Measures of Longitudinal Immune Dysfunction and Risk of AIDS and Non-AIDS Defining Malignancies in Antiretroviral Treated People With Human Immunodeficiency Virus (HIV)

BACKGROUND: Human immunodeficiency virus (HIV) infection leads to chronic immune activation/inflammation that can persist in virally suppressed persons on fully active antiretroviral therapy (ART) and increase risk of malignancies. The prognostic role of low CD4:CD8 ratio and elevated CD8 cell counts on the risk of cancer remains unclear. METHODS: We investigated the association of CD4:CD8 ratio on the hazard of non-AIDS defining malignancy (NADM), AIDS-defining malignancy (ADM) and most frequent group of cancers in ART-treated people with HIV (PWH) with a CD4 and CD8 cell counts and viral load measurements at baseline. We developed Cox proportional hazard models with adjustment for known confounders of cancer risk and time-dependent cumulative and lagged exposures of CD4:CD8 ratio to account for time-evolving risk factors and avoid reverse causality. RESULTS: CD4:CD8 ratios below 0.5, compared to above 1.0, were independently associated with a 12-month time-lagged higher risk of ADM and infection-related malignancies (adjusted hazard ratio 2.61 [95% confidence interval {CI }1.10-6.19] and 2.03 [95% CI 1.24-3.33], respectively). CD4 cell counts below 350 cells/μL were associated with an increased risk of NADMs and ADMs, as did infection, smoking, and body mass index-related malignancies. CONCLUSIONS: In ART-treated PWH low CD4:CD8 ratios were associated with ADM and infection-related cancers independently from CD4 and CD8 cell counts and may alert clinicians for cancer screening and prevention of NADM

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

Objectives: 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. Methods: Using logistic regression, 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: VL ≥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. Results: 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). Conclusion: In this large analysis of a real-world population, cTO and on-treatment success were similar between INSTIs and NNRTIs, but lower for PI/b, though residual confounding cannot be fully excluded. Obtaining favorable immunologic outcomes were more likely for INSTIs than the other drug classes

Clinical Outcomes of 2-Drug Regimens vs 3-Drug Regimens in Antiretroviral Treatment–Experienced People Living With Human Immunodeficiency Virus

BACKGROUND: Limited data exist comparing clinical outcomes of two-drug regimens (2DRs) and three-drug regimens (3DRs) in people living with HIV. METHODS: Antiretroviral treatment-experienced individuals in RESPOND switching to a new 2DR or 3DR from 1/1/12-1/10/18 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression. RESULTS: Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median 52.6 years [interquartile range 46.7-59.0] vs 47.7 [39.7-54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%).There were 619 events during 27,159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU [95% CI 20.7-24.5]) on 3DRs, 79 (30.9/1000 PYFU [24.8-38.5]) on 2DRs. The most common events were death (7.5/1000 PYFU [95% CI 6.5-8.6]) and non-AIDS cancer (5.8/1000 PYFU [4.9-6.8]). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio: 0.92 [0.72-1.19]; p=0.53). CONCLUSIONS: This is the first large, international cohort assessing clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes; further research on resistance barriers and long-term durability of 2DRs is needed

How to RESPOND to Modern Challenges for People Living with HIV: A Profile for a New Cohort Consortium

Background: the International Cohort Consortium of Infectious Disease (RESPOND) is a collaboration dedicated to research on HIV and other infectious diseases. Methods: RESPOND is a flexible organization, with several independent substudies operating under one shared governance. HIV-related variables, including full antiretroviral therapy (ART) history, are collected annually for all participants and merged with substudy specific data into a shared data pool. Incident clinical events are reported using standardized forms. Prospective follow-up started 1/10/17 (enrolment) with retrospective data collected back to 01/01/12. Results: Overall, 17 cohorts from Europe and Australia provided data on 26,258 people living with HIV (PLWH). The majority (43.3%) of the population were white, with men-sex-with-men accounting for 43.3% of the risk for HIV acquisition. The median age was 48 years (IQR 40&ndash;56) and 5.2% and 25.5% were known to be co-infected with hepatitis B or C. While 5.3% were ART-na&iuml;ve, the median duration on ART was 10.1 years (4.8&ndash;17.6), with 89.5% having a VL &amp;lt;200 copies/mL and the median CD4 count being 621 cells/&micro;L (438&ndash;830). Malignancies (n = 361) and cardiovascular disease (n = 168) were the predominant reported clinical events. Conclusion: RESPOND&rsquo;s large, diverse study population and standardized clinical endpoints puts the consortium in a unique position to respond to the diverse modern challenges for PLWH

