2019
| 18th December | Courlet et al., Pharmacokinetic profiles of antiretroviral drugs in the aging population |  |
Courlet et al. aimed to compare boosted darunavir, dolutegravir, and lamivudine plasma exposures between aging (≥ 65 years) and younger (< 65 years) people living with HIV (PLWH) involved in two observational studies to better document pharmacokinetics (PK) of antiretroviral drugs (ARVs) in this growing vulnerable population. Nineteen PLWH with a median age of 64 participated to the full PK investigations. Single point PK data were collected for 804 PLWH with a median age of 52. Boosted darunavir clearance was 40% lower in aging (≥ 65 years) compared to younger (< 65 years) PLWH, consistent with other drugs predominantly metabolized by CYP3A. Dolutegravir exposure was similar between age groups whereas lamivudine exposure increased by 11% in aging PLWH. Median boosted darunavir, dolutegravir and lamivudine t1/2 were 148%, 45% and 32% higher in aging compared to younger PLWH. In conclusion, boosted darunavir exposure was highly variable but modestly increased in aging PLWH. Dolutegravir and lamivudine exposure was minimally affected by age. Thus, dose adjustment based on age is a priori not warranted. Nevertheless, there is still a need for studies to allow a better understanding of ARVs PK in this vulnerable growing population. Additional comment PD Dr. Dominique Braun and Prof. Huldrych Günthard | ||
| 12th December | Surial et al., Switching from TDF to TAF in the SHCS | |
Surial et al. aimed to determine the proportion of patients with and without risk factors for tenofovir disoproxil fumarate (TDF-) related toxicity who had been switched from TDF to tenofovir alafenamide fumarate (TAF) and explored individual predictors for being switched. The authors included all participants of the Swiss HIV Cohort Study on TDF-containing antiretroviral therapy with follow-up visits after January 2016. They determined the proportion of switches from TDF to TAF overall, and among patients with risk factors for TDF toxicity, including osteoporosis, impaired renal function or marked proteinuria. Overall, the study included 5′012 patients, of whom 652 (13.0%) had risk factors for TDF toxicity. A switch from TDF to TAF was undertaken in 2′796 (55.8%) individuals overall, and in 465 (71.3%) with risk factors. Predictors of switching to TAF were male sex (adjusted odds ratio 1.27, 95% confidence interval 1.07–1.50), age>50years (1.43, 1.23–1.66) and the presence of risk factors for TDF toxicity (2.21, 1.77–2.75). In contrast, patients with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based single-pill regimen (0.11, 0.09–0.13), those treated in non-tertiary care centers (0.56, 0.46–0.70), as well as those with CD4 cell counts below 500/μL (0.77, 0.66–0.90) and with chronic hepatitis C infection (0.66, 0.54–0.80) were most likely to stay on TDF. In conclusion, the majority of patients at risk for TDF-toxicity were switched from TDF to TAF within two years after its introduction in Switzerland. Among 30% of patients at risk of TDF-toxicity who did not switch during this time-period, being on a NNRTI-based single-pill regimen seemed to be an important reason for remaining on TDF. However, large differences across clinics were observed and related reasons should be further explored. Since current recommendations on switching to TAF are based on limited data from selected groups of patients in randomized controlled trials, further data on clinical outcomes after the introduction of TAF in cohorts such as the SHCS remain essential to inform optimal patient management. | ||
| 5th December | Young et al., NRTI-sparing dual regimens | |
Young et al. used data from the Swiss HIV Cohort Study to estimate the effectiveness of dolutegravir dual regimens relative to alternative NRTI-sparing dual regimens. For that, they emulated two trials by propensity score matching case patients on the dolutegravir regimen with control patients on an alternative regimen. They analysed the case control sets using Bayesian Cox model and estimated effectiveness as the percentage still on their trial regimen without virological failure at week 48. The authors matched 58 cases treated with dolutegravir to 17 controls treated with boosted darunavir, both with lamivudine or emtricitabine. The estimated difference in effectiveness was 15% (95% credible interval [Crl] 2-33) and 12% (95% Crl 0-26) in two sequential analyses 1 year apart. In comparison of fully NRTI-sparing regimens, 54 cases treated with dolutegravir were matched to 32 controls treated with raltegravir (both with boosted darunavir). The estimated difference in effectiveness was 9% (95% Crl -1-21) and 5% (95% Crl -4-15) in the two sequential analyses. In conclusion, the estimates of relative effectiveness suggest that at 48 weeks both dolutegravir regimens would be at worst 4% less effective than the alternatives – the non-inferiority margin recommended by the FDA for HIV switch trials. All four regimens seem suitable for patients needing an NRTI-sparing regimen: there were few virological failures and few treatment changes due to toxicity. | ||
| 27th November | Mocroft et al., Clinical outcomes in persons coinfected with HIV and HCV | |
Mocroft et al. on behalf of the EuroSIDA Study aimed to investigate clinical outcomes in a large, European, multi-cohort study, according to hepatitis C (HCV) status in HIV-coinfected persons from across Europe, comparing persons who were HCV-negative, spontaneous clearers, with those who had chronic, untreated HCV, were cured, or were failing HCV treatment. Incidence rates were compared between HCV groups for end-stage liver disease (ESLD; including hepatocellular carcinoma [HCC]), non-acquired immunodeficiency virus defining malignancy (NADM; excluding HCC), and cardiovascular disease (CVD). There were 16’618 persons included (median follow-up 8.3 years, interquartile range 3.1–13.7). There were 887 CVD, 902 NADM, and 436 ESLD events; crude incidence rates/1000 person-years follow-up were 6.4 (95% confidence interval [CI] 6.0– 6.9) for CVD, 6.5 (95% CI 6.1–6.9) for NADM, and 3.1 (95% CI 2.8–3.4) for ESLD. After adjustment, there were no differences in incidence rates of NADM or CVD across the 5 groups. HCV-negative individuals (adjusted incidence rate ratio [aIRR] 0.22, 95% CI 0.14–0.34) and those with spontaneous clearance (aIRR 0.61, 95% CI 0.36–1.02) had reduced rates of ESLD compared to cured individuals. Persons with chronic, untreated HCV infections (aIRR 1.47, 95% CI 1.02–2.13) or treatment failure (aIRR 1.80, 95% CI 1.22–2.66) had significantly raised rates of ESLD, compared to those who were cured. In conclusion, this large European cohort study did not find differences in CVD or NADM across 5 well-defined HCV strata, whereas those cured had substantially lower incidences of ESLD, underlining the importance of successful HCV treatment for reducing ESLD. | ||
| 20th November | Lodi et al., Effectiveness of transmitted drug resistance testing | |
Lodi et al. on behalf of the HIV-CAUSAL Collaboration aimed to estimate the effectiveness of transmitted drug resistance (TDR) testing, when used according to current guidelines, on virological and clinical outcomes up to 5 years after HIV diagnosis among individuals diagnosed with HIV in Europe and Canada. The authors included individuals from the HIV-CAUSAL Collaboration who enrolled Of 25’672 eligible individuals (82% males, 52% diagnosed in 2010 or later), 17’189 (67%) were tested for TDR within 3 months of baseline. Of these, 6% had intermediate- or high-level TDR to any antiretroviral drug. The estimated 5-year proportion virologically suppressed was 77% under TDR testing and 74% under no TDR testing; HR 1.06 (95% confidence interval: 1.03 to 1.19). The estimated 5-year risk of AIDS or death was 6% under both strategies; HR 1.03 (95% confidence interval: 0.95 to 1.12). In conclusion, the study found a low prevalence of TDR in high-income countries. In individuals diagnosed with HIV in high-income countries, the authors estimated that current recommendations for TDR testing, compared with no TDR testing, increased the proportion achieving virological suppression by 5 years from diagnosis by 3.7% but with no effect on AIDS or death in this time frame. These results call for more evidence to establish which populations would benefit from selective TDR screening. | ||
| 14th November | Hatleberg et al., Predictors of ischemic and hemorrhagic strokes among people living with HIV | |
Hatleberg et al. for the Data Collection on Adverse events of anti-HIV Drugs (D:A:D) Study Group aimed to investigate systematically whether hypertension, other common cardiovascular disease (CVD) risk factors and HIV-related factors were differently associated with ischemic and hemorrhagic strokes. HIV-1-positive individuals were followed from the time of first blood pressure (BP) measurement after 1/1/1999 or study entry until the first of a validated stroke, 6 months after last follow-up or 1/2/2014. Five-hundred and ninety centrally validated strokes occurred over 339’979 person-years of follow-up. In formal comparison models (83 hemorrhagic and 296 ischemic strokes), they found the strongest common predictors to be hypertension and older age. Male gender, previous cardiovascular events, and smoking were stronger predictors of ischemic strokes, whereas hypertension, hepatitis C virus coinfection and estimated glomerular filtration rate b60 mL/min/1.72m3 were stronger predictors of hemorrhagic strokes. A CD4 count b200 cells/μL was associated with a borderline increased risk of hemorrhagic but not ischemic stroke, whereas a higher viral load and exposure to antiretroviral therapy were not associated with the risk of either stroke subtype. In conclusion, the risk factor profiles for ischemic and hemorrhagic strokes in people living with HIV (PLWHIV) appear to differ. While the study found no strong evidence to support the need for specific stroke risk prediction scores for PLWHIV, the findings do emphasize the importance of considering stratified stroke risk prediction for the different stroke subtypes to optimize preventive measures and screening. Further studies are needed to confirm these findings in order to provide more precise risk scoring systems in PLWHIV as well as in the general population. | ||
| 13th November | EACS conference in Basel and Hector Prizes 2019 |  |
Many thanks to all clinicians who attended and researchers who presented their work. We also want to thank the basic scientists who have presented their work. It is always a bit difficult to feel at home at a mostly clinical conference. Nevertheless, it is important that basic science is also present and at EACS, there is a steady improvement seen. After all, progress in medicine is only possible by joint work between basic and clinical science. At this occasion, we also want to congratulate Roger Kouyos who has won the Hector Prize for the best European translational paper Alison Rodgers who has won the Hector Prize for the best clinical paper On behalf of the SHCS, Andri Rauch Huldrych Günthard | ||
| 6th November | Congratulations to Catia Marzolini! | |
Use of physiologically based pharmacokinetic modelling to simulate dosing requirements of long-acting intramuscular antiretroviral drugs in special populations and to manage drug-drug interactions.
