The Evolution of Antiretroviral Therapy: Past, Present, and Future
On June 5th, 1981, the United States Centers for Disease Control and Prevention (CDC) published a Morbidity and Mortality Weekly Report (MMWR), describing five cases of a rare lung infection, Pneumocystis carinii pneumonia (PCP), in young, otherwise healthy, gay men.1 This would become the first report of what would later be called the Acquired Immune Deficiency Syndrome (AIDS) epidemic. Clusters of other cases of rare diseases such as Kaposi's Sarcoma continued to be reported.2 In the decades that followed these reports, the detection, diagnosis, and treatment of Human Immunodeficiency Virus (HIV) would evolve in rapid fashion. Clinicians, researchers, and patients constantly look to the future. Vaccine studies and cure research are met with cautious optimism.
This review will summarize the past, present, and future of antiretrovirals (ARVs) for the treatment and prevention of HIV.
Treatment of HIV has a long and rich history. The first decade after the initial report of HIV saw the first immunoassay test and the approval of zidovudine (1987).3 This was followed in the 1990s by many more therapies and the advent of triple drug therapy. Combination tablets and single tablet regimens then followed.
New formulations of existing products also simplified treatment (e.g. ritonavir tablets vs capsules) and improved bioavailability.3 The US President's Emergency Plan for AIDS Relief (PEPFAR) changed the discussion regarding the approach to universal access to treatment and care to accelerate control of the epidemic.4 The US Department of Health and Human Services Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV have been updated over 30 times.5
Early innovations, such as giving medication sequentially and alternating therapies, gave way to triple drug therapy with data provided by a small study with indinavir, zidovudine, and lamivudine.6,7 Initial use of the nucleoside reverse transcriptase inhibitors (NRTIs) also led to the discovery that treatment of HIV led to decreased rates of vertical transmission.8 The use of low-dose ritonavir as a "boosting" agent for saquinavir set the stage for the recommendations currently in use and the need for decreased doses of other protease inhibitors.7,9 Monitoring HIV RNA, or "viral load" was recommended after HIV in the plasma was shown to be predictive of disease progression and death.10 Despite a low quality of life with the older agents, HIV was now a manageable, chronic disease.
Currently there are 40 individual and combination medications approved for the treatment of HIV and one approved for the prevention of HIV infection.11 The life expectancy of a person living with HIV nears that of a person not living with HIV.12 There are enough options that patients may "switch" their therapy to one that requires fewer tablets or frequency of dosing, lesser food requirements, or has lesser side effects. Patients on "salvage" therapy also have options for effective treatment.13,14 "Treatment as prevention" and PrEP have led to a decrease in new infections.15,16 The newly endorsed "undetectable = untransmittable" data provides patients and those at risk of infection with important information about the virus.17 Test and treat is a new strategy to approaching the epidemic.18
However, there are many challenges that remain. While many of the newer agents are tolerable, long term side effects (e.g. metabolic and cardiovascular) and drug-drug interactions remain a concern.19 Patients faced with the need to take "lifelong" therapy for upwards of fifty years require agents with safer long term side effects. The approval of tenofovir alafenamide will likely reduce the incidence of bone and renal toxicity; however, long term data over a lifetime is needed to guide therapy.20 While there are many treatment options available to decrease HIV RNA, an agent to increase CD4 T-lymphocyte count remains elusive.
Safer alternatives may be available to some patients, however, global access to care continues to evolve. Even within the US, access to HIV therapy remains an issue for many patients faced with high deductibles and copayments.21,22 Disparities in treatment continue to exist for specific patient populations.23 Many programs are in place to close the gap between access in developed and non-developed countries.4 The current WHO guidelines recommend that all patients are started on ARV therapy regardless of CD4 T-lymphocyte count.24 The scale up of these programs requires the funding and infrastructure to treat a larger number of patients.
Special patient populations are also in the spotlight. Overall, the available data on treatment of pediatric and adolescent patients falls behind the availability of data for adults. If a drug is approved for use in children, dosage formulations may not be available for all stages of care. Women continue to face many issues surrounding contraception and ARV therapy.25 Disparities in PrEP efficacy for women versus men require more data and evidence for clinicians to be able to provide appropriate patient counseling.26 Management of comorbidities, drug-drug interactions, and polypharmacy in an aging population must be addressed by clinicians.19,27
As tolerability of medications is no longer a main concern, the conversation has shifted to medication adherence and engagement in care.28 The "HIV Cascade" has many steps for which intervention and research are required.29,30 Engagement and continuation of ARV therapy after transitions in care remains an issue. The transitions from adolescent to adult and prison to society each have their own unique challenges.31,32
Given the high efficacy, safety, tolerability, and convenience of contemporary ARV therapy, it can be challenging to identify where and to what extent improvements can be made. However, considering the vast advancements in treatment that have already occurred, it may be naive to think that the current approach to HIV treatment is the best and only way.
