Effectiveness of dolutegravir-based vs boosted darunavir-based first-line 3-drug regimens in people with HIV with advanced disease: A trial emulation

Background: No randomized comparisons exist between dolutegravir (DTG) and boosted-darunavir (DRV/b) for people initiating treatment with advanced HIV. Methods: Antiretroviral therapy (ART)-naïve people with HIV (PWH) with CD4 < 200 cells/mm3 or AIDS who started a first-line three-drug regimen with DTG or DRV/b were included. The primary outcome was a composite endpoint of newly diagnosed AIDS, serious non-AIDS events (SNAE), death, virological failure (VF), or discontinuation of the anchor drug due to failure or toxicity. A marginal structural Cox regression model was used to estimate the effect of starting DTG vs DRV/b-based regimens. Results: A total of 1323 advanced ART-naïve PWH were included, 895 starting DTG and 428 DRV/b. The unweighted risks of the composite endpoint by 48 months were 21.1% (95% CI: 18.1; 24.1%) for DTG vs 37.9% (95% CI: 32.7; 43.2%) for DRV/b (P < 0.001). First-line treatment with DTG showed a lower risk of experiencing the composite endpoint than DRV/b (wHR of DTG vs DRV/b 0.47, 95% CI: 0.35; 0.64, P < 0.001). Conclusion: Under the stated assumptions, this analysis indicates that in ART-naïve PWH with advanced disease, ART initiation with DTG vs DRV/b-based regimens leads to a 50% reduction in the risk of AIDS/SNAE/death/VF/discontinuation. This observed difference is partly explained by discontinuation of the anchor drug

Does Syphilis Increase the Risk of HIV-RNA Elevation >200 Copies/mL in HIV-Positive Patients under Effective Antiretroviral Treatment? Data from the ICONA Cohort

Background:To assess the impact of syphilis infection on the risk of HIV-RNA elevation in people living with HIV (PLWH) with current HIV-RNA ≤50 copies/mL.Setting:The Italian Cohort Naive Antiretrovirals.Methods:All PLWH (2009-2020) under antiretroviral treatment with at least 2 consecutive HIV-RNA values ≤50 copies/mL before the date of syphilis diagnosis and at least 1 HIV-RNA determination after the syphilis event were enrolled. A control group of PLWH without syphilis was matched for mode of HIV transmission. Outcomes were defined using the first HIV-RNA measure in the time window ranging between -2 and +6 months of the diagnosis/index date. The primary outcome used a single value >200 copies/mL to define HIV-RNA elevation associated with risk of transmission. The association between syphilis infection and the protocol defined outcome was evaluated using logistic regression analysis.Results:Nine hundred twenty-six PLWH with a syphilis event were enrolled and matched with a random sample of 1370 PLWH without syphilis. Eighteen of the 926 (1.9%) with syphilis had ≥1 HIV-RNA >200 copies/mL in the window vs. 29/1370 (2.1%) of the not exposed (P = 0.77). In the multivariable analysis adjusted for age, year of diagnosis/index date, and clinical site, syphilis infection was not associated with the risk of HIV-RNA >200 copies/mL (adjusted odds ratio 0.81; 95% confidence interval 0.43-1.52, P = 0.508).Conclusions:We did not find any evidence for an association between syphilis infection and viral elevation >200 copies/mL

Effectiveness of dolutegravir-based vs boosted darunavir-based first-line 3-drug regimens in people with HIV with advanced disease: a trial emulation

Background: No randomized comparisons exist between dolutegravir (DTG) and boosted-darunavir (DRV/b) for people initiating treatment with advanced HIV. Methods: ART-naïve people with HIV (PWH) with CD4 <200 cells/mm3 or AIDS who started a first-line three-drug regimen with DTG or DRV/b were included. The primary outcome was a composite endpoint of newly diagnosed AIDS, serious non-AIDS events (SNAE), death, virological failure (VF) or discontinuation of the anchor drug due to failure or toxicity. A marginal structural Cox regression model was used to estimate the effect of starting DTG vs DRV/b-based regimens. Results: A total of 1,323 advanced ART-naïve PWH were included, 895 starting DTG and 428 DRV/b. The unweighted risks of the composite endpoint by 48 months were 21.1% (95% CI: 18.1;24.1%) for DTG versus 37.9% (95% CI: 32.7;43.2%) for DRV/b (p<0.001). First-line treatment with DTG showed a lower risk of experiencing the composite endpoint than DRV/b (wHR of DTG vs DRV/b 0.47, 95% CI: 0.35;0.64, p<0.001). Conclusion: Under the stated assumptions, this analysis indicates that in ART-naïve PWH with advanced disease, ART initiation with DTG vs. DRV/b-based regimens leads to a 50% reduction in the risk of AIDS/SNAE/death/VF/discontinuation. This observed difference is partly explained by discontinuation of the anchor drug

