Performance evaluation of a self-administered point-of-care test for anal HPV screening in PrEP users: data from a community-based PrEP service.

OBJECTIVES: In this study, we compared the performance of a self-administered point-of-care test (POCT) for anal human papillomavirus (HPV) screening with laboratory gold-standard test in pre-exposure prophylaxis (PrEP) users and evaluated its feasibility. METHODS: We enrolled PrEP users from a local community-based PrEP service. Each participant self-collected an anal swab to test anal HPV with a PCR POCT capable of detecting 14 high-risk HPV genotypes. Anonymous questionnaires on self-sampling feasibility were completed. Participants were then referred to local clinics to undergo standard viral genotyping. Concordance between POCT and gold-standard test was measured with absolute agreement and Cohen's kappa. Receiver operating characteristic (ROC) curves were used to calculate POCT sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: 179 subjects got a valid POCT result, most of them men (98.3%) and men who have sex with men (90.4%). 68.2% tested positive for at least one high-risk HPV genotype on POCT. 150 feasibility questionnaires were collected: 92.7% of compilers found the self-swab easy to perform. For 178 subjects, a gold-standard test valid result was also available: 77% tested positive for at least one high-risk HPV genotype. The median time elapsed between the two tests was 9.8 months, due to COVID-19-related service interruptions. Agreement between POCT and gold-standard test was 79.3% (Cohen's kappa=0.49). POCT showed a sensitivity of 81.0%, a specificity of 73.8%, a PPV of 91.0% and an NPV of 54.4%. CONCLUSIONS: POCT showed a moderate agreement with gold-standard test and a discrete sensitivity and specificity, suggesting that it could be a useful and feasible additional tool for HPV screening, especially in low-resource and community-based settings.

Do we Still Need Eligibility Criteria to Recommend PrEP? Impact of National Prescribing Requirements on Retention in Care and Sexually Transmitted Infections Acquisition.

Italian guidelines recommend HIV pre-exposure prophylaxis (PrEP) only upon satisfying strict eligibility criteria. The objective of this study is to evaluate if PrEP candidates attending a community-based service comply with these criteria and whether these prescribing conditions affect retention in care and sexually transmitted infections (STIs) acquisition. A retrospective analysis was performed on PrEP candidates evaluated from January 2019 to June 2022. Data were collected from self-administered questionnaires and clinical files. The population was divided in subjects with 0/1 (0/1 C) and ≥ 2 (≥ 2 C) criteria. Descriptive statistics and non-parametric tests were employed to describe study population. Incidence of PrEP discontinuation and of STIs was estimated per 100 persons-year of follow up (PYFU), and incidence rate ratio (IRR) was calculated. Univariate and multivariable Cox regression analyses were used to evaluate the association strength between PrEP drop out and other variables. The analyses enrolled 659 individuals: 422 individuals were included in 0/1 C, 237 in ≥ 2 C group, respectively. Inconsistent condom use was the most reported prescribing criteria (399 individuals, 60.6%), followed by a previous STI (186 individuals, 28.2%). 0/1 C exhibited lower STIs incidence. PrEP discontinuation was 29% in 0/1 C and 38% in ≥ 2 C (p = 0.031). Cox model revealed that inconsistent condom use was the only prescribing criteria associated to PrEP persistence. The majority of PrEP candidate did not comply with prescribing conditions. Eligibility criteria failed to identify individuals with better retention in care. Our results suggest that Italian guidelines should be updated removing barriers to prescription.

Impact of predicted HLA class I immunopeptidome on viral reservoir in a cohort of people living with HIV in Italy.

The class I HLA genotype has been widely recognized as a factor influencing HIV disease progression in treatment-naïve subjects. However, little is known regarding its role in HIV disease course and how it influences the size of the viral reservoir once anti-retroviral therapy (ART) is started. Here, leveraging on cutting-edge bioinformatic tools, we explored the relationship between HLA class I and the HIV reservoir in a cohort of 90 people living with HIV (PLWH) undergoing ART and who achieved viral suppression. Analysis of HLA allele distribution among patients with high and low HIV reservoir allowed us to document a predominant role of HLA-B and -C genes in regulating the size of HIV reservoir. We then focused on the analysis of HIV antigen (Ag) repertoire, by investigating immunogenetic parameters such as the degree of homozygosity, HLA evolutionary distance and Ag load. In particular, we used two different bioinformatic algorithms, NetMHCpan and MixMHCpred, to predict HLA presentation of immunogenic HIV-derived peptides and identified HLA-B*57:01 and HLA-B*58:01 among the highest ranking HLAs in terms of total load, suggesting that their previously reported protective role against HIV disease progression might be linked to a more effective viral recognition and presentation to Cytotoxic T lymphocytes (CTLs). Further, we speculated that some peptide-HLA complexes, including those produced by the interaction between HLA-B*27 and the HIV Gag protein, might be particularly relevant for the efficient regulation of HIV replication and containment of the HIV reservoir. Last, we provide evidence of a possible synergistic effect between the CCR5 ∆32 mutation and Ag load in controlling HIV reservoir.

