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clinical therapeutics John A. Jarcho, M.D., Editor
Single-Pill Combination Regimens for Treatment of HIV-1 Infection Monica Gandhi, M.D., M.P.H., and Rajesh T. Gandhi, M.D. This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors’ clinical recommendations. From the Division of HIV/AIDS, University of California, San Francisco (UCSF), San Francisco (M.G.); and the Division of Infectious Diseases, Massachusetts General Hospital (MGH), Boston, and the Ragon Institute of MGH, Massachusetts Institute of Technology, and Harvard, Cambridge, MA (R.T.G.). Address reprint requests to Dr. Monica Gandhi at UCSF, 995 Potrero Ave., 4th Fl., San Francisco, CA 94110, or at [email protected]; or to Dr. Rajesh T. Gandhi at MGH, GRB 504, Infectious Diseases, 55 Fruit St., Boston, MA 02114, or at [email protected].
A 52-year-old man with a history of homelessness, depression, and polysubstance use received a diagnosis of human immunodeficiency virus type 1 (HIV-1) infection in 2005 but has declined antiretroviral therapy (ART) in the past. His CD4+ T-cell count is now 257 per cubic millimeter, and his plasma HIV-1 RNA level is 17,000 copies per milliliter. The patient was prescribed a multipill antiretroviral regimen 2 months ago but has not followed this regimen regularly because “taking out lots of pills in the shelter just announces to the world that I have AIDS [the acquired immunodeficiency syndrome].” The patient desires to keep his HIV status private and states that he would take medications regularly if he could take just “one pill once a day.” The patient is not taking any other medications; his renal function is normal. How should he be evaluated and treated?
* Drs. Gandhi and Gandhi contributed equally to this article.
The Cl inic a l Probl em
N Engl J Med 2014;371:248-59. DOI: 10.1056/NEJMct1215532 Copyright © 2014 Massachusetts Medical Society.
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Effective HIV treatment requires lifelong and daily consumption of multiple antiretroviral medications. With the advent and refinement of combination ART, the life expectancy of HIV-infected patients has risen dramatically.1,2 In addition to benefiting infected persons, ART almost completely blocks HIV-1 transmission to uninfected sexual partners.3 If we were able to treat most or all HIV-infected patients and thereby prevent new infections, “the beginning of the end of AIDS” would be in sight.4,5 For the benefits of ART to be realized at the individual and population levels, patients must maintain high levels of adherence to all components of the regimen. A number of factors are associated with lower levels of adherence,6 including the stigma associated with HIV infection,7 membership in a minority racial or ethnic group,8-11 depression,9,12,13 alcohol or drug use,14 cognitive impairment,15 young age,10 and medication side effects.16 Moreover, rates of adherence to ART may decline over time,10,12,17-20 even when antiretroviral agents are provided at no cost. There is therefore a compelling need for strategies that can help patients sustain lifelong adherence to treatment. When effective ART was first developed almost two decades ago, adherence was particularly challenging because patients had to consume handfuls of pills, often with substantial toxicity, multiple times per day. With the introduction of coformulated drugs that are less toxic and more potent, there have been dramatic reductions in the pill burden. This trend has culminated in single-pill combinations, in which all components of an ART regimen, typically three or more medications from two different drug classes, are formulated into one pill taken once daily. n engl j med 371;3 nejm.org july 17, 2014
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clinical ther apeutics
Biol o gic Fe at ur e s of HI V-1 infec t ion The rationale for lifelong combination therapy for HIV-1 infection and the interest in developing single-pill combinations to facilitate adherence are based on the biologic features of the virus (Fig. 1). Because of the high replication and mutation rates of HIV-1, multiple antiretroviral agents (usually three) must be taken simultaneously to suppress replication and prevent the development of viral resistance. ART can reduce HIV-1 RNA to extremely low levels in the blood, although the virus still persists in reservoirs found in specialized immune cells and tissues.21 Because antiretroviral regimens typically cannot eradicate infection, even when additional agents are added,22,23 therapy must be continued over a lifetime to suppress viral replication and prevent HIV-related complications. Owing to the ability of HIV-1 to mutate rapidly, the effect of suboptimal adherence to ART can be devastating (Fig. 2). Incomplete adherence leads to ongoing HIV-1 replication, which, in the presence of low-to-moderate levels of drug exposure, can select for viral strains with mutations conferring resistance to those agents. The rapidity with which drug-resistant strains emerge and the subsequent immunologic and clinical consequences vary according to the HIV-1 RNA level, the antiretroviral class, and the fitness of the mutant virus. At the individual level, inconsistent adherence can lead to drug resistance, permanently rendering particular agents or classes of drugs ineffective.24 At the population level, inconsistent use of antiretroviral agents can lead to ongoing transmission and the spread of drugresistant viral strains. Regimens with a low pill burden, such as single-pill combinations, may both facilitate adherence over a prolonged period and ensure that none of the components of a combination regimen are inadvertently missed.
