Uptake and Discontinuation of Integrase Inhibitors (INSTIs) in a Large Cohort Setting

Greenberg, Lauren; Ryom, Lene; Wandeler, Gilles; Grabmeier‐Pfistershammer, Katharina; Öllinger, Angela; Neesgaard, Bastian; Stephan, Christoph; Calmy, Alexandra; Rauch, Andri; Castagna, Antonella; Spagnuolo, Vincenzo; Johnson, Margaret; Stingone, Christof; Mussini, Cristina; Wit, Stéphane De; Necsoi, Coca; Campins, Antoni A; Pradier, Christian; Stecher, Melanie; Wasmuth, Jan‐Christian; Monforte, Antonella d’Arminio; Law, Matthew; Puhr, Rainer; Chkhartishvilli, Nikoloz; Tsertsvadze, Tengiz; Garges, Harmony P.; Thorpe, David; Lundgren, Jens D; Peters, Lars; Bansi‐Matharu, Loveleen; Mocroft, Amanda

doi:10.1097/qai.0000000000002250

Cited by 28 publications

(23 citation statements)

References 40 publications

(21 reference statements)

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“…From 2014 onwards, INSTI-based regimens already accounted for the majority of initial treatments resulting in a maximum of 86% in the year 2017. We found a higher risk for modification on RAL compared to EVG and DTG, mainly due to therapy simplification, which is comparable to previous studies [ 27 , 28 ]. Furthermore, we found that patients who received INSTI-based regimens as their first-line treatment had the highest probability of an undetectable viremia after 12 months.…”

Section: Discussionsupporting

confidence: 89%

Treatment modification after starting cART in people living with HIV: retrospective analysis of the German ClinSurv HIV Cohort 2005–2017

et al. 2020

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Objective Combination antiretroviral therapy (cART) has markedly increased survival and quality of life in people living with HIV. With the advent of new treatment options, including single-tablet regimens, durability and efficacy of first-line cART regimens are evolving. Methods We analyzed data from the prospective multicenter German Clinical Surveillance of HIV Disease (ClinSurv) cohort of the Robert-Koch Institute. Kaplan–Meier and Cox proportional hazards models were run to examine the factors associated with treatment modification. Recovery after treatment initiation was analyzed comparing pre-cART viral load and CD4+ T-cell counts with follow-up data. Results We included 8788 patients who initiated cART between 2005 and 2017. The sample population was predominantly male (n = 7040; 80.1%), of whom 4470 (63.5%) were reporting sex with men as the transmission risk factor. Overall, 4210 (47.9%) patients modified their first-line cART after a median time of 63 months (IQR 59–66). Regimens containing integrase strand transfer inhibitors (INSTI) were associated with significantly lower rates of treatment modification (adjusted hazard ratio 0.44; 95% CI 0.39–0.50) compared to protease inhibitor (PI)-based regimens. We found a decreased durability of first-line cART significantly associated with being female, a low CD4+ T-cell count, cART initiation in the later period (2011–2017), being on a multi-tablet regimen (MTR). Conclusions Drug class and MTRs are significantly associated with treatment modification. INSTI-based regimens showed to be superior compared to PI-based regimens in terms of durability.

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Section: Discussionsupporting

confidence: 89%

Treatment modification after starting cART in people living with HIV: retrospective analysis of the German ClinSurv HIV Cohort 2005–2017

et al. 2020

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“…Previous findings within RESPOND [20] have confirmed that INSTI toxicity only accounts for approximately 5% of the reasons for INSTI discontinuations, similar to findings from the Swiss cohort study [21]. Likewise, a recent, large online-questionnaire examination from the Brazilian Ministry of Health found that only 2.2% of participants experienced self-reported dolutegravir toxicity.…”

Section: Virologic Outcomessupporting

confidence: 73%

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

et al. 2020

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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.

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“…Treatment‐limiting neuropsychiatric adverse events occurred in about 3.5% of DTG recipients in cohort studies [36], more frequently with DTG ( vs . other INSTI) [37‐40], and with greater frequency in women, those aged 60 years and over, and DTG/ABC co‐administration in one study [37] but not others [38,39].…”

Section: Discussionmentioning

confidence: 99%

Bone mineral density, kidney function, weight gain and insulin resistance in women who switch from TDF/FTC/NNRTI to ABC/3TC/DTG

et al. 2020

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ObjectivesTenofovir disoproxil fumarate (TDF) is associated with reduced bone mineral density (BMD). We evaluated changes in BMD in women who switched from TDF, emtricitabine and a nonnucleoside reverse transcriptase inhibitor (TDF/FTC/NNRTI) to abacavir, lamivudine and dolutegravir (ABC/3TC/DTG).MethodsWe conducted a randomized controlled trial in which women aged ≥40 years were randomized 1:2 to continue TDF/FTC/NNRTI or switch to ABC/3TC/DTG. The primary endpoint was change in total hip BMD measured by dual‐energy X‐ray absorptiometry at week 48. Secondary endpoints were changes in BMD of the lumbar spine and femoral neck and markers of bone turnover and kidney function up to week 48. We conducted exploratory analyses of weight gain, insulin resistance and metabolic syndrome. Primary and secondary endpoints were analysed by linear regression, with multiple imputation for missing time points.ResultsIn all, 91 women [mean age = 50.4 (standard deviation [SD] = 6.6) years, median CD4 cell count = 600 (interquartile range: 479–800) cells/µL] were randomized. Women who switched to ABC/3TC/DTG maintained viral suppression and experienced improvements in total hip BMD (mean adjusted difference = 1%, P = 0.027) and lumbar spine BMD (3%, P = 0.002), with no change in specific markers of bone turnover or renal tubular function. Although participants in the ABC/3TC/DTG arm gained more weight (1.8 kg, P = 0.046), the switch strategy was not associated with reduced insulin sensitivity or new‐onset metabolic syndrome.ConclusionsSwitching from TDF/FTC/NNRTI to ABC/3TC/DTG resulted in improved BMD. Although weight gain was common in women who switched from TDF/FTC/NNRTI to ABC/3TC/DTG, we did not detect adverse effects on glucose homeostasis. Larger studies need to confirm these findings.

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Uptake and Discontinuation of Integrase Inhibitors (INSTIs) in a Large Cohort Setting

Cited by 28 publications

References 40 publications

Treatment modification after starting cART in people living with HIV: retrospective analysis of the German ClinSurv HIV Cohort 2005–2017

Treatment modification after starting cART in people living with HIV: retrospective analysis of the German ClinSurv HIV Cohort 2005–2017

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

Bone mineral density, kidney function, weight gain and insulin resistance in women who switch from TDF/FTC/NNRTI to ABC/3TC/DTG

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