2021

16th June Tarr et al., Longitudinal CAC/CCTA HIV-pos vs HIV-neg


Longitudinal progression of subclinical coronary atherosclerosis in Swiss HIV-positive compared with HIV-negative persons undergoing coronary calcium score scan and CT angiography.   Open Forum Infectious Diseases

Tarr et al. investigated whether HIV infection accelerates the progression of atherosclerosis over time comparing coronary computed tomography angiography (CCTA) of people with and without HIV infection.

Changes in coronary artery calcium scores over time were compared between asymptomatic people with HIV of the Metabolism and Aging Core Project from the SHCS and HIV-negative individuals who were referred for clinically indicated CCTA.

The study included 340 people with HIV, and 90 HIV negative controls. Compared to individuals without HIV, those with HIV were more likely to be male (85% vs. 79%), to smoke (36% vs. 12%) and to report illicit drug use (3% vs. 0), but had a similar 10-year Framingham risk score (8.9% vs. 9.0%, p-value 0.82). The majority of people with HIV had a suppressed HIV viral load during follow-up (94%).

Overall, increases in coronary artery calcium score were larger among individuals with a higher calcium score and a higher Framingham risk score at baseline, but did not differ substantially between people with and without HIV infection. After taking the Framingham risk score into account, there was no significant association between HIV infection and the development of any new plaques (incidence rate ratio [IRR] 1.21, 95% CI 0.62-2.35), calcified plaques (IRR 1.06, CI 0.56-2.00), mixed plaques (IRR 1.24, CI 0.69-2.21), high-risk plaques (1.46, CI 0.66-3.20) and coronary artery stenosis ≥70% (IRR 0.95, CI 0.30-3.03).

In conclusion, the present study found no accelerated coronary atherosclerosis progression in people with well-controlled HIV infection. The study findings underline once again the importance of conventional cardiovascular risk factors for the development of coronary artery disease in people with HIV.

PubMed

10th June Nguyen et al., Systematic screening of viral and human genetic variation identifies antiretroviral resistance and immune escape link


Systematic screening of viral and human genetic variation identifies antiretroviral resistance and immune escape link.   eLive

Nguyen et al. assessed whether certain human leukocyte antigen (HLA) class I alleles play a role in the development of HIV drug resistance mutations among untreated people with HIV.

SHCS participants with available HIV drug resistance testing and information on HLA were systematically screened for significant associations between HLA class I alleles and the development of drug resistance mutations using three types of analyses: logistic regression, Cox regression and a mechanistic model. Only data prior to the start of antiretroviral therapy was considered.

The study included 3’997 patients contributing 5’561 possible combinations between HLA-I alleles and drug resistance mutations. Of those, 255 combinations were sufficiently powered to warrant further analyses. Authors found significant associations between HLA-I alleles and the development of NNRTI drug resistance mutations, specifically between HLA-B18 and E138 (OR 3.78, 95% CI 2.27-6.19), between HLA-A24 and E138 (OR 1.72, 1.01-2.84), and between HLA-B35 and V179 (OR 2.14, 1.08 - 4.11). Two of these associations (HLA-B18:E138 and HLA-B35:V179) were significant in longitudinal Cox regression, and two associations (HLA-B18:E18 and HLA-B35:V179) showed clear relationships in the mechanistic model.

In summary, this study shows that immune escape conveyed by the interaction between HLA-I alleles and the virus play a role for the intrapatient development of HIV drug resistance. In addition to the transmission of resistant viruses and to the selection of drug resistance during antiretroviral therapy, these findings provide compelling evidence for a novel mechanism of HIV drug resistance development.

PubMed

2nd June Santos et al., Depressive symptoms and NCI in people with well-treated HIV in CH


Association between depressive symptoms and neurocognitive impairment in people with well-treated HIV in Switzerland.    International Journal of STD & AIDS

Santos et al. aimed to analyse the association between depressive symptoms and neurocognitive impairment (NCI) in a population of well-treated, ageing people with HIV (PWH).

PWH aged ≥45 years underwent neurocognitive assessment and grading of depressive symptoms using the Centre for Epidemiological Studies Depression Scale. Neurocognitive impairment categories were defined using Frascati criteria. Participants with NCI related to neurological or psychiatric confounders other than depression were excluded.

Excluding 79 participants with confounding factors, 902 participants were studied: 81% were men; 96% had plasma viral loads <50 copies/ml; 35% had neurocognitive impairment; 28% had Centre for Epidemiological Studies Depression scores ≥16. Higher Centre for Epidemiological Studies Depression scores were associated with female sex (p = 0.0003), non-Caucasian origin (p = 0.011) and current/past intravenous drug use (p =0.002). Whilst neurocognitive impairment was associated with higher Centre for Epidemiological Studies Depression scores, the Centre for Epidemiological Studies Depression score was a poor predictor of having neurocognitive impairment (area under the ROC curve 0.604). Applying a Centre for Epidemiological Studies Depression score threshold of 16 predicted the presence of neurocognitive impairment with a sensitivity of 38.3% (specificity 77.2%), increasing the threshold to 27 lowered sensitivity to 15.4% (specificity 93.6%).

