Hep C Discussion Forum

Canuck · Guru

RE: SOF/VEL and SOF/VEL/VOX

Cheddy · Moderator

Thanks, again, Canuck!

Canuck · Guru

Conference coverage coming out of the 2018 AASLD San Francisco "Liver Meeting" by "MD Magazine":

SOF/VEL/VOX Successful for Hepatitis C Virus Retreatment in Patients With and Without HIV

NOVEMBER 10, 2018

Danielle Mroz

A fixed-dose combination therapy of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX, Vosevi, Gilead) was highly effective after 12 weeks in retreating direct-acting antiviral-experienced patients with hepatitis C virus infection, with and without HIV co-infection, including those with prior noncompletion of treatment or poor adherence, according to results of a new study.

Hepatitis C virus infection can be successfully treated with the use of direct-acting antiviral agents. In rare cases, patients can relapse; however, they can still be retreated successfully. SOF/VEL/VOX is one such treatment for hepatitis C virus infection that has shown success in patients who are treatment-experienced; however, many studies have not assessed the success of retreatment in patients with HIV or hepatitis B virus co-infection.

"I think many people expect that the drugs will work the same in HIV-positive patients as in HIV negative patients because of the early data in ledipasvir/sofosbuvir (Harvoni, Gilead) especially showing similar efficacy like in the ERADICATE study," study lead investigator Eleanor MP Wilson, MD, MHS, assistant professor of medicine at the University of Maryland School of Medicine in Baltimore, Maryland, explained in an email with MD Magazine®. "[However,] some recent data has shown that in real-world studies, patients with HIV may be less likely to succeed, because of drug interactions, immunologic effects, or other factors. [Therefore,] the newer retreatment regimens need to be tested in people with HIV infection, to show that there are no drug interactions and that patients with HIV and hepatitis C virus [or hepatitis B virus] co-infection will have retreatment options."

A team of investigators led by Wilson, pulled data from the RESOLVE trial (NCT02745535), an open-label phase 2b study on the safety and efficacy of 12 weeks of a fixed dose of SOF/VEL/VOX (sofosbuvir 400mg/velpatasvir 100mg/voxilaprevir 100mg) in hepatitis C virus-infected patients with early and advanced liver disease, including those with HIV or hepatitis B virus infection, who failed previous combination direct-acting antiviral therapy. The primary endpoint was the proportion of patients who achieve sustained viral response at 12 weeks, as well as the incidence of grade 3 or grade 4 adverse events during treatment or within 30 days of treatment completion.

A total of 77 subjects were enrolled in the study at 3 sites in Baltimore and Washington, DC. The subjects were predominantly male (n = 64, 83%) and black (n = 66, 86%), with a mean age of 60 years (SD 8 years). Three-quarters of the patients (n = 58, 75%) were infected with hepatitis C virus genotype 1a, 17 patients (22%) were HIV-positive, and 2 (3%) were co-infected with HIV and hepatitis B virus.

A little over half of the participants (n = 39, 51%) had previously used intravenous drugs. About 40% (n = 31) had compensated cirrhosis at baseline and 35% (n = 27) had F2 or lower liver fibrosis.

Direct-acting antiviral experience included ledipasvir/sofosbuvir (n = 69, 89%); paritaprevir/ritonavir/ombitasvir plus dasabuvir (n = 3, 4%); elbasvir/grazoprevir (n = 2, 3%); simeprevir/sofosbuvir (n = 2, 3%); sofosbuvir/daclatasvir (n = 1, 1%), while 9 patients (12%) had received other regimens (not listed in the study abstract). A total of 19 patients (25%) had received more than 1 treatment for hepatitis C virus infection, which included 13 patients (17%) who had prior interferon experience and 11 patients (14%) who had experience with more than 1 direct-acting antiviral regimen.

A total of 22 patients (29%) did not complete their previous direct-acting antiviral treatment for reasons that included poor adherence (n = 14, 64%), interruption (n = 4, 18%), lost or stolen medication (n = 2, 9%), or adverse event (n = 1, 5%), according to the study.

Sustained viral response at 12 weeks was achieved by 70 of the 77 patients (90.9%). Of the 22 patients who did not complete their previous treatment with direct-acting antivirals, 18 achieved sustained viral response at 12 weeks. Two patients were awaiting sustained viral response determination and 2 had discontinued treatment early because of intercurrent illness, according to the study authors.

A total of 3 participants (4%) discontinued treatment early for non-SOF/VEL/VOX-related adverse events. These were traumatic subdural hematoma, hypertensive urgency, and colitis. Two patients (3%) were lost to follow up, and 1 patient died because of an unrelated newly diagnosed hepatocellular carcinoma. Furthermore, 1 patient had virologic relapse.

Adverse events that were related to SOF/VEL/VOX were reported by >5% of the participants and included fatigue, headache, diarrhea, abdominal pain, and constipation. Three grade 4 adverse events were reported, but they were determined to be unrelated to the study drug. These included subdural hematoma and new carcinoma diagnoses (squamous cell and hepatocellular).

"Our study shows that SOF/VEL/VOX is a good option, in terms of both safety and efficacy, for retreatment of hepatitis C virus infection in patients with HIV, those with hepatitis B virus infection on treatment, and in those patients who had previously not completed their initial direct-acting antiviral regimen (with either poor adherence or treatment interruption)," Wilson said. "We were able to show high retreatment responses for these traditionally difficult to treat groups, at rates similar to those reported in the registrational studies. It's important that these traditionally understudied groups have validation that they have options for retreatment, including options that minimize drug interactions and very safe toxicity profiles."

Looking to the future and next steps, Wilson stated that "we need to continue to show the real-world effectiveness of retreatment [for hepatitis C virus infection] to help further ongoing public health eradication efforts [of the disease]."

The study, "Retreatment with SOF/VEL/VOX in Treatment-Experienced Patients with and without HIV: The Resolve Study," was presented at the 2018 American Association for the Study of Liver Diseases (AASLD) Liver Meeting, November 9-13, 2018, in San Francisco, California.

Canuck · Guru

Conference coverage coming out of the AASLD San Francisco "Liver Meeting" via "MD Magazine":

Vosevi, Mavyret Report Strong HCV Efficacy in Real-World Setting

NOVEMBER 13, 2018

Kevin Kunzmann

@NotADoctorKevin

A new clinical trial has backed the efficacy of sofosbuvir/velpatasvir/voxilaprevir (S/V/V) and glecaprevir/pibrentasvir (G/P) for the treatment of hepatitis C virus (HCV) - complementing ongoing clinical pursuits for real-world data backing either therapy for the infection.

In a new study presented at the American Association for the Study of Liver Diseases (AASLD; Liver Meeting) in San Francisco, CA, this week, investigators led by Varun Saxena, MD, of the University of California San Francisco and Kaiser Permanente Northern California, assessed both therapies in 277 patients.

S/V/V (Vosevi; Gilead Sciences) was originally approved as a combination therapy for HCV by the US Food and Drug Administration in July 2017, while G/P (Mavyret; AbbVie) received FDA backing in the following month.

The investigators' cohort analysis of adult patients with HCV treated at the Kaiser Permanente facility assessed efficacy as sustained virologic response (SVR) at 4 and 12 weeks, and safety as adverse events (AEs) required hospitalization in the 12 weeks following treatment. Patients had been administered either S/V/V or G/P, with or without add-on ribavirin (RBV). Multivariate logistic regression was used to identify factors associated with AEs.

At baseline, mean patient age was 63 years, with 25% reported as female, 19% as black, and 14% as Hispanic. Comorbidities were frequent in patients - 54% reported hypertension, 23% diabetes, 21% hyperlipidemia, and 3% HIV. Median patient body mass index (BMI) was 29.

Regarding HCV characteristics, almost all patients were either genotype 1 (76%) or 3 (17%), and 46% suffered from cirrhosis. Another 85% of patients were treatment experienced, with a strong majority having been exposed to direct-acting antiviral (DAA) therapy.

Most patients (n= 227; 82%) were administered S/V/V (9% with RBV) for 12 weeks, while just 50 (18%) were administered G/P (2% with RBV) - the latter group treated for either 8 (34%), 12 (56%), or 16 (10%) weeks.

Investigators reported a low rate of treatment discontinuation - just 3 patients administered S/V/V, none related to the therapy itself. Only 21 (8%) of patients experienced AEs requiring hospitalization, with the most common reasons being infection (38%) or hepatic decompensation (24%). When adjusting for patient demographics, HIV infection, treatment regimen, and RBV use, patients with decompensated cirrhosis reported greater odds of AEs requiring hospitalization than patients with compensated/non-cirrhosis (OR 4.6; 95% CI: 1.0 - 20.8).

At the time of the last patient follow-ups, a majority (148; 53%) of patients had reached SVR by week 4, and a similar rate (128; 46%) had reached by week 12. Investigators reported that 100% of patients administered G/P reported SVR at weeks 4 and 12, and that 99% and 98% of patients administered S/V/V reported such rates at those weeks, respectively.

Investigators praised the "excellent effectiveness" of both therapies, but advised care regarding the increased odds of AEs requiring hospitalizations.

"We suggest caution if proceeding with protease-inhibitor regimens among decompensated cirrhosis patients," Saxena and colleagues concluded. "Baseline albumin could be useful in identifying those at higher risk for AEs requiring hospitalization."

The study, "Real-World Safety and Effectiveness of Sofosbuvir/Velpatasvir/Voxilaprevir and Glecaprevir/Pibrentasvir in Hepatitis C Infected Patients," was presented at the Liver Meeting in San Francisco, CA.

Canuck · Guru

So, talk about being a "tough nut" to crack! Like ... (in the old days) when it was not a good thing to be a GT3 (as we were considered problematic to cure). Being a GT3 alone, well that was quite enough of a disadvantage thank-you, but then try this ... compound being a GT3 with also being someone who might be co-infected with HBV? Oh dear, really not good - harder nuts and likely harder livers with 2 heps working away at damaging your liver. It can get even more complicated - throw in GT3, and HBV and HIV - triple co-infections? Oh my! So, this really does boast well for the profound potency and efficacy of Vosevi to be able to cure despite doing so under the worst conditions. And these patient DID sound as though they were even further disadvantaged than "just" having HCV, HBV and HIV all at the same time, they also seemed primed for lung infections, other viral infections and "came with" certain RAS! (They so politely refer to this as being "very challenging" to cure!) Man, that Vosevi can cure the toughest nuts in the world!

Helio - HCV/Next

Vosevi safe, effective in triple-infected patients with HCV, HBV, HIV

October 9, 2018

PHILADELPHIA The direct-acting antiviral Vosevi demonstrated an average sustained virologic response rate of 87% among patients who were triple-infected with hepatitis C genotype 3, hepatitis B and HIV, as presented at the American College of Gastroenterology Annual Meeting.

Chronic hepatitis C treatment is no longer challenging in the era of DAAs with an SVR of up to 97%. However, triple infection treatment with HCV, HIV and hepatitis B has not been explored in real life situations, Nimy John, MD, from the University of Massachusetts Medical School, said during her presentation.

The study comprised 22 patients with HCV, HBV and HIV who underwent a 12-week course of treatment with Vosevi (sofosbuvir/velpatasvir/voxilaprevir, Gilead Sciences).

Ten patients had genotype 3a, nine had genotype 3b, and three had genotype 3c. Nineteen patients were HBV e-antigen negative and three patients were positive.

