HIV continues to be a major global public health issue, with more than 35 million people worldwide living with this deadly viral disease. The first global approval of dolutegravir (Tivicay) by the US Food and Drug Administration (FDA) in August 2013 resulted in a new option for millions of people with HIV-1 infection, the most common strain of the disease.
ViiV Healthcare’s dolutegravir (formerly called GSK 1349572) belongs to the class of compounds known as the integrase inhibitors, which block replication of HIV by preventing the viral DNA from integrating into the genetic material of human immune cells (ie T cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection.
Dolutegravir is a follow-up compound to S 364375, which has since been discontinued. S 364375 was discovered and developed by a joint venture between GlaxoSmithKline (GSK) and Shionogi. These firms, along with Pfizer, now form the ViiV joint venture.
The US FDA specifically approved dolutegravir for use in adult patients with HIV-1 infection who have never received any antiretroviral therapy (ie ART-naïve or treatment-naïve) or who have already received prior ART (ie ART-experienced or treatment-experienced). In addition, the drug is also available for use in children/adolescents aged 12 years and above who weight at least 40kg (88lb) and who have not received treatment with another integrase inhibitor (raltegravir or elvitegravir). This approval occurred in August 2013, which was followed by approval in Canada in October 2013.
The EMA’s Committee for Medicinal Products for Human Use (CHMP) recommended approval of dolutegravir in November 2013, for use in combination with background ART for treatment of HIV-1-infected adults and children/adolescents aged over 12 years. Final marketing authorisation from the European Commission is expected in early 2014. ViiV also filed for regulatory approval of dolutegravir in Japan in December 2013, where it has already been granted orphan drug status.
Other integrase inhibitors
Raltegravir (Isentress; Merck) was the first integrase inhibitor to be approved by the US FDA in October 2007. Raltegravir has since been launched in several countries worldwide for use in combination with other antiretroviral agents in treatment-experienced patients with HIV-1 infection.
Elvitegravir (Vitekta; Gilead Sciences) is another oral HIV integrase inhibitor that has been developed for the treatment of HIV-1 infections. The first global approval of this drug as a monotherapy occurred in the European Union (EU) in November 2013 for use in treatment-experienced patients with HIV-1 infection who have no known mutations associated with elvitegravir resistance.
The drug itself has already been approved as once-daily, four-drug, fixed-dose combination (FDC) product (Stribild; Gilead Sciences, Japan Tobacco) comprising elvitegravir 150mg/emtricitabine 200mg/tenofovir disoproxil fumarate 245 or 300mg/cobicistat 150mg. The first global launch of Stribild occurred in the US in August 2012, and is approved for use in treatment-naïve adult patients with HIV-1 infections. EMA approval was also granted in May 2013.
Pivotal trials for dolutegravir
All of the submitted regulatory applications for dolutegravir have been supported by data from four pivotal phase III trials, which have been conducted in ART-experienced patients (SAILING and VIKING-3) and ART-naïve patients (SPRING-2 and SINGLE). Other trials, including FLAMINGO, have also been used to support these regulatory applications.
ART-experienced patients: SAILING (also known as ING111762) is a 48-week trial that compared dolutegravir with raltegravir (ie active comparator), which were given in combination with a background regimen of one or two active agents (one of which had to be fully active), in ART-experienced and integrase inhibitor-naïve HIV-1-infected patients. This randomised, double-blind, active-controlled, non-inferiority trial enrolled 688 such patients from various countries worldwide, including the US, Canada, EU and Latin American countries, Australia and South Africa.
The primary end-point of the trial was the percentage of patients with HIV-1 RNA levels of <50 copies/mL (defined as virological suppression) at week 48. Patients randomised to dolutegravir who successfully complete week 48 will continue to receive the drug until either it is locally available, until they no longer derive clinical benefit, until they meet a protocol-defined reason for discontinuation, or until development of the drug is terminated. The SAILING trial is due to be completed in 2015.
VIKING trials: Another area where dolutegravir looks very promising among the small group of patients who have resistance to both raltegravir and elvitegravir. The VIKING trials (VIKING-3 and VIKING-4) showed that dolutegravir remains active against many of these viruses, but not all of them. A 50mg BID regimen of dolutegravir was assessed in both of the VIKING trials.
