Tuesday, 12 February 2019 23:08

Confirmed: Hep C treatment saves lives

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So back in late 2017 the Cochrane Collaboration made the bold claim that treatment with Direct Acting Antivirals did not have any measurable impact on clinical outcomes. While the medical profession as a whole expressed a large and collective WTF sentiment new research published in the Lancet - "Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study" - puts this question to bed. The full text of the article and the editorial comment are attached, but here is the summary:

Findings of adjusted multivariable analyses showed that exposure to direct-acting antivirals significantly reduced all-cause mortality (hazard ratio [HR] 0·48, 95% CI 0·33–0·70; p=0·0001), liver-related mortality (0·39, 0·21–0·71; p=0·0020), non-liver-related mortality (0·60, 0·36–1·00; p=0·048), and hepatocellular carcinoma (0·66, 0·46–0·93; p=0·018), but not decompensated cirrhosis (1·14, 0·57–2·27; p=0·72). These associations persisted when the analysis was restricted to patients with cirrhosis who achieved sustained virological response. By contrast, failure to achieve sustained virological response was associated with increased risk for hepatocellular carcinoma (HR 2·23, 95% CI 1·37–3·64; p=0·0012).

Lancet daa hcv mortality

Wednesday, 06 February 2019 04:59

AASLD-EASL HCV Special Conference Miami 2019

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Jules Levin at NATAP has provided this awesome summary of the presentations from the combined AASLD/EASL HCV elimination conference. The first one starts with the elephant in the room, namely the prices...

When sofosbuvir first reached the market it was not approved for patients with CKD (Chronic Kidney Disease) stages 4 and 5 which means patients with an eGFR of < 30 ml/min. This was based on the observations that:

  1. Sofosbuvir is rapidly metabolised to GS-331007 (t1/2 0.4 hours), and
  2. GS-331007 (t1/2 27 hours) has renal excretion, and
  3. In the context of a reduced eGFR the AUC (Area Under The Curve) for this metabolite rises substantially

The concern was that the higher levels of GS-331007 might be toxic. This presents a real problem in countries that are dependent on generic DAA medication for HCV treatment because all these regimens are based on Sofosbuvir. There are currently no generic versions of Mavyret or Zepatier.

The short story is that experimentation has shown the following:

  1. The higher levels of the GS-331007 in patients with CKD are not toxic
  2. GS-331007 is cleared by haemodialysis or by the remaining GFR
  3. Reduced dose sofosbuvir (ie 200 mg daily) results in poor SVR12 rates (<50%) in patients with CKD
  4. Full dose sofosbuvir (ie 400mg daily) results in normal SVR12 rates (~95%) in patients with CKD +/- dialysis without problematic side effects

Here is a non-exhaustive list of published studies showing the use of full-dose sofosbuvir in patients with CKD is safe and effective:

  1. AASLD 2018 - Sofosbuvir/Velpatasvir for 12 Weeks Is Safe and Effective in Patients Undergoing Dialysis
  2. Hepatology Communications 2017 - Sofosbuvir‐based regimens for the treatment of chronic hepatitis C in severe renal dysfunction
  3. J Clin Transl Hepatol. - Sofosbuvir Use in the Setting of End-stage Renal Disease: A Single Center Experience 
  4. Kidney Int Rep. - Hemodialysis Patients Treated for Hepatitis C Using a Sofosbuvir-based Regimen
  5. Indian J Gastroenterol. - Efficacy and safety of sofosbuvir-based regimens in chronic hepatitis C patients on dialysis
  6. Liver Int. - Sofosbuvir-based treatment is safe and effective in patients with chronic hepatitis C infection and end-stage renal disease: a case series
  7. J Hepatol. - Pharmacokinetics, safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C

So, although the current EASL and AASLD guidelines suggest using an alternative to Sofosbuvir, these guidelines were written by people in live in countries with the luxury of having alternatives.

Where alternatives to Sofosbuvir are not available there is sufficient evidence in the public domain indicating it is safe to use Sofosbuvir in CKD, which, to me, makes it ethical given the usual benefits exceed the risks equation we all use to guide our clinical practice.

For those who are interested why here is the explanation.

Sofosbuvir is not an active drug. It is a prodrug that requires activation. This activation happens as follows:

  1. The concentration gradient of the Sofosbuvir prodrug depends almost entirely on the Cmax (rather than the AUC) so, in line with usual pharmacokinetics, the higher the dose administered the higher the Cmax
  2. The higher the concentration, the more Sofosbuvir penetrates the target cells as there is a higher concentration gradient driving this influx
  3. Once the sofosbuvir is intracellular it is cleaved and phosphorylated into the active entity which is a polar charged molecule trapped in the cell

In other words, Sofosbuvir is like Gentamicin where it is the Cmax peak that determines efficacy, not the AUC.

Reducing the administered Sofosbuvir dose

  1. reduces the Cmax, which
  2. reduces the concentration gradient driving it into target cells, which
  3. reduces the intracellular levels of the active cleaved/phosphorylated form and in turn
  4. reduces the time that this level exceeds the EC50

This also explains the lower efficacy in cirrhotic patients. Fibrous scar tissue has a reduced blood supply, this reduces the effective concentration gradient driving the Sofosbuvir into cells due to a dynamic depletion effect - although the concentration in the blood is the same, the small quantity of blood soon runs out of Sofosbuvir...

So while for many renally cleared drugs (including Ribavirin) we do need to decrease the dose in CKD we do not want to do this with Sofosbuvir. Fortunately for patients, the circulating metabolite that is renally cleared (GS-331007) has been proven to be non-toxic so the fact it will be circulating at higher levels in patients with CKD can be safely ignored. This metabolite is cleared by either a low eGFR or dialysis.

Unfortunately, I can't share it here at the moment, because it is in publication as we speak, but I am aware of a large multicentre trial in patients with CKD and haemodialysis who were given full dose Sofosbuvir 400 mg / Daclatasvir 60 mg daily and achieved 98% SVR12.

Friday, 18 January 2019 03:57

Sound Therapy for Tinnitus

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Perhaps it's age, perhaps it's Hep C, perhaps it's the medication. Whatever the reason, the reality is quite a few people with Hep C have issues with tinnitus. A friend of mine called Davo had this issue and resorted to Google where he found an Australian company called "Sound Therapy International". Lucky it was him, rather than me, as I tend to think anyone who calls them self International is about as "International" as the Democratic People's Republic of Korea is "Democratic". Anyway, I digress.

As a doctor I know we don't have a lot to offer drugs or surgery wise to help patients with tinnitus, so when he told me that it's 

  1. Not that expensive (not sure I agree on that one)
  2. Has reduced his tinnitus to such an extent it's pretty much gone
  3. Has had other benefits around sleep and general well being

He had my attention because Davo is rather inclined to call it as he sees it, and not prone to sugar coating stuff.

So, it's a case study of 1, and your results may differ.

It's also not cheap in that the basic package is $699 AUD ($500 USD) which seems quite a lot to pay for a few books, some headphones and what is essentially an MP3 player.

That said the results are currently 100% (1/1) (95% Confidence Interval 2.5-100%) so if you suffer from this debilitating problem maybe it's worth a try?


It's not one of the affiliate things where we ask you to tell them we sent you so we can collect a commission, but if you do decide to give it a try I'd be really interested to hear your results. It would be interesting to know how well this actually works and it seems reasonably common with HCV.

Saturday, 05 January 2019 05:54

Maviret (Mavyret) is an awesome drug for HCV

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It's come to my attention that some people on the Internet are "bad-mouthing" Maviret (Mavyret) and suggesting it's the worst option on the market and that you need Sofosbuvir. Anyone stating this does not, as they say, know their ass from their elbow - this drug is awesome where awesome means great cure rates, short duration of treatment, and minimal side effects. While there is no doubt Sofosbuvir based regimens are also great there are very few patients for whom they might be superior.

Let's start with the spelling. Is it Maviret or Mavyret? The answer is it's both! The combination of Pibrentasvir and Glecaprevir from Abbive goes by both names, depending on the market. Let's call it G/P for short, after all, that's what most doctors call it.

Common things happen commonly

Now let's have a look at the profile that fits the vast majority of patients - treatment naive, low fibrosis. Here is a link to the seminal study in the Journal of Hepatology: https://www.journal-of-hepatology.eu/article/S0168-8278(18)30165-X/fulltext looking at the results for G/P


SVR12 results for Glecaprevir/Pibrentasvir

 And I could probably stop here because let's face it, that's pretty amazing. Did I mention this G/P combination is awesome?

Now, by way of comparison let's pull out Gilead's latest and greatest 2 drug combination - Epclusa - aka Sofosbuvir + Velpatasvir. How does that perform in the most common case?

Here it is: http://www.natap.org/2016/DDW/DDW_13.htm and looking at the SVR12 results we see:

sof vel svr12

Hmm, that looks similar but, dare I say, a little worse. Not quite as good in the most common GT1 patients, or the next most common GT3 patients, or the next most common GT2 patients. Now don't get me wrong, it's far from shabby and there is, in fact, no statistical difference but it does rather put to rest the notion that G/P is inferior.

Patients with cirrhosis

Ok, so let's dig into the hard cases -patients with cirrhosis. For G/P  in GT1,2,4,5,6 it looks like this http://www.natap.org/2018/AASLD/AASLD_17.htm

g p 12456 cirrhosis

There's not a lot to say about that other than it's not what we usually expect with significantly reduced SVR12 in patients with cirrhosis.

