Long-Acting Antiretrovirals: The Next ‘Golden Age’ in HIV Treatment?

Even with the simplified once daily regimens, keeping the HIV virus in check has become a challenge: inconsistent adherence is causing treatment failure and resistance.

 “The holy grail of unaccomplished goals” is the development of a HIV vaccine, said Dr. Fauci in a recent interview.[1] In the absence of a vaccine, however, long-acting (LA) formulations sound like the next best solution. 

But, how do LA therapies fit in a real-world setting? Could they help end the HIV/AIDS epidemic?[2] Let’s dig in! 

 Where do we stand in HIV management?

 More than three decades after the HIV virus was discovered, the WHO reports close to 40 million people living with HIV, with the African region being most heavily impacted.[3]

 Current antiretroviral (ARV) therapy regimens consist of daily combination oral ARVs, for treatment as well as pre-exposure prophylaxis (PrEP).[4]

 These HIV treatments are highly effective… if they’re strictly adhered to.[3]

 Why long-acting (LA) treatments for HIV?

Convenience and discretion are two of the most important factors for people living with HIV when it comes to treatment. Therefore, the goal of LA treatment approaches is to produce more convenient and discreet formulations that could improve adherence and, consequently, enhance treatment outcomes.[4] 

Biotech labs worldwide are hard at work developing LA versions of existing oral HIV treatments, as well as alternative formulations like:[5] (Figure 1) 

·      injectables, 

·      implants, and 

·      topical dosage forms.

Long-acting HIV formulations could enhance adherence to HIV therapy by eliminating the need to remember to take pills every day, and being invisible to others.  

What makes for an ideal LA alternative in HIV?

In addition to being effective and safe, a good LA formulation should be potent enough to allow for low daily release. This affects the injectable dose volume or implant size: important factors in user acceptability. 

 Moreover, an ideal LA formulation should have a suitable duration of action and be:[7]

·      Socially acceptable 

·      Easy to use

·      Cost-effective

 Are any long-acting ARVs for HIV available now?

There are only three approved LA ARVs in the global market:

1.     Ibalizumab (an antibody) is FDA-approved in the USA (2018)[4]

2.     Albuvirtide (a fusion inhibitor) is approved only in China (2018)[4]

3.     Cabotegravir/rilpivirine (a combination integrase inhibitor/non-nucleoside reverse transcriptase inhibitor)is approved only in Canada (2020)[8]

This hardly provides users and clinicians with enough opportunity to assess accessibility and appeal for LA HIV therapy.

 What’s in the pipeline for LA HIV treatment?

Contrary to the limited number of approved LA HIV treatments, there are several long-acting formulations, fast moving up in different stages of clinical development.[7]

 Let’s have a look at a summary of some of these compounds (Table 1):

What are the challenges of LA formulations for HIV? 

The development of long-acting antiretrovirals is a slow process. Some of the roadblocks are:[4],[15],[16]

·       Adverse events

·      Risk of viral resistance after unplanned (non-adherence to treatment intervals), or planned (medical decision) termination of ARV treatment

·       Lack of sufficient technical resources

·       Lack of population representation for trials

·       Drug–drug interactions 

·       Lack of specific safety and efficacy studies in pregnancy and lactation

·       Special storage requirements (e.g. refrigeration), especially in low- and middle-income countries

What do users say? Surprisingly, little research has been done on the preferences of populations actually burdened with ARV therapy on a daily basis. 

Simoni et al.’s assessment of people living with HIV, in parts of the USA, suggests that the key points for choosing a treatment method are:[9]

1)    Effectiveness

2)    Cost (oral ARVs are mostly free)

 The same study identifies groups that would benefit most from LA injections. These people are:[9]

·      Younger

·      Not on other medication

·      Leading an active lifestyle

·      At higher risk due to homelessness, substance use, or mental illness

In reality, people in different geographical or social settings can have contradicting preferences. For example, while some women prefer vaginal rings, others choose injections because they are more discreet and interfere less with their chosen lifestyle.[12]

“Simplifying administration and reducing cost will be critical to the success of long-acting ARVs, especially in low-income and developing countries. ”

The future of long-acting ARVs for HIV

Enormous amounts of resources and efforts, worldwide, are going into developing long-acting ARVs as key players in controlling the HIV infection. 

