improving HAND include early initiation of and adherence to combination antiretroviral therapy.

pdf publication

27th July Brandenberg et al., Predicting HIV-1 antibody neutralization in vivo


Predicting HIV-1 transmission and antibody neutralization efficacy in vivo from stoichiometric parameters.     PLoS Pathogens

Brandenberg et al. experimentally determined molecular parameters of the HIV-1 envelope trimer – broadly neutralizing antibody interaction, and subsequently devised a mathematical model of HIV-1 infection and antibody neutralization in vivo. The reason for this work was that the potential of broadly neutralizing antibodies targeting the HIV-1 envelope trimer to prevent HIV-1 transmission has opened new avenues for therapies and vaccines. However, their implementation remains challenging and would profit from a deepened mechanistic understanding of HIV-antibody interactions and the mucosal transmission process.

The authors experimentally confirmed that binding of one antibody per HIV-1 envelope trimer is sufficient for trimer neutralization. This finding defines numerical requirements for HIV-1 virion neutralization and thereby enables mathematical modelling of in vitro and in vivo antibody neutralization efficacy.

In a next step, they employed the model for a post-hoc analysis of non-human primate infection studies, thereby obtaining estimates of HIV-1 neutralization in vivo and the probability for a single HIV-1 virion to initiate host infection. They found that the per-act likelihood of female HIV-1 infection is clearly driven by the size of the virus inoculum and retrieved per-act virus transmission probabilities in good agreement with empirical estimates. Furthermore, the model provided estimates for mucosal neutralizing antibody (nAb) concentrations required to provide protection from infection, indicating that nAb concentrations in the low μg/ml range may provide protection from mucosal HIV-1 transmission.

In conclusion, the combined experimental-mathematical approach delivers precise estimates of virion-antibody interaction stoichiometry, single-virion mucosal transmission probability, male to female per-act infection risk and in vivo nAb neutralization efficacy. These data represent novel quantitative insights into both the molecular details of HIV-1 antibody neutralization and the systemic level of mucosal HIV-1 infection.

pdf publication

19th July Podlekareva et al., Mortality in HIV patients with susceptible tuberculosis


One-year mortality of HIV-positive patients treated for rifampicin- and isoniazid- susceptible tuberculosis in Eastern Europe, Western Europe and Latin America.     AIDS

Podlekareva et al. on behalf of the TB:HIV Study writing Group aimed to assess and compare mortality rates of HIV patients with drug susceptible tuberculosis (TB) across regions and identify risk factors associated with mortality.

Proportion of patients on antiretroviral therapy (ART) was significantly higher at any time point in Western Europe and in Latin America compared to Eastern Europe. At 12 months 94% and 89% of patients in Western Europe and Latin America, respectively, were on ART compared with 69% in Eastern Europe (P<0.001). At 12 months after TB diagnosis, 48% of patients on ART in Eastern Europe had HIV RNA less than 500 copies/ml compared with 86% and 71% in Western Europe and Latin America, respectively (P<0.001). The 1-year probability of death was 16% in Eastern Europe, vs. 4% in Western Europe and 9% in Latin America (P<0.0001). After adjustment for IDU, CD4+ cell count and receipt of antiretroviral therapy, those residing in Eastern Europe were at nearly 3-fold increased risk of death compared with those in Western Europe/Latin America.

In conclusion, this study documents a high mortality among HIV-positive patients with drug susceptible TB in Eastern Europe despite widespread use of WHO recommended anti-TB treatment regimens as initial therapy. Management of HIV infection was suboptimal in this region, but did not fully explain the high mortality. These results call for improvement of care for TB/HIV patients in Eastern Europe.

pdf publication

21st June Casadellà et al., HIV tropism & AIDS progression


Plasma HIV-1 tropism and the risk of short-term clinical progression to AIDS or death.    PLoS One

Casadellà et al. on behalf of EuroSIDA aimed to investigate if plasma HIV-1 tropism testing could identify subjects at higher risk for clinical progression and death in routine clinical management.

In this nested case-control study, cases were subjects with AIDS or who died from any cause, with a plasma sample with HIV-1 RNA >1000 copies/mL available for tropism testing 3 to 12 months prior to the event.

