Incidence Of Treatment Discontinuation Research Articles

Real-World Experience of the Comparative Effectiveness and Safety of Molnupiravir and Nirmatrelvir/Ritonavir in High-Risk Patients with COVID-19 in a Community Setting.

Molnupiravir (MOV) and nirmatrelvir/ritonavir (NMV/r) are efficacious oral antiviral agents for patients with the 2019 coronavirus (COVID-19). However, little is known about their effectiveness in older adults and those at high risk of disease progression. This retrospective single-center observational study assessed and compared the outcomes of COVID-19 treated with MOV and NMV/r in a real-world community setting. We included patients with confirmed COVID-19 combined with one or more risk factors for disease progression from June to October 2022. Of 283 patients, 79.9% received MOV and 20.1% NMV/r. The mean patient age was 71.7 years, 56.5% were men, and 71.7% had received ≥3 doses of vaccine. COVID-19-related hospitalization (2.8% and 3.5%, respectively; p = 0.978) or death (0.4% and 3.5%, respectively; p = 0.104) did not differ significantly between the MOV and NMV/r groups. The incidence of adverse events was 2.7% and 5.3%, and the incidence of treatment discontinuation was 2.7% and 5.3% in the MOV and NMV/r groups, respectively. The real-world effectiveness of MOV and NMV/r was similar among older adults and those at high risk of disease progression. The incidence of hospitalization or death was low.

Impact of resistance mutations on efficacy of dolutegravir plus rilpivirine or plus lamivudine as maintenance regimens: a cohort study

The aim of this study was to evaluate the impact of resistance mutations on efficacy of dolutegravir-based two-drug regimens (2DR). Virologically suppressed patients with HIV-1 switching to dolutegravir+lamivudine or rilpivirine or to a dolutegravir-based three-drug regimen (3DR) with pre-baseline genotype were selected. Virological failure (VF) was defined as one HIV-RNA viral load (VL) >200 cps/mL or two consecutive VL >50 cps/mL; treatment failure (TF) was defined as VF or treatment discontinuation (TD). Resistance was defined as at least low-level resistance to at least one drug of the current regimen. Propensity score matching was used to conduct adjusted analyses within a competing risks framework. A total of 971 dolutegravir-based regimens were selected: 339 (34.9%) 2DR and 632 (65.1%) 3DR. The adjusted cumulative 48-week incidence of VF was 4.2% (90% CI 3.1%-5.3%) with 2DR and 4.7% (90% CI 3.5%-5.8%) with 3DR. The cumulative 48-week incidence of TF was 15.8% (90% CI 13.9%-17.9%) with 2DR and 24.5% (90% CI 22.2%-27.0%) with 3DR. For VF, the estimated hazard ratio (HR) for 2DR vs. 3DR was 1.02 (90% CI: 0.78-1.34), with evidence of effect modification by low-level resistance (HR 3.96, 90% CI: 2.10-7.46). The estimated HR of TF for 2DR vs. 3DR was 0.54 (90% CI: 0.48-0.60). The 48-week cumulative incidence of TD was 11.7% (8.7%, 14.6%) in 2DR and 19.6% (16.9%, 22.4%) in 3DR. Dolutegravir-based 2DR showed high virological efficacy and durability; however, past resistance increased the risk of VF, but not of TD or TF.

Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial

BackgroundDarolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here.MethodsIn this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS.ResultsIn Japan, 95 patients were enrolled and randomized to darolutamide (n = 62) or placebo (n = 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11–0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%.ConclusionsEfficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.

CLO19-025: Treatment Discontinuation Due to Adverse Events and the Risk of Gastrointestinal Toxicities in Patients With Hematologic Malignancies Treated With Ibrutinib

