High-throughput sequencing technologies are providing new insights into the genetic alterations involved in melanomagenesis. It appears likely that most genetic events important in the pathogenesis ...of melanoma will be discovered over the next few years. Genetic analysis is also increasingly being used to direct patient care. In parallel with the discovery of new genes and the elucidation of molecular pathways important in the development of melanoma, therapies targeting these pathways are becoming available. In other words, the age of personalized medicine has arrived, characterized by molecular profiling of melanoma to identify the relevant genetic alterations and the abnormal signaling mechanisms involved, followed by selection of optimal, individualized therapies. In this review, we summarize the key genetic alterations in melanoma and the development of targeted agents against melanomas bearing specific mutations. These developments in melanoma serve as a model for the implementation of personalized medicine for patients with all cancers.
Bulevirtide (BLV), a first-in-class entry inhibitor, is approved in Europe for the treatment of chronic hepatitis delta (CHD). BLV monotherapy was superior to delayed treatment at week (W) 48, the ...primary efficacy endpoint, in the MYR301 study (NCT03852719). Here, we assessed if continued BLV therapy until W96 would improve virologic and biochemical response rates, particularly among patients who did not achieve virologic response at W24.
In this ongoing, open-label, randomized phase III study, patients with CHD (N = 150) were randomized (1:1:1) to treatment with BLV 2 mg/day (n = 49) or 10 mg/day (n = 50), each for 144 weeks, or to delayed treatment for 48 weeks followed by BLV 10 mg/day for 96 weeks (n = 51). Combined response was defined as undetectable hepatitis delta virus (HDV) RNA or a decrease in HDV RNA by ≥2 log10 IU/ml from baseline and alanine aminotransferase (ALT) normalization. Other endpoints included virologic response, ALT normalization, and change in HDV RNA.
Of 150 patients, 143 (95%) completed 96 weeks of the study. Efficacy responses were maintained and/or improved between W48 and W96, with similar combined, virologic, and biochemical response rates between BLV 2 and 10 mg. Of the patients with a suboptimal early virologic response at W24, 43% of non-responders and 82% of partial responders achieved virologic response at W96. Biochemical improvement often occurred independently of virologic response. Adverse events were mostly mild, with no serious adverse events related to BLV.
Virologic and biochemical responses were maintained and/or increased with longer term BLV therapy, including in those with suboptimal early virologic response. BLV monotherapy for CHD was safe and well tolerated through W96.
In July 2023, bulevirtide was fully approved for the treatment of chronic hepatitis delta (CHD) in Europe based on clinical study results from up to 48 weeks of treatment. Understanding the efficacy and safety of bulevirtide over the longer term is important for healthcare providers. In this analysis, we demonstrate that bulevirtide monotherapy for 96 weeks in patients with CHD was associated with continued improvements in combined, virologic, and biochemical responses as well as liver stiffness from week 48 at both the 2 mg and 10 mg doses. Patients with suboptimal virologic responses to bulevirtide at week 24 also benefited from continued therapy, with the majority achieving virologic response or biochemical improvement by week 96.
NCT03852719
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•BLV for 96 weeks maintained and/or improved responses compared to 48 weeks of treatment.•Efficacy was similar between the 2 mg and 10 mg doses of BLV.•In patients with a suboptimal early virologic response, improvements were observed with continued BLV.•Even in the absence of a virologic response, biochemical improvement can occur.•BLV was well tolerated with no discontinuations for adverse events through 96 weeks.
The predictors of Fanconi syndrome (FS) accompanied by renal function decline with use of the antiretroviral tenofovir disoproxil fumarate (TDF) have not been assessed. In addition, the natural ...history of renal recovery from FS after TDF discontinuation is not well-described.
We prospectively enrolled HIV-infected patients receiving TDF with newly identified FS (defined as at least two markers of proximal tubulopathy and either a >25% decline in creatinine clearance (CrCl) from pre-TDF values or a CrCl <60 mL/min in those without a known pre-TDF CrCl) in a multicenter observational study. These case participants were matched 1:2 to controls; characteristics between the two groups were compared. Case participants with known pre-TDF CrCl values were then followed over 48 weeks to assess renal recovery.
