July 2018
Annette Gaudino
HCV TREATMENT PIPELINE: THE DEFERRED DREAM OF TREATMENT FOR ALL
Generic combinations of direct-acting antivirals (DAAs), including sofosbuvir/daclatasvir show bioequivalence compared to originators with equivalent sustained virological responses (SVR). Both sofosbuvir/daclatasvir and sofosbuvir/ravidasvir demonstrate SVR rates of 97% at 12 weeks of treatment across genotypes, with further studies underway for genotypes 3, 4, and 6, people with cirrhosis, and those with decompensated liver disease. Generic DAAs have become increasingly affordable at less than USD 100 per 12-week treatment course, which opens up access for people living with HCV in low- and middle-income countries (LMICs). Yet overall treatment uptake is still low: Of the estimated 71 million people living with chronic HCV, roughly 1.75 million people initiated treatment globally in 2016. By comparison, global diagnosis was only 8% in LICs compared to 43% in HICs.
Furthermore, the evidence that people with substance use disorders can achieve SVR with DAAs is now overwhelming. With each passing year, the story remains the same: we possess the necessary therapeutic tools to eliminate HCV infection as a public health threat, at affordable prices, and across all genotypes, if they can be delivered before liver function decompensates due to advanced cirrhosis. We also know these tools are effective among the key population driving incidence, people who inject drugs. Treatment for all is a necessity; treatment for all remains an unfulfilled promise.
Advocacy points
For companies:
- Close registration gaps for generic sofosbuvir and daclatasvir in countries covered under voluntary licenses to provide 100% access.
- Complete phase II/III clinical trials of sofosbuvir/ravidasvir in genotype 6 patients, and additional trials in genotype 5 patients, to confirm pangenotypic activity.
- Complete phase II/III clinical trials of sofosbuvir based regimes in patients younger than 12 years and weighing less than 35 kg.
- Conduct phase II/III clinical trials of pangenotypic regimes including G/P, SOF/DAC and SOF/RAV in adolescent patients younger than 17 years, and children weighing less than 35 kg.
- Complete phase II/III clinical trials in pregnant women to assess the safety and efficacy of DAAs as curative treatment and prophylaxis to prevent vertical transmission.
For governments:
- Waive in-country clinical registration trials for proven DAA combinations from validated generic manufacturers.
- Decriminalize the possession and distribution of harm reduction tools and interventions: syringe service programs, direct purchase and possession of syringes, and safe drug consumption spaces/safe injection facilities.
- Ensure competition between generic manufacturers.
- Explore all available means to accelerate and expand access to generics: compulsory licenses using TRIPS flexibilities or other legal approaches, parallel importation, and patent challenges.
- High-income countries must refrain from retaliatory trade practices in response to the use of TRIPS flexibilities for access to medicines.
- Enact opt-out screening of all individuals upon incarceration, with robust linkage to care during incarceration or post release.
- Align public health system payment/reimbursement to expand HCV screening beyond the birth cohort and individuals with identified high risk, with particular attention to pregnant women.
For donors:
- Commit to multilateral funding for universal access to generic DAA treatment in low- and middle-income countries.
- Facilitate the integration of disease-specific programs by supporting treatment of HCV monoinfected individuals at risk for HIV and other infectious diseases.
| Compound | Class/Type | Company/Sponsor | Patient Population | Status |
| EBR/GZR + SOF | NS5A/NA3-4A + NS5B inhibitor | Merck | Genotype 3 PEG-INF experienced | Approved |
| C-ISLE STUDY: Elbasavir/grazoprevir and sofosbuvir for genotype 3 treatment naïve and peginterferon/RBV experienced patients with compensated cirrhosis, a phase 2, randomized, open label study
Treatment naïve:
Treatment experienced:
Virologic failure = 2; Relapse = 2; Discontinued due to AE = 1; presence of baseline RASs and addition of ribavirin did not impact SVR. |
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| SOF/RAV | NS5B/NS5A inhibitor | DNDi/Pharco | Genotypes 1a/b, 2, 3, 4, 6; HIV coinfected; PWID | Approvals pending |
STORM-C-1 phase II/III trial stage 1 of 12 weeks ravidasvir/sofosbuvir in non-cirrhotic patients and 24 weeks in cirrhotic patients.