The purpose of the VIKING-3 trial (also known as ING112574) was to assess the efficacy and safety of a dolutegravir-containing regimen in treatment-experienced adults with HIV-1 infection who have failed prior therapy with elvitegravir or raltegravir. Adding dolutegravir to optimised background ART was associated with a 1.4 log10 copies/mL decline in mean HIV RNA levels after seven days of treatment (co-primary end-point). The proportion of patients who achieved virological suppression at week 24 (co-primary end-point) was 63 per cent.
In the VIKING-4 trial (also known as ING116529), the BID regimen of dolutegravir was assessed in patients who have failed prior therapy with, or have genotypic resistance to, raltegravir or elvitegravir.
Primary end-point data was presented at the 14th European AIDS Conference in Brussels, Belgium, in October 2013. It showed that functional monotherapy with the 50mg BID regimen of dolutegravir was superior to placebo in these highly ART-experienced, integrase inhibitor-resistant patients with HIV-1 infection. The primary end-point was the mean change from baseline in plasma HIV-1 RNA at day 8, which significantly favoured the dolutegravir-containing regimen (-1.06 log10 copies/mL) versus the placebo-containing regimen (+0.10 log10 copies/mL). Results from this trial were consistent with those seen in the larger VIKING-3 trial.
ART-naïve patients: The randomised, double-blind SPRING-2 trial (also known as ING113086) met its primary end-point of demonstrating non-inferiority of dolutegravir to raltegravir at 48 weeks, in 822 ART treatment-naïve patients with HIV-1. Virological suppression was achieved by 88 per cent of patients who received dolutegravir 50mg OD, compared with 85 per cent of patients who received raltegravir 400mg BID. Both drug regimens were administered with two nucleoside reverse transcriptase inhibitors.
In the subgroup of patients who had high baseline viral loads (HIV-1 RNA >100,000 copies/mL), the response rates were 82 per cent with dolutegravir-containing regimen, compared with 75 per cent with raltegravir-containing regimen. Furthermore, virological suppression rates at week 96 showed a similar trend in favour of dolutegravir (81 per cent of patients versus 76 per cent with raltegravir).
The SINGLE trial (also known as ING114467) assessed the long-term efficacy and safety of 50mg once-daily regimen of dolutegravir plus a FDC tablet of lamivudine/abacavir (Epzicom; ViiV Healthcare) versus that with efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla; Bristol-Myers Squibb, Gilead Sciences) in 833 ART-naïve patients with HIV-1 infection.
The proportion of patients who achieved virological suppression at week 48 (primary end-point) was 88 per cent among patients who received dolutegravir plus abacavir/lamivudine, compared with 81 per cent among patients who received Atripla.
Similar advantages with the dolutegravir-containing regimen were also seen among patients who had a baseline viral load of less than 100,000 copies/mL (90 per cent of patients with dolutegravir vs 83 per cent of patients with Atripla), or more than 100,000 copies/mL (83 per cent vs 76 per cent of patients).
Other supporting trial
The phase IIIb FLAMINGO trial (also known as ING114915) was also conducted to support the registration of dolutegravir, and is the third trial to be conducted in treatment-naïve patients with HIV-1 infection. Patients were randomised to receive dolutegravir 50mg OD or ritonavir-boosted darunavir OD, each in combination with fixed-dose, dual nucleotide reverse transcriptase inhibitor (NRTI) therapy (either lamivudine/abacavir or emtricitabine/tenofovir disoproxil fumarate). The primary efficacy end-point was the HIV-1 viral load at week 48, which was achieved by 90 per cent of patients who received the dolutegravir regimen, compared with 83 per cent who received the dual NRTI regimens.
A potential blockbuster?
Dolutegravir has the potential to capture a significant share of the HIV market, helped by positive data from head-to-head trials of the drug versus efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla) and raltegravir (Isentress). Some analysts have predicted that it could become a potential blockbuster by 2017, and will provide competition to some of the best selling single-agents and FDC therapies for HIV.
However, as with every other new HIV therapy, the cost of dolutegravir treatment has generated some controversy and could be a factor that limits its success in the marketplace. The US Wholesale Acquisition Cost (WAC) price of dolutegravir is $US1175 per month for 30 tablets ($US14,105 per year), which is slightly higher than the annual WAC costs of raltegravir ($US12,976) and ritonavir-boosted elvitegravir ($US13,428).