Cl inic a l E v idence There are currently three single-pill combinations marketed for HIV-1 treatment, each containing the same combination of one nucleotide reverse-transcriptase inhibitor and one nucleoside reverse-transcriptase inhibitor (NRTIs): tenofovir disoproxil fumarate (TDF) at a dose of 300 mg and emtricitabine (FTC) at a dose of 200 mg, respectively. The first agent (Atripla, Bristol-Myers
Squibb and Gilead Sciences), released in 2006, is a single pill that combines TDF–FTC with 600 mg of the nonnucleoside reverse-transcriptase inhibitor (NNRTI) efavirenz (EFV). The second agent (Complera, Gilead Sciences), approved in 2011, combines TDF–FTC with 25 mg of the NNRTI rilpivirine (RPV). The third agent (Stribild, Gilead Sciences), released in 2012, consists of TDF–FTC combined with 150 mg of the integrase strandtransfer inhibitor (INSTI) elvitegravir (EVG) and 150 mg of the pharmacoenhancer cobicistat (which boosts serum EVG levels). A fourth singlepill combination is in development and has not yet been approved for clinical use. This agent would combine two NRTIs — abacavir (ABC) at a dose of 600 mg and lamivudine (3TC) at a dose of 300 mg — with 50 mg of the recently approved INSTI dolutegravir (DTG). Studies of once-daily dosing of antiretroviral agents provide support for the concept that regimen simplification improves adherence. One metaanalysis examined adherence among patients with HIV-1 infection who received either oncedaily or twice-daily regimens in 19 randomized, controlled studies (6321 patients).20 Modestly better adherence, assessed by means of pill counts or medication-event monitoring systems, was observed among recipients of once-daily regimens (an increase of 2.55 percentage points, P50 ml/min). DTG has had a high genetic barrier to resistance in trials to date. DTG is not known to be teratogenic in humans (pregnancy class B).
DTG inhibits creatinine secretion, leading to a small rise in the serum creatinine level in some patients (mean increase at 48 wk, 0.1 mg/dl [range, −0.6 to 0.6]) — an increase similar to that observed with cobicistat. Use of ABCcontaining regimens requires genetic testing for HLA B5701, an allele that predicts hypersensitivity to this drug. DTG should be taken at least 2 hr before or 6 hr after oral administration of sucralfate or cation-containing antacids or laxatives with magnesium or aluminum; calcium or iron supplements can be administered with DTG with food (otherwise, DTG should be taken at least 2 hr before or 6 hr after the supplement is taken). Double the dose with concomitant rifampin or EFV; do not use with etravirine unless boosted protease inhibitors are being administered. No dose adjustments are needed with RPV. There is limited clinical experience with DTG to date (approved in August 2013). Some studies have shown a link between ABC and myocardial infarction, but there was no such relationship in other studies and an FDA meta-analysis.
In development for HIV-1 infection EVG–cobicistat– Data to 48 wk suggest TAF may be associated TAF–FTC with smaller reductions in bone density and estimated creatinine clearance than TDF.
Available data are from a phase 2 study; no data beyond 48 wk are available. More information is needed.
* ABC denotes abacavir, DTG dolutegravir, EFV efavirenz, EVG elvitegravir, FDA Food and Drug Administration, FTC emtricitabine, HBV hepatitis B virus, HIV human immunodeficiency virus, INSTI integrase strand-transfer inhibitor, NNRTI nonnucleoside reverse-transcriptase inhibitor, QTc corrected QT, RPV rilpivirine, TAF tenofovir alafenamide, TDF tenofovir disoproxil fumarate, and 3TC lamivudine. To convert the values for creatinine to micromoles per liter, multiply by 88.4.
