Retreatment Regimen Research Articles

Prevalence of Drug Resistance Associated Substitutions in Persons With Chronic Hepatitis C Infection and Virological Failure Following Initial or Re-treatment With Pan-genotypic Direct-Acting Antivirals: A Systematic Review and Meta-analysis.

The advent of short-course, curative treatment with direct-acting antivirals (DAA) has given promise for the global elimination of hepatitis C virus (HCV) infections by 2030. Virological failure occurs in 2%-12% of persons receiving curative DAA treatment and may be presaged by pre-existing polymorphisms or result from selection of drug resistant variants during therapy. We conducted a systematic review to assess the prevalence of HCV resistance associated substitutions (RAS) among individuals with chronic hepatitis C infection who had virological failure following initial or re-treatment with pan-genotypic DAA regimens. We included 34 and 22 studies assessing RAS in people with virological failure published between January 2014 and July 2023. Pooled RAS prevalence was estimated using random-effects meta-analysis. The pooled prevalence of RAS in people with virological failure following initial DAA treatment was 78.0% (95% confidence interval [CI]: 62.0-92.0) for sofosbuvir/velpatasvir, 81.0% (95% CI: 67.0-93.0) for sofosbuvir/daclatasvir, and 79.0% (95% CI: 70.0-87.0) for glecaprevir/pibrentasvir, with a high prevalence of resistance to the NS5A inhibitors. Among those with virological failure following re-treatment regimens, RAS were present in 93.0% (95% CI: 83.0-99.0) for sofosbuvir/velpatasvir/voxilepravir and in 100% (95% CI: 92.0-100) for glecaprevir/pibrentasvir, with resistance driven by RAS to NS5A inhibitors. At least 1 RAS is present in a high proportion of the few individuals with virological failure following initial or re-treatment with pan-genotypic DAA regimens. There is a need for ongoing surveillance for DAA-associated resistance, to assess risk factors for their development and clinical impact to inform best practice strategies for re-treatment.

Assessing thresholds of resistance prevalence at which empiric treatment of gonorrhea should change among men who have sex with men in the US: A cost-effectiveness analysis.

Since common diagnostic tests for gonorrhea do not provide information about susceptibility to antibiotics, treatment of gonorrhea remains empiric. Antibiotics used for empiric therapy are usually changed once resistance prevalence exceeds a certain threshold (e.g., 5%). A low switch threshold is intended to increase the probability that an infection is successfully treated with the first-line antibiotic, but it could also increase the pace at which recommendations are switched to newer antibiotics. Little is known about the impact of changing the switch threshold on the incidence of gonorrhea, the rate of treatment failure, and the overall cost and quality-adjusted life-years (QALYs) associated with gonorrhea. We developed a transmission model of gonococcal infection with multiple resistant strains to project gonorrhea-associated costs and loss in QALYs under different switch thresholds among men who have sex with men (MSM) in the United States. We accounted for the costs and disutilities associated with symptoms, diagnosis, treatment, and sequelae, and combined costs and QALYs in a measure of net health benefit (NHB). Our results suggest that under a scenario where 3 antibiotics are available over the next 50 years (2 suitable for the first-line therapy of gonorrhea and 1 suitable only for the retreatment of resistant infections), changing the switch threshold between 1% and 10% does not meaningfully impact the annual number of gonorrhea cases, total costs, or total QALY losses associated with gonorrhea. However, if a new antibiotic is to become available in the future, choosing a lower switch threshold could improve the population NHB. If in addition, drug-susceptibility testing (DST) is available to inform retreatment regimens after unsuccessful first-line therapy, setting the switch threshold at 1% to 2% is expected to maximize the population NHB. A limitation of our study is that our analysis only focuses on the MSM population and does not consider the influence of interventions such as vaccine and common use of rapid drugs susceptibility tests to inform first-line therapy. Changing the switch threshold for first-line antibiotics may not substantially change the health and financial outcomes associated with gonorrhea. However, the switch threshold could be reduced when newer antibiotics are expected to become available soon or when in addition to future novel antibiotics, DST is also available to inform retreatment regimens.

Managing Hepatotoxicity Caused by Anti-tuberculosis Drugs: A Comparative Study of Approaches.

