HIV Infection: The Future of Therapy

APRIL 24, 2017
David Cluck, PharmD, BCPS, AAHIVP, and Andrew Merker, PharmD
Approximately 35 million individuals are currently living with HIV/AIDS.1 Despite the great strides that have been made in antiretroviral therapy (ART), adherence remains a frequent challenge among patients. In the past 30 years, the ART regimen has evolved from multiple tablets or capsules several times each day to a single tablet once daily. Even with this, however, emerging therapies are being developed to reiterate the importance of preexposure prophylaxis (PrEP), treatment as prevention, and treatment simplification. ART is now on the brink of a new era in which patients could receive it via long-acting injectable formulations. The introduction of these agents in conjunction with ongoing efforts to develop a vaccine or cure will undoubtedly create a paradigm shift in how we provide patient care moving forward.
 
Available Therapies
Tenofovir alafenamide is the newest antiretroviral agent available. It was introduced in November 2016 as part of the single-tablet regimen Genvoya (tenofovir alafenamide/emtricitabine/cobicistat/elvitegravir) and is now available in other coformulated tablets as part of the Department of Health and Human Services (HHS) recommended initial regimens (Table7). In addition, the availability of Descovy (tenofovir alafenamide/emtricitabine) created a shift in therapy, as providers could switch patients from Truvada (tenofovir disoproxil/emtricitabine).
 
Table. Antiretroviral Regimens Preferred by the Department of Health and Human Services  
Generic Name Brand Name
Abacavir/lamivudine/dolutegravir Triumeq
Tenofovir disoproxil OR tenofovir alafenamide/emtricitabine plus dolutegravir Truvada OR Descovy plus Tivicay
Tenofovir disoproxil OR tenofovir alafenamide/emtricitabine plus raltegravir Truvada OR Descovy plus Isentress
Tenofovir alafenamide/emtricitabine/cobicistat/elvitegravir Genvoya
Tenofovir disoproxil OR tenofovir alafenamide/emtricitabine plus darunavir plus ritonavir Truvada OR Descovy plus Prezista plus Norvir
Adapted from reference 7.

The benefits of tenofovir alafenamide are emphasized when the 2 tenofovir salts are compared.
In clinical trials, tenofovir alafenamide resulted in decreased nephrotoxicity and diminished impact on bone mineral density secondary to greater concentrations in lymphocytes relative to plasma.2,3 Upon FDA approval, questions remained regarding whether the formulations were interchangeable, particularly whether the newer formulation was safe and efficacious for PrEP and hepatitis B virus (HBV) co-infection. Available data suggest that the lower systemic concentrations might hinder the newer formulation from being effective as PrEP treatment.4,5 Several months after tenofovir alafenamide (Vemlidy) was introduced for ART, clinical trials garnered it an FDA indication for HBV therapy.6
 
Future Therapies
Much of the anticipation regarding future therapies surrounds the potential for long-acting injectable ART to replace the current oral options for treatment and PrEP. However, clinicians will likely face difficult decisions regarding which patients qualify for these newer nontraditional regimens. Patient adherence will still be critical to optimal care and could become even more important.
 
Cabotegravir
Cabotegravir, currently entering phase 3 studies, will likely be the next available integrase inhibitor, as other potential agents are in early phases of development. Although there will likely be an oral formulation, much of the intrigue surrounding this agent lie in its potential to be used as a long-acting injectable. The findings of the LATTE-2 study revealed intramuscular administration of nanosuspensions of cabotegravir and rilpivirine resulted in similar virologic efficacy compared with oral administration.8 The study emphasized the pharmacokinetic appeal, suggesting it has the potential to be administered every 8 weeks. Cabotegravir was well tolerated in a small number of patients complaining of injection-site reactions, but patient satisfaction was reportedly higher with the injectable formulations.
 
Long-Acting Rilpivirine
Rilpivirine is the newest nonnucleoside reverse transcriptase inhibitor and is available by itself and coformulated within several single-tablet regimens. A long-acting formulation is being developed, but has only been studied when used with cabotegravir. Its place in therapy without concurrent cabotegravir is not defined; however, PrEP monotherapy has been suggested.9 Recent data indicate that rilpivirine concentrations are not sufficient in vaginal tissue; therefore, further studies are warranted.10
 
Tenofovir Implant
The focus of the tenofovir implant has largely been centered on its use as PrEP. The pharmacokinetics of a long-acting tenofovir alafenamide implant in animals have been described, and researchers concluded this formulation has potential as PrEP and as part of treatment regimens.11 Tenofovir is also being studied as a gel, dissolvable vaginal film, and vaginal ring.12,13 Because the efficacy of PrEP is directly linked to adherence, this formulation will likely result in complete adherence.
 
