With a low 50 mg once-daily dose, good efficacy, minimal toxicity, pregnancy category B, and the potential to be low cost and co-formulated, dolutegravir is an attractive contender for use in low- and middle-income countries.
Swiftly after the FDA approved dolutegravir its U.S. price was announced -- an eye-watering US$14,105 per patient per year.1,2 Few outside the originator company considered this a pricing victory and several groups declared it to be quite the reverse.3-5
Meanwhile discussions among those set on optimising treatment for poor countries have marked the drug as a potential replacement for efavirenz first line -- which would need it to be available at a similar price. The step from US$14,105 to US$48 is quite a steep one and much will need to be done to achieve this.6,7
This article borrows shamelessly from a previous one -- Seven Ways to Speed up the Pipeline8 -- in which we explore some of these issues in more depth.
The Clinton Health Access Initiative (CHAI) supports national governments to access HIV treatment and offers reduced prices for first and second line antiretrovirals to members of its procurement consortium, which includes over 70 countries.9
CHAI produces an ARV Ceiling Price List and many of the listed products are made available through voluntary licensing agreements between the originator and generic companies.
The ceiling price for efavirenz is currently US$48 and a fixed dose combination of this plus tenofovir is US$130.
Middle income countries outside Africa who are not eligible for this and/or other price reduction mechanisms can pay, on average, four times more for antiretrovirals than African countries with similar Gross National Income (see article in this issue of HTB).10
The originator manufacturer ViiV Healthcare has said it will provide dolutegravir (branded Tivicay) at a not-for-profit price to eligible customers in its access programme ie to least developed countries, low-income countries and sub-Saharan Africa, following registration and marketing approval of the product and on request.
The price at which the drug will be available has not yet been announced and will be based on production costs, transport and volume.
Uptake will be determined by a number of factors including World Health Organisation (WHO) treatment guidelines; national treatment guidelines; stringent regulatory authorities and national regulatory approval processes.
ViiV plans to calculate and communicate the not-for-profit price "at the earliest opportunity."
As there has been no announcement yet from the company, with a back-of-an-envelope calculation, considering that the not-for-profit price of raltegravir, with a high daily dose -- 400 mg twice daily (16 times dolutegravir 50 mg once daily) -- but with similar active product ingredients (API) is approx US$675 per patient per year, adding inactive ingredients, packaging and shipping, perhaps we could optimistically expect a price of about US$200.
Dolutegravir showed superiority to efavirenz at 48 weeks in naive patients in phase III trials, mainly driven by fewer side effects.11 Efavirenz fulfils many desirable characteristics for an ideal antiretroviral but the discontinuation rate for central nervous system side effects is about 25% in settings where people have options. It looks like this could be mitigated somewhat with a lower (400 mg) dose as shown in ENCORE 2.12 But tolerability might be increasingly unacceptable as eligibility criteria for ART continue to broaden and more asymptomatic people are starting treatment, which is why possible alternatives to efavirenz need to be considered.
The data from the comparisons with efavirenz and from studies comparing dolutegravir to raltegravir and in people with resistance to other integrase inhibitors13,14 were used to gain FDA approval of a broad indication for dolutegravir. The indication for children older than 12 years is based on a 24-week open-label label study in integrase-naive patients.
Although some of the trials have now almost two years worth of data, how it would perform in a real world, low- or middle-income setting still poses questions. A Médecins Sans FrontiÃ¨res (MSF) paper published in 2008 stressed that populations in these settings include significantly larger proportions of women of childbearing age, children, and people with tuberculosis (TB), malaria, and other co-infections -- but research is conducted in order to provide information to register drugs for rich countries.15 The authors considered four drugs that had been recently approved or were in the pipeline at the time of publication. They looked at dose selection, comparability and compatibility with other antiretrovirals, and use in specific populations -- none had enough information to make help decisions about treatment in low- and middle-income countries. The registrational trials for dolutegravir mostly had about 80% men and few non-white participants and hardly anyone co-infected (a few hepatitis B but none with TB or malaria).
ViiV seem to have been better than most with their development programme -- dolutegravir has been studied in several treatment scenarios and regimens (although in a fairly homogenous population) and there is some information from PK studies about interactions with oral contraceptives, methadone and rifampicin16,17 but more information from the company and independent investigator-led studies is essential to address important gaps and this work needs to be done in a coordinated way.
Treating HIV/TB co-infection simply is a downside to dolutegravir -- 50 mg twice-daily dosing will be required when it is co-administered with rifampicin to overcome UGT1A/CYP3A induction by this drug, which is used in standard first line TB treatment.
ViiV is planning a trial in TB co-infected people as well as a study of dolutegravir in women. The company is also looking at women who become pregnant on trials with dolutegravir.
A phase 3 investigator-led study comparing 400 mg efavirenz plus FTC/TDF to dolutegravir plus abacavir/3TC in naive patients, with sites in several African countries, is in the planning stage.18 This study has few exclusion criteria, includes people with TB co-infection and aims to be as close as possible to real life. Adding a third arm with dolutegravir plus TDF/3TC would be interesting.
The study will look at another potential role for dolutegravir currently under discussion -- in second line, not as a replacement for boosted atazanavir or lopinavir with two RTIs, but with boosted darunavir. This regimen has the potential to be a once-daily co-formulated second line option with no cross-resistance to the current recommended first line.
People starting in the efavirenz arm will switch to this second line and those in the dolutegravir one to darunavir/r plus TDF/FTC.
Results from this study are important and donors need to step up.
ViiV has said it will authorise FDA to cross-reference their data for generic production.
An article from Fierce Pharma quotes Marc Meachem that ViiV has "wrapped up a deal allowing a generic company to make a low-cost version of Tivicay, subject to regulatory approvals. That version would be intended for the globe's poorest countries and countries in sub-Saharan Africa."19
There has been no announcement so far from the company as to which generic manufacturers and when. It is also unclear whether it will negotiate the licences through its own voluntary licensing mechanism set up in 2010 -- which includes about 67 sub Saharan and low income countries -- or license dolutegravir to the Medicines Patent Pool (MPP) for which discussions are underway for adults, and there has been a promise for children along the lines of that in place for abacavir.20 Voluntary licences for only 67 countries will probably not be acceptable for the MPP so negotiations might take a bit of time but both parties have said to expect news by the end of the year. One of the advantages of the MPP is that terms are in the public domain and we won't have to continue to guess.
If dolutegravir is only recommended second line -- perhaps co-formulated with darunavir/r -- this will not be sufficient volume to produce a flurry of healthy generic competition and in turn a suitably low price.
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