How to RESPOND to Modern Challenges for People Living with HIV: A Profile for a New Cohort Consortium.

BACKGROUND the International Cohort Consortium of Infectious Disease (RESPOND) is a collaboration dedicated to research on HIV and other infectious diseases. METHODS RESPOND is a flexible organization, with several independent substudies operating under one shared governance. HIV-related variables, including full antiretroviral therapy (ART) history, are collected annually for all participants and merged with substudy specific data into a shared data pool. Incident clinical events are reported using standardized forms. Prospective follow-up started 1/10/17 (enrolment) with retrospective data collected back to 01/01/12. RESULTS Overall, 17 cohorts from Europe and Australia provided data on 26,258 people living with HIV (PLWH). The majority (43.3%) of the population were white, with men-sex-with-men accounting for 43.3% of the risk for HIV acquisition. The median age was 48 years (IQR 40-56) and 5.2% and 25.5% were known to be co-infected with hepatitis B or C. While 5.3% were ART-naïve, the median duration on ART was 10.1 years (4.8-17.6), with 89.5% having a VL <200 copies/mL and the median CD4 count being 621 cells/µL (438-830). Malignancies (n = 361) and cardiovascular disease (n = 168) were the predominant reported clinical events. CONCLUSION RESPOND's large, diverse study population and standardized clinical endpoints puts the consortium in a unique position to respond to the diverse modern challenges for PLWH

Incidence of dyslipidemia in people with HIV who are treated with integrase inhibitors versus other antiretroviral agents.

OBJECTIVE To compare the incidence of dyslipidemia in people with HIV receiving integrase inhibitors (INSTI) versus boosted protease inhibitors (PI/b) and nonnucleoside reverse transcriptase inhibitors (NNRTI) within RESPOND consortium of prospective cohorts. METHODS Participants were eligible if they were at least 18 years, without dyslipidemia and initiated or switched to a three-drug antiretroviral therapy (ART)-regimen consisting of either INSTI, NNRTI, or PI/b for the first time, between 1 January 2012 and 31 December 2018. Dyslipidemia was defined as random total cholesterol more than 240 mg/dl, HDL less than 35 mg/dl, triglyceride more than 200 mg/dl, or initiation of lipid-lowering therapy. Poisson regression was used to determine the adjusted incidence rate ratios. Follow-up was censored after 3 years or upon ART-regimen discontinuation or last lipid measurement or 31 December 2019, whichever occurred first. RESULTS Overall, 4577 people with HIV were eligible (INSTI = 66.9%, PI/b = 12.5%, and NNRTI = 20.6%), 1938 (42.3%) of whom were ART-naive. During 1.7 (interquartile range, 0.6-3.0) median years of follow-up, 1460 participants developed dyslipidemia [incidence rate: 191.6 per 1000 person-years, 95% confidence interval (CI) 182.0-201.7]. Participants taking INSTI had a lower incidence of dyslipidemia compared with those on PI/b (adjusted incidence rate ratio 0.71; CI 0.59-0.85), but higher rate compared with those on NNRTI (1.35; CI 1.15-1.58). Compared with dolutegravir, the incidence of dyslipidemia was higher with elvitegravir/cobicistat (1.20; CI 1.00-1.43) and raltegravir (1.24; CI 1.02-1.51), but lower with rilpivirine (0.77; CI 0.63-0.94). CONCLUSION In this large consortium of heterogeneous cohorts, dyslipidemia was less common with INSTI than with PI/b. Compared with dolutegravir, dyslipidemia was more common with elvitegravir/cobicistat and raltegravir, but less common with rilpivirine