The study included 266 subjects, 100 cases and 166 controls; one quarter had X4 HIV; 26% were antiretroviral therapy (ART) naïve. Baseline tropism (presence of X4 HIV) was not associated with the risk of clinical progression or death in any of the analyses and there was no statistically significant difference in CD4+T-cell count slope between X4 and R5 tropism groups. In addition, there was no evidence that the difference in slope between X4 and R5 tropism varied by ART status. Exposures independently associated with risk of clinical progression to AIDS and/or to death from any cause were: female gender (OR = 2.13 vs. male), CD4+T-cell count (OR = 0.90 per 100 cells/mm3 higher), being on ART at the time of testing (OR = 2.72 vs. being off ART) and calendar year of sample (OR = 0.84 per more recent year).

In conclusion, the study-results suggest that the predictive role of plasma tropism in the context of people receiving cART with detectable VL is not helpful to identify subjects at higher risk for clinical progression. Clinicians should rather consider gender, CD4+ counts and virological outcomes of ART for that purpose.

pdf publication

15th June Lifson et al., Improved QOL with immediate ART in START


Improved quality of life with immediate versus deferred initiation of antiretroviral therapy in early asymptomatic HIV infection.   AIDS

Lifson et al. on behalf of the INSIGHT Start Study Group assessed if immediate compared to deferred initiation of antiretroviral therapy (ART) in healthy persons living with HIV had a more favorable impact on health-related quality of life (QOL).

Participants completed a visual analog scale (VAS) for ‘perceived current health’ and the Short-Form 12-Item Health Survey version 2 from which the following were computed: general health perception; physical component summary (PCS); and mental component summary (MCS); the VAS and general health were rated from 0 (lowest) to 100 (highest).

Mean baseline VAS and perceived general health scores were high with 80.9 and 72.5, respectively. Throughout follow-up, changes in all four QOL measures favored the immediate group (P<0.001). Estimated differences were as follows: 1.9 for the VAS, 3.6 for general health perception, 0.8 for PCS, and 0.9 for MCS. When QOL changes were assessed across various demographic and clinical subgroups, treatment differences continued to favor the immediate group.

In summary, in this large randomized clinical trial of ART-naïve patients from multiple countries who were in generally good health and who had above 500 CD4+ cells/ml at enrollment, there were modest but significant QOL improvements during follow-up in those immediately initiating ART compared to those who deferred treatment. The improvement in patient-perceived health with immediate ART adds to the growing body of evidence that supports recommendations to start ART as soon as possible after HIV diagnosis, irrespective of CD4þ cell count.

PubMed

8th June Borges et al., Fractures and osteonecrosis during HIV


Antiretrovirals, fractures, and osteonecrosis in a large international HIV cohort.     Clinical Infectious Disease

Borges et al. on behalf of EuroSIDA aimed to study the association of exposure to antiretroviral drugs with incident fractures and osteonecrosis of the femoral head and to determine factors independently associated with these two bone outcomes.

Among 11’820 included participants during 86’118 person years of follow-up (PYFU), 496 persons had 619 incident fractures (incidence rate [IR]/1000 PYFU) and 73 persons developed 89 cases of osteonecrosis of the femoral head (IR: 1.0). After adjustment, an increased risk of incident fractures was independently associated with older age, white race, lower BMI, intravenous drug use, HCV coinfection, prior fracture, prior osteonecrosis of the femoral head, a recent non–AIDS-defining malignancy and recent cardiovascular disease. After adjustment, persons who had ever used tenofovir (TDF) (adjusted incidence rate ratio [aIRR], 1.40, P = .0008) or who were currently receiving TDF (aIRR 1.25, P = .012) had a significantly increased incidence of fractures. There was no association between cumulative exposure to TDF and fractures and no other antiretroviral was associated with fractures. Risk of osteonecrosis was associated with white race, lower nadir CD4, prior osteonecrosis, prior fracture, and prior AIDS. After mutual adjustment, no antiretroviral was associated with osteonecrosis.

To conclude, the risk of fractures and osteonecrosis seems to be determined by combination of host factors, HIV-specific variables and comorbidities. The study-results suggest that past and current exposure to TDF, but no other antiretroviral, was independently associated with higher incidence of fractures. The data support cautious use of TDF among HIV-positive persons at fracture risk initiating ART.

