Lower Pill Burden With Single-Tablet Antiretroviral Therapy for HIV-1 Infection - Infectious Disease Advisor
Key Takeaways
- Compared with multi-tablet regimens (MTRs) for antiretroviral therapy (ART), the lower pill burden of single-tablet regimens (STRs) may improve ART adherence and persistence.
- STRs that include an integrase inhibitor as the anchor drug and a nucleoside or nucleotide reverse transcriptase inhibitor (NRTI)-based backbone are recommended as the initial treatment for most patients, based on the high tolerability and simplified dosing associated with these regimens.
- Clinical guidelines support the use of a protease inhibitor-based STR for patients with pre-existing or possible drug resistance.
- Side effects of STRs and MTRs are typically associated with the components of each regimen, rather than the number of tablets required.
- Renal function is a key consideration when using STRs; some STRs may require dose adjustment and conversion to MTRs for patients with renal failure.
The introduction of ART regimens consisting of single-dose, once-daily pills has substantially improved the treatment landscape for people living with human immunodeficiency virus (HIV). The results of numerous studies have highlighted the benefits of STRs for ART in this population; a meta-analysis of 11 randomized controlled trials revealed significantly higher rates of adherence among patients taking STRs than among patients taking regimens that required 2 or 3 pills daily.1 Another study showed a 17% reduction in healthcare costs and a 23% reduction in hospitalizations among people with HIV receiving STRs rather than MTRs.2
Ken Ho, MD, MPH, is an associate professor of medicine in the Division of Infectious Diseases at the University of Pittsburgh School of Medicine in Pittsburgh, Pennsylvania, and medical director of the Pitt Men's Study (part of the Multicenter AIDS Cohort Study). His clinical interests include HIV care and pre-exposure prophylaxis (PrEP), and his research includes multiple studies investigating PrEP and the use of microbicides in HIV prevention. In this article, Ken Ho, MD, MPH, discusses the impacts of STRs on pill burden, adherence, and other outcomes in patients with HIV-1 infection, as well as clinical considerations regarding treatment selection and potential side effects associated with STRs.
Compared with MTRs for ART, how has the lower pill burden of once-daily STRs affected treatment adherence among patients with HIV-1 infection? Are there any unique challenges or advantages associated with once-daily dosing in terms of long-term treatment success?
Since the advent of effective combination ART in 1996, people living with HIV have had access to effective regimens that offer durable viral suppression. Early regimens — especially protease inhibitor-based regimens — involved a substantial pill burden that often required multiple pills to be taken several times each day. Many of these medications also had severe side effects.3
The ART landscape was transformed by the introduction of fixed-dose combination efavirenz, tenofovir disoproxil fumarate, and emtricitabine, which constituted the first US Food and Drug Administration (FDA)-approved once-daily STR for the treatment of HIV.4 Multiple STRs have been established since then, expanding the available treatment options for people living with HIV.
The advantages of STRs include a reduced pill burden, the convenience of a single copay, and a lower risk of selective nonadherence to components of the regimen.1 Forgetfulness is often regarded as a cause of nonadherence5; STRs are likely to mitigate this issue by reducing pill burden. There is also evidence that STRs are associated with greater adherence and persistence to ARTs among people living with HIV.1,2
There are relatively few disadvantages of STRs. For patients with swallowing difficulty who must crush or dissolve pills, certain STRs may not be recommended because crushing or dissolving those pills may impact drug release.6 In such situations, it is preferable to consult with a pharmacist who has extensive knowledge regarding antiretrovirals.
Can you discuss key factors to consider when selecting the optimal STR for a patient?