Tuberculosis (TB) is one of the oldest and most well-known diseases that has been associated with humans for many years and remains a global health challenge today. Timely diagnosis and proper treatment are crucial for controlling and preventing the spread of the disease. While anti-TB drugs offer many benefits, inadequate monitoring can lead to a range of side effects, including hepatotoxicity, which is a major concern and can cause treatment discontinuation. The aim of this study was to determine the approach to the hepatotoxicity of anti-TB drugs and to investigate potential relationships between demographic factors, underlying medical conditions, and successful retreatment outcomes for hepatotoxicity induced by anti-TB drugs. For this study, we reviewed the medical records of patients who experienced hepatotoxicity due to anti-TB treatment and were admitted to the infectious ward of Imam Khomeini Hospital between April 2015 and February 2019. The data were collected using a questionnaire. The findings indicated that the female gender, weight loss at the beginning of hospitalization, hepatitis C virus, hepatitis B virus (HBV), heart disease, and high levels of aspartate aminotransferase (AST) and alanine transaminase (ALT) at the beginning of hepatotoxicity are risk factors for failure to the retreatment of hepatotoxicity. There were two different approaches to the anti-TB retreatment regimen. The first approach involved gradually starting the drugs in full dose, while the second approach encompassed starting the drugs in the minimum dose and then increasing to the maximum dose. The results demonstrated no significant difference between the two approaches to managing hepatotoxicity induced by anti-TB drugs. Drug-induced hepatotoxicity is a common occurrence that often results in treatment discontinuation. Understanding the prevalence of this complication and identifying appropriate methods of rechallenge treatment is crucial to reducing complications and mortality rates.

High rate of adverse drug reactions with a novel tuberculosis re-treatment regimen combining triple doses of both isoniazid and rifampicin

ObjectivesHigh-dose rifampicin (R) and isoniazid (H) are known to be safe but were not yet combined in a single regimen. The primary objective of the TRIple-DOse RE-treatment (TRIDORE) study is to determine whether a 6-month firstline regimen with triple dose of both R and H (intervention arm; 6R3H3ZE) is non-inferior in terms of safety compared to a normal-dose regimen (6RHZE) in previously treated patients with R-susceptible (Rs) recurrent tuberculosis (TB). Design/methodsTRIDORE is an ongoing pragmatic open-label multi-stage randomized clinical trial. ResultsBetween March 2021 and February 2022, 127 consenting patients were randomly assigned to either the intervention or control arm: 62 and 65 were treated with 6R3H3ZE and 6RHZE, respectively. Of 127, 111 (87.4%) were male and the median age (interquartile range) was 37 (30-48) years. The median body mass index at enrollment was 18.1 (16.3-19.7) kg/m2. Drugrelated severe adverse events (AEs) (grade III-V) were significantly more frequent when 6R3H3ZE was used (5/62 vs 0/65, P = 0.03, difference weighted for site 8% [95% confidence interval: 1.0,14.3]). The Data and Safety Monitoring Board recommended publishing our interim safety data analysis. ConclusionWe show that the combination of triple-dose R with triple-dose H in a re-treatment regimen for patients with Rs-TB causes excess drug-related AEs.

Hepatitis C Retreatment With First-Line Direct Acting Antiviral Drugs

Sofosbuvir (S), daclatasvir (D), ledipasvir, or velpatasvir (V) containing first-line hepatitis C virus (HCV) treatment regimens fail to cure viremia in 5-10%. We report our experience of HCV retreatment using these first-line drugs, in a setting where second-line anti-HCV drugs are not available. Adults, who had relapsed after first complete course of a sofosbuvir-containing first-line, pegylated interferon free, anti-HCV treatment regimen with or without ribavirin (Riba) were included. Retreatment regimen, tailored to the failed anti-HCV regimen, was based on principle of using first-line drugs for 24 weeks with ribavirinand swapping between pangenotypic and genotype-specific regimens. Retreatment outcome was categorized as successful (achieved undetectable HCV RNA at the end of treatment [ETR] and sustained viral response at week 12 [SVR12]), non-responder (failed to achieve ETR), or relapse (achieved ETR but not achieved SVR12). Twelve patients (9 male; 7 cirrhosis; all genotype 3) who had relapsed to prior anti-HCV treatment (4 SD12, 4 SD24, 1 SDRiba12, 1 SDRiba24, 2 SV12) were included. Following retreatment (2 SDRiba24, 10 SVRiba24), all achieved ETR but only 9 (75%) achieved SVR12. Two among three, in whom retreatment failed, achieved SVR12 following another course of sofosbuvir/velpatasvir/ribavirin for 24 weeks. Overall, 11/12 (92%) patients achieved SVR12 following retreatment with the first-line anti-HCV drugs. HCV retreatment could be a treatment option if second-line anti-HCV drugs are not available. Successful retreatment could be achieved, in a large proportion, with the use of first-line drugs for 24 weeks with ribavirinand swapping of pangenotypic/genotype-specific regimens (NCT03483987).