Four patients stopped treatment due to severe bilateral pneumonia, rectal bleed at 3 weeks of treatment, virologic failure related to resistance-associated substitution (RAS) Y93, or the development of herpes zoster at 10 weeks.

Including the full cohort, the SVR was 87%. However, John noted that all but one patient who completed the 12-week course achieved SVR. The one patient who did not achieve SVR had RAS Y93.

The study demonstrates the efficacy of DAAs in 12-week treatment with an SVR of 87% in a very challenging triple-infected cohort, with significant efficacy, tolerability and safety, John said. A larger trial is needed to validate the results. by Talitha Bennett

Reference : Basu P, et al. Abstract 15. Presented at: American College of Gastroenterology Annual Scientific Meeting; Oct. 5-10, 2018; Philadelphia.

Disclosure: Nimy reports no relevant financial disclosures.

Canuck · Guru

Hi Mak,

I have posted to you over in the "All Aboard the Vosevi Train" thread. C.

Tig · Admin

Hi Mak,

It’s possible the L31M RAS could have reduced the susceptibility of your 1B genotype to treatment, but a lot more has to be known about the type of sequencing they did to your blood work. Just because you have a RAS (RAV) or resistant variant to a specific drug, doesn’t mean it won’t work, it can mean it is less effective than it would be in someone without it. Regardless, some people simply respond initially and fail to achieve SVR. With the new DAA’s, they typically have a combination of drugs that break the chain of replication at several points, NS5a, NS5b and NS3/4. As long as the virus is effectively blocked at one point in the chain and long enough to render the virus undetectable, your immune system then takes over and maintains or sustains the viral response (SVR).

Vosevi has been found to have extremely high rates of success, regardless of existing RAS in treatment naive or experienced patients. Time to stop worrying and just get started. You’ll defeat it this time. Do your part and Vosevi will do the job.

HCV Resistance Primer

mcmaklin · Senior Member

Hello, as I hope to start Vosevi in about 3 days.

I would ask you for some help so I am not already able to read all those articles. As I see you really understand a lot of it.

Please tell me,I have been treated with Viekira/Exviera 3 years ago and virus genotype 1b came back 1 month after EOT.

1.Do these data mean that L31M was resistant for Ombitasvir?

2.Does it mean that with Velpatasvir should be OK for L31M? I especially do not understand why somehwere there is only suspectible and sometimes "scored mutations". Sometimes it is suspectible and scored mutations 31M and sometimes none in place of socred mutations

3. I guess those other NS3 are not significant

Thank you for your reply

I am attaching this what I have been tested. It is hard for me to

-- Edited by mcmaklin on Sunday 9th of September 2018 07:01:58 AM

Canuck · Guru

What work has to be done to get Vosevi rolled out to patients!

Some of the good work that "they" (pacifichepc.org, hepctip.ca, help4hepbc.ca - Deb Schmitz/Daryl Luster/patients/caregivers and many more people involved) need to do, want to do, and HAVE to do (these CADTH inputs, hoops to jump) are efforts by everyone for the good of hep c patients (and also for the good of everyone who cares for them) - these are patients who are wanting and NEEDING the drugs and are WAITING for the drugs to be put into use - it takes MANY to "convince" things to get going in the right direction in a timely fashion in the often waaaay-too-late Canadian drug approval system. Thank you to them (these people and patients who submit their input into the review process for doing this hard, tiresome work, tirelessly) - ultimately, they perform important work to get important drugs into use (in this case it was their work to get access to Vosevi rolling).

https://www.cadth.ca/sites/default/files/cdr/relatedinfo/SR0529%20Vosevi_Patient_Input.pdf

Canuck · Guru

About Vosevi in relation to Gileads instructions to "take with food" - the degrees of drug absorption when taken with food and without food, and as well, degrees of drug absorption depending on the fat content of the meal (or food).

Why I would opt to take Vosevi with a moderate fat content meal.

Via: "Drugs.com" - Interactions - https://www.drugs.com/food-interactions/sofosbuvir-velpatasvir-voxilaprevir,vosevi.html

Via: "Vosevi" Monograph - http://www.gilead.ca/application/files/3215/2589/3935/Vosevi_English_PM_e192340-GS-001.pdf - In relation to "food", see pages 22, 25, 27, 51 (especially read page 25, Table 9 specifically in relation to fat content).

Canuck · Guru

So, Dr. Feld (and others) have been working on this outrageously exhaustive helpful guide, covers everything from a-z about treating hepc, I have pulled out ONLY a tidbit or 2 on the sof/vel/vox portion - just so I can throw it into this ongoing collection of info on Vosevi and Epclusa.

The whole of Dr. Feld's and Dr.s Shah and Zeuzem's collaborative work should be read - you can try googling up "Management of Hepatitis C Infection" (sourced from: Clinical Care Options - "Clinical Resources From inPractice Hepatology") - June 2018

Voxilaprevir. Sofosbuvir/velpatasvir/voxilaprevir is approved by the FDA for a duration of 12 weeks in patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) who either have genotypes 1-6 chronic HCV infection and were previously treated with an NS5A inhibitor or who have genotypes 1a or 3 chronic HCV infection and were previously treated with sofosbuvir (Table 21).[24]Sofosbuvir/velpatasvir/voxilaprevir is administered as a single 400/100/100-mg tablet once daily, with food (Table 22). There is no approved dose recommendation for patients with severe renal impairment or end-stage renal disease. Although the Committee for Medicinal Products for Human Use in Europe recommended marketing authorization for sofosbuvir/velpatasvir/voxilaprevir intended for the treatment of chronic hepatitis C, detailed recommendations for the use of this regimen are currently pending from the European Commission.[25]

Drug Resistance
In cell culture, substitutions at NS3/4A amino acid positions 41, 156, and 168 conferred reduced voxilaprevir susceptibility. In particular for NS3, A156L/T (genotype 1a), A156T/V (genotype 1b), A156L/V (genotype 2a), A156T/V (genotype 3a), and A156L/T/V (genotype 4) reduced voxilaprevir antiviral activity more than 100-fold. Moreover, combinations of these mutations were additive in their ability to reduce voxilaprevir activity.

During clinical study, in the phase III POLARIS-1 and POLARIS-4 trials, 12% to 15% of patients treated with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir harbored baseline NS3/4A RASs.[24] Nevertheless, SVR rates were unaffected by baseline mutation status and ranged from 97% to 100% (Table 10). Treatment-emergent RASs were rare in these trials, with only 2 patients in POLARIS-1 demonstrating novel mutations at virologic failure, neither in NS3 (Table 11).[26] One of these patients experienced virologic breakthrough (vs relapse) and had low plasma concentrations of study drugs indicative of treatment nonadherence.

Table 10. Impact of Baseline RASs (15% Detection Threshold) on Response Rates to Sofosbuvir/Velpatasvir/Voxilaprevir in the POLARIS Trials[26]

Table 11. Treatment-Emergent RASs in Patients Experiencing Virologic Failure With Sofosbuvir/Velpatasvir/Voxilaprevir in the POLARIS Trials[26]

DrugDrug Interactions
Voxilaprevir is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3.[24] Thus, as with many other DAAs used to treat HCV infection, coadministration with P-gp and/or CYP inducers such as carbamazepine or St Johns wort is not recommended because of an expected reduction in sofosbuvir/velpatasvir/voxilaprevir exposure. Voxilaprevir is also an inhibitor of P-gp, BCRP, OATP1B1, and OATP1B3, making coadministration of substrates of these transporters (eg, methotrexate) suboptimal. Simultaneous use of rifampin with sofosbuvir/velpatasvir/voxilaprevir is contraindicated. Significant drugdrug interactions may also occur when sofosbuvir/velpatasvir/voxilaprevir is coadministered with specific antiarrhythmics, anticonvulsants, antimycobacterials, HIV antiretroviral agents, HMG-CoA reductase inhibitors, or cyclosporine.

Sofosbuvir/velpatasvir/voxilaprevir is approved by the FDA for a duration of 12 weeks in patients without cirrhosis or with compensated cirrhosis (Child-Pugh A) who either have genotype 1-6 chronic HCV infection and were previously treated with an NS5A inhibitor or who have genotype 1a or 3 chronic HCV infection and were previously treated with sofosbuvir (Table 21).[24]Sofosbuvir/velpatasvir/voxilaprevir is administered as a single 400/100/100-mg tablet once daily, with food (Table 22). There is no approved dose recommendation for patients with severe renal impairment or end-stage renal disease. Although the Committee for Medicinal Products for Human Use in Europe recommended marketing authorization for sofosbuvir/velpatasvir/voxilaprevir intended for the treatment of chronic hepatitis C, detailed recommendations for the use of this regimen are currently pending from the European Commission.[25]

Table 21. Approved Regimens for Sofosbuvir/Velpatasvir/Voxilaprevir in Patients With HCV Infection[24]

Population Regime Duration

GT1-6 wihout cirrhosis or with compensated cirrhosis Sof/vel/vox 12 wks

(Childs-Pugh A), previous treatment with a NS5A inhibitor.

___________________________________________________________________________

GT 1a or 3 without cirrhosis or with compensated cirrhosis Sof/vel/vox 12 wks

(Childs Pugh A), previous treatment with sof but no NS5A inhibitor.

___________________________________________________________________________

Table 22. Sofosbuvir/Velpatasvir/Voxilaprevir: Dosing and Administration

Drug Resistance
One of the major advantages of sofosbuvir is its unique resistance profile. A substitution of a serine for a threonine at position 282 (S282T) leads to high-level sofosbuvir resistance,[36] but this substitution also markedly limits the replication fitness of the virus. Because of the poor ability of the S282T variant to replicate, it rarely emerges during sofosbuvir therapy and is likely to return to extremely low levels in the absence of drug pressure. However, data from a single-arm trial evaluating ledipasvir/sofosbuvir retreatment for 24 weeks in patients with genotype 1 HCV infection who experienced previous failure of ledipasvir/sofosbuvir for 8-12 weeks (with or without ribavirin) demonstrated that in this setting the emergence of NS5B resistance variants was relatively common, occurring in 33% of patients (4/12) with virologic failure.[37] The variants identified included S282T alone in 2 patients, L159F alone in 1 patient, and S282T plus L159F in 1 patient.

See Velpatasvir section below for information on sofosbuvir/velpatasvir resistance.

See Voxilaprevir section above for information on sofosbuvir/velpatasvir/voxilaprevir resistance.

DrugDrug Interactions
Sofosbuvir is not metabolized via CYP3A4, limiting the likelihood of drugdrug interactions with other agents. Sofosbuvir is a substrate for P-gp and should not be coadministered with potent P-gp inducers such as rifampin or St Johns wort.[29]

See Velpatasvir section below for information on sofosbuvir/velpatasvir interactions.

See Voxilaprevir section above for information on sofosbuvir/velpatasvir/voxilaprevir interactions.

