2018
| 20th December | Ingle et al., Risk of viral failure in treated HIV-infected patients using different measures of adherence |  |
Ingle et al. on behalf of the Antiretroviral Therapy Cohort Collaboration aimed to assess the utility of different adherence measures for identification of patients at risk of viral failure (VF). Eight cohorts contributed data from pharmacy refills or self-report questionnaires collected between 1996 and 2013 (N = 11689). For pharmacy data (N = 7156), associations of percentage adherence during the 1st year of ART with VF (>500 copies/mL) at 1 year were examined. For self-report data (N = 4533), 28 day adherence with VF based on closest viral load measure within 6 months after questionnaire date was examined. Since adherence differed markedly by measurement type, the authors defined different cut-off points for pharmacy (lower <45%, medium 45–99%, higher 100%) and self-report (lower ≤95%, medium 96–99%, higher 100%) data. Adjusted odds ratios (ORs) for VF in lower and medium, compared to higher adherence groups, were 23.04 (95% CI: 18.44–28.78) and 3.84 (3.36–4.39) for pharmacy data. For self-report data, they were 3.19 (2.31–4.40) and 1.08 (0.80–1.46). Both types of measure were strongly associated with VF. In conclusion, the study results suggest that both self-report and pharmacy refill adherence data can be used to predict viral failure and show evidence that increasing adherence decreases the risk of viral failure. In the current study, pharmacy measures were much more strongly associated with viral failure than self-reported measures, although this may be due, in part, to the longer time-frame used in the pharmacy data and the higher % with viral failure in the pharmacy cohorts. To make full use of adherence data, there needs to be an awareness of cohort-specific factors affecting adherence. In addition, harmonization of pharmacy refill data management should be attempted in order to ensure that all cohorts are using the same tools.
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| 19th December | Walti et al., TAF in multimorbid HIV-infected patients with prior TDF-associated renal toxicity | |
Walti et al. aimed to assess in a rea-life setting, whether a switch from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) due to prior TDF-induced renal toxicity is safe and efficacious in multimorbid individuals. In their case series, 10 patients with at least 1 year of follow-up were included in the analysis. The median age was 55 (53–70) years and at the time of switch all patients had a suppressed HIV virus load with a median CD4 cell count of 688 (437–828) cells/μL. Participants were heavily treatment-experienced (median time on antiretroviral therapy, 19 years) and had numerous changes of drug classes due to virological failure, side effects, and potential long-term toxicity. Nine patients had significant, mostly cardiovascular comorbidities, and 7 had more than 3 comedications. Osteoporosis was documented in 4 patients. Three patients had concomitant chronic hepatitis B virus (HBV) infection, and 2 had a chronic hepatitis C virus (HCV) infection. After switch from TDF to TAF, renal glomerular function remained stable, with a median change in eGFR (IQR) at 12 months of –0.5 (–3 to +3) mL/min. No Fanconi syndrome or other acute kidney injury was observed during the first year of TAF. Only small changes in tubular markers were seen, and the proportion of patients with a significant proteinuria (>20 mg/mmol) decreased from 70% to 30%. In conclusion, the findings of this case series support the use of TAF in HIV-monoinfected and HIV/HBV-coinfected patients with severe TDF-related toxicity, but prospective, long-term studies in similar populations are needed to confirm our findings. | ||
| 12th December | Martin et al., Killer cell immunoglobulin-like receptor 3DL1 and protection against HIV-1 | |
HLA-B*57 control of HIV involves enhanced CD8+ T cell responses against infected cells, but extensive heterogeneity exists in the level of HIV control among B*57+ individuals. Using whole-genome sequencing of untreated B*57+ HIV-1–infected controllers and noncontrollers, Martin et al. identified a single variant (rs643347A/G) encoding an isoleucine-to-valine substitution at position 47 (I47V) of the inhibitory killer cell immunoglobulin-like receptor KIR3DL1 as the only significant modifier of B*57 protection. The association was replicated in an independent cohort and across multiple outcomes. The modifying effect of I47V was confined to B*57:01 and was not observed for the closely related B*57:03. Positions 2, 47, and 54 tracked one another nearly perfectly, and 2 KIR3DL1 allotypes differing only at these 3 positions showed significant differences in binding B*57:01 tetramers, whereas the protective allotype showed lower binding. Thus, variation in an immune NK cell receptor that binds B*57:01 modifies its protection. In conclusion, these data highlight the exquisite specificity of KIR-HLA interactions in human health and disease. | ||
| 11th December | Mocroft et al., Greatest impact of uncontrolled HIV infection | |
Mocroft et al. for the EuroSIDA Study aimed to identify whether risk of HIV disease progression comparing controlled and uncontrolled HIV was different across age groups, year of follow-up or European regions of care between 2001 and 2016. EuroSIDA participants were followed after 1 January 2001 and grouped according to current HIV progression risk: high risk (CD4+ cell count ≤350/ml, viral load ≥10 000 copies/ml), low risk (CD4+ cell count ≥500 cells/ml, viral load <50 copies/ml) and intermediate (other combinations). A total of 16’839 persons were included with 136’688 person-years of follow-up. • In persons ≤30 years, those at high risk had a six-fold increased incidence of non-AIDS events compared with those at low risk, compared with a two-to-three-fold increase in older persons (P=0.0004, interaction). • Differences among high, intermediate and low risk of AIDS were similar across age groups, year of follow-up and Europe (P=0.57, 0.060 and 0.090, respectively, interaction). In conclusion, the study-results highlight that as person’s age, factors other than optimal control of HIV become more important for predicting non-AIDS events, demonstrating the role of biological ageing, whereas the development of AIDS is much more dependent on uncontrolled HIV in all age groups. | ||
| 5th December | Bachmann et al., Antiretroviral resistance and viral load monitoring | |
Bachmann et al. aimed to assess genotypic resistance patterns in two Sub-Saharan African cohorts (Uganda and Lesotho) compared to a sub-cohort of the Swiss HIV Cohort Study (SHCS). The Sub-Saharan cohorts included individuals prior to access to routine viral load (VL) monitoring who had virological failure while taking first-line NNRTI-containing antiretroviral therapy (ART). The SHCS sub-cohort included individuals taking NNRTI-based ART who had regular routine VL monitoring and a first-time genotypic resistance test (GRT) upon presentation with VL ≥1000 copies/mL. The authors found that 50.8% of individuals in the SHCS, 72.5% in Uganda and 81.0% in Lesotho harbored HIV with high-level resistance to at least two drugs from their current regimen. Stanford resistance scores were higher in Uganda compared with Switzerland for all drugs used in first-line treatment except zidovudine and tenofovir (P<0.01) and higher in Lesotho compared with Uganda for all drugs used in first-line treatment except zidovudine (P<0.01). In conclusion, frequent VL monitoring and possibly pretreatment GRT as done in the SHCS pays off by low levels of resistance even when treatment failure occurs. The high number of individuals among the Sub-Saharan cohorts with resistance to their current ART regimens is a serious public health concern that will not be reversed with the introduction of dolutegravir in Sub-Saharan Africa, as dolutegravir will also be prescribed with an NRTI backbone. Hence, the study-results highlight the importance of further upscaling virological monitoring in resource-limited settings. | ||
| 29th November | Bouatou et al., Lipodystrophy and chronic kidney disease in patients with HIV | |
Bouatou et al. aimed to test the hypothesis that lipodystrophy syndrome (LD) is independently associated with the development of chronic kidney disease (CKD), as defined by an eGFR Among the 5’384 patients included, 1’341 (24.9%) developed LD during the follow-up. The mean follow-up time was 72.3 months (SD ±48.4). In total, 252 patients (4.7%) reached the primary endpoint after a median time of 51.3 months (±SD 39.9 months) from inclusion. A diagnosis of LD significantly increased the risk of an eGFR on univariate analysis (hazard ratio [HR] = 2.72; 95% confidence interval [95% CI] = 2.07-3.58; P <0.001) and remained significantly higher after adjustment for known HIV and non-HIV risk factors for CKD (HR = 2.37; 95% CI = 1.67-3.36; P <0.001). The effect of LD on CKD was not mediated through the use of nephrotoxic antiretroviral drugs. In conclusion, this is the first study demonstrating that clinically diagnosed LD is associated with CKD independently of known risk factors in a large prospective nationwide cohort study. These findings suggest that HIV-positive patients with LD should be monitored more closely with respect to renal function. In addition, exposure to nephrotoxic ARTs (e.g., Tenofovir Disoproxil Fumarat) should be minimized in these patients. Additional works exploring the pathophysiology of this clear association are needed. | ||
| 28th November | Bibert et al., IFNL3/4 polymorphism and Kaposi’s sarcoma | |
Bibert et al. aimed to analyze whether single nucleotide polymorphisms (SNPs) within the Interferon lambda 3/4 region (IFNL3/4) variants are associated with susceptibility to AIDS-related Kaposi’s sarcoma among men who have sex with men (MSM) enrolled in the Swiss HIV Cohort Study. Of note, SNPs encoding for IFNL3/4 determine different haplotypic combinations (diplotypes) based on their capacity to produce IFNL4, that is, no production versus production as an active P70 or less active S70 form. Genomic DNA isolated either from blood or cell pellets was genotyped for haplotype tagging SNPs rs8099917 and rs12980275. Kaposi’s sarcoma was diagnosed in 221 of 2’558 MSM Caucasian participants. Both rs12980275 and rs8099917 were associated with an increased risk of Kaposi’s sarcoma (cumulative incidence 15 versus 10%, P=0.01 and 16 versus 10%, P=.009, respectively). Diplotypes predicted to produce the active P70 form (cumulative incidence 16 versus 10%, P=0.01) but not the less active S70 (cumulative incidence 11 versus 10%, P=0.7) form of IFNL4 were associated with an increased risk of Kaposi’s sarcoma, compared with those predicted not to produce IFNL4. The associations remained significant in a multivariate Cox regression model after adjustment for age at infection, combination antiretroviral therapy, median CD4+ T-cell count nadir and CD4+ slopes (hazard ratio 1.42, 95% confidence interval 1.06–1.89, P=0.02 for IFLN P70 versus no IFNL4). In summary, the data show an association between IFNL3/4 polymorphisms and the development of Kaposi’s sarcoma among HIV+ MSM patients. This new finding confirms that IFNLs mediate antiviral responses against a growing range of viruses. | ||
| 21st November | Pettit et al., Increased non-AIDS mortality among persons with AIDS-defining events after ART initiation | |
Pettit et al. for the Antiretroviral Therapy Cohort Collaboration investigators aimed to estimate the overall effect of AIDS-defining events (ADEs) on the risk of non-AIDS-defining events (NADE) mortality after antiretroviral therapy (ART) initiation in high-income settings. The analysis included HIV treatment-naive adults who initiated ART from 1996 to 2014. The ADES included, tuberculosis (TB), Pneumocystis jiroveci pneumonia (PJP), and non-Hodgkin’s lymphoma (NHL). • The adjusted hazard of overall non-AIDS mortality was higher among those with any ADE compared to those without any ADE (aHR 2.21, 95% confidence interval (CI) 2.00 to 2.43). • The adjusted hazard of each of the cause-specific non-AIDS related deaths were higher among those with any ADE compared to those without, except metabolic deaths:
• The risk of overall and cause-specific non-AIDS mortality differed depending on the specific ADE of interest (TB, PJP, NHL). In conclusion, NADE mortality rates were higher among those with an ADE after ART initiation compared to those without an ADE after ART initiation. Consistent with previous studies of overall mortality, NADE mortality rates after an ADE depended on the specific ADE diagnosed. Although there may be unmeasured confounders and associations may not be mechanistic, these findings suggest that a common pathway may be independently driving both ADEs and NADE mortality. ADE prevention, perhaps by more frequent HIV testing and initiating treatment at higher CD4+ counts, as well as the continued modification of risk factors such as tobacco use, may reduce subsequent NADE mortality. | ||
| 15th November | Satta et al., Anti-apolipoprotein A1 IgG in HIV patients | |
Satta et al. aimed to determine the existence of autoantibodies against apolipoproteinA-1 (anti-apoA-1 IgG) in HIV patients and explore their association with biological features of HIV infection and different inflammatory biomarkers. So far, anti-apoA-1 IgG positivity has been shown to vary between 0 and 5% in healthy blood donors, 20% in the general population, and reaching 30% in high CV risk populations. Anti-apoA-1 IgG plasma levels were assessed by ELISA in 237 HIV positive patients from the Swiss HIV Cohort Study with no current lipid-lowering therapy. Fifty-eight percent of patients were found positive for anti-apoA-1 IgG and were associated with lower CD4+ counts, but higher viremia and systemic inflammation. Logistic regression analyses indicated that high anti-apoA-1 IgG levels were associated with a 16-fold increased risk of displaying low CD4+ levels, independent of HIV RNA levels and treatment (adjusted Odds ratio [OR]:16.1, 95% Confidence Interval [95%CI]:1.80–143.6; p = 0.01), and a 6-fold increased risk of having a detectable viremia, independent of antiretroviral treatment (OR:5.47; 95% CI:1.63–18.36; p = 0.006). In vitro, anti-apoA-1 IgG induced dose and time-dependent CD4+ apoptosis that was increased by exposure to HIV RNA. In conclusion, this hypothesis generating pilot study indicates that anti-apoA-1 IgG levels are increased and associated with a pro-inflammatory cytokine profile, lower thrombocytes, CD4+ counts, and higher viremia. Furthermore, experimental evidence showed that stimulation with anti-apoA-1 IgG can negatively affect CD4+ lymphocyte survival trough novel and yet undefined pathways, an effect that was magnified by the concomitant presence of HIV RNA in vitro. Taken together, these results indicate that anti-apoA-1 IgG may represent a relevant prognostic biomarker in HIV patients. This working hypothesis needs to be challenged in large multicentre longitudinal trials before extrapolating the possible clinical implications of the present findings. | ||