Real-World Treatment Patterns and Outcomes of Daratumumab Retreatment in Multiple Myeloma in the United States

Background: Daratumumab (Dara) combination therapy is approved in transplant ineligible newly diagnosed multiple myeloma (MM), and ongoing trials evaluating Dara in transplant eligible newly diagnosed MM may result in increased first-line (1L) use. Because Dara combinations are also approved in relapsed/refractory MM, patients may receive Dara retreatment in subsequent lines of therapy (LOTs); however, data regarding optimal sequencing and benefit of Dara retreatment are lacking. Here, we present a real-world evaluation of treatment patterns and effectiveness of retreatment with Dara-based regimens. Methods: This retrospective observational study utilized deidentified electronic health records data from the Concert AI Patient360 database, representing primarily United States community-based oncology centers. The analysis included adult patients who met the following inclusion criteria: diagnosed with MM on or after January 1, 2011 through December 31, 2021, received ≥1 LOT postdiagnosis, had no prior stem cell transplantation, and had no other primary cancer diagnosis at baseline. Within this population, patients who received treatment with Dara (1L and beyond) and subsequent retreatment with Dara (second line [2L] and beyond) were identified. 1L was defined as all MM medications used within 35 days of MM-related medication initiation. Advancement of LOT was based on regimen change and documented progression events or stem cell transplant. The primary objective was to determine the proportion of MM patients initially treated and retreated with Dara-based regimens overall and by LOT. Key secondary objectives were to determine duration of treatment (DOT) and time to next treatment (TTNT) using the Kaplan-Meier method. A maximum follow-up date was determined for each patient using activity dates from multiple data files to identify the last active date of any medical encounter. Patients without subsequent LOT or death dates were censored at the maximum follow-up. Data were reported for the overall group and by the LOT in which initial Dara treatment was received. Results: Among 2367 patients with MM who met the inclusion criteria, 713 (30%) were treated with a Dara-based regimen, of which 97 (4%) were retreated with Dara and included in the analysis. Among the 97 patients analyzed, 21 (22%) started initial Dara treatment in 1L, 38 (39%) in 2L, 23 (24%) in third line (3L), and 15 (15%) in fourth or later line (4L+). Median age at diagnosis was 61-68.5 years across these groups, and 35%-50% of patients were male. Most patients had a baseline ECOG performance status of 1-2 (61%-65% for 1L, 2L, and 3L) with the exception of 4L+ (33%), and stage 2 (20%-42%) or 3 (27%-48%) disease at diagnosis. Patients were mostly treated at community (67%-81%) vs academic centers (19%-33%). Initial treatment regimens were Dara + immunomodulatory drug (IMiD) ± proteasome inhibitor (PI) (67%), Dara + PI (21%), or Dara monotherapy (12%). Dara retreatment occurred in the LOT subsequent to the initial Dara treatment episode for 90%-100% of patients; the most common retreatment regimen was Dara + IMiD (43%), followed by Dara + IMiD + PI (33%) and Dara + PI (15%). The Table shows clinical outcomes for initial Dara treatment and retreatment episodes in the same set of patients, with data by LOT indicating the line in which initial Dara treatment was received. Among 95 Dara retreated patients who had a maximum follow-up date, median DOT was 254 days and 196 days for initial Dara treatment and retreatment episodes, respectively. Median DOT by LOT for initial Dara treatment episodes ranged from 173 days (4L+ initiation) to 288 days (1L initiation). Median DOT by LOT for Dara retreatment episodes ranged from 149 days (4L+ initiation) to 304 days (1L initiation). Median TTNT was 308 days and 457 days for initial Dara treatment and retreatment episodes, respectively. Median TTNT by LOT for initial Dara treatment episodes ranged from 286 days (4L+ initiation) to 434 days (1L initiation). Median TTNT by LOT for Dara retreatment episodes ranged from 256 days (3L initiation) to not yet reached (1L initiation). Conclusion: This analysis of real-world data from adult patients diagnosed with MM showed that DOT and TTNT for Dara retreatment episodes were reasonably long and aligned with clinical expectations for subsequent therapy, suggesting that patients continue to receive meaningful clinical benefit with Dara retreatment despite prior exposure. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Direct-acting antiviral retreatment patterns for hepatitis C.