Bictegravir/Emtricitabine/Tenofovir Alafenamide Treatment: Efficacy and Tolerability in Clinical Practice.

Objective: Analysis of bictegravir/emtricitabine/tenofovir alafenamide (BFTAF) efficacy and safety in virologically suppressed people living with HIV (PLWH) in clinical practice. Patients and methods: The retrospective cohort study, which included adult treatment-experienced and virologically suppressed PLWH, switched to BFTAF from June 2019 to June 2021. Efficacy and safety were evaluated as virological failure (VF=2 consecutive HIV-RNA>50 copies/mL or a single HIV-RNA>400 copies/mL) and treatment failure (TF=VF or discontinuation for any reason) until data freezing (August 2022). Results: Of the 1040 PLWH included, 67.8% switched from elvitegravir/cobicistat/FTAF. VF occurred in 4.2% (n=44), with incidence rate of 1.63 per 1000 person-months of follow-up (PMFU) and probability at 24-30 months of 3.8%-4.0%, respectively. Out of the 44 VF, in 75% virological re-suppression was achieved while maintaining BFTAF. Discontinuation occurred in 15% after a median time of 13.5 months of follow-up, with an incidence rate of 5.67 per 1000 PMFU, and a probability at 24-30 months of 11.9%-15.3%, respectively. Main discontinuation reasons were simplification (51.3%) and toxicity (21.8%, involving CNS in half of cases). TF occurred in 18.6% with an incidence rate of 7.01 per 1000 PMFU after a median time of 13.6 observation months; probability at 24-30 months was 14.8%-18.4%, respectively. Conclusion: BFTAF has proven effective and well tolerated in clinical practice.

A four-drug combination oral tablet of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide for the treatment of HIV-1 infection in adults.

INTRODUCTION: Darunavir (DRV)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir alafenamide (TAF) is the only protease inhibitor-based single-tablet regimen (STR) approved for the treatment of HIV infection of adults and pediatric patients weighing at least 40 kg. DRV/COBI/FTC/TAF has demonstrated to be an effective regimen, to have a high genetic barrier to resistance, and to be well tolerated. AREAS COVERED: The authors summarize the chemistry and pharmacology of DRV, COBI, FTC, and TAF and discuss trials conducted on antiretroviral therapy (ART)-naïve and -experienced people living with HIV designed to evaluate safety, tolerability, and efficacy of the STR. This work also reports studies comparing DRV/COBI/FTC/TAF with competitive agents in real-world settings. EXPERT OPINION: Despite the availability of newer antiretroviral drugs and strategies in the management of HIV infection, including long-acting therapies, DRV/COBI/FTC/TAF is still considered an alternative regimen for the treatment of ART-naïve adults. DRV/COBI/FTC/TAF is an effective, well-tolerated, and safe antiretroviral regimen and represents a valid option for people who need to switch therapy due to tolerability issues, such as the onset of neuropsychiatric effects related to integrase strand transfer inhibitors, or virological failure.

Increasing incidence and prevalence of metabolic syndrome in people living with HIV during the COVID-19 pandemic.