PubMed

29th May Abujaber et al., No association of β-defensin copy number and HIV


No evidence for association of β-defensin genomic copy number with HIV susceptibility, HIV load during clinical latency, or progression to AIDS.    Annals of human genetics

The role of gene copy number variation, where the number of copies of the same gene differs between individuals, in affecting clinical parameters of HIV infection is of interest. Previous work has suggested that copy number variation of a cluster of β-defensin genes affects HIV load in treatment-naïve sub-Saharan Africans and rate of response to antiretroviral treatment.

In this work, Abujaber et al. aimed to explore the relationship between β-defensin copy number and HIV infection using a triplex paralogue ratio test for determining diploid copy number at the β-defensin region. The authors analyzed a total of 1’827 individuals from the International AIDS Vaccine Initiative (sub-Saharan Africans) and the Swiss HIV Cohort Study.

They found no evidence for association of copy number with viral load setpoint and HIV progression rate. They also compared distribution of β-defensin copy number between European cases and controls and found no differences, arguing against a role of β-defensin copy number in HIV acquisition.

Taken together, the data argue against an effect of copy number variation of the β-defensin region in the spontaneous control of HIV infection.

PubMed

18th May Trickey et al., Survival of HIV-positive patients starting ART between 1996-2013


Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies.     Lancet HIV

The Antiretroviral Therapy Cohort Collaboration aimed to examine changes in 3 year survival and life expectancy of patients starting combination antiretroviral therapy (ART) between 1996 and 2013. The study used data for 88’504 people with HIV who started antiretroviral treatment between 1996 and 2010 from 18 European and North American studies.

During 84’621 person-years, 2’106 (2%) patients died in the first year after starting ART and 2’302 (3%) died during the second or third year of ART. Compared with patients who started ART in 2000–03, all-cause mortality during the first year of ART was substantially lower for those who started ART in 2008–10 (adjusted hazard ratio [HR] 0.71). All-cause mortality in the second and third years after starting ART declined over calendar time (adjusted HR per calendar period 0.78). The decline in mortality was less in people who inject drugs (adjusted HR per calendar period 0.90). Rates of non-AIDS deaths were lower in patients who started ART in 2008–10 (vs 2000–03) in the first year (0·48) and second and third years (0·29) after initiation of ART. Between 1996 and 2010, life expectancy in 20-year-old patients starting ART increased by about 9 years in women and 10 years in men. Projections based on death rates in the second and third year of treatment for Europeans and North Americans, estimated that 20-year olds starting therapy between 2008-2010 who survived the first year of treatment would live to 73 for men and 76 for women.

In conclusion, even in the late ART era, survival during the first 3 years of ART continues to improve, which probably reflects transition to less toxic antiretroviral drugs, improved adherence, prophylactic measures, and management of comorbidity. Since modern ART is highly effective and has low toxicity, the excess mortality in people living with HIV is unlikely to be addressed by further development of antiretroviral drugs. Instead, lifestyle issues that affect adherence to ART and non-AIDS mortality, and diagnosis and treatment of comorbidities in people living with HIV should be addressed.

pdf publication

3rd May Shilaih et al., Factors associated with syphilis in the SHCS


Factors associated with syphilis incidence in the HIV-infected in the era of highly active antiretrovirals.     Medicine

Shilaih et al. aimed to examine the factors that affect syphilis incidence in the Swiss HIV Cohort Study. The incidence rate was 26.8 cases per 1000 person-years for men who have sex with men (MSM), 1.3 for intravenous drug users, and 1.8 for heterosexuals. There was a significant increase of syphilis incidence over time, however, without clear elevation directly after the introduction of the Swiss Statement in 2008. The MSM population was most affected by syphilis and accounted for 92% of incident cases (92%). Unexpectedly, nevirapine was associated with lower syphilis incidence in the multivariate model, whereas condomless sex and younger age were associated with higher syphilis incidence. Testing frequency higher than the recommended once a year routine testing was associated with a 2-fold higher risk of acquiring syphilis.

