Three-drug Regimen Research Articles

Treatment strategies with alternative treatment options for patients with Mycobacterium avium complex pulmonary disease.

Diseases caused by Mycobacterium avium complex (MAC) infection in the lungs are increasing worldwide. The recurrence rate of MAC-pulmonary disease (PD) has been reported to be as high as 25-45%. A significant percentage of recurrences occurs because of reinfection with a new genotype from the environment. A focus on reducing exposure to MAC organisms from the environment is therefore an essential component of the management of this disease as well as standard MAC-PD treatment. A macrolide-containing three-drug regimen is recommended over a two-drug regimen as a standard treatment, and azithromycin is recommended rather than clarithromycin. Both the 2007 and 2020 guidelines recommend a treatment duration of MAC-PD of at least one year after the culture conversion. Previous clinical studies have reported that ethambutol could prevent macrolide resistance. Furthermore, the concomitant use of aminoglycoside, amikacin liposomal inhalation, clofazimine, linezolid, bedaquiline, and fluoroquinolone with modification of guideline-based therapy has been studied. Long-term management of MAC-PD remains challenging because of the discontinuation of multi-drug regimens and the acquisition of macrolide resistance. Moreover, the poor compliance of guideline-based therapy for MAC-PD treatment worldwide is concerning since it causes macrolide resistance. Therefore, in this review, we focus on MAC-PD treatment and summarize various treatment options when standard treatment cannot be maintained, with reference to the latest ATS/ERS/ESCMID/IDSA clinical practice guidelines revised in 2020.

Bedaquiline–Pretomanid–Linezolid Regimens for Drug-Resistant Tuberculosis

BackgroundThe bedaquiline–pretomanid–linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear.MethodsWe enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated.ResultsA total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline–pretomanid–linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups.ConclusionsA total of 84 to 93% of the participants across all four bedaquiline–pretomanid–linezolid treatment groups had a favorable outcome. The overall risk–benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.)

Immune checkpoint inhibition improves antimyeloma activity of bortezomib and STING agonist combination in Vk*MYC preclinical model

Multiple myeloma (MM), a hematological malignancy of plasma cells, has remained incurable despite the development of novel therapies that improve patients’ outcome. Recent evidence indicates that the stimulator of interferon genes (STING) pathway may represent a novel target for induction of antitumor immune response in multiple myeloma. Here, we investigated antitumor effects of STING agonist with bortezomib with or without checkpoint inhibitor in the treatment of MM. Methods: STING expression in bone marrow plasma cells of 58 MM patients was examined by immunohistochemical staining. The effectiveness of the proposed therapy was evaluated in vivo in a syngeneic transplantable mouse model of MM (Vĸ*MYC) in immunocompetent mice. Flow cytometry was used to assess tumor burden and investigate activation of immune response against MM. ELISA was performed to measure serum inflammatory cytokines concentrations upon treatment. Results: Combining a STING agonist [2′3′-cGAM(PS)2] with bortezomib significantly decreased tumor burden and improved the survival of treated mice compared to either of the compounds used alone. The combination treatment led to secretion of pro-inflammatory cytokines and increased the percentage of neutrophils, activated dendritic cells and T cells in the tumor microenvironment. However, it resulted also in increased expression of PD-L1 on the surface of the immune cells. Addition of anti-PD1 antibody further potentiated the therapeutic effects. Conclusions: Our findings indicate high antimyeloma efficacy of the three-drug regimen comprising bortezomib, STING agonist, and a checkpoint inhibitor.

Superior Efficacy of a TBI-166, Bedaquiline, and Pyrazinamide Combination Regimen in a Murine Model of Tuberculosis.