Background: Ibrutinib targets Bruton’s tyrosine kinase, a kinase involved in signaling of B-cell and chemokine receptors, which are implicated in the pathogenesis of hematologic malignancies. Ibrutinib has been shown to improve survival in hematologic malignancies, and yet the tolerability has not been elucidated. We undertook systematic review and pooled analysis of randomized controlled trials (RTCs) to determine the risk of gastrointestinal toxicities and the rate of treatment discontinuation due to adverse events. Methods: We performed a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through September 2018. Phase 3 RCTs that mention gastrointestinal toxicities and the rate of treatment discontinuation due to adverse events were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% CI. Random effects model was applied. Results: 6 phase III RCTs with a total of 1,811 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia were included. Studies comparing ibrutinib vs ofatumumab, ibrutinib vs chlorambucil, ibrutinib + bendamustine + rituximab vs placebo + bendamustine + rituximab, ibrutinib vs temsirolimus, and ibrutinib vs rituximab were included in the analysis. The incidence of treatment discontinuation due to adverse events was 9.30% in the ibrutinib group vs 13.13% in the control arm. The relative risk (RR) for treatment discontinuation was 0.740 (95% CI: 0.385–1.423; P=.367). The pooled RR of all-grade side effects were as follows: diarrhea, 1.955 (95% CI: 1.304–2.933; P=.001); nausea, 1.038 (95% CI: 0.702–1.534; P=.852); vomiting, 1.048 (95% CI: 0.547–2.007; P=.888); and stomatitis, 1.262 (95% CI: 0.112–14.173; P=.850). The RR of high-grade adverse effects were as follows: diarrhea, 1.749 (95% CI: 0.866–3.530; P=.119); nausea, 2.237 (95% CI: 0.478–10.471; P=.306); vomiting, 0.429 (95% CI: 0.111–1.659; P=.220); and stomatitis, 0.309 (95% CI: 0.028–3.440; P=.340). Conclusion: Our study demonstrated that patients on ibrutinib arm noted increased risk of all-grade diarrhea. Nevertheless, other GI toxicities as well as treatment discontinuation due to adverse events were not statistically significant in the ibrutinib group compared with the control arm.

Safety Profile of Benznidazole in the Treatment of Chronic Chagas Disease: Experience of a Referral Centre and Systematic Literature Review with Meta-Analysis.

Benznidazole is the preferred drug for treatment of Chagas disease. However, it is toxic and of limited value in chronic infection. We aimed to estimate the rates of and factors related to adverse reactions (ARs) to benznidazole and treatment discontinuations (TDs). A meta-analysis was performed using an electronic search of the published literature with no language restrictions until June 2017. Prospective studies were included of chronically infected patients in which at least one treatment arm included benznidazole. Data were added from a prospective cohort of patients with Chagas disease at our centre (January 2007-June 2017). Weighted rates of ARs and TDs were estimated, and potentially related factors were analysed. Some 413 studies were found, from which we chose 42 (nine clinical trials and 33 observational studies, including ours), comprising data for 7822 patients. The weighted rate of ARs to benznidazole was 44.1% (95% confidence interval [CI] 37.2-51.2). ARs were more frequent in adults than in children (51.6 vs. 24.5%), with the most common being skin reactions (34%), gastrointestinal complaints (12.6%) and neurological symptoms (11.5%). Grade 4 ARs were recorded in 3% of cases. The weighted rate of TDs was 11.4% (95% CI 8.5-14.5); TDs were more frequent in adults than in children (14.2 vs. 3.8%). In our cohort, only female sex was related to an increased rate of ARs but not to TDs. Benznidazole had a poor tolerability profile, with a high incidence of TDs, especially in adult patients and women. Optimised dosing schedules and/or new drugs are urgently needed.

Rosuvastatin and atorvastatin preserve renal function in HIV-1-infected patients with chronic kidney disease and hyperlipidaemia

Background:Hyperlipidaemia is a risk factor for the progression of chronic kidney disease (CKD), which is a frequent comorbidity in patients with HIV-1 infection, but the renal effects of statins remain unclear.Methods:We performed an observational, prospective study of HIV-infected patients on suppressive antiretroviral therapy, with CKD and hyperlipidaemia, and starting a lipid-lowering treatment with rosuvastatin, atorvastatin or omega-3 fatty acids. CKD was defined as an estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m2 for >3 months.Results:As a whole, 69 patients (53 men, 58 Caucasian, median age 56.2 years) were enrolled. Overall, 25 patients started rosuvastatin (10 mg daily, group A), 23 patients atorvastatin (20 mg daily, group B), and 21 started omega-3 fatty acids (3 g daily, group C). At baseline, median eGFR was 54.4 mL/min/1.73 m2, and the eGFR ranged between 50 and 60 mL/min/1.73 m2 in 87% of patients. After 12 months, the median eGFR decline was significantly lower in group A (−0.84 mL/min/1.73 m2) and in group B (−0.91 mL/min/1.73 m2) in comparison with the group C (−1.53 mL/min/1.73 m2; p < 0.001 for both comparisons). The median decrease in prevalence of proteinuria and high-sensitivity C-reactive protein was also significantly greater in groups A and B than in group C, while the incidence of treatment discontinuations was comparable across the three groups.Conclusion: In our study, rosuvastatin and atorvastatin showed a significant protective effect on the renal function compared to omega-3 fatty acids in HIV-1-infected patients with CKD and dyslipidaemia.

