Combination antiretroviral therapy (ART) with three drugs has been the standard of care for almost two decades. While the efficacy of triple therapy is well-established, there are increasing concerns about long-term toxicities of the drugs, particularly in patients with comorbid illnesses like renal and cardiovascular disease. Margolis and colleagues compared the ability to maintain viral suppression of a two-drug regimen including cabotegravir, a integrase inhibitor and structural analogue of dolutegravir, and rilpivirine with conventional three-drug efavirenz-based ART.

The LATTE study was a phase 2 industry-sponsored, multicenter, randomized clinical trial that enrolled adults aged 18 years and older with HIV-1 RNA copies of at least 1000 per mL, a CD4 count of at least 200 per μL, were ART naïve, and had no major drug resistance mutations. In the initial induction phase of therapy, patients were randomized to receive oral cabotegravir (an integrase inhibitor) 10 mg once a day, 30 mg once a day, 60 mg once a day, or efavirenz 600 mg once a day with investigator-selected background NRTI (abacavir-lamivudine or tenofovir-emtricitabine). After 24 weeks, patients who received cabotegravir and had viral suppression (i.e., plasma HIV RNA levels < 50 per mL) had their NRTIs replaced with rilpivirine for an additional 72 weeks. Patients randomized to the efavirenz group continued NRTIs through the end of week 96. The primary endpoint of the study was the proportion of patients with HIV RNA copies < 50 per mL at week 48.

A total of 244 patients were randomized to the four treatment groups. For the primary endpoint, at 48 weeks 82% of patients in the cabotegravir group were virologically suppressed (95% confidence interval [CI]; 77-88) compared to 71% (95% CI; 60-82) in the efavirenz group. After 72 weeks of two-drug maintenance therapy, 76% of those given cabotegravir and rilpivirine and 63% continued on efavirenz plus dual NRTIs were virologically suppressed. Furthermore, there were more virological non-responders in the efavirenz group compared to the two-drug group (16% vs. 10%, respectively). After 24 weeks of maintenance therapy (week 48), the median increase in CD4 count from baseline was 219 cells per μL (141-343) in the two-drug group and 216 cells per μL (133-363) in the efavirenz group. Five patients had virologic failure: two in the cabotegravir 10 mg group, one in the 30 mg group, and two patients in the efavirenz group.

Two of the three patients in the cabotegravir-rilpivirine group were found to have the NNRTI resistance mutations K101K/E and E138E/A, while the third was lost to follow-up. Headache was reported in 22% of patients in the cabotegravir groups, compared with 11% in the efavirenz group. There was no association between the dose of cabotegravir and headache incidence. Serious adverse events occurred in 10% of the cabotegravir-treated patients, none of which were determined to be related to the drug, while 6% occurred in the efavirenz group, including one suicide attempt.

COMMENTARY

This study provides evidence for a potential paradigm shift in the treatment of HIV. Until now, experts, including those who write the HIV treatment guidelines, have considered dual therapy inferior to triple therapy for viral suppression. The LATTE trial has shown that the two-drug regimen of cabotegravir and rilpivirine is at least as effective as efavirenz and dual NRTIs for maintaining viral suppression. Avoiding tenofovir disoproxil fumarate (TDF) would help mitigate bone loss and nephrotoxicity, while avoiding abacavir could reduce the risk of cardiovascular disease. Cabotegravir was well-tolerated in the trial, with side effects similar to efavirenz in incidence and severity. Interestingly, the company developing cabotegravir has used the LATTE study to prove the concept that dual therapy is effective so they can further develop cabotegravir as a long-acting intramuscular (IM) injection. As noted in an accompanying commentary, both cabotegravir and rilpivirine have long pharmacokinetic half-lives, and theoretically a single combination injection of both drugs could be a powerful addition to the ART arsenal.1 Thus, the LATTE study may prove to be the seminal trial that ushered in the era of dual maintenance therapy, as well as laid the foundation for long-acting therapy.

As with all phase 2 trials, the LATTE study was not powered to make definitive conclusions about the performance of the experimental regimen. Therefore, additional trials (e.g., phase 3) are necessary before dual therapy for maintenance viral suppression can be advocated. Another limitation to the study design is that neither the patients nor the investigators were blinded as to whether the participants received efavirenz or cabotegravir, which may have affected the rate of patient retention and reporting of adverse events.

The LATTE-2 trial evaluating intramuscular cabotegravir and rilpivirine is currently underway. Long-acting IM injections might improve adherence and have the potential to be used for pre-exposure prophylaxis. However, sustained viral suppression, i.e., for years, must be the standard by which IM-ART is judged. Results from LATTE-2 are eagerly awaited.

REFERENCE

  1. Boyd MA, Cooper DA. The LATTE study: A provocative brew. Lancet Infect Dis 2015;15:1116-1117.