The amount funded is CHF 491’138 for a 3 years period starting March 2020 until end of February 2023. We wish Catia Marzolini all the best for her project! Kind regards, Huldrych Günthard | ||
| 31st October | Olearo et al., M184V/I impact in ART-experienced patients | |
Olearo et al. aimed to conduct a prospective study using data from 5 large HIV cohorts in four European countries (France, Italy, the Netherlands and Switzerland) to assess the efficacy of the ABC/3TC/DTG (Triumeq®) regimen in virologically-suppressed, antiretroviral therapy (ART-) experienced patients, with or without a previously documented M184V/I mutation. The primary outcome was the time to first virological failure (VF) (2 consecutive HIV-1 RNA >50 copies/mL or single HIV-1 RNA >50 copies/mL accompanied by change in ART). They also analyzed a composite outcome considering the presence of VF and/or virological blips. The study included 1’626 patients (median follow-up, 288.5 days; interquartile range, 154-441). Patients with a genotypically documented M184V/I mutation (n = 137) had a lower CD4 nadir and a longer history of antiviral treatment. The incidence of VF was 29.8 cases (11.2-79.4) per 1’000 person-years in those with a previously documented M184V/I, and 13.6 cases (8.4-21.8) in patients without documented M184V/I. Propensity score weighting in a restricted population (n = 580) showed that M184V/I was not associated with VF or the composite endpoint (hazard ratio [HR], 1.27; 95% confidence interval [CI], 0.35-4.59 and HR 1.66; 95% CI, 0.81-3.43, respectively). In conclusion, in this large international prospective study, there was an extremely low rate of VF among treatment-experienced patients receiving an ABC/3TC/DTG regimen, irrespective of the presence of a M184V/I mutation. Furthermore, no new mutations were observed in reverse transcriptase or integrase after VF in any of the patients in which genotyping was successfully performed, with the caveat that the genotypic resistance results were available for only a minority of patients (6 of 21). Additional analyses are required to demonstrate whether these findings will remain robust during an extended observation period. | ||
| 31st October | 2019 Swiss human rights award to Prof. Dr. Ruedi Lüthy | |
For the past 25 years, the IGFM-CH has granted the Swiss human rights award to people that reached outstanding achievements regarding the improvement of human rights. This year the committee decided to honor Prof. Dr. Ruedi Lüthy. The official ceremony will be held on Saturday, 7th December 2019 at 10:00 am in the Hotel Kreuz in Bern. Prof. Dr. Ruedi Lüthy has been fighting the HIV epidemic for decades. He founded and continues running the Newlands Clinic in Harare, Zimbabwe. Thanks to this clinic, our awardee can effectively fight this terrible disease. Today, more than 6'500 HIV patients that live in the poorest conditions receive lifelong medical support in his clinic. His enormous efforts and knowledge bring back hope to a myriad of desperate young people and their families. The medical support allows these people to live a self-determined, independent life again. Therewith Ruedi Lüthy can significantly increase the locals' Human Rights. As the founder of the Ruedi Lüthy Foundation and the Newlands Clinic, Ruedi Lüthy ensures that the patients are treated as well as possible. He also shares his great knowledge with the training center in his clinic in order to instruct local doctors and nurses with the best medical practices. AIDS-Expert ab initio In the late 1980s he and other specialists in the field founded the Zurich Lighthouse hospice - a place for people to die in peace. Ruedi Lüthy managed this place for many years. Thanks to effective medication, the HIV infection became a curable but chronic disease in Switzerland in the mid-1990s. In the southern parts of Africa this is unfortunately not the case. HIV is still omnipresent: In Zimbabwe 1.3 Million people carry the virus and every year more than 30'000 of them die of AIDS. Ruedi Lüthy perceived it as his ethic duty to help relieve the misery of these people in Zimbabwe. After a fulfilled professional life in Switzerland and just before his retirement, Ruedi Lüthy started collecting donations and the necessary equipment to finally be able to found an HIV clinic in the capital Harare in 2003. The SHCS is proud that Ruedi Lüthy receives such a prestigious and well deserved price and we send him our congratulations. On behalf of the SHCS, website Ruedi Lüthy Foundation interview with Dr. Ruedi Lüthy
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| 23rd October | Courlet et al., Escitalopram population pharmacokinetics in PLWH and in the psychiatric population | |
Courlet et al. aimed to develop (i) a population pharmacokinetics model for escitalopram in people living with human immunodeficiency virus (PLWH) and uninfected psychiatric individuals; (ii) to identify sources of variability that could influence drug exposure, and notably to evaluate drug-drug interactions (DDIs) involving antiretroviral agents; and (iii) to simulate expected exposures under standard dosage regimen and compare them with the established therapeutic reference range. A total of 159 plasma concentration measurements were obtained from 39 human immunodeficiency virus (HIV)‐infected and 71 uninfected psychiatric patients. The influence of age, weight, sex, HIV and psychiatric cohorts, racemic citalopram treatment, and comedications on oral clearance was examined. A 1‐compartment model with first‐order absorption and elimination described the data adequately. The average escitalopram clearance and volume of distribution were 23.1 L/h (interindividual variability 51%), and 920 L, respectively. Escitalopram disposition did not differ between HIV‐infected and uninfected patients, and was not affected by antiretroviral treatments. Coadministration of at least 1 proton‐pump inhibitor (CYP2C19 inhibitor) modestly influenced escitalopram elimination (clearance decreased by 19%), with limited clinical relevance. Model‐based simulations showed that, under a standard regimen of 10 mg once daily, a significant proportion of patients (56%) might be under‐exposed. In conclusion, the pharmacokinetic model proposed in this study confirmed that escitalopram exhibits important between‐subject variability. Simulations revealed that the standard 10 mg once‐daily regimen may lead to trough concentrations below the established therapeutic target of 15 ng/mL, with a risk of suboptimal antidepressant efficacy. Dosage adjustment may benefit from both therapeutic drug monitoring (TDM) and monitoring of clinical efficacy and tolerability, taking into account other risks factors for QT prolongation, especially in elderly patients. These results emphasize the importance of TDM under specific conditions, such as therapeutic failure or suspected DDIs, for a proper individualization of dosing regimens. This study finally brings reassuring data concerning the risk of DDIs between escitalopram and others medications, including antiretrovirals. | ||
| 16th October | Tate et al., Improved risk index for people with HIV infection | |
The Veterans Aging Cohort Study (VACS) Index incorporates clinical biomarkers of general health with age, CD4+ cell count, and HIV-1 RNA to discriminate mortality risk in a variety of HIV-positive populations. In the current study, the author team aimed to develop an improved VACS Index (2.0), externally validate using data from European and North American cohorts participating in the Antiretroviral Therapy Cohort Collaboration (ART-CC), and evaluate generalizability among important subgroups. They obtained laboratory values from a randomly selected visit from 2000 to 2014, at least 1 year after antiretroviral therapy initiation. Patients were then followed for 5-year, all-cause mortality through September 2016. Among 28’390 VACS patients and 12’109 ART-CC patients, 7’293 and 722 died, respectively. Nadir CD4+, CD8+, and CD4+ : CD8+ ratio did not improve discrimination. Addition of albumin, white blood count, and BMI, improved c-statistics in VACS from 0.776 to 0.805 and in ART-CC from 0.800 to 0.831. Results were robust in all nine ART-CC cohorts, all lengths of follow-up and all subgroups. In conclusion, VACS Index 2.0 was highly predictive of risk of all-cause mortality among those on treatment for HIV infection. With use of continuous variables, VACS Index 2.0 is now better suited to application for individual patients. With addition of parameters readily obtained during routine clinical practice, VACS Index 2.0 is more discriminating than the original VACS Index. Its superior discrimination is robust across development and validation sets, among important clinical subgroups, and among individual cohorts. | ||
| 3rd October | Chan et al., Predictors of viral suppression in infants with perinatal HIV | |
Chan et al. on behalf of the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) aimed to investigate predictors of faster virological suppression, focusing on infants with perinatal HIV initiating standard combination antiretroviral therapy (cART) living in Europe and Thailand. Infants with perinatal HIV starting cART aged less than 6 months with at least 1 viral load measurement within 15 months of cART initiation were included. Of 420 infants, 59% were female and 56% from Central/Western Europe, 26% United Kingdom/Ireland, 15% Eastern Europe and 3% Thailand; 46 and 54% started a boosted protease inhibitor-based or nonnucleoside reverse transcriptase inhibitor based regimen, respectively. At cART initiation, the median age, CD4+ % and viral load were 2.9 [interquartile range (IQR): 1.4–4.1] months, 34% (IQR: 24–45) and 5.5 (IQR: 4.5–6.0) log10 copies/ml, respectively. Overall, an estimated 89% (95% confidence interval: 86–92%) achieved virological suppression within 12 months of cART start. In multivariable analysis, younger age [adjusted hazard ratio (aHR): 0.84 per month older; P<0.001], higher CD4+% (aHR: 1.11 per 10% higher; P=0.010) and lower log10 viral load (aHR: 0.85 per log10 higher; P<0.001) at cART initiation independently predicted faster virological suppression. In conclusion, the study showed that effective treatment response was achieved in the majority of infants initiating cART within 6 months of life across Europe and Thailand. The currrent work identified the conditions needed to attain faster virological suppression in these infants, demonstrating that even amongst early treated infants, earlier cART initiation, higher baseline CD4+ % and lower baseline viral load independently predicted faster virological suppression. These results provide additional support for earlier cART initiation in infants with perinatal HIV and indicate that early treatment influences key virological and immunological parameters that could have important consequences for long-term health. | ||
| 1st October | Künzler-Heule et al., Screening HIV-positive MSM for HCV-infection risk using a single question on condom-use | |
Künzler-Heule et al. aimed to (1) describe sexual and drug-using behaviours participants reported during Swiss HCVree study baseline assessment and to compare those behaviours in men who have sex with men (MSM) who did and did not report condomless anal intercourse with non-steady partners (nsCAI) during the prior year and to (2) examine the condom-use question’s sensitivity and specificity in identifying men who engaged in other hepatitis C virus (HCV) relevant risk behaviours. Seventy-two (61%) of the 118 men meeting eligibity criteria reported nsCAI during the prior year. Many also engaged in other potential HCV transmission risk behaviours, e.g., 52 (44%) had used drugs. In participants disclosing drug use, 44 (37%) reported sexualised drug use and 17 (14%) injected drugs. Unadjusted odds ratios (95% CI) for two well-known risk behaviours were 2.02 (0.80, 5.62) for fisting and 5.66 (1.49, 37.12) for injecting drug use. The odds ratio for sexualised drug use - a potential mediator for increased sexual risk taking - was 5.90 (2.44, 16.05). nsCAI showed varying sensitivity in relation to the other risk behaviours examined (66.7–88.2%). In conclusion, the study-findings support existing research that MSM coinfected with HIV/HCV engage in various sexual and drug-use behaviours, potentially increasing their risk of HCV re-infection. Men who reported nsCAI were more likely to report engaging in the other sexual and drug-use behaviors measured although the differences were only statistically significant for the drug-use behaviors. nsCAI was fairly sensitive in identifying men who also engaged in other risk behaviours, but relying only on it to identify men at risk for HCV infection would miss a proportion of MSM with HIV practicing other potentially modifiable behaviours. Based on the study-findings comprehensive screening of potential risk behaviours should be applied to identify men whose sexual and drug use behaviors increase their risk for HCV infection. This work also points to the importance of providing access to behavioral interventions addressing other sexual and drug use practices as part of HCV treatment. | ||
| 26th September | Euler et al., Neutralizing antibody responses in HIV-1 infected injecting drug users | |
