Antiretroviral therapy: Time to change the paradigm?

Many patients with HIV infection receive triple therapy. However, according to a session at IAS 2021, modern regimens with two active agents are not inferior to this strategy.

Comparison of two-drug regimens and three-drug regimens

Many patients with HIV infection receive triple therapy. However, according to a session at IAS 2021, modern regimens with two active agents are not inferior to this strategy.

A brief review: From 1986, patients with HIV infection received azidothymidine. Highly active antiretroviral therapy (HAART) from 1996 finally brought the breakthrough in controlling HIV. The protease inhibitors indinavir and ritonavir were approved for this purpose. And with nevirapine, the first non-nucleoside reverse transcriptase inhibitor was available. At the end of 2000, zidovudine, lamivudine and abacavir were finally approved as a triple combination. In the meantime, there are several other pharmaceuticals. At IAS 2021, Prof. Dr. Jennifer Hoy from Monash University explored the question of the significance of dual or triple combination therapies - and where the journey will lead.

Professional societies mostly recommend three-drug regimens

"In 2021, physicians usually prescribe two nucleoside reverse transcriptase inhibitors and a third substance, such as an integrase inhibitor, as initial antiretroviral therapy," Hoy said. This strategy is found in guidelines from the World Health Organisation (WHO), the European AIDS Clinical Society, the US Department of Health and Human Services (DHHS) and the International Antiviral Society. "There are quite a few fixed combinations in tablet form, which makes it easier for patients to take them," the speaker emphasised. "Although these therapies are effective and well tolerated, experts are discussing regimens with two active ingredients," says Hoy.

Do two-drug regimes bring advantages?

The idea behind it: Patients with HIV infection take drugs for the rest of their lives. Fewer drugs could reduce the long-term risk of unwanted toxic effects. Hoy mentions dolutegravir plus lamivudine as options for initial treatment: A combination that is also suitable for maintenance therapy. For long-term treatment, she also mentions boosted protease inhibitors plus lamivudine, dolutegravir plus rilpivirine or long-acting cabotegravir plus rilpivirine.

Two-drug regimens are not suitable for all HIV-infected people because of pharmacokinetics, but also partly because of a lack of data. Patients with chronic hepatitis B, pregnant patients, with known resistance to one of the active agents, with missing information about the HIV genotype, with a viral load of more than 500,000 copies per millilitre, with a CD4 cell count of less than 200 per microlitre or with therapy start immediately after diagnosis should be excluded.

Studies show non-inferiority of the two-drug regimen

But what is the data situation in suitable patients? Hoy cites the GEMINI-1 study, for example. Here, a total of 719 patients were assigned to treatment with dolutegravir/lamivudine (N = 359) or with dolutegravir/emtricitabine/tenofovir disoproxil fumarate. There were no significant differences between the two treatment arms in terms of suppression of HIV, CD4 cell count or minimal residual viraemia. Patient adherence was also comparable. "So far, however, we lack comparisons between the two regimens with regard to side effects," says the speaker.

Further information comes from the TANGO study (dolutegravir/lamivudine versus triple therapy) and the SWORD study (dolutegravir/rilpivirine versus triple therapy). There was no evidence of disadvantages of the two-drug regimen in terms of minimal residual viraemia, in terms of greater CNS involvement in infection or in terms of viral load in the genital area.

Health economic aspects

However, the speaker sees major differences with regard to costs. Generic tenofovir disoproxil fumarate/lamivudine/dolutegravir costs 59 US dollars (50 euros) per person per year on the world market. The "UNAIDS 95/95/95" target stipulates that by 2030 at least 95 percent of people with HIV should know about their infection, at least 95 percent of them should receive appropriate medication and at least 95 percent of those treated should be successfully treated. This requires two billion US dollars (1.70 billion euros) per year, which is hardly affordable, Hoy comments.

In the USA, the dolutegravir/abacavir/lamivudine regimen costs 38,628 US dollars (32,737 euros) per person per year. If one theoretically replaced every second treatment with dolutegravir/lamivudine, one could save 800 million US dollars (678 million euros) in five years.

Conclusion: Two-drug regimes suitable in many cases

In summary, the expert sees advantages in the two-drug regimen. This strategy, she says, is similarly effective and similarly well tolerated as the three-drug regime, and at lower cost. A third agent is unnecessary in many - but not all - cases.

International AIDS Society Conferences (IAS) 2021, Session "Antiretroviral therapy: Time to change the paradigm?", 20 July 2021.