BACKGROUND: Despite the strong efficacy of direct-acting antivirals (DAAs) against the hepatitis C virus, many patients require a second regimen of DAA treatment. However, limited research exists to characterize rates of retreatment across different DAA agents or potential factors that may increase retreatment risk. OBJECTIVE: To characterize patterns and predictors of DAA retreatment among a large, generalizable, commercially insured US population of patients. METHODS: Using the IBM MarketScan Commercial Claims and Encounters data source, this retrospective cohort study examined retreatment patterns among patients receiving DAAs between 2013 and 2019. Descriptive statistics were used to compare patient characteristics predictive of retreatment risk and to examine rates of retreatment in patients initiating different DAA treatments. RESULTS: Among 31,553 DAA users, a total of 1,017 (3.2%) required DAA retreatment. Among the 1,017 patients re-treated, 44 (4.3%) received a third treatment regimen and 2 patients received a fourth treatment regimen. The average total cost for a retreatment regimen was $109,683, with patient out-of-pocket costs totaling $1,287 Patients requiring retreatment had higher rates of hypertension (32.0% vs 26.7%; P < 0.001), diabetes (16.9% vs 11.9%; P < 0.001), coagulopathy (9.9% vs 4.5%; P < 0.001), deficiency anemia (11.1% vs 7.4%; P < 0.001), alcohol abuse (3.3% vs 2.3%; P = 0.038), prior liver transplantation (3.4% vs 2.3%; P = 0.024), and hepatocellular carcinoma (6.1% vs 1.9%; P < 0.001) compared with patients not requiring retreatment. CONCLUSIONS: Although uncommon, some patients receiving DAAs require a second regimen of DAA treatment at substantial cost to both health plans and patients. These patients tend to have more comorbidities and markers of hepatic disease severity. Patients with high retreatment risk may benefit from careful monitoring for occurrences of retreatment.

Commentary: Usage of intravitreal steroids in endophthalmitis: Horns of a dilemma

The usage of steroids intravitreally along with antimicrobials for endophthalmitis management has been marred with controversy for decades. To a large extent, management of endophthalmitis has been based on physician discretion and has a lot of variability between cases. The rationale behind steroids/anti-inflammatory agents is that endophthalmitis leads to severe inflammation and bystander damage to intraocular tissues, especially the neurosensory retina, resulting in irreversible functional changes. Suppressing this inflammation may help reduce the irreversible damage and shorten the overall disease course. It is not well understood whether the damage to the visual function is due to the infectious agent or the immune response developed by the host in response to it. There is no unanimous understanding regarding whether steroids have any definite role in visual improvement as demonstrated by this metanalysis, and previous reports as well.[1] The current article evaluated studies dealing with bacterial endophthalmitis alone. Considering fungal endophthalmitis, there is even lesser amount of evidence regarding the status of steroids, as steroids are believed to flare up intraocular pathogens. One way to approach this conundrum is to consider steroids once an initial dose of intravitreal antimicrobials has been given and/or vitrectomy has been done to reduce the microbial load. Then, if the patient is undergoing further intravitreal injections, intravitreal steroids can be considered. However, steroids may have a definite role in preserving the anatomical integrity during initial endophthalmitis management, preventing outcomes such as phthisis bulbi or requirement of evisceration.[2] The inconsistencies in management rationale, type of outcomes reported, and follow-up protocols in previous studies make a uniform consensus difficult—more so because quantifying resolution or a successful management of endophthalmitis is not standardized. Steroids may reduce tissue inflammation in the initial period, which in turn can reduce the chances of eyes requiring further vitrectomies or IOL explantation procedures. Another point to ponder is that the older evidence of intravitreal steroids is from days when an initial intravitreal regimen of antibiotics with or without steroids with additional injections would be considered followed by a period of observation. A decision of vitrectomy would be taken after noting the resolution pattern and based on physician discretion. However, with complete and early vitrectomy, as is becoming the norm gradually, after the organism load has been reduced, intravitreal steroids may also be considered in the retreatment regimens.[3] The biggest gray zone is for cases of fungal endophthalmitis, where no clear evidence is available due to extreme variability in clinical presentations. Authors have noted that visual outcomes may be better in fungal endophthalmitis with the usage of systemic or topical steroids under a cover of antifungal therapy.[4] However, the sensitivity of the fungi to the antifungal agent and the timing and dosage of steroids must be considered before starting the same. Currently, although we have an armamentarium of drugs and surgical modalities, the outcomes of endophthalmitis remain poor because of unknown host and organism related factors, which cannot be treated using conventional methods. Experimental studies in animals have shown that infectious endophthalmitis can induce the expression of cytokines, chemokines, and apoptotic factors. Recently, authors have also studied inflammatory changes in the vitreous taken from endophthalmitis patients and tried to identify factors that can predict the clinical outcomes of the disease.[5678] Apoptotic proteins such as Bax and Fas expression peaks at 48 h after initial endophthalmitis onset, and apoptotic rate peaks at 72 h under experimental conditions.[9] Many such host innate immune pathways are under research to try and target for endophthalmitis management in addition to antimicrobials. Reducing the concentrations of individual inflammatory mediators might limit the bystander damage to tissues while allowing a more favorable wound healing response along with neuroprotection. A TLR2 agonist, Pam3Cys, has been explored as a molecule which attenuates clinical inflammation, reduces bacterial load in retina, and preserves retinal architecture with electroretinogram in mice retina.[10] Anti-TNFa therapy may also have role in improving endophthalmitis outcomes.[11] Other possible drug targets in stage of development are anti IL6, anti IL1beta, anti IL8, etc., Scientists have also employed macrophage membrane-coated nanosponges as decoys to bind excess cytokines and chemokines in the vitreous to prevent cytotoxicity.[12] Further studies are needed to identify molecules that can help in reducing inflammation in severe and fulminating endophthalmitis cases and salvage such eyes toward both optimum anatomical and functional outcomes.

