Kind of in line with what Mallani started here ... here is another recent historical synopsis article (a continuing evolution of HCV treatments).

I note, even though this is a recent U.S.A. 2017 article, and given, they have mentioned Vosevi, Vosevi is not really expounded on very much in the article, as it should have been, as compared to other historically exciting newcomer drugs that have arrived to us, such as Epclusa, nor is the Vosevi insert foot-noted below, perhaps just a "timing" oversight I am sure, as the Vosevi insert is now available - https://www.gilead.com/~/media/files/pdfs/medicines/liver-disease/vosevi/vosevi_pi.pdf?la=en

Mavyret is also not expounded on, nor foot-noted - http://www.rxabbvie.com/pdf/mavyret_pi.pdf

The changing HCV treatment cascade - Helio

Infectious Disease News, October 2017
Jocelyn Mason, PharmD; Kimberly D. Boeser, PharmD, MPH, BCPS, AQ-ID

Management of hepatitis C virus infection has drastically changed over the past 20 years - and even more so in the past 10 years - as a direct result of the evolution of pharmacologic therapy. HCV was discovered in 1989, and nearly 10 years later, in 1997, interferon was FDA approved as the first HCV treatment option. Unfortunately, interferon use was limited by inadequate rates of SVR and side effects. Standard of care shifted after the introduction of pegylated interferon and ribavirin, which overcame some of the pitfalls of interferon.

In 2011, the first direct-acting antivirals (DAAs), Incivek (telaprevir, Vertex Pharms) and Victrelis (boceprevir, Merck), were approved, boasting improved SVR and tolerability. Both drugs have since been removed from the market. The landscape of HCV treatment changed again in 2014, with the all-oral combination breakthrough DAAs Harvoni (ledipasvir/sofosbuvir, Gilead Sciences) and Viekira Pak (ombitasvir, paritaprevir/ritonavir plus dasabuvir, AbbVie), which nearly eradicated HCV with SVR rates of more than 90%. Since 2014, an astonishing six new DAAs have been approved: Technivie (ombitasvir/paritaprevir/ritonavir, AbbVie); Daklinza (daclatasvir, Bristol-Myers Squibb); Zepatier (grazoprevir/elbasvir, Merck); Epclusa (sofosbuvir/velpatasvir, Gilead Sciences); Vosevi (sofosbuvir/velpatasvir/voxilaprevir, Gilead Sciences); and Mavyret (glecaprevir/pibrentasvir, AbbVie). DAA combination products are commonly composed of two or three compounds that inhibit nonstructural (NS) proteins that facilitate hepatitis C RNA replication, including NS3/4A, NS5A or NS5B. One way to keep up with the pace of new DAAs and mechanism of action includes familiarity with the nomenclature. The suffix of the DAAs indicates the gene target. Thus, paritaprevir (previr's) targets NS3/4A, whereas ledipasvir (pasvir's) targets NS5A and sofosbuvir targets NS5B.

From 2010 to 2015, HCV infections nearly tripled, and almost half of people with HCV are unaware of their infection. The CDC estimates that approximately 3.5 million people in the United States have chronic HCV, with nearly 34,000 new cases diagnosed each year. Historically, treatment was prioritized to patients with the greatest need because of limited infrastructure and resources to manage all individuals with HCV. With more clinical experience and rapid emergence of effective treatment options, the current American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) guidelines recommend treating all patients with chronic HCV, except those with short life expectancies who cannot be remediated by HCV treatment, liver transplant or other directed therapy. The goal of treatment remains the same in reducing mortality, end-stage liver disease and hepatocellular carcinoma, by achieving virological cure as evidenced by SVR.

The shift in the HCV treatment paradigm is now heavily patient-centric and dependent on genotype, presence of cirrhosis, HIV coinfection, potential drug interactions, previous treatment failure, and renal impairment. In its simplest form, the backbone of HCV treatment requires a combination DAA with or without the addition of ribavirin and duration varies depending on the presence of cirrhosis. Those with HCV genotype 1, previously the most difficult to treat, now have the most treatment regimens. Options become limited beyond genotype 1 and even more so in the setting of decompensated cirrhosis. Daclatasvir, in combination with Sovaldi (sofosbuvir, Gilead Sciences), finds its niche in the treatment of genotype 3 and decompensated cirrhosis in combination with ribavirin. Grazoprevir/elbasvir and ombitasvir/paritaprevir/ritonavir with or without ribavirin are recommended for the treatment of genotype 4 without decompensated cirrhosis. The most exciting addition to the treatment arsenal is sofosbuvir/velpatasvir (Epclusa) It was FDA approved in June 2016 as the first DAA indicated for all HCV genotypes in patients with decompensated cirrhosis, taken in combination with ribavirin.

