The emergence of dual drug therapy

Potent combination anti-HIV therapy (ART) became available in 1996 in Canada and other high-income countries. The arrival of ART marked an important turning point in the history of the HIV pandemic: for the first time, treatment was able to durably suppress HIV levels in the blood, allowing the immune system to partially rebuild itself. As a result, many ART users experienced sustained recovery from life-threatening infections, inexorable weight loss and AIDS-related cancers. These effects of ART are so profound that researchers expect that many ART users will have near-normal life expectancy.

Grappling with complexity

In 1996 and for many years after, initial ART regimens were complex, consisting of multiple pills taken two or three times daily, oftentimes with food restrictions. Furthermore, these early regimens had unpleasant, sometimes distressing side effects.

The combinations of ART that became the mainstay in 1996 and thereafter set the standard for what was considered an acceptable treatment regimen: a combination of three or four drugs. Each regimen was anchored by a powerful drug such as a protease inhibitor or a non-nuke (non-nucleoside reverse transcriptase inhibitor; NNRTI). In first-line therapy today, the anchor drug in a regimen is usually an integrase inhibitor. Integrase inhibitors are powerful, generally well tolerated, and tend to have fewer drug interactions than other anchor drugs.

A move toward simplification

Some pharmaceutical companies are beginning to challenge the concept of triple- or quadruple-drug regimens for HIV. For instance, Viiv and Janssen have collaborated on a treatment that pairs the integrase inhibitor dolutegravir (Tivicay and also found in Triumeq) with the non-nuke rilpivirine (Edurant and in Complera) in a pill called Juluca.

Juluca is meant to be used as part of induction-maintenance strategies. That is, doctors first prescribe a more complex three- or four-drug regimen (induction phase) to suppress a person’s viral load. Once this happens and the person’s viral load continues to be suppressed, the regimen can be changed to Juluca (maintenance phase).

The use of induction-maintenance treatment is also being explored in phase III clinical trials with long-acting formulations of two drugs: the experimental integrase inhibitor cabotegravir and the non-nuke rilpivirine. These drugs are injected into the buttocks, where they are slowly released into circulation. Prior to starting the injectable formulations, patients are first started on oral formulations of triple therapy that includes rilpivirine and cabotegravir. The oral formulations are taken for about six months to ensure that there are no problems tolerating these drugs when the injectable formulations are used later on.

There are rumours that a powerful and long-acting experimental nucleoside analogue code-named MK-8591, made by the pharmaceutical company Merck, may be paired with another HIV medication for yet another dual-drug option for HIV treatment in the future.

Back to initial treatment

Although the examples provided above are about induction-maintenance, one pair of drugs is being tested for the initial treatment of HIV: dolutegravir + 3TC (lamivudine). Dolutegravir is a powerful integrase inhibitor and 3TC is a nuke that has a good track record of safety over the past 25 years. In clinical trials, initial treatment with the combination of dolutegravir + 3TC has similar effectiveness to a combination of dolutegravir + Truvada (tenofovir DF + FTC).

As several dual-drug regimens are being developed, their eventual licensure is likely to have an impact on HIV treatment guidelines in high-income countries. When helping patients choose a regimen, doctors have to balance many factors, including at least the following:

• the presence/absence of HIV that has partial or full resistance to a drug or class of drugs
• tolerability
• the ability to take pills every day
• interactions with medicines used to treat other common conditions (such as high blood pressure, type 2 diabetes, abnormal cholesterol levels, depression, sleeping problems, etc.). In general, integrase inhibitors tend to have the fewest interactions with other drugs.

HIV is a chronic infection that is kept under control with ART. Will dual-drug regimens provide long-lasting control? So far, clinical trials of dual drug regimens that have been tested for two years (such as Juluca) suggest that is the case. Two-year results from trials of dolutegravir + 3TC are eagerly awaited.

If the two-year data for dolutegravir + 3TC as initial HIV therapy are robust, doctors and patients will have to reckon with another challenge to the received wisdom accumulated since 1996—that dual-drug regimens may be, in some circumstances, as good as standard triple or quadruple therapy for the initial treatment of HIV. Changing accepted practices in medicine is not easy. Many patients and their doctors feel comfortable and safe with triple-drug therapy. Thus, the use of dual regimens will likely happen slowly over time. As more data from clinical trials accumulate, doctors and their patients may gain more confidence about the use of dual drug therapy for HIV.

—Sean R. Hosein