National Brazilian survey on the outcomes of hepatitis c retreatment in patients non-responders to direct antiviral agents

Background and aimsTreatment of hepatitis C with direct antiviral agents (DAA) is associated with almost 95% of sustained virological response. However, some patients need retreatment. In Brazil, it should be done according to the Ministry of Health guidelines, frequently updated to include newly available drugs. This study aimed to conduct a national survey about the characteristics and outcomes of retreatment of hepatitis C in previously non-responders to DAAs. Patients and methodsInstitutions from all over the country were invited to participate in a national registry for retreatment, including information about clinical and epidemiological characteristics of the patients, type and outcomes of retreatment regimens. Only patients previously treated with interferon-free regimens were included. ResultsAs previous treatments the distribution was: SOF/DCV (56%), SOF/SIM (22%), 3D (11%), SOF/LED (6%) and SOF/RBV (5%). For retreatment the most frequently used drugs were SOF/GP (46%), SOF/DCV (23%) and SOF/VEL (11%). From 159 patients retreated, 132/159 (83%) had complete information in the registry and among them only seven patients were non-responders (SVR of 94.6%). All retreatments were well tolerated, without any serious adverse events or interruptions. ConclusionThe retreatment of patients previously non-responders to DAAs was associated with high rate of SVR in this sample of Brazilian patients. This finding allows us to conclude that the retreatment options available in the public health system in Brazil are effective and safe and are an important component of the strategy of elimination of hepatitis C in our country.

Early pharmacokinetic evaluation of anti-tubercular treatment as a good indicator of treatment success in pulmonary tuberculosis patients on a retreatment regimen

Early pharmacokinetic evaluation of anti-tubercular treatment as a good indicator of treatment success in pulmonary tuberculosis patients on a retreatment regimen

Retreatment for hepatitis C virus direct acting antiviral therapy virological failure in primary and tertiary settings: the REACH-C cohort.

Virological failure occurs in a small proportion of people treated for hepatitis C virus (HCV) with direct‐acting antiviral (DAA) therapies. This study assessed retreatment for virological failure in a large real‐world cohort. REACH‐C is an Australian observational study (n = 10,843) evaluating treatment outcomes of sequential DAA initiations across 33 health services between March 2016 to June 2019. Virological failure retreatment data were collected until October 2020. Of 408 people with virological failure (81% male; median age 53; 38% cirrhosis; 56% genotype 3), 213 (54%) were retreated once; 15 were retreated twice. A range of genotype specific and pangenotypic DAAs were used to retreat virological failure in primary (n = 56) and tertiary (n = 157) settings. Following sofosbuvir/velpatasvir/voxilaprevir availability in 2019, the proportion retreated in primary care increased from 21% to 40% and median time to retreatment initiation declined from 294 to 152 days. Per protocol (PP) sustained virological response (SVR12) was similar for people retreated in primary and tertiary settings (80% vs 81%; p = 1.000). In regression analysis, sofosbuvir/velpatasvir/voxilaprevir (vs. other regimens) significantly decreased likelihood of second virological failure (PP SVR12 88% vs. 77%; adjusted odds ratio [AOR] 0.29; 95%CI 0.11–0.81); cirrhosis increased likelihood (PP SVR12 69% vs. 91%; AOR 4.26; 95%CI 1.64–11.09). Indigenous Australians had lower likelihood of retreatment initiation (AOR 0.36; 95%CI 0.15–0.81). Treatment setting and prescriber type were not associated with retreatment initiation or outcome. Virological failure can be effectively retreated in primary care. Expanded access to simplified retreatment regimens through decentralized models may increase retreatment uptake and reduce HCV‐related mortality.