Velpatasvir. Velpatasvir is an inhibitor of HCV NS5A, a protein that is required for HCV replication. It is approved by the FDA as part of a coformulation with sofosbuvir, a NS5B polymerase inhibitor for the treatment of chronic HCV infection from genotypes 1-6 HCV infection (Table 19).[33] Sofosbuvir/velpatasvir should be given with ribavirin in patients with decompensated cirrhosis (Child-Pugh B or C). It is administered orally as one 400/100-mg tablet once daily with or without a meal (Table 20). No dosage recommendations can be made for patients with severe renal impairment or end-stage renal disease.[33]

Drug Resistance
In cell culture, replicon variants with reduced susceptibility to velpatasvir were found in HCV genotypes 1a, 1b, 2a, 3a, 4a, 5a, and 6a.[33] Amino acid substitutions at NS5A positions 24, 28, 30, 31, 32, 58, 92, and 93 are associated with resistance. Substitutions associated with a > 100-fold reduction in velpatasvir susceptibility include single and double combinations of L31V and Y93H/N in genotype 1a, L31V and Y93H in genotype 1b, Y93H/S in genotype 3a, and L31V and P32A/L/Q/R in genotype 6. Single mutants F28S and Y93H in genotype 2 result in 91-fold and 46-fold reduction in velpatasvir susceptibility, respectively. The Y93H mutant results in a 3-fold reduced susceptibility in genotype 4a.

In a pooled analysis of phase III trials, ASTRAL-1, ASTRAL-2, and ASTRAL-3 in patients without cirrhosis or with compensated cirrhosis, 12 patients experienced virologic failure (2 with genotype 1 and 10 with genotype 3a).[33] The 2 patients with genotype 1 HCV infection had emergent resistance mutants, Y93N in 1 patient, and Y93H plus low-level K24M/T plus L31I/V in the other patient at virologic failure. Neither patient had sofosbuvir NS5B RASs at failure. Of the 10 patients with genotype 3a HCV infection who experienced virologic failure, all 10 had Y93H mutations (7 emerged posttreatment, 3 had Y93H at baseline and posttreatment). Sofosbuvir NS5B resistance mutations L314F/I were observed at a frequency of 15%, and L314P at a frequency of < 4% of patients with genotype 3a HCV infection who relapsed. In the ASTRAL-4 trial of patients with decompensated cirrhosis, 3 patients with virologic failure qualified for resistance analysis.[33] The 1 patient with genotype 1 HCV infection did not have any NS5A or NS5B resistance mutations at failure, and the 2 patients with genotype 3a HCV infection had the Y93H mutation as well as either low-level M28V or S38P mutations at failure. No patients with genotype 2, 4, 5, or 6 HCV infection experienced virologic failure in any of the phase III ASTRAL trials.

The persistence and long-term clinical impact of sofosbuvir or velpatasvir RASs is unknown.[33]

DrugDrug Interactions
Both sofosbuvir and velpatasvir are drug transporter P-gp and BCRP substrates, whereas the GS-331007 sofosbuvir metabolite is not.[33] Slow metabolic turnover of velpatasvir by CYP2B6, BYP2C8, and CYP3A4 was observed in vitro, and drugs that induce these enzymes may decrease plasma concentrations of sofosbuvir or velpatasvir resulting in a reduced therapeutic effect. Such agents are not recommended for use with sofosbuvir/velpatasvir. Velpatasvir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1, and coadministration of sofosbuvir/velpatasvir with drugs that are substrates of these transporters may increase exposure to these agents.

-- Edited by Canuck on Monday 13th of August 2018 07:48:06 PM

Canuck · Guru

Hi guys,

Well this is turning out to be quite a romping, twisty, interesting convo! biggrin It's usually so quiet around here on this thread!

Yes, very interesting RC in how they managed you - you WERE certainly a very unique situ. Me too, but only in a small way, only just because of my trial situ, my doc was confident i would be cured on 8 weeks, (he would not promise tho) - he could not promise tho, as his job dictated he should not - what brave soul could (except you my friend!), you knew and promised, and of course you were right and it all came true. Very powerful stuff this Vosevi triple. (He, like any other doc going by the regs right now, would not be giving out 8 weeks but 12). My doc DID "make a face" (professional like eye-roll) and basically went "phhht" when i expressed my pre-cure jitters looking with trepidation at my mere 8 weeks of drugs, that's why it surprised me a bit, long post-cure, when he suggested it worked (in part) due to my small body mass (I was approximately in the cirrhotic range, a "technical" F4 - 12.6 kPa's/some steatosis, a long-standing 3, and had an iron load - I was not so confident of course, but he was! - he had been involved in the prior Polaris trials and he knew how very high my chances were with this Vosevi triple. Gilead makes/has/procures good drugs. I agree with you when you speak of the early crashes to guide/predict what is happening, although ... there are those who cure even with slo-mo crashes and a load at EOT! just to confound us.

8 or 12 weeks of Vosevi, whether a lill dab 'l do ya, or not, Gilead decided in their infinite corporate wisdom (for whatever influencing reasons) to not do 8 weeks and to do "rescue only", "pan" and at 12 weeks only - if that ever changes (to pick up TN's) or if they ever shorten the course) we will just have to wait and see. I don't think there is any way to predict these things. The influential national/medical governing bodies and pharmaceutical companies seem so guarded and secretive!

I am glad lamassu you think you know what Gilead is doing. I certainly could not guess what Gileads plans are based on what info is available to me. I hope your doc does have those Vosevi stats/numbers at his disposal - I can't wait for you to ask him (I would be so pleased/excited) if he does have access to all those numbers! smile It has been really bugging me that we cannot find out how many people have received Vosevi! Hey, while you're at it, ask him again, if you are (for sure), BOTH a 2a AND a 2c, OR, if he meant that he simply sees that about 10-15% of the people who come through his offcie for treatment happen to be GT2's (period), compared to other GT's. I am still curious about your a/c designation, aren't you? You are the first I have seen with two sub-types here, and I thought that interesting.

I can only read into the different propoganda news, that many of the pharmaceutical companies, for now, have moved on more, to continue their ongoing research in other disease and drug areas, there are needs/customers and other profit margins to be addressed by concentrating on HBV, fatty livers, and other disease markets. Like the Gilead study I am in right now, where they are looking at (among other things) my LOXL2 and it's involvement/ties into the fibrosis formation process - (lysyl oxidase-like-2, extracullular matrix enzyme, thought to promote fibrosis via cross-linkage of collagen fibers ... ie. NASH and PSC). Seems there is endless potential for a lot of hard scarred up livers out there in this old world to cure. wink

Hey, man, am I stomping and tromping all over this thread, or, am I still techinically on topic? hee hee C.

lamassu · Senior Member

Viruses mutate. There is a confirmed Genotype 7 for HCV. Fortunately Genotype 7 has been shown to respond to sofosbuvir-velpatasvir (Epclusa) in the one case I could find reported so far. There will be more. Gilead is in the business of developing and selling DAAs. You should assume their researchers are already working on a successor to Vosevi.

robertsamx · Guru

Hi All, Just my thoughts on 8 weeks -V- 12 weeks on VOSEVI. If you go und in the first 2 weeks of treatment and your F score is Fo to F2 and you have no prior treatment experience you have a very good chance of SVR on 8 weeks of VOSEVI. Same is true for 8 weeks Epclusa, and the Same is true with 12 weeks. However if your F score is F3-F4 and you are proven to be cirrhotic and you are treatment experienced then I would push for 12 weeks VOSEVI.Epclusa most likely would get the job done buy why not add the third defense. As I was still not UND at 8 weeks on Vosevi they added an additional 4 weeks VOSEVI getting me to 16 weeks and started RIBA at 8 weeks. My case is unique and I dont think adding RIBA is necessary for all F4 Treatment EXP cases. Riba is a case by case decision And very rarely used. RC

(I dought that Gilead is working on a VOSEVI replacement as they are touting VOSEVI as a rescue treatment that covers all geno types and all treatment experienced patients )

-- Edited by robertsamx on Saturday 16th of June 2018 01:08:48 PM

Tig · Admin

In the spirit of the conversation, here's an article by Greg Jefferys related to the Big Pharma topic. The reason for Rx regulation is most definitely profit driven. This has been a sore subject forever. At the end of this article, you'll see why some doctors refuse to even write a prescription for a patient. It's also why there are so many medical vacations being established now to countries offering generic treatments. The cost savings are staggering.

Doctors, Generics and Big Pharma

A Short History: Sofosbuvir & Sovaldi

lamassu · Senior Member

Canuck,

I am not a conspiracy theorist. However I do believe Gilead intends to maximize profits from their DAAs. They have stockholders to report to. Harvoni is near the end of its' useful life since Epclusa and Mavyret (AbbVie pharma) came out. IMO in a few years, after Gilead has made their profits from Epclusa: Vosevi will then be relabeled and promoted as treatment of choice for treatment naive patients.

They (and AbbVie) almost certainly are working on a next generation replacement for Vosevi now which will undergo clinical trials and be released at the appropriate time. This may sound cynical but I know from experience Gilead cares more about profit than helping uninsured patients afford Epclusa. They now license generic Epclusa to pharmaceutical firms around the world. In India three months of locally manufactured generic Epclusa costs less than $900. At the advice of my hepatologist I did not pursue the 'buyer club' option and waited for Medicare to kick in so I could get brand name. I imagine for at least a year (or two) there will be no generic Vosevi from India.

I doubt Gilead would release the information you seek. Next time I see my hepatologist I will inquire as I imagine that subset of the medical community would know since they share information as colleagues.

Canuck · Guru

Nope, haven't heard of this (using Vosevi in treatment-naive). Came out first in US. Then Canada (only in-theory-lip-service mostly), seems UK is next - all three there is "language" in the regs about it being exclusive for "rescue"/for relapsers. Just because of it's efficacy I have read some other docs speak of this (the concept of using it for treatment naive), but it seems not too laboured a topic - we shall have to just wait and see what happens in future!

At the end of my trial, it seemed already decided that they would roll it out with the "rescue only" caveat. And, that's what they did, in the US, then Canada and now the same language is being used for the UK's roll-out.

Funny this article, a big portion of it happens to be quotes of the Egyptian doc re: affordability - as Egypt has been working very diligently in creating a powerful low-cost NS5A (RAV) and working (in many ways) to get their own people (and other various low to mid income populous countries) to affordable treatment.

My big bone of contention and curiousity (frustration) is that I CANNOT find out (even) HOW MANY scripts for Vosevi have been doled out in the USA, since it was rolled out! I have searched EVERYWHERE for this kind of clear data - how many people (relapsers) in the USA have now had a Vosevi ace-in-your-pocket rescue treatment! Where do these stats live/hide??!! You can't really make heads nor tails of stock gossip and quarterly reports, there seems to be no accurate "outlet" for this kind of number "news" I seek. I keep looking for the scripted Vosevi stats, but to no avail, I never find a good source for this kind of info! Canada?, ppht!, I kinda doubt many Vosevi treatments have been eked out to people. In the UK, (apparently) Vosevi has finally just got started (I think), so best numbers found should be in USA I figure.

Somebody brave, please phone Gilead and ask them to provide you will a breakdown of how many Vosevi prescriptions have been provided since roll out started, and where/what country(s)! wink

lamassu · Senior Member

I know Vosevi is supposed to be reserved for salvage re-treatment but are hepatologists starting to use it for treatment naive patients? I doubt Gilead cares.