| 14th November | Roen et al., Abacavir and hypersensitivity reactions | |
Roen et al. on behalf of the EuroSIDA study aimed to describe the proportion of individuals initiating abacavir (ABC) and to describe the incidence and factors associated with hypersensitivity reactions (HSR) among those prescribed ABC. Between 2009 and 2016, of 10’076 individuals receiving combination antiretroviral therapy (cART), 3’472 (34%) had ever received ABC-based cART. Poisson models showed lower ABC utilization in older individuals, and in those with higher CD4 cell counts, higher cART lines, and prior AIDS. Higher ABC utilization was associated with higher HIV RNA and poor renal function, and was more common in Central-East and Eastern Europe and lowest during 2014. During 779 person-years of follow-up (PYFU) in 2’139 individuals starting ABC after 1 January 2009, 113 discontinued ABC within 6 weeks of initiation for any reason [incidence rate (IR) 14.5 (95% confidence interval (CI) 12.1, 17.5) per 100 PYFU], 13 because of reported HSR [IR 0.3 (95% CI 0.1, 1.0) per 100 PYFU], and 35 because of reported HSR/ any toxicity [IR 4.5 (95% CI 3.2, 6.3) per 100 PYFU]. There were no factors significantly associated with ABC discontinuation because of reported HSR/any toxicity. In conclusion, ABC remains a commonly used drug throughout Europe, and the incidence of reported HSR among those on ABC is low, probably attributable to screening for HLA-B*5701, improved patient care and a greater understanding and awareness of HSR. Because EuroSIDA does not collect genetic screening information, it is unknown which individuals were tested for HLA-B*5701, or whether the frequency of testing varied between regions and/or over calendar time. | ||
| 8th November | Adland et al., HLA-B*27:02-mediated control of HIV-1 | |
The association between HLA-B*27:05 and protection against HIV disease progression in untreated HIV-seropositive individuals has been linked to immunodominant HLA-B*27:05- restricted CD8* T-cell responses toward the conserved Gag KK10. In this study, Adland et al. aimed to study the impact of the 3 amino acid differences between HLA-B*27:05 and the closely related HLA-B*27:02 on the HIV-specific CD8+ T-cell response hierarchy and on immune control of HIV. They found that both HLA-B*27:02 and HLA-B*27:05 were associated with slower disease progression and lower viral loads. However, the effect of HLA-B*27:02 appeared to be consistently stronger than that of HLAB*27:05. In contrast to HLA-B*27:05, the immunodominant HIV-specific HLA-B*27:02-restricted CD8+ T-cell response is to a Nef epitope. Analysis of autologous virus sequences showed that in HLA-B*27:02-positive subjects, all CD8+ T-cell responses impose selection pressure on the virus, whereas in HLA-B*27:05-positive subjects, there is no Nef mediated selection pressure. These findings indicate that the immunodominant HLA-B*27:02-restricted Nef response adds to protection mediated by the Gag and Pol specificities that dominate anti-HIV CD8+ T-cell activity in HLA-B*27:05-positive subjects. | ||
| 31st October | Naret et al., Population stratification correction in genome-to-genome analysis | |
Multiple genome-wide association studies (GWAS) of clinical outcomes have identified human genetic variants that play a modulating role in infectious diseases. To explore the potential impact of human genetic diversity on infection, Bartha et al. recently proposed to integrate host and pathogen genomic data in a single analytic framework, the so-called genome-to-genome analysis (G2G). In this work, Naret et al. aimed to explore the effects of population stratification in G2G analyses. For that, they simulated host and pathogen genetic variations using a broad array of parameters including stratification on both sides, which allowed to pinpoint the various effects of population stratification on different statistical models. They then tested for associations between genome-wide human genotypes and HIV-1 sequence diversity in a real-life dataset of 1’668 participants from the Swiss HIV Cohort Study. They showed that correcting for both host and pathogen stratification is necessary for unbiased G2G analysis and increases power to detect real associations in a variety of tested scenarios. They confirmed the validity of the simulations by showing comparable results in an analysis of paired human and HIV genomes. | ||
| 25th October | Conconi et al., Outcome analysis of diffuse large B‐cell lymphoma among people living with HIV and competent individuals | |
Conconi et al. aimed to compare the clinical features, prognostic variables, and the clinical outcome of a series of consecutive acquired immunodeficiency syndrome related diffuse large B‐cell lymphoma (AR‐DLBCL) patients from the Swiss HIV Cohort Study, with those of a series of consecutive immunocompetent (IC)-DLBCL patients from 2 centres in Switzerland and Northern Italy. Fifty‐eight AR‐DLBCLs from the SHCS were compared with 326 ICDLBCLs treated with a combination of rituximab and CHOP or a CHOP‐like chemotherapy. Median follow‐up was 6 years; 5‐year overall survival (OS) was 68% (95% CI: 63%‐73%) in IC‐DLBCL and 63% (95% CI: 49%‐75%) in AR‐DLBCL (P = .220). Among 148 patients younger than 61 years treated with RCHOP/RCHOP‐like regimens, 20 IC‐DLBCL and 9 AR DLBCL patients died and OS was not significantly different. A higher proportion of early deaths occurred in the AR‐DLBCL: indeed, 1‐year OS was 94% (95% CI: 87%‐97%) in IC‐DLBCL and 82% (95% CI: 66%‐91%) in AR‐DLBCL patients. In conclusion, after rituximab and active antiretroviral therapy introduction, AR‐DLBCL and IC‐DLBCL patients treated with curative intent have similar long‐term survival. The data support the current guidelines that HIV‐infected persons on ART with DLBCL should receive the same therapeutic approach as IC individuals. | ||
| 18th October | Kusejko et al., Inferring the age difference in HIV transmission pairs | |
Kusejko et al. aimed to study the age difference at infection in HIV transmission pairs using phylogenetic methods. The authors used HIV-1 pol-sequences of 11’922 Swiss HIV Cohort Study (SHCS) patients and approximately 240’000 Los Alamos background sequences to build a phylogenetic tree. Considering the tree with all 11’922 SHCS patients, 2’991 pairs could be extracted, with 31.9% men who have sex with men (MSM) pairs, 21.2% heterosexual (HET) pairs, 13.8% intravenous drug user (IDU) pairs, and 11.8% HET/IDU pairs. For all transmission groups, the age difference at infection was significantly (P<0.001) smaller for pairs in the tree compared with randomly assigned pairs, meaning that patients of similar age are more likely to be pairs. The mean age difference in the phylogenetic analysis was 9.2, 9.0, 7.3 and 5.6 years for MSM-, HET-, HET/IDU-, and IDU-pairs, respectively. Decreasing the cophenetic distance threshold from 0.05 to 0.01 significantly decreased the mean age difference. Similarly, repeated sampling of 100% down to 1% of the tips revealed an increased age difference at lower sample proportions. In summary, the study-results suggest that HIV-transmission is age-assortative, but the age difference of transmission pairs detected by phylogenetic analyses depends on both sampling proportion and distance criterion. The mean age difference decreases when using more conservative distance thresholds, implying an underestimation of age-assortativity when using liberal distance criteria. Similarly, overestimation of the mean age difference occurs for pairs from sparsely sampled trees, as it is often the case in sub-Saharan Africa. | ||
| 17th October | Sabin et al., Abacavir and recurrent myocardial infarction | |
Sabin et al. on behalf of the D:A:D study group aimed to investigate the association between abacavir use and subsequent myocardial infarction risk among the patients who had already experienced an myocardial infarction during prospective D:A:D follow-up. Nine-hundred-eighty-four individuals experienced an index myocardial infarction during the study (91.3% male, median age 51 at index myocardial infarction). Over 5’312 person-years of follow-up, there were 136 recurrent myocardial infarctions (rate 2.56/100 person-years, 95% confidence interval 2.13–2.99). Rates were: No association was seen with recurrent myocardial infarction and either cumulative exposure to abacavir [relative rate 0.86 (0.68–1.10)/5 years], receipt of abacavir at index myocardial infarction [0.90 (0.63–1.29)] nor recent post-myocardial infarction exposure to abacavir [1.19 (0.82–1.71)]. In summary, among people with a previous myocardial infarction, there was no evidence for an association between use of abacavir post-myocardial infarction and an elevated risk of a recurrent myocardial infarction. | ||
| 11th October | Kouyos et al., Imprinting broadly neutralizing antibody responses | |
Kouyos et al. aimed to identify the viral determinants of a broadly neutralizing immune response in HIV-infected humans. The study-hypothesis was that if viral factors determine the quality of the antibody response, individuals with closely related viral strains would have similar neutralization responses. The authors identified 303 transmission pairs from the SHCS based on the sequence similarity of their HIV-1 polymerase gene. They then tested the ability of the antibody response in these individuals to neutralize 14 different virus strains and to bind 13 antigens (‘antibody fingerprint’). They found that transmission pairs had a more similar antibody fingerprint than pairs that were randomly assigned. Specifically, the infecting virus determined 13.2% in the variability of neutralization responses and 7–19% of the IgG reactivity. When taking into account factors that are known to influence broadly neutralizing antibody (bnAb) development, such as duration of infection and HIV-1 subtype, the correlation between infecting virus and the neutralization fingerprint remained in a similar range. Although the association between virus genetics and neutralization was highly statistically significant, the average effect size was moderate, similar to the effect size of virus genetics on CD4+ T cell loss. Remarkably, the authors found one transmission pair of elite neutralizers: this pair had developed a broadly neutralizing response by testing 42 different HIV-1 strains; that is, the pair had neutralization levels in the top 1% of the original cohort in which the transmission pairs were identified. The authors determined that the probability of finding a pair with such a strong and similar bnAb response by chance is low at 0.017. In summary, the study shows that differences in HIV-1 genetics influence the development of antibody responses and that some viral variants can elicit bnAbs across individuals. Although such strong bnAb imprinting is likely to be rare, the viral strains and antigens that underlie this effect are prime candidates for vaccine development. | ||
| 10th October | Ryom et al., Cardiovascular disease and use of contemporary protease inhibitors | |
Ryom et al. on behalf of the D:A:D study aimed to assess whether cumulative use of ritonavir-boosted atazanavir and ritonavir-boosted darunavir was associated with increased incidence of cardiovascular disease in people living with HIV. Participants were monitored from Jan 1, 2009, until the earliest of a cardiovascular event, 6 months after the last visit, or until Feb 1, 2016. Cardiovascular disease was defined as centrally validated myocardial infarction, stroke, sudden cardiac death, or use of invasive cardiovascular procedures, including coronary bypass, coronary angioplasty, and carotid endarterectomy. 49’709 participants were enrolled with a median 6.96 years of follow-up. Overall, 1’157 people developed cardiovascular disease (incidence rate 5.34 events per 1’000 person-years). The incidence rate of cardiovascular disease progressively increased from 4.91 events per 1’000 person-years in individuals unexposed to ritonavir-boosted darunavir to 13.67 events per 1000 person-years in those exposed to the drug for more than 6 years. The changes associated with ritonavir-boosted atazanavir were less pronounced, showing an incidence rate of 5.03 cardiovascular events per 1’000 person-years in unexposed individuals to 6.68 events per 1’000 person-years (5.02–8.35) in participants exposed for more than 6 years. After adjustment, keeping factors on the potential causal pathway from boosted protease inhibitor use to cardiovascular disease fixed at baseline, ritonavir-boosted darunavir use was associated with increased risk of cardiovascular disease (incidence rate ratio 1.59 per 5 years additional use), but use of ritonavir-boosted atazanavir was not. This association remained after adjustment factors on the potential causal pathway. In conclusion, in this prospective multicohort study with rigorously defined cardiovascular disease endpoints and relatively long follow-up, a progressively increasing risk of cardiovascular disease with longer ritonavir-boosted darunavir use was identified. Although the strength of the association between ritonavir-boosted darunavir and cardiovascular disease was similar to that reported for the first-generation protease inhibitors, the ritonavir-boosted darunavir association did not seem to be moderated by dyslipidaemia. These findings should prompt evaluation of whether other antiretrovirals that do not impart a risk of cardiovascular disease are available as part of individual care, particularly for people with HIV who are at high risk of cardiovascular disease. | ||
| 4th October | Salazar-Vizcaya et al., Impact of DAA on the burden of HCV in the SHCS | |
Salazar-Vizcaya et al. aimed to describe and compare direct-acting antivirals (DAA) upscale and its impact on the number of replicating hepatitis C virus (HCV) infections among people who inject drugs (PWID) and men who have sex with men (MSM) in the Swiss HIV Cohort Study (SHCS). Five thousand two hundred sixty-seven MSM and 1’805 PWID were followed by the SHCS over the study period, resulting in 38’693 and 14’748 person-years of follow-up for MSM and PWID, respectively.