Euler et al. studied the prevalence of broadly neutralizing antibody (bNAb) responses in HIV-1 infected individuals in the Amsterdam Cohort, including 50 male and 35 female participants who reported injecting drug use as the only risk factor. The study revealed a significantly lower prevalence of bNAb responses in females compared to males. Gender, transmission route and CD4+ count at set point, but not viral load, were independently associated with the development of bNAb responses in intravenous drug users (IDUs). To further explore the influences of gender in the setting of IDU, the author group also looked into the Swiss 4.5k Screen. There we observed lower bNAb responses in female IDUs as well. In conclusion, the study found that women infected with HIV-1 using contaminated needles developed bNAb responses less efficiently than men that attracted HIV-1 via the same transmission route. This difference is most likely multifactorial, where early viral diversity caused by multivariant transmission, CD4+ T cell count, viral load and drug use may all play a role. Therefore, the effect of gender on the development of bNAb responses is a factor that should be considered when designing vaccine efficacy trials. | ||
| 25th September | Vannappagari et al., Prenatal exposure to dolutegravir and outcomes | |
Vannappagari et al. on behalf of the Antiretroviral Pregnancy Registry (APR) and the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) aimed to retrospectively assess fetal and neonatal outcomes following maternal dolutegravir use during pregnancy. Of 265 pregnancies reported to the APR, initial exposure to dolutegravir occurred at conception or first trimester in 173 pregnancies and during the second or third trimester in 92 pregnancies. There were 246 (92.8%) live births resulting in 255 neonates (9 twins), 6 (2.3%) induced abortions, 11 (4.2%) spontaneous abortions, and 2 (0.8%) stillbirths. Birth defects occurred in 7 (2.7%) of 255 live-born neonates, 5 (3.1%) of 162 (includes 6 twins) with conception/first-trimester exposure. Of 101 pregnancies reported to the EPPIC, outcomes were available for 84 pregnancies (16 continuing to term and 1 lost to follow-up). There were 81 live births (80 with known initial dolutegravir exposure at conception or first, second, and third trimesters in 42, 21, and 17 live births respectively), 1 stillbirth (second-trimester exposure), 1 induced abortion (first-trimester exposure), and 1 spontaneous abortion (first trimester exposure), respectively. Birth defects occurred in 4 live births (4.9%; 95% confidence interval: 1.4 to 12.2), 3 of 42 (7.1%) with exposure at conception or first trimester. In conclusion, the assessment of these collective 198 birth outcomes after first-trimester dolutegravir exposure from 2 prospective registries (APR, 156 outcomes; EPPICC, 42 outcomes) and data cited from 3 other studies with 104 pregnancy outcomes identified no birth defect signal, either in defect prevalence or in defect-type clustering. In addition, among birth defects reported after dolutegravir exposure during pregnancy or at the time of conception, none involved the neural tube. These findings may provide some reassurance to women whose pregnancies have already been exposed to dolutegravir or who have limited therapeutic options but remain inconclusive because of small study sample sizes. | ||
| 19th September | Willemse et al., Hepatocellular carcinoma screening in hepatitis B/C virus co‐infected HIV patients | |
Willemse et al. for the Collaboration of Observational HIV on behalf of Epidemiological Research Europe (COHERE) in EuroCoord aimed to assess compliance with hepatocellular carcinoma (HCC) screening guidelines in a large European cohort of HIV‐infected patients with hepatitis B virus (HBV-) and/or hepatitis C (HCV-) co‐infection and cirrhosis. Of note, it is recommended in multiple inter‐national guidelines (AASLD, EASL and EACS) to screen individuals with cirrhosis twice a year with ultrasound for the presence of HCC. Data from 646 individuals were selected for analysis. Of these patients, 518 (80%) were HCV co‐infected, 85 (13%) HBV co‐infected and 43 (7%) HCV and HBV co‐infected. The proportion of patients in whom HCC screening was performed according to screening guidelines varied between 5.4% in 2005, 18.4% in 2008 and 14.2% in 2014. In the multivariate analysis, longer follow‐up after cirrhosis diagnosis (OR 1.59; 95% CI 1.36‐1.87) and cirrhosis diagnosis based on liver biopsy or Fibroscan (OR 1.68; 1.11‐2.55) were independently associated with a higher compliance. Lack of ALT measurements (OR 0.52; 95% CI 0.31 0.86 compared with normal ALT levels) was associated with a lower compliance. More recent calendar year of follow‐up, included as a time‐updated variable to the model, was not significantly associated with better compliance. In conclusion, this study in a prospective European cohort of HBV and/or HCV co‐infected HIV patients with cirrhosis showed a very low rate of compliance to bi‐annual HCC screening guidelines of only 14%‐18%. In the context of an increasing incidence of HCC among ageing people living with HIV, this finding warrants urgent action to ensure better implementation of HCC screening guidelines in this population. | ||
| 18th September | Kusejko et al., Self-reported neurocognitive impairment in people living with HIV | |
Kusejko et al. aimed to study potential factors known to influence neurocognitive performance among people living with HIV. The author team included all SHCS patients who were assessed for self-reported neurocognitive impairment (srni) during at least 5 visits spanning at least 2.5 years in 2013-2017. Hierarchical cluster algorithm was used to identify groups of patients with similar changes of srni over time. In total, 79’683 questionnaires of 11’029 patients contained information about srni, and 8’545/11’029 (77.5%) patients had longitudinal information. The overall percentage of patients with srni decreased from 19.6% in 2013 to 10.7% in 2017. Compared to patients in the cluster with low-level srni over time, patients in the cluster with high-level persisting srni had more often a prior opportunistic infection of the central nervous system (OR=3.7, p<0.001), imperfect adherence to antiretroviral treatment (ART) (OR=2.8, p<0.001) and a depression (OR=1.9, p<0.001). In summary, the study-findings show that srni significantly decreased in 2013-2017, which most likely can be attributed to more potent and earlier initiation of therapies used in recent years and decreasing treatment failures in the SHCS. Furthermore, the study-results suggest that all patients with a history of central nervous system opportunistic infections should be screened in-depth for neurocognitive problems, even if the opportunistic infection occurred a long time ago and the patient has been on suppressive ART for many years. In addition, patients reporting imperfect adherence to ART or having a depression should be considered for further screening of neurocognitive problems. Selecting patients for in-depth neurocognitive screening based on these three criteria is in particular useful for cohorts and patients without longitudinal information about srni. | ||
| 12th September | Wojtowicz et al. Interleukin-4 polymorphism and Pneumocystis jirovecii pneumonia | |
Wojtowicz et al. aimed to describe the role of polymorphisms from 21 candidate genes encoding relevant fungal pattern recognition receptors (PRRs) and cytokines/chemokines with regards to the predisposition to Pneumocystis jirovecii pneumonia (PJP) in the patients from the Swiss HIV Cohort Study (SHCS). The analysis included patients with a nadir CD4+ T-cell count less than 200 cells/µl, divided into a discovery (N=1’645) and a replication (N=1’861) cohort. The minor allele of rs2243250 in IL-4 was associated with the risk of PJP in the discovery cohort (cumulative incidence 0.18 versus 0.12, P=0.002). This association was replicated in the validation cohort (0.16 versus 0.12, P=0.02). It was still significant in multivariate models, adjusted for HIV transmission mode, viral load, CD4+ T cells slope, age, antiretroviral therapy, tobacco smoking, hepatitis C virus coinfection, year of cohort entry and PJP prophylaxis (global subhazard ratio 1.42, 95% confidence interval 1.17–1.73, P=0.0004). In conclusion, this data demonstrates an association between PJP and the presence of the interleukin-4-590T/C polymorphism in a large cohort of HIV patients. This single nucleodide polymorphisms may influence the Th2/Th1 responses required for appropriate immunity against Pneumocystis spp. and increase susceptibility to infection in HIV-positive patients with low level of CD4+ T cells | ||
| 11th September | Ruffieux et al., Mortality from suicide among people living with HIV | |
Ruffieux et al. for the Swiss HIV Cohort Study (SHCS) and the Swiss National Cohort (SNC) aimed to assess the mortality rates due to suicide in persons living with HIV and the general population in Switzerland, to explore risk factors and time trends in suicide over almost 30 years, from the pre-cART era up to recent years. The author team analysed data from the Swiss HIV Cohort Study from the pre-cART (1988-1995), earlier cART (1996-2008) and later cART (2009-2017) eras. Overall, 20’136 persons living with HIV were included, of whom 204 (1.0%) died by suicide. In men, standardized mortality ratios (SMRs) for suicide declined from 12.9 (95% CI 10.4-16.0) in the pre-cART era to 2.4 (95% CI 1.2-5.1) in the earlier cART and 3.1 (95% CI 2.3-4.3) in the later cART era. In women, the corresponding ratios declined from 14.2 (95% CI 7.9-25.7) to 10.2 (3.8-27.1) and to 3.3 (95% CI 1.5-7.4). Factors associated with death due to suicide included:
There was no association with age. In conclusion, since the introduction of cART in 1996, mortality rates due to suicide have significantly decreased in men and women living with HIV in Switzerland, but no important improvements in SMRs were observed in men in more recent years, despite the advent of more tolerable, more efficacious and less complex antiretroviral drug regimens in the later cART period. Furthermore, it is noteworthy that the SMRs were larger than those reported in the literature for conditions with worse prognosis. Hence, in Switzerland and elsewhere, there is a continued need to monitor depression, suicidality in HIV-positive people, and to develop tailored suicide prevention programs aimed at reducing suicide risk in people living with HIV. | ||
| 5th September | Santos et al., Longitudinal CNS penetration effectiveness score and neurocognitive impairment | |
Santos et al. for the Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) Study Group aimed to examine (1) the relationship between neurocognitive impairment (NCI) and cross-sectional central nervous system (CNS) penetration effectiveness (CPE) score (CPE score at the time of neurocognitive assessment) and then (2) the longitudinal relationship between NCI and cumulative CPE scores (a summary of CPE scores from the time of ART initiation to the time of neurocognitive assessment). The authors hypothesized that cumulative CPE score might better predict the presence of NCI than the cross-sectional CPE score. In total, 981 patients were enrolled, all of whom underwent standardized neurocognitive assessment. Most patients were male (80%) and Caucasian (92%). Neurocognitive impairment was present in 40%: 27% with HIV-associated NCI (mostly asymptomatic neurocognitive impairment), and 13% with NCI related to other factors. None of the CPE scores, neither cross-sectional nor cumulative, was statistically significantly associated with NCI. In conclusion, neither cross-sectional nor cumulative CPE scores were statistically significantly associated with NCI in this large patient cohort. The NAMACO study patients will be reassessed at 2 and 4 years post inclusion, and the effect of antiretroviral therapy regimens, and therefore CPE score, will be examined on the appearance, persistence, or resolution of NCI with time. | ||
| 4th September | Chiappini et al., Neonatal prophylaxis toxicity in infants | |
The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord aimed to examine haematological toxicity in infants born to women with HIV infection at high risk of mother-to-child HIV transmission (MTCT), and specifically to identify whether neonatal prophylaxis (NP) type was associated with (1) the presence of severe or potentially life-threatening anaemia or neutropaenia within the first 6 months of life and (2) haemoglobin (Hb)level and NC at ages 0-18 months. The study group conducted an individual patient data meta-analysis within six European cohorts, in infants at high risk for acquiring HIV infection. Of 1’836 infants, 25% were preterm, 1’149 (63%) had antenatal combination antiretroviral therapy (cART) exposure and 395 (22%) received NP (125 received combination NP with three drugs). Overall, 117 (6.7%) infants had grade 3-4 anaemia at age 0-6 months and 140 (9.1%) had grade 3-4 neutropaenia. The presence of grade 3-4 anaemia or neutropaenia was not associated with NP type but was associated with preterm delivery. Overall, 7’746 Hb and NC results were available for 1’836 infants up to age 18 months; no significant differences in predicted Hb level or NC were apparent by NP type. In conclusion, in this population of infants at high risk of perinatal infection born in Europe to women with uncontrolled HIV replication, NP type was not associated with severe or potentially life-threatening haematological toxicity, and combination NP appeared to be relatively safe. | ||
| 20th August | Bachmann et al., Determinants of HIV-1 reservoir size and long-term dynamics during suppressive ART | |