Canuck · Guru

Just another blurb about Vosevi - late incoming news, not really any earth shatterig "new" news we haven't already been guessing at/hearing about, but still, news. I was more interested in some of the subtleties the article speaks of - and how it related to my own Vosevi treatment, like ... how my doc said (in a 'round about way, long after I was cured) he too (in other circumstances) would have given me 12 weeks of Vosevi versus the 8 weeks of Vosevi - (I did only 8 weeks because of my trial). Whew eh!? But ... this stuff IS so potent, such efficacy, even a little "dab 'l do ya"! heehee. Jes jokin! - always take the drugs as the doc and manufacturer and regs recommend! Another "small" part of the many reasons (only one of the reasons) why a mere 8 weeks of Vosevi worked so well for me ... was possibly my small body mass as well, many situ's come in to play when we achieve SVR, but nowadays with the likes of these wonderful new DAA's it has never been easier. The article just re-iterates how astoundingly effective this Vosevi stuff is at 97 and 100% for relapsers with and without RAV's! biggrin

From Medscape:

Sofosbuvir-Velpatasvir-Voxilaprevir Effective in Previously Treated Chronic Hep C

By Will Boggs MD

June 13, 2018

NEW YORK (Reuters Health) - Sofosbuvir-velpatasvir-voxilaprevir is effective as salvage treatment for patients with chronic hepatitis C previously treated with an NS5A inhibitor, according to results of an open-label substudy of the POLARIS-1 trial.

The phase 3 POLARIS-1 study demonstrated the effectiveness of this combination and served as the basis for U.S. and European approvals.

Dr. Marc Bourliere from Hopital Saint Joseph, in Marseilles, France, and colleagues now report the safety and efficacy of sofosbuvir-velpatasvir-voxilaprevir in 147 patients who received placebo in the primary study and were eligible for participation in the open-label substudy.

All but four patients (97%) achieved the primary efficacy outcome of sustained virological response at post-treatment week 12 (SVR12), and all 147 patients had HCV RNA concentrations below the lower limit of quantitation at the final treatment visit.

SVR12 rates were 97% (127/131) among patients with baseline resistance-associated substitutions and 100% among patients without resistance-associated substitutions or whose baseline resistance-associated substitutions could not be determined, the researchers report in The Lancet Gastroenterology & Hepatology, online May 30.

Common adverse events included fatigue, headache, diarrhea and nausea, but there were no serious adverse events deemed related to study treatment, and no patient discontinued treatment as a result of adverse events.

"A salvage regimen for this population represents an important advance for individual patients and public health initiatives," the researchers conclude.

Dr. Imam Waked from the National Liver Institute, in Menoufiya, Egypt, who wrote an accompanying editorial, told Reuters Health by email, "Patients who fail initial treatment can be retreated very effectively in almost all cases."

"The high response rates would encourage use as first line," he said. "However, the initial trial using it as first line used sofosbuvir-velpatasvir-voxilaprevir for 8 weeks compared to sofosbuvir-velpatasvir for 12 weeks, and the result was not 'non-inferior.' It was not tried for 12 weeks as initial therapy."

In his editorial, Dr. Waked notes, "The results presented in this article raise an important issue of whether this treatment will be available for the patients who need it most. 75% of patients with HCV infection live in low-income or middle-income countries (LMICs), where the number of patients treated annually has reached more than double the number of patients treated in high-income countries. Almost all therapy in LMICs is based on a combination of sofosbuvir plus an NS5A inhibitor, and patients who do not respond to therapy will need access to sofosbuvir-velpatasvir-voxilaprevir at reduced prices, similar to the access programs of the first-generation direct-acting antivirals."

Dr. Bourliere did not respond to a request for comments.

Gilead Sciences funded the study, employed several of the authors and had various relationships with the rest as well as with Dr. Waked.

SOURCE: https://bit.ly/2y1nBe1 and https://bit.ly/2JwKZWc

Lancet Gastroenterol Hepatol 2018.

Cite this article: Sofosbuvir-Velpatasvir-Voxilaprevir Effective in Previously Treated Chronic Hep C - Medscape - Jun 12, 2018.

Tig · Admin

This is excellent news and long awaited! I’m thrilled about the opportunities being offered to our UK family and hope those in need will seek treatment with these two very effective protocols.

Woohoo!

Canuck · Guru

Just another happy little snippet of an announcement from the "Hep C Trust" newsletter yesterday, about Vosevi coming into use in the U.K. for the treatment-experienced. biggrin C.

... As you will know, the situation has thankfully changed greatly over the last few years and we now have a variety of different treatments available - usually just 8 - 12 weeks in duration, with very few side effects and success rates of over 95%. However, that means that we are still hearing from a few of you who weren't successful, and as the expectation was so high, hearing that it hadn't worked was particularly devastating.

So we were delighted to hear recently that Vosevi (a combination of sofosbuvir, velapatasvir and voxilaprevir) is now available as an alternative for those who did not have success with one of the new treatments containing NS5A inhibitors. It has been approved for the retreatment of those with genotypes 1 - 6, with or without cirrhosis.

There has never been a better time to get treated and there are now excellent options for all genotypes and regardless of the level of liver damage. If you are having any difficulty accessing treatment, call or email us on the helpline 020 7089 6221 or helpline@hepctrust.org,uk

Canuck · Guru

News is starting starting to come out of the UK and Scotland about Vosevi finally becoming available over there (via recent chats with Mak who informed us he is lined up for it in October). Here is what has surfaced thus far.

Via an excerpt from a UK Hepatitis Trust newsletter today:

NEWS FROM SCOTLAND

We are delighted to hear that new treatment Vosevi (sofosbuvir-velpatasvir-voxilaprevir) treatment was recently approved byScottish Medicines Consortium for the following groups of people:

· Those who have failed to achieve a sustained viral response (SVR) with a direct-acting anti-viral (DAA)

· DAA-naïve, genotype 3 (GT3) HCV infection, with or without cirrhosis

Also, Epclusa ihas been approved for:

· Genotype 1 and 4 chronic HCV infection, including those with decompensated cirrhosis.

This is in addition to the earlier advice for those with Genotype 2, 3, 5 and 6 ...

Via Feb 21 industry news:

https://www.thepharmaletter.com/article/nice-says-vosevi-ok-for-nhs-use

Via NICE:

https://www.nice.org.uk/guidance/ta507

Canuck · Guru

Just another (recent) 2018 review, on Epclusa's performance, specifically in regard to those with higher Fscores.

Excerpt from: Medscape

Sofosbuvir/Velpatasvir in Patients With Hepatitis C Virus Genotypes 1-6 and Compensated Cirrhosis or Advanced Fibrosis

Tarik Asselah; Stefan Bourgeois; Stephen Pianko; Stefan Zeuzem; Mark Sulkowski; Graham R. Foster; Lingling Han; John McNally; Anu Osinusi; Diana M. Brainard; G. Mani Subramanian; Edward J. Gane; Jordan J. Feld; Alessandra Mangia

Liver International. 2018;38(3):443-450.

Abstract and Introduction

Abstract

... Background & Aims Patients with chronic hepatitis C virus infection and advanced fibrosis (Metavir F3) or cirrhosis (Metavir F4) have been identified as a priority group for immediate treatment. We evaluated the safety and efficacy of sofosbuvir-velpatasvir in patients with hepatitis C virus genotype 1-6 infection and compensated cirrhosis or advanced fibrosis.

Methods This retrospective analysis included 501 patients with compensated cirrhosis or advanced fibrosis (F3/F4), as defined by >0.59 on Fibrotest, >9.5 kPa on Fibroscan, or F3/F4 (Metavir) or F4 (Ishak) on liver biopsy. Patients received sofosbuvir-velpatasvir for 12 weeks. Sustained virological response 12 weeks after treatment was determined.

Results Forty-four per cent of patients had cirrhosis. Sustained virological response 12 weeks after treatment was achieved by 98% of patients (490/501; 95% confidence interval, 96-99). Sustained virological response 12 weeks after treatment rates were 100% for hepatitis C virus genotypes 2 (85/85), 4 (60/60), 5 (13/13), and 6 (20/20). Sustained virological response 12 weeks after treatment rates were 98% (167/170) in hepatitis C virus genotype 1 patients and 95% (145/153) in hepatitis C virus genotype 3 patients. Among patients with cirrhosis 96% (212/220) achieved sustained virological response 12 weeks after treatment, vs 99% (278/281) for those with advanced fibrosis. Sustained virological response 12 weeks after treatment was 98% (306/311) for treatment-naïve patients and 97% (184/190) for treatment-experienced patients. No patients discontinued treatment due to adverse events. Eight patients reported nine serious adverse events; none was considered related to study procedures or drugs.

Conclusions Sofosbuvir plus velpatasvir is highly effective and safe for treating patients with hepatitis C virus genotypes 1, 2, 3, 4, 5 or 6 and advanced fibrosis or compensated cirrhosis...

Tig · Admin

Well, prehistoric, tar laden and maybe even feathered Dragons deserve the best anti virals, too! While Canada and BC are behind the times, I’m pleased that steps (even baby steps) are welcomed in the giant world of Dragon slaying. With the latest and greatest oral 2 & 3 drug DAA’s, it’s only a matter of time that there will be no other options available but these effective protocols. Everyone will hopefully soon have access to them. If we could get governments onboard with the equally effective generics, we could make a huge dent in this global menace. Iceland has taken this approach and may be one of the first to pioneer wide scale treatment for everyone. Fingers crossed!

Canuck · Guru

WELL! Finally! As usual, a day late and a dollar short. In the slow-mo world of Canada (and especially in BC, at the pre-historic dinosaur-land tar-sands-speed quagmire of our drug approval system here, Vosevi approval happened at lightening speed (comparatively speaking!).

How many were in dire need of Vosevi, waiting, back when BC first started "thinkin' on it, waaaay back in August of 2017? I fear some of the stats are likely grossly underestimated in the article below. That was a long cruel wait, for Vosevi to be made available to relapsers in BC, those in need of salvage therapy, to be waiting from August 2017 to now! Being "on the mark" in the US - Vosevi was being rolled out (for the benefit of many) starting from DAY ONE (August 2017). Ontario only started doling out Vosevi recently and BC only starts doling it out now, 7 months later, when they have exhausted their wheeling and dealing. The US started helping people wtih Vosevi at DAY ONE, in Canada, we were still (systematically) "talking" about it 7 months later!

I question the puny "numbers" the bean counters have come up with for this article to quote. The "numbers" may well be off by MUCH! How many GT3's alone are there in BC, how many HCV cases are there REALLY in BC, how many relapser people are there requiring HCV salvage re-treatment in BC. I doubt we count HCV "heads", accurately, we cannot even know how many people we have with undiagnosed HCV for heavens sake!

So many in dire need, so little time. Drugs available, but doled out "too little, too late" as we often see happen here in BC and in some of our other Provinces. Vosevi should NOT have been treated like they do other "orphan" drugs in Canada! Some relapsers have been waiting decades for the likes of Vosevi, and, how many treatment-naive would benefit from the likes of Vosevi!, and what will the ultimate outcome of theirs lives reveal, with being offered such a great drug triple as Vosevi, on such delayed basis.

What drugs were relapsers forced to accept instead, in the interim, whilst waiting for BC to "get on it with Vosevi already!". Shameful the processes and delays that are caused to patients in need of superior, fast, effective action.