In conclusion, this large cohort study of PWH in Switzerland sheds light on the limitations of Centre for Epidemiological Studies Depression score thresholds in the context of HIV-associated NCI. Applying conventional Centre for Epidemiological Studies Depression score thresholds to predict NCI had no benefit. As NCI was associated with higher Centre for Epidemiological Studies Depression scores; however, the study data support the screening for and treatment of depression among PWH diagnosed with NCI.

PubMed

27th May Meier et al., Immune response against Mtb in HIV


HIV-infected patients developing tuberculosis disease show early changes in the immune response to novel Mycobacterium tuberculosis antigens.  frontiers in Immunology

Meier et al. performed a case-control study to evaluate the utility of novel M. tuberculosis antigens for early diagnosis of tuberculosis (TB) in people with HIV.

Authors included patients in the Swiss HIV Cohort Study who developed TB and matched controls without TB. In these individuals, stored lymphocytes were stimulated with 10 novel M. tuberculosis antigens at four time points prior to TB diagnosis and differences in cytokine responses between cases and controls assessed.

The study included 4 individuals who developed pulmonary TB, 4 who experienced extrapulmonary TB, one who received a diagnosis of both pulmonary and extrapulmonary disease, and 9 controls without TB. Median cytokine concentrations induced by 3 out of the 10 novel M. tuberculosis antigens were significantly higher in the TB cases compared with controls in the latest time point prior to TB diagnosis (at a median of 117 days prior to TB diagnosis, IQR 29-312). Cytokine levels induced by one of the novel antigens were significantly higher in cases compared to controls even at time point three, which was at a median of 440 days prior to TB diagnosis (IQR 68-846). Traditional interferon-gamma release assays did not discriminate cases from controls at any time point.

In summary, the present study showed that cytokine responses induced by novel M. tuberculosis antigens of patients with and without TB differed already more than 12 months prior to TB diagnosis, and for one cytokine already between 1 and 2 years prior to TB diagnosis. These findings underline that dividing TB disease into latent or active is an inadequate representation of the full spectrum of disease, and the results may provide new possibilities for early detection of TB disease in people with HIV.

PubMed

21st May Courlet et al., Pharmacokinetic parameters and weight change in HIV patients newly switched to dolutegravir-based regimes


Pharmacokinetic parameters and weight change in HIV patients newly switched to dolutegravir-based regimens in SIMPL'HIV clinical trial.    British Journal of Clinical Pharmacology

Courlet et al. aimed to evaluate the association between dolutegravir (DTG) pharmacokinetic parameters and weight changes in treatment-experienced people with HIV (PWHIV) from the Simpl'HIV study newly switched to a dual DTG-based regimen.

They used multivariable linear regressions to evaluate the association between DTG pharmacokinetic parameters at week 48 and weight change between week 0 and week 48 and adjusted their model for potential confounders including CD4 nadir, female sex, African origin, age, weight at week 0 and presence of a non-nucleoside reverse transcriptase inhibitor-based regimen before switch to DTG.

The analysis included data from 39 PWHIV. An average significant weight gain of 2.4 kg was observed between baseline and week 48. DTG plasma exposure was not significantly associated with weight gain, even after adjusting for potential confounders (P = .9).

In conclusion, the study did not find evidence for an association between DTG pharmacokinetic parameters and weight gain within a particular population of people living with HIV newly switched to DTG in the context of a randomized clinical trial. This might arise from the moderate between-subject variability in DTG concentration–time profile, compromising the power to detect an effect of pharmacokinetic parameters on weight gain.

PubMed

14th May Kovari et al., ALT changes after switching from TDF to TAF in HIV-monoinfected people


Changes in alanine aminotransferase levels after switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in HIV-positive people without viral hepatitis in the Swiss HIV Cohort Study.   HIV Medicine

Kovari et al. assessed the impact of switching from TDF to TAF on alanine aminotransferase (ALT) in people with HIV. Authors included all patients without viral hepatitis on a stable antiretroviral therapy containing TDF who either switched to TAF, or remained on TDF. Changes in ALT were estimated using discontinuity regression with linear mixed effect models.

The study population included 1712 individuals, of whom 75% were male, and the median age was 50 years (IQR 42-57). At the time of switch, 11% of participants had elevated liver enzymes for 6 months or longer. Switching from TDF to TAF led to an adjusted decrease in ALT of 3.7 U/L (95% CI 3.2-4.2). Among individuals with abnormal ALT levels at the time of switch, replacing TDF with TAF was associated with a larger decrease in ALT (17 U/L) compared with individuals with a normal ALT (3.3 U/L). Results were similar across sensitivity analyses, and decreases in ALT were also observed in individuals who switched from TDF to a tenofovir-free dual-therapy. Authors found no relevant effect modifications of the ALT change by gender, age, transmission risk group or BMI.

Taken together, the present shows that switching from TDF to TAF among people with HIV but without viral hepatitis is associated with improvements in liver enzymes. Switching away from TDF - including to a tenofovir-free dual treatment - should be considered among people with HIV and unexplained chronically elevated transaminases. Due to the absence of effect modification by known risk factors for hepatotoxicity, the mechanisms behind the hepatotoxic potential of TDF and its long-term impact remain unclear.

