December 8, 2013
Modern antiretroviral therapy is simple, potent and generally well tolerated. However, the need to take medication daily to suppress HIV replication has remained immutable. As therapy has progressed to the minimalistic, is the next step in antiretroviral therapy evolution something that need not be taken every day?
The NNRTI rilpivirine (Edurant) and GSK1265744 (also called 744), an integrase inhibitor in development, have both been formulated as nano-suspensions that once injected achieve therapeutic drug levels for weeks -- offering a potential injectable long-acting option for HIV treatment.
Whether these two antiretrovirals can maintain suppression of viremia is being studied in the LATTE trial, in which 744 was administered orally along with tenofovir/emtricitabine in treatment-naive patients at three doses. For those achieving viral suppression by week 24, the tenofovir/emtricitabine is jettisoned and oral rilpivirine added -- emulating the dual therapy that would be administered with future long-acting injectables of each drug. A control arm of efavirenz plus two NRTIs provides comparison.
The results of the first phase of LATTE were presented at the European AIDS Conference (EACS) this year and were impressive with 87% of the participants receiving 744 achieving a viral load of less than 50 copies/mL at week 24 compared to 74% of those in the efavirenz control arm. This is a good sign that 744, an analogue of dolutegravir, is a viable antiviral. Results of the second phase, following the switch to rilpivirine/744, are expected shortly and a follow-up study of the actual injectable formulations is about to launch.
A separate study presented at the International AIDS Society meeting in Kuala Lumpur, Malaysia, showcased the long life of the active drugs following injection in HIV-uninfected patients. Injection (subcutaneous or intramuscular) of 744 monthly or quarterly was able to achieve persistent levels of the drug above the protein binding-adjusted IC90 of wild type HIV. Monthly intramuscular injections of rilpivirine produced levels comparable to oral dosing of the drug at 25-mg daily. Injection site reactions were common with both agents (100% for 744 and 80% for rilpivirine), but were described as mild.
One of two things will happen: long-acting injectable formulations of antiretroviral therapy will be a big deal or they will not. My bet is that they will, and here is why.
Although treatment has become simple relative to the antiretroviral therapy of days gone by, people living with HIV would rather not be taking any medication at all. Zero. Zip. Long-acting injectables are the next step in a movement to make the treatment of HIV so effortless that it minimizes the impact of being infected -- "If I need only one pill a day, my HIV must not be that bad."
It will not be for everyone, but more than a few patients will jump at the chance to ditch their pillboxes and sign up to get a shot or two once a month. Long-acting therapy also offers an opportunity to truly monitor adherence, and will be a natural fit for those who may have challenges taking pills, especially those who are in semi-monitored settings where injections are feasible (i.e., opioid replacement clinics).
There are some kinks to work out. An oral lead-in phase will be necessary to assure that there are no serious adverse reactions to the agents before they are loaded into the body where they will circulate for months. The dynamics of drug resistance when injections are missed and drug levels slowly dissipate need to be worked out, as this risk can be a serious drawback of this strategy. Lastly, injection site reaction severity needs to be understood given the enfuvirtide (T-20, Fuzeon) experience.
Overall, this can be a revolutionary advance for HIV care and prevention (studies looking at these medications as PrEP [pre-exposure prophylaxis] are happening) and if these agents make it through the clinical trial proving ground, they can usher in entirely new ways for therapy to be delivered to our patients.
What are some other top clinical developments of 2013? Read more of Dr. Wohl's picks.
David Alain Wohl, M.D., is an associate professor of medicine in the Division of Infectious Diseases at the University of North Carolina and site leader of the University of North Carolina AIDS Clinical Trials Unit at Chapel Hill.
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