GT3 Cirrhotic Patients

And, finally, let's get into the really hard basket - GT3 patients with cirrhosis +/- treatment experience

For G/P in GT3 with cirrhosis +/- treatment experience it looks like this: http://www.natap.org/2017/HCV/092217_01.htm

g p gt3 cirrhosis

Does a sofosbuvir based regimen have any advantages over G/P?

So do Sofosbuvir based regimens have any advantages over G/P? Yes, there are several special use cases for it. For example, G/P can't be given to people with decompensated cirrhosis, whereas Sofosbuvir-based regimens can: http://www.natap.org/2015/AASLD/AASLD_64.htm and they work pretty well:

sof vel decomp

There are a few other circumstances where you would prefer a sofosbuvir-based regimen but these are rare and relate to treatment experience and retreatment and in this case you should be consulting an expert for advice, not the Internet.


Personally, I'd be happy to have either G/P or a Sofosbuvir based regimen. I would not be at all worried about being prescribed G/P, in fact I might well secretly be pleased, not only because of the short duration and favourable side effect profile but because if you add Sofosbuvir to G/P you have the most potent 3 drug combination for HCV that is available, ideal for retreatment, but that, as they say, is a story for another day.



Thursday, 27 December 2018 01:49

83 Hepatitis C Studies From AASLD 2018

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For the past 2 decades, Jules Levin at NATAP has done a fantastic job reporting what is presented at all the major scientific meetings on HIV, HBV and HCV around the world.

Here are 83 studies presented at the AASLD 2018 conference that cover the leading edge of Hep C research as it currently stands.

  1. Hepatitis Debrief: The Liver Meeting 2018 - (11/19/18)
  2. DAA HCV Retreatment Studies at AASLD 2018 - (12/07/18)
  3. Changing Cascade of Care for Hepatitis C in the Era of Direct-Acting Antivirals - (11/13/18)
  4. Impact of all-oral direct-acting antivirals on clinical and economic outcomes in chronic hepatitis C virus-infected patients in the U.S. - (11/13/18)
  5. Disparities in Accessing HCV Care under Medicaid Programs Across the US; Experience from the TRIO Network - (12/10/18)
  6. Universal HCV Screening on the Way? - (11/13/18)
  7. Hepatitis C Risk-Based vs. Universal Screening Among Pregnant Women: Implementation and Cost-Effectiveness Analysis - (11/19/18)
  8. Prevalence of Chronic Hepatitis C Virus Infection US States and District of Columbia, 2013-2016 - (12/10/18)
  10. Prevalence of NS3 and NS5A resistance-associated substitutions through European DAA-failures - (12/10/18)
  11. The prevalence of hepatitis C virus NS5A polymorphisms in Europe - (12/10/18)
  12. Endothelial function worsens with hepatitis C direct-acting antiviral treatment despite improvements in systemic measures of inflammation - (11/28/18)
  13. Baseline Polymorphisms and Phylogeographic Analysis of NS3, NS5A, and NS5B in HCV Genotype 1b-Infected Chinese Patients Enrolled in ONYX-1 - (11/28/18)
  14. Clinical Benefits, Economic Savings and Faster Time to HCV Elimination with a Simplified 8-Week Treatment and Monitoring Program in Chronic F0-F3 Naïve Patients in the US - (11/28/18)
  15. Effectiveness and Safety of DAA Treatment for CHC Patients with Previous HCC: A REAL-C Study - (11/28/18)
  16. Drug-Drug Interaction Potential of Glecaprevir/Pibrentasvir Based on Real-World Medication Use in Patients With Chronic Hepatitis C Virus Infection: Data From the German Hepatitis C-Registry (DHC-R) and PAN-Cohort - (11/27/18)
  17. Effectiveness of Sofosbuvir / Velpatasvir in Treating Hepatitis C Virus Infection in Real-world Setting / IDUs, British Columbia - (11/27/18)
  19. Treatment of Genotype 3 Cirrhotic patients with 12 weeks Sofosbuvir/Velpatasvir with or without ribavirin: Real life experience from Italy - (11/26/18)
  20. Improved Short-Term Survival in HCV Seropositive Kidney Transplant Recipients during the DAA Era in the United States - (11/26/18)
  21. Uptake of and factors associated with direct-acting antiviral therapy among patients in the CHeCS, 2014-2017 - (11/26/18)
  22. Risk-Based HCC Surveillance Strategies Using HCC Risk Prediction Models Have Greater Net Benefit Than the Current One-Size-Fits-All Strategy In Patients who Received Antiviral Treatment for HCV - (11/26/18)
  23. Preemptive DAA Therapy in Donor HCV-positive to Recipient HCV-negative Cardiac Transplantation - (11/19/18)
  24. HCV-RNA Is Readily Detectable in Nasal and Rectal Fluids of HCV Patients with High Viremia - (11/19/18)
  25. High SVR in PWID with HCV Despite Imperfect Medication Adherence: Data from the ANCHOR Study - (11/20/18)
  26. The Hepatitis C Continuum of Care for People Who Inject Drugs; Philadelphia, PA - young PWID 8% treated for HCV, older still only 25% - (11/20/18)
  27. Risk of Incident Diabetes in Hepatitis C Patients Following Completion of Direct-acting Antiviral Therapy - (11/19/18)
  28. The impact of HCV SVR from direct acting antiviral and interferon-based treatments on mortality in a large population based cohort study - (11/19/18)
  29. Hepatitis C Risk-Based vs. Universal Screening Among Pregnant Women: Implementation and Cost-Effectiveness Analysis - (11/19/18)
  30. Direct Antiviral Agents after Successfully Treated Early Hepatocellular Carcinoma Improve Survival in Cirrhotic Patients with Chronic Hepatitis C - (11/19/18)
  31. Sustained Virologic Response Reduces the Incidence of Extrahepatic Manifestations in Chronic Hepatitis C Infection - (11/16/18)
  32. Impact of Baseline HCV RNA Levels as Assessed by 2 Different Assays on the Efficacy of 8-Week Glecaprevir/Pibrentasvir in Patients With HCV GT1-6 Infection - (11/16/18)
  33. Risk of Cardiovascular Disease Events after HCV Treatment: Results from ERCHIVES - (11/16/18)
  34. Effectiveness of 8-week glecaprevir/pibrentasvir(G/P) for treatment naïve, non-cirrhotic patients with HCV infection in the TRIO Health network - (11/16/18)
  35. Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) for Prior Treatment Failures with Glecaprevir/Pibrentasvir (G/P) in Chronic Hepatitis C Infection - (11/16/18)
  38. Pharmacokinetics of Once-Daily Sofosbuvir or Ledipasvir/Sofosbuvir in HCV-Infected Pediatrics Aged 3-<6 Years - (11/16/18)
  39. Ledipasvir/Sofosbuvir for 12 Weeks Is Safe and Effective in Children 3 to <6 years old with Chronic Hepatitis C Virus Infection - (11/16/18)
  40. Efficacy and Safety of Glecaprevir/Pibrentasvir in Patients With Chronic HCV Infection and Moderate to Severe Renal Impairment: An Integrated Analysis - (11/16/18)
  41. Durability of Sustained Virologic Response and Liver-Related Safety in Patients Treated With Glecaprevir/Pibrentasvir: A Long-Term Follow-Up Study - (11/16/18)
  42. Sofosbuvir / Velpatasvir / Voxilaprevir in DAA Failure Patients with Cirrhosis. Final Results of the French Compassionate Use Program - (11/16/18)
  43. Retreatment with voxilaprevir/velpatasvir/sofosbuvir in patients with chronic hepatitis C virus infection and prior DAA failure - results from the German Hepatitis C-Registry (DHC-R) - (11/16/18)
  44. Safety and Efficacy of Sofosbuvir/Velpatasvir in Genotype 1-6 HCV-Infected Patients in China: Results From a Phase 3 Clinical Trial - (11/16/18)
  45. High SVR in PWID with HCV Despite Imperfect Medication Adherence: Data from the ANCHOR Study updated - (11/16/18)
  46. Safety and Efficacy of Sofosbuvir/Velpatasvir in Genotype 1-6 HCV-Infected Patients in China: Results From a Phase 3 Clinical Trial - (11/19/18)
  47. Incidence and Predictors of de Novo Hepatocellular Carcinoma Following Achievement of Sustained Virologic Response With Direct-Acting Antivirals: Results From the Gilead SVR and Cirrhosis Registries - (11/14/18)
  48. Retreatment with SOF/VEL/VOX in Treatment-Experienced Patients with and without HIV: The RESOLVE Study - (11/14/18)
  49. Effectiveness of Elbasvir/Grazoprevir in Black Persons With Genotype 1 Hepatitis C Virus - (11/14/18)
  50. Efficacy and Safety of Elbasvir/Grazoprevir for 8 or 12 Weeks in Participants With Hepatitis C Virus Genotype 4 Infection - (11/14/18)
  51. Utilization and Effectiveness of Elbasvir/Grazoprevir for the Treatment of Hepatitis C Virus Genotype 1b Infection: Updated Cohort From the US Veteran Affairs Healthcare System - (11/14/18)
  52. Sofosbuvir/Velpatasvir for Patients With Chronic Genotype 3 HCV Infection With Compensated Cirrhosis: an Integrated Analysis of Phase 2 and Phase 3 Clinical Trials - (11/14/18)
  53. Effectiveness of Sofosbuvir/Velpatasvir for 12 Weeks in HCV Genotype 3 Patients with Compensated Cirrhosis in Clinical Practice Cohorts from Around the World - (11/14/18)
  54. Sustained Viral Response Following Treatment With Direct-Acting Antiviral Regimens Is Durable in More Than 6600 Patients: Results of the Gilead Sustained Virologic Response Registry Study - (11/14/18)
  55. Efficacy and Safety of 8 Weeks of Glecaprevir/Pibrentasvir in Treatment-Naïve Adults With HCV Genotype 1-6 and Aspartate Aminotransferase to Platelet Ratio Index (APRI) ≤1 - (11/14/18)
  56. Response-Guided Therapy with DAA Shortens Treatment Duration in 50% of HCV Treated Patients - (11/14/18)
  57. Early Treatment with Direct-Acting Antivirals Saves Medical Costs in Non-Cirrhotic Patients with Chronic Hepatitis C Virus Infection in the United States - (11/14/18)
  58. Nivolumab in Patients With Child-Pugh B Advanced Hepatocellular Carcinoma in the CheckMate040 Study - (11/13/18)
  59. Changes in the characteristics of hepatitis C patients treated with direct-acting antivirals from 2014-2017 - (11/13/18)
  60. Short-Duration Sofosbuvir/Velpatasvir Safe and Effective in Treating HCV Infection Immediately After Liver Transplant - (11/13/18)
  61. Efficacy and Safety of Glecaprevir/Pibrentasvir in Patients With HCV Genotype 5 or 6 Infection: Final Results of the ENDURANCE-5,6 Study - (11/13/18)
  62. Changing Cascade of Care for Hepatitis C in the Era of Direct-Acting Antivirals - (11/13/18)
  63. Quality of Life in Patients with Psychiatric Disorders: Pooled Analysis from Glecaprevir/Pibrentasvir Registrational Studies - (11/13/18)
  64. Real-World Effectiveness of Glecaprevir/Pibrentasvir in 1,941 Patients with Hepatitis C Genotypes 1 through 4 - (11/13/18)
  65. Lower Likelihood of Graft Failure and Death after Liver Transplantation in the Era of Current Direct Acting Antivirals: An Analysis of the 2002-2018 United Network for Organ Sharing Registry - (11/13/18)
  66. Impact of all-oral direct-acting antivirals on clinical and economic outcomes in chronic hepatitis C virus-infected patients in the U.S. - (11/13/18)
  67. High efficacy of glecaprevir/pibrentasvir in patients with chronic HCV GT1 infection who failed prior treatment with NS5A-inhibitor plus sofosbuvir regimens - (11/13/18)
  68. Sofosbuvir/Velpatasvir for 12 Weeks Is Safe and Effective in Patients Undergoing Dialysis - (11/13/18)
  69. The impact of HCV SVR from direct acting antiviral and interferon-based treatments on mortality in a large population based cohort study - (11/13/18)
  71. Real World Effectiveness of Sofosbuvir/velpatasvir/voxilaprevir in 573 Treatment-Experienced Patients with Hepatitis C - (11/13/18)
  72. High SVR in PWID with HCV Despite Imperfect Medication Adherence: Data from the ANCHOR Study - (11/13/18)
  73. Retreatment with SOF/VEL/VOX in Treatment-Experienced Patients with and without HIV: The RESOLVE Study - (11/13/18)
  74. Incidence of Hepatocellular Carcinoma Among Patients With Hepatitis C Virus Infection Following Treatment With a Grazoprevir-Containing Regimen - (11/13/18)
  75. Real-World Impact of Resistance-Associated Substitutions on Re-Treatment after Ledipasvir/Sofosbuvir Virologic Failure in Hepatitis C Patients (VA) - (11/13/18)
  76. The Medicines Patent Pool Signs Licence with AbbVie to Expand Access to Key Hepatitis C Treatment, Glecaprevir/Pibrentasvir - (11/13/18)
  77. Universal HCV Screening on the Way? - (11/13/18)
  78. Real-life effectiveness and safety of velpatasvir/sofosbuvir/voxilaprevir for previously DAA treated patients with chronic hepatitis C - (11/13/18)
  79. Sofosbuvir/velpatasvir/voxilaprevir(SOF/VEL/VOX) in care of chronic hepatitis C patients; clinical practice experience from the TRIO network - (11/13/18)
  80. Glecaprevir/Pibrentasvir for the Treatment of Patients With Chronic Hepatitis C Virus Infection: Updated Real-World Data From the German Hepatitis C-Registry - (11/11/18)
  81. National Estimates for HCV Screening and Diagnosis Rates in the United States (2013-2016) Based on a Large Real-World Dataset - (11/11/18)
  82. National Examination of HCV Linkage to Care in the United States (2013-2016) Based on Large Real-World Dataset - (11/09/18)
  83. AbbVie Characterizes Evolving Hepatitis C (HCV) Patient Landscape in the United States Using Comprehensive Dataset - (11/09/18)
Monday, 17 December 2018 03:07