TBI-166, derived from riminophenazine analogues, shows more potent anti-TB activity than clofazimine and is being assessed against tuberculosis (TB) in a phase IIa clinical trial in China. Preclinical regimen studies containing TBI-166 will support the phase IIb clinical trials of TBI-166. In the present study, we compared the efficacy in three murine TB models of an all-oral drug-resistant TB drug regimen of TBI-166 with bedaquiline (BDQ) and pyrazinamide (PZA) with the first-line regimen of isoniazid (INH) with rifampin (RFP) and PZA (HRZ regimen), the most effective reported TBI-166-containing regimen of TBI-166 with BDQ and linezolid (LZD), and the Nix-TB clinical trial regimen of BDQ with pretomanid and LZD (BPaL regimen). In the C3HeB/FeJ murine TB model, for the TBI-166+BDQ+PZA regimen, the lungs of mice were culture negative at 4 weeks, and there were no relapses at 8 weeks of treatment. The reduction in bacterial burden and relapse rate were greater than those of the HRZ regimen and the TBI-166+BDQ+LZD regimen. Compared with the BPaL regimen, the TBI-166+BDQ+PZA regimen had similar or stronger early bactericidal activity, bactericidal activity, and sterilizing activity in the BALB/c murine TB model. The bacterial burden in the TBI-166+BDQ+PZA regimen group decreased significantly more than that in the BPaL regimen group and was almost or totally relapse free (<13.33% after 8 weeks). In conclusion, oral short-course three-drug regimens, including TBI-166 with high efficacy, were identified. The TBI-166+BDQ+PZA regimen is recommended for further study in a TBI-166 phase IIb clinical trial.

Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer

BackgroundInitial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches.MethodsFIRE-8 (NCT05007132) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m2 body surface area (BSA), orally twice daily on days 1–5 and 8–12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled.DiscussionTo the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy.Trial registrationEU Clinical Trials Register (EudraCT) 2019-004223-20. Registered October 22, 2019, ClinicalTrials.govNCT05007132. Registered on August 12, 2021.

Treatment With a Three-Drug Regimen for Pulmonary Tuberculosis Based on Rapid Molecular Detection of Isoniazid Resistance: A Noninferiority Randomized Trial (FAST-TB).

BackgroundThe rationale behind the use of ethambutol in the standard tuberculosis treatment is to prevent the emergence of resistance to rifampicin in case of primary resistance to isoniazid. We evaluated whether early detection of isoniazid resistance using molecular testing allows the use an ethambutol-free regimen.MethodsFAST-TB, a phase 4, French, multicenter, open-label, non-inferiority trial, compared 2 strategies: (1) polymerase chain reaction (PCR)-based detection of isoniazid and rifampicin resistance at baseline using Genotype MTBDRplus version 2.0 followed by ethambutol discontinuation if no resistance was detected (PCR arm) and (2) a standard 4-drug combination, pending phenotypic drug-susceptibility results (C arm). Adult patients with smear-positive pulmonary tuberculosis were enrolled. The primary endpoint was the proportion of patients with treatment success defined as bacteriological or clinical cure at the end of treatment. A non-inferiority margin of 10% was used.ResultsTwo hundred three patients were randomized, 104 in the PCR arm and 99 in the C arm: 26.6% were female, median age was 37 (interquartile range, 28–51) years, 72.4% were born in Africa, and 5.4% were infected with human immunodeficiency virus. Chest x-ray showed cavities in 64.5% of the cases. Overall, 169 patients met criteria of treatment success: 87 of 104 (83.7%) in the PCR arm and 82 of 99 (82.8%) in the C arm with a difference of +0.8% (90% confidence interval, −7.9 to 9.6), meeting the noninferiority criteria in the intention-to-treat population (P = .02).ConclusionsIn a setting with low prevalence of primary isoniazid resistance, a 3-drug combination with isoniazid, rifampicin, and pyrazinamide, based on rapid detection of isoniazid resistance using molecular testing, was noninferior to starting the recommended 4-drug regimen.

Assessment of the Carcinogenic Potential of Pretomanid in Transgenic Tg.rasH2 Mice.

