Minimum Costs to Produce Hepatitis C Direct-Acting Antivirals

This article offers a summary of the analysis about DAA treatment cost for HCV published in Clinical Infectious Diseases Advance Access in February 13, 2014 and updated on February 9, 2015 in Hepatology, Minimum target prices for production of direct-acting antivirals and associated diagnostics to combat hepatitis C virus. Hepatology. doi: 10.1002/hep.27641

BACKGROUND

Rationale

• Generic antiretrovirals are currently manufactured at very low cost, for treatment of over ten million people with HIV in low and middle-income countries.
• DAAs for HCV infection have similar mechanisms of action and chemical structures to antiretrovirals for HIV infection.
• For widespread treatment of HCV in developing countries to be feasible, we need short-course of antiviral treatment available at very low cost.
• Using the cost of HIV drugs as a framework, we can make estimates for the potential cost of HCV DAAs.

Aim

The aim was to estimate the minimum cost of HCV treatment.
Three assumptions:

1. The same methods of generic manufacturing used to supply antiretrovirals to people with HIV/AIDS in developing countries.
2. No patent restrictions on mass drug production
3. Procurement of large orders for drug manufacture by generic companies (over 5 million people treated).

METHODS

Selection of DAAs for analysis

Clinical trials of HCV DAAs were reviewed to identify combinations with:

• Phase 2 or 3 trial results available
• Consistently high rates of Sustained Virological Response (SVR)
• Safety data available
• Future program of clinical trials in different genotypes

Patent expiry dates were found for all DAAs in this analysis.

HCV drug development: Direct Acting Antivirals

DAAs in Phase II and Phase III trials:

Patent Expiry Dates of DAAs

Calculation of treatment costs

For each selected DAA, costs of mass production were estimated from:

• molecular structures,
• doses,
• treatment duration,
• components of retro-synthesis, with costs of API (active product ingredient)
• 40% margin for formulation (including profit margin for generic supplier).

Manufacturing costs per gram of DAA were projected as formulated product cost, based upon treating at least 5 million patients/year (to arrive at volume demand)

RESULTS

^acurrent mid-point cost of API from 3 Chinese suppliers
^b shows cost for 1200mg daily dose; $41 for 1000mg daily dose of ribavirin

Daclatasvir + Sofosbuvir combination treatment

Duration: 12 weeks
Predicted unit cost of combination HCV treatment (US$): 122
Predicted cost for 5 million people (US$ millions): 610

Sofosbuvir + Ribavirin combination treatment

Duration: 12 weeks
Predicted unit cost of combination HCV treatment (US$): 152
Predicted cost for 5 million people (US$ millions): 760

Duration: 24 weeks
Predicted unit cost of combination HCV treatment (US$): 304
Predicted cost for 5 million people (US$ millions): 1,520

Sofosbuvir + Ledipasvir combination treatment

Duration: 8 weeks
Predicted unit cost of combination HCV treatment(US$): 130
Predicted cost for 5 million people (US$ millions): 650

Duration: 12 weeks
Predicted unit cost of combination HCV treatment (US$): 195
Predicted cost for 5 million people (US$ millions): 975

MK-8742 + MK-5172 combination treatment

Duration: 12 weeks
Predicted unit cost of combination HCV treatment (US$): 115
Predicted cost for 5 million people (US$ millions): 575

Diagnostic testing in HCV

At present, HCV diagnosis and monitoring is complex, requiring a number of different tests.

^{Adapted from the european association for the study of the liver. easl clinical practice guidelines: management of hepatitis c virus infection}.

HCV diagnostic testing – the future?

• If treatments are pan-gentotypic, do we still need genotyping pre-treatment?
• If treatments work in >90% of people, do we still need to evaluate predictors of response (IL-28B, AFP, baseline HCV RNA)?
• If DAA combinations work in >90% of people, do we still need on-treatment monitoring of HCV RNA by PCR?
• Genotyping and HCV RNA PCR are expensive and complex to include in mass treatment programmes.
• HCV antigen assays have lower detection limits of 2000 IU/mL – is this low enough to detect either chronic infection (before treatment) and relapse or re-infection (6-12 months post treatment)?

The favorable safety profiles of these DAA combinations suggest that minimal laboratory monitoring will be necessary to assess safety during treatment.

Diagnostics and monitoring could be limited to:

• two HCV antigen tests to confirm infection and clearance after treatment (detection limit HCV RNA >2000 IU/mL: US$34 for two tests
• two full blood counts + clinical chemistry tests (AST / platelets): US$22
• genotyping if necessary: US$90 (not needed if treatment is pan-genotypic)

Projected minimum costs for treatment and diagnostics

+Additional genotyping if necessary: US$90 (not needed if treatment is pan-genotypic)

Limitations of the analysis

More detailed analysis of the chemical synthesis and APIs and formulation is necessary to produce more accurate estimates of the commercial costs.
These cost estimates assume a large volume demand: over 5 million people treated per year. Support from donor agencies/governments is required to reach this demand.
The estimates assume that there is pressure in the market to lower costs of generic manufacture; while DAAs remain on patent, this generic competition may be limited.
The results of DAA clinical trials are not representative of all patient subpopulations and genotypes. Additionally, the high SVR rates need to be proven in real-world situations.
These estimates are based on a 12-week treatment course; 4- and 6-week courses are being evaluated in clinical trials. Furthermore, the HCV pipeline includes several other promising candidates that may be included in further analyses.

Authors

Andrew Hill, Liverpool University, UK
Bryony Simmons, Imperial College, London, UK
Nikolien van de Van, Imperial College, London, UK
Nathan Ford, University of Cape Town, South Africa
Saye Khoo, Liverpool University, UK
Joe Fortunak, Howard University, Washington DC, USA