The understanding of HCV and the treatment cascade has come a long way since its discovery almost 30 years ago. The diagnosis and treatment of this disease will lead to billions of associated health care dollars; however, the current and future treatment strategies are promising cure. The rapid development of DAA combinations provides simplified regimens, shorter durations, improved efficacy and greater tolerability, unlike the previous interferon and ribavirin cornerstone regimens. Although the IDSA/AASLD guidelines provide the map to managing HCV, they do not identify the ideal interferon-free regimen to begin with, nor have they given a clear path to treating genotype 3 and those with decompensated cirrhosis. This ever-changing field will require collaboration among health care providers, including those specializing in infectious diseases, hepatology and gastroenterology, as well as pharmacists, to optimize treatment strategies. As the landscape of HCV continues to update with new literature and new medications, this subspecialty continues to be dynamic.

·         References:

·         AASLD/IDSA/IAS-USA. Recommendations for testing, managing and treating hepatitis C. Available at: www.hcvguidelines.org. Accessed June 20, 2017.

·         CDC. Surveillance for Viral Hepatitis - United States, 2015. Available at: www.cdc.gov/hepatitis/statistics/2015surveillance. Accessed June 20, 2017.

·         CenterWatch. Hepatitis C; Chronic Clinical Trials. Available at: https://www.centerwatch.com/clinical-trials/listings/condition/670/hepatitis-c-chronic. Accessed June 20, 2017.

·         Daklinza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2016.

·         Epclusa [package insert]. Foster City, CA: Gilead Sciences Inc; 2016.

·         Harvoni [package insert]. Foster City, CA: Gilead Sciences Inc; 2016.

·         Technivie [package insert]. North Chicago, IL: AbbVie Inc; 2015.

·         Viekira Pak [package insert]. North Chicago, IL: AbbVie Inc; 2015.

·         Zepatier [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2016.

·         

Malcolm,
I was fortunate to be on treatment the same time as you 
and we both achieved SVR. So glad you have stayed on this forum
as you give others the same clarity you gave everyone 2 years ago.
Back then, it had been 10 years with no new treatments available.
Now there are so many it's overwhelming and you help make it easier.
Thanks again for all you do!!!!

Groupsetter, I hope you beat Hep C and be treatment free soon!

-- Edited by JoAnneh on Tuesday 28th of April 2015 04:21:43 AM

Thanks Malcolm, I truly appreciate you taking the time to put this together.  Only wish I hadn't had to try 4 of the tx's on your list.  :)  Hopefully the Harvoni will be the last go round.  Have labs tomorrow and expect all to be good.  Crossing fingers, toes, and eyes, for the four week to be und.  :)  Also throwing in a lot of prayers.  The knowledge and insight you share is appreciated by all.   Thank you sir.

Matt: Thanks. I forgot ACH-3422 so I've added it to the list of new drugs. It has the potential to be better than Sovaldi.

Rubye: I understand your fondness for Olysio. I have similar feelings for Victrelis. In Australia, Olysio replaced Victrelis and Incivek, and was used with Peg/Riba for Geno 1's. Results have not been great, with SVR rates slightly inferior to Victrelis. It's not a very potent antiprotease compared with MK-5172. It's also very expensive. Sorry, I don't see a future for it in the real world.

Tess: From the previous treatments, I knew I was Interferon sensitive. My biopsy in 2000 showed A3, F2-3 which was later reviewed by my new Hepatologist and changed to A3, F3-4. I went through the slides with the Pathologist and there were very few reasons to downgrade it. The new protocol then was 48 weeks of Peg/Riba. I had never tried Peg before and it is much more efficient compared with the X3 weekly Interferon. The previous treatments had disrupted my work so I was unwilling to do another 48 weeks. If I had done this treatment, I'm sure I would have achieved SVR. Instead I waited and progressed to cirrhosis by 2008. I was extremely lucky to have been given a chance on the Victrelis triple.

IMHO, 8 weeks of treatment is not enough. Even though the SVR rates are good, for those who relapse life gets difficult. We are seeing that retreatment options are not as easy as was initially thought. I may change my mind on that.