Back when this GT3a was treated with Vosevi (luckily, only by the skin of my teeth, by gaining an entry seat into a drug trial), had I not been fortunate enough to gain one of the few seats available for that trial - I would have faced extremely limited drug choices in BC at that time - without successfully pursuing and winning a trial seat, I would have been "told" to do sof/riba for 24 weeks, and only IF and AFTER I failed that, then and only then, would I then be considered for 24 weeks of sof/dacla! And, the kicker was that dac, then, had still not yet even waded it's way through to the end of the BC drug approval pipeline!. At F4, was I glad I won my seat in a Vosevi trial and got cured?, versus any idea of waiting for Vosevi (or dacla for that matter) to come available to me via the "system"?, yup - you bet I was! Another kicker, although Vosevi was and would still be today, an ideal/superior first treatment for me - I would still not be able to get it today (as a treatment-naive GT3a) - it is only being doled out for relapser salvage re-treatment. Man, talk about ideal health care choices - NOT! Something else that should be changed, (Vosevi for the masses when it is in the patients best interests) if we are truly serious about trying to eradicate HCV in a timely fashion, with the least amount of harm, as it (along with all the other good DAA's we now have in our arsenal) would benefit many and the most.

Ya,ya - small hurray, about erasing the restriction of having a certain Fscore in BC (a common sense thing the rest of US have all LONG ago understood) - a lot of unhealthy delay has occured to many due to that demand, that a patient had to hold a certain Fscore. About time! - long overdue for that to be "un-done".

Still, with so many needing treatment, not enough budgets, prioritizing people (line up's) based on things like "signs of disease severities" (and thus Fscores), Fscores then, as part of the assessments, cannot be excluded from considerations.

Better late than never though - welcome Vosevi! - for the "few" lucky ones to whom the bean counters may dole it out to in BC.

http://www.cbc.ca/news/canada/british-columbia/hep-c-dix-announcement-2018-1.4574365

Tig · Admin

Good Stuff!!

Canuck · Guru

References belonging to the (prior) post (below) - had to post ref. here as I get message that the prior post was too long to submit in it's entirety! confuse So, here are the references that belong to the prior post below.

References

1. Christensen S, Ingiliz P, Mauss S, et al. Do resistance associated substitutions (RAS) or ribavirin (RBV) use influence treatment success of sofosbuvir (SOF)/velpatasvir (VEL) in chronic hepatitis C genotype 3 (GT 3) infection? Results from the German hepatitis C cohort (GECCO). Program and abstracts of the 2017 Annual Meeting of the American Association for the Study of Liver Diseases; October 20-24, 2017; Washington DC. Abstract 63.

2. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med. 2015;373:2608-2617.

3. American Association for the Study of Liver Diseases/Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. September 2017. Available at: http://www.hcvguidelines.org. Accessed October 26, 2017.

Canuck · Guru

(Earlier) trial data (presented this year) re: Epclusa GT3 trials (from Germany) with or without riba - similar performance as we have seen in other GT3 Epclusa trials data released just before Epclusa was adopted for use in US.

From Clinical Care Options - Conference coverage - Capsule Summary

GECCO: Sofosbuvir/Velpatasvir With or Without RBV Demonstrates High Efficacy in Genotype 3 HCV - Infected Patients, Including Cirrhotics in Real-World Setting

Source: 2017 Annual Meeting of the American Association for the Study of Liver Diseases* (October 2017 - Washington)

Date posted: 10/26/2017

· GECCO: prospective, multicenter German cohort study^[1]

Summary of Key Conclusions

· High sustained virologic response (SVR) rates at 12 weeks post treatment observed in genotype 3 HCV-infected patients receiving 12 weeks of sofosbuvir/velpatasvir with or without ribavirin (RBV) in "real-world" clinical cohort, including patients with cirrhosis

· No evidence that RBV increased efficacy in cirrhotic patients

· SVR in intent-to-treat (ITT) population: 95% in all patients

· SVR in cirrhotic patients: 94% without RBV vs 87% with RBV

· SVR in per protocol (PP) population: 99% in all patients

· SVR in cirrhotic patients: 94% without RBV vs 100% with RBV

· Baseline resistance associated substitution (RAS) had no impact on treatment efficacy

Background

· Sofosbuvir/velpatasvir approved for treatment of genotype 1-6 HCV infection

· FDA-approved regimen duration:

· 12 weeks of sofosbuvir/velpatasvir in treatment-naive and treatment-experienced patients without cirrhosis or with compensated cirrhosis (Child-Pugh A)

· 12 weeks of sofosbuvir/velpatasvir plus RBV in treatment-naive and treatment-experienced patients with decompensated cirrhosis (Child-Pugh B and C)

· Phase III ASTRAL-3 compared 12 weeks of sofosbuvir/velpatasvir vs 24 weeks of sofosbuvir plus RBV in treatment-naive and treatment-experienced patients with genotype 3 HCV infection, including those with compensated cirrhosis^[2]

· SVR rates in sofosbuvir/velpatasvir arm across subpopulations:

· 91% in cirrhotic patients vs 97% in noncirrhotic patients

· 90% in pretreated patients vs 97% in treatment-naive patients

· 88% in patients with baseline NS5A RAS (A30K, L31M, and Y93H) vs 97% in patients with no baseline NS5A RAS; 84% in patients with baseline Y93H

· American Association for the Study of Liver Diseases/Infectious Diseases Society of America HCV management guidelines recommend use of 12-week sofosbuvir/velpatasvir in genotype 3 HCV-infected populations^[3]

· Addition of RBV recommended in treatment-naive patients with compensated cirrhosis and Y93H mutation, and those with cirrhosis having previous NS5A or peginterferon/ribavirin treatment experience

· Current study explored impact of baseline RASs, cirrhosis, RBV use on response to sofosbuvir/velpatasvir in genotype 3 HCV-infected patients receiving HCV therapy within clinical cohort setting

Summary of Study Design

· Patients participating in ongoing GECCO cohort enrolled from 9 sites in Germany

· GECCO includes data from 2312 patients initiating direct-acting antiviral therapy since February 2014

· 576 patients in GECCO infected with genotype 3 HCV

· Current analysis restricted to 232 genotype 3 HCV-infected patients treated with 12 weeks of sofosbuvir/velpatasvir with or without RBV since July 2016

Baseline Characteristics (graphs missing)

· N = 232 genotype 3 HCV-infected patients included

· n = 200 (86%) receiving sofosbuvir/velpatasvir

· n = 32 (14%) receiving sofosbuvir/velpatasvir plus RBV

Description of Current Analysis

· SVR rates evaluated in ITT and PP populations

· 12-week follow-up data available for 141 of 232 (61%) treated patients

· Data pending in 84 of 232 (36%) patients

· 7 of 232 (3%) patients lost to follow-up

· ITT analysis includes data from 148 of 232 patients

· PP analysis includes data from 141 of 232 patients

Main Findings

· High SVR rates observed in genotype 3 HCV-infected patients receiving 12 weeks of sofosbuvir/velpatasvir with or without RBV, including patients with cirrhosis

· No evidence that RBV increased efficacy in cirrhotic patients

· SVR in ITT population: 95% in all patient

· SVR in cirrhotic patients: 94% without RBV vs 87% with RBV

· SVR in PP population: 99% in all patients

· SVR in cirrhotic patients: 94% without RBV vs 100% with RBV

*SVR, n/N (%)*	*All Patients*	*Cirrhotic Patients*
*SVR, n/N (%)*	*Sofosbuvir/Velpatasvir ± RBV*	*Sofosbuvir/Velpatasvir*	*Sofosbuvir/Velpatasvir + RBV*
ITT analysis	140/148 (95)	16/17 (94)	13/15 (87)
PP analysis	140/141 (99)	16/17 (94)	13/13 (100)

· Relapse occurred in 1 cirrhotic patient receiving sofosbuvir/velpatasvir without RBV

· Previously treated with sofosbuvir plus RBV for 6 months with subsequent relapse

· Primary RAS not detected at baseline

· Y93H detected at relapse following sofosbuvir/velpatasvir

· Baseline characteristics generally comparable in cirrhotic patients treated with vs without RBV, except INR

Baseline RAS had no impact on treatment efficacy

· SVR in ITT population: 94% no RAS vs 100% with RAS

· SVR in PP population: 99% no RAS vs 100% with RAS

*SVR, n/N (%)*	*All Patients Receiving Sofosbuvir/Velpatasvir ± RBV*
*SVR, n/N (%)*	*No Baseline RAS*	*With Baseline RAS*
ITT analysis	98/104 (94)	10/10 (100)
PP analysis	98/99 (99)	10/10 (100)

· PP analysis included 109/141 patients with baseline RAS data available

· All 10 of 109 (9%) patients with RAS achieved SVR

· n = 5/10 with A30K including n = 1 pretreated, n = 3/5 received RBV (all 3 had cirrhosis)

· n = 5/10 with Y93H including n = 1 pretreated, n = 1/5 received RBV (all 5 had cirrhosis)

Canuck · Guru

Re: LT patients - This is an excerpt from AASLD recommendations dated September 21, 2017

Sofosbuvir/Velpatasvir

To date, there have been no studies evaluating the safety and efficacy of the fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) in liver transplant recipients. For this reason, very limited recommendations on its use post liver transplantation can be made. However, with no treatment options for liver transplant recipients with genotype 2 or 3 infection who have decompensated cirrhosis, expert opinion led to the recommendation to use sofosbuvir/velpatasvir with weight-based ribavirin for these patients.

_________________________________________________________________________________________________________________________

News Releases from Gilead - dated October 20, 2017 - poster #1069 is just one of 25 presentations Gilead was doing at "The Liver Meeting" - Washington

Epclusa in Liver Transplant Patients (Poster #1069)

In an open-label Phase 2 study evaluating once-daily Epclusa for 12 weeks among 79 liver transplant patients with genotype 1-4 chronic HCV infection, treatment with Epclusa resulted in an overall SVR12 rate of 96 percent, including patients with cirrhosis and prior treatment failure, and was well tolerated.

Patient Population	SVR12	Patient Population	SVR12
Genotype 1	95% (35/37)	Genotype 1-4 without cirrhosis	97% (70/72)
Genotype 2	100% (3/3)	Genotype 1-4 with cirrhosis	86% (6/7)
Genotype 3	97% (34/35)	Genotype 1-4, treatment-naïve	94% (30/32)
Genotype 4	100% (4/4)	Genotype 1-4, treatment-experienced	99% (46/47)

Baseline resistance mutations did not impact SVR rates. Two patients relapsed in this study - one treatment-naïve non-cirrhotic patient with HCV genotype 1a and one treatment-experienced non-cirrhotic patient with HCV genotype 3.

Common adverse effects (AEs) (>10 percent) were headache (24 percent), fatigue (20 percent) and cough (10 percent). Three patients (4 percent) experienced serious AEs; none was related to study drug. One patient discontinued treatment after one week due to hyperglycemia. There were no deaths, graft loss or episodes of acute liver transplant rejection.

Epclusa is approved for patients with genotype 1-6 without cirrhosis or with compensated cirrhosis, and in combination with RBV for patients with decompensated cirrhosis. The safety and efficacy of Epclusa in liver transplant recipients has not been established.

Canuck · Guru

Here's yet another review of new drugs now out on the market, namely Vosevi - this thread tries to confine itself to info mostly about Gileads "Epclusa (sof/vel) and "Vosevi" (sof/vel/vox), but so as to not break the below article up, the article is pasted here in it's entirety, and includes info about another regime - AbbVies "Mavyret" (glec/pib).

EDITORIAL

Two Approvals Offer Even More Options for HCV Treatment - HCV Next, September/October - Ira M. Jacobson, MD

The approval of two new regimens for treating hepatitis C comes as a very welcome development in the field. It is great news for patients and providers because both regimens offer new options for therapy.

