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Once Daily Dual Antiretroviral Therapy for the Treatment of HIV Infection

Wednesday, August 21, 2019  
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Matty Zimmerman, PharmD Student, Jefferson College of Pharmacy

Preceptor: Jason Schafer, PharmD, MPH, BCPS AQ-ID, BCIDP, AAHIVP, Professor, Jefferson College of Pharmacy

 

 In 1987, the FDA approved zidovudine as the first drug for the treatment of Acquired Immune Deficiency Syndrome (AIDS).1 Thirty years later we now have more than 30 drugs spanning 7 classes for the treatment of human immunodeficiency virus (HIV) infection.1 In the mid-1990s, combination therapy with 2 nucleoside reverse transcriptase inhibitors (NRTIs) and a protease inhibitor (PI), termed highly active antiretroviral therapy (HAART) led to sustained virologic suppression, immune reconstitution and prolonged survival.1,2 Despite advances, regimens were complicated, costly and poorly tolerated with significant toxicities.1 Now regimens are simpler and well tolerated, but still largely consist of three antiretroviral therapy (ART) agents.1 A dual ART regimen, consisting of only two agents, is enticing because exposing patients to fewer drugs may help reduce toxicity, side effects, drug-drug interactions, and costs.3 However, a dual ART regimen needs to also be as safe and effective as current triple therapy regimens, as well as have a high barrier to resistance.3

 The idea for an ART regimen comprised of two drugs is not a new one. There have been previous attempts to simplify ART with varying and limited success, but more recent attempts have been more successful.3 DTG is an integrase inhibitor (INSTI) that works by blocking the action of the HIV integrase enzyme and preventing viral replication.4 DTG was approved in 2013 for treatment of HIV-1 infection and is a good candidate for use in a dual ART regimen due to its potent antiviral activity, high barrier to resistance and long half-life.4,5

 

Dolutegravir + Rilpivirine

The FDA approved the first dual ART regimen in November 2017 under the brand name Juluca®.6 Juluca® is a single tablet that contains DTG and rilpivirine (RPV).6 RPV is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and works by blocking HIV reverse transcriptase, an enzyme integral to the replication of HIV.6 DTG+RPV is indicated in virologically suppressed patients who have been on their current ART regimen for at least 6 months and have no history of treatment failure or mutations conferring resistance to DTG or RPV.6 In addition to the SWORD 1 & 2 trials discussed in this article, the JUNGLE trial is an ongoing clinical trial evaluating the long term efficacy of DTG+RPV and is detailed in Table 1.7,8,9

 

SWORD-1 and SWORD-2

The efficacy and safety of DTG+RPV was investigated in the SWORD-1 and SWORD-2 clinical trials.7,8 In these two identical, multicenter, international, open-label trials, 1,024 individuals were randomly assigned to either continue their current ART regimen or switch to DTG+RPV.7 Participants were 18 years or older on a stable ART for at least 6 months. Each group was receiving their first or second ART regimen with no prior evidence of virologic failure. At week 48, those who switched to DTG+RPV and those who continued their usual ART regimen had similar rates of viral suppression.7 After 100 weeks of treatment,  89% of participants maintained their viral suppression with dual ART.8 More adverse events were associated with the DTG+RPV group but that should be expected since people continuing their ART are accustomed to their treatment and are therefore less likely to report adverse events.7 One drug resistance mutation was found in a non-adherent participant in the DTG+RPV group, but it did not result in decreased susceptibility to either agent.

Overall, the results of the SWORD studies establish DTG/RPV as a dual ART treatment option for patients eligible for switching to this combination.  However, the studies were limited in terms of their external validity. First, participants were mostly white males under the age of 50 and had limited ART experience. These factors need to be taken into consideration when determining appropriate candidates for DTG/RPV in clinical practice.

 

Dolutegravir + Lamivudine

The FDA approved the first dual regimen for ART-naïve individuals in April 2019 under the brand name Dovato®.10 This regimen is a single tablet containing DTG and lamivudine (3TC), an NRTI.11 In addition to the GEMINI 1 & 2 studies detailed here, the PADDLE and TANGO studies are also of significance.12,13,14 PADDLE was a proof of concept trial that assessed the efficacy and safety of DTG+3TC in a small number of treatment naïve patients.12 The purpose of the TANGO study is to investigate the safety, efficacy and tolerability of the ART regimen in those patients who switch to the regimen from an existing ART regimen.13 More information about PADDLE and TANGO can be found in Table 1.