 The question now is: are we paying sufficient attention to the needs of developing countries, which are hit the hardest? Can they afford the new treatments? Are new technologies easy to implement where they’re needed most?

 If these considerations are made, along with the impressive advancements made so far, long-acting ARVs could be the key to finally controlling the HIV epidemic.[7] The future looks bright!

References

1.         Interview with Dr. Fauci. AJMC. https://www.ajmc.com/interviews/fauci-countless-lives-have-been-saved-but-a-vaccine-and-cure-remain-elusive

2.         UNAIDS. https://www.unaids.org/en/whoweare/about

3.         WHO | HIV/AIDS. WHO. http://www.who.int/gho/hiv/en/

4.         Singh K, Sarafianos SG, Sönnerborg A. Long-Acting Anti-HIV Drugs Targeting HIV-1 Reverse Transcriptase and Integrase. Pharm Basel Switz. 2019;12(2). doi:10.3390/ph12020062

5.         Future Directions for HIV Treatment Research | NIH: National Institute of Allergy and Infectious Diseases. http://www.niaid.nih.gov/diseases-conditions/future-hiv-treatment

6.         Infographic: Long-Acting Forms of HIV Prevention | NIH: National Institute of Allergy and Infectious Diseases. https://www.niaid.nih.gov/diseases-conditions/long-acting-forms-hiv-prevention

7.         Barnhart M. Long-Acting HIV Treatment and Prevention: Closer to the Threshold. Glob Health Sci Pract. 2017;5(2):182-187. doi:10.9745/GHSP-D-17-00206

8.         Government of Canada HC. Health canada Drug Product Database. Published April 25, 2012. https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=98706

9.         Simoni JM, Beima-Sofie K, Mohamed ZH, et al. Long-Acting Injectable Antiretroviral Treatment Acceptability and Preferences: A Qualitative Study Among US Providers, Adults Living with HIV, and Parents of Youth Living with HIV. AIDS Patient Care STDs. 2019;33(3):104-111. doi:10.1089/apc.2018.0198

10.       Weld ED, Flexner C. Long-acting implants to treat and prevent HIV infection. Curr Opin HIV AIDS. 2020;15(1):33-41. doi:10.1097/COH.0000000000000591

11.       Peet MM, Agrahari V, Anderson SM, et al. Topical Inserts: A Versatile Delivery Form for HIV Prevention. Pharmaceutics. 2019;11(8). doi:10.3390/pharmaceutics11080374

12.       Tolley EE, Li S, Zangeneh SZ, et al. Acceptability of a long‐acting injectable HIV prevention product among US and African women: findings from a phase 2 clinical Trial (HPTN 076). J Int AIDS Soc. 2019;22(10). doi:10.1002/jia2.25408

13.       Dashi A, DeVico AL, Lewis GK, Sajadi MM. Broadly Neutralizing Antibodies against HIV: Back to Blood. Trends Mol Med. 2019;25(3):228-240. doi:10.1016/j.molmed.2019.01.007

14.       Larijani MS, Ramezani A, Sadat SM. Updated Studies on the Development of HIV Therapeutic Vaccine. Curr HIV Res. 2019;17(2):75-84. doi:10.2174/1570162X17666190618160608

15.       LEAP. https://longactinghiv.org/content/who-we-are

16.       Gulick RM, Flexner C. Long-Acting HIV Drugs for Treatment and Prevention. Annu Rev Med. 2019;70(1):137-150. doi:10.1146/annurev-med-041217-013717