Agents in Development for Use in Single-Pill Combinations
A r e a s of Uncer ta in t y
Tenofovir alafenamide (TAF), a prodrug of tenofovir that is converted to the active form in lymphocytes, is an agent being developed for use in single-pill combinations. The virologic activity of TAF was similar to that of TDF when each was coformulated with cobicistat–EVG–FTC and taken for 48 weeks.74 The TAF-containing regimen caused a smaller decline in bone mineral density and estimated creatinine clearance than the TDF-containing combination. Further studies of TAF-containing single-pill combinations, including ones that include protease inhibitors, are under way. Applications for the fixed-dose combinations of atazanavir– cobicistat75,76 and darunavir–cobicistat77,78 are under review at the FDA, and a single-pill combination regimen of darunavir–cobicistat–TAF– FTC is being studied in clinical trials.
The potential benefits of single-pill combinations must be weighed against the higher costs of these branded combinations as compared with multipill regimens containing generic antiretroviral agents. One analysis projected that switching patients with HIV-1 infection from the branded EFV–TDF–FTC single-pill combination to a three-pill regimen of generic EFV (not yet available), branded TDF, and generic 3TC would save almost $1 billion per year in the United States, with a relatively small reduction in treatment efficacy.79 A study from Denmark showed that switching patients from a branded singlepill combination to a cheaper multipill regimen did not compromise virologic efficacy.80 In patients who struggle with adherence, however, the decreased pill burden of a single-pill combina-
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tion could be crucial for successful treatment. Moreover, if a multipill regimen requires multiple copayments, the cumulative cost may be prohibitive for some patients. On a global scale, country- and region-specific pharmacoeconomic analyses are needed for single-pill combinations and other formulations (e.g., long-acting agents) designed to improve adherence.
Guidel ine s Of the single-pill combinations currently available, EFV–TDF–FTC is recommended in guidelines from the U.S. Department of Health and Human Services (DHHS),19 the International Antiviral Society–USA,45 and the British HIV Association.81 The WHO recommends EFV–TDF– FTC or EFV–TDF–3TC, formulated as a single-pill combination, as first-line agents.54 EVG–cobicistat– TDF–FTC is recommended for previously untreated patients in the DHHS and British guidelines.19,81 RPV–TDF–FTC is recommended by the DHHS only for patients with pretherapy HIV-1 RNA levels of less than 100,000 copies per milliliter and CD4+ T-cell counts of more than 200 per cubic millimeter.19 The European AIDS Clinical Society recommends the following single-pill combination regimens: EFV–TDF–FTC, EVG–cobicistat–TDF– FTC, and, if the HIV-1 RNA level is less than 100,000 copies per milliliter, RPV–TDF–FTC.82 The use of fixed-dose combinations was listed as an adherence-boosting strategy (level of evidence, IIIB)83 in a statement by an International Association of Physicians in AIDS Care panel.84 However, the panel called for future research comparing single-pill combinations with their individual drug components, including analyses of cost. References 1. May MT, Gompels M, Delpech V, et al. Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy: UK cohort study. AIDS 2014 February 19 (Epub ahead of print). 2. Bor J, Herbst AJ, Newell ML, Bärnig hausen T. Increases in adult life expectancy in rural South Africa: valuing the scale-up of HIV treatment. Science 2013; 339:961-5. 3. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365:493-505. 4. Havlir D, Beyrer C. The beginning of the end of AIDS? N Engl J Med 2012;367: 685-7.
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R ec om mendat ions The first step in evaluating the patient described in the vignette would be to check the HIV-1 genotype to determine whether prior inconsistent use of ART has selected for drug resistance. If not, a singlepill combination is an attractive option owing to the low pill burden and the patient’s stated preference. TDF–FTC, the only NRTI backbone in currently available single-pill combinations, would be reasonable for this patient, given his normal renal function. Although a regimen containing a protease inhibitor as the anchor is sometimes selected if adherence is uncertain, the patient indicates that he is more likely to adhere to a single-pill combination. Each of the anchor drugs in currently available single-pill combinations would be suitable because of his normal renal function and relatively low HIV-1 RNA level and because he is not taking other medications. The selection of a regimen should be based on potential side effects, food requirements, dosing schedule, and, possibly, anticipated adherence; cost may also be a consideration. Regardless of which regimen is chosen, careful clinical, virologic, and immunologic monitoring, along with regular adherence assessment and counseling, will be key contributors to treatment success. Dr. Rajesh Gandhi reports receiving grant support through his institution from ViiV Healthcare, Abbott Laboratories, and Janssen Pharmaceuticals. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Drs. Diane Havlir, David Bangsberg, Rochelle Walensky, Harry Lampiris, Joseph Eron, and Rakesh Mishra for helpful input in reviewing the content, Kelsey Han for her assistance, and our patients at Ward 86 and Massachusetts General Hospital for providing the inspiration.