PHARMAC announces funded Maviret from Feb 1st 2019

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In an announcement worthy of 3 dancing bananas Woohoo!, PHARMAC in New Zealand have just announced:

We are pleased to announce a decision to fund a new treatment for chronic hepatitis C infection, glecaprevir and pibrentasvir (Maviret) from 1 February 2019, and to widen access to adalimumab (Humira) for patients with psoriasis from 1 July 2019, through an agreement with AbbVie Ltd.

In summary, this decision will result in the following:

On 1 February 2019:

  • Glecaprevir with pibrentasvir (Maviret) tablets will be funded in the community and DHB hospitals without restrictions for patients with chronic hepatitis C. Maviret treats all genotypes of hepatitis C.
  • Maviret will replace the currently funded open-listed hepatitis C treatment, Viekira Pak (+/- RBV), which will be delisted on the same day. Viekira Pak can only be used to treat patients with genotype 1 hepatitis C.

For more details see the attached press release.

Here is a summary slide set where expert faculty members summarize key viral hepatitis studies from AASLD 2018 in San Francisco. Use these slides to review data on newer HCV regimens, the HCV continuum of care, posttreatment HCV outcomes, HCV D+R- transplantation, NA cessation in chronic hepatitis B, and investigational HBV/HDV therapeutics.

The usual way we detect Hepatitis C is using an Antibody test. Following infection with Hepatitis C the body forms antibodies to the virus and these antibodies persist lifelong. In about 25% of patients the antibodies successfully remove the virus, however, the remaining 75% of patients go on to develop chronic Hepatitis C (persistent infection).

Counting how many of the Hepatitis C virus particles are present in a patient's blood is possible through the Quantitative HCV PCR RNA test, the result is called Viral Load, and is usually measured in IU/mL (international units per millilitre) although some laboratories use copies/ml. Most patients believe that a low viral load pre-treatment (less than 800,000 IU/L) is good since a smaller virus count should, in theory, translate to less liver damage, and should make it easier to achieve cure, while many with high viral loads are worried that their treatment may not work. But is any of this actually true? With the advent of the newer HCV medications, the answer is no, none of it is. Strange as it may seem, your viral load has very little correlation to either liver damage or cure rate. Patients with very high viral loads have the same excellent cure chances as anyone else, 95% for Genotypes 1,2,4,5,6 and 90% for Genotype 3, when treated with the modern direct-acting antiviral medications, or DAAs (e.g. Harvoni®, Epclusa®, Mavyret®, Zepatier®).

A high viral load pre-treatment may not be a bad thing

You have a high viral load because your body (immune system) is not really trying to do much. The upside is that less liver damage occurs because your immune system is not destroying your liver in its attempt to kill the virus. The downside is that, well, actually there is no downside, besides the extra ink to print the extra zero after the average 1-3 million viral load. 10 million viruses, for example, don't eat much, maybe half a hamburger a year, they are very small, so you can afford to feed them.

Additionally, both low and high viral load patients respond extremely well to the new DAAs. It's common to see a patient with a 10 million viral load fall below 1000 in the first week of treatment - these drugs are remarkably effective.

Viral load monitoring after start of treatment

DAA medications do not require a lot of monitoring (unless Ribavirin® is involved). After starting treatment, viral loads decline quickly and profoundly. The data indicates that almost 100% of patients taking DAA drugs will suppress the virus to incredibly low levels and generally do this very quickly. At week 4 of the standard 12 weeks treatment, a whopping 82% of patients will become undetectable (UND). Once you fall to UND, you will remain UND for the duration of treatment, so further measurements are a waste of time and money.

Eventually, we may only do one HCV viral load test after commencing treatment, either 12 or 24 weeks post-treatment. For now it is very reasonable to do the test at week 4 (mostly for your peace of mind) and then 12 or 24 weeks post-treatment.

It's worth noting that patients should not be too alarmed if their viral load remains detectable at week 4, or even at end of treatment, as there is still a high likelihood of being cured. When treated with DAAs, having low-level detectable HCV RNA at the end of treatment does not preclude cure and several studies have duplicated this result. Some specialists advise patients who are still detected at week 4 to extend their treatment to 16-24 weeks (instead of 12) as extra insurance, while others see no benefit in doing this, so there is no consensus on this point. However, if money is no object, or if you can access high-quality generics, extending treatment is known to add a small single digit % to cure rates.

When can a patient be declared cured?