PubMed

5th May Castillo-Mancilla et al., Incomplete ART adherence and cardiovascular events and mortality


Association of incomplete adherence to antiretroviral therapy with cardiovascular events and mortality in virologically suppressed persons with HIV: The Swiss HIV Cohort Study.    Open Forum Infectious Diseases

Castillo-Mancilla et al. aimed to assess the clinical implications of incomplete antiretroviral therapy (ART) adherence on the occurrence of cardiovascular events (CVD) and non-CVD-related death.

Persons with HIV (PWH) enrolled in the Swiss HIV Cohort Study without a history of CVD who initiated ART between 2003 and 2018 and had viral suppression (<50 copies/mL) for ≥6 months were evaluated for the association between incomplete self-reported ART adherence and (1) any CVD event (myocardial infarction, revascularization, cerebral hemorrhage, stroke, and/or death due to CVD event) or (2) non-CVD-related death. Incomplete ART adherence was defined as 1 or ≥2 self-reported missed doses in the last month.

A total of 6’971 PWH (74% male) were included in the analysis (median age [interquartile range {IQR}], 39 [32–47] years). The median (IQR) follow-up was 8 (4–11) years, with 14 (8–23) adherence questionnaires collected per participant. In total, 205 (3%) participants experienced a CVD event, and 186 (3%) died a non-CVD-related death. In an adjusted competing risk model where missing data were imputed, missing ≥1 ART dose showed an increased, but not statistically significant, risk for CVD events (hazard ratio [HR], 1.23; 95% CI, 0.85–1.79; P = .28). Non-CVD-related mortality showed a statistically significantly increased risk with missing ≥1 ART dose (HR, 1.44; 95% CI, 1.00–2.07; P = .05) and missing ≥2 ART doses (HR, 2.21; 95% CI, 1.37–3.57; P = .001).

In conclusion, the study demonstrated that incomplete (i.e., <100%) ART adherence is associated with an increased risk for non-CVD-related mortality in PWH who are virologically suppressed to <50 copies/mL. These findings suggest the potential critical role that ART adherence could have in improving clinical outcomes and open the door for further research on the role that increasing adherence - beyond suppression - could have in preventing morbidity/mortality in PWH who are considered optimally treated. Future studies to confirm this association and to understand its clinical implications are needed.

PubMed

29th April Surial et al., Impact of binge drinking on mortality and liver disease


The impact of binge drinking on mortality and liver disease in the Swiss HIV Cohort Study.    Journal of Clinical Medicine

Surial et al. assessed whether binge drinking contributes to all-cause and liver-related mortality and to the occurrence of liver-related events among people living with HIV. Previous reports from the general population showed that individuals who reported binge drinking behaviour had a substantially increased risk of developing liver disease.

Based on the Alcohol Use Disorder Identification Test (AUDIT-C) score, time-varying alcohol drinking patterns were categorized into one of four groups: “abstinence”, “non-hazardous drinking”, “hazardous but not binge drinking”, and “binge drinking” (defined as ≥ 6 drinks/occasion at least monthly).

The study included 11’849 individuals with a median follow-up of 6.8 years. Overall, 470 individuals died, of whom 37 experienced a liver-related death, and 239 liver-related events occurred. Compared to individuals who reported non-hazardous drinking, those reporting binge drinking were more likely to die (adjusted incidence rate ratio [aIRR] 1.9, 95% CI 1.3-2.7 for all-cause mortality; aIRR 3.6, CI 0.9-13.9 for liver-related mortality) and to experience a liver-related event (aIRR 3.8, CI 2.4-5.8). Authors did not observe differences in outcomes between participants reporting non-hazardous and hazardous drinking without binge drinking.

In summary, this study shows that binge drinking is associated with an increased mortality and an increased risk for the development of liver disease among people living with HIV. Considering the high proportion of individuals who report harmful alcohol consumption and the high prevalence of liver disease in HIV cohorts, these patients may benefit from tailored risk reduction counselling.

PubMed

22nd April Hovaguimian et al., Long-term risk of HIV infection in individuals seeking post-exposure prophylaxis


Data linkage to evaluate the long-term risk of HIV infection in individuals seeking post-exposure prophylaxis.   Nature Communications

Hovaguimian et al. aimed to estimate the long-term risk of HIV infection in post-exposure prophylaxis (PEP-) seekers in a tertiary referral center. As previous evidence suggests that sexual risk taking occurs in phases lasting 12 to 24 months, they hypothesized that HIV infections would be clustered shortly after the time of PEP consultation.

Overall, there were 975 PEP-seekers between 2007 and 2013. Using privacy preserving probabilistic linkage, the authors linked these 975 records with two observational databases providing data on HIV events, the Zurich Primary HIV Infection study and the Swiss HIV Cohort Study, respectively. With this approach, they identified 22 HIV infections and obtained long-term follow-up data, which reveal a median of 4.1 years between consultation for post-exposure prophylaxis and HIV diagnosis. Even though men who have sex with men constituted only 35.8% of those seeking post-exposure prophylaxis, all 22 events occur in this subgroup.

In conclusion, in this retrospective data linkage study, the proportion of PEP seekers tested positive for HIV after PEP intake was 2.3%, and this proportion reached 6.3% in MSM. This study identified that most seroconversions occurred 4 years after PEP consultation, thereby bringing long-term insights into the risk of contracting HIV following PEP seeking. Those who seroconverted were all MSM, which should strongly encourage early consideration of PrEP in MSM after a first episode of PEP.