Three regimens for re-treatment failure of Sofosbuvir-based therapy for chronic hepatitis-C genotype-4: a cohort study.

ABSTRACTDespite the high sustained virologic response (SVR) rates of direct-acting antiviral (DAAs) therapy, a small number of patients does not eradicate the virus, and these patients represent a challenge. This study aims to compare the outcomes of three second-line regimens for DAAs-experienced patients with chronic hepatitis C (CHC). This prospective observational study was conducted at the Damanhur Viral Hepatitis Center from January 2017 to February 2020. We included patients with CHC who did not achieve SVR after the complete course of Sofosbuvir/Daclatasvir±Ribavirin (SOF/DAC±RBV). The primary endpoint was SVR-12 after re-treatment. This study included 360 patients (with a mean age of 51.53±11.38 years). Approximately 51.1% of the patients were males, and 65.5% had liver cirrhosis. All patients of group 1 (45 patients) received SOF/VEL/VOX over 12-weeks; SVR-12 was achieved in 44 patients (97.8%). Group 2 (28 patients) received SOF/DAC/RBV over 24-weeks; (one patient was lost during follow-ups and one patient discontinued treatment due to hepatic decompensation). SVR-12 was achieved in 25 patients (96.2%). Group 3 (287 patients) received SOF/Ombitasvir/Paritaprevir/Ritonavir/RBV) over 12-weeks. Eight patients were lost during follow-ups, and one patient discontinued treatment due to grade 4 adverse events. SVR-12 was achieved in 276 patients (99.3%). There was no difference between the groups regarding their age, gender distribution, baseline viral load or comorbidities. Adverse events (thrombocytopenia, anemia, hyperbilirubinaemia and prolonged INR) were significantly higher in group 3, while group 1 did not experience any. The three studied retreatment regimens can be used for DAAs treatment-experienced patients considering availability. The SOF/VEL/VOX combination had the least adverse events.

S1113 Management of Hepatitis C Genotype 4 Treatment Failure: A Real World Single Center Experience

Introduction: Treatment failure with direct-acting antiviral (DAA) therapy is uncommon but it can be associated with significant worsening of liver disease especially in patients with liver cirrhosis. Retreatment of Hepatitis C (Hep C) patients who failed DAA therapy remains a challenge. Data on retreatment of HCV genotype 4 patients (G4) with DAA failure is limited and these patients are underrepresented in most clinical trials.The purpose of this study is to evaluate the efficacy of retreatment of HCVG4 DAA failure patients using a different DAA class from the currently available first-generation DAA regimens other than the regimen the patient had relapsed to. Methods: Out of 431 HCV G4 patients treated with DAAs in our center, 29 (6.7%) failed to achieve SVR. These patients were retreated by switching to a new DAA class from the first-generation DAA regimens independent of RAS testing. Twenty five out of these 29 patients completed retreatment regimen while 4 patients were lost for follow–up. Results: Among other risk factors, by logistic regression analysis, only older age, high CTP score and high base-line viral load were independent predictors of DAA failure among our cohort. Also, Sofosbuvir/Ribavirin regimen was the most common DAA regimen associated with treatment failure (48.3%). All our DAA failure patients had liver cirrhosis and ∼50% of them had advanced cirrhosis (Child´s class B or C), that made prompt retreatment of them a rescue strategy to halt viral replication and disease progression. After retreatment, 22 (88%) of the 25 patients who completed retreatment achieved SVR12 and the remaining 3 (12%) failed. The 3 patients who failed retreatment were all males, diabetics with advanced cirrhosis (mean CTP=9.33), and 2 of them were retreated by mistake with another drug from the same DAA class they had relapsed to (NS5A). These 3 patients completed a second retreatment, one patient achieved SVR and 2 patients relapsed for the second time (re-relapsers). Conclusion: The overall SVR rate (88%) demonstrated in this real–world study, clearly shows that, the retreatment policy of DAA failure patients by switching to or adding a new drug class independent of RAS testing is a good retreatment option that may be of importance for many areas of the world with no or difficult access to RAS testing or second-generation rescue regimens.