For patient populations that we have been accustomed to treating with high levels of efficacy and tolerability, we now have new features like shorter duration of therapy. For those who previously failed direct- acting antiviral therapy who previously had no treatment, we now have an approved regimen.

Vosevi

Fortunately, only a small number of our patients - under 5% - falls into the category of having failed previous DAA therapy. Yet it has been a cherished goal in the field to be able to cure every single patient and leave no patient without a cure. Vosevi (sofosbuvir/velpatasvir/voxilaprevir; SOF/VEL/VOX, Gilead Sciences) should go a long way in helping us do that.

Vosevi is a combination of voxilaprevir, a potent and pangenotypic protease inhibitor that covers the most protease inhibitor resistant variants capable of emerging after exposure to first generation members of the protease inhibitor class, with the components of an already approved product, Epclusa (sofosbuvir/velpatasvir; SOF/VEL, Gilead Sciences), a combination of the pangenotype NS5A inhibitor, velpatasvir, and the familiar nucleotide polymerase inhibitor sofosbuvir. That dual combination has had the distinction being the first approved pangenotypic regimen and it's already in widespread use. Because of the incremental efficacy it offers in genotypes 2 and 3 compared with earlier regimens, including genotype 3 patients with cirrhosis, it represented a particular step forward for patients with genotypes 2 and 3 and has become the treatment of choice for these genotypes, as reflected in the AASLD Guidance (hcvguidelines.org) since its approval in 2016.

There have been a number of studies looking at various regimens for patients who fail first-generation DAAs. The regimens studied have sometimes consisted of a longer duration of treatment of the same regimen the patient received before or the same regimen for the same or longer duration combined with ribavirin. Less often, researchers have studied a combination of regimens made by different manufacturers combined in an individualized non-FDA approved manner. Some of these regimens such as Viekira Pak (ombitasvir/paritaprevir/ritonavir/dasabuvir, AbbVie) combined with Sovaldi (sofosbuvir, Gilead Sciences) have high levels of efficacy. Unfortunately, these combinations are quite expensive and are less accessible due to their unapproved status and lack of large pivotal trials that demonstrate their efficacy.

Vosevi was studied extensively in the POLARIS studies, of which there were four in total.

The two that have emerged as most relevant, because they evaluated the patient populations for which approval has been garnered, were POLARIS-1 and -4. In POLARIS-1, patients who previously failed an NS5A-containing DAA received Vosevi for 12 weeks. In POLARIS-4, the participants previously failed a DAA regimen that did not contain an NS5A inhibitor.

Of these two studies POLARIS-1 was more impactful because most patients who have been treated with DAA regimens so far have received an NS5A inhibitor. They have become foundational to the way we treat HCV in recent years. Only simeprevir/sofosbuvir, an early DAA combination used extensively in the early DAA era, falls into the POLARIS-4 category, but it is seldom used anymore.

POLARIS-1, demonstrated very high levels of efficacy for 12 weeks of SOF/VEL/VOX in patients with all genotypes who had been treated with an NS5A inhibitor previously. The comparator group was a placebo-recipient group which produced no SVRs.

The efficacy rate in the Vosevi group was 96% rate of SVR - 99% in those without cirrhosis and 93% in those with cirrhosis. There were six relapses in the cirrhosis group (n = 121) and no virologic failures in those without cirrhosis (n = 142).

A distinctive feature of this regimen that sets it apart from earlier regimens is that baseline resistance associated substitutions in the protease and NS5A domains did not affect efficacy. Moreover, the few patients who relapsed did not have treatment emergent resistant-associated substitutions. This leaves open the possibility, that deserves to be explored further, of whether repeated treatment with a longer duration of Vosevi with or without ribavirin might work in these failures.

In POLARIS 4, patients had failed DAAs that did not contain NS5A, so most of the patients had received sofosbuvir (85%) with or without a protease inhibitor. In POLARIS 4, the comparator group was 12 weeks of SOF/VEL.

Here there was a distinct advantage for 12 weeks of the triple regimen, with SVR rates of 97% vs 90% with SOF/VEL alone. It could be questioned why the results of SOF/VEL were distinctly under 95% in contrast to all other studies of POLARIS. This probably has something to do with the fact that whatever made patients fail a sofosbuvir-containing regimen previously, whether it's a bioavailability issue, an absorption issue or something else, this likely underlies a failure to succeed with sofosbuvir that was presumably again at play despite the addition of velpatasvir. The numerically higher SVR12 rates with SOF/VEL/VOX versus SOF/VEL in POLARIS-4 were limited to patients with genotypes 1a and 3.

With regard to safety, there is a slight increase in GI side effects with Vosevi, most of which were mild, consisting of nausea or diarrhea, and resulted in no treatment discontinuations.

The results of POLARIS-1 and -4 garnered FDA approval in July 2017, for 12 weeks of Vosevi in patients with genotypes 1 through 6, with or without compensated cirrhosis, who failed a regimen with an NS5A inhibitor, and for patients who had failed a sofosbuvir-containing regimen, without an NS5A, with genotypes 1a and 3. It should be underscored that Vosevi is only approved for compensated cirrhosis at this point; protease inhibitors are either not recommended or contraindicated in child's B or C patients across the board due to pharmacokinetic considerations.

In my practice, we have already recalled the few patients who failed DAA regimens with the intention to offer them this regimen.

Worthy of mention are the POLARIS-2 and -3 studies in DAA-naive patients. POLARIS-2 compared 8 weeks of SOF/VEL/VOX 12 weeks of SOF/VEL in more than 900 patients with genotypes 1 through 6 except for genotype 3 patients with cirrhosis, and demonstrated SVR12 rates of 95% and 98%. The SVR12 rate in the triple therapy group failed to meet the protocol-specified noninferiority endpoint, a difference in efficacy driven almost entirely by lower SVR12 rates with triple therapy in the genotype 1a patients. Curiously, the Q80K protease polymorphism highly prevalent in genotype 1a, which historically reduced efficacy of the protease inhibitor simeprevir with pegylated interferon and ribavirin, was associated with lower SVR12 rates in the genotype 1a patients of POLARIS-2, even though the sensitivity of the Q80K-containing virus is not reduced in vitro to voxilaprevir as it was to simeprevir. The reason for the divergent results in the genotype 1a patients between the two treatment arms in POLARIS-2 remains unclear. In POLARIS-3, containing exclusively genotype 3 patients with cirrhosis, the trial design was identical and so were the SVR12 rates: 96% with 8 weeks of SOF/VEL/VOX and 12 weeks of SOF/VEL. Thus, SOF/VEL/VOX is an excellent genotype 3 regimen, but because it was equivalent to SOF/VEL in efficacy, rather than superior, it did not garner regulatory approval for this group of patients nor for the larger population of genotypes 1 through 6 DAA-naive patients.

Mavyret

Mavyret (glecaprevir/pibrentasvir, AbbVie) is a novel second generation regimen that includes two drugs: glecaprevir, a protease inhibitor, and pibrentasvir, an NS5A inhibitor. Both of these are true second-generation drugs individually, so this is a true second-generation regimen. This means they are pan-genotypic and they cover the resistance variants particular to the protease class and the NS5A class that confer loss of sensitivity in vitro or have characterized the viral populations of patients who have failed first generation regimens.

The Mavyret studies included a broad spectrum of patients - cirrhotics, non-cirrhotics, treatment-naive, interferon failures, DAA failures, HIV coinfection, renal failure, kidney and liver transplants. However, patients with decompensated cirrhosis were not included. This regimen, which has been abbreviated as G/P regimen, was studied without ribavirin.

One of the largest of these phase 3 trials was the ENDURANCE-1 study, which evaluated patients without cirrhosis receiving 8 weeks of therapy vs. 12 weeks of therapy. Patients could be either interferon-experienced or treatment-naive.

The SVR rates were 99.1% in more than 300 patients who received 8 weeks of therapy and 99.8% in the patients who received 12 weeks of therapy. These SVR rates reflect only one virologic failure in the 8-week group and none in the 12-week group.

Genotype 3 was studied in a separate study called ENDURANCE-3, which compared 8 or 12 weeks of G/P vs. 12 weeks daclatasvir plus sofosbuvir and showed statistically noninferior SVR rates of 95% for each of the two Mavyret regimens and 97% for daclatasvir plus sofosbuvir, though there were a few more relapsers in the Mavyret groups.

The ENDURANCE-2 and -4 studies evaluated 12 weeks of G/P in patients with genotype 2 and genotype 4 through 6, respectively with SVR rates of 99% in each study. In SURVEYOR-2, part 4, an 8-week regimen of G/P was studied in patients with genotypes 2, 4, 5 and 6 without cirrhosis with SVR 12 rates by modified intent-to-treat analysis of 98% to 100%. In EXPEDITION-1, the G/P regimen proved to be robust in patients with compensated cirrhosis, with an overall SVR rate of 99% in patients with genotypes 1, 2, 4 and 5. In patients with all genotypes and renal impairment, studied for 12 weeks with G/P there were no virologic failures in 104 patients. The regimen also proved to be robust in studies evaluating HIV/HCV coinfected patients, patients with renal impairment (with zero virologic failures out of 104 patients given G/P), and patient with renal or liver transplants.

In MAGELLAN-1, part 2, which evaluated Mavyret in patients with prior DAA failure, the regimen did very well except in patients who had been exposed to both a protease and an NS5A inhibitor, the latter finding attributable to the presence of dual class resistance substitutions. Most of the DAA-failure patients studied had genotype 1. Therefore this regimen is approved for the treatment of patients with genotype 1, who previously received a regimen containing an NS5A inhibitor or an NS3/4A protease inhibitor, but not both.

Overall, the results with G/P are very robust and established 8 weeks of G/P as a newly approved regimen, as of August 2017, for non-cirrhotic patients with all HCV genotypes. Although not the first approved 8-week regimen - that distinction belonging to Harvoni (ledipasvir/sofosbuvir, Gilead Sciences) - G/P is approved for 8 weeks in interferon-experienced patients as well as treatment-naive patients across all genotypes and is independent of the patient's baseline viral load. Many clinicians value the concept of giving the shortest duration of therapy necessary without sacrificing SVR. Additionally, the regimen is approved for 12 weeks in cirrhosis and is highly efficacious.

We do have to be mindful of drug-drug interactions and clinicians would be well advised to review that list. There is no issue with proton-pump inhibitors.

Bottom Line

The availability of the first approved regimens in DAA failure patients, although affecting relatively few patients because of the high SVR rates with existing regimens, is a major advance toward the universal goal of "leaving no patient behind" without cure of their HCV. The data base from phase 3 trials for SOF/VEL/VOX is larger for DAA-failure patients than for G/P, and the approved DAA-failure is more expansive, with no genotype restrictions, a uniform duration of treatment of 12 weeks (vs. 16 weeks for G/P in prior NS5A treatment failures), and applicability to patients who have been exposed to both protease and NS5A inhibitors. Further data on G/P in DAA failures would be valuable and plans are in progress to obtain such data, and even for SOF/VEL/VOX we will have to explore approaches for 12-week failures, which among NS5A-experienced patients was confined to cirrhotics in the POLARIS-1 trial. Perhaps simply retreating for a longer time will suffice, given the lack of impact of baseline RASs on outcome with this regimen and the infrequency of treatment-emergent RASs in the few patients who fail.