PubMed

15th April Chammartin et al., non-AIDS-defining and AIDS-defining cancer and timing of ART initiation


Risk for non–AIDS-defining and AIDS-defining cancer of early versus delayed initiation of antiretroviral therapy.    Annals of Internal Medicine

Chammartin et al. aimed to assess the impact of deferred and immediate start of antiretroviral therapy (ART) on the development of non-AIDS and AIDS-defining cancer.

Authors estimated the occurrence of cancer among participants from the D:A:D study and used causal inference methods to emulate a pragmatic trial comparing 3 treatment strategies: Immediate treatment irrespective of CD4 cell count, and treatment start at a CD4 cell count of less than 500 cells/µL or less than 350 cells/µL.

The study population included 8’318 individuals with a median age of 36 years (IQR 29–43), 77% were men, and the median CD4 cell count at baseline was 410 cells/µL (IQR 260–583). Over a median follow-up of 8.3 years, 231 persons developed non-AIDS defining (mainly Hodgkin lymphoma, lung, anal and prostate cancer) and 272 developed AIDS-defining cancer (Non-Hodgkin lymphoma, Kaposi sarcoma and cervical cancer). With immediate ART, the 10-year risk for AIDS-defining cancer was 2.50%, compared to 2.80% when treatment was started with a CD4 cell count below 500 cells/µL (difference to immediate treatment 0.32 percentage points, 95% CI 0.21–0.44), and 3.51% with a CD4 cell count below 350 cells/µL (difference 1.00 percentage points, CI 0.67–1.44). Differences in risk between the three strategies for the development of non-AIDS defining cancers were not statistically significant.

Taken together, this study shows that compared to a delayed ART start, immediate therapy leads to lower rates of AIDS-defining cancers. However, the risk reduction with immediate therapy is small and remains inconclusive for non-AIDS defining cancer. This is reassuring since almost half of patients currently start ART with a CD4 cell count below 500 cells/µL due to delayed diagnosis. Future research will need to better characterize the mechanisms behind the increased risk of cancer among people living with HIV compared with the general population.

PubMed

8th April funding of the SHCS by the SNSF from 2021 to 2024 - thanks to all


Dear all,

We are very pleased to inform you that the SHCS will be funded with CHF 8,75 Mio from the Swiss National Science Foundation (SNSF) for the next 3,5 years (CHF 2,5 Mio/year). The reason we are still supported in these fast-moving times after 33 years is excellence in clinical care and outstanding research. There is a direct benefit from our work for patients but also for the society at large.

Therefore, we would like to thank first

  • all the patients participating in the SHCS

We also thank all of you who are working tireless for the SHCS

  • study nurses, physicians at the cohort centers and HIV-practitioners
  • technicians, FAMH physicians, virologists, microbiologists and immunologists taking care of the biobank
  • the data managers, the data center, the coordination center, all the administrative support we get at all levels
  • the Positivrat for actively participating in the SHCS Scientific Board
  • the many PhD, Postdocs, physician-scientists and master students who work in the research labs and in front of their computers analyzing all the data that is being generated on the many exciting research projects that are ongoing in the SHCS
  • all the national and international collaborators with whom the SHCS works together
  • the SNSF for funding, the SHCS research foundation
  • the Federal Office of Public Health for supporting public health initiatives of the SHCS
  • pharmaceutical companies
    • AbbVie, Gilead, MSD, ViiV for support of the SHCS research foundation by unrestricted grants to support the SHCS core projects
    • AbbVie, BMS, Gilead, Janssen, MSD, ViiV for the collaboration with the SHCS association
    • Some companies also support specific investigator initiated studies. We also thank you for this.

Thanks again for all your continuous support of the SHCS. We are looking forward to our further collaboration.

Best regards,

Huldrych Günthard Andri Rauch Marcel Stöckle
President of the SHCS Chairman of the
Scientific Board
Chairman of the Clinical
and Laboratory Board
31st March Surial and Mugglin et al., Metabolic changes after replacing TDF with TAF


Weight and metabolic changes after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in people living with HIV.    Annals of Internal Medicine.

Surial and Mugglin et al. evaluated the impact of switching from Tenofovir disoproxil fumarate (TDF) to Tenofovir alafenamide (TAF) on weight, the development of obesity and other metabolic outcomes among participants on stable antiretroviral therapy.

Authors analyzed data from all individuals who received a TDF-containing therapy for 6 months or longer and compared weight trajectories and changes in lipid levels over 18 months between individuals who switched from TDF to TAF and those who continued TDF.

The study population included 4375 individuals; the median age was 50 years (IQR 43–56), 26% were women, and 52% had a normal body mass index. Overall, 3484 (79.6%) switched to TAF and 891 (20.4%) continued TDF. After 18 months, participants who switched to TAF experienced a mean weight increase of 1.7 kg (95% CI 1.5–2.0), compared with 0.7 kg (CI 0.4–1.0) with the continued use of TDF (between group difference 1.1 kg, CI 0.7–1.4). The difference between both groups was largest among women of African (1.5 kg) and non-African origin (1.4 kg), and among individuals who received integrase inhibitors (1.7 kg), but weight increases were greater with TAF than TDF with all third drugs used. Among individuals with a normal BMI, 13.8% who switched to TAF became overweight or obese, compared with 8.4% who remained on TDF. In a sensitivity analysis, patients who switched from abacavir (ABC)-containing regimens to TAF also experienced larger weight increases compared with those who continued ABC. Finally, the use of TAF was associated with greater increases in levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides compared with the continued use of TDF.