In conclusion, the increase in treatment uptake and efficacy observed after the approval of DAAs boosted the decline of replicating HCV infections among PWID in the SHCS. However, among MSM, the potential beneficial impact of new treatments was counterbalanced by the high rate of incident HCV infections and by postponing treatment because of reimbursement limitations. | ||
| 2nd October | Kusejko et al., Drivers of the HIV epidemic in MSM | |
Kusejko et al. aimed to identify and quantify the drivers of the HIV epidemic of men who have sex with men (MSM) in Switzerland and to assess the potential impact of interventions to limit transmission. The authors simulated the HIV epidemic in MSM in Switzerland by stratifying a mathematical model by CD4 count, the care cascade and condom use. The model was parametrised with clinical, epidemiological and behavioural data from the Swiss HIV Cohort Study and surveys in the HIV-negative population. According to their model, 3.4% of the cases that would otherwise have occurred in 2008–2015 were prevented by early initiation of antiretroviral therapy (ART). Only 0.6% of the cases were attributable to a change in condom use in the HIV-positive population, as less usage is mainly seen in virally suppressed MSM. Most new infections were attributable to transmission from recently infected undiagnosed individuals. It was estimated that doubling the diagnosis rate would have resulted in 11.8% fewer cases in 2001–2015. Moreover, it was estimated that introducing pre-exposure prophylaxis (PrEP) for 50% of those MSM not using condoms with occasional partners would have resulted in 22.6% fewer cases in 2012–2015. In conclusion, the study found that most new infections are attributable to undiagnosed individuals in the recent phase of the infection and that the ‘test and treat’ strategy hence has the highest impact in reducing the number of new HIV infections. Moreover, protecting individuals who are not using condoms with occasional sexual partners with preexposure prophylaxis (PrEP) was shown to have a major impact even in a short time period. Only a moderate population-level effect was estimated for early initiation of ART and a weak effect for the change in condom use of diagnosed MSM. This very small impact can be explained by the fact that the increase in condomless sex is mainly observed in virally suppressed individuals, that is, individuals who cannot transmit the virus. | ||
| 27th September | Peters et al., Direct-acting antivirals in HIV/hepatitis C virus patients | |
Peters et al. the EuroSIDA Study Group aimed to investigate regional differences in the rate of hepatitis C virus (HCV) treatment uptake, and type of therapy used among HIV/HCV-coinfected patients in the pan-European Euro-SIDA study between 2011 and 2016. Among 4’308 HCV-RNA positive patients with 11’863 person-years of follow-up, 1’113 (25.8%) started any HCV therapy. Among patients with at least F3 fibrosis, more than 50% in all regions remained untreated. The incidence (per 1’000 person-years of follow- up, 95% confidence interval) of starting DAA increased from 7.8 (5.9–9.8) in 2014 to 135.2 (122.0–148.5) in 2015 and 128.9 (113.5–144.3) in 2016. The increase was highest in North and West and intermediate in South, but remained modest in Central East and Eastern Europe. After adjustment, women, individuals from Central East or East, genotype 3, antiretroviral therapy naïve and those with detectable HIV-RNA were less likely to start direct acting agents (DAA). Older persons, those with HCV-RNA more than 500’000 IU/ml and those with more advanced liver fibrosis were more likely to start DAA. In conclusion, this study shows that although the use of effective and well tolerated DAAs against HCV have increased markedly among HIV/HCV-coinfected patients in Europe in general since 2014, cost of the drugs and other barriers to treatment prevent them from reaching some of the patients most at need of HCV treatment. Further follow-up to monitor access to DAA therapy to achieve the WHO HCV elimination goal in 2030 among HIV/HCV-coinfected in Europe is warranted. | ||
| 26th September | Leon-Reyes et al., Cost of HIV care and antiretroviral therapy | |
Leon-Reyes et al. aimed to study the costs for HIV-related and non-HIV-related conditions and their main determinants by matching Swiss HIV Cohort Study (SHCS) and claims data from the largest Swiss health insurer. All policyholders from the health insurance Helsana with an antiretroviral therapy (ART) record (n = 2355) and patients from the SHCS receiving ART (n = 9326) during 2012 and or 2013 were considered for anonymous data linkage. The primary end points were total healthcare costs per year per patient in the HIV-infected population of Switzerland. Patients were classified into low, moderate, high, and unclassified risk groups for resource use. The corrected mean (standard error) total costs in 2012 and 2013 were The low-risk group for resource use had mean (standard error) annual costs of In the moderate- and high-risk groups, annual costs for 2012 and 2013 were higher by In conclusion, in this representative subsample of SHCS patient from a pilot linkage study with claims data, ART was the major cost factor. Patient profiling allowed identification of multiple factors related to higher resource use, including age, previous AIDS, psychiatric comorbid conditions, illicit drug and alcohol use, and lower adherence to ART. Repeated matching of SHCS and claims data in a larger sample could provide essential data to model important future costs that will inform health policy making on different levels. | ||
| 6th September | Reinschmidt et al., Incidental findings and HIV | |
Reinschmidt et al. aimed to assess the prevalence and factors associated with incidental findings among HIV-positive and HIV-negative participants ≥45 years from the Metabolic&Aging study undergoing coronary computed tomography angiography (CCTA). Findings were defined as incidental if not previously known. A finding was deemed to be significant if medical referral or radiological workup was recommended. A total of 553 persons, 341 with and 212 without HIV infection, were included in the study. Incidental findings were observed in 291 of 553 (53%) patients. In 42 of 553 (7.6%) participants, an incidental finding resulted in additional workup. A malignancy was diagnosed in 2 persons. In the HIV-positive group, age (1.31 per 5 years, 1.10–1.56) and smoking (2.29, 1.43–3.70) were associated with incidental findings; in the HIV-negative group, age (1.26, 1.01–1.59) and a coronary artery calcification score >0 (2.08, 1.09–4.02) were associated with incidental findings. HIV seropositivity did not affect the risk of incidental findings. In sum, the study showed that CCTA, a promising imaging tool to diagnose subclinical atherosclerosis in patients with increased cardiovascular risk including HIV infection, was associated with a remarkable rate of incidental findings. These included clinically significant findings that had implications for patient care and were associated with significant additional expenses. However, HIV infection was not associated with an increased risk of incidental findings. | ||
| 30th August | Hatleberg et al., Antiretroviral drugs and hypertension | |
Hatleberg et al. on behalf of the D:A:D study group aimed to re-investigate the potential associations between exposure to individual antiretroviral (ARV) drugs and the risk of hypertension, as well as to identify non-ARV predictors of hypertension. Hypertension was defined to have two consecutive systolic blood pressure (SBP) measurements >140 mmHg and/or diastolic blood pressure (DBP) measurements > 90 mmHg. Of 33 278 included persons, 7636 (22.9%) developed hypertension over 223 149 person-years (PY) [incidence rate: 3.42 (95% confidence interval (CI) 3.35–3.50) per 100 PY]. In univariable analyses, cumulative exposure to most ARV drugs except darunavir/ritonavir was associated with an increased risk of hypertension. After adjustment for demographic, metabolic and HIV-related factors, only associations for nevirapine [rate ratio 1.07 (95% CI: 1.04–1.13) per 5 years] and indinavir/ritonavir [rate ratio 1.12 (95% CI: 1.04–1.20) per 5 years] remained statistically significant, although effects were small. The strongest independent predictors of hypertension were male gender, older age, black African. There was no association between current smoking and the risk of hypertension. CD4 count < 100 cells/lL was the strongest HIV-related predictor of hypertension. In conclusion, the study did not find evidence for any significant clinically relevant independent associations between exposure to any of the investigated ARV drugs and hypertension risk, but did confirm the importance of traditional risk factors. These findings provide reassurance that, in addition to preventing immunosuppression in HIV-positive individuals by prompt initiation of antiretroviral therapy, screening policies and preventive measures for hypertension in HIV-positive persons should follow the algorithms used for the general population. However, continued pharmaco-vigilance is warranted for newer ARV drugs not investigated in this study. | ||
| 23rd August | Braun, Hampel et al., Grazoprevir/elbasvir in HIV/HCV-coinfected MSM | |
Braun, Hampel et al. aimed to investigate the efficacy and safety of grazoprevir-elbasvir guided by baseline resistance- associated substitutions (RASs) in the Swiss HCVree Trial. Individuals with replicating HCV genotype 1 or 4 infection were eligible for grazoprevir-elbasvir treatment. Genotype 1a-infected individuals with baseline RASs and genotype 4–infected individuals with prior failure of HCV treatment received 16 weeks of grazoprevir-elbasvir combined with ribavirin. All other individuals received 12 weeks of grazoprevir-elbasvir alone. Patients reporting unprotected sex with occasional partners were offered a HCV risk reduction-oriented behavioral intervention. A total of 122 individuals (3.3%) were eligible for study treatment with grazoprevir-elbasvir. Six of 76 patients infected with genotype 1a (7.3%) harbored baseline RASs. Sustained virological response after 12 weeks of follow-up was achieved in 121 patients (99%), including all with genotype 1a infection. Overall, 8 serious adverse events occurred, none of which was related to the study drug. Seventy-five percent of eligible MSM participated in the risk-counseling program. In conclusion, the study confirmed the high efficacy and excellent safety and tolerability of treatment with once-daily grazoprevir-elbasvir for 12 or 16 weeks, with or without ribavirin. A patient-individualized treatment approach based on the presence of baseline RASs in genotype 1a-infected patients was feasible and resulted in 100% SVR12 rates among those harboring RASs. Although the effectiveness of this approach for preventing reinfection is currently unclear and was not explicitly assessed in the current study, models suggest that sustained reductions in high-risk behavior in the MSM population could rapidly curb the epidemic. | ||
| 22nd August | Braun et al., HCV-RNA-based screening among HIV-seropositive MSM in the SHCS | |
Braun et al. aimed to perform a systematic hepatitis C virus (HCV) RNA–based screening among HIV-infected men who have sex with men (MSM) participating in the Swiss HIV Cohort Study (SHCS). HCV antibodies were measured from all HCV RNA–positive samples. Of 4’257 MSM recorded in the SHCS database, the investigators screened 3722 (87%) by HCV polymerase chain reaction and identified 177 (4.8%) with replicating HCV infection. Of those, 24 individuals (14%) had an incident HCV infection. Notably, one-third of individuals with incident HCV infection had a negative HCV antibody result at the time of HCV RNA positivity. The investigators calculated a median delay of 197 days (range, 53–366 days) in the diagnosis of incident HCV infection when following the SHCS standard-of-care annual HCV antibody testing. In a multivariable model, elevated liver enzyme values (odds ratio, 14.52; 95% confidence interval, 9.92–21.26), unprotected sex with occasional partners (2.01; 1.36–2.98), intravenous drug use (7.13; 4.36–11.64), noninjectable drug use (1.94; 1.3 2.88), and previous syphilis diagnosis (2.56; 1.74–3.76) were associated with HCV RNA positivity. In conclusion, the systematic HCV RNA–based screening among HIV-infected MSM revealed a high number of potential transmitters. A substantial subpopulation of MSM had incident infection, one-third of whom had a negative HCV antibody test result at the time of the HCV RNA positivity. These data reveal that one-time RNA testing of a high-risk population for HCV RNA might identify more infected persons than routine testing for HCV antibodies and liver enzymes. Hence, HCV RNA–based screening should be considered in sexually active MSM, particularly when they indulge in highrisk behavior. | ||
| 2nd August | Achhra et al., Body Mass Index and the risk of serious non-AIDS events | |
