Instead of having to take HIV medication every day, what if antiretroviral treatment lasted weeks—or even months? David A. Margolis, MD, MPH, is an infectious disease specialist who has spent the last eight years as medical director of HIV drug development at GlaxoSmithKline and ViiV Healthcare, helping to oversee clinical programs from initial human tests through final testing before FDA approval. He is leading ViiV’s effort to develop cabotegravir as a long-acting HIV drug. Margolis discusses cabotegravir and other long-term options being considered.
What can you tell us about long-acting antiretrovirals?
There is only one long-acting antiretroviral currently approved for the treatment of HIV, ibalizumab, which is indicated for heavily treatment experienced patients with resistant virus. Ibalizumab is an antibody that blocks the attachment of HIV to CD4 cells, and is administered by intravenous infusion every two weeks, in combination with daily oral therapies. There are currently no completely long-acting regimens approved for HIV treatment.
The two long-acting (LA) drugs that are the most advanced in clinical development are cabotegravir (CAB) and rilpivirine (RPV) LA. CAB is an HIV integrase inhibitor and RPV is a non-nucleoside reverse transcriptase inhibitor (NNRTI), and both drugs are in development as gluteal intramuscular injections, which can be administered every month or every other month as a two-drug regimen. There are currently three ongoing Phase 3 clinical trials evaluating the safety and efficacy of this injectable regimen. Two compare the long acting regimen to standard oral therapy and the other directly compares monthly to every other month dosing. Neither CAB LA or RPV LA is approved for use at this time.
Other long-acting drugs with novel mechanisms of action in targeting HIV are in very early clinical development and will not be available for several years, if proven successful.
Why do we need LA ART?
The current treatment of HIV requires life-long adherence to a combination of oral medications. While the available treatments for HIV are very effective at controlling viral replication, several challenges remain for patients living with HIV. Three areas where patients may benefit from an LA ART (antiretroviral therapy) option are with medication adherence, freedom from pill taking and a more discreet dosing option.
Effective HIV treatment requires continual drug levels to prevent HIV replication, necessitating strict adherence to medicines. Some patients have difficulty taking daily medications and a less frequent dosing option may improve overall adherence, and treatment outcomes. In patients who already maintain good overall compliance with pills, there may be a desire to reduce the number of pills taken on a daily basis.
Additionally, having a pill bottle or bottles with HIV medication may make it harder to maintain privacy around an HIV diagnosis. By shifting dosing of HIV medicines from the patient’s home to the health care provider’s office, some patients may feel that they have greater control over their diagnosis, and from unwanted disclosures. The more frequent interactions with the health care team to receive LA ART does come with a greater time commitment from the patient, but could also have advantages in re-enforcing linkage and retention in care.
Ultimately, the goal for HIV treatment is to provide patients with as many safe and effective options as possible, allowing for people living with HIV to choose the option that will work best for their lives, while protecting their health over time.
What have we learned about how people feel about using LA ART? Are long-acting agents used for treating other conditions?
Until now, LA ART has been a theoretical concept for patients living with HIV. There have been a number of surveys looking at the preferences of patients for various treatment options. One recent survey by Weld and colleagues evaluated interest in long-acting antiretrovirals in 303 young people (13–24 years old) living with HIV in the U.S. This survey showed that 88% of these patients reported a probable or definite willingness to use LA ART. Other studies have shown a similar level of interest in injectable dosing options for HIV, including once-monthly dosing.
The largest experience we have to date in patients actually taking LA ART comes from the Phase 2b LATTE-2 study, which evaluated every 4 week or every 8 week dosing with CAB + RPV LA, compared to once daily oral dosing in 286 individuals with suppressed HIV virus (HIV-1 RNA VL <50 c/ml). Preference data from this trial through both 48 and 96 weeks showed a high level of satisfaction with LA therapy and a high percentage of the study participants stated a desire to continue with LA dosing beyond week 96. LATTE-2 was the precursor study to the ongoing Phase 3 trials with CAB + RPV LA.
Long-acting therapies have been used successfully in other therapeutic areas. One notable area is hormonal contraception, where various forms of long-acting contraceptive agents (injectables, implants, IUDs) provide a wide array of options for women seeking to prevent or delay pregnancy. Additionally, there are a number of long-acting antipsychotic medications which have proven beneficial for the treatment of mental health disorders.
How will injections be administered if CAB/RPV-LA is approved?
Cabotegravir and rilpivirine are administered as gluteal intramuscular injections, at separate injection sites. The ATLAS and FLAIR Phase 3 studies are evaluating once-monthly CAB + RPV LA dosing. A third Phase 3 study, ATLAS-2M, is being conducted to evaluate an every two month dosing option, when compared to monthly dosing.
Do you believe there is a sweet spot for frequency of dose?
There will likely be several factors a patient will need to consider when deciding to initiate LA ART therapy. The largest difference for them will be trading away pharmacy prescriptions for more frequent visits to their health care provider to receive injections. For patients who are interested in moving off of daily oral therapy, the frequency of these visits, and their ability and flexibility to set a routine around monthly or every other month clinic visits, may define their level of interest. Most of the patient survey data on LA ART to date suggests that injections administered at least monthly would reach that threshold where patients would consider initiating an LA ART regimen.
What has surprised or excited you the most when doing your research on LA ART?
The most meaningful area of this research for me has been learning about the persistent struggles and challenges that people living with HIV bear, even in the age of highly effective oral treatment options. One area where LA ART has the potential to impact patient lives is in providing them a sense of freedom from their daily reminder of HIV that can come with pill taking. LA ART could also increase options for maintaining greater discretion over their diagnosis and may allow patients to travel more freely, without having to carry or refill prescriptions. Providers will be able to consider some of these additional challenges that patients bear in their daily lives, when these may become more evident as different treatment modalities become available.
What other forms of long-acting agents are being looked at other than injectables?
In addition to injectable therapies, there are very early research efforts looking at either dissolvable or non-dissolvable medication implants, similar to those currently being used for hormonal contraception.
What can you tell us about long-acting PrEP?
There is considerable interest in looking for medications to complement daily oral Truvada for use as PrEP (pre-exposure prophylaxis). There is a large body of data supporting the efficacy of Truvada for preventing the acquisition of HIV in men and women who are at risk of acquiring HIV. One of the biggest challenges identified in these trials is the variable adherence to oral medications that was observed, limiting the overall effectiveness of this approach. Long-acting PrEP may overcome some of these hurdles. Intravaginal cervical rings containing dapivirine, an NNRTI, have been evaluated in large Phase 3 trials and continue to be researched in open label extension studies. CAB LA is currently being evaluated as a once every 2 month injection in two large, global Phase 3 trials in men and women to determine the safety and efficacy of this approach, relative to daily oral Truvada, for preventing the acquisition of HIV. Neither dapivirine rings or CAB LA are approved for use as PrEP at this time.
David A. Margolis, MD, MPH, is an Infectious Diseases trained physician. He is lead physician for the cabotegravir long-acting clinical development program at ViiV Healthcare. Raised in southern California, he attended Duke University medical school and completed a combined Master’s in Public Health at the University of North Carolina, Chapel Hill and an ID fellowship at the University of California, San Diego. He is also medical director of HIV drug development at GSK and ViiV Healthcare, and continues to see patients on a weekly basis as an assistant consulting professor in infectious diseases at Duke University.