Introduction: The aim of this study was to analyze the impact of COVID-19 pandemic restrictions on the prevalence and incidence of metabolic syndrome (MS), and to identify predictors of new MS cases in people living with HIV (PLWH). Methods: This cohort study included PLWH followed at the IRCCS San Raffaele, Milan, Italy, with at least one body mass index (BMI) determination during the pre-pandemic period (1 December 2018 to 29 February 2020) and the pandemic period (1 March 2020 to 31 May 2021). MS diagnosis was based on NCEP ATP III 2005 criteria. Univariable Poisson regression model was used to compare MS incidence rates. Univariable mixed linear models estimated the crude mean change in metabolic parameters during each time period. Multivariable Cox proportional hazards model was used to assess risk factors for MS. Results: This study included 1,564 PLWH, of whom 460 and 1,104 were with and without a diagnosis of MS, respectively, at the beginning of the pre-pandemic period, with an overall prevalence of MS of 29.4%. During the pre-pandemic period, 528/1,564 PLWH had MS, with a prevalence of 33.8% (95%CI = 31.5%-36.1%), while during the pandemic period, the number of PLWH with a diagnosis of MS increased to 628/1,564, with a prevalence of 40.2% (95%CI 37.8%-42.6%; McNemar's test: p < 0.0001). Similarly, the MS incidence rate increased from 13.7/100 person-years of follow-up (PYFU; 95%CI = 11.7-16.0) in the pre-pandemic period to 18.5/100 PYFU (95%CI = 16.2-21.1) in the pandemic period (p = 0.004), with 201 subjects developing MS during the pandemic period. In addition, we observed a significant increase in the crude mean change during the pandemic period compared with the pre-pandemic period for: total cholesterol, LDL cholesterol, plasma glucose, blood pressure, and atherosclerotic cardiovascular disease (ASCVD) risk score. Finally, after adjustment for HIV risk factors, HBV, HCV, ART duration, duration of virologic suppression and use of INSTIs, age [adjusted hazard ratio (AHR) per 3 years older = 1.12 (95%CI = 1.08-1.17)], sex [AHR female vs. male = 0.62 (95%CI = 0.44-0.87)] and CD4+ cell count [AHR per 100 cells/µL higher = 1.05 (95%CI = 1.01-1.09)] were associated with the risk of MS. Conclusion: The COVID-19 pandemic affected the metabolic profile of PLWH and increased the prevalence and incidence of MS.

Trends in Cancer Incidence in Different Antiretroviral Treatment-Eras amongst People with HIV.

Despite cancer being a leading comorbidity amongst individuals with HIV, there are limited data assessing cancer trends across different antiretroviral therapy (ART)-eras. We calculated age-standardised cancer incidence rates (IRs) from 2006-2021 in two international cohort collaborations (D:A:D and RESPOND). Poisson regression was used to assess temporal trends, adjusted for potential confounders. Amongst 64,937 individuals (31% ART-naïve at baseline) and 490,376 total person-years of follow-up (PYFU), there were 3763 incident cancers (IR 7.7/1000 PYFU [95% CI 7.4, 7.9]): 950 AIDS-defining cancers (ADCs), 2813 non-ADCs, 1677 infection-related cancers, 1372 smoking-related cancers, and 719 BMI-related cancers (groups were not mutually exclusive). Age-standardised IRs for overall cancer remained fairly constant over time (8.22/1000 PYFU [7.52, 8.97] in 2006-2007, 7.54 [6.59, 8.59] in 2020-2021). The incidence of ADCs (3.23 [2.79, 3.72], 0.99 [0.67, 1.42]) and infection-related cancers (4.83 [4.2, 5.41], 2.43 [1.90, 3.05]) decreased over time, whilst the incidence of non-ADCs (4.99 [4.44, 5.58], 6.55 [5.67, 7.53]), smoking-related cancers (2.38 [2.01, 2.79], 3.25 [2.63-3.96]), and BMI-related cancers (1.07 [0.83, 1.37], 1.88 [1.42, 2.44]) increased. Trends were similar after adjusting for demographics, comorbidities, HIV-related factors, and ART use. These results highlight the need for better prevention strategies to reduce the incidence of NADCs, smoking-, and BMI-related cancers.

Detection of Asymptomatic Mpox Carriers among High-Ri Men Who Have Sex with Men: A Prospective Analysis.

Mpox is traditionally considered a zoonotic disease with endemic circulation in Africa, but the 2022-2023 outbreak reached an unprecedented high number of cases in non-endemic countries, so that it was declared a public health emergency of international concern. The reasons for this extensive global spread, characterized by sexual transmission amongst men who have sex with men (MSM), have not been fully clarified. The existence of asymptomatic carriers with viable viral shedding might be an explanation and is under-debated after retrospective studies suggested that infection without symptoms might have a prevalence of 6.5%. We aimed to prospectively assess the presence of mpox infection in asymptomatic high-risk MSM using HIV pre-exposure prophylaxis and living with HIV. We selected individuals with no signs of active infection nor suggestive symptoms in the previous 21 days. Eligible individuals collected oral and anal swabs to undergo point-of-care testing for mpox and completed a 21-days follow-up. Seventy-two individuals were enrolled, and none tested positive for mpox infection nor developed symptoms during follow-up. We selected a high-risk population with a significant history of sexual exposure, but we failed to detect any asymptomatic infection. This observation might have important consequences in terms of contact management and epidemic control.