This study highlights that replacing TDF with TAF is associated with adverse metabolic changes, including weight increase, the development of obesity and worsening of blood lipid values. The increases in weight observed after switching from TDF and ABC to TAF further show that weight changes cannot only be explained by stopping TDF. Taken together, these findings underscore the need of a balanced evaluation of the advantages and potential harms when recommending TAF over TDF.

PubMed

25th March Stader et al., Effect of ageing on antiretroviral drug pharmacokinetics


Effect of ageing on antiretroviral drug pharmacokinetics using clinical data combined with modelling and simulation.    British Journal of Clinical Pharmacology

Stader et al. aimed to investigate age-related pharmacokinetic changes of HIV drugs by using a previously developed and verified physiologically based pharmacokinetic (PBPK) framework in combination with clinically observed data sampled as part of the Swiss HIV Cohort Study in ageing people living with HIV (PLWH).

Plasma concentrations for 10 first-line antiretrovirals were obtained in PLWH ≥55 years, participating in the Swiss HIV Cohort Study, and used to proof the predictive performance of the PBPK model. The verified PBPK model predicted the continuous effect of ageing on HIV drug pharmacokinetics across adulthood (20–99 years). The impact of ethnicity on age-related pharmacokinetic changes between whites and other races was statistically analyzed.

Clinically observed concentration-time profiles of all investigated antiretrovirals were generally within the 95% confidence interval of the PBPK simulations, demonstrating the predictive power of the modelling approach used. The predicted decline in drug clearance drove age-related pharmacokinetic changes of antiretrovirals, resulting in a maximal 70% [95% confidence interval: 40%, 120%] increase in antiretrovirals exposure across adulthood. Peak concentration, time to peak concentration and apparent volume of distribution were predicted to be unaltered by ageing. There was no statistically significant difference of age-related pharmacokinetic changes between studied ethnicities.

In conclusion, the impact of advanced ageing on antiretroviral drug pharmacokinetics is not clinically relevant considering the large therapeutic index of the current first-line treatment. In the current study, neither sex nor ethnicity appear to impact age-related pharmacokinetic changes. Overall, antiretroviral drug dose adjustment is a priori not necessary in ageing male and female PLWH in the absence of severe comorbidities.

PubMed

12th March Roen et al., Health care index predicts TB-HIV mortality


A new health care index predicts short term mortality for TB and HIV co-infected people.    International Journal of Tuberculosis and Lung

Roen et al. aimed to re-evaluate a previously generated health care index (HCI) in a prospective cohort of tuberculosis (TB-) HIV co-infected individuals and to asses if additional factors, which parallel recent changes in TB-HIV health care management, predict mortality. They evaluated nine aspects of health care in Cox proportional hazards models on time from TB diagnosis to death.

Of 1’396 eligible individuals (72% male, 59% from Eastern Europe), 269 died within 12 months. Use of rifamycin/isoniazid/pyrazinamide based treatment (HR 0.67, 95% CI 0.50–0.89), TB drug susceptibility testing (DST) and number of active TB drugs (DST + <3 drugs (HR 1.09, 95% CI 0.80–1.48), DST + ≥3 drugs (HR 0.49, 95% CI 0.35–0.70) vs. no DST), recent HIV-RNA measurement (HR 0.64, 95% CI 0.50–0.82) and combination antiretroviral therapy use (HR 0.72, 95% CI 0.53–0.97) were associated with mortality. These factors contributed respectively 5, –1, 8, 5 and 4 to the HCI. Lower HCI was associated with an increased probability of death; 30% (95% CI 26–35) vs. 9% (95% CI 6–13) in the lowest vs. the highest quartile.

In conclusion, the authors improved their previous HCI to reflect recent changes in health care practices that predict 12-month mortality, even after adjusting for factors known to be associated with mortality among TB-HIV-positive individuals. The HCI has value in both high- and middle-income settings in Western and Eastern Europe, as well as Latin America. The proposed model suggests that five simple factors can be used to improve mortality among TB-HIV-positive individuals and to benchmark clinics and serve as a guide to improved health care provision to people with HIVTB.

PubMed

4th March Thorball et al., Host genomics of the HIV-1 reservoir


Host genomics of the HIV-1 reservoir size and its decay rate during suppressive antiretroviral treatment.    JAIDS

Thorball et al. aimed to assess host genetic factors associated with the HIV-1 reservoir size and its long-term dynamics in a cohort of 797 HIV-1 positive individuals on suppressive antiretroviral therapy (ART) for at least 5 years.

The authors measured total HIV-1 DNA in peripheral blood mononuclear cells from study participants, as a proxy for the reservoir size at 3 time points over a median of 5.4 years, and searched for associations between human genetic variation and 2 phenotypic readouts: the reservoir size at the first time point and its decay rate over the study period. They assessed the contribution of common genetic variants using genome-wide genotyping data from 797 patients with European ancestry enrolled in the Swiss HIV Cohort Study and searched for a potential impact of rare variants and exonic copy number variants using exome sequencing data generated in a subset of 194 study participants.