Wow, this is a nice history Malcolm. Previous to this, my mind was the only history I had for hcv and that can be sketchy at best.

I saw this study on Sovaldi/Olysio the other day that makes it look like S/O should not be so easily dismissed though. Janssen's Optimist studies indicate that there is a 97% SVR12 rate for those without cirrhosis and for those with cirrhosis 84% to 88% SVR12.

http://hcvadvocate.blogspot.com/2015/04/janssen-announces-svr12-rates-with.html

It makes me think that perhaps the shorter treatment time with cirrhosis may put this combination back in the running since you have to do Harvoni for 24 weeks with cirrhosis. What do you guys think? Or maybe since S/O "cured" me, I am biased. 

Thank's Malcolm.  This helps us all find our place in our treatment journey.  RC

Hey Malcolm

Thanks for the clarity on where we been and where we are going.

It seems that the next step in improvement will occur with better NS-5A blockers to limited the RAV's that have been causing relapses in patients that have baseline NS5A RAV's and more common among patients with longer previous course of ledipasvir / sofosbuvir based therapy. 

This link exposes some data on the NS5A issue http://hepatitiscnewdrugs.blogspot.com

Then Scroll down to the article - "SVR12 in 71% of GT1 Patients Receiving 24 Weeks of Ledipasvir/Sofosbuvir Following Previous Treatment Failure With 8 or 12 Weeks of Ledipasvir/Sofosbuvir-Based Therapy"

The interesting report from Achillion NS5A ACH-3102, though its small number study its looks likes it has a great RA's profile 

http://hepatitiscnewdrugs.blogspot.com/2015/04/achillion-presents-results-on-ach-3102.html

matt

Thanks Malcolm,

That summary was very enlightening and informative. I appreciate you taking the time to explain past, present and future opportunities to treat this disease. Nicely done!

I think it's worthy of a sticky...

Malcolm, wow, thank you for a great summary of where we've been and where we are now in the battle against HCV! Brings back some memories.  I expect I got HCV from blood transfusions during surgery in 1982. My brother had AIDS in the '80s and was treated unsuccessfully with interferon, and when I found out I had HCV I decided to avoid interferon as long as possible, after seeing its effects on my brother.   Now we have viable treatments with more on the way.  Thank you for putting it all together.

Wondering why you think it was a mistake for you to decline Interferon/Riba for 48 wks in 2001? You seem to be doing so well now!

- Tess

-- Edited by Tess on Monday 27th of April 2015 06:10:30 AM

Hi all,

It is worth looking back at the development of treatments for HCV, and where we stand today. I think it helps understand our disease and gives us some input into a proposed treatment regime.

Hepatitis, or liver inflammation has been around forever. There are many causes. In 1963 and 1973, the Hepatitis A  virus (HAV)  and the Hepatitis A virus (HBV) were identified. Some cases of hepatitis now had a label, but no treatment options were available. It was noted that some cases of hepatitis were related to blood transfusions. As neither HAV or HBV could be found, these cases were called transfusion hepatitis or ' non-A, non-B  hepatitis. Again, there were no treatment options. When the 'AIDS' virus (HIV) was discovered in 1983, the search was on for anti-viral treatments.

There was also a condition called auto-immune hepatitis. As I was diagnosed with chronic hepatitis in 1982, I was put on a year long course of prednisone and Imuran (azathioprine) to ' see if this helped'. It didn't.

It was then thought that the liver inflammation might be helped by using Interferon, a naturally occurring cytokine. This was used in the late 1980's and appeared to reduce liver inflammation. At last, in 1989, the hepatitis C virus (HCV) was identified. The FDA gave approval for the use of Interferon for this new disease. We only had the old, crude RIBA test to decide whether treatment was effective. In 5-10% of cases, the RIBA test became negative (thought to be a cure). In 1990, blood donors began to be screened, and by 1992, this screening was effective enough to ensure that patients could not ' catch' HCV via blood transfusions, or use of blood products. The number of patients with this new disease began to explode. Trials were done, mostly in the USA and France, using various forms and doses of Interferon. It was found that Interferon alfa-2a or 2b gave the best results, and the best doses were decided on. Some brave patients had dreadful side effects. I had my first 48 weeks of Interferon alfa-2a in 1996. The dosage was 3 times a week as a subcutaneous injection. I became RIBA -ve after 8 weeks, but relapsed a month after treatment finished. Ribavirin (Riba)then enters the picture. It had been tried for HIV patients with little effect but was known to have antiviral activity. After various trials, with and without interferon, it was FDA approved for use in HCV in 1998, as Interferon/ Riba. The optimal Riba  dosage was uncertain, and I was on a trial of Interferon/ Riba in 1998. The Riba dosage was 2000mg/day in 2 doses. The trial was supposed to be for 24 weeks, but I only lasted 12 weeks due to profound anaemia. Nobody finished the trial! The Riba dosage was eventually decided as 1,200mg/day, so I went on another 24 week trial in 2000. This time I was RIBA -ve after 4 weeks, but relapsed 7 months after EOT. In 2001, it had been decided that 48 weeks of Interferon/Riba gave the best results, so I was I offered another lot of Interferon/Riba for 48 weeks. I declined, which was probably a mistake.

