June 15, 2016
7 min read

Injectable antiretrovirals: The future of HIV management?

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HIV therapy has dramatically improved over the past few decades due to advances in new drug discoveries and reformulations allowing for simple oral regimens. These advancements have helped to combat resistance and reduce pill burden for patients. Once-daily antiretroviral regimens are quickly becoming new standards for new patients; however, adherence is still a concern. But what if patients no longer had to take a pill every day? This could be possible with the new, long-acting injectable antiretrovirals cabotegravir and Edurant.

Kimberly D. Boeser

Bethanne Carpenter

Dynamic duo

The components of the injectable regimen consist of a non-nucleoside reverse transcriptase inhibitor (NNRTI), Edurant (rilpivirine, Janssen Therapeutics), and a new integrase strand transfer inhibitor (INSTI), cabotegravir (ViiV Healthcare). Rilpivirine is a second-generation NNRTI approved in 2011 for the indication of treatment-naive patients with HIV-1 RNA less than 100,000 copies/mL. Its increased potency, longer half-life (oral: 50 hours; intramuscular: 20-40 days) and reduced adverse effect profile in comparison with a first-generation NNRTI such as Sustiva (efavirenz, Bristol-Myers Squibb) made it ideal to combine with the new INSTI.

The discovery of integrase inhibitors in the late 2000s was pivotal for drug regimens as these agents were associated with few adverse reactions and were very effective for treatment-naive patients. Despite being new agents, Isentress (raltegravir, Merck) and Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, Gilead Sciences), already have documented resistance in treatment-naive and previously treated patients, thus prompting the development of the second-generation Tivicay (dolutegravir, ViiV Healthcare), an INSTI that is more sustained against resistance and has an improved administration profile. Cabotegravir, a potent analog of dolutegravir, possesses a long half-life (oral: 40 hours; intramuscular: 30-90 days), allowing for once-daily dosing with no need for a booster.

LATTE trial

In 2015, the Long-Acting antireTroviral Treatment Enabling (LATTE) trial, a phase 2b study, tested the combination of the new INSTI with the NNRTI as a once-daily oral maintenance regimen after induction therapy. This was a randomized, multicenter, parallel-group, partly masked induction and maintenance study. Participants were aged older than 18 years, treatment-naive, diagnosed with HIV-1 and had at least 1,000 copies/mL and a CD4 count of at least 200 cells/L. These patients were randomly assigned in a 1:1:1:1 ratio to groups receiving the following combinations: cabotegravir (n = 181) 10 mg, 30 mg, 60 mg or efavirenz (n = 62) 600 mg once-daily regimens paired with the investigators’ choice of NRTI backbones, including Epzicom (abacavir/lamivudine, ViiV Healthcare) or Truvada (emtricitabine/tenofovir disoproxil fumarate, Gilead Sciences). A maintenance phase of the study occurred when patients completed 24 weeks of therapy and achieved viral suppression (HIV RNA < 50 copies/mL) before transitioning to the combination of cabotegravir and rilpivirine 25 mg daily for an additional 72 weeks. This was compared with a full 96 weeks of the triple regimen group with efavirenz.

By the end of 24 weeks, a robust response was observed with 86% patients in the cabotegravir groups vs. 74% in the efavirenz group. Additionally, a significantly shorter time to viral suppression in the cabotegravir group was reported (P < .0001). The primary outcome of the proportion of patients with HIV-1 RNA less than 50 copies/mL at weeks 24 and 48 was higher in the cabotegravir group (82%) than in the efavirenz group (71%). Viral suppression was sustained in 76% of participants in the cabotegravir group vs. 63% in the efavirenz group after 96 weeks of therapy. Virologic nonresponse was documented in 10% of participants in the cabotegravir group — nine (15%) in the 10-mg group, six (10%) in the 30-mg group and three (5%) in 60-mg group. Overall nonresponse in the cabotegravir group was still lower than the efavirenz group with 10 (16%).


Very few patients discontinued therapy due to adverse events or death — 3% in the cabotegravir group compared with 13% in the efavirenz group. Common adverse events (> 10%) were headache, nausea and diarrhea for cabotegravir, and dizziness, abnormal dreams, nausea, fatigue and insomnia for efavirenz. Ten percent of participants in the cabotegravir group discontinued treatment for other reasons (protocol deviation, loss to follow-up, investigator discretion, lack of efficacy despite viral load < 50 copies/mL, and withdrawal of consent) vs. only 6% in the efavirenz group.

The study showed that sustained viral suppression can be achieved with a two-drug regimen of cabotegravir and rilpivirine after induction with triple therapy. Only one patient was documented to develop treatment-emergent resistance mutations (Q148R and E138Q) at week 48, which coincided with low concentrations of cabotegravir and rilpivirine. Based on the results of the study, cabotegravir 30 mg was selected as the dose to combine with rilpivirine. With the success of the dual oral maintenance regimen, the development of injectable formulations of this combination was initiated.