At the end of treatment, one of two things will happen. If there is any remaining viable virus then it will begin growing back. This will start as soon as the treatment medications wash out of a patients system (about 1 week to fall below any useful level).

Patients should take either a Qualitative HCV  PCR RNA test or a Quantitative HCV PCR RNA  12 weeks after the end of treatment to learn if they were cured. Cure can be declared with 99.7% certainty when a patient has an undetectable test 12 weeks after end of treatment (SVR12 - Sustained Virological Response @ 12 weeks). The certainty increases to 99.99% when the test yields an undetectable result 24 weeks after end of treatment (SVR 24) and is the gold standard for declaring a patient cured.

It's worth noting that patients will continue to have a positive HCV antibody test. This is the marker of exposure to the disease, not of current infection.

Waiting 12 or 24 weeks after end of treatment to learn the outcome can be understandably nerve-racking, even with cure rates as high as 95%+ with the new DAA medicines. So the results of this large trial may provide some relief. Investigators have calculated the consistency between SVR at 4 weeks post-treatment (SVR4) and SVR at 12 weeks post-treatment (SVR12), as well as between SVR12 and SVR24. Overall, 98.0% of patients with an SVR4 also achieved an SVR12, and 99.7% of patients with an SVR12 also achieved an SVR24. As a side note, of patients who relapsed post-treatment, 77.6% did so within 4 weeks of finishing treatment.


Contrary to common belief, a viral load result does not predict a patient's cure chances, nor does it provide any information about the condition of his/her liver or level of scarring. It's a number that is used to monitor a patient's progress during treatment by measuring it at baseline (before starting treatment), then again during treatment to learn how patients are responding to the medications. When treated with the modern Hep C medications, patients with very high viral loads have the same extremely high cure chances of those with low viral loads. Only the HCV PCR RNA test can be used to assess cure as the Antibody test used for screening is expected to remain positive.

Monday, 12 November 2018 21:38

Generic Mavyret (Maviret) Coming Soon!

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The Medicines Patent Pool Signs Licence with AbbVie to Expand Access to Key Hepatitis C Treatment, Glecaprevir/Pibrentasvir

SAN FRANCISCONovember 12, 2018 /PRNewswire/ --

Important collaboration will ensure affordable hepatitis C treatment options in low- and middle-income countries.  

The Medicines Patent Pool (MPP) has today announced a new, royalty-free licence agreement with AbbVie for glecaprevir/pibrentasvir (G/P) - a World Health Organization (WHO)-recommended treatment for people living with chronic hepatitis C (HCV). The licence will enable quality-assured manufacturers to develop and sell generic medicines containing G/P in 99 low- and middle-income countries (LMICs) and territories at affordable prices, enabling access to and treatment scale-up with the most effective pan-genotypic regimens. The agreement was launched at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2018 in San Francisco.

"G/P is a priority therapy for licensing for the MPP, so this agreement with AbbVie is very good news for public health," said Dr Marie-Paule Kieny, Chair of the MPP Governance Board. "It is a really important new option for a significant proportion of HCV patients throughout the world. As with previous MPP licences, we look forward to facilitating access to generic versions of this product as quickly as possible in as many territories as possible."

Globally, 71 million people are currently living with chronic HCV, many of them in LMICs. By the end of 2015, only 20 percent had been diagnosed and a mere seven percent of them had received treatment. In February 2017, the MPP issued its annual report on priority medicines for in-licensing. Given its favourable clinical profile and high potential in LMICs, G/P was listed as a key priority treatment.

G/P is an all-oral, once-daily, pan-genotypic combination regimen and was originally approved in 2017. It has achieved high cure (SVR12) rates of 98 per cent in treatment-naïve non-cirrhotic patients across all six genotypes of the virus. It is recommended by the WHO as a first-line treatment for eight weeks in treatment- naïve non-cirrhotic patients. Treatment-naïve patients with compensated liver cirrhosis require a 12-week treatment course.

Further, the regimen is also indicated for use in HCV patients with any degree of renal impairment, including patients on dialysis. Globally between five and ten percent of all people living with chronic HCV infection are estimated to be living with kidney disease and this treatment will be very helpful for them.

There are 95 countries and four territories included in the MPP/AbbVie licence for G/P at this point.

More details: www.medicinespatentpool.org  

What the MPP's partners are saying:

"Central to our vision at AbbVie is developing therapies, such as our pan-genotypic HCV treatment, for the most serious diseases and providing access to those treatments. We are pleased to have reached today's agreement with the MPP."

Laura Schumacher, Executive Vice President, External Affairs, General Counsel and Corporate Secretary, AbbVie 

"The new agreement is an important step towards achieving elimination of hepatitis C worldwide. We urge national governments to take action now to make such curative treatments available for the millions of people in need."

Dr Gottfried Hirnschall, Director of Department of HIV and Global Hepatitis Programme, World Health Organization 

"Unitaid aims to maximise the public health response by enabling equitable access to better health for all. We welcome this agreement between the MPP - a Unitaid grantee - and AbbVie that will accelerate a more effective HCV response worldwide."

Lelio Marmora, Executive Director, Unitaid 

"Claiming over one million lives each year, viral hepatitis is one of the world's major public health challenges and disproportionately affects people living in LMICs. Therefore access to safe, quality-assured treatments, affordable for all, has to be the fundamental aim of the public health community. This is a big step in that direction. The next step is to see more territories included in the agreement. Each step makes the dream of hepatitis C elimination more real."

Raquel Peck, CEO, World Hepatitis Alliance 

"The Government of Pakistan warmly welcomes the agreement between the Medicines Patent Pool and AbbVie to expand access to glecaprevir/pibrentasvir - a very important therapy for the treatment of HCV - into territories including Pakistan. The HCV burden in Pakistan is endemic, affecting over eight million of our country's population and the prevention and treatment of HCV is a national priority. This agreement will considerably aid our efforts and, ultimately, accelerate the permanent elimination of the HCV virus." 

Mr Aamer Mehmood Kianai, Ministry of National Health Services, Regulations and Coordination, Government of Pakistan 

The MPP has an existing collaboration with AbbVie and has two agreements in place in the field of HIV. These are:

  • Licence on paediatric formulations of lopinavir/ritonavir, signed in November 2014, which is facilitating the development of improved paediatric formulations for at least 102 LMICs
  • Licence on adult formulations of lopinavir/ritonavir for use in Africa, signed in December 2015.

In HCV, the MPP has agreements with Bristol-Myers Squibb on daclatasvir and Pharco on ravidasvir.

About the Medicines Patent Pool 

The Medicines Patent Pool is a United Nations-backed public health organisation working to increase access to, and facilitate the development of, life-saving medicines for low- and middle-income countries. Through its innovative business model, the MPP partners with civil society, governments, international organisations, industry, patient groups and other stakeholders, to prioritise and license needed medicines and pool intellectual property to encourage genetic manufacture and the development of new formulations. To date, the MPP has signed agreements with nine patent holders for thirteen HIV antiretrovirals, one HIV technology platform, three hepatitis C direct-acting antivirals and a tuberculosis treatment. The MPP was founded and is funded by Unitaid.


Abbvie's MAVIRET (glecaprevir/pibrentasvir) 

EU Indication  

MAVIRET is indicated for the treatment of chronic hepatitis C virus (HCV) infection in adults.

Important EU Safety Information  


MAVIRET is contraindicated in patients with severe hepatic impairment (Child-Pugh C). Concomitant use with atazanavir containing products, atorvastatin, simvastatin, dabigatran etexilate, ethinyl oestradiol-containing products, strong P-gp and CYP3A inducers, such as rifampicin, carbamazepine, St. John's wort, phenobarbital, phenytoin, and primidone.

Special warnings and precautions for use:

Hepatitis B virus reactivation  

Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral agents. HBV screening should be performed in all patients before initiation of treatment.

Hepatic impairment  

MAVIRET is not recommended in patients with moderate hepatic impairment (Child-Pugh B).

Patients who failed a prior regimen containing an NS5A- and/or an NS3/4A-inhibitor  

MAVIRET is not recommended for the re-treatment of patients with prior exposure to NS3A/4A and/or NS5A-inhibitors.

Adverse Reactions  

Most common (≥10%) adverse reactions for MAVIRET were headache and fatigue.

Globally, prescribing information varies; refer to the individual country product label for complete information.

SOURCE Medicines Patent Pool via www.natap.org

Thursday, 08 November 2018 06:09

Liver Cancer (HCC) Treatment Options

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One of the feared complications of Hepatitis C is HepatoCellular Carcinoma (HCC) aka Liver Cancer. While anyone can get this type of cancer it is most common in patients who have liver cirrhosis from any cause. We look for it using a blood test for AlphaFeto Protein (AFP) and/or Ultrasound, CT or MRI.

Ok, so the news has come back that you have an HCC. What are the treatment options?

  1. Do Nothing
  2. Chemotherapy with Sorafenib or Cabozantinib
  3. RFA
  4. TACE
  5. Resection
  6. Transplantation
  7. Experimental/Unproven/Deprecated Procedures

For a detailed rundown of current best practice please see https://bestpractice.bmj.com/topics/en-us/369

For a brief executive summary, please read on.

Do Nothing

While this sounds (and is) very nihilist the reality for some unfortunate patients is that nothing we do is likely to help.


Sorafenib, and more recently Cabozantinib are tyrosine kinase inhibitors. They are both tablets and can both slow down the progression of HCC in some patients. The key words are "slow down" and "in some patient" because neither drug can cure the HCC and they don't work in all patients. 