In conclusion, this study demonstrates that syphilis incidence has been continuously increasing in recent years with the main driver being high-risk behavior, namely condomless sex. This observation entails targeted interventions and frequent screening of high-risk populations. Antiretroviral treatment generally does not provide a protective effect against syphilis. The intriguing protective association of nevirapine against syphilis incidence demands further investigation.

pdf publication

27th April Bartha et al., Host and viral genomic contribution to HIV control


Estimating the respective contributions of human and viral genetic variation to HIV control.   PLoS Computational Biology

Bartha et al. evaluated the fraction of variation in HIV-1 set point viral load (spVL) attributable to viral or human genetic factors by using joint host/pathogen genetic data from 541 HIV infected individuals. On the host side, the authors focused on amino acid variations in the HLA-A, B and C genes. They built three linear mixed models, one containing human variants, one derived from phylogenetic trees, and one including both host and virus information.

The genetic relatedness matrix created from 33 amino acid polymorphisms of the human class I HLA genes explained 8.4% (standard deviation = 4%) of the observed variance in spVL. In contrast, 28.8% (SD = 11%) of phenotypic variation was attributable to the viral phylogenetic tree. Combining the two relatedness matrices in one model yielded a total variance explained of 29.9% (SD = 12%) less than the sum of the latter two models.

In conclusion, the study shows that a major fraction of inter individual variability is explained by the similarity of the viral genotypes, and that human genetic variation in the HLA region provide little additional explanatory power. The results suggest that host genetic association studies not taking the virus into account underestimate the population level effect of host genetic variation. Combining host and pathogen data provides additional insight into the genetic determinants of the clinical outcome of HIV infection, which can serve as a model for other chronic infectious diseases.

pdf publication

20th April Marzel et al., Mining for transmission pairs


Mining for pairs: shared clinic visit dates identify steady HIV positive partnerships.    HIV Medicine

Marzel et al. examined the hypothesis that some stable HIV-infected partnerships can be found in cohort studies, as the patients frequently attend the clinic visits together. Their method to identify steady transmission pairs and serosorting couples was based on the intuition that pairs of patients who share a larger number of visits than expected by chance are more likely to represent pairs who coordinate their visits to the clinics, which might reflect being either steady transmission pairs or serosorting couples. Transmission pairs were identified based on three validation criteria: (i) monophyletic clustering on the phylogenetic tree and a maximal genetic distance of 2.5% between sequences; (ii) a self-report of having an HIV-positive steady partner by both members of the pair; and (iii) belonging to the same HIV transmission risk group.

The authors analyzed 434’432 visits for 16’139 Swiss HIV Cohort Study patients from 1990 to 2014. For 89 pairs, the number of shared visits exceeded the number expected. Of these, thirty-three pairs (37%) were confirmed using all three criteria. Notably, 12 of the validated transmission pairs (36%) were of a mixed ethnicity with a large median age gap, harbouring HIV-1 of predominantly non-B subtypes, suggesting imported infections.

In conclusion, the study suggests that steady, mixed-ethnicity partnerships with a large age gap (with the man being white and older) contribute to heterosexually driven migration events. This observation opens up a targeted prevention opportunity. In addition, this simple method widens the horizons of research on within-pair quasi-species exchange, transmitted drug resistance and viral recombination at the biological level.

PubMed

13th April Negoescu et al., Differentiated monitoring of HIV viral load


Differentiated HIV RNA viral load monitoring in resource-limited settings: an economic analysis.   Clinical Infectious Diseases

Negoescu et al. developed a mathematical model using person-level longitudinal data to personalize decisions for timing of viral load monitoring. Moreover, they performed a cost-effectiveness analysis to inform the optimal monitoring interval in different resource contexts. The authors compared the cost-effectiveness of the personalized monitoring strategies to fixed monitoring intervals every 1, 3, 6, 12 and 24 months.

The authors found that shorter fixed viral load monitoring intervals yielded increasing benefits at increasing average costs. The adaptive policy optimized for low-income contexts achieved quality-adjusted life-years (QUALYs) and costs similar to the fixed 12-month policy. The adaptive policy optimized for middle-income resource settings yielded fewer QALYs per person, but saved costs compared to monitoring every three months.

