2021

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