Role of low-frequency integrase strand transfer inhibitor resistance mutations on virological outcomes in antiretroviral therapy-naïve individuals initiating second-generation integrase inhibitors

Objectives: This study investigated the role of low-frequency integrase strand transfer inhibitor (INSTI) resistance mutations, detectable by next-generation sequencing (NGS), at predicting virological rebound (VR) among people with HIV (PWH) starting second-generation INSTI-based first-line regimens. Methods: This case-control study compared PWH (retrieved from the ICONA cohort; www.icona.org) who experienced VR (cases) with those who maintained virological control (controls) under first-line regimens based on dolutegravir or bictegravir. NGS data obtained through the Illumina platform were interpreted using the HIVdb algorithm version 9.7. Major (MRM), accessory (ARM), and other (ORM) INSTI resistance mutations were analysed at 5%, 10%, and 20% NGS cut-offs, respectively. Conditional logistic regression was used to evaluate the association between INSTI resistance and risk of VR. Results: Among 266 PWH (90 cases, 176 controls), cases experienced VR with a median (interquartile range) viremia of 317 (93–6060) copies/mL after 15 (8–28) months from antiretroviral therapy start. The prevalence of MRM was low (NGS cut-off 5%, 10%, 20%: 1.9%, 0.8%, 0.4%, respectively), while it was moderate for ARM (7.5%, 7.1%, 6.4%) and high for ORM (50.0%, 44.7%, 42.1%). There was no evidence of a difference in prevalence of ≥1 MRM, ARM, or ORM between cases and controls. At 5% NGS cut-off, the prevalence of ≥2 ORM was higher in cases compared with controls. After adjusting for confounders, including HIV-1 subtype, ≥2 ORM detected as minority variants remained associated with VR risk. Conclusion: Our findings suggest that combinations of low-frequency ORM may increase the risk of VR in individuals starting dolutegravir or bictegravir-based regimens. Further studies are needed to better understand these findings

Determinants of worse liver‐related outcome according to HDV infection among HBsAg positive persons living with HIV: Data from the ICONA cohort

Objectives: We aimed to study hepatitis D virus (HDV) prevalence and risk of progression to severe liver-related events (SLRE) in HBsAg positive people living with HIV (PLWH) in Italy; role of HDV-RNA copy levels, HCV coinfection and nadir CD4 counts were also investigated.Methods: People living with HIV (PLWH) from Italian Foundation cohort Naive antiretrovirals (ICONA) with available HBsAg and HDV Ab were enrolled. HBsAg, HDV Ab, HDV-RNA and HDV genotypes were tested. Primary end-point: time from first HDV screening to Severe Liver Related Events (SLRE: decompensated cirrhosis, liver transplantation, HCC). Fine-grey regression models were used to evaluate the association of HDV Ab, HDV-RNA, HDV/HCV coinfection, CD4 nadir and outcome. Secondary end-points: time to SLRE or death; HDV Ab and HDV-RNA prevalence.Results: A total of 152/809 (18.8%) HBsAg positive PLWH showed HDV Ab reactivity; 63/93 (67.7%) were HDV-RNA positive. Being male, persons who inject drugs (PWID), HCV Ab positive, with FIB-4 > 3.25 were independent factors of HDV Ab positivity. In a median follow-up of 5 years, 37 PLWH (4.1% at 5-year) developed SLRE and 97 (12.0%) reached the SLRE or death end-point. HDV-RNA positive (independently from HDV-RNA copy level) PLWH had a 4.6-fold (95%CI 2.0-10.5) higher risk of SLRE than HDV negatives. PLWH positive for both HCV Ab and HDV Ab showed the highest independent risk of SLRE (ASHR: 11.9, 95%CI: 4.6-30.9 vs. HCV neg/HDV neg). Nadir CD4 < 200/mL was associated with SLRE (ASHR: 3.9, 95% 1.0-14.5).Conclusions: One-fifth of the HBsAg positive PLWH harbour HDV infection, and are at high risk of progression to advanced liver disease. HCV contributes to worse outcomes. This population needs urgently effective treatments