Details on Sorafanib can be found here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702892/

Details on Cabozantinib (the new kid on the block) can be found here: https://www.nejm.org/doi/full/10.1056/NEJMoa1717002

While Cabozantinib is probably better than Sorafanib, it is yet to be widely available. I have had a single patient who was already failing Sorafenib get 2 good extra years on Cabozantinib, but eventually, that too failed.


RFA stands for Radio Frequency Ablation. The simplest way to look at it as like this. We have a needle we stick into the tumour and the tip of it is like a miniature microwave oven. We then switch this on an cook the surrounding tissue. The idea is to kill all the cancer tissue and the minimal amount of surrounding healthy tissue. All things going well it can cure an HCC. For more details on the procedure: https://en.wikipedia.org/wiki/Radiofrequency_ablation

And for an analysis of the success rates: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011083/


TACE stands for Trans Arterial Chemo Embolisation. It is a little like RFA but in this case the "needle" is flexible, and rather than stick it straight through the skin we thread it up through an artery. This bit is similar to an angioplasty for the heart. We continue threading it up the arteries until we find the artery that is supplying the tumour.  We then inject some stuff to block off this artery and release some very toxic routine chemotherapy medications (doxorubicin or cisplatin). The idea is that everything downstream is killed. All things going well it can cure HCC. For more details on the procedure: https://en.wikipedia.org/wiki/Transcatheter_arterial_chemoembolization

And for an analysis of the success rates: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915316/


If the HCC is in a favourable position in the liver it may be possible to cut it out. You don't need all your liver so throwing a segment, or a 1/2 of it out is possible.


Where resection is not possible, complete replacement of the liver may be possible. This becomes impossible if the tumour invades vital structures like the blood supply pipes or the bile ducts. Transplantation is complicated, expensive, requires long term immune supression, and there are not enough donor livers or transplant centers available.

Experimental/Unproven/Deprecated Procedures


TARE stands for Trans Arterial Radio Embolisation and in principle is like TACE except instead of chemotherapy laden spheres being use, radioactive spheres are used. For more information https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497664/

Ethanol Ablation

The technique of Ethanol Ablation is similar to that of RFA in that a needle is inserted into the tumour through the skin, thus the other name PAE (Percutaneous Alcohol Ablation). It has largely fallen out of favour as it is not as effective as RFA and has more side effects. For more information https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296972/


It remains possible that there are natural medicines, largely unknown to science that may impact on HCC. I am personally aware of one patient who appears to have been cured using this modality.


The sad reality is that the cirrhosis that predisposes to getting one HCC predisposes to getting another, so curing one fixes the immediate problem, but more tumours may appear in the future. Long term follow up and monitoring is vital.

Hepatitis C and HCC

In the context of having Hepatitis C it's important to treat the HCC first, then treat the Hep C. For more details please see https://fixhepc.com/blog/item/108-daas-and-hcc-when-to-do-what-in-plain-english.html

The Good News Front

Without SVR one study showed liver cancer rates of 2.63% per year falling to 0.55% per year so Hep C treatment drops the risk of HCC development to about 1/5 of what it is untreated.

Wednesday, 07 November 2018 22:44

Hep C Guidelines - An Executive Summary

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Detailed expert guidelines are great but often run to hundreds of pages meaning it can be hard to find the specific information you want.

Giten Khwairakpam from TREAT Asia / amfAR just shared this awesome executive summary with me, so I'm sharing it here with you.

As a part of TREAT Asia/ amfAR’s efforts to increase access to hepatitis C and HIV co-infection diagnosis and treatment, we are pleased to share a new fact sheet that summarizes and simplifies key updates from the July 2018 version of the WHO Guidelines for the Screening, Care, and Treatment of Persons with Hepatitis C Infection. It can be accessed at https://www.amfar.org/guidelines/.

A full list of our hepatitis-related resource materials is available at https://www.amfar.org/facts/

We hope that this fact sheet will be useful for treatment advocates, primary care physicians and public health experts in understanding the recommendations better and help in shaping implementation strategies.

Saturday, 27 October 2018 00:48

So you're cured of Hepatitis C - What next?

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So you've made it! SVR12 and you are cured of Hep C. Maybe you battled your insurance company for access to the medications. Maybe you sourced generic medications yourself.

For most patients at this point that's it. It's over. You're cured and Hepatitis C can drift quietly into the past, but there is one group of patients who do need ongoing follow up. That group is the group of patients who have cirrhosis. If this is you please follow the advice below:

Every 6 months arrange for an ultrasound of your liver and an AlphaFetoProtein (AFP) blood test. This is suggested by both AASLD and EASL because cirrhosis carries an increased risk for the development of HepatoCellularCancer (HCC). Prior to treatment that risk was about 3% per year, and with SVR12 it falls to less than 1% but it does not fall to zero. With any form of cancer early detection allows for early treatment and cure, so keeping an eye out for this issue is a great way to protect your health.

 If you look at the impact of SVR you can see quite clearly why treatment is probably the single best thing a patient with Hepatitis C can do for their health.

Hepatitis C SVR12 all cause mortality

Here is an article from the South Centre in Geneva.

Abstract: In late 2013, a new Hepatitis C treatment called direct-acting antivirals (DAAs) was introduced in the market at unaffordable prices. The eradication of the disease is possible if medicines can be purchased at AFFORDABLE prices within health budgets. IF THIS IS NOT THE CASE, governments should consider the use of the TRIPS flexibilities to facilitate access to the treatment.

This article starts like this:

General Context and Background on the Debate over Access to Medicines

The problem of access to medicines until 2014 was concentrated in developing countries where one third of the world’s population had no access to medicines, while industrial countries, thanks to public (Europe) and private (the United States of America) insurances managed to pay the cost of medicines. Currently the situation in developing countries remains the same but the great novelty, unprecedented, is that the industrialized countries are beginning to have difficulties in ensuring the supply of certain medicines to their citizens. The debate and international negotiations on access to medicines began in 1995 with the creation of the World Trade Organization (WTO), at the end of the Uruguay Round, and the generalization of the mandatory use of patents for pharmacological products for all WTO member countries (currently totalling 164).

And in the middle find this:

Pharmaceutical innovation has significantly diminished in recent years

According to the data published by the French review Prescrire in recent years, we find that the number of medicines that constant “an important therapeutic advance” introduced into the French market in the last 10 years are not more than 14 per year; furthermore, innovation appears to be diminishing, as the maximum number of 14 is significantly higher than the average number of yearly therapeutic advances over the past decade:

  • 2007: 14 products
  • 2008: 6 products
  • 2009: 3 products
  • 2010: 3 products
  • 2011: 3 products
  • 2012: 3 products
  • 2013: 6 products
  • 2014: 5 products
  • 2015: 3 products
  • 2016: 1 products

You can read the full article here: https://www.southcentre.int/wp-content/uploads/2018/10/PB54_The-Use-of-TRIPS-Flexibilities-for-the-Access-to-Hepatitis-C-Treatment_EN.pdf but, in short, we are in a "Houston we have a problem" kind of a situation. Despite very high prices, we are seeing very little innovation.

Thursday, 11 October 2018 13:10

Understanding AFP (Alpha Feto Protein)

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AFP is short for Alpha FetoProtein.

As the "feto" in the name suggests this is a protein we see in a fetus. In adults we switch off the genes that produce it so we don't see much (usually <12 units)

Hepatocellular Carcinoma (HCC) represents a loss of control over liver cell growth. These liver cells tend to become more primitive, like the liver cells in a fetus. What often happens is that the genes that produce AFP get switched on again, so instead of seeing <12 units of AFP we see more.

In pragmatic terms:

Most patients will have an AFP <12 and will not have HCC

Some cirrhotic patients will have a slightly elevated AFP in the range 12-24, despite not having HCC. We invariably see this fall during and after treatment. Sitting on my desk I have these results from a cirrhotic patient who is now at SVR

Most, but not all, patients who develop HCC will have a detectable rise of AFP, usually to a level of over 100

Here is a patient who had HCC in whom we treated the HCV and the HCC (with Sorafanib). Notice both the fall in AFP and the fact this lab uses <6 rather than <12 as the cutoff

Please note this: while most HCC expresses AFP and therefore can be detected by an AFP blood test it is possible to have HCC with a normal AFP. Rare but possible. High risk patients with cirrhosis should have 6 monthly screening with U/S (or CT or MRI)

Also note that if you have had HCV but have not developed cirrhosis then your risk of HCC is almost exactly the same as the general population. It happens, but it is rare. AFP screening is more than adequate. If you want to have a look use U/S or MRI as a CT carries about a 1:1000 risk of giving you a cancer (it might be a little lower than this but is does carry a real risk).

Thursday, 11 October 2018 01:34

Are The New Hepatitis C Treatments Poisonous?

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So today, on the chat a patient mentioned "My doctor here is scaring me from getting treated. He is tell that the treatment can be poisonous."

5 years ago this doctor would have been correct, in fact, I used to think the same, going so far as to say "The treatment is worse than the disease".

So what has changed?

5 years ago the mainstay of treatment was PEG Interferon injections and Ribavirin tablets. Both of these drugs have a lot of side effects and with a 1 year treatment required to deliver a 50% chance of cure it's easy to understand why the treatment was not popular. The side effect list looked like this:

  • Flu-like (headache, fatigue, fever, chills, muscle ache)
  • Arthritis-like pain in back, joints
  • Gastrointestinal (low appetite, nausea, vomiting, diarrhea)
  • Low blood cell counts
  • Depression
  • Insomnia
  • Hair loss
  • And lots more...