Nineteen cases and 37 controls were enrolled. In multivariable analysis, previous or concurrent use of lopinavir/ritonavir OR 16.37, 95% CI (2.28, 117.68); P = 0.006 and reduced creatinine clearance prior to initiation of TDF OR 1.44 for every 5 mL/min reduction, 95% CI (1.09, 1.92); P = 0.012; OR 19.77 for pre-TDF CrCl lower than 83 mL/min, 95% CI (2.24, 174.67); P = 0.007 were significantly associated with FS. Of the 14 cases followed for resolution, 7 (50%) achieved at least partial resolution (defined as recovering CrCl >70% of pre-TDF values) although most participants had full normalization of proximal tubulopathy markers within two months of TDF discontinuation.
FS, defined by specific CrCl decreases and markers of tubulopathy, is more likely in those who have received or are currently receiving concomitant lopinavir/ritonavir or who had lower CrCl prior to TDF initiation. Half of those with protocol-defined FS had CrCl recover to near pre-TDF values during the first year after TDF discontinuation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tenofovir alafenamide (TAF), a prodrug of tenofovir, delivers high levels of active drug to hepatocytes and is given in a lower dose than tenofovir disoproxil fumarate (TDF). TAF reduces viral ...replication in patients with chronic hepatitis B (CHB) similar to TDF and has shown a lower risk of the renal and bone toxicities associated with TDF use. This post‐marketing surveillance study examined the safety and effectiveness of TAF in treatment‐naïve and ‐experienced CHB patients who received TAF for 144 weeks at real‐world clinical sites in Japan. Safety assessments included the incidence of adverse drug reactions (ADRs), renal and bone events, and changes in selected laboratory parameters. Effectiveness was based on the proportion of patients with HBV DNA levels below the lower limit of quantitation or <29 IU/mL. This analysis included 580 patients; 18.4% of whom were treatment‐naïve. The cumulative incidence of ADRs was 0.21 per 100 person‐months, and the incidence of serious ADRs was 0.01 (95% CI, 0.00–0.04) per 100 person‐months. There were no ADRs of declines in estimated glomerular filtration rates, renal failure or proximal tubulopathy. The most common ADR was hypophosphataemia in seven (1.2%) patients. Two (0.4%) patients each had decreased blood phosphorus, bone mineral density decreased, dizziness and alopecia. Overall, the proportion of virologically suppressed patients increased from 68.8% at baseline to 97.5% at Week 144. These results confirm the real‐world safety and effectiveness of TAF in Japanese patients with CHB and are consistent with the findings of other evaluations of the safety and efficacy of TAF in CHB.
Once-daily treatment of chronic hepatitis delta (CHD) with bulevirtide is well tolerated and associated with significant reductions in HDV RNA in the blood and in biochemical liver disease activity. ...This study explored the effects of 48-week bulevirtide treatment on health-related quality of life (HRQoL) in patients with CHD.
In an open-label, randomised, Phase 3 trial, 150 patients with CHD and compensated liver disease were stratified by liver cirrhosis status and randomised 1:1:1 to no treatment (control), bulevirtide 2 mg/day, or bulevirtide 10 mg/day for 48 weeks. HRQoL was evaluated by the following patient-reported outcome (PRO) instruments at baseline, 24 weeks, and 48 weeks: EQ-5D-3L, Hepatitis Quality of Life Questionnaire (HQLQ), and Fatigue Severity Scale (FSS).
Patient characteristics and HRQoL scores were balanced at baseline between the treatment (2 mg, n = 49; 10 mg, n = 50) and control (n = 51) groups. Patients receiving 2-mg bulevirtide reported significant improvements compared with controls on the HQLQ domains of role physical, hepatitis-specific limitations, and hepatitis-specific health distress. Numerically higher scores for general health, hepatitis-specific limitations, and hepatitis-specific health distress domains were reported by patients with cirrhosis who received bulevirtide vs control. FSS scores remained stable across treatment groups throughout. At week 48, patients in the 2-mg group showed greater mean improvement from baseline in health status compared with controls on the EQ-5D-3L visual analogue scale.
PROs indicate that 48-week treatment with bulevirtide monotherapy may improve aspects of HRQoL in patients with CHD.
Bulevirtide 2 mg is the only approved treatment for patients with chronic hepatitis delta (CHD) in the EU. Patients with CHD have worse quality of life scores than those with chronic hepatitis B. Bulevirtide treatment for 48 weeks reduced HDV RNA and alanine aminotransferase levels and was well tolerated among patients with CHD. For the first time, this study shows that patients who received bulevirtide therapy for 48 weeks reported improvements in physical and hepatitis-related quality of life domains compared to those who did not receive therapy (control group).
