HIV Therapy: Safer, simpler and longer-lasting

World AIDS day on Sunday, December 1 drew attention to the 38 million people still living with the human immunodeficiency virus (HIV), and the over 777,000 deaths claimed in 2018 by the virus. But there is lots of good news, too. Well over half of those with HIV can now access effective anti-retroviral therapy – three times as many as in 2010. The rate of new infections has fallen by 40% since the 1997 peak, according to UNAIDS.

HIV therapy researchers are now focused on developing more convenient regimens with fewer side-effects, but equal or better efficacy. These include combinations that involve fewer daily pills, or implants that may remove the need for any daily therapy at all. There is also promising work developing a vaccine for the condition.

HIV is a retrovirus that infects immune system cells, weakening the body’s defences and ultimately resulting in acquired immunodeficiency syndrome (AIDS).

Gilead – with over half of the estimated $28 billion global HIV therapy market – is the player to beat. The company sells a range of combination therapies, including Atripla (a triple combination of efavirenz/emtricitabine/tenofovir disoproxil fumarate), Truvada (a dual combo of emtricitabine/tenofovir disoproxil fumarate), or Complera (emtricitabine / rilpirivine/tenofovir disoproxil fumarate). Newer drugs like Genvoya and Biktarvy have rapidly gained share, however, thanks to improved, safer constituent chemicals.

Genvoya is Gilead’s largest drug (2018 sales: $4.62 billion). It is a single-tablet regimen which combines elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide (shortened to TAF). It is the top-prescribed drug in the US in all patients, thanks in part to safety advantages of TAF over the older tenofovir disoproxil fumarate (TDF) formulation.

Those advantages relate to renal and bone mineral density side-effects. (TAF is a pro-drug formulation of tenofovir with lower serum concentrations as a result.) Given that these therapies are taken over long time periods, keeping the virus at bay for many millions, the

risk profile is particularly important. All TAF-based regimens are gradually gaining market share over older alternatives.

Yet Genvoya faces a rival in Gilead’s own Biktarvy (bictegravir/emtricitabine/TAF) in treatment-naïve patients. That’s because of an improvement to another of the constituent drugs, the integrase inhibitor. By using longer-lasting bictegravir instead of elvitegravir, drug resistance reduces, and there is no need for a metabolic booster, cobicistat, to inhibit breakdown. That means fewer chemicals, and a lower risk of GI-related side-effects. Biktarvy is also, like Genvoya, a single-pill, and “it is a relatively cheap treatment option,” according to one German KOL.

GlaxoSmithKline is going after a two-drug regimen it hopes will be as effective as Gilead’s three-way Biktarvy, in its bid to gain market share. Its majority-owned ViiV subsidiary recently announced results of a 96-week trial of Dovato, combining dolutegravir and lamivudine. The data showed that Dovato was as effective as a three-drug treatment at suppressing the virus, and no patients developed resistance, which is another problem for HIV treatments.

It will take time – and more than a single study – to convince physicians to abandon what they know works. But GSK has provided a tail-wind for Dovato by pricing it lower than Biktarvy (though actual prices paid for medicines are notoriously opaque, especially in the US).

Ultimately, however, fewer drugs are likely to mean fewer side-effects, and that should mean greater compliance and hence better outcomes. Treatments that are administered less regularly may also lead to better outcomes: that is what Merck & Co. is betting on with MK-8591, a Phase IIb compound with a novel mechanism of action that is more potent than other treatments, and which has a long-half life, meaning it stays in the cells for longer than existing therapies. That could reduce the likelihood of drug resistance, and could also allow it to be delivered as an implant. Other early stage research is looking at implant-based HIV therapies that are released slowly into the circulation and remove the need for daily pills.

Prevention is another important line of attack against HIV. Experts are optimistic that an HIV vaccine may become a reality; late-stage trials of three vaccine candidates are underway, with the first results due in early 2021. HVTN 702 completed enrolment of over 2500 women in southern Africa earlier in 2019 (women between the ages of 18-25 have a 50% infection rate). Imbokodo and Mosaico use a variety of immunogens to protect against a wide range of HIV strains; their trials are slightly further behind.

If these vaccines do prove effective, they will likely require multiple injections, and different doses. So they are unlikely to prove a panacea. But prophylaxis is already gaining traction: PrEP (pre-exposure prophylaxis) involves administering HIV therapy to patients who don’t show any signs of disease, in order to prevent infection. Gilead’s Truvada is used as PrEP, but the approach is not sufficiently widespread to prevent the virus’ spread.

Gilead continues to cover its bases. It is working on positioning Descovy (emtricitabine/TAF) as a PrEP drug of choice, given pending generic competition to Truvada, and claims of better

safety, faster onset and longer duration of action. In early November 2019, the company presented promising Phase 1 data from GS-6207, which may be effective dosed only every six-months. The candidate is an HIV-1 capsid inhibitor, which has shown potent activity and good tolerability among a broad range of patients with varying treatment histories.

As HIV therapy becomes safer, more convenient and longer-acting, Gilead hopes that its current and future candidates will remain a core component of that future treatment landscape. Competition from GSK is good news for patients and payers, since it brings in pricing as a key differentiator.