All that changed in 2013 when a drug called Sovaldi® (Sofosbuvir) reached the market. This was rapidly followed by other drugs like Harvoni®, Viekira®, Zepatier®, Epclusa®, Vosevii® and Mavyret® (Maviret® in some countries). With these new drugs what we got was this:

  1. A typical 3 month treatment period
  2. Taking 1 (or a few) tablets a day
  3. Where there were minimal side effects (and the average patient actually felt better on treatment rather than worse)
  4. And where the treatment delivers a 95%+ chance of cure at the end

To tell you the truth it all sounded a bit too good to be true, but, having treated 3000 patients myself, and seen the results repeated by doctors around the world there is no doubt we have some really good solutions to curing Hepatitis C.

Getting access to these new medications can be a bit of a problem in some countries due to the cost, but affordable generics are available and they deliver the same results at a small fraction of the originator pricing. So, if you have Hep C, and would like to get back to better, do yourself a favour and look into getting treated. If you local doctor can't help, we can help with both your prescription and getting access to the medication.

Tuesday, 09 October 2018 03:35

Why Does Hepatitis C Treatment Fail Sometimes?

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Here is a question I was asked: I am a biochemist myself and studied virology many years ago. Unlike HIV, HEP C doesn’t seem to reside in reservoirs. So looking at your SVR rates they are impressive but could you maybe give me a high level reason why treatment fails? Apart from reinfection where could the virus hide? I have bought 20 weeks worth of meds and now I am on week 18. Was undetectable at week 3 so by the end of treatment I will have kept it at bay for a further 17 weeks. They should surely be enough to eradicate it?

Here's the answer.

There are multiple reasons treatment fails. They can broadly be divided into

  1. Viral Vector Factors
  2. Host Factors
  3. Drug Factors
  4. Resistance and Selective Pressure

Viral Vector Factors

The genetic code of the Hepatitis C virus is single-stranded RNA. Unlike DNA, which has two mirror image strands that deliver error checking, HCV RNA is duplicated like this:

  1. First, the RNA polymerase makes a mirror image (non-sense) strand of RNA from the viral RNA.
  2. Then it uses this to make another mirror image (sense) strand.

There is no error checking and 50% of the RNA produced is non-sense. This process is inefficient and error-prone. Every time the RNA duplicates there is about a 1:1000-1:10,000 chance the new RNA copy is inaccurate. Mostly this means it does not work properly, but sometimes it confers resistance. The so-called “wild type” is the most common form of the virus simply because it duplicates itself better than any other variants, however, some of the resistant variants are known as “fit mutants” because these RAVs (Resistance Associated Variants) reproduce almost as well as the wild type. These are the problem children.

Within one person there are a whole range of similar, but slightly different, variants of HCV RNA – this is why it is called a quasi-species.

The RNA itself is used to code a number of proteins of which the NS3/4A, NS5A and NS5B proteins form the 3 different targets for our drugs. The drugs work in a key/lock fashion where the drug is the key and the protein is the lock. The drug keys occupy a vital space in the protein which needs to be vacant for the protein to do its job. Small changes to these proteins change the lock so the key does not fit as well. Small changes to the RNA genetic sequence underlie these changes to the proteins.

Most of our drugs are what is known as competitive inhibitors, so they compete with usual substrate (the thing that normally fits the lock) and therefore need to be above a certain concentration to do their job. This concentration is known as the EC50 (Effective Concentration for 50% of the maximal inhibition). Sofosbuvir works on the NS5B RNA Polymerase protein. The reason it is so good is that this protein is the engine room making new viral RNA and Sofosbuvir is a suicide inhibitor – it binds permanently to the active site so can’t then be displaced when the concentration falls.

The different genotypes of HCV represent similar (but different) RNA sequences. Some genotypes of the virus are naturally resistant to some of the drugs. For example, Ledipasvir does not work well on Genotypes 2 and 3 because the NS5A protein target is a poor fit.

Logically you’d expect the longer you’ve had the virus, and the higher the viral load the more duplication cycles have happened and the greater the chance of resistance. There are hints that this is the case, but no solid proof.

What we do know to be true is that to be resistant to 1 drug is not that hard, but to be resistant to 2 (or more) is much harder. This relates to the 1:1000 probability of a mutation. To get one (on a single strand of viral RNA is 1:1000) but to get 2 is 1:1000 x 1:1000 = 1:1,000,000 and to get 3 it is 1: 1,000,000,000.

HIV is another RNA virus where we have seen this. When we only had one drug resistance happened quite quickly, with 2 drugs it took years, and with current 3+ drug combinations, resistance and virological breakthrough is rare.

Finally, HCV is very infectious. We know from monkey experiments that just 10 virus particles (virions) injected gives a 50% infection probability, and 100 virions deliver a near 100% infection probability. To get rid of this beast we need to kill it down to very nearly the last virion. It’s truly remarkable we can do this.

Host Factors

There is a disease called pernicious anaemia. Patients get this because they cannot absorb the small drug-like molecule vitamin B12. Similarly, some patients do not absorb some drugs very well. For the Hepatitis C DAAs, if we look at the blood levels of a group of patients, the patient with the highest levels may be absorbing 2-10x as much as the patient with the lowest levels. Ledipasvir and Velpatasvir are more problematic in this realm than Sofosbuvir and Daclatasvir.

While the drugs do much of the work, our immune systems still play a role in mopping up the stragglers. We know that 25% of people can clear the virus themselves, and obviously they have strong anti-HCV immune systems. We also know some people run low viral loads – they have moderately strong anti-HCV immune systems. People with high viral loads have weak anti-HCV systems but this is not as bad as you might think. Firstly the virus does not “eat” much so just letting it do its thing causes very little harm (less than fighting it all the time but not quite winning) and with our current drugs people with high viral loads enjoy similar cure rates, albeit sometimes requiring slightly longer treatment.

Unlike HIV there are no known “reservoirs” where HCV can hide, although that said there kind of are. By "kind of are" I’m referring to damaged cirrhotic liver and probably HCC. With cirrhosis parts of the liver are replaced by scar tissue. This tissue has very little blood supply meaning that a drug circulating in the blood does not reach very high levels in this tissue due to the distance it has to diffuse. This makes cirrhotic patients harder to cure, unless we transplant them when, despite the immunosuppression, they are easy to cure. We also see patients with HCC as being harder to cure. This probably relates to the background cirrhosis, but could also relate to the fact that cancer cells refuse to obey apoptosis (die now) signals they get from the immune system.

Drug Factors

As mentioned earlier some drug keys are a poor fit for the protein locks of certain genotypes. This can be a real problem when a patient is co-infected with 2 types of HCV – say genotype 1 and genotype 2. The genotype 1 will be dominant so that patient may get their genotype reported as simply genotype 1, but with ledipasvir not working well on genotype 2, if this patient is treated with Harvoni they will clear the GT1, but relapse with GT2.

Different drugs have different potencies. A drug with a high potency has a low EC50, and a drug with a low potency has a high EC50. For the drug to work it needs to remain above the EC50 throughout the day, otherwise there are times when it is below the level required to contain viral replication. Here is a table for GT3.

GT3 EC50

ABT-493 and ABT-530 are the Glecaprevir and Pibrentasvir in Mavyret (Maviret). GS-9857 is the Voxilaprevir in Vosevii and MK-8408 was Ruzasvir (now discontinued).

As mentioned before, some patients do not absorb some drugs as well as other patients so, even if properly dosed they may wander below the critical drug levels.

Some patients do not take their medication every day, and this results in blood levels potentially falling below what is required.

Some medications, supplements and foods interfere with the absorption of the DAAs. Sometimes this increases the blood levels, which, although it leads to more side effects, does not compromise treatment. However, sometimes medications (such as antacids with Harvoni and Epclusa) decrease the blood levels of the drugs and this can lead to treatment failure.

The duration of treatment is vital. The disappearance of the virus follows a pattern of exponential decay meaning (for example) on day 1 we have ½ the virus, day 2 we have ½ of that ½ ie ¼ and on day 3 we have ⅛. Now when we remember we need to go from zillions to < 10 actual viruses we can see that this takes time. Although it saves money we see a lot more GT1 Harvoni failures who took 8 weeks than those who took 12 weeks. The extra weeks are a form of insurance. For almost anyone who achieves SVR at some point we are pouring medication into a body that no longer harbours HCV – we have to overtreat to make sure, and we need to pick a “one size fits all” duration.

Another reason duration is vital relates to the half-life of a viral replicon. This is several weeks. If we don’t treat for long enough a replicon can be suppressed from working, but remove the drugs and it can recover. We need to display no mercy and keep kicking it while it is down until there is no chance it can recover.

Just a quick note on Ribavirin. The log kill on Sofosbuvir is 4.5 meaning it will kill 31,999/32,000. For the NS3/4A and NS5A agents is more like log 3 meaning they will kill 999/1000. Ribavirin is weak in comparison with a log kill of 0.5 meaning it will kill only 2/3 but that may just come in handy mopping up the stragglers. Of note is that Ribavirin is not a DAA – it is a fake letter U in the genetic alphabet so not prone to the same resistance mechanisms as the DAAs.