Treatment success of rescue regimens after dual therapy failure in people living with HIV in a real-life setting.

OBJECTIVES: Few data on management of two-drug regimen (2DR) failure in people living with HIV (PLWH) are available. METHODS: Retrospective study of treatment-experienced PLWH on a 2DR who experienced virological failure (VF) [two consecutive viral loads (VLs) ≥50 copies/mL, single VL ≥1000 copies/mL, or antiretroviral therapy (ART) switch after single VL ≥50 copies/mL with previous blips] or discontinuation for toxicity (baseline). Integrase strand transfer inhibitor (INSTI)-based [one INSTI plus one nucleoside reverse transcriptase inhibitor (NRTI) (n = 78) or one non-NRTI (n = 20)] or boosted protease inhibitor (PI/b)-based [one PI/b plus one NRTI (n = 116) or one INSTI (n = 12)] 2DRs were included. Probabilities of treatment success (TS), VF and discontinuation for any other cause of rescue regimens were estimated by Kaplan-Meier curves. A stepwise Cox model was performed to assess predictors of TS. RESULTS: Overall, 226 PLWH were evaluated: at baseline, 144 individuals discontinued 2DR for toxicity and 82 had VF [median viraemia 81 (63-212) copies/mL]; 171 switched therapy (49.7% to triple regimen, 40.9% to different 2DR), while 55 (exclusively with VF) maintained failing regimens. Probabilities of 12- and 24-month TS were 75.6% and 64.7%, respectively. Higher TS probabilities were observed in individuals who switched ART at 2DR failure (P = 0.003) and PLWH who discontinued 2DR for toxicity (P = 0.008). Therapy switch was the only predictor of TS (P = 0.002). CONCLUSIONS: Overall probability of rescue regimens' TS introduced after 2DR failure is good. Prompt ART switch after 2DR failure is advisable.

Meningococcus B Vaccination Effectiveness Against Neisseria gonorrhoeae Infection in People Living With HIV: A Case-Control Study.

BACKGROUND: We assessed the vaccination effectiveness (VE) of multicomponent meningococcal serogroup B (4CMenB) vaccine against gonorrhea among people living with HIV (PLWH) with a previous diagnosis of sexually transmitted infection. METHODS: Unmatched case-control study on men who have sex with men living with HIV, in care at San Raffaele Scientific Institute, Milan, Italy, with gonorrhea, syphilis, chlamydia, or anal human papillomavirus between July 2016 (beginning of 4CMenB vaccination) and February 2021 (date of freezing). For the analysis, cases were people with ≥1 gonorrhea infection since July 2016, and controls were people with ≥1 syphilis, chlamydia, or anal human papillomavirus infection since July 2016. Logistic regression was used to provide the estimate of 4CMenB VE against gonorrhea. RESULTS: Included people living with HIV were 1051 (103 cases, 948 controls); 349 of 1051 (33%) received 2 doses of 4CMenB vaccination. The median follow-up was 3.8 years (2.1-4.3 years). The unadjusted estimate for VE against gonorrhea was 42% (95% confidence interval, 6%-64%; P = 0.027). Logistic regression showed that VE against gonorrhea remained significant (44%; 95% confidence interval, 9%-65%; P = 0.020) after adjusting for some factors that might have a potential influence on VE or those with significant unbalanced distributions between cases and controls at univariable analysis. CONCLUSIONS: 4CMenB vaccination is associated with a lower risk of gonorrhea in the setting of men who have sex with men living with HIV with a previous sexually transmitted infection.

Should we expect weight changes in people with HIV and a reported weight gain only by switching antiretroviral therapy?

Weight gain following the initiation or the switch of antiretroviral therapy (ART) is well documented and mainly associated with some of the most recent drugs, such as integrase strand transfer inhibitors and tenofovir alafenamide. However, limited data have been published on weight trends in ART-experienced people living with HIV (PLWH) with a long exposure to HIV infection and antiretroviral drugs. In our study, we assessed changes in weight after switching ART among PLWH who reported weight gain under a previous regimen.

Association of high-risk sexual behaviours with sexually transmitted infections among men who have sex with men living with HIV.