Pegylated interferon was FDA approved in 2001. This gave more consistent blood levels and only required one s/c injection a week. SVR rates began to improve and we now had the more accurate PCR Viral Load test. More accurate Genotype tests were also available. SVR rates with Peg/Riba were about 30% for Geno 1's and up to 70% for Geno 2's and 3's. 48 weeks treatment duration was the norm, and this was often extended. It was recognised that the IL28B test was important. Those with the CC allele did much better, and this was regarded as a indicator of likely response to interferon.

HCV could not be cultured, so when the first replicon was produced in 1999, researchers started work on inhibiting viral replication.The antiprotease site (NS-3) was thought to be easiest to block. Various antiproteases were tried with little success until 2007 when VX-950 (Incivek) was trialled. Boceprevir (Victrelis) soon followed. SVR rates started to improve(for Geno 1's)and both drugs received FDA approval in May 2011. The first DAA's had arrived and SVR rates for Geno 1's improved to about 70%. Geno 2's and 3's still used Peg/Riba with SVR rates of ~80% and 70% respectively. Those with CC at IL28B and non-cirrhotics did much better. Side effects were difficult and many patients had to stop treatment.

Many drugs were being trialled- some caused deaths and were discontinued. Improved relicons allowed other viral replication sites to be studied and blocked. The NS-5A and NS-5B sites were of most interest. Pharmasset had developed PSI- 7977, now known to us as Sovaldi. It was a potent nucleoside blocker of NS-5B and had remarkable Clinical Trials under it's new owner, Gilead Sciences. It was trialled with Daclatasvir, a NS-5A blocker from BMS, with SVR rates approaching 100%. Sovaldi was FDA approved in Dec 2013, together with other drugs like Simeprevir and Viekira Pak, which brings us up to present day.

Best Current Treatments available (in some countries):

Harvoni (Sovaldi/Ledipasvir): For Geno 1's. Treatment duration 12 or 24 weeks/ with or without Riba.

Viekira Pak: For Geno 1's. Treatment duration 12 or 24 weeks, again with or without Ribavirin.

Sovaldi/Simeprevir(Olysio): Geno 1's. 24 or 48 weeks. Not highly recommended.

Sovaldi/Daclatasvir(Daklinza): Geno 1's and Geno 3's. 12, 24 weeks. For Geno 4- 24 or 48 weeks.

Sovaldi/Ribavirin: For Geno 2- 12 weeks. For Geno 3-24 weeks.

New treatments coming:

1.GS-5816, a new NS-5A blocker from Gilead. Hoped to be combined with Sovaldi and give pan-genotype coverage, including previous DAA treatment failures.

2. Grazoprevir (MK-5172)/Elbasvir(MK-8742). Merck's new combo which will be pan-genotype and effective against known RAV's at NS-3 and NS-5A.

3. Sovaprevir (ACH-1625)/ACH-3102. Achillion's 3rd generation antiprotease and a potent NS-5A blocker. Achillion also is Trialling ACH-3422, a nucleoside NS-5B blocker, which appears to be as good if not better, as Sovaldi.

Personally, I would forget the miRNA drugs from Indenix and others. Also, a vaccine appears to be as far away as ever.

Trials are continuing, and we are beginning to see results from the real world, where SVR rates are not as good as some Trials suggested. Previous treatment failures, cirrhotics and Geno 3's still have a long way to go before we can approach 100% SVR. This will happen but some fine-tuning of choice of drugs and treatment duration will be required. I will be happy when the generics from India etc. begin to trickle in Africa and Asia and we can begin to eradicate this fascinating disease.