Pretomanid is a nitroimidazooxazine antimycobacterial drug that was approved as part of a three-drug oral regimen, consisting of bedaquiline, pretomanid, and linezolid, for 6-months treatment of adults with pulmonary extensively drug-resistant tuberculosis or with complicated forms of multidrug-resistant tuberculosis by the food and drug administration in the United States and regulatory bodies in over 10 other countries. Nitroaromatic compounds as a class carry a risk of genotoxicity and potential carcinogenicity based on reactive metabolite formation. A battery of good laboratory practice genotoxicity studies on pretomanid indicated that the compound was not genotoxic, however its hydroxy imidazole metabolite (M50) was genotoxic in the Ames assay. To assess the in vivo carcinogenic potential of pretomanid, hemizygous Tg.rasH2 mice were administered pretomanid once daily by oral gavage for 26 weeks. Male mice were given pretomanid in vehicle at doses of 0, 5, 15 and 40 mg/kg/day and female mice were given pretomanid in vehicle at doses of 0, 10, 30 and 80 mg/kg/day. Positive control mice of both sexes received intraperitoneal injections of urethane at 1000 mg/kg on Days 1, 3 and 5. There were no pretomanid-related early deaths, tumors, non-neoplastic microscopic findings, or gross necropsy findings at any dose level. The positive control gave the anticipated response of lung tumors. Oral administration of pretomanid to mice produced plasma exposure to the parent compound (high dose AUC of pretomanid 3 times the clinical AUC at the maximum recommended human dose) and exposure to the M50 metabolite (less than 10% of pretomanid) at all dose levels in both sexes. These data show that pretomanid was not carcinogenic in a transgenic mouse model at systemic exposures greater than human therapeutic exposures.

Role of islatravir in HIV treatment and prevention: an update.

To summarize recent updates on the potential role of islatravir for HIV treatment and prevention. Islatravir is an investigational antiretroviral agent with unique pharmacologic properties that facilitate flexible dosing regimens. Islatravir has demonstrated potent antiviral activity and a high barrier to resistance when combined with doravirine and lamivudine. A simplified two-drug HIV treatment regimen of islatravir combined with doravirine has also demonstrated comparable efficacy to standard of care three-drug regimens. The long half-life and high potency of islatravir's active metabolite may support its use as a long-acting option for HIV preexposure prophylaxis (PrEP). A once monthly oral dose of islatravir maintains effective concentrations of its active metabolite over the entire dosing interval. Furthermore, an investigational implantable formulation has been projected to provide efficacious concentrations for at least a year and exhibits comparable distribution into vaginal and rectal tissues making it a promising PrEP option for male and female individuals. Islatravir has minimal risks of drug interactions as it is not a substrate, inducer, or inhibitor of major drug metabolizers and transporters. Finally, clinical trials demonstrate islatravir's favorable safety profile revealing only mild and transient adverse events. Leveraging the unique pharmacological properties of islatravir offers opportunities for simplified HIV treatment regimens and long-acting PrEP making it a valuable addition to the antiretroviral arsenal.

Response to Commentary: Long-term Changes of Inflammatory Biomarkers in Individuals on Suppressive Three-Drug or Two-Drug Antiretroviral Regimens.

Response to Commentary: Long-term Changes of Inflammatory Biomarkers in Individuals on Suppressive Three-Drug or Two-Drug Antiretroviral Regimens.

P-57 An observational/translational study of BRAF inhibitor combination therapy for BRAF-mutant metastatic colorectal cancer including biomarker research: BEETS trial (JACCRO CC-18)

BRAF inhibitor combination therapy became the standard of care for BRAF -mutated metastatic colorectal cancer (mCRC) based on the BEACON CRC trial, which showed a survival benefit of the three-drug combination regimen with BRAF and MEK inhibitors plus anti-EGFR antibody as well as the two-drug combination regimen with BRAF inhibitor and anti-EGFR antibody over standard chemotherapy. The two-drug combination regimen is approved in Europe and the US, while both three- and two-drug combination regimens are approved in Japan.

Regorafenib (REGO) plus FOLFIRINOX as frontline treatment in patients (pts) with RAS-mutated metastatic colorectal cancer (mCRC): A phase I/II, dose-escalation and dose-expansion study.