Resistance and Selective Pressure

We know from HIV that a patient who has a detectable viral load is at risk of a virological breakthrough. Why is that?

When we start treatment, pretty much all the easy to kill virus in the quasi-species is rapidly killed off, however not all of it is. Some of the variants will be partially resistant and the drugs are exerting a selective pressure. Now, despite the fact these RAVs may not be as fit as the wild-type, we have removed the competition. If one of these RAVs “lucks out” and mutates in a way that makes it either more resistant to the current drugs, or more resistant to (the usually missing) 3rd drug on a 3rd target we have a “Houston, we have a problem” kind of a moment.

Wrapping Up

Considering the ask – kill down to the last 10 virions - it’s truly remarkable that Sofosbuvir alone can deliver a ~66% cure rate. We know that adding in an NS5A agent improves that to ~95%. We also see that highly potent NS3/4A+NS5A combinations like Glecaprevir/Pibrentasvir can also kick ass, but here is a lesson from HIV. 3 drugs work better than 2. This is particularly relevant for patients being offered G/P for retreatment. The expected SVR is “only” 90% but if it was me… I’d add in the best NS5B ever invented (Sofosbuvir) to the best NS3/4A and the best NS5B.


Sunday, 07 October 2018 23:57

Buying Generic Harvoni® Online

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When the drug Harvoni® was announced back in 2014, it was very welcome news for Hepatitis C sufferers around the world. Finally, a single pill treatment for this notorious disease was available. Taken once daily for just 12 weeks, it cured 95% of patients with minimal side effects. Unfortunately, the excitement lasted only until the new drug's price was announced, $94,000 USD. This meant that patients had to be either super rich or eligible for insurance coverage and unfortunately, 90% of patients were neither. Because of Harvoni's astronomical price tag, many insurance companies refused to cover patients unless they were in a very late disease stage, defined as severe liver fibrosis (i.e. F3 or F4). This left 90% of patients unable to access originator (brand name) Harvoni® and having to look for overseas online sellers who supplied generic Harvoni®. But how can a patient safely access generic Harvoni® on the internet that is of the same quality as originator Harvoni®? If you take the following 5 factors into consideration, you will be able to find a trustworthy and affordable online supplier.

1. Watching out for Scammers

We hear a lot about scam websites on the Internet, especially foreign sites in developing countries. So how can you make sure you don't get taken? To avoid scam artists, patients need to do a bit of research to separate honest medicine suppliers from scammers. Google is your friend here - it's a great tool for discovering information. You should search Google for the website's name, the name of its founder (if available), and find out about their track record. If you find none or multiple bad reviews, definitely avoid that supplier as it will be quite risky. Here's a guide: https://fixhepc.com/fixhepc-scam-check.html

Additionally, if media outlets (such as TV networks, newspapers, or well-known websites) publish good or bad information about the website you're researching, that will give you excellent insight about it. It's worth noting that FixHepC Buyers Club was mentioned positively in about a dozen prestigious media outlets, such as The Lancet medical journal, WebMD, BBC Newsnight, The Sydney Morning Herald, and many others. Here is a BBC Newsnight video investigation of one of the early FixHepC patients.

2. Verifying the Quality of the Harvoni® Generic

Just like with all other products, there are good and bad quality generic medications. So how to ensure the quality of the Harvoni® generic you buy? There are two factors that decide the quality of all generic medications: Bioequivalence and GMP (Good Manufacturing Practice).


A generic drug is considered bioequivalent to its originator (brand name) counterpart if their pharmacological effects are exactly the same. The easiest way to ensure this is when the generic manufacturer is granted a license by the originator company to produce the drug. This license notionally guarantees that both the generic and originator drugs are exactly the same however the Gold Standard is a thing called bioequivalence. This is explained in detail in this post: https://fixhepc.com/blog/item/107-bioequivalent-pharmacokinetics-for-generic-and-originator-hepatitis-c-direct-acting-antivirals.html

At FixHepC we only use medication from manufacturers that have proven bioequivalence.


Good Manufacturing Practice certificates, as the name implies, are issued by the US FDA and EMA (European Medicines Agency) when a drug manufacturer meets all the requirements for highest quality mass production of pharmaceuticals. Needless to say, you should choose manufacturers that were awarded this certificate. GMP is the only thing that guarantees the latest batch of medication meets the same high quality standards as the batch that passed bioequivalence testing.

3. Avoiding Fake Drugs

Unfortunately, fake drugs are a real problem in many developing countries, such as India and Bangladesh, and almost all generic Hepatitis C drugs are sourced from there. So how can you make sure that you’re buying authentic generic Harvoni® (or other Hep C generics like Epclusa®, Sofosbuvir®, and Daclatasvir®) and not fall victim to dishonest or incompetent online suppliers? The answer is that you have to check the Supply Chain Integrity of the online seller, but that is easier said than done. Here is a primer on how to do that: https://fixhepc.com/supply-chain-integrity.html

4. Getting Guaranteed Delivery

Patients in most countries are not sure if they can legally import generic medications from abroad, and are worried that the medications they will pay for may be stopped by border customs and confiscated. In some countries, importing 3 months worth of personal medications is perfectly legal, as long as a doctor’s prescription is attached with the medications. However in some other countries, this is a gray area, and delivery is not guaranteed. It requires expertise by the shipper and learning how to abide by these countries laws and preparing the required paperwork. To make sure that you will not lose your medicines package due to an overzealous customs officer, only buy from suppliers who offer guaranteed delivery or 100% of your money back. It’s rare to find an overseas medicines supplier who would take that risk and provide that guarantee. To give patients peace of mind, FixHepC does just that, and they are able to do it because they have learned over 4 years now how to deliver drugs successfully all over the world. https://fixhepc.com/delivery-guarantee

5. Getting a Prescription and Medical Support

For one reason or another, many patients are not able to get a prescription for generic Harvoni from their doctor, so how can they get one? Also, many doctors will not monitor patients if they didn’t write their prescription, so what if you need medical support during treatment? It’s inconceivable, you may say, that online drug suppliers would provide such services, after all they are not doctors. Well, you would be right, except in the case of FixHepC. FixHepC was founded and is managed by a licensed Australian doctor, Dr. James Freeman, who is is arguably a leading expert in the field of Hepatitis C treatment. If patients have any questions during or after treatment, they can pose them for free on the site’s live chat platform and get them answered by one of FixHepC’s excellent doctors, or they can post them to the FixHepC Forum and get them answered directly by people who have been there and done that. If patients need a prescription for medications, they can easily get one by booking an online video appointment on GP2U (the Australian online doctor service). The cost for this service is 70 USD. Follow up can be via email or further video appointments.


You don’t have to be super rich or wait many years and get very sick before somebody agrees to treat you. You owe to yourself and to your family to take matters into your own hands and to get treated and cured now. Visit FixHepC to learn how to access high-quality generic Harvoni® for only $1300 USD all inclusive, and rediscover what it feels like to be well again.


Monday, 24 September 2018 21:45

Hep C generics set to be released in the USA in 2019!

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The good news is that Gilead plans to launch generic versions of Harvoni and Epclusa in the USA. The bad news is the $24,000 USD price tag. Although this price is substantially lower than list price, the reality is that the VA negotiated a $25,000 price nearly a year ago, so the payers have been seeing this pricing for a while. The biggest bit of upside is that patients could save up to $2500 in out of pocket costs and that's got to be a good thing. Here is the full press release...

FOSTER CITY, Calif.--(BUSINESS WIRE)--Sep. 24, 2018-- Gilead Sciences, Inc.(NASDAQ: GILD) announced today plans to launch authorized generic versions of Epclusa® (sofosbuvir 400mg/velpatasvir 100mg) and Harvoni® (ledipasvir 90mg/sofosbuvir 400mg), Gilead’s leading treatments for chronic hepatitis C virus (HCV), in the United States, through a newly created subsidiary, Asegua Therapeutics LLC. The authorized generics will launch at a list price of $24,000 for the most common course of therapy and will be available in January 2019.

Since the launch of Gilead’s first HCV medication in 2013, the average price paid for each bottle of medicine in the United States has decreased by more than 60 percent off of the public list prices, across health insurers and government payers. Due to the complexity and structure of the U.S. healthcare system, however, these discounts provided by Gilead may not always translate into lower costs for patients. Further, existing contracts, together with laws associated with government pricing policies, make it challenging to quickly lower a product’s list price once it is on the market.

The authorized generics are priced to more closely reflect the discounts that health insurers and government payers receive today. Insurers will have the choice of offering either the authorized generics or the branded medications for both Epclusa and Harvoni. In the Medicare Part D setting, the authorized generics could save patients up to $2,500 in out-of-pocket costs per course of therapy. The authorized generics will also offer substantial savings to state managed Medicaid plans that do not currently benefit from negotiated rebates and that represent a significant number of people in need, potentially opening up access to our medications to beneficiaries who were previously denied coverage.

“Launching these authorized generics is the best solution available to us today to quickly introduce a lower-priced alternative to our HCV medications without significant disruption to the healthcare system and our business,” said John F. Milligan, PhD, President and Chief Executive Officer, Gilead Sciences. “This launch also will hopefully help increase transparency by more closely aligning our medications’ list prices with their cost. Our ultimate goal is to lower the list price of Epclusa – a medication we believe is of great importance given its clinical profile across genotypes – and Harvoni. We are committed to working with all of our partners in the healthcare system to help enable list price reductions of our HCV medications and find better solutions to reduce patients’ out-of-pocket costs.”