Dapivirine Vaginal Insert
Dapivirine is a nonnucleoside reverse transcriptase inhibitor that has been studied as a vaginal insert formulation for use as PrEP. The findings of the ASPIRE study emphasized potential adherence problems, as this study found poor adherence in younger patients relative to other age groups.14
 
HIV Vaccine Research
With more resources going toward various therapeutic areas, the introduction of new agents for HIV infection has decreased compared with what was introduced in the past. There are several challenges in producing an effective HIV preventive vaccine. HIV quickly inserts itself into the host cell DNA within days to weeks, where it can become latent and nearly invisible to the host’s immune system, making virus eradication difficult. Another challenge is that HIV mutates frequently and rapidly, so that by the time the immune system develops neutralizing antibodies for one HIV strain, already there are other mutated HIV strains, against which circulating antibodies are ineffective. With HIV, established immunity does not develop after transmission, as with other infections, such as measles.15
 
Preventive Vaccine Development
Six clinical trials have assessed the efficacy of different vaccines for HIV prevention. RV144 was the first to demonstrate modest efficacy through the implementation of a new vaccination method, “prime boost.” This technique first delivers the “prime” vaccine to stimulate cell-mediated immunity (T-cell response) by using a canarypox viral vector with different HIV proteins and follows it up with the “boost” that stimulates antibody production (B-cell response) with the use of a recombinant HIV surface protein. RV144 demonstrated an efficacy rate of approximately 30% in heterosexual Thai men and women.16
 
As a result of RV144, prime boost is being adapted for future clinical trials. HVTN 702 is the newest vaccine trial; it started enrolling patients in November 2016. This trial is using a similar method to RV144, but with slight adjustments to the boost in an attempt to elicit a stronger immune response.17
 
Additional areas of study and development in the search for an HIV vaccine include using other viral vectors or eliciting an immune response in the gut mucosa, where HIV replicates early during transmission.18,19 Another promising, yet challenging, area of vaccine development involves broad neutralizing antibodies. In a subset of patients with HIV, these antibodies develop after years of infection and would be able to block the transmission of various HIV strains into HIV-negative hosts. However, a vaccine for inducing these antibodies in individuals without HIV has not been developed due to the complexity of the antibodies.20
 
Therapeutic Vaccine Development
A new area of research for HIV is the development of a therapeutic vaccine. This type of vaccine may allow patients with HIV to delay initiation of therapy, simplify their current antiretroviral regimen, or interrupt ART. Additionally, an effective therapeutic vaccine may reduce HIV transmission, reduce the HIV reservoir within the host, or delay progression to AIDS.21 However, therapeutic vaccines have limitations. Because patients are infected with HIV, they may have compromised immunocompetence, which may reduce the immunologic effects by hindering the elicitation and strength of the immune response. Therefore, patients who receive a therapeutic vaccine may benefit most if it is administered early in the course of infection. Several different types of therapeutic vaccines are being studied in phase 1 and 2 clinical trials.21
 
Role of the Pharmacist
Pharmacists play an integral role in caring for patients with HIV/AIDS through treatment and prevention. This role is expected to expand as newer agents are introduced. Pharmacists have become essential contributors to the multidisciplinary team in inpatient and outpatient settings in terms of selecting regimens and identifying drug–drug interactions.22 Their positive influence on patient health continues to grow through vaccination services. Pharmacists are often the first health care providers patients reach out to regarding medication problems or questions on disease state management. Therefore, it is important for pharmacists to understand the new antiretroviral agents.
 
Conflicts of Interest
Both authors have no conflicts of interest to report.
 
David Cluck, PharmD, BCPS, AAHIVP, is a clinical assistant professor in the Department of Pharmacy at Bill Gatton College of Pharmacy, East Tennessee State University Practice.

Andrew Merker, PharmD, BCPS, is a clinical pharmacist and residency rotation preceptor at Mount Sinai Hospital in Chicago, Illinois.


