|27th April||Bartha et al., Host and viral genomic contribution to HIV control|
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.
|20th April||Marzel et al., Mining for transmission pairs|
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.
|13th April||Negoescu et al., Differentiated monitoring of HIV viral load|
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.
|5th April||Béguelin et al., Impact of tenofovir on hepatitis delta virus replication|
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.
|23rd March||Trickey et al., Mortality after 10 years of ART|
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.
|16th March||Gebreselassie et al., Travel to the tropics and HIV viral control|
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.
|2nd March||Bader et al., Immune function suppresses X4-tropic HIV|
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.
|22nd February||Fidler et al., Predictors of post treatment control after stopping ART|
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.
|9th February||Kovari et al., HCV and non-liver-related morbidity|
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.
|2nd February||Combes et al., Human papillomavirus antibody response following HAART in MSM|
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.
|26th January||Cecchinato et al., Migration of CCR6+ and CXCR3+ Th cells in HIV|
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.
|18th January||Schäfer et al., Physical activity in the SHCS|
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.
|12th January||Shilaih et al., Role of marginalized populations in HIV-1 transmission in Switzerland|
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.
|5th January||Gueler et al., Life expectancy among HIV-infected people|
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.
|4th January||successful migration of the SHCS database from Lausanne to Zurich!|
The very important and almost last step of the transfer of the SHCS datacenter from Lausanne to Zurich has happened at the end of the year: the migration of the database was successful! This was a difficult undertaking and only possible by the help of many highly motivated and skilled people!
For this I want to thank the key players involved in this endeavor:
With this, I wish you a happy new year and I am sure that with all your help the SHCS will continue to produce important scientific output at all levels. The database and the datacenter are ready!