Risk of clinical events in virologically suppressed people with HIV switching to a two-drug regimen vs. remaining on a three-drug regimen: a target trial emulation

Background: Guidelines support the switch to a two-drug regimen (2DR) in virologically suppressed people with HIV (PWH) on a three-drug regimen (3DR). Randomized clinical trials have not included clinical outcomes in study endpoints. We provide estimates of 3-year clinical risk by means of a target trial emulation using the data of a large cohort of PWH in Italy. Methods: PWH from the Icona Foundation Study who were virologically suppressed (HIV-RNA ≤50 copies/mL) for ≥6 months on a 3DR on or after November 2014, were enrolled (database closure on July 31, 2024). PWH were classified according to therapeutic strategies: switching to 2DR (protease inhibitors or dolutegravir plus lamivudine or dolutegravir plus rilpivirine) or remaining on 3DR (any combination). The primary endpoint was the time to the first clinical composite event (cardiovascular disease [CVD], cancer [AIDS and non-AIDS related], or death). We calculated the difference in 3-year risk between therapeutic strategies, estimated using a weighted non-parametric Kaplan–Meier estimator. Findings: 7672 participants entered the analysis: 629 (8.2%) switching to 2DR and 7043 (91.8%) remaining on 3DR. Over the 3-year follow-up, 408 events were registered (64 CVD, 234 cancer, and 110 deaths). The 3-year adjusted risk estimate was 2.55 (95% CI 1.72, 5.33) in 2DR vs. 4.69 (95% CI 4.48, 6.17) in 3DR. The difference (−2.15% [95% CI −3.56%, −0.20%]) in favor of 2DR was mainly driven by events of non-AIDS related cancer and mortality. Interpretation: This study provides evidence that virologically suppressed PWH can be safely switched to 2DR, and may slightly reduce the 3-year risk of a composite clinical outcome. Funding: The Icona Foundation Study is supported by unrestricted grants from Gilead Sciences, ViiV Healthcare, Merck Sharpe & Dohme

Determinants of worse liver‐related outcome according to HDV infection among HBsAg positive persons living with HIV: Data from the ICONA cohort

Objectives: We aimed to study hepatitis D virus (HDV) prevalence and risk of progression to severe liver-related events (SLRE) in HBsAg positive people living with HIV (PLWH) in Italy; role of HDV-RNA copy levels, HCV coinfection and nadir CD4 counts were also investigated.Methods: People living with HIV (PLWH) from Italian Foundation cohort Naive antiretrovirals (ICONA) with available HBsAg and HDV Ab were enrolled. HBsAg, HDV Ab, HDV-RNA and HDV genotypes were tested. Primary end-point: time from first HDV screening to Severe Liver Related Events (SLRE: decompensated cirrhosis, liver transplantation, HCC). Fine-grey regression models were used to evaluate the association of HDV Ab, HDV-RNA, HDV/HCV coinfection, CD4 nadir and outcome. Secondary end-points: time to SLRE or death; HDV Ab and HDV-RNA prevalence.Results: A total of 152/809 (18.8%) HBsAg positive PLWH showed HDV Ab reactivity; 63/93 (67.7%) were HDV-RNA positive. Being male, persons who inject drugs (PWID), HCV Ab positive, with FIB-4 > 3.25 were independent factors of HDV Ab positivity. In a median follow-up of 5 years, 37 PLWH (4.1% at 5-year) developed SLRE and 97 (12.0%) reached the SLRE or death end-point. HDV-RNA positive (independently from HDV-RNA copy level) PLWH had a 4.6-fold (95%CI 2.0-10.5) higher risk of SLRE than HDV negatives. PLWH positive for both HCV Ab and HDV Ab showed the highest independent risk of SLRE (ASHR: 11.9, 95%CI: 4.6-30.9 vs. HCV neg/HDV neg). Nadir CD4 < 200/mL was associated with SLRE (ASHR: 3.9, 95% 1.0-14.5).Conclusions: One-fifth of the HBsAg positive PLWH harbour HDV infection, and are at high risk of progression to advanced liver disease. HCV contributes to worse outcomes. This population needs urgently effective treatments