Based on their results, genome-wide and exome-wide analyses did not reveal any significant association with the size of the HIV-1 reservoir or its decay rate on suppressive antiretroviral treatment.

In conclusion, the study suggests that human individual germline genetic variation has little, if any, influence on the control of the HIV-1 viral reservoir size and its long-term dynamics. Complex, likely multifactorial biological processes govern HIV-1 viral persistence. Larger genomic studies, taking into account defined biological phenotypes and the differential biological importance of replication-competent and defective proviruses, will possibly clarify the role of common or rare genetic variants explaining small proportions of the variability of the phenotypes related to viral latency.

PubMed

25th February Neesgaard et al., Outcomes of integrase inhibitors treatment


Virologic and immunologic outcomes of treatment with integrase inhibitors in a real-world setting: The RESPOND cohort consortium.   PLoS One

Neesgaard et al. for The RESPOND study group aimed to compare virologic and immunologic outcomes of integrase inhibitor (INSTI)-containing, contemporary boosted protease inhibitor (PI/b)-containing and non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens in a real-life setting.

Virologic and immunologic outcomes of INSTI use were compared to outcomes of PI/b or NNRTI treatment 12 months after treatment start or switch, for participants in the RESPOND cohort consortium. A composite treatment outcome (cTO) was used, defining success as viral load (VL) <200 copies/mL and failure as at least one of: ≥200 copies/mL, unknown VL in the time window, any changes of antiretroviral therapy (ART) regimen, AIDS, or death. In addition, on-treatment analysis including only individuals with known VL and no regimen changes was performed. Favorable immunologic response was defined as a 25% increase in CD4 count or as reaching ≥750 CD4 cells/μL.

Between January 2012 and January 2019, 13’703 (33.0% ART-naïve) individuals were included, of whom 7’147 started/switched to a regimen with an INSTI, 3’102 to a PI/b and 3’454 to an NNRTI-containing regimen. The main reason for cTO failure in all treatment groups were changes in ART regimen. Compared to INSTIs, the adjusted odds ratio (aOR) of cTO success was significantly lower for PI/b (0.74 [95% confidence interval, CI 0.67–0.82], p <0.001), but similar for NNRTIs (1.07 [CI 0.97–1.17], p = 0.11). On-treatment analysis and sensitivity analyses using a VL cut-off of 50 copies/mL were consistent. Compared to INSTIs, the aORs of a 25% increase in CD4 count were lower for NNRTIs (0.80 [CI 0.71–0.91], p<0.001) and PI/b (0.87 [CI 0.76–0.99], p = 0.04).

In conclusion, this large, real-world based analysis of a heterogeneous population of PLWH seen in routine clinical care showed that treatment with INSTI and NNRTI-containing regimes was preferable to PI/b with regard to virologic outcomes, although the potential for residual confounding cannot be fully excluded. Favorable immunologic responses were more likely with INSTI-containing regimens than with NNRTI-containing regimens, and to a lesser degree with PI/b-containing regimens. Crude numbers did not reveal any major differences in the occurrence of AIDS or death. These data supports the use of INSTI treatment and suggest that 12 months efficacy and durability of INSTIs are independent of prior treatment status and on-going viremia.

PubMed

17th February Livio et al., Inappropriate prescribing in elderly people living with HIV


Analysis of inappropriate prescribing in elderly patients of the Swiss HIV Cohort Study reveals gender inequity. Journal of Antimicrobial Chemotherapy

Livio et al. aimed to determine the prevalence of and risk factors for inappropriate prescribing in geriatric medicine among individuals aged ≥75 years enrolled in the Swiss HIV Cohort Study.

The authors did a retrospective review of medical records to gain more insights into non-HIV comorbidities. Inappropriate prescribing was screened using the Beers criteria, the STOPP/START criteria and the Liverpool drug–drug interactions (DDIs) database.

For 175 included individuals, the median age was 78 years (IQR 76–81) and 71% were male. The median number of non-HIV comorbidities was 7 (IQR 5–10). The prevalence of polypharmacy and inappropriate prescribing was 66% and 67%, respectively. Overall, 40% of prescribing issues could have deleterious consequences. Prescribing issues occurred mainly with non-HIV drugs and included: incorrect dosage (26%); lack of indication (21%); prescription omission (drug not prescribed although indicated) (17%); drug not appropriate in elderly individuals (18%) and deleterious DDIs (17%). In the multivariable logistic regression, risk factors for prescribing issues were polypharmacy (OR: 2.5; 95% CI: 1.3–4.7), renal impairment (OR: 2.7; 95% CI: 1.4–5.1), treatment with CNS-active drugs (OR: 2.1; 95% CI: 1.1–3.8) and female sex (OR: 8.3; 95% CI: 2.4–28.1).