Body Mass Index and the risk of serious non-Aids events and all cause mortality in treated HIV-positive individuals: D: A: D Cohort Analysis. Journal of Acquired Immune Deficiency Syndrome Achhra et al. on behalf of the D:A:D Study Group aimed to assess the relationship between latest body mass index (BMI) and the subsequent risk of various serious non-AIDS events (SNAEs) and all-cause mortality. The endpoints were cardiovascular disease (CVD); diabetes; non–AIDS-defining cancers (NADCs) and BMI-NADCs (i.e., cancers known to be associated with BMI in general population), and all-cause mortality. A total of 41’149 individuals with 295’147 person-years of follow-up (PYFU) for the all-cause mortality outcome were included. Participants were largely male (73%) with the mean age of 40 years and baseline median BMI of 23.3. Overall, BMI showed a statistically significant J-shaped relationship with the risk of all outcomes except diabetes. The relative risk (RR) for the BMI of<18.5 and <30 compared with 23–25, respectively, was as follows: CVD: 1.46 and 1.31; NADCs: 1.78 and 1.17 and “BMI-NADCs”: 1.29 and 1.92. For all-cause mortality, there was an interaction by sex (P <0.001): RR in males: 2.47 and 1.21 and in females: 1.60 and 1.02. RR remained around 1 for intermediate categories of BMI. The risk of diabetes linearly increased with increasing BMI (P <0.001). In summary, the authors found that low BMI was associated with high risk of several individual SNAEs as well as all-cause mortality. The relative risk of SNAEs and mortality did not increase at intermediate/moderately high BMI (around 23–30) and only tended to increase at BMI >30. These findings suggest that BMI of 25–30, thought to be “overweight/mildly obese” in general population, may in fact confer some survival advantage in HIV-positive individuals. Also, these findings seem to suggest that obesity at BMI >30 is likely harmful in the long term even in HIV-positive individuals. Future studies should assess how short-term and long-term changes in BMI relate to the risk of SNAEs. Ultimately, whether change in BMI or weight gain or loss interventions (depending on current BMI) would actually improve outcomes in this population will need trials on carefully designed behavioral and nutritional interventions. | ||
| 19th July | Judd et al., Mortality and AIDS in children on ART in Europe and Thailand | |
Judd et al. on behalf of the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord aimed to describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries. Children with perinatal HIV aged < 18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. At cART initiation, median age was 5.2 (IQR 1.4±9.3) years; 35% of children aged < 5 years had a CD4 lymphocyte percentage < 15% in 1997-2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count 400 c/mL predicted late death. In conclusion, this study shows that mortality rates fell after the introduction of cART in 1997 but have remained stable since 2006, and the prevalence of low CD4 at initiation of cART decreased over the period. Five-year survival probability after initiating cART across the whole period studied was 97.6%. Almost half of the deaths observed were in the first 6 months of cART, suggesting that close clinical follow-up is recommended over the first 6 months after cART initiation, with enhanced prophylaxis against infections in those presenting with advanced disease. The indication of raised early mortality risk in infants and those in Eastern Europe and Thailand raises concern and warrants vigilance. It highlights the need to direct additional clinical resources to the care of these groups, as well as further prospective studies evaluating morbidity and mortality in older adolescents. | ||
| 18th July | Kühnert et al., Phylodynamic quantification of HIV-1 drug resistance fitness cost | |
Kühnert et al. aimed to employ a phylodynamic approach to quantify the fitness costs of major resistance mutations in the Swiss HIV cohort. The authors modelled the transmission tree using stochastic birth-death-sampling processes, including hosts infected by a sensitive or resistant strain. In terms of the transmission tree a “birth” event corresponded to the infection of a new host, a “death” event corresponded to the host's removal from the infectious pool (e.g. successful treatment). For this study, the following resistance mutations were included: 41L, 67N, 70R, 184V, 210W, 215D, 215S and 219Q (nRTI-related) and 103N, 108I, 138A, 181C, 190A (NNRTI-related) in the reverse transcriptase and the 90M mutation in the protease gene. Among these resistance mutations, only the 90M mutation in the protease gene was found to have significantly higher fitness than the drug sensitive strains. The following mutations associated with resistance to reverse transcriptase inhibitors were found to be less fit than the sensitive strains: 67N, 70R, 184V, 219Q. For the remaining resistance mutations included in this study, all the mutations did not have a significant effect on viral transmissibility within the Swiss HIV cohort. In conclusion, the authors present a phylogenetic approach that allows direct quantification of population-level fitness costs of HIV resistance mutations from viral sequence data alone. Hence, this approach may become particularly useful in assessing the risk of transmitted drug resistance in resource limited settings where resistance testing is possible but epidemiological, demographic and clinical data are missing. Furthermore, this new approach is not only applicable to HIV but to any measurably evolving pathogen. | ||
| 12th July | change in the staff of the SHCS coordination centre |  |
Mirjam Minichiello will leave the SHCS at the end of July 2018 after 6 years of dedicated work for the cohort. It was a great pleasure to work with Mirjam. We highly appreciated her warm and open-hearted personality as well as her very competent way of working. She will begin her new period of live with a journey through Asia - travelling with her family for 3 months. Have fun! Mirjam, we will miss you! Marianne Amstad will take over Mirjam's job. In order to guarantee a smooth handover, Marianne already started on 1st July 2018. Please address your mails to marianne.amstad@usz.ch from now on. Welcome to the SHCS coordination centre, Marianne. We wish Mirjam all the best for the future and Marianne a good start in the cohort. | ||
| 4th July | Marzel et al., Diet and exercise in HIV-positive people | |
Marzel et al. et al. aimed (1) to describe the predictors of total cholesterol in an aging HIV-positive population living in a resource-rich setting; (2) describe the major dietary patterns of this population; (3) and examine whether behavioral determinants such as dietary patterns and physical activity independently correlate with total cholesterol after adjustment for highly active ART, lipid-lowering drugs, and other confounders. Information on diet was obtained by a short and validated Food-Frequency Questionnaire (FFQ) among patients ≥45 years old. Linear mixed-effects model with per center random intercept was used to assess the correlation between dietary patterns and total cholesterol. In total, 395 patients were included. Forty percent (158 of 395) had elevated total cholesterol (>5.2 mmol/L), and 41% (164 of 395) were not regularly physically active. In multivariable analysis, 2 factors were positively associated with total cholesterol; female sex (β = 0.562; 95% confidence interval [CI], 0.229–0.896) and the combined consumption of meat, refined/milled grains, carbonated beverages, and coffee (β = 0.243; 95% CI, 0.047–0.439). On the other hand, regular physical activity (β = −0.381; 95% CI, −0.626 to −0.136), lipid-lowering drugs (β = −0.443; 95% CI −0.691 to −0.196), ART containing tenofovir (β = −0.336; 95% CI−0.554 to −0.118), and black ethnicity (β = −0.967; 95% CI −1.524 to −0.410) exhibited a negative association. In summary, this cross-sectional study suggests that there are independent associations between certain dietary patterns and physical activity with total cholesterol. Physical activity should be substantially scaled up in this population to meet WHO guidelines and to achieve cardiovascular and other health benefits. The reported dietary patterns pave the way for further investigations in in prospective cohort studies and randomized controlled trials. | ||
| 20th June | Kadelka et al., Shifted antibody responses in HIV-1 bnAb inducers | |
Kadelka et al. aimed to define immune regulatory principles that underlie the link between the identified factors and broadly neutralizing antibodies (bnAb) evolution. Building on the systematic survey of bnAb activity in 4,484 chronically HIV-1–infected individuals (“Swiss 4.5K Screen”), the authors established comprehensive antibody signatures based on IgG1, IgG2, and IgG3 activity to 13 HIV-1 antigens in the Swiss 4.5K Screen cohort. They showed that the same four parameters that were significantly linked with neutralization breadth, namely viral load, infection length, viral diversity, and ethnicity, also strongly influenced HIV-1– binding antibody responses. However, the effects proved selective, shaping binding antibody responses in an antigen and IgG subclass–dependent manner. IgG response landscapes in bnAb inducers indicated a differentially regulated, IgG1-driven HIV-1 antigen response, and IgG1 binding of the BG505 SOS IP trimer proved the best predictor of HIV-1 neutralization breadth in plasma. In conclusion, the IgG1-driven landscape of HIV specific responses in potent neutralizers identified in this study unveils the need of creating a specific immune regulatory environment for the development of neutralization breadth. Deciphering the basis of these regulatory shifts will be important to determine the triggers of this bnAb-favoring environment in forthcoming HIV pathogenicity studies and vaccine trials and to explore how this environment can be induced and maintained in healthy individuals to make bnAb-based vaccines possible. | ||
| 18th June | Hatleberg et al., Cardiovascular interventions in HIV-positive persons | |
Hatleberg et al. on behalf of the D:A:D study group aimed to investigate potential gender differences in the use of cardiovascular interventions in HIV-positive persons. Cardiovascular disease (CVD) interventions included lipid-lowering drugs (LLDs), angiotensin-converting enzyme inhibitors (ACEIs), anti-hypertensives, and invasive cardiovascular procedures (ICPs). Women (n = 12’955) were generally at lower CVD risk than men (n = 36,094). Overall, initiation rates of CVD interventions were lower in women than men; LLDs: incidence rate 1.28 vs. 2.40; ACEIs: 0.88 vs. 1.43; anti-hypertensives: 1.40 vs. 1.72 and ICPs: 0.08 vs. 0.30. This was also true for most CVD interventions when exclusively considering periods of follow-up for which individuals were at high CVD risk. In fully adjusted models, women were less likely to receive CVD interventions than men (LLDs: relative rate 0.83; ACEIs: 0.93; ICPs: 0.54) except for the receipt of anti-hypertensives (1.17). In conclusion, the study shows that HIV-positive women were less likely than men to receive most CVD-related interventions, with the exception of anti-hypertensive drugs. These findings are mostly consistent with those from the general population. The reasons why women are less likely to receive interventions than men are multiple, but insufficient monitoring and awareness of CVD risk in women, and the more heterogeneous clinical presentations of CVD probably play a major role. As HIV-positive individuals in general are potentially at higher risk of CVD, further efforts are needed to ensure that both women and men are appropriately monitored for CVD risk and, if required, receive relevant CVD-related interventions. Furthermore, studies are warranted on why these gender related differences exist in the prevention and management of CVD in HIV-positive individuals. | ||
| 13th June | Marzel et al., Overall impact of HIV harm reduction | |
Marzel et al. aimed to perform a quantitative evaluation of the cumulative impact of implemented harm reduction measures in Switzerland on the HIV incidence and prevalence among injecting drug users (IDUs). For that, they constructed a compartmental, deterministic transmission model represented as a nonlinear system of 32 ordinary differential equation. This model reconstructed the national epidemic into the IDUs population from the first HIV case in 1980 until 2015. The authors used phylogenetic cluster analysis of HIV-1 pol sequences to quantify the epidemic spillover from IDUs to the general population. Overall, harm reduction prevented 15’903 (range, 15’359–16’448) HIV infections among IDUs until the end of 2015, 5’446 acquired immune deficiency syndrome (AIDS) deaths (range, 5’142–5’752), and a peak HIV prevalence of 50.7%. Introduction of harm reduction 2 years earlier could have halved the epidemic, preventing 3’161 (range, 822–5’499) HIV infections and 1’468 (range, 609–2’326) AIDS deaths. Suddenly discontinuing all harm reduction in 2005 would have resulted in outbreak re-emergence with 1’351 (range, 779–1’925) additional HIV cases. Without harm reduction, the estimated additional number of heterosexuals infected by HIV-positive IDUs is estimated to have been 2’540 (range, 2’453–2’627), which is equivalent to the total national reported incidence among heterosexuals in the period of 2007 to 2015. In conclusion, the proposed model estimated that a very high prevalence of HIV (~50%) among IDUs would have occurred in the absence of harm reduction. The study-results highlight, based on the Swiss experience, the pivotal role of harm reduction for successful curbing of HIV transmission among IDUs and prevention of grave repercussions for the general population. | ||
| 6th June | Collins et al., Switch to second-line ART in children | |
Collins et al. on behalf of the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) Study Group in EuroCoord aimed to assess time to switch to second-line antiretroviral therapy (ART) for any cause and associated factors in the context of routine viral load (VL) monitoring among cohorts across 16 European countries and Thailand. Children aged Of 3’668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7–10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%–23%), with significant regional variations. Median time to switch was 30 (IQR, 16–58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher VL at ART start, and NVP-based initial regimens were associated with increased risk of switch. In conclusion, in this cohort of children with routine VL monitoring, a fifth had switched to second-line ART whereas the large majority remained on their first-line regimen at 5 years of ART. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch. The estimates of this study provide an insight on the expected use of second-line regimens as the global pediatric HIV population matures and access to VL monitoring expands. A commitment to the availability of affordable pediatric drugs with high resistance barriers and low pill burden will be essential to ensure these needs are met. | ||