ClinicalTrials.gov Identifier, NCT03852719
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•Bulevirtide (BLV) 2 or 10 mg is a new treatment for patients with chronic hepatitis delta (CHD)•This study reports the first data on the health-related quality of life (HRQoL) of patients with CHD who received BLV•Patients who received BLV vs no therapy for 48 weeks had improved physical and hepatitis-related QoL•BLV 10 mg may improve physical and general HRQoL for patients with CHD who have advanced liver disease•BLV was well tolerated, as supported by the maintenance and improvement of overall HRQoL
Tenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited ...data are available for its resistance profiles. In two clinical trials, 1,298 hepatitis E antigen-positive and -negative patients with CHB were randomized 2:1 and treated with TAF (
= 866) or TDF (
= 432). Baseline nucleos(t)ide analog resistance substitutions in HBV polymerase/reverse transcriptase (Pol/RT) were assessed using INNO-LiPA Multi-DR v2/v3. Resistance surveillance was conducted for patients with viremia (HBV DNA ≥ 69IU/ml) by HBV Pol/RT sequencing at week 96 or at discontinuation.
phenotypic analysis was performed for patients with conserved site substitutions or virologic breakthrough while adherent to the study drug. At baseline, the majority of patients harbored virus with wild-type Pol/RT (89.2%), with 10.8% harboring resistance associated mutations. A similar percentage of patients in the TAF or TDF groups qualified for sequence analysis through week 96 (TAF, 11.1%; TDF, 10.9%). Of these, a small percentage of patients experienced virologic breakthrough (TAF, 2.8%; TDF, 3.2%) that was often associated with drug nonadherence (TAF, 30%; TDF, 50%). Across treatment groups, 132 patients qualified for sequence analysis through week 96, with nearly half having no sequence changes from baseline (43.2%). Most sequence changes occurred at polymorphic positions, and no isolates showed a reduction in susceptibility
After 96 weeks, the proportion of patients achieving virus suppression (HBV DNA < 69 IU/ml) was similar across treatment groups, and no substitutions associated with resistance to TAF or TDF were detected. (These studies have been registered at ClinicalTrials.gov under identifiers NCT01940471 and NCT01940341.).
In patients with chronic hepatitis B (CHB), loss of hepatitis B surface antigen (HBsAg) is considered a functional cure. However, HBsAg loss is uncommon with existing therapies, and predictive ...factors associated with HBsAg seroreversion are unknown. Using pooled data from three phase 3 clinical trials of patients with CHB treated with nucleos(t)ide analogue (NUC) monotherapy or peginterferon (Peg‐IFN) ± NUC combination therapy, we conducted a retrospective analysis to characterize patients who achieved sustained HBsAg loss, the predictors of HBsAg seroreversion, and the impact of hepatitis B surface antibody (anti‐HBs) seroconversion on durability of HBsAg loss. In these three international trials, 1,381 adults with CHB received either NUC monotherapy for up to 10 years or Peg‐IFN‐containing regimens for up to 1 year. A total of 55 patients had confirmed HBsAg loss, defined as two or more consecutive negative‐qualitative HBsAg results, with a minimum of one repeat result after the end of treatment. Throughout a median of 96 (quartile Q1, Q3, 46, 135) weeks follow‐up after HBsAg loss, HBsAg loss was durable in 82% (n = 45) of patients, with 10 patients experiencing HBsAg seroreversion. Anti‐HBs seroconversion was observed during follow‐up in 78% of patients who lost HBsAg and in 60% of those who subsequently seroreverted. In analyzing predictors of HBsAg seroreversion, study treatment was significant, yet anti‐HBs seroconversion and treatment duration after initial HBsAg loss were not. Risk of HBsAg seroreversion was observed to be lower if HBsAg loss was sustained through the off‐treatment week 24 visit (8/10 seroreversions occurred by posttreatment week 24). Conclusion: HBsAg loss after NUC or Peg‐IFN‐containing regimens was durable in 82% of patients with CHB. Anti‐HBs seroconversion and treatment duration after initial HBsAg loss were not significantly associated with durability of HBsAg loss.
Summary
Background
The nucleos(t)ide analogues (NAs) entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are preferred treatment options for patients with chronic ...hepatitis B infection (CHB). However, resistance to ETV has been reported, especially with prior exposure to other NAs, and long‐term TDF treatment has been associated with decline in renal function and loss of bone mineral density in some patients. Consequently, TAF may be preferable to ETV, TDF or other NAs in specific circumstances such as in patients with risk of bone or renal complications, elderly patients or those with previous NA experience.