In conclusion, focusing on patients most at risk of virologic failure improves the efficiency of viral load monitoring, most prominently in high-resource settings. The analysis suggests that in resource-limited settings monitoring at fixed 12-month intervals performs closely to the adaptive monitoring policies that define the cost-effectiveness frontier. Thus, monitoring at fixed 12-month intervals may be a good alternative to implement in resource-limited settings. In higher resource contexts, however, adaptive monitoring policies could lead to significant cost savings.

PubMed

5th April Béguelin et al., Impact of tenofovir on hepatitis delta virus replication


Impact of tenofovir on hepatitis delta replication in HIV-coinfected patients in the Swiss HIV Cohort Study.   Clinical Infectious Diseases

Béguelin et al. assessed the impact of long-term Tenofovir Disoproxil Fumarat (TDF) therapy on hepatitis B virus (HBV) and hepatitis delta virus (HDV) replication in the Swiss HIV Cohort Study (SHCS). All SHCS participants with a positive Hepatitis B surface antigen (HBsAg) test between January 1988 and December 2014 were considered. Patients were followed for a median of 4.9 years on TDF.

Median HDV RNA was 7.0 log10 cp/ml before TDF initiation and 6.7 log10 cp/ml at the last follow-up visit. Sixteen of the 21 patients (76%) reached HBV suppression (<20 IU/ml) after a median of 2.9 years (IQR 2.0-3.1) and the 5 remaining patients had low-level viremia. Six (28.6%) patients experienced >2 log10 HDV RNA reduction during follow-up, and HDV RNA became undetectable in three of them (14.3%). No differences in HBV DNA levels, quantitative HBsAg, liver enzymes or HIV-1 related characteristics were noted between individuals with and without HDV RNA reduction during TDF treatment. HBsAg loss was only observed in one patient who initiated TDF with a very low baseline quantitative HBsAg. Two-thirds of patients had a positive anti-hepatitis C virus (HCV) serology (66.7%) whereas only 2/21 (9.5%) patients had detectable HCV RNA.

In conclusion, TDF is highly efficient in suppressing HIV and HBV replication in patients coinfected with HDV. However, in the majority of these patients TDF did not result in a reduction of HDV RNA or quantitative HBsAg. As replicating HDV infection is strongly associated with liver-related mortality, there is an urgent need for new treatment options.

pdf publication

23rd March Trickey et al., Mortality after 10 years of ART


Cause-specific mortality in HIV-positive patients who survived ten years after starting antiretroviral therapy.   PLoS One

Trickey et al. on behalf of the Antiretroviral Therapy Cohort Collaboration aimed to estimate mortality rates and prognostic factors in HIV-positive patients who started combination antiretroviral therapy (cART) between 1996–1999 and survived for more than ten years.

During 50’593 person years of follow up, 656 out of 13’011 (5%) patients died. The following factors were associated with a higher mortality: age, male sex, intravenous drug use, AIDS, and a lower CD4 cell count or a detectable HIV viral load 10 years after starting cART, respectively. Notably, a low CD4 cell count nadir before cART initiation was not associated with a higher mortality. The most common causes of death were non-AIDS-related liver cancer (25%), AIDS (19%), cardiovascular disease (12%), and liver-related disease (10%). Older age was strongly associated with cardiovascular mortality and with non-AIDS and non-liver malignancies, IDU with non-AIDS infection and liver-related mortality, and low CD4 count and detectable viral replication at ten years after starting ART with AIDS mortality.

In summary, this study shows that CD4 count and viral load remain important for prognosis in patients who have survived ten years after starting cART. However, deaths were mostly non-AIDS-related, and care for these patients should focus on improving management of non-HIV morbidity, in particular risk factors for cardiovascular disease and screening for non-AIDS cancer.

pdf publication

16th March Gebreselassie et al., Travel to the tropics and HIV viral control


Ethnicity predicts viral rebound after travel to the tropics in HIV-infected travellers to the tropics in the Swiss HIV Cohort Study.    HIV Medicine

Gebreselassie et al. aimed to describe the characteristics of the population in the Swiss HIV Cohort Study (SHCS) travelling to the tropics and to determine the frequency and risk factors of viral rebound following a travel episode vs. a nontravel episode if the viral load at the beginning of the episode was suppressed.