Immunotherapy in non-small cell lung cancer and the abscopal effect.

e18104 Background: Advanced research and better understanding of the human immune system has led to the development of targeted immunotherapy such as PD-1 inhibitors. We studied patients with both squamous and non-squamous Non-Small Cell Lung Cancer in a community setting who are being treated with Nivolumab. Our primary objective was to determine response to therapy (overall response rate-ORR). Our secondary objective was to study the abscopal response of our population and if the tumor response was better in those patients who received radiotherapy in the preceding 6 months of the start of immunotherapy Methods: Data were summarized using descriptive statistics including means, standard deviations, medians, frequencies and percentages. Chi square analyses were used to make comparisons between response and categorical variables. Overall response rate was calculated by combining people with partial and complete response. All p-values were two tailed and a level of ≤ 0.05 was considered significant. Results: Out of 21 patients, eight (38%) did not show any disease progression. Five out of these eight patients (23% of total study population) had stable disease. Three remaining patients had partial response to the treatment. The ORR was 14% which is comparable to 20% and 19% ORR in the CheckMate trials for nivolumab. Thirteen (62%) patients had progressive disease. Our study showed no significant effect of radiotherapy on disease response to nivolumab. There was one incidence of treatment discontinuation permanently due to the side effects of Nivolumab. Conclusions: Immunotherapy is a promising new option in lung cancer treatment. Fewer side effects and improved survival compared to traditional second line chemotherapy makes it more appealing. In our study group, nivolumab has shown ORR of 14% and stable disease in an additional 23% of the patients resulting in a disease control rate of 37%.

Oral Lapacho-Based Medication: An Easy, Safe, and Feasible Support to Prevent and/or Reduce Oral Mucositis During Radiotherapy for Head and Neck Cancer

The aim of our Phase II study is to demonstrate the benefits, safety, and tolerance of Orasol Plus, an easy and feasible Lapacho-based medication. Orasol Plus is a nutritional, swallowable solution, useful to support the defenses of the oropharyngeal mucosa. Between January and June 2014, 40 consecutive adult patients affected by head and neck cancer were enrolled. Orasol Plus was administered 3 times a day from the first day till the end of radiotherapy. Primary endpoint was to evaluate tolerance and safety of Orasol Plus; secondary endpoint was to evaluate the effect of Orasol Plus on the incidence of treatment discontinuation. Nearly all patients used Orasol Plus easily till the end of radiotherapy without interruptions. Only 11 (27.5%) patients developed oral mucositis (OM) Grade 2 and only 4 (10%) patients OM Grade 3, no patient developed OM Grade 4. No patient discontinued radiotherapy because of OM. Orasol Plus was well tolerated and the compliance of patients was optimal, mainly due to the fact that it can be swallowed. Data from our study are encouraging and they need to be confirmed by a Phase III study.

Switching to lamivudine plus darunavir/r dual therapy in a cohort of treatment-experienced HIV-positive patients: the experience of an Italian centre.

IntroductionAccording to recent evidence about boosted protease inhibitors (PIs/r)-simplified regimens, the combination of 3TC and DRV/r 800/100 mg could represent a feasible option for optimizing antiretroviral therapy (ART) in treatment-experienced HIV+ patients.Patients and MethodsWe retrospectively evaluated patients switching to 3TC+DRV/r, with at least six months of viral suppression, no resistance mutation to DRV or 3TC and not HBV-coinfected: incidence of ART discontinuation and of virological failure (VF: 2 consecutive HIV-RNA determinations>49 cps/mL or a single one≥1000 cps/mL) and the probability of remaining discontinuation-free during one-year follow-up (FU), as well as changes in laboratory parameters at 1, 3, 6 and 12 months were estimated.ResultsWe included 94 patients: 74 males, mostly MSM (39.4%), with 49 years old, 9 years of HIV disease, 8 years of ART (median values). Median nadir CD4 count and zenith viral load (log10) were 194 cells/µL and 4.90, respectively. Ten patients were HCV-coinfected and 38 had at least a previous VF. Seventy-four patients were on an NRTIs-based triple regimen (mainly TDF/FTC or 3TC/ABC) whereas 14 on another PI-based dual therapy (mainly LPV/r). Incidence of treatment discontinuation was 12.4 per 100 patients-year follow-up (PYFU), but only 2 patients experienced a VF (3.5 per 100 PYFU). Mean time free from discontinuation was 5 years (95% CI 4–6), with a cumulative one-year estimated probability of staying on 3TC+DRV/r of 85.9%. At three months, a trend of increased CD4 cells count (+42 cells/µL, p 0.059) was observed, but not confirmed at later time point; an increase of total cholesterol (TC, +17mg/dL, p 0.008) and LDL (+19 mg/dL, p 0.002), and a decreased level of AST and ALT (−2 UI/L, p 0.045; −5 UI/L, p 0.009, respectively) were also detected. Total bilirubin was reduced (−0.71 mg/dL, p 0.038). At 6 and 12 months, alteration of lipid profile was similar, with also an increased TC/HDL ratio (+0.48, p=0.030, at six months) and HDL/LDL ratio (−0.04, p=0.035, at 12 months). A significant decrease in ALT levels (−6 UI/L, 0.013) and a diminishing trend for AST and total bilirubin, as well as a significant increase in renal function (GFR +4mL/min, p 0.048) were observed at 12 months.ConclusionsThese observations on 3TC+DRV/r-based dual therapy simplification in virologically suppressed patients show a good profile of efficacy and safety. An extended FU time is needed in order to establish the real impact of this promising therapeutic choice.