Bachmann et al. aimed to examine how the size of the HIV-1 reservoirs changes in the long term and what factors affect the changes or size of the reservoir. In this longitudinal observational study including patients from the Swiss HIV Cohort Study, the team of researchers carried out extensive test series on blood samples and the corresponding data from 1,057 people who have successfully been receiving ART for many years. The data collection provided at least three samples from each of the 1,057 people in order to measure the HIV reservoirs. On average, the samples were taken 1.5, 3.5, and 5.4 years after starting ART. For 412 individuals, data was available that enabled the status of the HIV reservoirs to be monitored over a period of ten years. On average, the size of the HIV-1 reservoir during the first 5.4 years after starting ART decreased, with an estimated half-life of 5.6 years. During the observation period, the shrinking of the reservoirs leveled off considerably and appeared to reach a plateau. Contrary to expectations, however, 281 people (26.6%) in the analysis exhibited no decline but rather an increase in the size of the reservoirs despite successful antiretroviral therapy. Viral blips between 50 and 199 HIV-1 RNA copies/ml plasma occurred in 126 individuals within 0.5–1.5 years after initiation of ART and were significantly associated with a larger HIV-1 reservoir size. In addition to viral blips, high viral load pre-ART and slower time to viral suppression were found to be independently associated with a larger HIV-1 reservoir size. Nonwhite ethnicity was significantly associated with a smaller HIV-1 reservoir size, while HIV-1 non-B subtype only showed a significant association with a small HIV-1 reservoir in the univariable model. In conclusion, this study found a small but continuous decay of the HIV-1 reservoir after initiation of suppressive ART. The decay slowed down over time and approached a plateau. Strikingly, viral blips were related to larger reservoirs and a less pronounced reduction of them over time. These blips were previously considered clinically irrelevant or negligible, but the study shows that these are biologically significant. | ||
| 15th August | Rohner et al., Regional cervical cancer risk in HIV-pos women | |
Rohner et al. compared invasive cervical cancer (ICC) incidence rates in Europe, South Africa, Latin and North America among women living with HIV who initiated antiretroviral therapy (ART) between 1996 and 2014. They analyzed cohort data from the International Epidemiology Databases to Evaluate AIDS (IeDEA) and the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. They used flexible parametric survival models to determine regional ICC rates and risk factors for incident ICC. The authors included 64’231 women from 45 countries. During 320’141 person-years (pys), 356 incident ICC cases were diagnosed (Europe 164, South Africa 156, North America 19 and Latin America 17). Raw ICC incidence rates per 100’000 pys were Compared to European women ICC rates at 5 years after ART initiation were more than double in Latin America (adjusted hazard ratio [aHR]: 2.43, 95% CI: 1.27-4.68) and 11 times higher in South Africa (aHR: 10.66, 95% CI: 6.73-16.88), but similar in North America (aHR: 0.79, 95% CI: 0.37-1.71). Overall, ICC rates increased with age (>50 years vs. 16-30 years, aHR: 1.57, 95% CI: 1.03-2.40) and lower CD4 cell counts at ART initiation (per 100 cell/μl decrease, aHR: 1.25, 95% CI: 1.15-1.36). Improving access to early ART initiation and effective cervical cancer screening in women living with HIV should be key parts of global efforts to reduce cancer-related health inequities. | ||
| 13th August | Lodi et al., Comparing randomized and observational studies | |
It is important to have valuable methods to compare effects found in randomized trials with such found in observational studies. Effect estimates from randomized trials and observational studies may not be directly comparable because of differences in study design, other than randomization, and in data analysis. Lodi et al. for the INSIGHT START and HIV_CAUSAL collaboration propose a three-step procedure to facilitate meaningful comparisons of effect estimates from randomized trials and observational studies: 1) harmonization of the study protocol (eligibility criteria, treatment strategies, outcome, start and end of follow-up, causal contrast) so that the studies target the same causal effect, 2) harmonization of the data analysis to estimate the causal effect, and 3) sensitivity analyses to investigate the impact of discrepancies that could not be accounted for in the harmonization process. To illustrate their approach, they compared estimates of the effect of immediate with deferred initiation of antiretroviral therapy in individuals positive to the human immunodeficiency virus from the START randomized trial and the observational HIV-CAUSAL Collaboration. | ||
| 8th August | Nguyen et al., HLA-B homogeneity within HIV phylogeny | |
HIV's capacity to escape immune recognition by Human Leukocyte Antigen (HLA) is a core component of HIV pathogenesis. A better understanding of the distribution of HLA Class I in HIV-infected patients would improve our knowledge of pathogenesis in relation to host HLA type, and could better improve therapeutic strategies against HIV. Nguyen et al. identified 301-325 potential transmission pairs and 469-496 clusters were identified for analysis among Swiss HIV Cohort Study (SHCS) participants using HIV pol sequences from the drug resistance database. HLA Class I data was compiled at three specificity levels: four-digit, two-digit alleles, and HLA-B supertype. The analysis tabulated HLA-I homogeneity as two measures: the proportion of transmission pairs, which are HLA-concordant, as well as the average percentage of allele matches within all clusters. These measures were compared to the mean value across randomizations with randomly assorted individuals. The analyses were repeated for different HLA classification levels and separately for HLA-A, -B, and -C. Subanalyses by risk group were performed for HLA-B. HLA-B showed significantly greater homogeneity in the transmission chains (2-digit clusters: 0.291 vs.0.251, p-value=0.009; supertype clusters: 0.659 vs. 0.611, p-value=0.002; supertype pairs: 0.655 vs. 0.608, p-value=0.014). Risk group restriction caused the effect to disappear for men-who-have-sex-with-men (MSM) but not for other risk groups. They also examined if protective HLA alleles B27 and B57 were under- or overrepresented in the transmission chains, though this yielded no significant pattern. In conclusion, the HLA-B alleles of patients within HIV-1 transmission chains segregate in homogenous clusters/pairs, potentially indicating preferential transmission among HLA-B concordant individuals. | ||
| 7th August | Bailey et al., NRTI backbones and pregnancy outcomes | |
The aim of the study of the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) with MoCHIV was to investigate whether specific nucleoside reverse transcriptase inhibitor (NRTI) backbones are associated with risk of adverse pregnancy outcomes among pregnant women starting antiretroviral therapy (ART). For this purpose, seven observational studies across eight European countries of pregnancies in HIV-positive women joined. Individual-level data were pooled on singleton pregnancies conceived off-ART in which a single combination ART regimen was initiated at least 2 weeks before delivery, and ending in a live birth in 2008-2014. Preterm delivery (PTD) was defined as less than 37 gestational weeks and small-for-gestational-age (SGA) as less than 10th percentile according to INTERGROWTH standards. Poisson regression models were fitted to investigate associations between NRTI backbones and PTD/SGA. Out of 7’193 pregnancies, 45% (3’207) were in UK/Ireland, 44% (3'134) in Ukraine. 10% (722/7’193) of deliveries were preterm and 11.1% (785/7’089) of newborns SGA. The most common NRTI backbones were zidovudine (ZDV)-lamivudine (3TC) (71%), tenofovir (TDF)-XTC (16%) and abacavir (ABC)-3TC (10%) with TDF-containing backbone use increasing over time. Overall, 77% of regimens contained ritonavir-boosted lopinavir (LPV/r). There was no association between NRTI backbone and PTD in main adjusted analyses [adjusted prevalence ratios (aPRs) 0.97 (95% confidence interval, 95% CI 0.73-1.28] for ABC-3TC and aPR 1.06 (95% CI 0.83-1.35) for TDF-XTC, both vs. ZDV-3TC) or in 4’720 pregnancies on LPV/r [aPR 1.03 (95% CI 0.74-1.43) for ABC-3TC and aPR 1.16 [0.85-1.57] for TDF-XTC, both vs. ZDV-3TC]. Infants exposed to ABC-3TC or TDF-XTC in utero were less likely to be SGA than those exposed to ZDV-3TC [aPR 0.72 (95% CI 0.53-0.97) and aPR 0.70 (95% CI 0.53-0.93), respectively]. In conclusion, these results support the safety of TDF-XTC backbones initiated in pregnancy with respect to gestation length and birthweight. | ||
| 31st July | Salazar-Vizcaya et al., Dissimilar trends in sexual behavior | |
To understand behavioural patterns it is probably key to interfere successfully with the global increase in sexually transmitted diseases. Separately addressing specific groups of people who share patterns of behavioural change might increase the impact of behavioural interventions to prevent transmission of sexually transmitted infections. Salazar-Vizcaya et al. propose a method based on machine learning to assist the identification of such groups among men who have sex with men (MSM). By means of unsupervised learning, they inferred "behavioural clusters" based on the recognition of similarities and differences in longitudinal patterns of condomless anal intercourse with non-steady partners (nsCAI) in the Swiss HIV cohort study over the last 18 years. They then used supervised learning to investigate whether sociodemographic variables could predict cluster membership. They identified four behavioural clusters. The largest behavioural cluster The other two clusters displayed more drastic changes: nsCAI frequency in In conclusion, the authors identified highly dissimilar behavioural patterns across behavioural clusters, including drastic, atypical changes. These patterns suggest that the overall increase in the frequency of nsCAI is largely attributable to two clusters, accounting for a third of the population. Future studies will show, how these new method, respectively identified behavioural clusters will correlate with effectively transmitted STIs. | ||
| 25th July | Courlet et al., Emtricitabine and lamivudine concentrations in saliva | |
ART constitutes the cornerstone of HIV treatment and prevention. Successful ART results in suppressed viral load (VL) levels. Courlet et al. tested whether non-invasive saliva sampling could represent an alternative or clinically useful addition to VL measurements and genotype determination among patients suspected of non-adherence. If available as a point-of-care test, it would provide the clinicians with an objective assessment of recent adherence during the clinical visit. The authors aimed to evaluate whether saliva would constitute a suitable matrix for ART adherence monitoring, by examining the correlation between emtricitabine and lamivudine levels simultaneously measured in plasma and saliva. 73 patients participating in the SHCS agreed to donate a non-stimulated saliva sample simultaneously to the blood sample collected as part of the biannual SHCS follow-up visit. Emtricitabine and lamivudine levels were quantified by an LC/MS-MS assay, using stable isotopically labelled internal standards also adapted for saliva concentration determination. Overall, 47 and 26 paired plasma and saliva concentrations were collected for emtricitabine and lamivudine determination, respectively. In addition, six saliva samples were collected from three SHCS patients not receiving emtricitabine or lamivudine, and from three HIV-negative individuals, to evaluate the selectivity of the method. Emtricitabine plasma and saliva concentrations ranged from 8 to 2’471 ng/mL and 23 to 1’017 ng/mL, respectively. The time between sampling and last drug intake (time after dose; TAD) ranged from 0.8 to 37.3 h. For lamivudine, plasma and saliva concentration varied between 45 and 3’183 ng/mL and between 15 and 718 ng/mL, respectively, with a TAD of 1.3 to 27 h. The results show that emtricitabine and lamivudine saliva concentrations are moderately correlated with plasma concentrations (correlation coefficient 0.63 and 0.58 for emtricitabine and lamivudine, respectively). Median saliva/plasma ratios were 0.61 for emtricitabine and 0.35 for lamivudine, with high variability (coefficient of variation 89% and 101% for emtricitabine and lamivudine, respectively). This variability can be explained by multiple factors involving drug properties (i.e. protein binding, saliva pH, salivary flow rates and degree of ionization) or patient characteristics (i.e. renal clearance or adherence issues). Importantly, saliva concentrations from individuals not receiving emtricitabine or lamivudine were below the limit of quantification (LOQ) in saliva (<10 ng/mL), confirming the specificity of the method. Assuming that emtricitabine in saliva follows the same kinetics as in plasma, the t½ of emtricitabine in saliva calculated for each patient using a population pharmacokinetics model of emtricitabine gave a mean t½ of 9.4 ± 0.88 h (minimum = 8.4 h, maximum = 12.1 h). It can be extrapolated that after 31 h (i.e. 3.3 × t½) emtricitabine levels in saliva would lie above the assay LOQ of 10 ng/mL in all patients, whereas after 60 h and 72 h (2.5 days and 3 days TAD, respectively) the saliva emtricitabine concentration would fall below the LOQ cut-off of the assay in 91% and 100% of patients, respectively. Thus, knowing the emtricitabine or lamivudine concentrations determined in saliva allows the identification of non-adherent patients who have missed their ART for at least the last 3 days. In conclusion, despite a limited correlation between plasma and saliva concentrations, saliva constitutes a suitable non-invasive surrogate to identify patients who are non-adherent to ART. These first results have been obtained using an MS assay. However, if developed as a qualitative, immunoassay-based, easy-to-use and non-invasive point-of-care test, this assay would be of invaluable clinical usefulness to reduce the number of unnecessary VL measurements and genotype determinations in cases of proven non-adherence, and may thus prevent unnecessary switches to second-line ART. | ||