Aim
To provide a summary of the available efficacy and safety data following switch to TAF from other NAs in patients with CHB in clinical studies and real‐world settings.
Methods
Literature searches were performed on PubMed and s from three major international liver congresses between 2019 and 2021. Studies that included efficacy and/or safety data for patients with CHB switching from any NA to TAF were selected.
Results
Thirty‐six papers and s were included in this narrative review. Switching from TDF to TAF maintained or improved virological and biochemical responses with improved bone and renal safety. Switching from ETV or other NAs to TAF maintained or improved virological and biochemical responses and varying results for bone and renal safety.
Conclusions
Switching to TAF appears to maintain or improve virological, biochemical and bone‐ and renal‐related safety outcomes. These data support the concept of switching to TAF in some patients with CHB based on their individual circumstances.
These data, together with recommendations from various CHB treatment guidelines, support the concept of switching to TAF in individual patients with CHB, including those at risk of bone or renal complications, elderly patients and those with previous NA treatment.
Results from two Phase 3 studies, through 2 years, in chronic hepatitis B infection (CHB) showed tenofovir alafenamide (TAF) had similar efficacy to tenofovir disoproxil fumarate (TDF) with superior ...renal and bone safety. Here, we report updated results through 5 years.
Patients with HBeAg-negative or -positive CHB with or without compensated cirrhosis were randomized (2:1) to TAF 25 mg or TDF 300 mg once daily in double-blind (DB) fashion for up to 3 years, followed by open-label (OL) TAF up to 8 years. Efficacy (antiviral, biochemical, serologic), resistance (deep sequencing of polymerase/reverse transcriptase and phenotyping), and safety, including renal and bone parameters, were evaluated by pooled analyses.
Of 1298 randomized and treated patients, 866 receiving TAF (DB and OL) and 432 receiving TDF with rollover to OL TAF at year 2 (n = 180; TDF→TAF3y) or year 3 (n = 202; TDF→TAF2y) were included. Fifty (4%) TDF patients who discontinued during DB were excluded. At year 5, 85%, 83%, and 90% achieved HBV DNA < 29 IU/mL (missing = failure) in the TAF, TDF→TAF3y, and TDF→TAF2y groups, respectively; no patient developed TAF or TDF resistance. Median eGFR (by Cockcroft-Gault) declined < 2.5 mL/min, and mean declines of < 1% in hip and spine bone mineral density were seen at year 5 in the TAF group; patients in the TDF→TAF groups had improvements in these parameters at year 5 after switching to OL TAF.
Long-term TAF treatment resulted in high rates of viral suppression, no resistance, and favorable renal and bone safety.
We evaluated the antiviral response of patients with chronic hepatitis B (CHB) who had baseline high viral load (HVL), defined as having hepatitis B virus (HBV) DNA ≥9 log10 copies/mL, after 240 ...weeks of tenofovir disoproxil fumarate (TDF) treatment. A total of 641 hepatitis B e antigen (HBeAg)‐negative and HBeAg‐positive patients (129 with HVL) received 48 weeks of TDF 300 mg (HVL n = 82) or adefovir dipivoxil (ADV) 10 mg (HVL n = 47), followed by open‐label TDF for an additional 192 weeks. Patients with confirmed HBV DNA ≥400 copies/mL on or after week 72 had the option of adding emtricitabine (FTC). By week 240, 98.3% of HVL and 99.2% of non‐HVL patients on treatment achieved HBV DNA <400 copies/mL. Both groups had similar rates of histologic regression between baseline and week 240. Patients with HVL generally took longer to achieve HBV DNA <400 copies/mL than non‐HVL patients, but by week 96, the percentages of patients with HBV DNA <400 copies/mL were similar in both groups. Among HVL patients, time to achieving HBV DNA <400 copies/mL was shorter among those initially receiving TDF, compared to ADV. No patient with baseline HVL had persistent viremia at week 240 or amino acid substitutions associated with TDF resistance. Conclusion: CHB patients with HVL can achieve HBV DNA negativity with long‐term TDF treatment, although time to HBV DNA <400 copies/mL may be longer, relative to patients with non‐HVL. (Hepatology 2013;58:505–513)
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