| 31st May | Caniglia et al., What cART to start and neuroAIDS | |
Caniglia et al. on behalf of the HIV-CAUSAL Collaboration aimed to investigate the potential effect of commonly prescribed combination antiretroviral therapy (cART) regimens among HIV-infected individuals from Europe and the Americas on the clinical diagnoses of the following 4 neuro AIDS conditions: HIV dementia and the opportunistic infections toxoplasmosis, cryptococcal meningitis, and progressive multifocal leukoencephalopathy. The analysis was restricted to previously ART–naïve HIV-positive individuals who initiated a first-line cART regimen in 2004 or later containing a nucleoside reverse transcriptase inhibitor (NRTI) backbone and either boosted atazanavir, boosted lopinavir, boosted darunavir, or efavirenz. Only a small number of individuals started cART with integrase strand transfer inhibitors (InSTIs) and were therefore excluded. 26’172 individuals initiated efavirenz, 5’858 initiated atazanavir, 8’479 initiated lopinavir, and 4’799 initiated darunavir. Compared with efavirenz, the adjusted HIV dementia hazard ratios (95% confidence intervals) were The respective hazard ratios (95% confidence intervals) for the combined end point were The results varied in subsets defined by calendar year, nucleoside reverse transcriptase inhibitor backbone, and age. In conclusion, the study-findings are consistent with an increased risk of HIV dementia after initiating cART regimens containing lopinavir or atazanavir and with an increased risk of neuro-AIDS opportunistic infections after initiating cART regimens containing lopinavir, compared with efavirenz. However, the findings need to be interpreted with caution because a large proportion of the cases were diagnosed within a few months of initiation, and the increased relative risk was substantially attenuated among individuals initiating cART in 2008 or later. It is therefore possible that the increased risk found in the main analysis could be the result of changes in prescribing trends over time, prescribing InSTI-based regimens to individuals who could be at higher risk for neuro-AIDS, or starting cART at higher CD4 levels. | ||
| 30th May | Aebi-Popp et al., Contraceptive use and unintended pregnancies in the SHCS | |
Aebi-Popp et al. aimed to assess the rates of contraceptive use and the types of methods used according to the type of combination antiretroviral therapy (cART), dual contraception use, and the number of unintended pregnancies among women participating in the SHCS. The study was a cross-sectional multicentre survey including all 18 to 46 years old women from the SHCS with at least one follow-up visit after January 2012. Women were asked to complete a self-report anonymous questionnaire on contraceptive methods, adherence to them, and unintended pregnancies. Of 462 women included, 164 (35.5%) reported not using any contraception. Among these, 65 (39.6%) reported being sexually active, although 29 (44.6%) were not planning a pregnancy. Of 298 women using contraception, the following methods were reported: condoms, 219 (73.5%); oral hormonal contraception, 32 (10.7%); and intrauterine devices, 28 (9.4%). Among all women on contraception, 32 (10.7%) reported using more than one contraceptive method and 48 (16%) had an unintended pregnancy while on contraception (18, condoms; 16, oral contraception; 4, other methods). Of these, 68.1% terminated the pregnancy and almost half (43.7%) continued using the same contraceptive method after the event. In conclusion, the use of effective contraception is challenging in HIV-positive women of reproductive age. HIV care physicians should be attentive both to women’s choices and to their needs for contraception. In Switzerland, condoms remained the predominant reported contraceptive method, with a high rate of unintended pregnancies, despite clear contraindications/restrictions on hormonal contraception and IUDs for HIV-positive women. Health care providers should discuss all available possibilities, with a particular emphasis on prescribing oral and long-acting reversible contraceptives with low interactions with cART. | ||
| 24th May | Efsen et al., Management of HIV-positive patients with MDR-TB in Eastern Europe | |
Efsen et al. on behalf of the TB: HIV study in EuroCoord aimed to describe the tuberculosis (TB) treatment regimens of patients with multi-drug resistant (MDR) TB and use of antiretroviral therapy (ART) in Eastern Europe. MDR-TB was defined as TB resistant to rifampicin and isoniazid, whereas extensively drug-resistant tuberculosis (XDR-TB) had additional resistance against a fluoroquinolone and a second-line injectable drug. Overall, 105 HIV-positive patients had MDR-TB (including 33 with extensive drug resistance) and 130 pan-susceptible TB. Adequate initial TB treatment was provided for 8% of patients with MDR-TB compared with 80% of those with pan-susceptible TB. By twelve months, an estimated 57.3% (95% CI 41.5– 74.1) of MDR-TB patients had started adequate treatment. While 67% received ART, HIV-RNA suppression was demonstrated in only 23%. In conclusion, the study shows that in Eastern Europe there is an urgent need for access to rapid diagnostics to guide initial TB treatment, to extend susceptibility testing to all patients diagnosed with rifamycin-resistant or MDR-TB and to provide better access to second line drugs to allow the administration of optimally active MDR-TB regimens. Integration of TB and HIV services can ensure better management and support for people with HIV who frequently have IDU and hepatitis C virus coinfection, including rapid initiation of fully suppressive ART. | ||
| 23rd May | Dolutegravir containing ART regimens in HIV-1-infected pregnant women and their infants | |
Due to actual reasons, the press release of this week summarizes the latest news of the IMPACT 2010 study, investigating the efficacy and safety of dolutegravir containing antiretroviral therapy in pregnant women. So far, productive toxicology studies and other data on the use of dolutegravir in pregnancy, including data from the Antiretroviral Pregnancy Registry (APR), clinical trials and post-marketing use did not indicate a risk of neural tube defects. The IMPACT 2010 study was launched by the National Institute of Healthy, is a phase 3 study, and aimed to enroll 639 women who are 14 to 18 weeks pregnant, are living with HIV, and are not currently taking antiretroviral treatment. The women were randomly assigned to be administered efavirenz/emtricitabine/tenofovir fumarate disoproxil (EFV/FTC/TDF), dolutegravir/FTC/tenofovir alafenamid fumarate (DTG/FTC/TAF), or DTG/FTC/TDF. Their infants were also enrolled in the study and received local standard-of-care interventions for HIV prophylaxis following birth. Both the women and their infants were followed for 50 weeks after delivery. Participating clinical trial sites included the United States, Zimbabwe, Botswana, Brazil, Haiti, India, Malawi, South Africa, Tanzania, Thailand, and Uganda. The final results of the study are expected in about a year. So far, the study looked at babies born to 11’558 HIV-infected women in Botswana and showed that 0.9% of babies (4 of 426) whose mothers became pregnant while taking dolutegravir had a neural tube defect, compared with 0.1% of babies (14 of 11’173) whose mothers took other HIV medicines. No cases were reported in infants born to women who started dolutegravir later during pregnancy. In conclusion, this preliminary data suggest that the potential safety issue arises from a woman’s exposure to dolutegravir at the time of conception, rather than during pregnancy. Currently, there is no evidence of any infant born with a neural tube defect to a woman who started dolutegravir during her pregnancy. As a precaution, healthcare are advised of the following:
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| 17th May | Santos et al., Effectiveness of boosted PI-based therapy in Europe | |
Santos et al. on behalf of the EuroSIDA study group aimed to evaluate the long-term effectiveness of different protease inhibitor (PI) containing regimens initiated at various stages during participants’ antiretroviral therapy (ART) history and the factors associated with virological failure (VF), treatment discontinuation, and CD4 cell count recovery in a large European cohort of HIV-1-infected patients. Data were analysed for 5’678 EuroSIDA-enrolled patients starting a darunavir/ritonavir (DRV/r)-, atazanavir/ritonavir (ATZ/r)- or lopinavir/ritonavir (LPV/r)-containing regimen between 1 January 2000 and 30 June 2013. VF was defined as two consecutive viral load measurements >200 copies/mL ≥24 weeks after PI/r initiation. Of these 5678 patients, a total of 431 (8%) were ART-naïve patients of whom 220 (51%) were receiving LPV/r, 119 (28%) were on ATZ/r, and 92 (21%) were on DRV/r-based regimens. The median (IQR) time of follow-up was 28 (11–57) months. The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log-rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART-naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment-experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r-based ART. Injecting drug use, higher HIV-1 RNA at baseline, black ethnicity, having historic genotyping tests available, and a higher number of prior failures on non-PI-based ART were independent predictors of an increased hazard of VF. The risk of PI/r discontinuation for any reason was > 2.5 times higher in patients who started LPV/r-based ART than in those initiating a DRV/r-based ART, while no significant difference was observed when ATZ/r and DRV/r regimens were compared. In summary, assuming no unmeasured confounding factors, the long-term effectiveness of boosted PI-containing regimens in ART-experienced subjects appears to be greater in people receiving DRV/r than in those receiving ATZ/r and LPV/r. The same tendency was observed in ART-naïve patients, although the analysis was likely to be underpowered in this population. Strategies to improve clinical care and treatment response continue to be necessary in some subsets of the HIV-infected population such as women, injecting drug users, hepatitis virus-coinfected patients and ethnic minorities. | ||
| 16th May | Raisaro et al., Privacy-enhancing technologies for genomic data | |
Raisaro et al. aimed to describe end-users’ perception of genome privacy and their attitude toward the use of sophisticated PETs in an operational clinical setting. The participating physicians had access to the system for privacy-preserving genetic testing through a Java front-end application installed at each of the participating SHCS hospitals. The application included a graphical user interface enabling physicians to select patients using a unique identifier and the genetic tests to be performed on the patient’s encrypted genotype. The request was then sent to the system back-end deployed at the Data Center in Lausanne. Patients’ genomic data were never decrypted and the encrypted test results were returned to the local front-end for decryption. A standardized text report indicated an increased or decreased risk of the tested trait due to genetic factors, or a result of “no relevant alleles found” was presented to the physician. After using the system, the physicians were asked to answer an electronic survey directly embedded in the front-end application. Overall, 38 out of 55 (69%) physicians participated in the study. Two thirds of them acknowledged genetic privacy as a key aspect that needs to be protected to help building patient trust and deploy new-generation medical information systems. All of them successfully used the tool for evaluating their patients’ pharmacogenomics risk and 90% were happy with the user experience and the efficiency of the tool. Only 8% of physicians were unsatisfied with the level of information and wanted to have access to the patient’s actual DNA sequence. In conclusion, this survey represents the first evaluation of privacy-preserving models for genomic-based medicine. In particular, the study-results show that a clinical information system that uses homomorphic encryption to provide clinicians with risk information based on sensitive genetic test results can offer information that clinicians feel sufficient for their needs and appropriately respectful of patients’ privacy. The study presented here derives unique insights that maybe will guide the design and facilitate the adoption of these systems in the future, by better addressing physicians’ requirements. | ||
| 9th May | Anderegg et al., Immunodeficiency at cART Initiation | |