| 24th July | Dietrich et al., Genetics of chronic Kidney disease in HIV | |
In HIV, the relative contribution of genetic background, clinical risk factors, and antiretrovirals to chronic kidney disease (CKD) is unknown. Dietrich et al. applied a case-control design and performed genome-wide genotyping in white Swiss HIV Cohort participants with normal baseline estimated glomerular filtration rate (eGFR >90 mL/min/1.73 m2). Uni- and multivariable CKD odds ratios (OR) were calculated based on the D:A:D score that summarizes clinical CKD risk factors and a polygenic risk score that summarizes genetic information from 86’613 single nucleotide polymorphisms. They included 322 controls (eGFR drop <15%; 81% male; median age, 39 years, baseline eGFR 107 mL/min/1.73 m2). Polygenic risk score and D:A:D score contributed to CKD. In multivariable analysis, CKD ORs were 2.13 (95% confidence interval, 1.55-2.97) in participants in the 4th (most unfavorable) vs. 1st (most favorable) genetic score quartile; 1.94 (1.37-2.65) in the 4th vs. 1st D:A:D score quartile; and 2.98 (2.02-4.66), 1.70 (1.29-2.29), and 1.83 (1.45-2.40), per 5-years exposure to atazanavir/ritonavir, lopinavir/ritonavir, and tenofovir disoproxil fumarate, respectively. Participants in the 1st genetic score quartile had no increased CKD risk, even if they were in the 4th D:A:D score quartile. In summary, the genetic score increased CKD risk similar to the clinical D:A:D score and potentially nephrotoxic antiretrovirals. Irrespective of the D:A:D score, individuals with the most favorable genetic background may be protected against CKD. | ||
| 18th July | Collins et al., Switch to second-line ART in children with HIV | |
Estimates of incidence of switching to second-line antiretroviral therapy (ART) among children with HIV are necessary to inform the need for paediatric second-line formulations. They aimed to quantify the cumulative incidence of switching to second-line ART among children in an international cohort collaboration. In this international cohort collaboration study, Collins et al. pooled individual patient-level data for children younger than 18 years who initiated ART (two or more nucleoside reverse-transcriptase inhibitors [NRTI] plus a non-NRTI [NNRTI] or boosted protease inhibitor) between 1993 and 2015 from 12 observational cohort networks in the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration. Patients who were reported to be horizontally infected with HIV and those who were enrolled in trials of treatment monitoring, switching, or interruption strategies were excluded. Switch to second-line ART was defined as change of one or more NRTI plus either change in drug class (NNRTI to protease inhibitor or vice versa) or protease inhibitor change, change from single to dual protease inhibitor, or addition of a new drug class. They used cumulative incidence curves to assess time to switching, and multivariable proportional hazards models to explore patient-level and cohort-level factors associated with switching, with death and loss to follow-up as competing risks. At the data cutoff of Sept 16, 2015, 182’747 children with HIV were included in the CIPHER dataset, of whom 93'351 were eligible, with 83’984 (90,0%) from sub-Saharan Africa. At ART initiation, the median patient age was 3,9 years (IQR 1,6-6,9) and 82’885 (88·8%) patients initiated NNRTI-based and 10 466 (11·2%) initiated protease inhibitor-based regimens. Median duration of follow-up after ART initiation was 26 months (IQR 9-52). 3883 (4,2%) patients switched to second-line ART after a median of 35 months (IQR 20-57) of ART. The cumulative incidence of switching at 3 years was 3,1% (95% CI 3,0-3,2), but this estimate varied widely depending on the cohort monitoring strategy, from 6,8% (6,5-7,2) in settings with routine monitoring of CD4 (CD4% or CD4 count) and viral load to 0,8% (0,6-1,0) in settings with clinical only monitoring. In multivariable analyses, patient-level factors associated with an increased likelihood of switching were male sex, older age at ART initiation, and initial NNRTI-based regimen (p<0,0001). Cohort-level factors that increased the likelihood of switching were higher-income country (p=0·0017) and routine or targeted monitoring of CD4 and viral load (p<0.0001), which was associated with a 166% increase in likelihood of switching compared with CD4 only monitoring (subdistributional hazard ratio 2,66, 95% CI 2,22-3,19). In summary, this global paediatric analysis found wide variations in the incidence of switching to second-line ART across monitoring strategies. These findings suggest the scale-up of viral load monitoring would probably increase demand for paediatric second-line ART formulations. | ||
| 17th July | Gras et al., Immunological restoration during suppressive ART | |
Restoration of CD4 cell counts and normalization of CD8 cell counts is one major goal of antiretroviral therapy. Over the last years, an increasing number of HIV-positive individuals start antiretroviral therapy (ART) with high CD4 cell counts. Gras et al. from the ART-CC collaboration investigated whether this makes restoration of CD4 and CD8 cell counts and the CD4:CD8 ratio during virologically suppressive ART to median levels seen in HIV-uninfected individuals more likely and whether restoration depends on gender, age, and other individual characteristics. They determined median and quartile reference values for CD4 and CD8 cell counts and their ratio using cross-sectional data from 2’309 HIV-negative individuals and used longitudinal measurements of 60’997 HIV-positive individuals from the Antiretroviral Therapy Cohort Collaboration in linear mixed-effects models. When baseline CD4 cell counts were higher, higher long-term CD4 cell counts and CD4:CD8 ratios were reached. Highest long-term CD4 cell counts were observed in middle-aged individuals. During the first 2 years, median CD8 cell counts converged toward median reference values. However, changes were small thereafter and long-term CD8 cell count levels were higher than median reference values. Median 8-year CD8 cell counts were higher when ART was started with In summary, starting ART with a CD4 cell count of ≥500 cells/mm makes reaching median reference CD4 cell counts more likely. However, median CD4:CD8 ratio trajectories remained below the median levels of HIV-negative individuals because of persisting high CD8 cell counts. To what extent these subnormal immunological responses affect specific clinical endpoints requires further investigation. | ||
| 11th July | Compagno et al., MTCT of antiretroviral drug-resistant HIV strains is low | |
Combination antiretroviral therapy (cART) has reduced mother-to-child transmissions (MTCT) and improved the prognosis of HIV-infected newborns. However, drug resistance mutations (DRM) in HIV-infected children, either transmitted by MTCT (HIV-tDRM) or selected by suboptimal adherence and drug levels (HIV-sDRM), remain a concern. In this study Compagno et al. determined the rate of HIV-tDRM and HIV-sDRM in MTCT pairs in Switzerland. They performed a retrospective analysis of prospectively collected clinical data and from available stored samples from MTCT pairs participating in the Swiss Mother-Child HIV (MoCHiV) cohort. They identified 22 HIV-infected mother-child pairs with delivery between 1989 and 2009 who had 15 years of follow-up (33% white ethnicity). Twenty-one women (96%) were treatment-naïve before pregnancy, 8 (36%) had an unknown HIV status and delivered vaginally, 2 were diagnosed but not treated, and 11 (50%) received antiretrovirals during pregnancy or at delivery, of whom only 6 cases (27%) had cART. HIV subtypes were concordant in all mother-child pairs (subtype B 13/22 [59%]). Using stored plasma (n = 66) and mononuclear cells (n = 43) samples from the children, HIV-tDRM (M184V) was identified in 1 of 22 (4.5%) mothers (1/11 treated, 9%) and was followed by HIV-sDRM at 10 months of age. HIV-sDRM (M184V 23%; K103N 4.5%; D67N 13.6%) occurred in 16/22 (73%) after 4 years, half of whom were treatment naïve. HIV-sDRM were associated with a lower CD4 T-cell nadir (p<0.05) and tended to have higher viral loads and more frequent cART changes. In conclusion, HIV-tDRM were low in the Swiss MoCHiV cohort, making them a minor yet preventable complication of prenatal HIV care, whereas HIV-sDRM are a significant challenge in paediatric HIV care. | ||
| 10th July | Amele et al., Establishing HCV CoC in HIV-positive individuals | |
Amele et al. within EuroSIDA assessed how many patients in a given population are hepatitis C positive, have a replicating HCV infection (HCV-RNA positive), receive treatment and are cured is of importance (also called the continuum of care). The aim of this study was to establish a methodology for evaluating the hepatitis C continuum of care in HIV/hepatitis C virus (HCV)-coinfected individuals and to characterize the continuum in Europe on 1 January 2015, prior to widespread access to direct-acting antiviral (DAA) therapy. The following stages included in the continuum were as follows:
Sustained virological response (SVR) could only be assessed for those with a follow-up HCV RNA test and was defined as a negative HCV RNA result measured >12 or 24 weeks after stopping treatment. They found the following numbers and percentages for the stages of the HCV continuum of care within EuroSIDA:
The proportion that achieved SVR was 52.6% (629 of 1’195). There were significant differences between regions at each stage of the continuum (P <0.0001). In conclusion, in the proposed HCV continuum of care for HIV/HCV-coinfected individuals, major gaps at all stages were found, with almost 20% of anti-HCV-positive individuals having no documented HCV RNA test and a low proportion achieving SVR, in the pre-DAA era. | ||
| 4th July | Barcelo et al., Dolutegravir population pharmacokinetics | |
Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. Barcelo et al. within the SHCS characterized dolutegravir's pharmacokinetic profile and variability in a real-life setting and identified individual factors and co-medications affecting dolutegravir disposition. A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug-drug interactions. A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h-1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12 h with rifampicin compared with a standard dosage of 50 mg/24 h without rifampicin. Average trough concentrations after 100 mg/24 h and 100 mg/12 h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively. In conclusion, patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases. | ||
| 3rd July | Kovari et al., Antiretroviral drugs associated with subclinical CAD in the SHCS | |
The question whether certain antiretroviral drugs are associated with coronary artery disease (CAD) is of importance and some associations have been identified over the years. However, the influence of ART on subclinical atherosclerosis is not clear. Kovari et al. assessed within the SHCS associations between subclinical atherosclerosis and specific antiretroviral therapies (ART). Coronary artery calcium (CAC) scoring and coronary CT angiography (CCTA) were performed in ≥45year old Swiss HIV Cohort Study participants. The following subclinical CAD endpoints were analysed separately: CAC score >0, any plaque, calcified plaque, non-calcified/mixed plaque, segment involvement score (SIS) and segment severity score (SSS). Logistic regression models calculated by inverse probability of treatment weights (IPTW) were used to explore associations between subclinical CAD and cumulative exposure to the ten most frequently used drugs. Overall, 403 patients underwent CCTA. CAC score >0 was recorded in 188 (47%), any plaque in 214 (53%), calcified plaque in 151 (38%), and non-calcified/mixed plaque in 150 (37%) participants. CAC score >0 was negatively associated with efavirenz (IPTW adjusted OR per 5 years 0.73 [0.56-0.96]), tenofovir disoproxil fumarate (0.68 [0.49-0.95]), and lopinavir (0.64 [0.43-0.96]). Any plaque was negatively associated with tenofovir disoproxil fumarate (0.71 [0.51-0.99]). Calcified plaque was negatively associated with efavirenz (0.7 [0.57-0.97]). Non-calcified/mixed plaque was positively associated with abacavir (1.46 [1.08-1.98]), and negatively associated with emtricitabine (0.67 [0.46-0.99]). For SSS and SIS we found no association with any drug. In conclusion, an increased risk of non-calcified/mixed plaque was only found in patients exposed to abacavir. Emtricitabine was negatively associated with non-calcified/mixed plaque, while tenofovir disoproxil fumarate and efavirenz were negatively associated with any plaque and calcified plaque, respectively. | ||
| 27th June | Wandeler et al., Incidence of HCC in HIV/HBV-coinfected patients on tenofovir | |
Wandeler et al., in a collaboration of the SHCS, ATHENA, ANRS CO3 Aquitaine Cohort and EUROSIDA performed a study on screening strategies for hepatocellular carcinoma (HCC) in HIV/HBV co-infected patients on antiretroviral treatment. For this high quality HCC incidence, data are needed. Specifically, they aimed to evaluate the incidence and risk factors of HCC among HIV/HBV-coinfected individuals on tenofovir disoproxil fumarate (TDF)-containing ART in a large multi-cohort study. They included all HIV-infected adults with a positive hepatitis B surface antigen test followed in 4 prospective European cohorts. The primary outcome was the occurrence of HCC. Demographic and clinical information was retrieved from routinely collected data, and liver cirrhosis was defined according to results from liver biopsy or non-invasive measurements. Multivariable Poisson regression was used to assess HCC risk factors. A total of 3’625 HIV/HBV-coinfected patients were included, of whom 72% had started TDF-containing ART. Over 32’673 patient-years (py), 60 individuals (1.7%) developed an HCC. The incidence of HCC remained stable over time among individuals on TDF, whereas it increased steadily among those not on TDF. Among individuals on TDF, the incidence of HCC was 5.9 per 1’000 py (95% CI 3.60-9.10) in cirrhotics and 1.17 per 1’000 py (0.56-2.14) among non-cirrhotics. Age at initiation of TDF (adjusted incidence rate ratio per 10-year increase: 2.2, 95% CI 1.6-3.0) and the presence of liver cirrhosis (4.5, 2.3-8.9) were predictors of HCC. Among non-cirrhotic individuals, the incidence of HCC was only above the commonly used screening threshold of 2 cases per 1’000 py in patients aged >45 years old at TDF initiation. In conclusion, the incidence of HCC was high in cirrhotic HIV/HBV-coinfected individuals but remained below the HCC screening threshold in patients without cirrhosis who started TDF aged <46 years old. | ||