OBJECTIVES: To explore different sexual behaviours as risk factors for STI among men who have sex with men (MSM) living with HIV. METHODS: This is a cross-sectional study on MSM living with HIV followed at the Infectious Diseases Unit of San Raffaele Hospital, Milan, with at least one diagnosis of gonorrhoea, syphilis, chlamydia or anal human papilloma virus (HPV), between July 2016 and February 2021. We conducted a survey on high-risk sexual behaviours with regard to (1) mean number of partners per month, (2) estimated percentage of condom use and (3) most frequent type of sexual intercourse during 2016-2021. Data on these variables were grouped as follows: (1a) ≤5 vs >5, (1b) >10 vs ≤10, (2a) 0% vs >0%, (2b) ≤50% vs >50%, (2c) 100% vs <100%, (3a) ≥50% vs <50% receptive, (3b) 100% vs <100% insertive, and (3c) 100% vs <100% receptive. A high-risk group was defined as >5 partners, <100% use of condom and ≥50% receptive intercourse. Univariate logistic regressions were applied to assess the association between sexual behaviours and the risk of each STI. RESULTS: Out of 1051 MSM with at least one STI diagnosis, 580 (55%) answered the survey. The risk of chlamydia was lower among individuals with ≤5 partners (≤5 partners vs >5 partners: OR=0.43, 95% CI 0.28 to 0.66, p=0.001) and among those using condoms more frequently (≤50% use of condom vs >50% use of condom: OR=1.55, 95% CI 1.06 to 2.27, p=0.025; 100% vs <100%: OR=0.35, 95% CI 0.20 to 0.59, p=0.001). Individuals using condoms more frequently also had lower risk of gonorrhoea (100% use of condom vs <100% use of condom: OR=0.37, 95% CI 0.17 to 0.79, p=0.011). The risks of chlamydia (OR=3.07, 95% CI 1.92 to 4.90, p<0.001) and gonorrhoea (OR=2.05, 95% CI 1.12 to 3.75, p=0.020) were higher among individuals belonging to the high-risk group. CONCLUSIONS: Chlamydia and gonorrhoea are more likely associated with high-risk sexual behaviours than syphilis and anal HPV among MSM living with HIV.

Recent abacavir use and incident cardiovascular disease in contemporary-treated people with HIV.

OBJECTIVE: Assessing whether the previously reported association between abacavir (ABC) and cardiovascular disease (CVD) remained amongst contemporarily treated people with HIV. DESIGN: Multinational cohort collaboration. METHODS: RESPOND participants were followed from the latest of 1 January 2012 or cohort enrolment until the first of a CVD event (myocardial infarction, stroke, invasive cardiovascular procedure), last follow-up or 31 December 2019. Logistic regression examined the odds of starting ABC by 5-year CVD or chronic kidney disease (CKD) D:A:D risk score. We assessed associations between recent ABC use (use within the past 6 months) and risk of CVD with negative binomial regression models, adjusted for potential confounders. RESULTS: Of 29 340 individuals, 34% recently used ABC. Compared with those at low estimated CVD and CKD risks, the odds of starting ABC were significantly higher among individuals at high CKD risk [odds ratio 1.12 (95% confidence interval = 1.04-1.21)] and significantly lower for individuals at moderate, high or very high CVD risk [0.80 (0.72-0.88), 0.75 (0.64-0.87), 0.71 (0.56-0.90), respectively]. During 6.2 years of median follow-up (interquartile range; 3.87-7.52), there were 748 CVD events (incidence rate 4.7 of 1000 persons-years of follow up (4.3-5.0)]. The adjusted CVD incidence rate ratio was higher for individuals with recent ABC use [1.40 (1.20-1.64)] compared with individuals without, consistent across sensitivity analyses. The association did not differ according to estimated CVD (interaction P  = 0.56) or CKD ( P  = 0.98) risk strata. CONCLUSION: Within RESPOND's contemporarily treated population, a significant association between CVD incidence and recent ABC use was confirmed and not explained by preferential ABC use in individuals at increased CVD or CKD risk.

Subclinical atherosclerosis as detected by carotid ultrasound and associations with cardiac and HIV-specific risk factors; the Archi-Prevaleat project.