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phase III randomized trials. AIDS 2013; 27:939-50. 59. Cohen C, Wohl D, Arribas JR, et al. Week 48 results from a randomized clinical trial of rilpivirine/emtricitabine/ tenofovir disoproxil fumarate vs. efavirenz/ emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults. AIDS 2014;28:989-97. 60. Custodio JM, Yin X, Hepner M, et al. Effect of food on rilpivirine/emtricitabine/ tenofovir disoproxil fumarate, an anti retroviral single-tablet regimen for the treatment of HIV infection. J Clin Pharmacol 2014;54:378-85. 61. Palella FJ Jr, Fisher M, Tebas P, et al. Simplification to rilpivirine/emtricitabine/ tenofovir disoproxil fumarate from ritonavirboosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants. AIDS 2014; 28:335-44. 62. Sax PE, DeJesus E, Mills A, et al. Coformulated elvitegravir, cobicistat, emtricit abine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012; 379:2439-48. [Erratum, Lancet 2012;380: 730.] 63. Zolopa A, Sax PE, DeJesus E, et al. A randomized double-blind comparison of coformulated elvitegravir/cobicistat/ emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir dis oproxil fumarate for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr 2013;63:96100. 64. Wohl DA, Cohen C, Gallant JE, et al. A randomized, double-blind comparison of single-tablet regimen elvitegravir/cobicistat/ emtricitabine/tenofovir DF versus singletablet regimen efavirenz/emtricitabine/ tenofovir DF for initial treatment of HIV-1 infection: analysis of week 144 results. J Acquir Immune Defic Syndr 2014;65(3): e118-e120. 65. DeJesus E, Rockstroh JK, Henry K, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet 2012;379:2429-38. 66. Pozniak A, Markowitz M, Mills A, et al. Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of non-nucleoside reverse transcriptase inhibitor with emtri cita bine and tenofovir in virologically suppressed adults with HIV (STRATEGYNNRTI): 48 week results of a randomised, open-label, phase 3b non-inferiority trial. Lancet Infect Dis 2014;14:590-9. 67. Arribas JR, Pialoux G, Gathe J, et al. Simplification to coformulated elvitegra-
vir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial. Lancet Infect Dis 2014;14:581-9. 68. Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir–lamivudine for the treatment of HIV-1 infection. N Engl J Med 2013;369:1807-18. 69. Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitornaive adults with HIV: week 48 results from the randomised, double-blind, noninferiority SAILING study. Lancet 2013; 382:700-8. [Erratum, Lancet 2014;383:30.] 70. Eron JJ, Clotet B, Durant J, et al. Safety and efficacy of dolutegravir in treatmentexperienced subjects with raltegravir- resistant HIV type 1 infection: 24-week results of the VIKING Study. J Infect Dis 2013;207:740-8. 71. Castagna A, Maggiolo F, Penco G, et al. Dolutegravir in antiretroviral-experienced patients with raltegravir- and/or elvitegravirresistant HIV-1: 24-week results of the phase III VIKING-3 Study. J Infect Dis 2014 February 23 (Epub ahead of print). 72. Weller S, Chen S, Borland J, Savina P, Wynne B, Piscitelli S. Bioequivalence of a dolutegravir, abacavir and lamivudine fixed-dose combination tablet and the effect of food. J Acquir Immune Defic Syndr 2014;66:393-8. 73. ViiV Healthcare announces US regulatory submission for a single-tablet regimen combining dolutegravir with abacavir and lamivudine for people living with HIV. Press release of ViiV Healthcare, October 22, 2013 (http://www.viivhealthcare.com/ media/press-releases/2013/october/viiv -healthcare-announces-us-regulatory -submission-for-a-single-tablet-regimen -combining-dolutegravir-with-abacavir -and-lamivudine-for-people-living-with -hiv.aspx). 74. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr 2014 May 27 (Epub ahead of print). 75. Gallant JE, Koenig E, Andrade- Villanueva J, et al. Cobicistat versus r i t onavir as a pharmacoenhancer of atazan avir plus emtricitabine/tenofovir dis oproxil fumarate in treatment-naive HIV type 1 -infected patients: week 48 results. J Infect Dis 2013;208:32-9. 76. Bristol-Myers Squibb submits new drug application to U.S. FDA for a fixeddose combination tablet of atazanavir sulfate with cobicistat for people living with HIV-1. Press release of Bristol-Myers Squibb, April 14, 2014 (http://news.bms.com/press -release/bristol-myers-squibb-submits -new-drug-application-us-fda-fixed-dose