Retreatment of Irinotecan in Later Lines of Therapy for Metastatic Colorectal Cancer: A Retrospective Study

Background: Due to few efficacious options in later lines of therapy in metastatic colorectal cancer (mCRC), there has been considerable interest in the possibility of retreatment with previously administered agents. This study investigated the efficacy and safety of irinotecan retreatment (IRI2) in patients with refractory mCRC. Methods: We performed a retrospective analysis of patients with mCRC who were retreated with irinotecan-based regimens. The retreatment regimens with anti-epidermal growth factor receptor therapies were excluded. Results: A total of 64 patients were included. Patients had a median age of 56 years and were offered mainly in the setting of third- or fourth-line therapy with IRI2. The disease control rate was 78.2% including an objective response of 23.5%. Median progression-free survival and overall survival were 5.5 and 19.3 months, respectively. The most frequent grade 3 or higher toxicities were nausea/vomiting (27.9%) and neutropenia (25%). Conclusion: IRI2 might be a reasonable option for heavily pretreated patients with mCRC who achieved disease control with prior irinotecan therapy.

Relapses shortly after rituximab treatment in neuromyelitis optica spectrum disorder

ObjectiveRituximab (RTX), an anti-CD20 monoclonal antibody, has been demonstrated to be a useful maintenance therapy for neuromyelitis optica spectrum disorder (NMOSD). However, few patients may suffer from relapses shortly after RTX. In order to investigate the clinical features of RTX-related relapses and guide therapeutic strategy, 3 patients in our department were reported and literatures were reviewed. MethodsWe reported three NMOSD patients suffered from relapses shortly after rituximab treatment in our hospital and reviewed 13 patients reported in literatures. Their demographic characteristics, clinical features and therapeutic strategy were retrospectively analyzed. ResultsSixteen patients, including three cases reported in this study, experienced 21 attacks within 1 month after RTX infusion. All of them were women with an age at onset of 34.0 ± 15.0 years. Fourteen patients were seropositive for aquaporin-4 antibody, and one was seropositive for myelin oligodendrocyte glycoprotein antibody. 57.1% (12/21) of RTX-related relapses occurred after the first use of RTX. Their clinical manifestations included optic neuritis (8/21), myelitis (11/21), and the other two relapses without detailed descriptions. Also, 62.5% (10/16) of patients had a history of prior relapses within 3 months before RTX infusions, and the location of nine relapses overlapped with previous relapses. RTX was given again after the first RTX-related relapse in eight patients, three of them with low-dosage RTX stayed stable for years, and five patients with full-dosage RTX experienced another RTX-related relapse. ConclusionsRelapses may occur shortly after RTX treatment in NMOSD. RTX-related relapse did not necessarily mean that RTX was ineffective in low-dosage regimen. Timely and sufficient treatment of RTX is crucial to prevent a relapse. It may be more reasonable to monitor B cell repopulation so as to determine a re-treatment regimen. RTX-related relapse following full-dosage RTX may be a predictor for a second time RTX-related relapse and it may be reasonable to switch to other immunosuppressants in early stage.

Retreatment of Chronic Hepatitis C Infection: Real-World Regimens and Outcomes From National Treatment Programs in Three Low- and Middle-Income Countries.

Access to recommended second-line treatments is limited for patients who fail initial hepatitis C virus (HCV) therapy in low- and middle-income countries. Alternative regimens and associated outcomes are not well understood. Through a pooled analysis of national program data in Egypt, Georgia, and Myanmar, we observed SVR rates >90% for alternative retreatment regimens.

Real world SOF/VEL/VOX retreatment outcomes and viral resistance analysis for HCV patients with prior failure to DAA therapy.