LATTE II trial

In February, the investigators of LATTE presented 32-week results of the long-acting injectable nanosuspension at CROI 2016. The study investigated the safety and efficacy of the intramuscular regimen of cabotegravir and rilpivirine as maintenance therapy in comparison to triple ART with cabotegravir and abacavir/lamivudine. This was a phase 2b study to determine the efficacy and safety of long-acting nonsuspensions. During the induction phase of the study, participants received an oral regimen of cabotegravir and abacavir/lamivudine for 20 weeks, and the addition of rilpivirine for the last 4 weeks, to achieve viral suppression. The maintenance phase transitioned participants in a 2:2:1 fashion to either an injection regimen of cabotegravir and rilpivirine every 4 weeks or every 8 weeks, or they continued with a triple oral regimen of cabotegravir and abacavir/lamivudine. The injections were administered in the gluteal region when participants visited the clinic at the designated weeks.

The median age of participants included in this study was 35 years, they were primarily male (92%), with a median CD4 count of 489 cells/mm3. Only 18% of participants had a viral load of at least 100,000 copies/mL at initiation of therapy. A notable virologic success rate was reported for both the 4-week (109/115, 94%) and 8-week (108/115, 95%) injection regimens compared with the oral regimen (51/56, 91%). Very few patients had virologic nonresponse due to RNA greater than 50 copies/mL — 1/115 (0.9%) in the 4-week arm, 3/115 (2.6%) in the 8-week arm and 1/56 (1.8%) in the oral arm. Thus far, only 10 patients have discontinued treatment due to adverse events or other reasons such as pregnancy or loss to follow-up.

The most common adverse events included injection site pain (67%), swelling (7%) and nodule formation (6%). The reporting of these reactions dramatically decreased from 86% on the first visit to approximately 30% on subsequent visits. Thus far, other adverse events not related to injection site reactions are minimally reported, most common ( 3%) being pyrexia, fatigue and influenza-like illness, which only occurred in 2% to 3% of each arm.

A greater number of participants reported satisfaction with the maintenance injection regimens than with the oral regimen. Patients were asked whether they were “more” satisfied or “less” satisfied with current treatment and the level of their satisfaction in continuing their present form of treatment. In the 4-week and 8-week injection arms, 96% to 98% responded they were more satisfied to both of these questions, while only 71% responded they were “more” satisfied with the oral regimen. Under the current protocol, patients are required to visit the site for administration of the injection into the gluteal area, but other areas such as the thigh could be explored as potential administration sites.


Lastly, the pharmacokinetic profiles of the injectable agents are favorable, displaying sustained plasma levels of the drugs similar to the oral regimens. Concentrations of the cabotegravir injection fell within range of the established plasma concentration of a daily oral regimen of 10 mg and 30 mg. Rilpivirine injection showed slightly lower plasma concentrations initially, but rose to established levels similar to an oral regimen by week 12. There appears to be an accumulation effect by week 32, when levels were measured as higher than those from oral administration. Further study will reveal the clinical significance of this trend, but current plasma concentrations of the rilpivirine injection are well below levels associated with severe adverse events such as QT prolongation.

In conclusion, both injectable regimens of cabotegravir and rilpivirine (every 4 weeks and every 8 weeks) appear to be effective and safe for maintenance therapy as compared with the oral regimen of cabotegravir and abacavir/lamivudine. Data from week 48 are yet to be reported but will help establish the final regimen for the injection maintenance therapy.

Impact of an injectable regimen

Current results appear promising for this new injectable therapy option. It is unique to have a two-drug regimen for maintenance therapy of HIV, but thus far development of resistance does not appear significant. The utility of an injection could pose several challenges for the patient. Adherence may continue to be an issue given that the initial induction phase is similar to many other current once-daily oral regimens. Patients still need to prove adherence to the oral regimen before starting an injectable maintenance therapy. Additionally, adherence to an injectable may pose its own setbacks. While satisfaction was reported to be high, it may be unfavorable to request that patients visit the clinic every 1 to 2 months when it could be reduced to once- or twice-yearly visits. If patients are able to administer the injections at home, this regimen could be a game-changer for those who are nonadherent. However, a gluteal injection may be too complicated for self-administration. The company expressed the possibility of investigating administration of the thigh, which sounds very reasonable as a new standard regimen. Lastly, the cost of these injectables will be another debate as current oral regimens are well-covered by insurance companies. The price of these new formulations is not currently available, but to incentivize use, they will likely need to be comparable to oral regimens. The question becomes, “How much are patients and insurance companies willing to pay for a regimen such as this?”

More results from the phase 2b study and a future phase 3 study will determine if this is a feasible therapy regimen from an efficacy and safety standpoint. The once-daily, triple-therapy oral regimens show good tolerability and low resistance rates, making this regimen fit within the current standards. The major appeal to an injectable regimen would be the potential for improved adherence. This could dramatically change a patient’s quality of life as they are able to return to a pill-less (or at the least, a lower pill burden) life.

Disclosures: Boeser and Carpenter report no relevant financial disclosures.