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clinical ther apeutics -combination-tablet#sthash.CKqvvBOS .dpuf ). 77. Kakuda TN, Opsomer M, Timmers M, et al. Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared with coadministration of daruna vir and ritonavir as single agents in healthy volunteers. J Clin Pharmacol 2014 March 19 (Epub ahead of print). 78. Janssen submits new drug application to U.S. FDA for a fixed-dose combination tablet of HIV-1 medicine darunavir with cobicistat as part of combination HIV therapy. Press release of Johnson & Johnson, April 1, 2014 (http://www.investor.jnj.com/ releasedetail.cfm?ReleaseID=836924). 79. Walensky RP, Sax PE, Nakamura YM, et al. Economic savings versus health
losses: the cost-effectiveness of generic antiretroviral therapy in the United States. Ann Intern Med 2013;158:84-92. 80. Engsig F, Gerstoft J, Helleberg M, Kronborg G, Mathiesen L, Obel N. Virological response in patients, who for economic reasons were changed from Atripla to a multitablet cART regimen. Presented at the 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, March 3–6, 2013. abstract. 81. Williams I, Churchill D, Anderson J, et al. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012 (updated November 2013: all changed text is cast in yellow highlight). HIV Med 2014;15:Suppl 1:1-85.
82. European AIDS Clinical Society guide-
lines: version 7.02, updated June 2014 (http:// www.eacsociety.org/guidelines.aspx). 83. Oxford Centre for Evidence-Based Medicine Levels of Evidence Working Group. The Oxford levels of evidence 2, updated 2011 (http://www.cebm.net/index.aspx?o=5653). 84. Thompson MA, Mugavero MJ, Amico KR, et al. Guidelines for improving entry into and retention in care and antiretroviral adherence for persons with HIV: evidencebased recommendations from an International Association of Physicians in AIDS Care panel. Ann Intern Med 2012;156: 817-33. Copyright © 2014 Massachusetts Medical Society.
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clinical therapeutics John A. Jarcho, M.D., Editor
Single-Pill Combination Regimens for Treatment of HIV-1 Infection Monica Gandhi, M.D., M.P.H., and Rajesh T. Gandhi, M.D. This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors’ clinical recommendations. From the Division of HIV/AIDS, University of California, San Francisco (UCSF), San Francisco (M.G.); and the Division of Infectious Diseases, Massachusetts General Hospital (MGH), Boston, and the Ragon Institute of MGH, Massachusetts Institute of Technology, and Harvard, Cambridge, MA (R.T.G.). Address reprint requests to Dr. Monica Gandhi at UCSF, 995 Potrero Ave., 4th Fl., San Francisco, CA 94110, or at [email protected]; or to Dr. Rajesh T. Gandhi at MGH, GRB 504, Infectious Diseases, 55 Fruit St., Boston, MA 02114, or at [email protected].
A 52-year-old man with a history of homelessness, depression, and polysubstance use received a diagnosis of human immunodeficiency virus type 1 (HIV-1) infection in 2005 but has declined antiretroviral therapy (ART) in the past. His CD4+ T-cell count is now 257 per cubic millimeter, and his plasma HIV-1 RNA level is 17,000 copies per milliliter. The patient was prescribed a multipill antiretroviral regimen 2 months ago but has not followed this regimen regularly because “taking out lots of pills in the shelter just announces to the world that I have AIDS [the acquired immunodeficiency syndrome].” The patient desires to keep his HIV status private and states that he would take medications regularly if he could take just “one pill once a day.” The patient is not taking any other medications; his renal function is normal. How should he be evaluated and treated?
* Drs. Gandhi and Gandhi contributed equally to this article.
The Cl inic a l Probl em
N Engl J Med 2014;371:248-59. DOI: 10.1056/NEJMct1215532 Copyright © 2014 Massachusetts Medical Society.