Survival outcomes associated with different sunitinib dosing regimens in metastatic renal cell carcinoma.

417 Background: Standard dosing regimen of sunitinib for metastatic renal cell carcinoma (mRCC) consists of 4 weeks treatment followed by 2-weeks rest (intermittent dosing, ID). Alternative regimens have been suggested, including continuous daily dosing (continuous dosing, CD) and non-conventional dosing (non-conventional dosing: e.g. 2 weeks on / 1-week off, ND) to provide more individualized therapy with less toxicities. It is unclear whether non-standard sunitinib dosing affects survival outcomes. Methods: mRCC patients treated with sunitinib between July 1, 2007 and July 1, 2011 were identified from the British Columbia Cancer Agency (BCCA) pharmacy database, a publicly funded cancer care organization. Medical records and dispensing data were reviewed retrospectively to categorize sunitinib dosing as ID, CD or ND. Primary outcome was to compare overall survival (OS) associated with varying regimens, with secondary outcomes of progression free survival (PFS) and incidence of treatment discontinuation due to adverse effects (AE). Results: A total of 180 patients were identified. Heng prognostic risk criteria were assessable in 162 patients. Of these, 34 (21%), 80 (49%) and 48 (30%) had low-, intermediate- and high-risk disease. Most patients received ID (120, 67%), followed by CD (32,18%) and ND (28,16%). Compared to ID, CD was associated with similar OS (median 9 vs. 13 months, HR 0.67, 95% CI 0.43-1.06, p=0.088) while ND was associated with significantly longer OS (median 9 vs. 23 months, HR 0.55, 95% CI 0.34-0.90, p=0.016). PFS was significantly better for CD (median 4 vs. 9 months, HR 0.61, 95% CI 0.40-0.94, p=0.025) and ND (median 4 vs. 10 months, HR 0.61, 95% CI 0.39-0.95, p=0.03) when compared to ID. Similar to prior sunitinib trials, a significant proportion of patients (20%) discontinued sunitinib therapy due to AE. Conclusions: In comparison to the standard ID regimen, dosing sunitinib with alternative regimens appears to be associated with improved OS and PFS in patients with mRCC. Presently, a prospective Canadian trial is underway investigating the efficacy and safety of individualized sunitinib dosing regimens.

Meta-Analysis of the Safety, Tolerability, and Efficacy of Lopinavir/Ritonavir-Containing Antiretroviral Therapy in HIV-1–Infected Women

Purpose: Women comprise ≯50% of HIV-infected patients, yet safety, tolerability, and efficacy data in women taking antiretrovirals (ARVs) are limited. Lopinavir/ ritonavir (LPV/r)–anchored regimens are globally the most widely prescribed HIV-1 protease inhibitor regimens. The objective was to investigate the safety and efficacy of LPV/r-based therapy in women. Methods: A database query yielded all available data in HIV-1–infected subjects receiving LPV/r-based triple-ARV regimens from randomized clinical trials lasting ≥48 weeks from Abbott or Abbott-supported AIDS Clinical Trials Group studies. Efficacy (HIV-1 RNA levels, CD4+ T-cell counts) and safety and tolerability (treatment discontinuation, treatment-related adverse events [AE], and clinical laboratory abnormalities) at 48 weeks were assessed for total women, women by age (≥50, <50 years) and body mass index (BMI; <25, ≥25 to <30, ≥30 kg/m2), and sex. Results: Nine hundred ninety-two women initiated LPV/r-based therapy (of whom 79.2% were ARV-naïve), with 83.6% completing 48 weeks of treatment. There were 75.5% of women who achieved a threshold of HIV RNA <400 copies/mL by intent-to-treat, non-completer equals failure (ITT, NC = F) analysis, with a mean ± SE CD4+ T-cell count increase of 191.6 ± 4.92 cells/mm3 from baseline. Women aged ≥50 versus <50 years had higher incidence of moderate-to-severe treatment-related AEs and certain laboratory abnormalities, better virologic response (HIV RNA <400 copies/mL by ITT, NC = F), similar immunologic responses, and similar overall incidence of treatment discontinuations. Higher incidences of certain moderate-to-severe treatment-related AEs and laboratory abnormalities occurred in women with BMI ≥30 kg/m2; however, no effect of BMI on efficacy or discontinuation was observed. Conclusions: LPV/r-based regimens were efficacious and well-tolerated in women without marked differences based on age and BMI categories evaluated.