New agents under investigation are challenging the current treatment paradigm of three active antiretroviral medications by mouth every day to maintain viral suppression. Several two drug therapy options are emerging that may simplify treatment and reduce cost.33 Long-acting medications dosed every week or every month may be easier for some patients, improve medication adherence, and increase cost effectiveness.34
A few longer acting antiretrovirals in development will provide additional oral therapy options, but the majority will likely be delivered via alternative drug delivery systems.34,35 This includes the potential delivery of agents such as cabotegravir and rilpivirine as long acting injectables, dapivirine within a vaginal ring, and tenofovir alafenamide as a subdermal implant.35-37 These methods of drug delivery may seem foreign to some providers of HIV medicine, but they are common methods for delivering medications in other areas of healthcare and may represent a novel and effective method to ensure medication adherence and effective treatment.38
In addition to challenging the number of medications necessary for HIV treatment and their modes of delivery, new agents with novel drug therapy targets may also challenge the status quo. Capsid assembly, glycoprotein 120 attachment, and Rev-dependent mRNA expression are among the novel drug therapy targets under current investigation.39-41 Agents in these classes along with the recent approval of a novel anti-CD4 monoclonal antibody may provide future therapy options, particularly for those with heavy treatment experience.42
The last component of the treatment paradigm, the consistent need for antiretroviral medications, may be the most challenging of all to change. Will broadly neutralizing antibodies, therapeutic vaccines, latency reversing agents, or CRISPR technology ever become routine methods for inhibiting, suppressing, or eliminating HIV? Evidence for these approaches and others continue to emerge and provide optimism that the future may hold a potential cure.43,44
The remaining articles in this magazine take a deeper dive into the future of HIV medicine, providing more in-depth discussion of emerging treatment and prevention options. From new agents and drug therapy targets, approaches to drug delivery, and novel practice models, these articles demonstrate that the future of HIV treatment and prevention is evolving and the status quo is likely to change again.
Milena Mclaughlin, Pharm.D, M.S.C., BCPS-AQ ID, AAHIVP, is an Assistant Professor in the Department of Pharmacy Practice at Midwestern University's Chicago College of Pharmacy in Downers Grove, IL. She is also an HIV/ID Clinical Pharmacist in the Department of Pharmacy at Northwestern Memorial Hospital in Chicago, IL.
Jason Schafer, Pharm.D., M.P.H., BCPS, AAHIVP, is an Associate Professor in the Department of Pharmacy Practice at Jefferson College of Pharmacy at Thomas Jefferson University in Philadelphia, PA.
- Centers for Disease C. Pneumocystis pneumonia -- Los Angeles. MMWR Morb Mortal Wkly Rep. 1981;30:250-252.
- Centers for Disease C. A cluster of kaposi's sarcoma and pneumocystis carinii pneumonia among homosexual male residents of los angeles and orange counties, california. MMWR Morb Mortal Wkly Rep. 1982;31:305-307.
- A Timeline of HIV and AIDS. Available at: www.hiv.gov/hiv-basics/overview/history/hiv-and-aidstimeline. Accessed 25 FEB 2018.
- The United States President's Emergency Plan for AIDS Relief. Available at: www.pepfar.gov/index.htm. Accessed 25 FEB 2018.
- United States Department of Health and Human Services Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Available at: https://aidsinfo.nih.gov/guidelines/html/1/adult-andadolescent-arv/0. Accessed 25 FEB 2018.
- Gulick RM, Mellors JW, Havlir D, et al. 3-year suppression of HIV viremia with indinavir, zidovudine, and lamivudine. Ann Intern Med. 2000;133:35-39.
- Vella S, Schwartlander B, Sow SP, Eholie SP, Murphy RL. The history of antiretroviral therapy and of its implementation in resource-limited areas of the world. AIDS. 2012;26:1231-1241.
- Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric aids clinical trials group protocol 076 study group. N Engl J Med. 1994;331:1173-1180.
- Cameron DW, Japour AJ, Xu Y, et al. Ritonavir and saquinavir combination therapy for the treatment of HIV infection. AIDS. 1999;13:213-224.
- Mellors JW, Rinaldo CR, Jr., Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996;272:1167-1170.
- FDA-Approved HIV Medicines. Available at: https://aidsinfo.nih.gov/understanding-hiv-aids/factsheets/21/58/fda-approved-hiv-medicines. Accessed 25 FEB 2018.
- Antiretroviral Therapy Cohort C. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: A collaborative analysis of cohort studies. Lancet HIV. 2017;4:e349-e356.
- Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of tmc125 (etravirine) in treatment-experienced HIV-1-infected patients in duet-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:39-48.
- Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359:339-354.
- Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral therapy for the prevention of HIV-1 transmission. N Engl J Med. 2016;375:830-839.
- National Institute of Allergy and Infectious Diseases. New HIV Infections Drop 18 Percent in Six Years. Available at: www.hiv.gov/blog/new-hivinfections-drop-18-percent-in-six-years. Accessed 25 FEB 2018.
- HIV & AIDS in the United States. Information from CDC's Division of HIV/AIDS Prevention. Letter: September 27, 2017. Available at: https://docs.wixstatic.com/ugd/de0404_1f9f737da1674cdda5a42f7857cd4fa6.pdf. Accessed 25 FEB 2018.
- Montaner JS, Lima VD, Barrios R, et al. Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in british columbia, canada: A population-based study. Lancet. 2010;376:532-539.