Long-acting injectable antiretrovirals for HIV treatment in the ICONA cohort: physicians’ and nurses’ points of view

Background: Implementation level of long-acting injectable agents cabotegravir/rilpivirine (LAI CAB/RPV) for human immunodeficiency virus (HIV) treatment in Italy is still not known. The aim of this study is to identify the status of implementation of LAI CAB-RPV and its barriers. Materials and methods: A cross-sectional online survey was conducted among infectious diseases (ID) physicians and nurses belonging to the ICONA network in Italy. Three validate 4-items measures were used: Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM) and Feasibility of Intervention Measure (FIM). Results: Out of 61 ICONA centres, 38 (62%) completed the survey: 57.9% were academic centres, 42.1% were hospital-based. In total, 104 respondents were ID physicians (57.4%), 77 were nurses (42.5%); 4.5% of all PWH followed at the 38 centres started LAI CAB/RPV at time of study. Centres taking care of >1000 PWH reported 95% application of procedures for LA implementation, higher than other centres (P = 0.009). Mean score of AIM was (16.0, standard deviation, SD, 3.3), of IAM (16.0, SD 3.0) and FIM (16.0, SD 2.9). A linear correlation was found between AIM and the number of people with HIV who started LAI CAB/RPV (25-50 versus <25, coefficient of correlation [b] 2.57, 95%CI 0.91-4.60, P = 0.004), academic versus hospital-based centres (b -1.59, 95%CI -2.76-0.110044, P = 0.007) and the absence of preliminary systematic assessment of staff (b -1.98, 95%CI -3.31-0.65, P = 0.004). Implementation barriers were not significantly different according to the number of PWH/centre. Conclusions: LAI CAB/RPV implementation was low, with a great variability according to centre size. Tailored and centre-specific interventions to address barriers and to optimize the LA treatment implementation should be designed

Selected comorbidities and the probability of ART switch in PWH with undetectable HIV-RNA: a retrospective analysis in Italy

Objectives To estimate the incidence of comorbidities in persons with HIV (PWH) with a stable viral load (VL) of <= 50 copies/mL and evaluate the likelihood of treatment switch (TS) according to the new development of dyslipidaemia (DP), kidney disease and a weight change that determined overweight. Methods We carried out six case-control studies nested within the Icona Foundation Study cohort with the outcome of TS of the current regimen (due to intolerance/toxicity or simplification) and investigated the incident comorbidities. Conditional logistic regression models were employed. Results Overall, the median age of study participants was 45 years (IQR: 36-52), 19% were female, 48% were MSM and 17% were migrants. DP was confirmed to be the most frequent incident comorbidity [138 events; incidence rate (IR) = 28.4%; 95% CI: 22.7%-34%], followed by estimated glomerular filtration rate (eGFR) deterioration and BMI elevation. None of the studied factors was associated with the risk of TS because of simplification. TS because of toxicity was predicted by incident DP [adjusted OR (aOR) = 2.49, 95% CI: 1.19-5.19, P = 0.02] and by a decline in eGFR of >10 mL/min/1.73 m2 (aOR = 1.51, 95% CI: 0.98-2.32, P = 0.06). The association with DP was stronger in participants who were receiving a boosted PI-based regimen at baseline (aOR = 3.38, 95% CI: 1.11-10.30, P = 0.03). Therapy discontinuation because of toxicity/simplification has remained common in PWH with VL of <= 50 copies/mL in recent years. Conclusions The onset of DP and a decline in eGFR was associated with discontinuations due to toxicity. Interventions aiming to mitigate the risk of developing lipid abnormalities in PWH are likely to also reduce the number of ART changes, which can potentially affect future drug options