Timeline for access to generic dolutegravir: what still needs to be done
Polly Clayden, HIV i-Base
Dolutegravir (DTG) is widely predicted to both provide better antiretroviral options for low-income countries (LMICs) and reduce the cost of global ART. But a number of steps need to happen before DTG is widely available and recommended for all populations.
The originator (ViiV Healthcare) manufacturer’s DTG 50 mg single tablet was approved a few weeks ago in South Africa. It is now approved or under regulatory review across the African continent and in many LMICs.
The DTG price in South Africa will be around R770 per month (approx US $600 pppy) and it should be on the shelves in early June.
ViiV licensed DTG to Aurobindo in 2014 and subsequently, through the Medicines Patent Pool (MPP), to other generic manufacturers. [1, 2, 3]
Several Indian companies have also completed the development of generic DTG.
The Aurobindo single DTG 50 mg tablet is currently under review for tentative approval with the US Food and Drug Administration (FDA) and there should be an answer from them very soon. This version will be available to generic accessible countries for about US $44 pppy under an agreement with ViiV and the Clinton Health Access Initiative (CHAI). 
Other generic companies will follow suit.
The Aurobindo fixed dose combination (FDC) of DTG/tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) is expected be filed with the FDA in the third quarter of this year and there are other similar generic products on the way. 
Assuming all goes according to plan, countries could begin procuring DTG/TDF/3TC in 2017, with World Health Organization (WHO) pre-qualification and FDA approval by end 2017.
One concern for access to the Indian generics is that the department within the Indian Central Drugs Standard Organisation of the Ministry of Health responsible for regulating medical devices and drugs, the Drug Controller General of India (DCGI), requests clinical trials in India for all new drugs. This request can also affect the export of new drugs. 
The use of Indian generics to treat HIV is global: Mylan has 30% of the most recent South African tender, covering the three-year period from 1 April 2015 to 31 March 2018. 
Indian approval of DTG is sufficiently critical to the success of treating everyone with HIV worldwide. The DCGI waivered the local clinical trial requirement for sofosbuvir for hepatitis C, for example,  and DTG represents a clear case for such an exception.
Generic manufacturers expect to make the first DTG-based FDCs available for a similar price to EFV-based ones – about US $100 pppy. Active pharmaceutical ingredients (API) and manufacturing costs for DTG and later tenofovir alafenamide (TAF) will help get this down to about $85 for DTG/TAF/FTC by 2018/19.
Missing information and ongoing or planned clinical trials
DTG is now recommended by WHO as part of an alternative adult first-line regimen with restrictions, notably use in pregnancy and with concomitant rifampicin-based treatment for TB. It will not be a preferred regimen until we have more data to guide ART in low-income countries (LMICs), particularly in these two populations.
Several studies designed to address these evidence gaps are ongoing or planned. These include a three-arm, non-inferiority study comparing DTG/TAF/FTC with either DTG/TDF/FTC (currently a recommended first-line regimen in most high-income countries) or EFV/TDF/FTC (currently recommended in WHO guidelines and the most widely used first-line ART globally). The inclusion criteria will reflect clinical practice and populations in LMICs. Other studies will look at the interaction with rifampicin and DTG use in pregnant women.
Our next annual update of ART optimisation trials and generic products in the pipeline will describe these studies in detail. 
- CHAI. Press release. ViiV Healthcare and CHAI collaboration delivers second milestone with first filing with the FDA of generic dolutegravir by Aurobindo Pharma for the treatment of HIV. 26 May 2015.
- Medicines Patent Pool. Press release. Medicines Patent Pool, ViiV Healthcare sign licence for the most recent HIV medicine to have received regulatory approval. 1 April 2014.
- Medicines Patent Pool. MPP licences for dolutegravir (DTG).
- UNAIDS. Press release. Three new agreements announced with the potential to expand access to innovative HIV treatment in low- and middle-income countries. 30 November 2015.
- Central Drugs Standard Control Organization.
- Smart T. Weak rand means South Africa pays more for ARVs in latest tender. NSP review. Edition 12. June 2015.
- The Times of India. Hepatitis C cure may cost as low as Rs 67k. 29 November 2015.
- Clayden P. Fit for purpose: antiretroviral treatment optimisation. 17 July 2015.