- Guaraldi G, Palella FJ, Jr. Clinical implications of aging with HIV infection: Perspectives and the future medical care agenda. AIDS. 2017;31 Suppl 2:S129-S135.
- De Clercq E. Role of tenofovir alafenamide (taf) in the treatment and prophylaxis of HIV and hbv infections. Biochem Pharmacol. 2017.
- Martin EG, Schackman BR. Treating and preventing HIV with generic drugs - barriers in the United States. N Engl J Med. 2018;378:316-319.
- Wohl DA, Kuwahara RK, Javadi K, et al. Financial barriers and lapses in treatment and care of HIVinfected adults in a southern state in the United States. AIDS Patient Care STDS. 2017;31:463-469.
- Centers for Disease Control and Prevention. Racial and Ethnic Disparities in Sustained Viral Suppression and Transmission Risk Potential Among Persons Receiving HIV Care -- United States, 2014. MMWR. Feb 2018;67(4);113-118.
- World Health Organization. Treat all people living with HIV, offer antiretrovirals as additional prevention choice for people at "substantial" risk. Available at: www.who.int/mediacentre/news/releases/2015/hiv-treat-allrecommendation/en/. Accessed 25 FEB 2018.
- Fok WK, Blumenthal PD. HIV and contraception. Curr Opin Obstet Gynecol. 2017;29:419-426.
- Cottrell ML, Yang KH, Prince HM, et al. A translational pharmacology approach to predicting outcomes of preexposure prophylaxis against HIV in men and women using tenofovir disoproxil fumarate with or without emtricitabine. J Infect Dis. 2016;214:55-64.
- Smit M, Brinkman K, Geerlings S, et al. Future challenges for clinical care of an ageing population infected with HIV: A modelling study. Lancet Infect Dis. 2015;15:810-818.
- Blake Helms C, Turan JM, Atkins G, et al. Interpersonal mechanisms contributing to the association between HIV-related internalized stigma and medication adherence. AIDS Behav. 2017;21:238-247.
- Centers for Disease Control and Prevention. HIV Care Outcomes Among Men Who Have Sex With Men With Diagnosed HIV Infection -- United States, 2015. MMWR. Sept 2018:66(37);969-974.
- Hoots BE, Finlayson TJ, Wejnert C, Paz-Bailey G, National HIVBSSG. Updated data on linkage to human immunodeficiency virus care and antiretroviral treatment among men who have sex with men-20 cities, United States. J Infect Dis. 2017;216:808-812.
- Wohl DA, Golin CE, Knight K, et al. Randomized controlled trial of an intervention to maintain suppression of HIV viremia after prison release: The impact trial. J Acquir Immune Defic Syndr. 2017;75:81-90.
- Cervia JS. Easing the transition of HIV-infected adolescents to adult care. AIDS Patient Care STDS. 2013;27:692-696.
- Cahn P, Rolon MJ, Figueroa MI, et al. Dolutegravirlamivudine as initial therapy in HIV-1 infected, ARV-naive patients, 48-week results of the PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) study. J Int AIDS Soc. 2017;20(1):21678.
- US National Library of Medicine. A Study of MK-8591 in Anti-Retroviral Therapy-Naive, Human Immunodeficiency Virus-1 Infected Participants (MK-8591-003). July 11, 2017; https://clinicaltrials.gov/ct2/show/study/NCT02217904?term=mk-8591&rank=2 Accessed February 20, 2017.
- Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 2017;390:1499-1510.
- 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):3913-9.
- 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.
- Mommers E, Blum GF, Gent TG, et al. Nexplanon, a radiopaque etonogestrel implant in combination with a next-generation applicator: 3-year results of a noncomparative multicenter trial. Am J Obstet Gynocol. 2012;207:e1-6.
- Tse WC. Discovery of novel potent HIV capsid inhibitors with long-acting potential. Webcast presented at: Poster session presented at: Conference of Retroviruses and Opportunistic Infections; 2017 Feb 13-16; Seattle, WA.
- Drugs. Department of Health and Human Services. Available at https://www.aidsinfo.nih.gov/drugs. Accessed February 5, 2018.
- Scherrer D, Rouzier R, Noel Barrett P, et al. Pharmacokinetics and tolerability of ABX464, a novel first-in-class compound to treat HIV infection, in healthy HIV-uninfected subjects. J Antimicrob Chemother. 2017;72(3):820-828.
- Lewis S, Fessel J, Emu B, et al. Long-acting ibalizumab in patients with multi-drug resistant HIV-1: a 24-week study. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, Washington. Poster 449LB.
- National Institute of Allergy and Infectious Diseases. Future Directions for HIV Treatment Research. Available at: www.niaid.nih.gov/diseases-conditions/future-hiv-treatment. Accessed March 9, 2018.
- Chaoran Y, Zhang T, Qu X, et al. In vivo excision of HIV-1 provirus by saCas9 and multiplex single-guide RNAs in animal models. Mol Ther. 2017;25:1168-1186.
[Note from TheBodyPRO: This article was originally published by AAHIVM in April 2018. We have cross-posted it with their permission.]