Sustained viral response (SVR) rates for direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection routinely exceed 95%. However, a small number of patients require retreatment. Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is a potent DAA combination primarily used for the retreatment of patients who failed by DAA therapies. Here we evaluate retreatment outcomes and the effects of resistance-associated substitutions (RAS) in a real-world cohort, including a large number of genotype (GT)3 infected patients. 144 patients from the UK were retreated with SOF/VEL/VOX following virologic failure with first-line DAA treatment regimens. Full-length HCV genome sequencing was performed prior to retreatment with SOF/VEL/VOX. HCV subtypes were assigned and RAS relevant to each genotype were identified. GT1a and GT3a each made up 38% (GT1a n=55, GT3a n=54) of the cohort. 40% (n=58) of patients had liver cirrhosis of whom 7% (n=4) were decompensated, 10% (n=14) had hepatocellular carcinoma (HCC) and 8% (n=12) had received a liver transplant prior to retreatment. The overall retreatment SVR12 rate was 90% (129/144). On univariate analysis, GT3 infection (50/62; SVR=81%, p=.009), cirrhosis (47/58; SVR=81%, p=.01) and prior treatment with SOF/VEL (12/17; SVR=71%, p=.02) or SOF+DCV (14/19; SVR=74%, p=.012) were significantly associated with retreatment failure, but existence of pre-retreatment RAS was not when viral genotype was taken into account. Retreatment with SOF/VEL/VOX is very successful for non-GT3-infected patients. However, for GT3-infected patients, particularly those with cirrhosis and failed by initial SOF/VEL treatment, SVR rates were significantly lower and alternative retreatment regimens should be considered.

Real-world re-treatment outcomes of direct-acting antiviral therapy failure in patients with chronic hepatitis C.

Direct-acting antiviral (DAA) drugs are associated with high (>95%) sustained virological response at 12 weeks (SVR12) in chronic hepatitis C (CHC) patients. There is a paucity of data regarding the characteristics and re-treatment outcomes of DAA treatment failure patients. In a retrospective analysis of the prospectively collected database, we assessed the outcomes of re-treatment among patients with previous DAA failure. Patients' characteristics, viral characteristics, including resistance-associated substitutions (RAS) in a subgroup of patients, SVR12, and clinical outcomes were studied. Of 40 patients with DAA failure, among whom 36 were retreated, mean age was 45.7 years, 63.9% (n = 23) were male, 63.9% (n = 23) had agenotype-3 infection and 63.9% (n = 23) were cirrhotic. The re-treatment regimens included a combination of pan-genotypic DAA, mainly sofosbuvir and velpatasvir with or without ribavirin. Three patients who declined retreatment and one who was still on treatment was excluded. For patients who completed re-treatment, SVR12 was 100% irrespective of genotypes. SVR12 among genotype 3 was 75% (15 of 20) when lost to follow-up was considered a treatment failure. Six patients died due to liver-related causes, including five (83.3%) with hepatocellular carcinoma. RAS analysis in 17 randomly selected patients did not reveal any dominant substitutions in NS5A or NS5B region affecting SVR12, though several novel mutations were observed. In conclusion, re-treatment of CHC patients with prior DAA failure using pan-genotypic DAA is associated with high SVR12 rates irrespective of genotype or the presence of RAS.

From the Editor’s Desk...

From the Editor’s Desk...

Dramatic Responses of Recurrent Upper Urinary Tract Urothelial Carcinoma Harboring FGFR3 and TP53 Activating Mutations to Pembrolizumab in Combination with Erdafitinib: A Case Report

BackgroundUpper tract urothelial carcinoma (UTUC) has a high recurrence rate and is likely refractory to systemic chemotherapy. The long-term outcomes and responses to immunotherapy and retreatment regimen after tumor recurrence for such cases had not yet been well-documented.Case PresentationHere we report a unique case of long-term follow-up with a 67-year-old woman, who was diagnosed with advanced UTUC, received radical nephroureterectomy with bladder cuff, and was refractory to chemotherapy with cisplatin and gemcitabine. Positive PD-L1 expression and somatic mutation of Ser249Cys in FGFR3 were identified in the tumor tissue. The patient then received pembrolizumab monotherapy and achieved complete response (CR) after 6 cycles of treatment. She discontinued pembrolizumab treatment thereafter but remained in CR for 3 years and 7 months until the recurrence of tumor in the right mid-ureter. The patient was then retreated with a combination of pembrolizumab and erdafitinib, and achieved CR again after the third cycle of treatment.ConclusionWe reported here a rare case of UTUC with concurrent pathogenic mutations in FGFR3 and TP53 with positive PD-L1 expression. The patient archived exceptional therapeutic responses to PD-1 blockade treatment and retreatment with combination of pembrolizumab and erdafitinib. Our results provide new insight into the duration of immunotherapy and the retreatment strategy after tumor recurrence based on individual genomic profiles.