Anderegg et al. on behalf of IeDEA and COHERE examined global trends in CD4 cell counts at combination antiretroviral therapy (cART) initiation among adults from low-income (LICs), lower-middle-income (LMICs), upper-middle-income (UMICs), and high-income (HICs) countries. A total of 951’855 adults were included. Overall, the modeled median CD4 cell count at the start of cART increased from 2002 to 2015, from 78/μL to 287/μL in LICs, In LICs, LMICs, and UMICs, the increase was more pronounced in women; in HICs, the opposite was observed. There were important differences between regions: the estimated median CD4 cell count in 2014 among individuals starting cART in North America rose to 435/μL in 2014; at the other end of the spectrum, it was 186/μL in individuals starting cART in West Africa in the same year. In LICs, the estimated proportion of adults starting with severe immunodeficiency (= CD4 cell count <200/μL) declined from 95% in 2002 to 31% in 2015. Corresponding declines were from 75% to 40% in LMICs, from 79% to 26% in UMICs, and from 59% to 29% in HICs. In conclusion, the study-results show that median CD4 cell counts at the start of cART have increased in all country income groups over the last few years, and the proportion of individuals starting cART with severe immunodeficiency has decreased. However, the median CD4 cell count at cART start generally remained below 350/μL in 2015 and the decline in severe immunodeficiency appears to have plateaued in some countries. Clearly, substantial additional efforts and resources will be needed to achieve early diagnosis, rapid linkage to care, and prompt initiation of cART globally. | ||
| 25th April | Young et al., Pill count and clinical outcome in HIV | |
Young et al. assessed whether the one-pill combination of efavirenz, emtricitabine and tenofovir reduces the risk of AIDS or death in treatment-naïve HIV-infected patients starting ART compared with two- or three-pill formulations of the same regimen. The analysis was based on data from the Antiretroviral Therapy Cohort Collaboration (ART-CC) of observational HIV-infected cohorts from Europe and Northern America to predict the potential consequences of exposing a future population to either a one-pill regimen or a three-pill regimen. Among 11’739 treatment-naïve patients starting the regimen, there were 386 AIDS events and 87 deaths. Follow-up often ended when patients switched to the same regimen with fewer pills. After the first month, two pills rather than one was associated with an increase in the risk of AIDS or death [hazard ratio (HR) 1.39; 95% confidence interval (CI) 1.01-1.91], but three pills rather than two did not appreciably add to that increase (HR 1.19; 95% CI 0.84-1.68). The authors estimated that 77 patients would need to be exposed to a one-pill regimen rather than a three-pill regimen for 1 year to avoid one additional AIDS event or death. In conclusion, the study-results show that the one-pill combination of efavirenz, emtricitabine and tenofovir was associated with a modest decrease in the risk of progression to AIDS or death compared with two- or three-pill formulations of the same regimen. However, the authors conclude that this does not imply that a single tablet regimen should be used rather than a multiple-pill formulation of the same regimen using generic drugs. Rather, the authors provided statistics that could be used to evaluate whether single tablet regimen are more cost-effective than other formulations. | ||
| 19th April | Strouvelle, Braun et al., Effect of pIFN-α on total HIV-1 DNA load | |
Strouvelle, Braun et al. aimed to examine the effect of pegylated interferon-alpha (pIFN-α) treatment in reducing total HIV-1 DNA levels in 40 HIV-1/hepatitis C virus (HCV-) coinfected patients from the Swiss HIV Cohort Study and the Zurich Primary HIV Infection Study. Unique to other studies, they included patients from 3 groups: (1) HIV-1 chronic; (2) HIV-1 acute (both stratified according to time to initiation of ART after HIV-1 infection); and (3) a no-ART HIV-1–infected group. Total HIV-1 DNA was quantified in 247 samples with a mean number of time points (range) per patient of 6.6 (2-12), 5.6 (2-10), and 5.7 (3-9) in the chronic, acute, and no-ART groups, respectively. In no-ART patients, pIFN-α treatment decreased the HIV-1 RNA viral load by 0.8 log10 on average. Pre-pIFN-α HIV-1 DNA levels were on average 0.66 log higher in the chronic versus the acute group. Total HIV-1 DNA levels remained stable before, during, and after pIFN-α treatment in all three groups. In conclusion, the study did not reveal any effect of pIFN-α on the latent reservoir as measured by total HIV-1 DNA in PBMCs. The study-results question the benefit of pIFN-α as an immunotherapeutic agent for reducing the HIV-1 latent reservoir. | ||
| 18th April | Lodi et al., Immediate initiation of antiretroviral treatment | |
Lodi et al. on behalf of the HIV-CAUSAL collaboration aimed to estimate and to compare the 7-year risks of acquired drug resistance under immediate antiretroviral therapy (ART) initiation and the previously recommended CD4+ cell count-based initiation strategies. The authors defined acquired drug resistance using the Stanford classification as resistance to any antiretroviral drug that was clinically identified at least 6 months after ART initiation. In 50’981 eligible individuals, 10% had CD4+ cell count more than 500 cells/ml at baseline, and 63% initiated ART during follow-up. Of 2’672 tests for acquired drug resistance, 794 (30%) found resistance. The estimated 7-year risk of acquired drug resistance was 3.2% for immediate initiation, 3.1% for initiation with CD4 + cell count less than 500 cells/ml, and 2.8% for initiation with CD4+ cell count less than 350 cells/ml. In analyses restricted to individuals with baseline in 2005–2015, the corresponding estimates were 1.9%, 1.9%, and 1.8%. In conclusion, the study-results show that the risk of acquired drug resistance was similar under immediate and delayed ART initiation. Compared with ART initiation with CD4+ less than 500 cells/ml or AIDS and CD4+ less than 350 cells/ml or AIDS, immediate ART initiation increased the 7-year risk of acquired drug resistance by only 0.13 and 0.37%, respectively. The estimated 7-year risk of clinically identified acquired drug resistance was approximately 3% under all ART initiation strategies. These risks and risk differences were even lower in individuals with initial CD4+ cell count more than 500 cells/ml and individuals who entered the study after 2004. | ||
| 12th April | Aebi-Popp et al., Post-treatment HCV antibody dynamics | |
Aebi-Popp et al. investigated HCV antibody level dynamics following an incident HCV infection in HIV-infected MSM with different clinical outcomes: treatment-induced sustained virological response (SVR), spontaneous clearance, and untreated HCV infection progressing to chronic infection. At baseline, median HCV antibody levels were similar in the three groups. Over 3 years of follow-up, SVR was associated with a more pronounced decrease in anti-HCV levels compared with spontaneous clearance and untreated infection [median decline 71% [interquartile range (IQR: 43–87%), 38% (IQR: 29–60%) and 12% (IQR: 9–22%), respectively; P < 0.001]. Seroreversions occurred in five of 33 (15%) patients with SVR and in one of 12 (8%) with spontaneous clearance. A shorter delay between time of infection and treatment start correlated with higher rates of decline in antibody levels. Seven (16%) patients with treatment-induced or spontaneous HCV clearance experienced a reinfection, and all but one had detectable HCV antibodies before reinfection. In conclusion, SVR was associated with a more pronounced decline in anti-HCV antibody levels and with a higher frequency of seroreversions compared with spontaneous clearance or untreated replicating HCV infection among HIV-infected MSM with incident HCV infections. The high rate of reinfections in patients with detectable HCV antibodies before reinfection suggest that detectable HCV antibodies do not confer protection against reinfection. | ||
| 11th April | Tarr et al., Subclinical coronary artery disease in Swiss HIV+ and HIV- persons | |
Tarr et al. aimed to compare the prevalence of subclinical atherosclerosis in HIV-positive and HIV-negative persons in Switzerland using coronary artery calcium (CAC)/computed tomography angiography (CCTA), and to assess associations between cardiovascular risk factors, HIV infection, and subclinical coronary artery disease. They enrolled 428 HIV-positive participants of the Swiss HIV Cohort Study and 276 HIV-negative controls concurrently referred for clinically indicated CCTA. HIV-positive participants were younger than HIV-negative participants (median age 52 vs. 56 years; P < 0.01) but had similar median 10-year Framingham risk scores (9.0% vs. 9.7%; P = 0.40). The prevalence of CAC score > 0 (53% vs. 56.2%; P = 0.42) and median CAC scores (47 vs. 47; P = 0.80) were similar, as was the prevalence of any, non-calcified/ mixed, and high-risk plaque. In multivariable adjusted analysis, HIV-positive participants had a lower prevalence of calcified plaque than HIV-negative participants [36.9% vs. 48.6%, P < 0.01; adjusted odds ratio (aOR) 0.57; P < 0.01], lower coronary segment severity score (aOR 0.72; P = 0.04), and lower segment involvement score (aOR 0.71; P = 0.03). Advanced immunosuppression was associated with non-calcified/mixed plaque (aOR 1.97; P = 0.02). In conclusion, in this study HIV infection was not associated with more subclinical atherosclerosis. On the contrary, HIV was associated with less calcified coronary plaques and lower coronary atherosclerosis involvement and severity scores than HIV-negative persons with similar Framingham risk scores. In addition, the study found no evidence of advanced coronary age in HIV-positive patients, and thus was unable to confirm previous reports. Taken together, these reports somewhat attenuate concerns about accelerated subclinical atherosclerosis in HIV-positive persons. | ||
| 5th April | Rasmussen et al., Phylodynamics on networks | |
Phylodynamic models are widely used in infectious disease epidemiology to infer the dynamics and structure of pathogen populations. However, these models generally assume that individual hosts contact one another at random, ignoring the fact that many pathogens spread through highly structured contact networks. In the current work, Rasmussen et al. presented a new framework for phylodynamics on local contact networks based on pairwise epidemiological models that track the status of pairs of nodes in the network rather than just individuals. By considering how local interactions among hosts shape the phylogeny of a pathogen, their models offered a “pathogen's eye view” of these networks. By considering pathogen phylogenies in a probabilistic framework, these coalescent models could also be used to estimate the statistical properties of contact networks directly from phylogenies using likelihood-based inference. The authors used this framework to explore how much information phylogenies retain about the underlying structure of contact networks and to infer the structure of a sexual contact network underlying a large HIV-1 sub-epidemic in Switzerland. In conclusion, the authors provided a simple theoretical framework to explore the relationship between contact networks, epidemic dynamics, and phylogenies. They showed that phylodynamic modeling framework provides a good approximation to the coalescent process on random networks and can recapitulate the major features of pathogen phylogenies simulated on different types of random graphs. | ||
| 4th April | Congratulations! | |
This shows that research conducted in the SHCS is continuously highly competitive and is considered worth to be funded! Best wishes, Huldrych Günthard | ||
| 28th March | Prague et al., Dynamic models for estimating the effect of HAART on CD4 in observational studies | |
Prague et al. aimed to estimate the effect of HAART on CD4 count using four dynamic models and compared estimates with those from a naive regression model. In their work, they presented three discrete-time dynamic models based on linear increments models (LIM): the first one based on one difference equation for CD4 counts, the second with an equilibrium point, and the third based on a system of two difference equations, which allowed jointly modeling CD4 counts and viral load. The authors considered continuous-time models based on ordinary differential equations with non-linear mixed effects (ODE-NLME). They compared the different approaches in simulation and in illustration on the ANRS CO3 Aquitaine Cohort and the Swiss HIV Cohort Study. The authors found that the proposed mechanistic models allowed incorporating biological knowledge when available, which lead to increased statistical evidence for detecting treatment effect. Because inference in ODE-NLME was numerically challenging and required specific methods and softwares, LIM were a valuable intermediary option in terms of consistency, precision, and complexity. | ||
| 22nd March | Nakagawa et al., Estimating number living with HIV in the United Kingdom | |
Nakagawa et al. aimed to demonstrate a novel approach using a mathematical model with the United Kingdom (UK) as an example, to present key public health outputs on the national level, including the size of the undiagnosed population and HIV incidence. They used an individual-based stochastic simulation model to calibrate to routinely collected surveillance data in the UK. An estimated 106’400 people were living with HIV in the UK in 2013. Twenty-three percent of these people, 24’600 (90% plausibility range: 15’000–36’200) were estimated to be undiagnosed; this number has remained stable over the last decade. An estimated 32% of the total undiagnosed population had CD4+ cell count less than 350 cells/ml in 2013. Twenty-five and 23% of black African men and women heterosexuals living with HIV were undiagnosed respectively. In conclusion, the authors presented a method to generate national-level estimates about the size and characteristics of HIV-positive populations incorporating migrants from sub-Saharan Africa. These estimates should help inform and evaluate current and future public health responses to the epidemic by providing more information about the affected population than can be understood and achieved solely from surveillance. | ||
| 21st March | McLaren et al., Exome sequencing and HIV-1 control | |