There were 6’084 (36.5%) patients who had ever travelled to the tropics. Travel frequency increased over time, with travellers having a less advanced median clinical Centers for Disease Control and Prevention stage and a higher median CD4 count nadir than nontravellers. Viral rebound was not more common in travel episodes than in nontravel episodes. Evident risk factors for viral rebound after travel were being of sub-Saharan African origin, current intravenous drug use, being younger, having a lower CD4 count, a history of antiretroviral therapy (ART) failure, using nonrobust ART, and demonstrating poor overall adherence. Among the 477 post-travel viral rebounds, 44% of the resistance tests showed new resistance mutations.

In conclusion, travelling was not per se a risk factor for loss of viral control. However, sub-Saharan African HIV-positive travellers were at highest risk of viral rebound even in nontravel episodes, but especially in travel episodes. Thus, pre-travel adherence counselling should focus on patients of sub-Saharan African origin.

pdf publication

2nd March Bader et al., Immune function suppresses X4-tropic HIV


Therapeutic immune recovery and reduction of CXCR4-tropic HIV-1.   Clinical Infectious Diseases

Bader et al. aimed at assessing the tropism of viral integrates in 35 HIV-positive patients’ blood during fully suppressive combination antiretroviral therapy (cART) by applying next-generation sequencing.

The relative frequencies of proviral X4-tropic HIV-1 variants decreased or stayed stable over time in the vast majority of patients (28 of 35 patients: 80%). In the remaining 7 patients (20%) with an increase of proviral X4-tropic HIV-1 variants, the documented expansion of X4-tropic provirus was based on the outgrowth of single viral variants from minority populations already present before therapy initiation. In 80% of the patients in this study decreasing proviral DNA loads were noted during successful treatment. However, in cases, in which overall proviral loads increased during therapy, there was no increase of the percentage of X4 tropic strains in the entire provirus population. Of note, all patients with an increasing percentage of X4 variants were homozygous for the wild-type CCR5 gene and did not carry a heterozygous or homozygous Δ32 genotype.

In conclusion, the study somewhat unexpectedly revealed that for patients with effectively suppressed viral loads X4-tropic HIV variants follow a persistent downward trend. The recently implemented World Health Organization strategies of immediate therapy initiation are fully in line with this gradual loss of X4 tropism during therapy. Moreover, the early use of coreceptor antagonists against the remaining CCR5-tropic viruses may be indicated.

PubMed

22nd February Fidler et al., Predictors of post treatment control after stopping ART


Virological blips and predictors of post treatment viral control after stopping ART started in Primary HIV infection.   Journal of Acquired Immune Deficiency Syndromes

Fidler et al. on behalf of CASCADE collaboration in EuroCoord explored the frequency, magnitude, and predictive value of measured viral blips on the probability of achieving post treatment control (PTC) among a cohort of treated HIV-1 seroconverters interrupting ART initiated in primary HIV infection (PHI).

The authors used a modified definition of blip as a single plasma HIV-RNA measure >400 cp/mL in a previously suppressed individual followed by subsequent viral suppression (<400 cp/mL) without change in antiretroviral treatment (ART) regimen. PTC was defined as remaining <50 cp/mL for at least 24 months after ART stops.

Seven-hundred-seventy-eight individuals started ART within 6 months of seroconversion and had at least 3 HIV-RNA measurements, of these 228 (30%) subsequently stopped ART. Median ART duration was 16.2 months. Among the 228 individuals stopping ART, 22 (10%) individuals fulfilled the definition of PTC. Each blip >400 cp/mL was associated with a 71% increased risk of loss of control. Conversely, longer time spent on ART was independently associated with a decreased risk in loss of control. There was no evidence of an association between loss of control and CD4 T-cell count at ART initiation, ART initiation class, seroconversion age, sex, or HIV-1 transmission risk group.

In conclusion, the study-findings indicate that the absence of viral blips >400 copies HIV-1 RNA/mL on therapy in individuals treated with early ART predict a better chance of subsequent post treatment viremic control after ART cessation.

pdf publication

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.

pdf publication
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.

pdf publication

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.

pdf publication

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.

pdf publication

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 data center 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 data center, 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 data center are ready!

Kind regards,

Huldrych Günthard
President SHCS