3561 Background: Standard treatment options for RAS-mutated mCRC pts include the combination of bevacizumab with FOLFIRINOX, a three-drug chemotherapy regimen. Unlike bevacizumab, REGO – an oral multi-tyrosine kinase agent - exhibits not only antiangiogenic properties with cytostatic effects but also true cytotoxic effects. We report the preliminary results of the FOLFIRINOX-R trial (NCT03828799), in which we evaluated the safety and the efficacy of REGO in combination with FOLFIRINOX in pts with RAS-mutated mCRC. Methods: FOLFIRINOX-R trial is a prospective, dose-finding, phase I/II study whose dose-escalation part has been completed. Dose escalation was implemented following a 3 + 3 design and included three dose levels (DL). FOLFIRINOX regimen includes oxaliplatin (85 mg/m²), folinic acid (400 mg/m²), irinotecan (150–180 mg/m²), 5-fluorouracil (400 mg/m² in bolus then 2400 mg/m² over 46h), and was administered every 14 days. REGO (80 to 160 mg per day, as per DL) was administered on days 4 to 10 of each cycle. Treatment was continued up to 12 cycles or until progression or unacceptable toxicity. The primary objectives of the dose-finding part of the study were to determine the maximum tolerated dose (MTD) using as endpoint the incidence of DLTs during the three first cycles of treatment, and to select the recommended phase 2 dose (RP2D). Key eligibility criteria include ECOG PS ≤1 and RAS-mutated mCRC not amenable to surgery with curative intent and not previously treated for metastatic disease. Patients with the 7/7 variant of the UGT1A1*28 polymorphism were not eligible. Prophylactic G-CSF was administered from Day-7 to Day-12. Results: Thirteen pts were enrolled across the 3 DL (DL 1: 3 pts, DL 2: 6 pts, DL 3: 4 pts); 46% of pts were female, the median age was 65 yo [range: 40 ; 76]. One pt (at DL 3) was not evaluable for DLT because of poor observance during the first 2 cycles. At data cut-off, median treatment duration and median follow-up were 4.6 mo. (range: 2.3; 10) and 13.4 mo. (range: 3.8; 18.0), respectively. One DLT (a grade 3 hypokalaemia related to grade 2 diarrhoea) occurred at DL 2. MTD was not reached at DL 3 (REGO 160 mg/day). The most common grade ≥3 TRAE per patient were grade 3 neutropenia (n = 1), grade 4 neutropenia (n = 1), grade 3 neuropathy (n = 2) and grade 3 diarrhoea (n = 7). Dose reductions/discontinuations due to grade ≥3 TRAE were necessary in 12/13 (92%) pts. The ORR was 62% (95% CI 32%-86%) and median PFS was 9.1 mo (range: 3.1; 15.4). Conclusions: Full-dose FOLFIRINOX plus full-dose REGO (160mg/day, days 4 to 10) can be administered safely. Due to the manageable toxicity profile and the promising efficacy observed in the dose-escalation stage, this regimen deserves to be evaluated in the dose-expansion stage. Clinical trial information: NCT03828799.

A phase II single-center single-arm study of PD-1 inhibitor in combination with albumin paclitaxel and apatinib as second-line treatment of metastatic gastric cancer (mGC).

e16024 Background: Immune checkpoint inhibitors have been approved for first- or third-line treatment of metastatic gastric cancer. However, pembrolizumab alone did not improve overall survival compared to second-line chemotherapy in the KEYNOTE-061 study. We aimed to explore the safety and efficacy of a three-drug regimen by carrying out a clinical study of PD-1 inhibitor combined with albumin paclitaxel and apatinib (VEGFR inhibitor) in the second-line treatment for patients with metastatic gastric cancer(mGC). Methods: This study was a single-center, single-arm phase II clinical study. patients harboring microsatellite stable (MSS) who had previously failed in first-line treatment were enrolled. The enrolled patients were given PD-1 inhibitor (PD-1 inhibitor selected according to the patients’ requirements) in combination with albumin paclitaxel (125 mg/m2 IV, D1, 8 days or 250 mg/m2 IV, D1, 250 mg and apatinib 250 or 500 mg orally for D1-21 days, every 3 weeks as a cycle). The primary endpoints were progression-free survival (PFS) and objective response rate (ORR), while the secondary endpoints were overall survival (OS) and safety (AEs), disease control rate (DCR). Results: From July 11, 2019 to December 1, 2021, a total of 23 patients were enrolled, of whom 10 had negative PD-L1 expression, 1 had PD-L1 &gt; 70% expression, and 4 had positive PD-L1 expression. Preliminary results showed 8 cases had partial response (PR), 10 cases had stable disease (SD), and 5 cases of progression disease (PD). ORR was 34.8% and DCR was 78.3%. The median PFS was 5.04 m, and the median OS was not reached. The main adverse reactions of grade 1 to 2 were bone marrow suppression (42.8%), hand-foot reaction (21.4%), hypertension (21.4%), gastrointestinal bleeding (13.0%), hypothyroidism (8.7%), and liver function damage (8.7%). No grade 3-4 adverse reactions were reported. Conclusions: PD-1 inhibitor combined with albumin paclitaxel and apatinib in the second-line treatment of metastatic gastric cancer showed certain efficacy and safety. At present, this study is ongoing to further confirm the anti-tumor effect and survival benefit of this regimen. Clinical trial information: NCT04182724.