Human genetic variation plays a large role in determining the outcome of HIV-1 infection. However, common, genome-wide genetic factors identified by genome-wide association studies can only explain up to 25% of the observed variability in HIV setpoint viral load. To assess the evidence for an additional impact of functional variation in HIV progression, McLaren et al. combined exome sequence data across 5 independent studies that evaluated 3 related models of HIV control in a total of 1’327 individuals with high-quality data. The authors found that multiple single variants within the major histocompatibility complex (MHC) region were observed to be strongly associated with HIV-1 outcome, consistent with the known impact of classical HLA alleles. However, no single variant or gene located outside of the MHC region was significantly associated with HIV progression. Set-based association testing focusing on genes identified as being essential for HIV replication in genome-wide small interfering RNA and clustered regularly interspaced short palindromic repeats (CRISPR) studies did not reveal any novel associations. In conclusion, the study-results suggest that exomic variants with large effect sizes are unlikely to have a major contribution to host control of HIV infection. | ||
| 15th March | Monge et al., Immunovirological response to cART in migrants | |
Monge et al. on behalf of COHERE in EuroCoord aimed to evaluate differences in immunovirological response to combination antiretroviral therapy (cART) in migrant and native men and women. Of 32’817 individuals, 25’799 (78.6%) were men. The percentage of migrants was higher in women (48.9%) than in men (21.2%) and migrants from sub-Saharan Africa accounted for the largest migrant group (29.9% in men and 63.3% in women). Migrant men and women from sub-Saharan Africa started at lower CD4 cell counts than native individuals, which remained lower over time. Virological response was ≥ 85% at 12 months for all groups except Caribbean women (77.7%). Compared with native individuals men and women, lower virological response was experienced by North Africa and the Middle East (subdistribution hazard ratios [sHR] 0.91] and sub-Saharan Africa (sHR 0.88) men and Caribbean (sHR 0.77) women, respectively. In conclusion, immunovirological response to cART in Western Europe varies by geographical origin and sex of patients. The study-results have implications for clinical management and policy changes regarding earlier HIV testing and cART entitlement; they can help clinicians be alert to particular groups, especially women, who will require extra support with their treatments. | ||
| 14th March | Boyd et al., Combined CVD and CKD risk in the D:A:D study | |
The D:A:D study has developed specific models to predict the risk for CVD and CKD events in HIV-positive people. Boyd et al. on behalf of the D:A:D study aimed to study whether participants in D:A:D at high (>5%) predicted risk for both cardiovascular disease (CVD) and chronic kidney disease (CKD) would be at even greater risk for CVD and CKD events. CKD was defined as confirmed estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2. The authors calculated the CVD and CKD event rates by predicted 5-year CVD and CKD risk groups (≤1%, >1%±5%, >5%). A total of 27,215 participants contributed 202,034 person-years of follow-up. Participants at high CVD risk had a 5.63-fold (p < 0.001) increase in CKD events compared to those at low risk; participants at high CKD risk had a 1.31-fold (p = 0.005) increase in CVD events compared to those at low risk. Participants' CVD and CKD risk groups had multiplicative predictive effects, with no evidence of an interaction. In conclusion, the study found that people at high predicted risk for both CVD and CKD have substantially greater risks for both CVD and CKD compared with those at low predicted risk for both, and those at high predicted risk for only CVD or only CKD. This suggests that CVD and CKD risk in HIV-positive persons should be assessed together. The results should further encourage clinicians to prioritize addressing modifiable risks for CVD and CKD in HIV-positive people. | ||
| 5th March | Wittkop et al., CD4 cell count response to first-line cART in HIV-2+ versus HIV-1+ patients | |
Wittkop et al. on behalf of the COHERE in EuroCoord and the ACHIeV2e Study Group aimed to assess CD4 cell recovery following first-line combination ART (cART) in HIV-2+ infected individuals compared to HIV-1+ infected individuals. ART-naive HIV+ adults were included, if they started first-line combination antiretroviral therapy (without NNRTIs or fusion inhibitors) between 1997 and 2011. Overall, the study included 185 HIV-2+ and 3’0321 HIV-1+ patients with a median age of 46 years and 37 years, respectively. Median observed pretreatment CD4 cell counts/mm3 were 203 in HIV-2+ patients and in HIV-1+ patients. Mean observed CD4 cell count changes from start of cART to 12months were 105 in HIV-2 patients and 202 in HIV-1 patients, an observed difference of 97 cells/mm3 in 1 year. In adjusted analysis, the mean CD4 cell increase was overall 25 CD4 cells/mm3/year lower in HIV-2 patients compared with HIV-1 patients. In conclusion, differences in CD4 cell dynamics between HIV-2 and HIV-1 were consistent in all analyses, with a poorer CD4 cell increase after start of treatment in HIV-2 patients, even after adjustment for pretreatment plasma viral load. The study-results underline the need to identify other factors contributing to this lower CD4 cell response, such as more potent drugs against HIV-2, adapted to the particularities of the virus replication when compared with HIV-1, in order to improve case management. | ||
| 1st March | Veit et al., Yellow fever vaccine in HIV-infected individuals | |
Veit et al. studied the immune response over time to yellow fever vaccination (YFV) and the necessity for booster vaccination in 247 HIV-infected individuals from the Swiss HIV Cohort Study. A plaque reduction neutralization titer (PRNT) of 1:≥10 was regarded as reactive and protective. At vaccination, 82% of the vaccinees were taking combination antiretroviral therapy (cART), 83% had suppressed HIV RNA levels (<400 copies/mL), and their median CD4 T-cell count was 536 cells/μL. PRNT was reactive in 46% before, 95% (95% CI, 91%–98%) within 1 year, 86% at 5 years, and 75% at 10 years postvaccination. In those with suppressed plasma HIV RNA at YFV, the proportion with reactive PRNTs remained high: 99% within 1 year, 99 at 5 years, and 100% at 10 years. In conclusion, the study-results suggest that long-term immune response up to 10 years to YFV is primarily dependent on the control of HIV replication at the time of vaccination. Vaccinees on successful cART had high levels of reactive PRNT, and protective titers were maintained up to 10 years. The results point toward acceptable safety of YFV in HIV-infected individuals on cART. Until further data on long-term immunity are available, the authors recommend that HIV-infected patients should be vaccinated against YF once their HIV RNA is suppressed and receive a YFV booster after 10 years if they stay on uninterrupted successful cART to restimulate the vaccine response. However, HIV-infected persons who were vaccinated with replicating HIV should either have their PRNT measured or receive a booster YFV while on successful cART, irrespective of time elapsed since primary YFV. | ||
| 28th February | Congratulations to Gilles Wandeler! | |
Towards the functional cure of hepatitis B virus infection Congratulations to Gilles Wandeler! Great to have you on board Gilles, and we wish you all the best for this exciting project! Kind regards, Huldrych Günthard, | ||
| 22nd February | Thorne et al., Coinfection with HIV and HCV in children and young adults living in Europe | |
Thorne et al. on behalf of EuroCoord aimed to conduct a study of HIV/hepatitis C virus (HCV) coinfection in children, adolescents and young adults infected with HIV/HCV vertically or before age 18 years to characterize this subpopulation with respect to mode of acquisition, HCV genotype, clinical status and treatment. Of 229 patients included, 62% had vertically acquired infection. Median age at last follow-up was 16.2 years. Most children had HCV genotype 1 (55%) or 3 (31%). One-fifth had a previous AIDS diagnosis. At their last clinic visit, 70% had no/mild immunosuppression (CDC stage 1), and 73% on antiretroviral therapy had undetectable HIV RNA. Overall, 55% had alanine aminotransferase levels of more than 40 IU/l at their last test. Of 97 patients with transient elastography, 12 had results of more than 9 kPa; this was associated with duration of HCV infection (P=0.033), but not with CD4+ cell count, antiretroviral therapy use or sex in univariable analysis. Of 17 patients with liver biopsies, six had bridging fibrosis and one had cirrhosis. The SVR24 rates among the individuals treated with pegylated interferon and ribavirin were 32% (8/25) for genotype 1 and 79% (15/19) for genotype 3; the one treated patient with genotype 2 achieved an SVR24, but none of the three treated patients with genotype 4 did so. In conclusion, the current study is the first one describing a large population of HIV/HCV coinfected children and young people across Europe. As clinical management of coinfected children has previously relied on extrapolation from adult studies, the findings will contribute to better understanding of this coinfection in childhood. The study describes a substantial proportion of HIV/HCV coinfected children and young people with progressive liver disease, with low response to standard treatment with pegIFN/RBV among the minority treated to date. Considering this, the improved life expectancy in HIV-infected children and the excellent outcomes in adults with HIV/HCV infection treated with direct acting agents, illustrate the need for these HCV treatments in HIV/HCV coinfected children. | ||
| 21st February | Ryom et al., eGFR after chronic renal impairment | |
Ryom et al. on behalf of the D:A:D study group aimed to investigate the improvement in estimated glomerular filtration rate (eGFR) after development of chronic renal impairment (CRI) in HIV-positive individuals. The median of all eGFRs measured 24–36 months after CRI was compared with the median eGFR defining CRI, and changes were grouped into improvement (>+10 ml/min), stabilization (-10 to +10 ml/min) and progression ( Of 2006 individuals developing CRI, 21% subsequently improved eGFR, 67% stabilized and 12% progressed. Individuals remaining on tenofovir (TDF) or atazanavir boosted with ritonavir ATV/r 24 months post-CRI had worse eGFR outcomes compared with those unexposed (TDF: 0.47 and ATV/r: 0.63). Individuals off TDF for 12-24 months or off ATV/r for more than 12 months had similar eGFR outcomes as those unexposed to these antiretrovirals. Older age, hypertension, later date of CRI and diabetes were associated with worse eGFR outcomes. In conclusion, the study-results suggest that eGFR improvement after CRI is relatively common, with one in five individuals experiencing significant eGFR improvement, and 23% experiencing complete resolution of CRI. Likewise, most HIV-positive individuals progressing to CRI subsequently stabilized eGFR at moderate levels of renal impairment rather than continued to decline. These observations offer reassurance for HIV-positive persons and their healthcare providers, as it seems that at least some of the excess renal risk among HIV-positive persons can be modified with appropriate management. | ||
| 14th February | Rhee et al., Mutational correlates of virological failure in individuals receiving WHO-recommended tenofovir-containing regimen | |
Tenofovir disoproxil fumarate (TDF) genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure on a WHO-recommended TDF-containing first-line regimen. Rhee et al. aimed to identify TDF regimen-associated mutations (TRAMs) by comparing the proportion of each reverse transcriptase mutation in 2’873 individuals with virological failure on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50’803 antiretroviral-naïve individuals. The authors identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen: A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F. In conclusion, the study shows that the spectrum of TDF-selected mutations extends beyond K65R/N and K70E/G/Q. Several of the additional TDF-selected mutations are non-polymorphic mutations that are currently not considered surveillance drug resistance mutations yet may be important for monitoring TDF associated transmitted drug-resistance. Additionally, the clinical significance of several mutations that occurred commonly in combination with K65R including A62V, S68G/N/D, L74I, V75L and Y115F requires further phenotypic and clinical studies to better understand their effects on both TDF and the newly developed prodrug tenofovir alafenamide (TAF). | ||
| 1st February | Caniglia et al., Comparison of monitoring strategies based on CD4 cell counts in virally suppressed HIV-positive individuals | |