Beyond the company’s efforts to reduce patient costs, Gilead is continuing to pursue innovative collaborations and long-term financing models, such as a potential subscription model, that could not only expand access, but aim to eliminate HCV in the United States and around the world.


Sunday, 23 September 2018 04:25

Why me? Why do I have Hepatitis C?

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The stigma and stereotype associated with Hepatitis C says "you only get that from IV drug use". While you certainly can get it from IV drug use, the majority of my Baby Boomer patients didn't. How do I know? Well, of course, I can't know for sure how anybody caught any communicable disease, but when talking to the 3000+ patients I've helped access affordable generic medication there is a recurrent theme. That theme is "Hey doc, I never did drugs, I don't have any tattoos, and I've never had a blood transfusion, so how did I get HCV?" That led me to look for the answer. The real answer, not the stereotype.

The short answer is the medical or dental profession probably gave it to you, but how do I know that?

Well, for a start, we know the disease requires blood-blood contact for transmission and, outside of IVDU, tattoos and blood transfusions most of us don't share our blood with friends. So for people who have the disease, but don't have these risk factors, what other blood-blood exposures did they have? The answer to that is clear, they had two distinct exposure risks:

  • Doctors giving vaccinations using reusable glass syringes, reusable needles, and multi-dose vials and jet guns for vaccinations.
  • Dentists drilling and scraping away at damaged teeth using reusable tools.

Nowadays with disposable everything, it's easy to forget what medicine looked like in the 50s, 60s, 70s, 80s and (believe it or not) the early 90s.

As a young child in the 60s I followed my father around. He worked in Intensive care and I got to play with all sorts of cool stuff. Glass syringes, reusable needles, liquid mercury from the blood pressure machines (shudder). My father and the other staff routinely got blood all over their neatly pressed white lab coats with barely a glove or facemask to be seen. Surgeons used that stuff, but not the doctors and nurses in the rest of the medical world.

I was immunized several times in a gymnasium line up with all my school friends. It was a wham bam thank you ma'am type thing. I thought the jet gun was nifty as there was no needle but discovered it hurt more.  As a medical student in the 80s I was aware of HIV but the notion of universal precautions was still a decade in the future. If we got blood on our hands we just washed it off. The world was very different and the acronym OH&S barely existed. 

Here are some timelines:

400 B.C. Campaign Jaundice: Hippocrates (yes, the Hippocratic oath guy) described a condition he called “epidemic jaundice.”

8th century A.D.: Pope Zacharias quarantined men and horses with jaundice. This was meant to control the spread of the disease.

1861-1865: More than 40,000 cases of jaundice were recorded in the Union Army during the Civil War.

1942-1945 Hepatitis and World War II: Approximately 182,383 US service members were hospitalized for hepatitis during World War II. The disease was contracted in two different ways. An epidemic of hepatitis broke out among many service members who were vaccinated against yellow fever. The source of the infection was traced to the serum that was used in the vaccine. A different form of hepatitis, acute hepatitis, was found among soldiers who had received blood transfusions.

1951: Rothauser produced the first injection-molded syringes made of polypropylene, a plastic that can be heat-sterilized. 

1956: New Zealand inventor Colin Murdoch was granted New Zealand and Australian patents for a disposable plastic syringe, it will catch on but will take time.

1964: Ansell manufactures the first disposable latex medical glove based on the production technique for making condoms, but universal use (as part of universal precautions) will take close to 3 decades to catch on.

1965: The hepatitis B virus was discovered by Dr. Baruch Blumberg.

1973: The hepatitis A virus was discovered at the National Institutes of Health by a team led by Steven Feinstone.

1973: Cases of hepatitis not caused by either hepatitis A or hepatitis B come to be called "non A, non B hepatitis".

1989: Hepatitis C virus (previously known as non A, non B) is discovered by scientists at a California biotechnology company called Chiron.

1991: A test for Hepatitis C in the blood supply becomes available.

1992: The Occupational Health and Safety Administration (OHSA) published its Bloodborne Pathogens Standard. Around this time, there was increased awareness regarding HIV, and OHSA implemented the rule to protect workers who would come in contact with bodily fluids. OSHA’s standard required employers to provide personal protective equipment, including disposable gloves, to these workers.

So, we know that Baby Boomers are more at risk of Hepatitis C than any other group? Why? It's actually pretty simple.

Some of the soldiers that returned to the USA from WWII came back with Hepatitis C. Poor medical hygiene spread it, and this spread was almost certainly by vaccination in the 1950s, NOT by IVDU in the 1960s and 1970s. Nice theory, but how can we be sure? One word - genomics. Here is the study, published in the most prestigious journal in the world "The Lancet".

Abstract here: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2816%2900124-9/fulltext

Full text here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5245154/

Here it is in plain English, thanks to Sheryl Ubelacker from The Canadian Press.

Canadian researchers have determined the peak of the hepatitis C epidemic in North America occurred about 15 years earlier than previously believed, suggesting it wasn’t youthful indiscretions that put baby boomers at a high risk for the disease.

It was long thought that boomers who were infected with the blood-borne virus likely contracted the disease in their late teens or early 20s, due to such risky behaviours as IV drug use or sexual experimentation.

But a study by B.C. researchers found the peak of the hepatitis C epidemic occurred about 1950, when many baby boomers were young children and had plateaued by 1960 — well before the zenith of injection drug use at the end of that decade.

The oldest of the baby boomers were just 5 years old at the peak of the epidemic, the researchers say.

“The spread of hepatitis C in North America occurred at least 15 years earlier than it was suspected before, and if that is the case, the baby boomer epidemic ... cannot be explained by behavioral indiscretions on the part of the baby boomers,” said co-investigator Dr. Julio Montaner, director of the BC Centre of Excellence in HIV/AIDS.

“We suspect that this is more likely attributable to medical practices at the time,” said Montaner, explaining that hepatitis C hadn’t yet been identified and injections and blood transfusions were given employing reusable glass-tube syringes and metal needles, which were subject to contamination despite boiling.

“The baby boomers in North America ought to be offered hepatitis C screening,” he said, “not because they did anything wrong but because they are baby boomers, and so they were alive at a time in which the standard of care was such that we are all potentially at risk of having contracted hepatitis C.”

If you or a loved one have Hepatitis C, but can't get access to insurance-funded treatment, then maybe getting cured with generic HCV medication is worth a thought. Visit our home page to learn more about generic hepatitis C treatment.

For patients with Hepatocellular Carcinoma (HCC) the options are limited. Caught early enough RadioFrequency Ablation (RFC), TransArterial ChemoEmbolisation (TACE) or surgical resection can potentially be curative. For some patients with advanced disease a liver transplant may be an option, but what about everyone else?

Up until recently, Sorafanib was the mainstay of treatment and the only real option to slow down the progression of the HCC and give patients some extra months or years of time. Nivolumab (Opdivo) appeared in 2017 but remains prohibitively expensive for most patients.

A couple of months ago the New England Journal of Medicine published the Phase 3 results for Cabozantinib which has been shown to work where patients are failing Sorafenib.


Although it's not a cure it can add some precious time. While it is anecdotal, back in 2015, I had a patient who was failing Sorafenib and was rejected from this very trial having been fully worked up. He was shattered and asked for help. Given this drug was, at the time, very experimental we went through an extensive informed consent process, including enlisting the assistance of his oncologist who said "We really don't have much to lose..." As it turned out he did very well on the Cabozantinib and got  2 extra years of good quality life.

It's not a cure, but it does provide cause for hope, as we inch ever closer to more effective treatments for HCC.

Friday, 03 August 2018 01:36

U=U - Undetectable = Untransmissable

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Strictly speaking, this relates to HIV but it also applies the Hepatitis C.

Undetectable = Untransmissable

Get tested, get treated, get cured!


News Flash

MAVIRET® (glecaprevir/pibrentasvir) was listed on the PBS in Australia today.

  • AbbVie is pleased to announce that MAVIRET is to be listed on the PBS on 1 August 2018 for the treatment of chronic hepatitis C virus (HCV) infection in adults.
  • MAVIRET is a new 8 week pangenotypic treatment for treatment-naïve non-cirrhotic HCV adult patients.
  • In clinical trials, MAVIRET demonstrated 98% cure* rate in the ITT population (n/N=943/965) and 99% in the mITT population‡ (n/N=943/952) in treatment-naïve, non-cirrhotic patients pooled across GT1-6 with 8 weeks of treatment3, and a 0.1% discontinuation rate due to adverse events

*Cure defined as HCV RNA below the lower limit of detection at 12 weeks post end-of-treatment (SVR12)

An estimated 9 out of 10 of the remaining people living with chronic HCV are treatment-naïve and non-cirrhotic and may be eligible for 8 weeks of therapy with MAVIRET

Tuesday, 24 July 2018 14:43

Hep C Awareness - Images and Poster

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Most of the messaging to people about Hepatitis C is boring with as much cut through as a blunt knife through a block of titanium. If you were born between A and B, if this, if that, etc. It's time to change the paradigm and speak to the simple reason for getting tested which is get treated and feel better.

Feeling Old & Tired?
Get Tested,
Get Treated,
Get Cured

We owe a debt of gratitude to Marty2Bulls who designed the butter(fly)man logo for us. You can check out Marty's work here: https://www.facebook.com/martytwobulls/


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