Approach to Resectable Gastric Cancer: Evolving Paradigm of Neoadjuvant and Adjuvant Treatment.

Recent therapeutic advances have prolonged survival in patients with metastatic gastric cancer, though the prognosis for patients with locally advanced resectable gastric cancer remains poor. Long-term survival after resection of locally advanced gastric adenocarcinoma is dependent on early eradication of micrometastatic disease and optimal surgical resection. Preoperative therapy with a docetaxel-containing three-drug regimen has recently been shown to be superior to an anthracycline-containing three-drug regimen or two-drug therapy with a fluoropyrimidine and platinum. Chemoradiation is not essential and is reserved for patients with suboptimal resection. Emerging research strategies include introduction of pre- and postoperative checkpoint blockade and biomarker-directed therapy.

Preemptive multimodal analgesia and post-operative pain outcomes in total hip and total knee arthroplasty.

Use of multimodal analgesia (MMA) prior to orthopedic surgery has been adopted by many practitioners as a strategy to minimize use of opioid medications. The purpose of this investigation was to quantify the effect of a preemptive three-drug regimen (acetaminophen, celecoxib, and gabapentin) in terms of post-operative opioid consumption and pain control in the field of total joint arthroplasty. A retrospective chart review was conducted on 1691 patients who underwent total hip arthroplasty (THA) or total knee arthroplasty (TKA) and stratified by whether they received a preemptive three medication analgesic therapy (acetaminophen, celecoxib, and gabapentin) within 30 to 60min prior to entering the operating room. Post-operative opioid consumption as well as subjectively reported patient pain scores were assessed throughout their hospital stay. A total of 1416 eligible patients were identified with 485 undergoing THA and 931 undergoing TKA. Statistically significant reductions in oral morphine equivalents were shown on post-operative day zero and two within the TKA cohort, and non-significant reductions were demonstrated in other intervals for both procedure types. Statistically significant reductions in patient reported pain scores were shown in nearly every time interval in both procedure types. The receipt of preemptive acetaminophen, celecoxib, and gabapentin 30-60min prior to total joint arthroplasty demonstrated modest reductions in opioid requirements post-operatively. Patients receiving preemptive MMA reported lower pain scores throughout nearly every time interval during their admission after surgery. Further investigations are warranted regarding optimal preoperative medication therapies to promote adequate post-operative pain control-and ultimately diminished opioid consumption-in the setting of total joint arthroplasty.

Commentary: Long-Term Changes of Inflammatory Biomarkers in Individuals on Suppressive Three-Drug or Two-Drug Antiretroviral Regimens.

Commentary: Long-Term Changes of Inflammatory Biomarkers in Individuals on Suppressive Three-Drug or Two-Drug Antiretroviral Regimens.

Shorter Time to Discontinuation Due to Treatment Failure in People Living with HIV Switched to Dolutegravir Plus Either Rilpivirine or Lamivudine Compared with Integrase Inhibitor-Based Triple Therapy in a Large Spanish Cohort.