Caniglia et al. on behalf of the HIV-CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems aimed to establish whether information about an individual’s time-varying CD4 cell count can provide any additional benefit in determining when monitoring frequency can be decreased. The authors compared three strategies using different CD4 cell count thresholds to determine whether CD4 cell count and HIV RNA viral load was measured every 3–6 months (when below the threshold) or every 9–12 months (when above the threshold). The threshold was 200 cells per μL in the first strategy, 350 cells per μL in the second strategy, and 500 cells per μL in the third strategy. They found that the different strategies had no effect on survival, AIDS-free survival, and mean CD4 cell count at 2 years, suggesting that decreasing monitoring to annually when CD4 count is higher than 200 cells per μL compared with higher than 500 cells per μL does not worsen the short-term clinical and immunological outcomes of HIV-positive individuals with viral suppression. However, the authors found that decreasing monitoring frequency when CD4 count is higher than 200 cells per μL compared with higher than 500 cells per μL results in an increased risk of virological failure at 2 years. Compared with threshold 500, the 24 month risk ratios of virological failure (viral load more than 200 copies per mL) were 2.01 (1.17–3.43) for threshold 200 and 1.24 (0.89–1.73) for threshold 350. In conclusion, the study-results suggest that in virologically suppressed individuals on ART in resource-rich settings, the CD4 threshold at which monitoring frequency can be decreased to annually might be as low as 200 cells per μL with no effect on clinical and immunological outcomes after 2 years. However, more frequent virological monitoring might be necessary to reduce the risk of virological failure. Further research is warranted to obtain more precise effect estimates over longer periods of follow-up, and to determine the generalisability of these results to resource-limited settings. | ||
| 29th January | Lodi et al., Immediate ART in older HIV positive patients | |
Clinical guidelines recommend immediate initiation of combined antiretroviral therapy for all HIV-positive individuals. However, those guidelines are based on trials of relatively young participants. Lodi et al. on behalf of the HIV-CAUSAL Collaboration of HIV cohorts from Europe and the Americas aimed to estimate the 5-year risk of all-cause mortality and non-AIDS mortality among ART-naive, AIDS-free individuals aged between 50 and 70 years. The study included 9’596 individuals (28% US Veterans) with median age of 55 (52–60) years and CD4 count of 336 (182–513) at baseline. The 5-year risk of all-cause mortality was 0.40% (95% confidence interval (CI): 0.10 to 0.71) lower for the general HIV population and 1.61% (95% CI: 0.79 to 2.67) lower for US Veterans when comparing immediate initiation vs initiation at CD4 <350 cells/mm3. The 5-year risk of non-AIDS mortality was 0.17% (95% CI: 20.07 to 0.43) lower for the general HIV population and 1% (95% CI: 0.31 to 2.00) lower for US Veterans when comparing immediate initiation vs initiation at CD4 <350 cells/mm3. In conclusion, immediate initiation of ART seems to be beneficial in reducing all-cause mortality in AIDS-free patients aged 50 years or older, despite their low baseline CD4 count. More effort should be made into diagnosing HIV earlier, particularly in older patients to ensure timely initiation of treatment and follow-up for concomitant comorbidities, thereby maximizing the benefit of early treatment for HIV. | ||
| 25th January | Leitman et al., HLA-B*14:02-env-restricted CD8+ T-cells in HIV control | |
Immune control of HIV infection is typically associated with effective Gag-specific CD8+ T-cell responses. To investigate further the potential role of non-Gag-specific CD8+ T-cell responses in control of HIV infection, Leitman et al. focused here on HLA-B*14, where the dominant HIV-specific CD8+ T-cell response is in Env but not Gag specific. The authors demonstrated that Env-specific HLA-B*14-restricted activity was substantially more efficacious than the subdominant HLA-B*14-restricted Gag response. Env immunodominance over Gag and strong Env-mediated selection pressure on HIV were observed only in subjects expressing HLA-B*14:02, and not HLA-B*14:01. This was reflected by an increased functional avidity of the Env response over Gag, substantially more marked for HLA-B*14:02. Finally, they showed that HLA-B*14:02 was significantly more strongly associated with viremic control than HLA-B*14:01. In conclusion, the studies indicate that, although Gag-specific CD8+ T-cell responses may usually have greater antiviral efficacy against HIV for the several reasons described above, influences such as functional avidity of individual responses are also critically important factors that may override protein specificity in contributing to immune control of HIV infection. This finding is relevant to the development of vaccines designed to generate effective antiviral CD8+ T-cell responses. | ||
| 18th January | Del Amo et al., Educational level and response to antiretroviral treatment | |
Del Amo et al. on behalf of COHERE in Euro-Coord aimed to investigate differences by educational level in virological and immunological response to combined antiretroviral treatment (cART), as well as incidence of all-cause mortality and new AIDS-defining events in HIV-positive men and women in COHERE data from 1996 to 2013. Of 24’069 HIV-positive patients, 9% had not completed primary education, 32% had completed primary, 44% secondary, and 15% tertiary education. Overall, 21% were women, who were overrepresented in lower educational strata. During 132’507 person-years of follow-up, 1’081 individuals died; cumulative mortality decreased with higher educational level (P<0.001). Over 122 765 person-years, new AIDS events or death occurred in 2598 individuals; differences by education were more marked than for death alone (P<0.001). Virological response was achieved by 67% of patients without completed basic education, 85% with completed primary education, 82% with secondary, and 87% with tertiary (P<0.001). Patients with higher education had higher CD4+ cell count at cART initiation and at each time after cART but rate of CD4+ cell count recovery did not differ. In conclusion, the study-results support the argument for sustained educational efforts at the European level to improve active citizenship, social cohesion, and health impacting on the macro-level determinants. They also reinforce the need for proximal down-stream interventions on clinical and preventive care among less educated HIV-positive patients once they are linked to care to address inequities. | ||
| 17th January | Bouteloup et al., Reference curves for CD4 response | |
Bouteloup et al. on behalf of COHERE in EuroCoord aimed to provide ‘reference curves’ for CD4 T-cell responses during the first 12 months of combination antiretroviral therapy (cART) for patients with virological suppression, according to the characteristics of the patients at cART initiation. Data on 27 cohorts across 35 European countries were provided for the present analysis. All persons aged ≥ 18 years who started cART for the first time between 1 January 2005 and 1 January 2010 and who had at least one available measurement of CD4 count and a viral load ≤ 50 HIV-1 RNA copies/mL 6 months after cART initiation were included in the study. A total of 28 992 patients were included in the study. The median CD4 T-cell count at treatment initiation was 249. The median observed CD4 counts at 6, 9 and 12 months were 382, 402 and 420 cells/lL. The two main factors explaining the variation of CD4 count at 6 months were AIDS stage and CD4 count at cART initiation. A CD4 count increase of ≥ 100 cells/mL was generally required in order that patients stayed ‘on track’ (i.e. with a CD4 count at the same percentile as when they started), with slightly higher gains required for those who started with CD4 counts in the higher percentiles. In conclusion, the study proposes reference curves for the CD4 count that may be used as an additional tool for the clinician when evaluating responses to cART. A web tool is available at http://shiny.isped.u-bordeaux.fr/CD4refcurves | ||
| 11th January | Monge et al., Combined antiretroviral treatment in migrants in Europe | |
The Migrant Health Working Group on behalf of COHERE in EuroCoord aimed to evaluate differences in timing of combined antiretroviral treatment (cART) initiation by geographical origin in male and female HIV-positive patients in COHERE. They included 151 674 individuals (72.9% men) from Western Europe between January 1997 and March 2013, with known geographical origin and at least 1 CD4+ cell count measurement while cART-naïve. Median CD4+ cell count falls far below 250 cells/ml in all groups and was lowest in sub-Saharan African (SSA: 161), Caribbean men (161) and in Asian women (185). Among men, the adjusted probability of cART initiation was lower in migrants compared with natives, but differences depended on initial CD4+ cell count. In women, no meaningful differences were observed between natives and most migrant groups. However, SSA women had a 31% higher probability of cART initiation when recruited at a CD4+ more than 500 cells/ml and 9% (4–14%) lower when recruited at CD4+ less than 100 cells/ml. In conclusion, the study-results highlight late initiation of cART in the migrant population in Western Europe and differences in timing of cART initiation for some groups within migrant communities, especially for men. Addressing existing barriers to access HIV testing and care and ensuring universal and free access to cART is important to advance in the elimination of inequities and in the control of the HIV epidemic in Western Europe. | ||
| 10th January | Judd et al., Triple-class failure by age and perinatal HIV | |
Judd et al. on behalf of COHERE in EuroCoord aimed to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection. A total of 5’972 participants starting antiretroviral therapy (ART) from 1998, aged 500 HIV-1 RNA copies/mL despite ≥4 months of use. The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall (17 vs. 8 weeks) and highest in perinatally infected participants aged 10–14 years (49 weeks). The cumulative proportion with TCVF 5 years after starting ART was 9.6% in participants with perinatally acquired infection and 4.7% in participants with heterosexually acquired infection. Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10–14 years, African origin, pre-ART AIDS, NNRTI based initial regimens, higher pre-ART viral load and lower pre-ART CD4. In conclusion, for participants with perinatal HIV infection, these findings indicate the need to diagnose and start ART earlier in childhood, and adopt a strategic approach in ART selection to prevent the emergence of resistance. These measures may help children and adolescents achieve and sustain virological suppression as they approach adulthood. | ||
| 4th January | Stirrup et al., Predictors of CD4 recovery following initiation of ART | |
Stirrup et al. on behalf of CASCADE Collaboration in EuroCoord aimed to investigate factors that predict speed of recovery and long-term CD4 cell count in HIV-1 seroconverters initiating combination antiretroviral therapy (cART), and to quantify the influence of very early treatment initiation. They used data from the CASCADE multinational cohort collaboration of HIV-1 seroconverters and analysed pre- and post-treatment data of patients with seroconversion dates estimated January 2003 - March 2014 (n=7600). The authors found that “true’ CD4 count at cART initiation was the strongest predictor of CD4 count beyond 3 years on cART. CD4 recovery was more rapid for patients in whom treatment was initiated within 4 months. For a given CD4 count, higher viral load (VL) at initiation was strongly associated with higher post-treatment CD4 recovery. Use of an integrase-inhibitor regimen at treatment initiation was found to be associated with a moderate improvement in post-treatment recovery in CD4 relative to the NNRTI regimen. In conclusion, CD4 count at cART initiation is the most important factor in predicting post-treatment recovery, but VL provides substantial additional information. If cART is initiated in the first 4 months following seroconversion, recovery of CD4 counts appears to be more rapid. The finding that higher plasma VL at treatment initiation predicts more rapid CD4 cell recovers is maybe explained by some evidenced that higher VL levels are associated with sequestration of CD4 cells in lymphoid tissue and that this is associated with a more rapid initial increase in circulating CD4 cells following the initiation of cART. | ||
| 3rd January | Trickey et al., CD4:CD8 and CD8 as Markers for Mortality | |
Trickey et al. on behalf of the Antiretroviral Therapy Cohort Collaboration aimed to investigate whether the CD4:CD8 ratio or CD8 counts were independently associated with all-cause, AIDS, and non-AIDS mortality in patients treated with antiretroviral therapy (ART) with suppressed viral load and CD4 count >350 cells/μL For the analysis, the authors combined data from 13 European and North American cohorts participating in the Antiretroviral Therapy Cohort Collaboration. During 276’526 person-years, 1’834 of 49’865 patients (3.7%) died (249 AIDS-related; 1’076 non-AIDS-defining; 509 unknown/unclassifiable deaths). There was little evidence that CD4:CD8 ratio was prognostic for all-cause mortality after adjustment for other factors: the adjusted hazard ratio (aHR) for lower vs middle tertile was 1.11. The association of CD8 count with all-cause mortality was U-shaped with a higher mortality for those with higher and lower values compared with those with values near the median (aHR 1.13 and 1.11, respectively). AIDS related mortality declined with increasing CD4:CD8 ratio and decreasing CD8 count. In conclusion, the study does not lend strong support to use CD4:CD8 ratio and CD8 count as a prognostic marker for non-AIDS related mortality in virally suppressed patients on ART. However, the failure of many patients in this long-term treated HIV-infected population to reach the levels of CD4:CD8 ratio or CD8 count considered to be normal in the general population may indicate ongoing immune dysregulation. This may have longer-term consequences than the authors have been able to study here, or associations may be only with specific causes of death. | ||