With the G/P regimen we have a highly effective new option for 8-week treatment, in patients who are non-cirrhotic and DAA-naive. Clinicians will have to decide whether the capacity to shorten the duration of therapy is significant for them and their patients, but many clinicians have expressed the feeling that so long as there is no discernible impact on SVR, a shorter duration of treatment would be viewed favorably. Reduced costs, if facilitated by a shorter duration regimen, may also result in expanded access to therapy nationally and internationally. Whether in cirrhotics treated with 12 weeks of G/P, HIV/HCV coinfected patients or patients with renal or liver transplants, the efficacy of G/P appears to be excellent, and the regimen is very attractive for patients with renal impairment (sofosbuvir for patients with GFR <30 ml/min is still unapproved).

Finally, no discussion of the POLARIS studies would be complete without acknowledging the affirmation in these studies of the very high level of efficacy of SOF/VEL demonstrated in the previous ASTRAL studies, which led to its approval in 2016. This efficacy was reaffirmed abundantly in the studies of SOF/VEL/VOX, in which 12 weeks of SOF/VEL performed very well when compared to the triple regimen in DAA-naive patients.

All in all, we are living in a time when we can still marvel at our abilities to cure nearly every single patient with HCV who walks into our offices. These approvals and expansions further our ongoing goal of eradicating HCV.

Ira M. Jacobson, MD - HCV Next - Co-Chief Medical Editor

Canuck · Guru

Hm, not only in Canada you say! This is a welcome and "nice" announcement, BUT, we shall see. Just like many other good drugs in Canada that are announced as "being approved/available" to us (in theory), in practise ... how it "actually" gets doled out (once it gets down to each provincial and health authority bodies and their "rules and exceptions") is to be seen. Believe me, a lot of good drugs "truly" being available here have historically been lip-service in actuality. I hope Vosevi IS HEAVILY utilized here, across ALL provinces and jurisdictions without all the "read the fine print" arm-tying restrictions. C.

Health Canada approves Vosevi for retreatment of chronic HCV - August 17, 2017 - Helio

Canuck · Guru

Angel,

Read this Vosevi one (especially for the GT1 info) and cure rates, etc. - it was down below, in this thread, if you have not already read it before. smile C. http://www.natap.org/2017/EASL/EASL_57.htm

Tig · Admin

The overall cure rates of Vosevi are 91% to 100% in patients who had been previously treated with sofosbuvir-containing therapies. Failure rates of Harvoni are approximately 5% average across the board. That's a fairly standard failure rate with all DAA's however. We're beginning to see upper 90 percentile success rates in many regimens, but that depends on genotype. Vosevi is a 12 week protocol for all patients.

This Merck trial is recruiting now.

ClinicalTrials.gov Identifier:

NCT02613403 w/wo Ribavirin

Grazoprevir NS3/4A, Ruzasvir NS5A, and Uprifosbuvir NS5B (16 weeks w/Ribavirin and 24 weeks wo/Ribavirin)

Canuck · Guru

Hey angel,

That's nice that Gilead called you back! smile

Yup, thats the info that was already out there!

Epclusa and Vosevi have a proven track record of stellar results for GT1-6.

So, in other words, what we were saying prior and what you are saying now, is the same thing ... that Vosevi has worked, very well, for relapsers of many varied regimes, and for gentotypes 1 -6!

Right back to where we started! wink

If you search the "actual" Vosevi studies, you will find even more specific info re: cure rates, relating exactly to your parameters, GT1a/previous failure on ledi/ and re-treated with vosevi. If you are interested in doing more research. biggrin C.

BTW - I hope you are still not confused about who vosevi could possibly be for (any GT) ... re: other treatment-experienced relapsers, including ... "prior treatment experience included sofosbuvir with or without any of the following: peginterferon alfa/ribavirin, ribavirin, HCV NS3/4A protease inhibitor (boceprevir, simeprevir or telaprevir)" ...

-- Edited by Canuck on Friday 11th of August 2017 04:31:38 PM

angelseven · Senior Member

A very nice and knowlegable gentlemen actually called me back from Gilead today regarding Vosevi (pronounced Vah-so-vaaa) Sounds french actually... anyway regarding this statement:

vosevi is good for:

genotype 1a or 3 infection and have previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor

(In other words if you took sofobuvir with riba, or interferon ,this treatment is no good for you, if you took harvoni you are ok to treat with it)

He said in section 14 (of the insert info) it shows the success rate for treatment in the clinical trials for the 51% that had treated with harvoni and relapsed as 96% (this is not broken down by genotype)

I would probably be in the 4% that relapses... LOL.. that's how i am feeling....waiting for merck trial!!

Have a nice weekend!! connie/angelseven

Canuck · Guru

The so-called (Aug 8th) roll-out (in USA ) for Vosevi IS highly anticipated/waited on, by some. This tidbit (excerpt) indicates that ... "within hours" the docs were scribbling scripts, in the EU, according to Gilead and the writer of this (larger) article.

... John Milligan, company president and chief executive officer, concluded the conference by reviewing the details of Vosevi's (sofosbuvir/velpatasvir/voxilaprevir) recent FDA approval. "We are aware that prescriptions of Vosevi were written within hours of its approval," Milligan said. Gilead anticipates approval in the EU for Vosevi in the third quarter of 2017. - by Talitha Bennett

Canuck · Guru

No test, and, No contest ... it's Vosevi all the waaay, hands down, or ... even with one hand tied behind your back!!!!!! heeheewheee biggrin

JimmyK · Guru

Is there going to be a test? wink

Your Loving Big Brother

Jimmy

Canuck · Guru

Finally! The full Vosevi package insert (all 35 pages).

Vosevi - Gilead Sciences, Inc.

Canuck · Guru

HEY! biggrin Finally!

I still can't find the "full prescribing information" for Vosevi as yet, only this thus far! Man, Gilead sure is tight-shipped, tight-lipped and they sure know how to keep gossip under wraps and make announcements a somewhat long and drawn out affair!

BOXED WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN HCV/HBV COINFECTED PATIENTS

Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with Vosevi. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals (DAAs) and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive, in patients with serologic evidence of resolved HBV, and also in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV DAAs may be increased in patients taking these other agents. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.

Contraindications

· Vosevi is contraindicated with rifampin.

Warnings and Precautions

· Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with Vosevi due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. A fatal cardiac arrest was reported in a patient taking amiodarone who was coadministered a sofosbuvir containing regimen. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

· Risk of Reduced Therapeutic Effect Due to Concomitant Use of Vosevi with P-gp Inducers and/or Moderate to Potent Inducers of CYP2B6, CYP2C8 or CYP3A4: St. John's wort and carbamazepine are not recommended for use with Vosevi as they may significantly decrease sofosbuvir, velpatasvir, and/or voxilaprevir plasma concentrations.

Adverse Reactions

· The most common adverse reactions (>10%, all grades) with Vosevi were headache, fatigue, diarrhea, and nausea.

Drug Interactions

· Coadministration of Vosevi is not recommended with phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifapentine, atazanavir, lopinavir, tipranavir/ritonavir, efavirenz, rosuvastatin, pitavastatin, and cyclosporine due to changes (decreased or increased) in concentrations of sofosbuvir, velpatasvir, voxilaprevir, and/or the other agent.

Consult the full Prescribing Information for Vosevi for more information on potentially significant drug interactions, including clinical comments

JimmyK · Guru

Making the Dragon Extinct has a good ring to it.

wink

Tig · Admin

Outstanding news, RC! There's an FDA webpage with additional information. This is going to be a hard protocol to better based on several factors. The one thing alternative treatments offer though, is a lower price. Let's wait to see what price Gilead tacks on this gold mine... The generic market will be inviting to those wanting something like this and are unable to get approval through their insurance carrier. The entire treatment picture is changing at light speed now. It's hard to believe how many different treatments are available now and in just a few years. Incredible stuff happening...

FDA Release: Vosevi Approved

robertsamx · Guru

Vosevi....FDA approved today.!!!

Canuck · Guru

Just more Vosevi gossip ...

Prediction of Gilead's "Vosevi" sales (over AbbVie's "Mavriet") 2017 to 2022- article from BMI Research, June 29, 2017

Antiviral drug companies are set to struggle with the improving cure rates associated with the current hepatitis C (HCV) drugs, which are reducing the patient pool and the possibility for new drug opportunities. A potential bright spot is the approval of pan-genotypic HCV therapies that offer a significant advantage over current therapies. Both Gilead Sciences and AbbVie have received a positive opinion from the EMA's CHMP and are looking for approval in the EU and US later in 2017.

The EMA's CHMP has adopted a positive opinion on Gilead's MAA for Vosevi, an investigational, once-daily, single-tablet regimen of sofosbuvir 400mg, velpatasvir 100mg, and voxilaprevir 100mg (SOF/VEL/VOX) for the treatment of chronic HCV(cHCV)-infected patients. The data included in the application support the use of SOF/VEL/VOX in patients with and without compensated cirrhosis, with all genotypes (GT1-6) of HCV infection regardless of prior therapy, including eight weeks of treatment for HCV direct-acting antiviral (DAA)-naive patients without cirrhosis, as well as 12 weeks of treatment for patients who have previously failed therapy with a DAA-containing regimen.

Gilead To Lead The Battle

Estimated Product Revenues (USDmn)

story-Europe-Antiinfectiv-2017-06-26-11-

Source: Bloomberg, BMI

Canuck · Guru

More about sof/vel/vox (Vosevi) - (roll-out date Aug 8, 2017?) - just reiterating how well this regime is performing across all GT's, nearly irrespective of prior failures, presence of cirrhosis and RAV's.

Exerpt from - Digestive Disease Week (DDW) 2017 - William F. Balistreri, MD -July 03, 2017

Sofosbuvir/Velpatasvir/Voxilaprevir

A pangenotypic combination of sofosbuvir (SOF), velpatasvir (VEL), and voxilaprevir (VOX) was designed to inhibit three distinct HCV targets: the NS5B polymerase, the NS5A protein, and NS3/4A protease, respectively.

Flamm and colleagues^[3] presented cumulative data from 1056 patients with and without compensated cirrhosis who were infected with HCV genotype 1-6 and treated with the once-daily fixed-dose combination tablet of SOF/VEL/VOX in phase 3 studies.

Of the DAA-experienced patients, 59% had received an NS5A inhibitor-containing regimen, whereas 20% of the DAA-naive patients had prior treatment failure with pegylated interferon plus ribavirin.

The studies enrolled a diverse patient population that included a significant number of patients with historically negative predictors of response, including cirrhosis and prior exposure to DAA-containing regimens.

SOF/VEL/VOX was administered to DAA-experienced patients with HCV genotype 1-6 infection for 12 weeks, and DAA-naive patients received treatment for 8 weeks. Cirrhosis was observed in 38% of patients, and 70% had an HCV RNA level > 800,000 IU/mL.

The resultant SVR12 rate was 96% in NS5A inhibitor-experienced patients and 97% in DAA-experienced patients who had not previously received an NS5A inhibitor. Thus, this ribavirin-free regimen of SOF/VEL/VOX achieved high rates of SVR across subgroups.

Predicting Treatment Outcomes

Reddy and colleagues^[4] evaluated the effect of baseline resistance-associated substitutions (RASs) on treatment outcome and sought the emergence of RASs in patients who experienced virologic failure.