| 26th June | Hachfeld et al., Why do Africans present late for Swiss HIV care? | |
Late presentation (LP) to care of HIV-1 infected individuals remains a problem, although for many years now it is clear that early initiation of antiretroviral therapy is highly beneficial for the individual but also on the population level. Hachfeld et al. , explored reasons for LP to HIV care in individuals from sub-Saharan Africa (SSA) in the Swiss HIV Cohort study because this group is disproportionally affected. They compared the prevalence of LP between patients from Western Europe (WE) and those from SSA, enrolled between 2009 and 2012. Patients were asked about HIV testing, including access to testing and reasons for deferring it, during face-to-face interviews. The proportion of LP was 45.8% (435/950) among patients from WE, and 64.6% (126/195) among those from SSA (P<0.001). Women from WE were slightly more likely to present late than men (52.6% versus 44.5%, respectively; P=0.06), whereas there was no sex difference in patients from SSA (65.6% versus 63.2%, respectively; P=0.73). Compared with late presenters from WE, those from SSA were more likely to be diagnosed during pregnancy (9.1% versus 0%, respectively; P<0.001), but less likely to be tested by general practitioners (25.0% versus 44.6%, respectively; P=0.001). Late presenters from SSA more frequently reported 'not knowing about anonymous testing possibilities' (46.4% versus 27.3%, respectively; P=0.04) and 'fear about negative reaction in relatives' (39.3% versus 21.7%, respectively; P=0.05) as reasons for late testing. Fear of being expelled from Switzerland was reported by 26.1% of late presenters from SSA. In conclusion, the majority of patients from SSA were late presenters, independent of sex or education level. Difficulties in accessing testing facilities, lack of knowledge about HIV testing and fear-related issues are important drivers for LP in this population. | ||
| 18th June | Carlisle et al., Time since infection from HIV diversity | |
To determine the accurate time of an HIV-1 infection is often very difficult respectively impossible because of a lack of negative HIV-testing, lack of symptoms of an acute retroviral syndrome or a misinterpretation of such, or a long-interval between a negative and a positive test. In 2011, the SHCS for the first time has provided a method to estimate the date of infection based on the fraction of ambiguous nucleotides (FAN) (Kouyos et al, CID, 2011). This method was based on sanger sequencing. The current work by Carlisle et al. now presents a new method based on next generation sequencing data to estimate the time of infection and compares it to the FAN. HIV-1 genetic diversity increases over the course of infection, and can be used to infer time since infection (TSI) and consequently also infection recency, crucial quantities for HIV-1 surveillance and the understanding of viral pathogenesis. They considered 313 HIV-infected individuals for whom reliable estimates of infection dates and next-generation sequencing (NGS)-derived nucleotide frequency data were available. FAN obtained by population sequencing were available for 207 samples. They assessed whether average pairwise diversity (APD) calculated using NGS sequences provided a more exact prediction of TSI and classification of infection recency (<1 year post-infection) compared to FAN. They found that NGS-derived APD classifies an infection as recent with a sensitivity of 88% and specificity of 85%. When considering only the 207 samples for which FAN were available, NGS-derived APD exhibited a higher sensitivity (90% vs 78%) and specificity (95% vs 67%) than FAN. Additionally, APD can estimate TSI with a mean absolute error of 0.84 years, compared to 1.03 years for FAN. Thus, this work clearly shows that estimates of time of infection can be improved by using NGS sequences. | ||
| 12th June | Caniglia et al., Emulating a trial monitoring treatment HIV | |
Caniglia et al. from the HIV-Causal collaboration performed a study emulating a clinical trial investigating the question whether monitoring frequency could be lowered. Decisions about when to start or switch a therapy often depend on the frequency with which individuals are monitored or tested. For example, the optimal time to switch antiretroviral therapy depends on the frequency with which HIV-positive individuals have HIV RNA measured. This paper describes an approach to use observational data for the comparison of joint monitoring and treatment strategies and applies the method to a clinically relevant question in HIV research: when can monitoring frequency be decreased and when should individuals switch from a first-line treatment regimen to a new regimen? They outline the target trial that would compare the dynamic strategies of interest and then describe how to emulate it using data from HIV-positive individuals included in the HIV-CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems. When, as in their example, few individuals follow the dynamic strategies of interest over long periods of follow-up, they describe how to leverage an additional assumption: no direct effect of monitoring on the outcome of interest. They compare their results with and without the "no direct effect" assumption. They found little differences on survival and AIDS-free survival between strategies where monitoring frequency was decreased at a CD4 threshold of 350 cells/μl compared with 500 cells/μl and where treatment was switched at an HIV-RNA threshold of 1000 copies/ml compared with 200 copies/ml. The "no direct effect" assumption resulted in efficiency improvements for the risk difference estimates ranging from a 7- to 53-fold increase in the effective sample size. | ||
| 6th June | Barido-Sottani et al., Detection of HIV transmission clusters from phylogenetic trees | |
The Swiss HIV Cohort Study (SHCS) for many years uses phylogenetic methods to better understand transmission of HIV to ultimately improve public health interventions. Barido-Sottani et al., a collaborating group from ETHZ/BSSE Basel, developed a new method for identifying transmission clusters and applied it to data from the SHCS. HIV patients form clusters in HIV transmission networks. Accurate identification of these transmission clusters is essential to target effectively public health interventions. One reason for clustering is that the underlying contact network contains many local communities. They present a new maximum-likelihood method for identifying transmission clusters caused by community structure, based on phylogenetic trees. The method employs a multi-state birth-death (MSBD) model, which detects changes in transmission rate, which are interpreted as the introduction of the epidemic into a new susceptible community, i.e. the formation of a new cluster. They show that the MSBD method is able to reliably infer the clusters and the transmission parameters from a pathogen phylogeny based on their simulations. In contrast to existing cutpoint-based methods for cluster identification, the new method does not require that clusters be monophyletic nor is it dependent on the selection of a difficult-to-interpret cutpoint parameter. They present an application of their method to data from the SHCS. The method is available as an easy-to-use R package. | ||
| 5th June | Abela et al., Analysis of ADR in the Swiss HIV Cohort Study | |
In the Swiss HIV Cohort Study, the rate of acquired drug resistance (ADR) has fallen dramatically since introduction of combined antiretroviral therapy (ART). To further identify, why some people still fail ART respectively develop ADR, Abela et al. systematically characterized risk factors for ADR, in order to improve patient care, prevent emergence of drug resistance, and treatment failure. For this, they performed a case-control study to identify risk factors for ADR in all patients starting their first cART in the Swiss HIV Cohort Study (SHCS) since 1996. The SHCS is highly representative and includes over 75% of patients receiving ART in Switzerland. To this end, they implemented a systematic medical chart review to obtain more detailed information on additional parameters, which are not routinely collected in the SHCS. The collected data was analyzed by univariable and multivariable conditional logistic regressions. They included 115 cases and 115 matched controls. Unemployment (multivariable odds ratio (mOR) 2.9 [95% CI: 1.3-6.4], p=0.008), African origin (mOR 3.0 [95%CI: 1.0-9.2], p=0.047), co-medication with anti-infectives (mOR 3.7 [95%CI: 1.0-12.6], p=0.045) and symptoms of mental illness (mOR 2.6 [95% CI: 1.2-5.5], p=0.012) were associated with ADR in the multivariable model. Only four of 115 cases did not have any risk factor identified in this study with the emergence of drug resistance. Although ADR has become very rare with cART due to new potent therapies, patients in socially challenging life situations or presenting with mental health issues are at higher risk for drug resistance. Prompt identification and adequate support of these patients before ADR will prevent treatment failure and HIV-1 transmission. | ||
| 2nd May | Kusejko et al., Interaction of HIV-1 with comorbidities | |
Kusejko et al. aimed to systematically test whether coinfections spread along the HIV-1 transmission network and whether similarities in HIV-1 genomes predict AIDS-defining illnesses and comorbidities. A maximum-likelihood phylogenetic tree was built using sequences of 11’915 patients from the genotypic resistance test database of the Swiss HIV Cohort Study (SHCS) and non-Swiss background sequences from the Los Alamos database. Among the coinfections, hepatitis C virus (HCV), hepatitis B virus (HBV), syphilis, cytomegalovirus CMV, and latent tuberculosis all clustered significantly on the tree, even after adjusting for risk factors. Several opportunistic diseases such as Kaposi sarcoma clustered significantly on the phylogeny. For most noncommunicable diseases analyzed, patients were likewise not distributed randomly on the phylogeny. In most cases, however, the clustering was not significant in the multivariable analysis. Clustering of patients with psychiatric problems and neurocognitive complaints became weaker in the multivariable mixed effects model, but the odds of having psychiatric problems and neurocognitive complaints if the other patient in the cherry had these problems remained significantly increased. In conclusion, this work for the first time presents a systematic analysis of interrogating the HIV phylogeny at a population level for the syndemic nature of coinfections and noncommunicable diseases for virus traits potentially relevant for certain diseases. The large variety of conditions tested implies that no universal explanation or interpretation of the clustering can be given. There is evidence for 3 different reasons for clustering: shared transmission routes of pathogens, similar social networks of patients close in the phylogeny, and direct viral genetic impact. Overall, the strategy proposed by the authors together with adjustment for numerous known confounding factors, demonstrates the potential for a new type of analysis, extending conventional epidemiological analyses. | ||
| 23rd April | obituary Dr. Joseph Jost | |
Dear all, It is with great sadness that I inform you of the passing of our dear colleague Dr. Joseph "Seppi" Jost. He died suddenly and unexpectedly during the ECCMID meeting in Amsterdam last week. Seppi was a highly talented and dedicated ID physician, a pioneer of HIV medicine in Switzerland and instrumental in setting up the Swiss HIV Cohort Study. He worked at the Division of Infectious Diseases and Hospital Epidemiology of the University of Zurich as an "Oberarzt" from 1986-1999. In 1999, he went into private practice in Zurich and continued to care for hundreds of patients living with HIV. Seppi was a member of the KOHEX physicians (physicians participating in the Swiss HIV Cohort Study in Zurich) and remained always a highly motivated partner of the SHCS. On behalf of the SHCS, I want to thank Seppi for all the great work he has done for his patients and for his commitment to the SHCS. On a personal note, I want to thank him for all I was able to learn from him during my ID fellowship at the USZ in 1991-1993. Seppi was not only a great physician but had also a great sense of humor and it was always true fun to work with him. Seppi will be truly missed. Our deepest sympathies go to his wife and two children. for the SHCS, | ||
| 17th April | Salazar-Vizcaya et al., International versus local HCV transmission | |