References
  1. The Gap report. Geneva: Joint United Nations Programme on HIV/AIDS, 2014. UNAIDS website. http://www.unaids.org/sites/default/files/media_asset/UNAIDS_Gap_report_en.pdf. Accessed March 13, 2017.
  2. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015;385(9987):2606-2615.
  3. Gallant JE, Daar ES, Raffi F, et al. Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial. Lancet HIV. 2016;3(4):e158-e165. doi: 10.1016/S2352-3018(16)00024-2.
  4. Massud I, Mitchell J, Babusis D, et al. Chemoprophylaxis with oral FTC/TAF protects macaques from rectal SHIV infection [abstract 107]. Conference on Retroviruses and Opportunistic Infections (CROI) ; Boston, MA; February 22-25, 2016.
  5. Garrett KL Cottrell ML, Prince HM, et al. Concentrations of TFV and TFVdp in female mucosal tissues after a single dose of TAF [abstract 102LB]. Conference on Retroviruses and Opportunistic Infections (CROI); Boston, MA; February 22-25, 2016.
  6. Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;Sep 22.
  7. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. aidsinfo.nih.gov website. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf  Accessed January 2, 2017.
  8. Margolis DA, González-Garcia J, Stellbrink HJ, et al. Cabotegravir + rilpivirine as long-acting maintenance therapy: LATTE-2 week 32 results [abstract 31LB]. Program and abstracts of the 2016 Conference on Retroviruses and Opportunistic Infections. Boston, MA; February 22-25, 2016.
  9. Williams PE, Crauwels HM, Basstanie ED. Formulation and pharmacology of long-acting rilpivirine. Curr Opin HIV AIDS. 2015;10(4):233-238. doi: 10.1097/COH.0000000000000164.
  10. Dezzutti C, Else LJ, Yandura SE, et al. Distinct pharmacodynamic activity of rilpivirine in mucosal explant tissue [poster abstract 874]. Conference on Retroviruses and Opportunistic Infections (CROI); Boston, MA; February 22-25, 2016.
  11. Gunawardana M, Remedios-Chan M, Miller CS, et al. Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis. Antimicrob Agents Chemother. 2015;59(7):3913-3919. doi: 10.1128/AAC.00656-15.
  12. Bunge KE, Dezzutti CS, Hendrix C, et al. Phase I trial to assess safety, PK, and PD of film and gel formulations of tenofovir [poster abstract 871]. Conference on Retroviruses and Opportunistic Infections (CROI); Boston, MA; February 22-25, 2016.
  13. Ott AK, Halavaty K, Su J, et al. Transport of drug and virus in FRTs of macaques 922 treated with a TDF intravaginal ring [oral abstract 877]. Conference on Retroviruses and Opportunistic Infections (CROI); Boston, MA; February 22-25, 2016.
  14. Baeten JM, Palanee-Phillips T, Brown ER, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med. 2016;375(22):2121-2132.
  15. Johnston MI, Fauci AS. An HIV vaccine: challenges and prospects. N Engl J Med. 2008;359(9):888-890. doi: 10.1056/NEJMp0806162.
  16. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV transmission in Thailand. N Engl J Med. 2009;361(23):2209-2220. doi: 10.1056/NEJMoa0908492.
  17. National Institute of Allergy and Infectious Diseases  websitePivotal phase 2b/3 ALVAC/bivalent gp120/MF59 HIV vaccine prevention safety and efficacy study in South Africa (HVTN702). ClinicalTrials.gov website. https://clinicaltrials.gov/show/NCT02968849. Accessed March 13, 2017.
  18. Hammer SM, Sobieszczyk ME, Janes H, et al. Efficacy trial of a DNA/rAd5 HIV-1 preventative vaccine. N Engl J Med. 2013;369(22):2083-2092.  doi: 10.1056/NEJMoa1310566.
  19. McElrath MJ, Smythe K, Randolph-Habecker J, et al. Comprehensive assessment of HIV target cells in the distal human gut suggests increasing HIV susceptibility toward the anus. J Acquir Immune Defic Syndr. 2013;63(3):263-271.
  20. Sadanand S, Suscovich TJ, Alter G. Broadly neutralizing antibodies against HIV: new insights to inform vaccine design. Annu Rev Med. 2016;67:185-200. doi: 10.1146/annurev-med-091014-090749. 
  21. Ensoli B, Cafaro A, Monini P, Marcotullio S, Ensoli F. Challenges in HIV vaccine research for treatment and prevention. Front Immunol. 2014; 5:417. doi: 10.3389/fimmu.2014.00417.
  22. Cocohoba J, Comfort M, Kianfar H, Johnson MO. A qualitative study examining HIV antiretroviral adherence counseling and support in community pharmacies. J Manag Care Pharm. 2013;19(6):454-460


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