NS3, NS5A, and NS5B deep sequencing was performed at baseline for all patients and at the time of virologic failure. The investigators found that 79% of NS5A inhibitor-experienced patients had baseline NS3 and/or NS5A RASs. Of these patients, 75% had NS5A RASs - the most common RAS - at baseline.

SVR12 rates were similar in patients with and those without NS3 and/or NS5A RASs, and in those with and those without VOX- or VEL-specific RAS. Specifically, RASs at NS5A position Y93 were present in 25% of patients, of whom 95% achieved SVR12. All patients with more than two NS5A RASs achieved SVR12. In addition, 95% of patients with NS5B nucleoside inhibitor RASs achieved SVR12; two patients had S282T present at baseline, and both achieved SVR12. The overall prevalence of baseline NS3 and/or NS5A RASs was 47%, and all achieved SVR12. No NS3, NS5A, or NS5B RASs emerged in any patient who had relapse after treatment with SOF/VEL/VOX for 12 weeks.

Therefore, the investigators documented that baseline RASs had no impact on the virologic response in DAA-experienced patients in this cohort after treatment with SOF/VEL/VOX for 12 weeks, and that virologic relapse was not associated with the emergence of viral resistance.

Canuck · Guru

Ragdoll and Tig found and posted this, about Gilead's "Vosevi" (sof/vel/vox) .... yay! biggrin

http://www.businesswire.com/news/home/20170623005247/en/

Interestingly enough, on the exact same announcement dates, Europe ia also looking at AbbVie's "Mivaret" (glec/pib - no sof).

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004430/smops/Positive/human_smop_001152.jsp&mid=WC0b01ac058001d127

Canuck · Guru

More conversation about sof/vel/vox. (Excerpt from a larger commentary) - the second emerging therapy mentioned was glec/pib.

Digestive Disease Week (DDW) 2017

Nancy S. Reau, MD

June 13, 2017

Emerging Treatments

The fixed-dose combination (FDC) of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX; polymerase inhibitor/NS5A replication complex inhibitor/protease inhibitor) is one of two new second-generation pangenotypic therapies anticipated later this year.

POLARIS-1 evaluated this FDC in patients who previously did not respond to NS5A-containing direct-acting antiviral (DAA) therapy, and POLARIS-4 evaluated this FDC in patients who failed DAA therapy without NS5A exposure.

Reddy and colleagues^[3] presented the integrated resistance analysis from these two studies. Deep sequencing was performed for all patients at baseline and at the time of virologic failure. Both NS3 or NS5A class resistance-associated substitutions (RAS), as well as VOX or VEL-specific RAS, were evaluated and reported using a 15% cutoff. RAS was noted in 83% of POLARIS-1 patients, of whom 29% had RAS to both NS3 and NS5A. SVR12 was 98% in those without RAS and 97% in those with RAS. Prevalence of RAS was lower in POLARIS-4, with 51% having no detectable RAS at a 15% cutoff, of which 99% achieved SVR12. There was 100% SVR12 in those with RAS in POLARIS-4. The authors concluded that baseline RAS had no impact on virologic response in this DAA-experienced study. Of note, there were no treatment-emergent RAS in those who relapsed after 12 weeks of SOF/VEL/VOX. Testing for RAS before re-treating a DAA failure is currently recommended; however, these data suggest that identifying the presence of resistance may not modify therapeutic decisions or efficacy.

Canuck · Guru

(From Helio - Journal Summary)

Investigational HCV regimen shows promise in two phase 3 trials

SHOW CITATION

May 31, 2017

An investigational fixed-dose combination regimen containing Sovaldi, velpatasvir and voxilaprevir for the treatment of hepatitis C virus resulted in high rates of sustained virologic response after 12 weeks of treatment among patients with or without compensated cirrhosis in whom previous therapy with direct-acting antiviral agents had failed, according to results of two international, phase 3 trials.

Marc Bourliére, MD, of Hospital Saint Joseph, France, and colleagues reported in The New England Journal of Medicine that the proportion of patients with hepatitis C virus (HCV) in whom therapy with direct-acting antiviral agents (DAAs) had failed is small; however, the number of these patients is substantial and will likely increase as more people are treated for HCV.

"This population of patients has been underrepresented in clinical trials and has limited retreatment options," they wrote.

Therefore, the researchers conducted two phase 3 trials, POLARIS-1 and POLARIS-4, to assess the safety and efficacy of an investigational regimen containing the nucleotide polymerase inhibitor Sovaldi (sofosbuvir, Gilead Sciences), the NS5A inhibitor velpatasvir and the protease inhibitor voxilaprevir in patients with chronic HCV infection, including those with compensated cirrhosis, in whom previous therapy has failed.

In POLARIS-1, the researchers randomly assigned patients with HCV genotype 1 whose previous treatment included an NS5A inhibitor to receive a once-daily, single-tablet regimen containing 400 mg of sofosbuvir and 100 mg each of velpatasvir and voxilaprevir (n = 150) or placebo (n = 150) for 12 weeks. An additional 114 patients with other genotypes were enrolled in the sofosbuvir/velpatasvir/voxilaprevir arm.

In POLARIS-4, patients with HCV genotypes 1, 2 or 3 whose previous regimen did not include an NS5A inhibitor were assigned to receive either sofosbuvir/velpatasvir/voxilaprevir (n = 163) or Epclusa (sofosbuvir/velpatasvir, Gilead Sciences; n = 151) for 12 weeks. An additional 19 patients with HCV genotype 4 were enrolled in the sofosbuvir/velpatasvir arm.

All study participants in both trials were enrolled at more than 100 sites in the United States, Canada, New Zealand, Australia, France, Germany and the United Kingdom. Among patients who received an active treatment, 46% had compensated cirrhosis.

In POLARIS-1, the overall rate of sustained virologic response was 96% (95% CI, 93-98) among patients who received sofosbuvir/velpatasvir/voxilaprevir, which is significantly superior to a prespecified goal of 85% (P < .001), according to the researchers. Of 253 patients with a sustained virologic response, 249 returned for a 24-week visit post-treatment, and all still had a sustained virologic response. None of the patients in the placebo arm had a sustained virologic response.

In POLARIS-4, the overall rate of sustained virologic response was 98% (95% CI, 95-99) among those who received sofosbuvir/velpatasvir/voxilaprevir, which also was superior to the same prespecified goal as in POLARIS-1 (P < .001), and 90% (95% CI, 84-94) among those who received sofosbuvir/velpatasvir. Of 177 patients in the sofosbuvir/velpatasvir/voxilaprevir arm and 136 patients in the sofosbuvir/velpatasvir arm who had a sustained virologic response, 173 and 133 returned for the 24-week visit, and all had a sustained virologic response.

Across the study arms, the most common adverse events included headache, fatigue, diarrhea and nausea. The percentage of patients who discontinued active treatment due to adverse events was 1% or lower, the researchers reported.

"In conclusion, these results show that daily treatment with the single-tablet regimen of sofosbuvir-velpatasvir-voxilaprevir for 12 weeks is highly effective for patients infected with HCV of any genotype, with or without compensated cirrhosis, who did not have a sustained virologic response after treatment with DDA-based regimens, including NS5A inhibitors," they wrote.

Following these data, Gilead Sciences filed a New Drug Application with the FDA for sofosbuvir/velpatasvir/voxilaprevir. According to a press release, the regimen was previously granted breakthrough therapy designation by the FDA for the treatment of patients with chronic HCV genotype 1 in whom an NS5A inhibitor-containing regimen failed. If approved, it would be the first once-daily single tablet regimen available as a salvage therapy for patients with HVC genotypes 1 through 6 infection. - by Stephanie Viguers

Disclosure: Bourliére reports receiving grant support, consulting fees, lecture fees and fees for serving on an advisory board for AbbVie, Gilead Sciences and Merck Sharp & Dohme, as well as consulting fees, lecture fees and fees for serving on an advisory board for Janssen Pharmaceutical and Bristol-Myers Squibb, and meeting fees paid for by Genfit and Intercept Pharmaceuticals. Please see the full study for a list of all other authors. relevant financial disclosures.

Canuck · Guru

(From Helio - Journal Summary)

Sofosbuvir-velpatasvir safe, effective for patients with HIV/HCV coinfection

SHOW CITATION

May 4, 2017

Treatment with sofosbuvir and velpatasvir produced a safe, sustained virologic response in patients with HIV who were coinfected with hepatitis C virus, according to findings from a phase 3 study.

"As HIV - related morbidity and mortality has decreased, liver-related complications have become a leading cause of death in coinfected patients," Mark Sulkowski, MD, medical director of the Viral Hepatitis Center at Johns Hopkins University and an Infectious Disease News Editorial Board member, and colleagues wrote.

Researchers wrote that direct-acting antiviral agents offered safe and effective treatment for patients coinfected with HIV and HCV, and that current guidelines recommend coinfected patients receive the same treatment as patients with HCV monoinfection.

"However, choosing an appropriate regimen can be complex ..." Sulkowski and colleagues wrote. "There remains an unmet clinical need for a simple well-tolerated, ribavirin-free, oral regimen with limited potential for interaction with HIV ART agents that is highly effective against all HCV genotypes."

The researchers conducted an open-label, single-arm study at 17 centers in the United States, with all patients receiving sofosbuvir-velpatasvir once daily for 12 weeks (n = 106). The main endpoint was sustained virologic response at the end of treatment. Sulkowski and colleagues assessed safety and efficacy in all patients who received at least one dose.

Most patients were men (n = 91; 86%), and slightly less than half (45%) were black. About one-fifth (18%; n = 19) had cirrhosis. Overall, 101 patients achieved a sustained virologic response at 12 weeks (95%; 95% CI, 89-99). Patients who achieved sustained virologic response included 74 of 78 patients with genotype 1 (95%; 95% CI, 87-99), all 11 patients with genotype 2 (100%; 95% CI, 72-100), 11 out of 12 with genotype 3 (92%; 95% CI, 62-100) and all five with genotype 4 (100%; 95% CI, 48-100), Sulkowski and colleagues wrote. All patients with cirrhosis experienced sustained virologic response, the researchers reported. One withdrew consent, two were lost to follow-up and two patients relapsed.

Two patients experienced serious adverse events, and two discontinued treatment because of adverse events, the researchers wrote. Overall, the most common adverse events were fatigue (25%), headache (13%), arthalgia (8%) and upper respiratory tract infection (8%).

"In conclusion, sofosbuvir-velpatasvir for 12 weeks provides a simple, safe and highly effective treatment for patients coinfected with HCV and HIV," Sulkowski and colleagues wrote. "Its effectiveness in a broad range of patients across a wide range of ART regimens suggests that it could be used by the majority of patients with HIV/HCV coinfection including those with prior treatment experience, compensated cirrhosis and non-genotype 1 HCV infection." - by Andy Polhamus

Disclosure: Sulkowski reports advisory roles with Abbvie, Cocrystal, Gilead, Janssen, Merck and Trek, as well as research grants from Abbvie, BMS, Gilead, Janssen and Merck.

Tig · Admin

The one and done triplet! What's the hold up? Big Pharm and the regulators need to get this approved now. It's more about the size of the pie and how many slices are given to the least effective protocols. The final approval is held up by the lawyers, not the proof of effectiveness. Time to stop the legal dance and get down to curing Hep C.