IntroductionStandard therapy for HIV treatment has consisted of two nucleoside analogue reverse transcriptase inhibitors (NRTI) paired with a third agent. Use of two-drug regimens (2DR) has been considered for selected patients in part to avoid toxicities associated with the use of NRTIs. This study aimed to compare the real-world outcomes of integrase inhibitor (INSTI)-based three-drug regimens (3DR) versus 2DR of dolutegravir (DTG) + rilpivirine (RPV) or DTG + lamivudine (3TC).MethodsAll patients in the Spanish VACH cohort switching to INSTI-based 3DR or a 2DR consisting of DTG + RPV or DTG + 3TC between May 2, 2016 and May 15, 2019 were included. Kaplan–Meier curves and Cox proportional hazard models were used to assess time to/risk of discontinuation due to treatment failure (TF) (defined as virologic failure [VF], immunologic failure, or disease progression) and adverse events (AEs). Three secondary analyses were performed: (1) in restricting the analysis to patients who were virologically suppressed (HIV RNA < 50 copies/mL) at switch; (2) matched analysis (2:1, matched by age, sex, number of previous VFs, and line of regimen), and (3) using VF as the primary endpoint in all patients.ResultsOverall, 5047 3DR and 617 2DR patients were analyzed. Baseline characteristics differed between groups; 2DR patients were older, more treatment experienced, and more likely to be virologically suppressed at switch. Time to discontinuation due to TF was significantly shorter for 2DR (P = 0.002). The hazard ratio (HR) for discontinuation due to TF on 2DR vs 3DR was 2.33 (P = 0.003). No difference was observed for time to discontinuation (P = 0.908) or risk of discontinuation due to AEs (HR = 0.80; P = 0.488). Results were qualitatively similar in virologically suppressed patients, matched analysis, and for VF.ConclusionIn the real world, the risks of discontinuation due to TF and VF were more than two times higher in patients switching to DTG-based 2DR than INSTI-based 3DR, with no difference in discontinuation due to AEs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00630-y.

Similar CD4/CD8 Ratio Recovery After Initiation of Dolutegravir Plus Lamivudine Versus Dolutegravir or Bictegravir-Based Three-Drug Regimens in Naive Adults With HIV

BackgroundThe initiation of antiretroviral treatment based on a 2-drug regimen (2DR) with dolutegravir plus lamivudine has demonstrated non-inferior efficacy than dolutegravir-based three-drug regimens (3DR). We aimed to assess whether the treatment initiation with this 2DR has a different impact on the CD4/CD8 ratio recovery than INSTI-based 3DR.MethodsWe emulated a target trial using observational data from the Spanish HIV Research Network cohort (CoRIS). The outcomes of interest were the normalization of the CD4/CD8 ratio at 48 weeks using three different cutoffs: 0.5, 1.0, and 1.5. We matched each participant who started 2DR with up to four participants who received 3DR. Subsequently, we fitted generalized estimating equation (GEE) models and used the Kaplan–Meier method for survival curves.ResultsWe included 485, 805, and 924 participants for cutoffs of 0.5, 1.0, and 1.5, respectively. At 48 weeks, 45% of participants achieved a CD4/CD8 ratio >0.5, 15% achieved a ratio >1.0, and 6% achieved a ratio >1.5. GEE models yielded a similar risk of reaching a CD4/CD8 ratio >0.5 (OR 1.00, 95% CI 0.67 - 1.50), CD4/CD8 >1.0 (OR 1.03, 95% CI 0.68 - 1.58), and CD4/CD8 >1.5 (OR 0.86, 95% CI 0.48 - 1.54) between both treatment strategies. There were no differences between 2DR and 3DR in the incidence ratio of CD4/CD8 ratio normalization at 0.5, 1.0 and 1.5 cut-offs.ConclusionsIn this large cohort study in people with HIV, ART initiation with dolutegravir plus lamivudine vs. dolutegravir or bictegravir-based triple antiretroviral therapy showed no difference in the rates of CD4/CD8 normalization at 48 weeks.

Virological and Immunological Outcomes of an Intensified Four-Drug versus a Standard Three-Drug Antiretroviral Regimen, Both Integrase Strand Transfer Inhibitor-Based, in Primary HIV Infection.