Conversion from Tacrolimus (TAC) to Sirolimus(SRL)-Based Immunosuppressive Regimen in Kidney Transplant Recipients: 1 Year Results

Introduction: This multicenter prospective study evaluates renal function of kidney transplant recipients who underwent planned conversion from TAC to SRL-based regimen 3 months after transplantation. Methods: Low risk recipients of first kidney transplant receiving TAC, mycophenolate sodium (MPS) and prednisone showing good renal function, no proteinuria and no previous severe acute rejection at 3 months were randomized after the transplant surgery to be converted from TAC to SRL. The primary outcome is calculated glomerular filtration rate (cGFR, Cockroft-Gault) at 24 months using intention-to-treat analysis. Here we show results observed at 12 months. Results: Of 296 patients enrolled in this study and reaching 12 months, 277 were randomized to be converted to SRL (n=136) or to stay on TAC (n=141). The mean age of this population was 45.0 ± 13.3 years; 55.4% caucasian, 70.9 % male and 46.4% RKT from deceased donor. During the first 3 months 14 (5%) patients discontinued the study. Of 263 patients reaching month 3, 58 (22%) did not meet criteria for intervention, 110 were converted to SRL and 95 were maintained on TAC. At 3 months, TAC mean trough blood concentration was 7.1 ng/mL, mean MPS dose was 1349.3±244.4 mg/day and mean prednisone dose 8.0±4.9 mg/day. No differences were observed in mean cGFR at 3 months (64.4±19.8 and 66.2±19.5 ml/min) and 12 months (74.8±25.7 vs. 70.2±19.1 ml/min), respectively. The incidence of biopsy proven acute rejection (BCAR) was comparable at 3 months (15% vs. 17%), but higher in patients on SRL (5.2% vs. 1.8%) between 3 and 12 months. At month 12, patients receiving SRL showed mean trough blood concentrations of 8.5±3.1 ng/ mL and mean MPS dose of 1316.8±234.8 mg/day while patients receiving TAC showed mean trough blood concentration of 5.8±2.7ng/mL and mean MPS dose of 1365.2 ± 213.3 mg/day. There were no differences in the incidence of treatment discontinuation (7.4% vs. 5.4%), graft loss (1.1% vs. 0.9%) or death (0.9% vs. 1.8%), respectively. Conclusions: This preliminary analysis indicates that 78% of KTR reaching 3 months fulfilled the criteria to undergo conversion from TAC to SRL. Conversion was associated with increased risk of acute rejection, comparable tolerability but no difference in cGFR at 12 months compared to patients maintained on TAC.

Tipranavir

Tipranavir is a non-peptidic HIV-1 protease inhibitor. It binds strongly and selectively, has a favourable resistance profile, and is administered orally twice daily with a subtherapeutic dosage of ritonavir in a 'boosted' regimen (TPV/r) in order to increase its bioavailability. Analysis of clinical isolates from treatment-experienced patients identified the following tipranavir resistance-associated HIV protease mutations: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, I84V. In two large, well designed phase III trials in protease inhibitor-experienced, HIV-infected patients, the RESIST (Randomised Evaluation of Strategic Intervention in multidrug reSistant patients with Tipranavir)-1 and -2 studies, oral TPV/r 500mg/200mg twice daily achieved a significantly better virological response after 24 weeks than standard ritonavir-boosted protease inhibitors. This held true for the proportion of patients achieving a >or=1 log(10) decrease in plasma HIV-RNA levels (viral load) [42% and 41% vs 22% and 15%; both p < 0.0001; primary endpoint] and other virological parameters (the proportion of patients with undetectable viral load and total viral load reduction). In addition, a significantly larger increase in CD4+ cell count was achieved with TPV/r than comparator regimens in these trials. The most common adverse events in clinical trials of tipranavir were gastrointestinal. The incidence of treatment discontinuation because of adverse events in the RESIST trials was 8% (pooled data).