In conclusion, prescribing issues are common in elderly people living with HIV, consistent with reports in uninfected elderly individuals. Inappropriate prescribing represents a risk for the patient, although it should be noted that it does not necessarily lead to harm. Medication reconciliation and periodic review prescriptions by experienced physicians, ideally as part of multidisciplinary consultations, could reduce the risk of inappropriate prescribing. However, in clinical practice, this approach can be difficult to implement due to the pressure from hospitals and healthcare systems to reduce consultation times. Finally, the study shows that female individuals are at higher risk of inappropriate prescribing, thus doctors should be careful to avoid bias and attention is needed when prescribing for women.

PubMed

10th February Dietrich et al., Kidney dysfunction and HIV


Rapid progression of Kidney dysfunction in Swiss people living with HIV: Contribution of polygenic risk score and D:A:D clinical risk score.    Journal of Infectious Diseases

Dietrich et al. aimed to assess and quantify the contribution of genetic background, D:A:D chronic kidney disease (CKD) risk score, and relevant antiretroviral therapy (ART) exposures to rapid progression of kidney dysfunction.

They obtained univariable and multivariable hazard ratios (HR) for rapid progression, based on the clinical D:A:D CKD risk score, antiretroviral exposures, and a polygenic risk score based on 14’769 genome-wide single nucleotide polymorphisms in white Swiss HIV Cohort Study participants. For the non-genetic risk factors, only variables included in the CKD risk score (mode of HIV transmission, hepatitis C coinfection, age, baseline eGFR, sex, CD4 nadir, hypertension, prior cardiovascular disease, and diabetes mellitus) were included.

The study included 225 participants with rapid progression and 3’378 rapid progression-free participants. In multivariable analysis, compared to participants with low D:A:D risk, participants with high risk had rapid progression (HR = 1.82 [95% CI, 1.28–2.60]). Compared to the first (favorable) polygenic risk score quartile, participants in the second, third, and fourth (unfavorable) quartiles had rapid progression (HR = 1.39 [95% CI, 0.94–2.06], 1.52 [95% CI, 1.04–2.24], and 2.04 [95% CI, 1.41–2.94], respectively). Recent exposure to tenofovir disoproxil fumarate was associated with rapid progression (HR = 1.36 [95% CI, 1.06–1.76]).

In conclusion, some people living with HIV experience rapidly deteriorating kidney dysfunction and these analyses reveal an independent contribution of an individual polygenic risk score to explaining interindividual variation in rapid progression. The study extends the our previous observation that genetic background associates with CKD risk and highlight the importance of longitudinal study design to quantify the effect size of polygenic risk score on rapid progression, in the context of multiple shifting environmental risk factors, most notably clinical D:A:D CKD risk score and potentially nephrotoxic antiretroviral exposures.

PubMed

27th January Gryaznov et al., Smartphone app and CO self-monitoring support for smoking cessation


Smartphone app and carbon monoxide self-monitoring support for smoking cessation: A randomised controlled trial nested into the Swiss HIV Cohort Study.   JAIDS

Gryaznov et al. investigated whether exhaled carbon monoxide (CO) self-monitoring in conjunction with a smoking cessation app may improve smoking cessation in HIV-positive smokers.

They nested a randomized controlled into the Swiss HIV Cohort Study and randomly allocated during biannual cohort visits patients smoking ≥3 cigarettes a day via a trial website to counselling by SHCS center physicians (usual care) or to a combined intervention of CO self-monitoring with mobile phone-based feedback and app-based smoking cessation support.

At the start of the trial on June 1, 2017, 3’293 of 10’493 (34%) patients in the SHCS smoked ≥3 cigarettes and these 2’444 (74%) indicated at any cohort visit in the previous 48 months to have quit once and then resumed smoking. During a recruitment period of 1.5 years, 1’807 patients were screened for inclusion and a total of 81 patients were enrolled. Six of 42 (14%) participants in the intervention group and 5 of 39 (13%) in the standard of care group quit smoking at 6 months follow-up (adjusted odds ratio 1.06, 95% CI: 0.29 to +3.86) and 3 participant were lost to follow-up. Based on the 12-month cohort data, one individual had resumed smoking and 5 trial participants reported to have quit smoking. The adjusted mean difference in smoked cigarettes between the intervention and control groups at 6 months was −1.38 (95% CI: −4.45 to 1.69).

In conclusion, results from this pragmatic trial remained inconclusive and underpowered because of recruitment difficulties, although the nested trial design allowed for the potential to recruit from a large group of smokers with a self-reported history for quitting. Patients included in the trial reported more cessation attempts which was identified as the best predictor for successful quitting from observational data analysis of the SHCS. This information, however, did not translate into a high recruitment rate. Overall, 11% of the trial population - irrespective of the intervention - quit, which is considerably higher than the 1.6% smokers in the remaining cohort who had indicated to have quit.

PubMed

20th January Reichmuth et al., HIV-1 transmission drivers


Using longitudinally sampled viral nucleotide sequences to characterize the drivers of HIV-1 transmission.   HIV Medicine

Reichmuth et al. aimed to develop and to test a molecular epidemiology method based on phylogeny reconstruction and cluster analysis to characterize potential HIV-1 transmitters and understand the drivers of the HIV-1 epidemic in Switzerland. This method was developed and validated using longitudinally sampled HIV-1 partial polymerase (pol) nucleotide sequences, routinely and retrospectively obtained, in the drug resistance database (DRDB) of the Swiss HIV Cohort Study (SHCS).

