The Future of 2-Drug Regimens for People With HIV

Josep M. Llibre, M.D., Ph.D.
Josep M. Llibre, M.D., Ph.D.
Myles Helfand

Triple-drug antiretroviral regimens have achieved unprecedented rates of treatment success. They are available as once-daily single-tablet regimens and are preferred strategies both in initial and simplification/switch regimens.

However, the maintenance of virological suppression can be achieved with less powerful regimens than are required in initial therapy. This has been proven with regimens that have been successful in this scenario but not in initial therapy. Among these regimens are unboosted atazanavir (Reyataz), boosted protease inhibitor (PI) monotherapy and rilpivirine (Edurant) in treatment-naive patients with high viral loads. Standard triple-drug regimens based on dolutegravir (Tivicay, DTG) or elvitegravir (Vitekta) with cobicistat (Tybost) are equally effective in initial treatment or simplification.

Reducing the number of drugs in a regimen lowers long-term drug exposure and potential drug toxicity or drug interactions, as well as protecting the activity of the drugs spared for the future. However, we must be very demanding with these new two-drug (or single-drug) regimens due to the safety and efficacy achieved with current triple-drug regimens.

After reports of lower-than-expected virological efficacy and the consequent interruption of some randomized studies by Data and Safety Monitoring Board committees, boosted-PI monotherapy is no longer a recommended strategy.

Interest is thus focused on two-drug regimens. Some rules must be met before their use in the clinic due to both scientific evidence and ethics issues:

  • The drugs included should be preferred drugs with lower toxicity proven in their pivotal trials.
  • There should be low potential for drug-drug interactions.
  • The regimen should have demonstrated non-inferiority in the main efficacy endpoint in a fully powered randomized clinical trial with a real active control arm.
  • The regimen should be associated with a potential benefit for the patient.
  • The cost-efficacy ratio of the regimen should be similar or better than the standard triple-drug regimen.

So far, the two-drug regimens closest to meeting these features include a boosted PI plus lamivudine (3TC, Epivir), as shown in the SALT trial, the ATLAS-M trial, the DUAL study and the OLE study. Due to the designs of the studies, these regimens were applicable only to subjects already receiving every boosted PI in their triple-drug regimen. However, toxicity issues (worsening lipid profile and gastrointestinal adverse events, kidney issues, hyperbilirubinemia and jaundice, and a potential association with cardiovascular events) make these regimens far from optimal when compared with new triple-drug regimens including integrase strand transfer inhibitors (INSTI) and abacavir (Ziagen) or tenofovir alafenamide (TAF).

The INSTIs dolutegravir and cabotegravir have emerged as substitutes for boosted PIs as anchor drugs in two-drug regimens. They also have a high barrier against the development of resistance, as well as optimal pharmacokinetic and pharmacodynamic features. Moreover, they are administered once daily as a single pill, are formulated as parenteral long-acting drugs and do not seem to have any class-specific toxicity -- thus representing a step forward versus boosted PIs.

[Editor's note: In the spirit of full disclosure, Llibre is the lead author on "Genetic Barrier to Resistance for Dolutegravir," the study referenced above.]

Three strategies are currently under development: dolutegravir + 3TC, dolutegravir + rilpivirine and parenteral long-acting cabotegravir + rilpivirine.

Dolutegravir + 3TC

Dolutegravir + 3TC has demonstrated a high efficacy (90% at 48 weeks with viral loads below 50) in a pilot trial called PADDLE. This has paved the way for two fully powered phase-3 non-inferiority studies in treatment-naive patients: GEMINI 1 (NCT02831673) and GEMINI 2 (NCT02831764), which are fully recruited and should have results very soon. Dolutegravir + 3TC is also under evaluation as a switch strategy in the TANGO study in subjects specifically receiving a tenofovir alafanamide-including triple therapy (recruitment not yet started). Meanwhile, in a non-comparative two-step open-label trial called LAMIDOL, the strategy showed 92% of patients with therapeutic success at 48 weeks.

Dolutegravir + Rilpivirine

Dolutegravir + rilpivirine has demonstrated non-inferiority in two phase-3 switch studies known as SWORD 1 and SWORD 2, with 95% efficacy at 48 weeks.

[Editor's note: Llibre is the lead author on SWORD 1 and SWORD 2, the studies referenced above.]

The study has a real active control arm with triple-drug regimens based on current INSTIs, PIs or non-nucleoside reverse transcriptase inhibitors (NNRTIs), plus two nucleoside reverse transcriptase inhibitors (NRTIs) also known as "nukes." Subjects switching to this two-drug regimen experienced a significant benefit in bone biomarkers. Only one out of 513 study participants experienced virologic failure with a NNRTI mutation and no one developed integrase resistance mutations. The incidence of discontinuation due to adverse events at week 48 was higher in the two-drug regimen arm (3% versus 1%). Sub-studies evaluating bone, kidney, lipid profile, cardiovascular health and health-related quality of-life are ongoing. A fixed-dose combination tablet of dolutegravir/rilpivirine at 50/25 mg has demonstrated bioequivalence. Regulatory submission is being evaluated in the European Medicines Agency and the U.S. Food and Drug Administration for this single-tablet once-daily two-drug regimen, which, if approved, would be the first of its kind to enter routine clinical practice.

Long-Acting Cabotegravir + Rilpivirine

Parenteral long-acting cabotegravir + rilpivirine is being evaluated only as a switch strategy. It has shown non-inferiority to oral cabotegravir (at 30 mg) + abacavir/lamivudine (Epzicom, Kivexa) in the LATTE-2 study, which evaluated switching from the oral regimen to long-acting cabotegravir + rilpivirine administered as an intramuscular injection either once every four weeks (4W) or once every eight weeks (8W). At week 48, the efficacy rate was 91% for the 4W group and 92% for the 8W group, compared with 89% of participants who stayed on the oral regimen. Only one participant (who was in the 8W group) out of 230 participants developed drug resistance against both dolutegravir (Q148R) and rilpivirine (K103N, E138G and K238T). Due to pharmacokinetic concerns, enthusiasm about the frequency of administration has been tempered, and long-acting cabotegravir + rilpivirine is being evaluated only as a once-every-four-weeks regimen in the phase-3 FLAIR (which will compare with abacavir/dolutegravir/lamivudine [Triumeq]) and ATLAS (which will compare with any triple-drug regimen) studies. The long terminal pharmacokinetic tail of these drugs will pose serious challenges to resistance development if patients undergo an uncontrolled treatment interruption with extended periods of subtherapeutic drug concentrations.

None of these two-drug regimens has yet been compared against TAF-based triple-drug regimens, but all of these will probably show tubular kidney and bone health benefits in subjects discontinuing TDF (tenofovir disoproxil fumarate, Viread), which has already been shown in switch studies of TDF-based regimens to TAF-based regimens.

In the near future, long-term data on TAF (beyond three years), pharmacoeconomic issues and the yet-to-be-proven benefits of two-drug regimens will improve our understanding of the landscape of two-drug regimens.

Josep M. Llibre, M.D., Ph.D., is a senior consultant physician at the Infectious Diseases Department of the Hospital Universitari Germans Trias i Pujol, in Barcelona, Spain. He is a member of the Panel of the Spanish Antiretroviral Treatment Guidelines, and consultant of the Catalan Health Service in antiretroviral treatment, and collaborates on peer reviewing with many top medical journals. He is widely published and lectures both at international and domestic levels, and is involved in HIV medical educational training in Spain and other European, as well as Asian countries. In the past, Llibre has received funding for research or payment for conferences or participation on advisory boards from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, Merck Sharp & Dohme and ViiV Healthcare.