The optimal therapeutic approach for primary HIV infection (PHI) is still debated. We aimed to compare the viroimmunological response to a four- versus a three-drug regimen, both INSTI-based, in patients with PHI. This was a monocentric, prospective, observational study including all patients diagnosed with PHI from December 2014 to April 2018. Antiretroviral therapy (ART) was started, before genotype resistance test results, with tenofovir/emtricitabine and either raltegravir plus boosted darunavir or dolutegravir. Cumulative probability of virological suppression [VS] (HIV-1 RNA< 40 cp/mL), low-level HIV-1 DNA [LL-HIVDNA] (HIV-1 DNA < 200 copies/106PBMC), and CD4/CD8 ratio ≥1 were estimated using Kaplan–Meier curves. Factors associated with the achievement of VS, LL-HIVDNA, and CD4/CD8 ≥ 1 were assessed by a Cox regression model. We enrolled 144 patients (95.8% male, median age 34 years): 110 (76%) started a four-drug-based therapy, and 34 (24%) a three-drug regimen. Both treatment groups showed a comparable high probability of achieving VS and a similar probability of reaching LL-HIVDNA and a CD4/CD8 ratio ≥1 after 48 weeks from ART initiation. Higher baseline HIV-1 RNA and HIV-1 DNA levels lowered the chance of VS, whereas a better preserved immunocompetence increased that chance. Not statistically significant factors associated with LL-HIVDNA achievement were found, whereas a higher baseline CD4/CD8 ratio predicted the achievement of immune recovery. In PHI patients, the rapid initiation of either an intensified four-drug or a standard three-drug INSTI-based regimen showed comparable responses in terms of VS, viral reservoir size, and immunological recovery.

Short Communication:Outcomes of Dual Versus Triple Antiretroviral Drug Regimens Among Virally Suppressed Adults in the DC Cohort.

This study explored virological outcomes of two-drug (2DRs) and three-drug (3DRs) antiretroviral regimens in adults with HIV in the DC Cohort. We analyzed 310 treatment-experienced adults with sustained HIV RNA ≤50 copies/mL at baseline, 53 of whom switched to 2DRs and 257 continued 3DRs. Adults on 2DRs and 3DRs had similar demographics (median age 53.3 years, 76.8% cisgender male, 76.1% Black). Adults on 2DRs had more participants with ≥2 comorbidities (62.3% vs. 42.8%, p = .019), had a longer time since HIV diagnosis (median years 20.4 vs. 13.2, p = .017), and received the regimen of interest for a shorter duration (median years 1.3 vs. 3.3, p < .001) compared with adults on 3DRs. Adults receiving 2DRs had a higher, although nonsignificant, risk for virological failure (two consecutive HIV RNA ≥50 copies/mL) at 24 months follow-up than adults on 3DRs (6.7% vs. 1.7%, respectively; p = .10). Future analysis of the effectiveness of 2DRs is needed.

Effects of adding a neurokinin-1 receptor antagonist to 5\xa0mg olanzapine, a 5-hydroxytryptamine-3 receptor antagonist, and dexamethasone for preventing carboplatin-induced nausea and vomiting: a propensity score-matched analysis

BackgroundOlanzapine has been reported to be an effective antiemetic in patients receiving carboplatin-based chemotherapy. However, the efficacy of a neurokinin-1 receptor antagonist (NK1RA) added to olanzapine, a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA), and dexamethasone (DEX) has not been proven. This study aimed to assess the efficacy and safety of NK1RA, in combination with three-drug antiemetic regimens containing olanzapine, in preventing nausea and vomiting induced by carboplatin-based chemotherapy.MethodsData were pooled for 140 patients receiving carboplatin-based chemotherapy from three multicenter, prospective, single-arm, open-label phase II studies that evaluated the efficacy and safety of olanzapine for chemotherapy-induced nausea and vomiting. The propensity score of the co-administration of NK1RA was estimated for each patient using a logistic regression model that included age, sex, and carboplatin dose. We analyzed a total of 62 patients, who were treated without NK1RA (non-NK1RA group: 31 patients) and with NK1RA (NK1RA group: 31 patients). The patients were selected using propensity score matching.ResultsThe complete response rate (without emetic episodes or with no administration of rescue medication) in the overall period (0–120 h post carboplatin administration) was 93.5% in the non-NK1RA group and 96.8% in the NK1RA group, with a difference of -3.2% (95% confidence interval, -18.7% to 10.9%; P = 1.000). In terms of safety, there was no significant difference between the groups in daytime sleepiness and concentration impairment, which are the most worrisome adverse events induced by olanzapine.ConclusionsThe findings suggest that antiemetic regimens consisting of olanzapine, 5HT3RA, and DEX without NK1RA may be a treatment option for patients receiving carboplatin-based chemotherapy.