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| G/P | NS3-4A/NS5A inhibitor | AbbVie | GT 5, 6 | FDA approved |
ENDURANCE-5,6 Study: ongoing phase 3b, non-randomized, open-label, multicenter study of glecaprevir/pibrentasvir in South Africa (GT5), Myanmar, and Vietnam (GT6).
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| G/P | NS3-4A/NS5A inhibitor | AbbVie | HIV Coinfected | FDA approved |
EXPEDITION 2 Study: a phase II, open label, multicenter study of glecaprevir/pibrentasvir in HIV-1 coinfected patients for 8 weeks in patients without cirrhosis and 12 weeks in patients with compensated cirrhosis.
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| G/P | NS3-4A/NS5A inhibitor | AbbVie | Retreatment after DAA failure | FDA approved |
A phase 3b, open-label, multi-arm randomized study of glecaprevir/pibrentasvir +/- RBV for GT1 patients who previously failed an NS5A inhibitor + SOF therapy; patients with and without compensated cirrhosis evaluated; interim results reported:
MAGELLAN-1 Part 2: phase 3, open label, randomized study to evaluate the efficacy and safety of ribavirin free glecaprevir/pibrentasvir in patients with previous virologic failure on therapy containing NS3/4A protease and/or NS5A inhibitor; GT 1, 4, 5, 6; patients with compensated cirrhosis were included.
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| SOF/LDV | NS5B/ NS5A inhibitor | Gilead | Adolescents 12-17 years old | FDA approved |
Safety and efficacy of SOF/LDV for 12 weeks in GT1 patients 12 years of age and older, or weighing at least 35kg (~70 lbs), without cirrhosis or with compensated cirrhosis, a phase 2, open label, multicenter study.
Sofosbuvir and ribavirin in adolescents 12-17 years old with GT 2,3 infection: GT2 received 12 weeks, GT3 received 24 weeks; 40% assessed as non-cirrhotic, remainder were undetermined.
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| SOF/LDV | NS5B/ NS5A inhibitor | Gilead | HIV coinfected | FDA approved |
ANRS TAC Trial: open label multicenter trial in Senegal, Cote d’Ivoire and Cameroon, GT 1, 4 patients with or without compensated cirrhosis receiving 12 weeks of treatment with SOF/LDV.
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| EBR/GRZ | NS5A/NS3-4A inhibitor | Merck | GT 1, 4 HIV coinfected MSM | FDA approved |
DAHHS 2 Study: 8 weeks of grazoprevir/elbasvir for acute HCV, single arm, prospective multicenter clinical trial; all patients with acute infection and all but one patient coinfected with HIV.
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| EBR/GRZ | NS5A/NS3-4A inhibitor | Merck | GT 4, treatment naïve | FDA approved |
Ongoing randomized phase IV clinical trial of 8 weeks vs 12 weeks of EBR/GRZ in GT4 treatment naïve patients with F0-F2 fibrosis
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ABBREVIATIONS
ALT: Alanine aminotransferase
APRI: AST to Platelet Ratio Index
CE: Conformité Européene/European Conformity
DAA: Direct-acting antivirals
DAC: Daclatasvir
EBR/GRZ: Elbasvir/grazoprevir
F0-F4: Fibrosis stage range
FIB-4: Fibrosis-4 index
GT: Genotype
G/P: Glecaprevir/pibrentasvir
HCV: Hepatitis C virus
HIC: High-income countries
HIV: Human immunodeficiency virus
HRCs: Harm reduction centers
IDU: Injection drug use
IU/mL: International unit per milliliter
LDV: Ledipasvir
LMIC: Low- and middle-income countries
MSM: Men who have sex with men
ND: No data
OAT: Opioid agonist therapy
OST: Opioid substitution therapy
PQ: Prequalification
PWID: People who use drugs
RAV: Ravidasvir
RBV: Ribavirin
RNA: Ribonucleic acid, or HCV RNA test
SOF: Sofosbuvir
SVR: Sustained virological response
TRIPS: Trade-Related Aspects of Intellectual Property Rights
uL: unit of liquid volume equal to one millionth of a liter, or 1 mm3
VEL: Velpatasvir
VL :Viral load
WHO: World Health Organization