Salazar-Vizcaya et al. aimed to classify hepatitis C virus (HCV) infections in HIV-positive men who have sex with men (MSM) in Switzerland as domestically or internationally acquired, and to estimate how this classification changed over time. The authors sequenced HCV subtype 1a genomes from 99 persons enrolled in the Swiss HIV Cohort Study and diagnosed with replicating HCV infections. Sixty-six of these sequences were from MSM. They inferred maximum-likelihood phylogenetic trees and time trees containing a fragment of the NS5B region of these and 374 circulating strains. They inferred transmission clusters from these trees and used the country composition of such clusters to attribute infections to domestic or international transmission. Of HCV transmissions, 50% to 80% were classified as domestic depending on the classification criterion. Between 2000 and 2007, the fraction attributable to domestic transmission was 54% (range 0%–75%). It increased to 85% (range 67%–100%) between 2008 and 2016. The authors found no significant trace of transmission bridging from persons who became infected with HIV through drug injection and MSM within Switzerland, suggesting that the HCV epidemics in these 2 HIV transmission groups are likely disconnected. In conclusion, this molecular epidemiological study suggests that both international and local transmission have played major roles in the Swiss epidemic of HCV among HIV-positive MSM, and that, while international transmission persists, Swiss domestic transmission has gained importance over time. | ||
| 10th April | Wymant et al., Reconstruction of whole HIV genomes from short-read sequence | |
Studying the evolution of viruses and their molecular epidemiology relies on accurate viral sequence data, so that small differences between similar viruses can be meaningfully interpreted. Despite its higher throughput and more detailed minority variant data, next-generation sequencing has yet to be widely adopted for HIV. The difficulty of accurately reconstructing the consensus sequence of a quasispecies from reads (short fragments of DNA) in the presence of large between and within-host diversity may have presented a barrier. In particular, mapping (aligning) reads to a reference sequence leads to biased loss of information; this bias can distort epidemiological and evolutionary conclusions. De novo assembly avoids this bias by aligning the reads to themselves, producing a set of sequences called contigs. However, contigs provide only a partial summary of the reads, misassembly may result in their having an incorrect structure, and no information is available at parts of the genome where contigs could not be assembled. To address these problems, Wymant and colleagues on behalf of the BEEHIVE collaboration developed the tool shiver to pre-process reads for quality and contamination, then map them to a reference tailored to the sample using corrected contigs supplemented with the user’s choice of existing reference sequences. Run with two commands per sample, it can easily be used for large heterogeneous data sets. The authors used shiver to reconstruct the consensus sequence and minority variant information from paired-end short-read whole-genome data produced with the Illumina platform, for sixty-five existing publicly available samples and fifty new samples. They showed the systematic superiority of mapping to shiver’s constructed reference compared with mapping the same reads to the closest of 3,249 real references: median values of 13 bases called differently and more accurately, 0 bases called differently and less accurately, and 205 bases of missing sequence recovered. They also successfully applied shiver to whole-genome samples of Hepatitis C Virus and Respiratory Syncytial Virus. In conclusion, the authors developed the tool shiver to preprocess and map reads from each sample to a custom reference, constructed using de novo assembled contigs supplemented by existing reference genomes. Tailoring the reference to be as close as possible to the expected consensus before mapping maximizes the accuracy of the mapping, and therefore of the resulting consensus. Shiver’s identification, ranking, and use of the closest existing references to fill in gaps between contigs boosts data recovery for samples with amplification failure or assembly failure. In addition, shiver also produces a global alignment containing all of the consensuses separately generated for each sample, which is usually required for comparative analysis of the sequences such as for phylogenetics or genome wide association studies. Shiver is publicly available from https://github.com/ChrisHIV/shiver | ||
| 4th April | Wymant et al., Inferring transmission from within- and between-host pathogen genetic diversity | |
A central feature of pathogen genomics is that different infectious particles (virions and bacterial cells) within an infected individual may be genetically distinct, with patterns of relatedness among infectious particles being the result of both within-host evolution and transmission from one host to the next. In the current work, Wymant and colleagues on behalf of the BEEHIVE Collaboration present a new software tool, phyloscanner, which analyses pathogen diversity from multiple infected hosts. The show that phyloscanner provides unprecedented resolution into the transmission process, allowing inference of the direction of transmission from sequence data alone. In addition, phyloscanner allows to identify multiply infected individuals, as they harbor subpopulations of infectious particles that are not connected by within-host evolution, except where recombinant types emerge. Low-level contamination is flagged and removed. The authors illustrate phyloscanner on both viral and bacterial pathogens, namely HIV-1 sequenced on Illumina and Roche 454 platforms, Hepatitis C virus sequenced with the Oxford Nanopore MinION platform, and Streptococcus pneumoniae with sequences from multiple colonies per individual. In conclusion, phyloscanner aims to simplify identification of transmission, multiple infection, recombination, and contamination across pathogen genomics by providing a tool for automatic phylogenetic analysis of next generation sequencing deep sequencing data, or multiple genotypes per host generated by other means. Phyloscanner is available from https://github.com/BDI-pathogens/phyloscanner. | ||
| 28th March | Peters et al., Uptake of TDF-based ART among HIV/HBV co-infected patients | |
Peters et al. on behalf of the EuroSIDA study aimed to study regional differences in uptake of tenofovir disoproxil fumarate (TDF-) based combination antiretroviral therapy (cART) and factors associated with its use among HIV/hepatitis B virus (HBV) co-infected patients across Europe. Overall, 953 HBsAg+ patients were followed up after 1 March 2002. Median age was 41 years and patients were predominantly male (85%), white (82%) and ART experienced (88%). 697 and 256 were from Western and Eastern Europe, respectively. Fifty-five started cART during follow-up, the proportion starting with CD4
In conclusion, in this large pan-European observational study we have shown a large proportion of HIV/HBV co-infected patients have started cART late and seem to receive sub-optimal coverage against HBV, in particular in Eastern Europe. Discontinuations of TDF without replacement with antiviral agents with sufficient antiviral coverage against HBV are common, and put the patients at risk of hepatic flares and progression of liver disease. Longer follow-up is warranted to investigate whether treatment with less potent HBV active antivirals translates into greater risk of clinical liver disease and death among HIV/HBV co-infected patients. | ||
| 20th March | Gran et al., Estimating treatment effect under time-dependent confounding | |
When comparing time varying treatments in a non-randomized setting, one must often correct for time-dependent confounders that influence treatment choice over time and that are themselves influenced by treatment. In the current work, Gran and colleagues present a new two-step procedure, based on additive hazard regression and linear increments models, for handling such confounding when estimating average treatment effects on the treated. The approach can also be used for mediation analysis. The method is applied to data from the Swiss HIV Cohort Study, estimating the effect of antiretroviral treatment on time to acquired immune deficiency syndrome or death. Compared with other methods for estimating the average treatment effects on the treated the method proposed is easy to implement by using available software packages in R. In sum, compared with other methods that estimate average total treatment effect under time-dependent confounding on a time-to-event outcome, the proposed method is a two-step approach, where each step has the benefit of being easy to implement by using two simple existing statistical software packages. The outcome model also has the benefit of being a hazard regression model in the traditional sense, which typically is not so in the g-estimation approach. The authors claim that there are advantages in considering several approaches for handling the thorny issue of time-dependent confounding, and that the procedure that is described in this paper serves as a valuable addition. | ||
| 14th March | Shepherd et al., Risk factors for Non-Hodgkin and Hodgkin lymphoma | |
Shepherd et al. on behalf of the Data Collection on Adverse events Cohort (D:A:D) aimed to identify independent risk factors of Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) and to identify factors that differentially affect NHL and HL risk in order to develop an understanding of different mechanistic pathways, which may then suggest different preventive approaches for reducing NHL and HL risk.
In conclusion, the study shows that whereas CD4 depletion similarly increased risk of both types of lymphomas, current and accumulated HIVVL was more predictive of NHL than HL. This suggests that NHL development is related to both CD4 cell depletion and added immune dysfunction derived from ongoing HIV replication. This latter factor was not associated with HL risk. These findings stress the importance of early HIV diagnosis and treatment, and of ensuring sustained viral suppression. | ||
| 28th February | Laut et al., Disparities in ART coverage and virological suppression across Europe | |
Laut et al. on behalf of the EuroSIDA Study Group aimed to characterize country-specific levels of antiretroviral therapy (ART) coverage and ART-induced HIV RNA suppression (HIV RNA < 500 copies/mL) within the EuroSIDA study, and to monitor temporal trends. Of note, the cut-off of 500 copies/mL for viral suppression was chosen as not all countries have access to assays with a lower limit of detection of 50 copies/mL Overall, the percentage of people on ART increased from 2004–05 (67.8%) to 2014–15 (78.2%), as did the percentage among those on ART who were virologically suppressed (75.2% in 2004–05, 87.7% in 2014–15). However, the rate of improvement over time varied significantly between regions (p < 0.01). In 2014–15, six of 34 countries had both ART coverage and virological suppression of above 90% among those on ART. The pattern varied substantially across clinics within countries, with ART coverage ranging from 61.9% to 97.0% and virological suppression from 32.2% to 100%. Compared with Western Europe, patients in other regions were less likely to be virologically suppressed in 2014–15, with the lowest odds of suppression (adjusted odds ratio = 0.16; 95% confidence interval (CI): 0.13–0.21) in Eastern Europe. In conclusion, the study was able to directly compare data from a large number of clinics across Europe, including some countries that do not have national registries. The authors found persistent between-country disparities in the level of ART coverage and virological suppression, as well as the rate of improvement over the last decade. EuroSIDA will continue the surveillance of changes and variation in countries’ performance in the ‘test and treat’ era. Current EuroSIDA work aims to explore the underlying reasons for the observed variation, with the goal to identify a best practice and to benchmark HIV care. | ||
| 21st February | Huges et al., Trends in CD4+:CD8+ ratio on ART | |
HIV infection leads to persistent immune activation and inflammation, which may accelerate deterioration of the immune system due to ageing (so called “immunosenescence”). In the general population, a low CD4+:CD8+ ratio is a surrogate marker for immunosenescence and an independent predictor of all-cause mortality. Among HIV-positive individuals, low CD4+:CD8+ ratio has been associated with higher levels of immunosenescence and inflammation, although the results regarding whether a low or inverted CD4+:CD8+ ratio predicts non-AIDS-related morbidity and mortality have been conflicting. In the current work, Hughes et al. on behalf of the ART Cohort Collaboration aimed to quantify long-term trends in CD8+ cell counts and CD4+:CD8+ ratios, up to 15 years after starting antiretroviral therapy (ART), in a large cohort of antiretroviral-naïve individuals starting ART, and assess the impact of baseline CD4+ cell count on these trends. Eligible patients from the ART Cohort Collaboration were antiretroviral-naïve, started ART after 1997, had at least one CD4+ and CD8+ measurement within the baseline period and one or moreCD4+ and CD8+ measurements 6 months after starting ART. A total of 39’979 patients were included (median follow-up was 53 months). Among patients with baseline CD4+ cell count at least 50 cells/ml, predicted mean CD8+ cell counts continued to decrease between 3 and 15 years post-ART, partly driving increases in the predicted mean CD4+:CD8+ ratio. During 15 years of follow-up, normalization of the predicted mean CD4+:CD8+ ratio (to >1) was only observed among patients with baseline CD4+ cell count at least 200 cells/ml. A higher baseline CD4+ cell count predicted a shorter time to normalization. In conclusion, there are long-term decreases in CD8+ cell counts and long-term increases in CD4+:CD8+ ratios, among patients who start ART with CD4+ cell count as low as 50–199 cells/ml. However, starting ART at high CD4+ cell counts is paramount for attainment of a maximal CD4+:CD8+ ratio. | ||