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Effective HIV treatment requires lifelong and daily consumption of multiple antiretroviral medications. With the advent and refinement of combination ART, the life expectancy of HIV-infected patients has risen dramatically.1,2 In addition to benefiting infected persons, ART almost completely blocks HIV-1 transmission to uninfected sexual partners.3 If we were able to treat most or all HIV-infected patients and thereby prevent new infections, “the beginning of the end of AIDS” would be in sight.4,5 For the benefits of ART to be realized at the individual and population levels, patients must maintain high levels of adherence to all components of the regimen. A number of factors are associated with lower levels of adherence,6 including the stigma associated with HIV infection,7 membership in a minority racial or ethnic group,8-11 depression,9,12,13 alcohol or drug use,14 cognitive impairment,15 young age,10 and medication side effects.16 Moreover, rates of adherence to ART may decline over time,10,12,17-20 even when antiretroviral agents are provided at no cost. There is therefore a compelling need for strategies that can help patients sustain lifelong adherence to treatment. When effective ART was first developed almost two decades ago, adherence was particularly challenging because patients had to consume handfuls of pills, often with substantial toxicity, multiple times per day. With the introduction of coformulated drugs that are less toxic and more potent, there have been dramatic reductions in the pill burden. This trend has culminated in single-pill combinations, in which all components of an ART regimen, typically three or more medications from two different drug classes, are formulated into one pill taken once daily. n engl j med 371;3 nejm.org july 17, 2014
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clinical ther apeutics
Biol o gic Fe at ur e s of HI V-1 infec t ion The rationale for lifelong combination therapy for HIV-1 infection and the interest in developing single-pill combinations to facilitate adherence are based on the biologic features of the virus (Fig. 1). Because of the high replication and mutation rates of HIV-1, multiple antiretroviral agents (usually three) must be taken simultaneously to suppress replication and prevent the development of viral resistance. ART can reduce HIV-1 RNA to extremely low levels in the blood, although the virus still persists in reservoirs found in specialized immune cells and tissues.21 Because antiretroviral regimens typically cannot eradicate infection, even when additional agents are added,22,23 therapy must be continued over a lifetime to suppress viral replication and prevent HIV-related complications. Owing to the ability of HIV-1 to mutate rapidly, the effect of suboptimal adherence to ART can be devastating (Fig. 2). Incomplete adherence leads to ongoing HIV-1 replication, which, in the presence of low-to-moderate levels of drug exposure, can select for viral strains with mutations conferring resistance to those agents. The rapidity with which drug-resistant strains emerge and the subsequent immunologic and clinical consequences vary according to the HIV-1 RNA level, the antiretroviral class, and the fitness of the mutant virus. At the individual level, inconsistent adherence can lead to drug resistance, permanently rendering particular agents or classes of drugs ineffective.24 At the population level, inconsistent use of antiretroviral agents can lead to ongoing transmission and the spread of drugresistant viral strains. Regimens with a low pill burden, such as single-pill combinations, may both facilitate adherence over a prolonged period and ensure that none of the components of a combination regimen are inadvertently missed.
Cl inic a l E v idence There are currently three single-pill combinations marketed for HIV-1 treatment, each containing the same combination of one nucleotide reverse-transcriptase inhibitor and one nucleoside reverse-transcriptase inhibitor (NRTIs): tenofovir disoproxil fumarate (TDF) at a dose of 300 mg and emtricitabine (FTC) at a dose of 200 mg, respectively. The first agent (Atripla, Bristol-Myers
Squibb and Gilead Sciences), released in 2006, is a single pill that combines TDF–FTC with 600 mg of the nonnucleoside reverse-transcriptase inhibitor (NNRTI) efavirenz (EFV). The second agent (Complera, Gilead Sciences), approved in 2011, combines TDF–FTC with 25 mg of the NNRTI rilpivirine (RPV). The third agent (Stribild, Gilead Sciences), released in 2012, consists of TDF–FTC combined with 150 mg of the integrase strandtransfer inhibitor (INSTI) elvitegravir (EVG) and 150 mg of the pharmacoenhancer cobicistat (which boosts serum EVG levels). A fourth singlepill combination is in development and has not yet been approved for clinical use. This agent would combine two NRTIs — abacavir (ABC) at a dose of 600 mg and lamivudine (3TC) at a dose of 300 mg — with 50 mg of the recently approved INSTI dolutegravir (DTG). Studies of once-daily dosing of antiretroviral agents provide support for the concept that regimen simplification improves adherence. One metaanalysis examined adherence among patients with HIV-1 infection who received either oncedaily or twice-daily regimens in 19 randomized, controlled studies (6321 patients).20 Modestly better adherence, assessed by means of pill counts or medication-event monitoring systems, was observed among recipients of once-daily regimens (an increase of 2.55 percentage points, P50 ml/min). DTG has had a high genetic barrier to resistance in trials to date. DTG is not known to be teratogenic in humans (pregnancy class B).