OBJECTIVES: To evaluate the prevalence of carotid intima-media thickness (IMT) and plaques in a cohort of people living with HIV (PLWH), the role of cardiovascular risk factors, the impact of the antiretroviral regimens and the difference between naïve and experienced patients in the onset of carotid lesions. METHODS: This project was initiated in 2019 and involves eight Italian centres. Carotid changes were detected using a power colour-Doppler ultrasonography with 7.5 MHz probes. The following parameters were evaluated: IMT of both the right and left common and internal carotids, data regarding risk factors for cardiovascular disease, HIV viral load, CD4 cell counts, serum lipids, glycaemia and body mass index. The associations between pathological findings and potential risk factors were evaluated by logistical regression, with odds ratios (ORs) and 95% confidence intervals (95% CI)s. RESULTS: Among 1147 evaluated PLWH, with a mean age of 52 years, 347 (30.2%) had pathological findings (15.8% plaques and 14.5% IMT). Besides the usual risk factors, such as older age, male sex and dyslipidaemia, CD4 cell nadir < 200 cells/mL (adjusted OR = 1.51, 95% CI: 1.14-1.99) and current use of raltegravir (adjusted OR = 1.54, 95% CI: 1.01-2.36) were associated with higher prevalence of pathological findings. CONCLUSIONS: Our data show that the current overall percentage of carotid impairments remains high. Colour-Doppler ultrasonography could play a pivotal role in identifying and quantifying atherosclerotic lesions among PLWH, even at a very premature stage, and should be included in the algorithms of comorbidity management of these patients.

Associations between integrase strand-transfer inhibitors and cardiovascular disease in people living with HIV: a multicentre prospective study from the RESPOND cohort consortium.

BACKGROUND: Although associations between older antiretroviral drug classes and cardiovascular disease in people living with HIV are well described, there is a paucity of data regarding a possible association with integrase strand-transfer inhibitors (INSTIs). We investigated whether exposure to INSTIs was associated with an increased incidence of cardiovascular disease. METHODS: RESPOND is a prospective, multicentre, collaboration study between 17 pre-existing European and Australian cohorts and includes more than 32 000 adults living with HIV in clinical care after Jan 1, 2012. Individuals were eligible for inclusion in these analyses if they were older than 18 years, had CD4 cell counts and HIV viral load measurements in the 12 months before or within 3 months after baseline (latest of cohort enrolment or Jan 1, 2012), and had no exposure to INSTIs before baseline. These individuals were subsequently followed up to the earliest of the first cardiovascular disease event (ie, myocardial infarction, stroke, or invasive cardiovascular procedure), last follow-up, or Dec 31, 2019. We used multivariable negative binomial regression to assess associations between cardiovascular disease and INSTI exposure (0 months [no exposure] vs >0 to 6 months, >6 to 12 months, >12 to 24 months, >24 to 36 months, and >36 months), adjusted for cardiovascular risk factors. RESPOND is registered with ClinicalTrials.gov, NCT04090151, and is ongoing. FINDINGS: 29 340 people living with HIV were included in these analyses, of whom 7478 (25·5%) were female, 21 818 (74·4%) were male, and 44 (<1%) were transgender, with a median age of 44·3 years (IQR 36·2-51·3) at baseline. As of Dec 31, 2019, 14 000 (47·7%) of 29 340 participants had been exposed to an INSTI. During a median follow-up of 6·16 years (IQR 3·87-7·52; 160 252 person-years), 748 (2·5%) individuals had a cardiovascular disease event (incidence rate of 4·67 events [95% CI 4·34-5·01] per 1000 person-years of follow-up). The crude cardiovascular disease incidence rate was 4·19 events (3·83-4·57) per 1000 person-years in those with no INSTI exposure, which increased to 8·46 events (6·58-10·71) per 1000 person-years in those with more than 0 months to 6 months of exposure, and gradually decreased with increasing length of exposure, until it decreased to similar levels of no exposure at more than 24 months of exposure (4·25 events [2·89-6·04] per 1000 person-years among those with >24 to 36 months of exposure). Compared with those with no INSTI exposure, the risk of cardiovascular disease was increased in the first 24 months of INSTI exposure and thereafter decreased to levels similar to those never exposed (>0 to 6 months of exposure: adjusted incidence rate ratio of 1·85 [1·44-2·39]; >6 to 12 months of exposure: 1·19 [0·84-1·68]; >12 to 24 months of exposure: 1·46 [1·13-1·88]; >24 to 36 months of exposure: 0·89 [0·62-1·29]; and >36 months of exposure: 0·96 [0·69-1·33]; p<0·0001). INTERPRETATION: Although the potential for unmeasured confounding and channelling bias cannot fully be excluded, INSTIs initiation was associated with an early onset, excess incidence of cardiovascular disease in the first 2 years of exposure, after accounting for known cardiovascular disease risk factors. These early findings call for analyses in other large studies, and the potential underlying mechanisms explored further. FUNDING: The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands National Observational HIV cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort and The University of Cologne HIV Cohorts, ViiV Healthcare, and Gilead Sciences.