Cutting Down HIV Treatment to a 2-Drug Regimen

An estimated 1.2 million people in the United States are currently living with the human immunodeficiency virus-1 (HIV-1).¹ There are currently no cures or vaccines to prevent HIV but the availability of antiretroviral therapy (ART) has significantly decreased HIV-associated morbidity and mortality. Moreover, HIV has become a chronic, long-term condition in many parts of the world thanks to the availability of more than 20 approved anti-HIV drugs targeting different steps in the viral life cycle. While they do not eradicate HIV, combinations of these agents routinely drive viral loads down to undetectable levels.¹

Combination ART is resulting in longer lifespans and simplified medication regimens are needed to reduce pill-burden in an aging population with HIV. Two-drug regimens are potentially attractive because they may minimize drug exposure; reduce risks for adverse effects, drug-drug interactions, and long-term toxicities; and potentially increase patient adherence. Previous studies using two-drug regimens have had mixed results.² Many of these studies were too small or too short to support robust conclusions. The success of any two-drug regimen likely depends on choosing drugs with complementary therapeutic, pharmacokinetic, and pharmacodynamic properties.

Current treatment guidelines for adults with HIV-1 infection recommend HAART regimens comprising of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a third drug from either the boosted protease inhibitor (PI), integrase strand transfer inhibitor (INSTI), or non-NRTI (NNRTI) classes.³ Although effective, NRTIs are associated with long-term adverse effects that impact mitochondrial, renal, cardiovascular, and bone health.

The potency, safety, and limited resistance observed with dolutegravir make it a potentially ideal core agent for a two-drug regimen. Dolutegravir has minimal drug-drug interactions and pharmacokinetic variability. Its safety and efficacy has been extensively studied in both treatment-naïve and treatment-experienced patients.^4,5,6 Treatment-emergent resistance is not yet a concern, as dolutegravir has been shown to retain activity against most drug-resistant mutations. The favorable safety, tolerability, and potent efficacy of rilpivirine, as well as evidence suggesting compatibility with dolutegravir, make it a suitable combination in a once-daily two-drug regimen. In the SWORD-1 and SWORD-2 studies, the efficacy and safety of dolutegravir plus rilpivirine was compared with continuation of current HAART regimen for 48 weeks.⁷

SWORD-1 and SWORD-2 were identically designed multinational, open-label, parallel-group, active-control non-inferiority phase 3 studies.⁷ Participants were randomized to either continue their current anti-HIV drugs or switch to dolutegravir plus rilpivirine in an early or late switch phase. Of the 1,339 subjects initially screened, 513 patients were assigned to the early switch phase and started a once-daily regimen of dolutegravir 50 mg plus rilpivirine 25 mg. The remaining participants (n=511) were assigned to the late switch phase, starting dolutegravir plus rilpivirine only after completing 52 weeks of their current HAART regimen. Participants were at least 18 years old, had achieved viral suppression on a stable regimen of 3-4 ART drugs for at least 6 months, and had no history of virologic failure, resistance to either of the drugs in the regimen, or evidence of current Hepatitis B virus infection. Potential participants were excluded if they used a second line treatment regimen, were pregnant or breastfeeding, had severe hepatic impairment, or had a viral count higher than 50 copies/mL within 6 months prior to screening.

The primary endpoint was the proportion of participants in the intention-to-treat population with plasma viral load lower than 50 copies per mL at week 48. Secondary endpoints included measuring changes in CD4 counts, proportion of participants who discontinued treatment due to adverse events, and changes in renal, bone, and cardiovascular biomarkers from baseline.

Table  1: Baseline characteristics for Subjects Enrolled in SWORD-1/SWORD-2 Studies

Baseline characteristics between the two groups were similar (see Table 1). The subgroup analysis of the SWORD-1 and SWORD-2 studies showed that switching participants to a once daily regimen of dolutegravir plus rilpivirine was non-inferior to continuing current ART in patients who had already achieved virologic suppression by age, race and gender. ⁸ These findings are consistent with clinical trial results when dolutegravir was compared to other medications such as raltegravir, and efavirenz and darunavir.⁹

Table 2: Percentage of Patient Who Experienced an Adverse Event in SWORD-1/SWORD-2

The most frequent adverse events observed in the SWORD-1/SWORD-2 studies included nasopharyngitis and headaches (see Table 2).  Adverse effects related to dolutegravir were mild including headaches, rash, and hypersensitivity reaction. Although generally well tolerated, rilpivirine contributed to adverse events such as headaches, rash, and insomnia. These adverse events are consistent with the known side effect profiles of dolutegravir and rilpivirine. Psychiatric disorders were the most frequent reason for treatment discontinuation. More drug-related adverse events were found in the investigational arm.  It is possible that the open-label study design may have contributed to higher numbers of neuropsychiatric events in the investigational arm. Treatment discontinuation in the dolutegravir plus rilvirine group may be due to the fact that the patients in continuation arm had already established tolerance to their ART regimen.  No patients who switched to dolutegravir plus rilpivirine had detectable changes in viral susceptibility.

Strengths of this study include the assessment of multiple secondary efficacy and safety endpoints. The sample size was sufficiently large — there was 90% power to infer non-inferiority.  The inferiority margin defined (-8%) was appropriate. The investigators were able to recruit commonly under-represented populations such as women and participants aged 50 years and older. However, one significant limitation of this study was the open-label design which can potentially result in bias and impact adverse event reporting. Lastly, as the risk of drug-drug interactions and the number of comorbidities increase, it is unclear if the aging HIV population will benefit from switching to a dolutegravir plus rilpivirine combination product.

Results from the SWORD-1 and SWORD-2 studies demonstrate that dolutegravir plus rilpivirine is non-inferior to the continuation of triple therapy. These studies, which comprise the largest trial population in which the efficacy and safety of a two-drug regimen has been evaluated, provide a robust demonstration of dolutegravir plus rilpivirine for maintenance of HIV-1 suppression in treatment-experienced adults. Planned secondary analyses of long-term SWORD endpoints will provide important longitudinal data about the safety of dolutegravir plus rilpivirine as well as treatment-emergent resistance long-term.

In light of the positive results from the SWORD-1 and SWORD-2 trials, the Food and Drug Adminstration (FDA) approved Juluca^TM the first two-drug, once-daily, single pill for maintenance treatment in HIV-1 infected patients who have already achieved virologic suppression.¹⁰ The Department of Health and Human Services (DHHS) updated the Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV to reflect new recommendations for regimen switching in the setting of virologic suppression.³

Two drug regimens are poised to challenge the current standard of care. With new treatments on the horizon, the role of the ambulatory care pharmacists in the care of HIV-infected patients will likely expand. What is the future of HIV therapy and will primary care providers, including ambulatory care pharmacists, play a bigger role in managing HIV infection?