The relationship between smoking, current CD4, viral load and cancer in persons living with HIV

BACKGROUND: It is unknown if the carcinogenic effect of smoking is influenced by CD4 count and viral load (VL) in persons living with HIV. MATERIAL AND METHODS: RESPOND participants with known smoking status were included. Poisson regression adjusting for baseline confounders investigated the interaction between current CD4/VL strata (good [CD4≥500/mm and VL200 copies/ml] and intermediate [all other combinations]), smoking status and all cancers, non-AIDS defining cancers (NADC), smoking-related cancers (SRC), and infection-related cancers (IRC). RESULTS: Of 19602 persons, 41.3% were never smokers 44.4% current and 14.4% previous smokers at baseline. CD4/VL strata were poor in 3.4%, intermediate in 44.8% and good in 51.8%. There were 513 incident cancers; incidence rate 6.9/1000 PYFU (95% CI 6.3-7.5). Current smokers had higher incidence of all cancer (adjusted incidence rate ratio 1.45; 1.17-1.79), NADC (1.65; 1.31-2.09), SRC (2.21; 1.53-3.20), and IRC (1.38; 0.97-1.96) vs never smokers. Those with poor CD4/VL had increased incidence of all cancer (5.36; 95% CI 3.71-7.75), NADC (3.14; 1.92-5.14), SRC (1.82; 0.76-4.41) and IRC (10.21; 6.06-17.20) versus those with good CD4/VL. There was no evidence that the association between smoking and cancer subtypes differed depending on the CD4/VL strata (p > 0.1, test for interaction). CONCLUSIONS: In the large RESPOND consortium, the impact of smoking on cancer was clear and reducing smoking rates should remain a priority. The association between current immune deficiency, virological control and cancer was similar for never smokers, current smokers and previous smokers suggesting similar carcinogenic effects of smoking regardless of CD4 count and VL

Uptake and discontinuation of integrase inhibitors (INSTIs) in a large cohort setting.

BACKGROUND Despite increased INSTI use, limited large-scale, real-life data exists on INSTI uptake and discontinuation. SETTING International multicohort collaboration. METHODS RESPOND participants starting dolutegravir (DTG), elvitegravir (EVG) or raltegravir (RAL) after 1/1/2012 were included. Predictors of INSTI used were assessed using multinomial logistic regression. Kaplan Meier and Cox proportional hazards models describe time to and factors associated with discontinuation. RESULTS Overall, 9702 persons were included; 5051 (52.1%) starting DTG, 1933 (19.9%) EVG, 2718 (28.0%) RAL. The likelihood of starting RAL or EVG versus DTG decreased over time and was higher in Eastern and Southern Europe compared to Western Europe.At 6 months after initiation, 8.9% (95% CI 8.3%-9.5%) had discontinued the INSTI (6.4% DTG, 7.4% EVG, 14.0% RAL). The main reason for discontinuation was toxicity (44.2% DTG, 42.5% EVG, 17.3% RAL). Nervous system toxicity accounted for a higher proportion of toxicity discontinuations on DTG (31.8% DTG, 23.4% EVG, 6.6% RAL). Overall, treatment simplification was highest on RAL (2.7% DTG, 1.6% EVG, 19.8% RAL).Factors associated with a higher discontinuation risk included increasing year of INSTI initiation, female gender, hepatitis C coinfection, and prior non-AIDS defining malignancies. Individuals in Southern and Eastern Europe were less likely to discontinue. Similar results were seen for discontinuations after 6 months. CONCLUSION Uptake of DTG versus EVG or RAL increased over time. Discontinuation within 6 months was mainly due to toxicity; nervous system toxicity was highest on DTG. Discontinuation was highest on RAL, mainly due to treatment simplification