DTG inhibits creatinine secretion, leading to a small rise in the serum creatinine level in some patients (mean increase at 48 wk, 0.1 mg/dl [range, −0.6 to 0.6]) — an increase similar to that observed with cobicistat. Use of ABCcontaining regimens requires genetic testing for HLA B5701, an allele that predicts hypersensitivity to this drug. DTG should be taken at least 2 hr before or 6 hr after oral administration of sucralfate or cation-containing antacids or laxatives with magnesium or aluminum; calcium or iron supplements can be administered with DTG with food (otherwise, DTG should be taken at least 2 hr before or 6 hr after the supplement is taken). Double the dose with concomitant rifampin or EFV; do not use with etravirine unless boosted protease inhibitors are being administered. No dose adjustments are needed with RPV. There is limited clinical experience with DTG to date (approved in August 2013). Some studies have shown a link between ABC and myocardial infarction, but there was no such relationship in other studies and an FDA meta-analysis.
In development for HIV-1 infection EVG–cobicistat– Data to 48 wk suggest TAF may be associated TAF–FTC with smaller reductions in bone density and estimated creatinine clearance than TDF.
Available data are from a phase 2 study; no data beyond 48 wk are available. More information is needed.
* ABC denotes abacavir, DTG dolutegravir, EFV efavirenz, EVG elvitegravir, FDA Food and Drug Administration, FTC emtricitabine, HBV hepatitis B virus, HIV human immunodeficiency virus, INSTI integrase strand-transfer inhibitor, NNRTI nonnucleoside reverse-transcriptase inhibitor, QTc corrected QT, RPV rilpivirine, TAF tenofovir alafenamide, TDF tenofovir disoproxil fumarate, and 3TC lamivudine. To convert the values for creatinine to micromoles per liter, multiply by 88.4.
Agents in Development for Use in Single-Pill Combinations
A r e a s of Uncer ta in t y
Tenofovir alafenamide (TAF), a prodrug of tenofovir that is converted to the active form in lymphocytes, is an agent being developed for use in single-pill combinations. The virologic activity of TAF was similar to that of TDF when each was coformulated with cobicistat–EVG–FTC and taken for 48 weeks.74 The TAF-containing regimen caused a smaller decline in bone mineral density and estimated creatinine clearance than the TDF-containing combination. Further studies of TAF-containing single-pill combinations, including ones that include protease inhibitors, are under way. Applications for the fixed-dose combinations of atazanavir– cobicistat75,76 and darunavir–cobicistat77,78 are under review at the FDA, and a single-pill combination regimen of darunavir–cobicistat–TAF– FTC is being studied in clinical trials.
The potential benefits of single-pill combinations must be weighed against the higher costs of these branded combinations as compared with multipill regimens containing generic antiretroviral agents. One analysis projected that switching patients with HIV-1 infection from the branded EFV–TDF–FTC single-pill combination to a three-pill regimen of generic EFV (not yet available), branded TDF, and generic 3TC would save almost $1 billion per year in the United States, with a relatively small reduction in treatment efficacy.79 A study from Denmark showed that switching patients from a branded singlepill combination to a cheaper multipill regimen did not compromise virologic efficacy.80 In patients who struggle with adherence, however, the decreased pill burden of a single-pill combina-
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tion could be crucial for successful treatment. Moreover, if a multipill regimen requires multiple copayments, the cumulative cost may be prohibitive for some patients. On a global scale, country- and region-specific pharmacoeconomic analyses are needed for single-pill combinations and other formulations (e.g., long-acting agents) designed to improve adherence.
