From sky high to CHAI* – what needs to be done about dolutegravir pricing?
Polly Clayden HIV i-Base and Mark Harrington, TAG
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 US 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, 4, 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 Pipeline  – 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. 
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). 
Not-for-profit price from the originator
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.
Real world research
Dolutegravir showed superiority to efavirenz at 48 weeks in naïve patients in phase III trials, mainly driven by fewer side effects.  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.  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 inhibitors [13, 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-naïve 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 Frontières (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.  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 rifampicin [16, 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.  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.
Generic formulations and licensing
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.” 
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.  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.
In Seven Ways to Speed up the Pipeline we wrote: “Regulatory delay has posed as much of an obstacle to timely access to antiretrovirals in developing countries as has patent protection, yet it has attracted none of the advocacy attention”.
Tables 1 and 2 show the respective delays from approval by the FDA to that by South Africa’s Medicines Control Council (MCC) and between FDA approval for the US market and tentative approval (TA) for low-income countries.
|ARV single or combination||FDA US approval||MCC approval||Delay (years)|
*Aluvia (Abbott lopinavir/ritonavir co-formulation produced for developing countries in a different colour to Kaletra) was registered by the MCC in 2008.
Source: Clayden and Harrington. Seven Ways to Speed up the Pipeline. 2013.
|FDA US approval||FDA TA approval||Delay (years)||From 2004*|
* Tentative approval began in 2004.
Source: Clayden and Harrington. Seven Ways to Speed up the Pipeline. 2013.
We noted that, in the past, license agreements were negotiated several years after products were already approved in rich countries and more recently, with newer antiretrovirals, agreements have been signed a year or two before FDA approval, and ViiV is already negotiating licenses for dolutegravir.
For TA, the FDA Guidance for Industry Fixed Dose Combinations, Co-Packaged Drug Products, and Single-Entity Versions of Previously Approved Antiretrovirals for the Treatment of HIV 2006 includes a list of regimens and components for which the agency is satisfied that safety and efficacy have been established (and demonstrated in product labelling or peer reviewed literature). 
It suggests FDC or co-packaged products for combinations on this list could be developed without conducting new clinical trials. It is important for the list to be updated to include acceptable dolutegravir regimens and FDCs that can be approved without further trials, to guide generic manufacturers.
Many developing countries rely on WHO prequalification – the scheme has helped countries to build regulatory capacity as it engages their regulators in the process and offers training in evaluation.
There is an agreement with the FDA that tentatively approved antiretrovirals are also prequalified. Although generally considered to be useful, WHO PQ is horribly slow, taking about two years to prequalify a drug. [25, 26]
ViiV needs to ensure that originator dolutegravir is pre-qualified as soon as possible and support generic tentative approval.
As far as national agencies are concerned, the company plans submissions in stages targeting the highest burden countries first. This part of the process will be highly dependent on national regulatory capacity, which is lacking in most countries with large HIV epidemics. 
Inclusion in WHO and National Guidelines
Recommending new antiretrovirals in the WHO guidelines poses a classic chicken and egg conundrum and boosted darunavir is an example from the most recent guideline update [28, 29]. Despite being generally considered to be a better tolerated PI (with better virological response in some studies) than boosted lopinavir, darunavir was only included as a footnote for second line treatment due to the lack of availability of a heat stable, co-formulated generic version. Meanwhile generic manufacturers are reluctant to make the investment to produce one, without a strong signal from WHO.
Whether dolutegravir is included first or second line in subsequent guideline updates, the recommendation from WHO needs to be clear. Any change in recommendations and introduction of new generic products will hopefully lead to changes in national guidelines and will require massive support, from organisations such as UNITAID and CHAI, to make the transition.
Although manufacturing costs of dolutegravir are estimated to be low – about $US30  – only a first line recommendation would mean that a generic version could be produced in sufficient volume to make a tempting profit if it were pegged at a similar price to efavirenz.
Pricing in middle income countries
MSF greeted the news of the FDA approval with concern that “…ViiV’s business strategy will result in dolutegravir being priced out of reach in countries excluded from ViiV’s licensing deals”  – ie those outside the 67 countries in its access programme. MSF encourages the company to make a licence agreement with the MPP, but this will need to include “all low- and middle-income countries and have no restrictions on where the drug can be manufactured or active pharmaceutical ingredients can be sourced”.
The pricing analysis of middle-income countries outside Africa – ineligible for access prices and other discounts – summarised above shows they can pay, on average, four times more for antiretrovirals than African countries with similar incomes.