 

GEMINI-1 and GEMINI-2

The GEMINI-1 and GEMINI-2 studies are identical, double-blind, multicenter, international clinical trials comparing DTG+3TC to DTG + tenofovir disoproxil fumarate

(TDF) + emtricitabine (FTC) in HIV-1 infected, treatment naïve adults.13 These studies investigated efficacy, safety and tolerability.14 The studies began in July of 2016 and monitored subjects for 148 weeks with an initial analysis at 48 weeks.14 Overall, DTG+3TC was no less efficacious than DTG+TDF+FTC and most participants achieved a viral load of <50 copies/mL by week 4.14 No participants developed resistance to INSTIs or NRTIs.14 Adverse events were more commonly reported in the triple ART therapy group and bone and renal markers were more favorable in the dual ART therapy group.14 This could be due to the inclusion of TDF in the triple ART therapy group which is known to be associated with impaired renal function and reduced bone mineral density. The participants in this study were mostly white males under the age of 50 with viral loads of less than 100,000 copies per mL and CD4 cell counts of >200 cells per mL which should be taken into consideration when applying these data to clinical practice.

Treatment guidelines currently recommend using dual ART regimens only in certain clinical scenarios These include instances when it is necessary to avoid abacavir (ABC), TDF and tenofovir alafenamide (TAF).2 For example, ABC should be avoided in individuals who are HLA-B*5701 positive or at high risk of cardiovascular disease and TDF should be avoided in patients with significant renal impairment.2 While their role may be limited in current treatment guidelines, theaddition of dual ART regimens to the market may revolutionize the treatment of HIV infection due to their reduced toxicity, side effects, drug-drug interactions, and costs.15

 

 

References

  1. A Timeline of HIV and AIDS. HIV.gov. https://www.hiv.gov/hiv-basics/overview/history/hiv-and-aids-timeline. Accessed November 15, 2018.
  2. Guidelines for the use of Antiretroviral Agents for Adults and Adolescents with HIV. AIDS Info. https://aidsinfo.nih.gov/contentfiles/lvguidelines/glchunk/glchunk_11.pdf. Accessed August 7, 2019.
  3. Back D. 2-Drug regimens in HIV treatment: pharmacological considerations. Germs. 2017;7(3)113-114.
  4. Dolutegravir. AIDS Info. https://aidsinfo.nih.gov/drugs/509/dolutegravir/0/patient. Updated March 23, 2018. Accessed October 11, 2018.
  5. Cahn P. Candidates for inclusion in a universal antiretroviral regimen: dolutegravir. Curr Opin HIV AIDS. 2017;12:318-23.
  6. Dolutegravir / Rilpivirine. AIDS Info. https://aidsinfo.nih.gov/drugs/588/juluca/0/patient. Updated November 27, 2017. Accessed October 10, 2018.
  7. Llibre JM, Hung C-C, Brinson C, Castelli F, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391(10123):839-849.
  8. Aboud M, Orkin C, Podzamczer D, et al. Durable suppression 2 years after switch to the DTG+RPV 2-drug regimen: SWORD-1 and SWORD-2 studies. Presented at the 22nd International AIDS Conference (IAC); July 23-27, 2018; Amsterdam, the Netherlands. Poster THPEB047.
  9. Dolutegravir/Rilpivirine, Antiretroviral Efficacy Study Using Real-world Data in Subjects with Human Immunodeficiency Virus (HIV)-1 (JUNGLE). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03518060. Published May 8, 2018. Updated October 9, 2018. Accessed October 10, 2018.
  10. US FDA approve ViiV Healthcare’s Dovato (dolutegravir/lamivudine), the first, once-daily, single-tablet, two-drug regimen for treatment-naïve HIV-1 adults. ViiV Healthcare. https://www.viivhealthcare.com/en-gb/media/press-releases/2019/april/us-fda-approves-viiv-healthcares-dovato-the-first-once-daily-single-tablet-two-drug-regimen-for-treatment-naive-hiv1-adults/. Published April 8, 2019. Accessed May 24, 2019.
  11. Lamivudine. AIDS info. https://aidsinfo.nih.gov/drugs/126/lamivudine/0/patient. Updated July 10, 2018. Accessed October 10, 2018.
  12. Rolón MJ, Figueroa MI, Gun A, Patterson P, Sued O. Dolutegravir–lamivudine as initial therapy in HIV-1 infected, ARV-naive patients, 48-week results of the PADDLE (Pilot Antiretroviral Design with Dolutegravir Lamivudine) study. Journal of the International AIDS Society. 2017;20(1):21678.
  13. Switch Study to Evaluate Dolutegravir Plus Lamivudine in Virologically Suppressed Human Immunodeficiency Virus Type 1 Positive Adults (TANGO). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03446573. Published February 27, 2018. Updated October 5, 2018. Accessed October 10, 2018.
  14. Cahn P, Madero JS, Arribas JR, et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2018. Advance online publication. doi:10.1016/S0140-6736(18)32462-0
  15. Girouard MP, Sax PE, Parker RA, et al. The Cost-effectiveness and Budget Impact of 2-Drug Dolutegravir-Lamivudine Regimens for the Treatment of HIV Infection in the United States. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America. 2016;62(6):784-791.

 


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