Guidel ine s Of the single-pill combinations currently available, EFV–TDF–FTC is recommended in guidelines from the U.S. Department of Health and Human Services (DHHS),19 the International Antiviral Society–USA,45 and the British HIV Association.81 The WHO recommends EFV–TDF– FTC or EFV–TDF–3TC, formulated as a single-pill combination, as first-line agents.54 EVG–cobicistat– TDF–FTC is recommended for previously untreated patients in the DHHS and British guidelines.19,81 RPV–TDF–FTC is recommended by the DHHS only for patients with pretherapy HIV-1 RNA levels of less than 100,000 copies per milliliter and CD4+ T-cell counts of more than 200 per cubic millimeter.19 The European AIDS Clinical Society recommends the following single-pill combination regimens: EFV–TDF–FTC, EVG–cobicistat–TDF– FTC, and, if the HIV-1 RNA level is less than 100,000 copies per milliliter, RPV–TDF–FTC.82 The use of fixed-dose combinations was listed as an adherence-boosting strategy (level of evidence, IIIB)83 in a statement by an International Association of Physicians in AIDS Care panel.84 However, the panel called for future research comparing single-pill combinations with their individual drug components, including analyses of cost. References 1. May MT, Gompels M, Delpech V, et al. Impact on life expectancy of HIV-1 positive individuals of CD4+ cell count and viral load response to antiretroviral therapy: UK cohort study. AIDS 2014 February 19 (Epub ahead of print). 2. Bor J, Herbst AJ, Newell ML, Bärnig hausen T. Increases in adult life expectancy in rural South Africa: valuing the scale-up of HIV treatment. Science 2013; 339:961-5. 3. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365:493-505. 4. Havlir D, Beyrer C. The beginning of the end of AIDS? N Engl J Med 2012;367: 685-7.
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R ec om mendat ions The first step in evaluating the patient described in the vignette would be to check the HIV-1 genotype to determine whether prior inconsistent use of ART has selected for drug resistance. If not, a singlepill combination is an attractive option owing to the low pill burden and the patient’s stated preference. TDF–FTC, the only NRTI backbone in currently available single-pill combinations, would be reasonable for this patient, given his normal renal function. Although a regimen containing a protease inhibitor as the anchor is sometimes selected if adherence is uncertain, the patient indicates that he is more likely to adhere to a single-pill combination. Each of the anchor drugs in currently available single-pill combinations would be suitable because of his normal renal function and relatively low HIV-1 RNA level and because he is not taking other medications. The selection of a regimen should be based on potential side effects, food requirements, dosing schedule, and, possibly, anticipated adherence; cost may also be a consideration. Regardless of which regimen is chosen, careful clinical, virologic, and immunologic monitoring, along with regular adherence assessment and counseling, will be key contributors to treatment success. Dr. Rajesh Gandhi reports receiving grant support through his institution from ViiV Healthcare, Abbott Laboratories, and Janssen Pharmaceuticals. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Drs. Diane Havlir, David Bangsberg, Rochelle Walensky, Harry Lampiris, Joseph Eron, and Rakesh Mishra for helpful input in reviewing the content, Kelsey Han for her assistance, and our patients at Ward 86 and Massachusetts General Hospital for providing the inspiration.
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KM, Williams BG. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet 2009;373:48-57. 6. Bangsberg DR, Mills EJ. Long-term adherence to antiretroviral therapy in resource-limited settings: a bitter pill to swallow. Antivir Ther 2013;18:25-8. 7. Earnshaw VA, Smith LR, Chaudoir SR, Amico KR, Copenhaver MM. HIV stigma mechanisms and well-being among PLWH: a test of the HIV stigma framework. AIDS Behav 2013;17:1785-95. 8. O’Connor JL, Gardner EM, Mannheimer SB, et al. Factors associated with adherence amongst 5295 people receiving antiretro
viral therapy as part of an international trial. J Infect Dis 2013;208:40-9. 9. Kong MC, Nahata MC, Lacombe VA, Seiber EE, Balkrishnan R. Association between race, depression, and antiretroviral therapy adherence in a low-income population with HIV infection. J Gen Intern Med 2012;27:1159-64. 10. Mannheimer S, Friedland G, Matts J, Child C, Chesney M. The consistency of adherence to antiretroviral therapy predicts biologic outcomes for human immunodeficiency virus-infected persons in clinical trials. Clin Infect Dis 2002;34: 1115-21. 11. Simoni JM, Huh D, Wilson IB, et al. Racial/ethnic disparities in ART adherence in the United States: findings from
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