The proposed method was able to identify 279 potential HIV-1 transmitters and allowed the authors to determine the main epidemiological and virological drivers of transmission. They found that the directionality of transmission was consistent with infection times for 72.9% of 85 potential HIV-1 transmissions with accurate infection date estimates. Being a potential HIV-1 transmitter was associated with risk factors including viral load [adjusted odds ratiomultivariable (95% confidence interval): 1.86 (1.49–2.32)], syphilis coinfection [1.52 (1.06–2.19)], and recreational drug use [1.45 (1.06–1.98)]. By contrast for the potential HIV-1 recipients, this association was weaker or even absent [1.18 (0.82–1.72), 0.89 (0.52 –1.55) and 1.53 (0.98–2.39), respectively], indicating that inferred directionality of transmission is useful at the population level.

In conclusion, identifying drivers of HIV-1 transmission by not only identifying transmission clusters but also characterizing individuals who may have potentially transmitted HIV-1 is of great importance for understanding the drivers of the HIV-1 epidemic. The associated risk factors at an individual level are crucial to better understanding the dynamics and mechanisms of an HIV-1 epidemic and will help to tackle the various ongoing epidemics at the population level, but in a more individualized manner. The proposed method was validated using the densely sampled setting of the SHCS as a case study. This lays the groundwork to study evolution and transmission of HIV-1, as well as the risk factors of HIV-1 transmitters, and allows large transmission clusters to be characterized.

PubMed

13th January Mocroft et al., Outcomes in antiretroviral-naïve adults


Treatment outcomes of integrase inhibitors, boosted protease inhibitors and non-nucleoside reverse transcriptase inhibitors in antiretroviral naïve persons starting treatment.   HIV Medicine

Mocroft et al. on behalf of the RESPOND study-group aimed to compare shorter term virological and immunological outcomes and clinical events of AIDS/death in ART-naïve persons starting antiretroviral therapy (ART) in RESPOND with either an integrase strand transfer inhibitor (INSTI), contemporary boosted protease inhibitors (PI/b) or nonnucleoside reverse transcriptase inhibitors (NNRTIs) in key subgroups.

The International Cohort Consortium of Infectious Diseases (RESPOND) is a collaboration of 17 cohort studies, including 29’432 HIV-1-positive persons from across Europe and Australia. The composite treatment outcome (cTO) defined success as viral load (VL) <200 HIV-1 RNA copies/mL with no regimen change and no AIDS/death events. Immunological success was defined as a CD4 count >750 cells/lL or a 33% increase where the baseline CD4 count was ≥500 cells/lL.

Of 5’198 ART-naıve persons in RESPOND, 45.4% started INSTIs, 26.0% PI/b and 28.7% NNRTIs; 880 (17.4%) were aged >50 years, 2539 (49.4%) had CD4 counts <350 cells/lL and 1891 (36.8%) had VL >100 000 copies/mL. Differences in virological and immunological success and clinical failure among ART classes were similar across age groups (≤40, 40 –50 and >50 years), CD4 count categories (≤350 vs. >350 cells/lL) and VL categories at ART initiation (≤100 000 vs. >100 000 copies/mL), with all investigated interactions being nonsignificant (P >0.05).

In conclusion, differences among ART classes in virological, immunological and clinical outcomes in ART-naïve participants were consistent irrespective of age, immune suppression or VL at ART initiation. While confounding by indication cannot be excluded, this provides reassuring evidence that such subpopulations will equally benefit from modern ART.

PubMed

6th January Kusejko et al., The interplay of HIV and latent tuberculosis


Diagnosis of latent tuberculosis infection is associated with reduced HIV viral load and lower risk for opportunistic infections in people living with HIV.     PLoS Biology

Kusejko et al. aimed to investigate the association of Mycobacterium tuberculosis (MTB) status with HIV disease progression, including both the HIV set point viral load (SPVL) and the occurrence of opportunistic infections (OIs).

The authors sorted all participants of the Swiss HIV Cohort Study (SHCS) with at least 1 documented MTB test into one of the 3 groups: MTB uninfected, latent TB infection (LTBI), or active TB. In adjusted models, they corrected for baseline demographic characteristics, i.e., HIV transmission risk group and gender, geographic region, year of HIV diagnosis, and CD4 nadir.

A total of 13’943 SHCS patients had at least 1 MTB test documented, of whom 840 (6.0%) had LTBI and 770 (5.5%) developed active TB. Compared to MTB uninfected patients, LTBI was associated with a 0.24 decreased log HIV SPVL in the adjusted model (p < 0.0001). Patients with LTBI had lower odds of having candida stomatitis (adjusted odds ratio (OR) = 0.68, p = 0.0035) and oral hairy leukoplakia (adjusted OR = 0.67, p = 0.033) when compared to MTB uninfected patients.

In conclusion, the study demonstrated that LTBI was associated with a reduced HIV SPVL and fewer cases of the most prevalent OIs on a population level. These associations were robust to adjusting for the most important demographic and clinical confounders. Independently, various sensitivity analyses further strengthened these observations. These findings support the hypothesis that LTBI can benefit host immune responses and provides new avenues for future research to continue to unravel the complex interactions between mycobacteria and humans.

PubMed