| 20th February | Kurioka et al., CD161-expressing NK cells | |
Natural killer (NK) cells are the most classical population of innate lymphoid cells, expressing a heterogeneous repertoire of germline-encoded receptors that allows them to distinguish infected or stressed cells from healthy cells. CD161 is a C-type lectin-like receptor expressed on the majority of natural killer (NK) cells; however, the significance of CD161 expression on NK cells has not been comprehensively investigated. Recently, the author-group has found that CD161 expression identifies a transcriptional and innate functional phenotype that is shared across various T cell populations. In the current work, Kurioka et al. demonstrated using mass cytometry and microarray experiment that this functional phenotype extends to NK cells. CD161 marks NK cells that have retained the ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. These pro-inflammatory NK cells are present in the inflamed lamina propria where they are enriched for integrin CD103 expression. In summary, the study has shown that CD161 is a marker of NK cell function, particularly marking pro-inflammatory NK cells, which is expressed on all NK cells in cord blood, downregulated upon proliferation, and lost upon CMV-induced terminal differentiation. CD161 expression on CD56dim NK cells marks cells that have retained the capacity to respond to inflammatory cytokines alone. CD161, thus, identifies “innate” cells within both NK cells and CD161bright T cell family, previously described, with shared innate-type responses that are independent of receptorligation. | ||
| 13th February | Laut et al., Variation among HIV key populations | |
Laut et al. on behalf of the EuroSIDA study group aimed to assess differences in antiretroviral treatment (ART) coverage and virological suppression across the three HIV transmission categories i) men who have sex with men, ii) injection drug users (IDU) and iii) heterosexuals. Among 12’872 participants followed from 1 July 2014 to 30 June 2016, the percentages of ART-coverage and virological suppression varied between transmission categories, depending on geographical region (global P for interaction: P=0.0148 for ART-coverage, P=0.0006 for virological suppression). • In Western [adjusted odds ratio (aOR) 1.41 (95% confidence interval 1.14–1.75)] and Northern Europe [aOR 1.68 (95% confidence interval 1.25–2.26)], heterosexuals were more likely to receive ART than MSM. In conclusion, the study found that levels of ART-coverage and virological suppression varied depending on HIV transmission category, both across and within regions. Overall, people infected through IDU were the least likely to receive ART and to achieve virological suppression on ART, but the pattern varied significantly by region of residence. These results demonstrate that national estimates of ART coverage and virological suppression may represent an average that covers large differences across key populations. Hence, a differentiated HIV-response remains crucial to reaching control of the HIV epidemic and underline that high-quality disaggregated data are needed to inform and strengthen interventions. | ||
| 6th February | Rohner et al, Regional NHL risk in HIV-positive adults | |
Rohner et al. for the AIDS-defining Cancer Project Working Group of IeDEA and COHERE in EuroCoord aimed to compare non-Hodgkin lymphoma (NHL) incidence rates in adults who started antiretroviral therapy (ART) after 1995 across the Asia-Pacific, South Africa, Europe, Latin, and North America. The authors included 210’898 adults with 1.1 million person-years (pys) of follow-up and 1’552 incident NHL cases (raw overall incidence rate 142/100 000 pys). After adjusting for age at ART start, first-line ART regimen, calendar period of ART start, and especially current CD4+ cell count, NHL rates were similar across regions for most population groups. However, South African women remained at increased risk of developing NHL compared with their European counterparts [adjusted hazard ratio [aHR] 1.79, 95% CI 1.19–2.70]. In Europe, Latin, and North America, NHL risk was highest in MSM (aHR 1.30, 95% CI 1.14–1.48), followed by heterosexual men (referent), and women (aHR 0.66, 95% CI 0.57–0.78). In conclusion, the risk of developing NHL is higher in women in South Africa than in Europe and higher in MSM compared with heterosexual men and women. Co-infection patterns might contribute to the increased NHL rates in MSM and South African women. A better understanding of lymphomagenesis and associated etiologic factors is needed to eventually be able to develop specific preventive measures against NHL in adults living with HIV. In the meantime, early access to ART and regular patient monitoring to avert low current CD4+ cell counts remain key for NHL prevention. | ||
| 30th January | Ronit et al., Serum albumin and non-AIDS events | |
Ronit et al. for the D:A:D Study Group aimed to undertake a detailed evaluation of the association between serum albumin (sAlb) and serious non-AIDS events (SNAE) in a large and heterogeneous study population with long follow-up. SNAE was defined as cardiovascular disease (CVD) (myocardial infarction, stroke, invasive cardiovascular procedure or death from CVD); end-stage renal disease (ESRD) or death from renal disease; end-stage liver disease (ESLD) or death from ESLD; non-AIDS-defining malignancies (NADMs, except for basal cell or squamous cell skin cancer) or death from cancer; and any other non-AIDS death. Of 16’350 participants (71.8% male, median age 44 years), 1’463 developed an SNAE (371 CVD, 200 ESLD, 40 ESRD, 553 NADM, 299 deaths from other non-AIDS causes) over 80’264 person-years. Increased sAlb was associated with a decreased risk of an SNAE [adjusted rate ratio per 5 g/l: SNAE 0.79 (95% confidence interval: 0.76, 0.83); CVD 0.87 (0.80, 0.94); NADM 0.88 (0.82, 0.95)]. The association did not appear to wane with additional years of follow-up (P-interaction =0.79) but was stronger for current smokers than for never smokers (P-interaction <0.01). In conclusion, in this study sAlb was found to be independently associated with SNAE, including CVD and NADM. This association did not appear to wane over time and was strongest in current smokers. The pathophysiology underlying the relationship between sAlb and SNAE, and its effect modifiers, are poorly understood, and warrants further mechanistic investigation. One potential explanation is that a low sAlb level might be a consequence of pathways of immune activation and that sAlb may exert a protective effect due to antioxidant activity. | ||
| 29th January | Shepherd et al., Cessation of cigarette smoking and cancer in HIV | |
Despite the well characterized harms of smoking in people living with HIV (PLWH), the clinical benefits of smoking cessation on cancer risk have not previously been reported in large epidemiological studies. The aim of this study was to estimate cancer rates after smoking cessation in PLWH from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study. Participants were followed from 1 January 2004 until first cancer diagnosis, death, or 1 February 2016. Smoking status was defined as ex-smoker, current smoker, and never smoker. Of note, smoking information is reported in the D:A:D Study as current smoker (yes/no) and ever smoker (yes/no) at each visit, but more specific information, such as cigarette or pipe smoking, or intensity of smoking, is not available. In total 35’442 persons from the D:A:D study contributed 309’803 person-years of follow-up. At baseline, 49% were current smokers, 21% were ex-smokers, and 30% had never smoked. • Incidence of all cancers combined (n = 2’183) was highest <1 year after smoking cessation compared to never smokers (aIRR, 1.66 [95% confidence interval {CI}, 1.37–2.02]) and not significantly different from never smokers 1–1.9 years after cessation. • Lung cancer incidence (n = 271) was elevated <1 year after cessation (aIRR, 19.08 [95% CI, 8.10–44.95]) and remained 8-fold higher 5 years after smoking cessation (aIRR, 8.69 [95% CI, 3.40–22.18]). • Incidence of other smoking-related cancers (n = 622) was elevated in the first year after cessation (aIRR, 2.06 [95% CI, 1.42–2.99]) and declined to a level similar to nonsmokers thereafter. In conclusion, incidence of lung cancer incidence in PLWH was >8-fold higher than never smokers several years after cessation, at a similar level to current smokers, and with no evidence of a decline after the first year. This suggests that the oncogenic potential for smoking is not reduced for lung cancer in the time frame that was investigated. This is in contrast with similar studies in HIV-uninfected people, which show a consistent decline in lung cancer incidence with increasing time since cessation. Deterring uptake of smoking and smoking cessation efforts should be a priority to reduce the risk of cancer; however, monitoring and awareness of lung cancer should continue in those who stop smoking. Studies following PLWH throughout their lifetimes are needed to determine when the benefit of cessation will be seen. | ||
| 23rd January | Slogrove et al., The epidemiology of adolescents living with perinatally acquired HIV | |
Slogrove et al. for the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration aimed to describe the global epidemiology of adolescents living with perinatally acquired HIV (APH) in terms of geographic and temporal trends of patient and treatment characteristics at entry into care, ART start, entry into adolescence (age 10 years), and last visit. All children from 12 cohort networks infected with HIV who entered care before age 10 years and had acquired HIV around the time of birth or through breastfeeding, were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Among 38’000 adolescents living with perinatally acquired HIV, 79% were living in sub-Saharan Africa. Analysis by country income group suggested that patients in high-income countries (North America and Europe) had younger age, higher CD4 percent, and less impaired height when starting antiretroviral therapy compared to middle- or low-income countries. Lost to follow-up rate was lowest in South America and the Caribbean and highest in sub-Saharan Africa. HIV-associated mortality during adolescence was substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. In summary, the analysis of a large cohort of APHs between 1982 and 2014 across several regions of the globe suggests that APHs generally entered HIV care at an earlier age in high-income countries compared to other country income groups. Despite probable under-ascertainment, mortality continued to be substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe and warrants further monitoring and understanding. | ||
| 17th January | Ramsuran et al., Inhibiting natural killer cells in AIDS | |
The highly polymorphic human leukocyte antigen (HLA) locus encodes cell surface proteins that are critical for immunity. HLA-A expression levels vary in an allele-dependent manner, diversifying allele-specific effects beyond peptide-binding preference. Ramsuran et al. examined data from 9’763 HIV-infected individuals from 21 cohorts. They found that higher HLA-A levels confer poorer control of HIV. Expression of the HLA-A and -B alleles was associated with: Higher levels of HLA-A expression increased expression of HLA-E, which blocks a specific receptor (NKG2A) on the immune cells that normally eliminate virus-infected cells. In conclusion, the data suggest that antagonizing HLA-E/NKG2A interactions, perhaps in combination with other therapies, may provide benefit in HIV disease. This might be an attractive approach in HIV cure strategies. Genetic validation of NKG2A as a therapeutic target in additional diseases by testing for effects of HLA-A and HLA-B –21 genotypes may rationalize the use of anti-NKG2A therapy in other disorders. | ||
| 16th January | Pelchen-Matthews et al., Comorbidities in people living with HIV | |
Pelchen-Matthews et al. for the EuroSIDA study aimed to characterize the evolution of the prevalence of chronic kidney disease (CKD) and cardio-vascular disease (CVD) and related risk factors in the aging people living with HIV (PLWHIV) population in Europe. 9’798 individuals were under active follow-up in EuroSIDA during 2006 and 12’882 during 2014. Compared with study participants in 2006, those in 2014: Individuals in the 2014 cohort had higher odds for CKD (unadjusted OR 2.62, 95% CI2.30–2.99, P<0.0001) and CVD (OR 1.88, CI 1.68– 2.10, P<0.0001), but after multivariable adjustment for age group, comorbidities and other factors, year of cohort was no longer significantly associated with the odds of CKD [adjusted OR (aOR) 0.97, CI 0.52– 1.82, P=0.92) or of CVD (aOR 0.94, CI 0.54 –1.63, P=0.82). In conclusion, this study of risk factors and comorbidities in a large cohort of HIV-positive individuals in Europe has shown an increase in the prevalence of non-AIDS comorbidities, including diabetes, CKD and CVD, along with increased prevalence of hypertension and a high prevalence dyslipidemia, which was largely explained by the aging of persons included. Higher prevalence of comorbidities was particularly evident for individuals at least 50 years old, highlighting the increase in non-AIDS-related conditions in the aging PLWHIV population. This shows a need for careful management not only to control HIV through optimal selection of ART, but also to address the effect of aging, including screening and regular monitoring of the major comorbidities and risk modification measures. | ||