ViiV needs to take all the necessary steps to make sure dolutegravir will be affordable and available for all those who could benefit from it.
- FDA press statement. FDA approves new drug to treat HIV infection. 12 August 2013.
- ViiV healthcare press statement. ViiV Healthcare announces U.S. approval of Tivicay. 12 August 2013.
- Fair Pricing Coalition. FPC commends ViiV on price of its new drug Tivicay. 14 August 2013.
- Collins S. ViiV goes for gold: US premium pricing may threaten dolutegravir use in Europe. HTB. 15 August 2013.
- Poll: At $14,105/year, is dolutegravir fairly priced? NEJM Journal Watch. 28 August 2013.
- Clayden P. Retrofitting for purpose: treatment optimisation. The Pipeline Report 2013.
- The second conference on antiretroviral drug optimization (CADO 2) meeting report. July 2013.
- Clayden P and Harrington M. Seven Ways to Speed up the Pipeline. The Pipeline Report June 2013.
- Clinton Health Access Initiative. ARV Ceiling Price List. May 2013.
- Clayden P. High prices for antiretrovirals in middle-income countries outside Africa. HTB. October 2013.
- Walmsley S et al. Dolutegravir (S/GSK 1349572) and abacavir/lamivudine once daily is statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results – Single (ING11467). 52nd ICAAC, 9-12 September 2012. San Francisco, California. Oral abstract H-556b.
- Puls R et al. A daily dose of 400mg efavirenz (EFV) is non-inferior to the standard 600mg dose: week 48 data from the ENCORE1 study, a randomised, double-blind, placebo controlled, non-inferiority trial. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 30 June – 3 July 2013, Kuala Lumpur. Oral late breaker abstract WELBB01.
- Cahn P et al. Dolutegravir (DTG) is superior to raltegravir (RAL) in ART-experienced, integrase naive subjects: week 48 results from SAILING (ING111762). 7th IAS, Kuala Lumpur, 2013. Late breaker oral abstract WELBB03.
- Nichols G et al. Phase 3 assessment of dolutegravir (DTG) 50mg twice daily in HIV-1-infected subjects with raltegravir (RAL) and/or elvitegravir (EVG) resistance in VIKING-3: week 24 results of all 183 patients enrolled. 7th IAS, Kuala Lumpur, 2013. Late breaker poster TULBPE19.
- van Roey Jet al. How developing world concerns need to be part of drug development plans: a case study of four emerging antiretrovirals. Drug Discov Today. 2008 Jul;13(13-14):601–5. doi: 10.1016/j.drudis.2008.04.009.
- Song I et al. Dolutegravir has no effect on pharmacokinetics of methadone or oral contraceptives with norgestimate and ethinyl estradiol. 20th CROI, 2013, Atlanta. Poster abstract 535.
- Dooley K et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin: results of a phase I study among healthy subjects. 19th CROI, 2012, Seattle. Oral late breaker abstract 148.
- Personal communication to Polly Clayden Alexandra Calmy (September 2013).
- Staton T. ViiV’s newly minted HIV fighter Tivicay to cost $14K per year. FiercePharma. 13 August 2013.
- Medicines Patent Pool. Abacavir Licence Agreement. 13 February 2013
- MCC data personal communication to Polly Clayden Andy Gray and Nathan Geffen (April 2013); and
The MCC lacks a publicly accessible database of antiretrovirals registered since 2004, so some of these dates may be imprecise.
- Food and Drug Administration (US). Antiretroviral drugs used in the treatment of HIV infection.
- Food and Drug Administration (US). Approved and tentatively approved antiretrovirals in association with the President’s Emergency Plan.
- US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Co-Packaged Drug Products, and Single-Entity Versions of Previously Approved Antiretrovirals for the Treatment of HIV 2006 October.
- World Health Organisation. Prequalification of medicine by WHO. 2012.
- World Health Organisation. WHO list of prequalified medicinal products. 2012.
- World Health Organisation. 2010. Assessment of medicines regulatory systems in sub-Saharan-African Countries.
- World Health Organisation. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach. June 2013.
- Clayden P. WHO 2013 guidelines: what about the missing formulations? HTB, July 2013.
- Hill A. Antiretroviral dose optimisation: what are the opportunities? UK Clinical Pharmacology Workshop, Turin, January 2013.
- MSF Access Campaign Press Release. As US FDA approves promising new HIV drug dolutegravir, MSF asks when people in developing countries will have access. 13 August 2013.