There are several options for STRs and several factors to consider when selecting the best STR for a patient, including the patient's treatment history, viral load, renal function, concurrent medications, and ability to swallow pills.7
Fixed-dose emtricitabine/tenofovir alafenamide/bictegravir (FTC/TAF/BIC) is 1 of the most frequently used antiretroviral regimens. Patients must have a creatinine clearance of at least 30 mL/minute (at least 15 mL/minute among patients with no history of antiretroviral treatment) to begin taking FTC/TAF/BIC. There are relatively few drug-drug interactions with FTC/TAF/BIC, but the cardiac medication dofetilide and the microbial medication rifampin are contraindicated.8
Fixed-dose abacavir/lamivudine/dolutegravir is another option; however, this regimen requires HLA-B*5701 testing prior to initiation, which limits its use in rapid-start contexts. Patients with the HLA-B*5701 allele should avoid any abacavir-containing regimens to prevent life-threatening hypersensitivity reactions.9 Additionally, this regimen involves a very large pill, which may be problematic for patients with swallowing difficulty.
Fixed-dose dolutegravir/lamivudine, a 2-drug regimen, should not be used for initial treatment of HIV if the viral load exceeds 500,000 copies/mL.7 Patients with chronic hepatitis B may consider alternative regimens that contain tenofovir; these regimens enable simultaneous treatment of hepatitis B.10
In what patient populations has darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) demonstrated significant clinical benefits, and should clinicians consider any specific factors or contraindications when selecting this regimen?
Fixed-dose D/C/F/TAF is the only protease inhibitor-based, fixed-dose, single-pill, once-daily regimen available.11 Protease inhibitor-based regimens have advantages and disadvantages. Historically, protease inhibitor-based regimens have been preferred for patients with a history of resistance or nonadherence because multiple mutations are required to develop clinically significant resistance; these regimens tend to be more forgiving with respect to nonadherence.12
Current guidelines support using protease inhibitor-based regimens in the context of pre-existing drug resistance or in cases of potential resistance.13 For example, they could be used for the treatment of a patient who exhibits seroconversion while on long-acting injectable cabotegravir and might develop integrase inhibitor resistance.
Although protease inhibitors such as darunavir are generally well tolerated, they can cause gastrointestinal side effects, including nausea, vomiting, and diarrhea, as well as metabolic effects (eg, weight gain, lipid abnormalities, and an increased risk for diabetes).14 A notable disadvantage of protease inhibitor-based regimens — both STRs and MTRs — is the potential for drug-drug interactions arising from the pharmacologic boost provided by cobicistat, a potent cytochrome P450 3A4 (CYP3A4) inhibitor. Clinically significant interactions may occur with statins, anticoagulants, and certain steroids. This concern is also applicable to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, an integrase inhibitor-based STR that contains the CYP3A4 inhibitor cobicistat.15
Based on the available evidence and your observations in clinical practice, how do STRs impact other patient outcomes, such as virologic suppression and hospitalization?
For most patients, STRs optimize adherence by reducing pill burden.2 In my experience, providers generally prefer STRs over MTRs for antiretroviral-naive patients newly diagnosed with HIV, if possible, to minimize pill burden. This preference is supported by evidence from retrospective studies. A study published in 2012 (concerning data from 2006 to 2008) showed that once-daily STRs were associated with greater ART adherence and fewer hospitalizations, relative to MTRs.16
In another study, Hines and colleagues examined recent regimens based on claims data from 2016. Adherence was assessed by recording gaps longer than 5 days between medication refills. Similar to the findings from the 2012 study, patients taking STRs were more likely to be adherent than patients taking MTRs. At 12 months, approximately 25% of patients taking STRs continued to display adherence, compared with approximately 12% of patients taking MTRs.17
Although this evidence is largely collected from retrospective studies, it suggests that STRs are associated with adherence. Despite the potential for confounding variables in these studies, the results are generally consistent with clinical practice. There is extensive documentation in the HIV literature that adherence is strongly associated with viral load suppression,18 supporting the inference that better adherence is linked to improved survival outcomes and other benefits, such as reduced HIV transmission.
Can you discuss the relative safety profiles of STRs and MTRs for ART? What strategies can be used to monitor and manage side effects with STRs?
When clinicians consider medication safety profiles, they typically focus on side effects. With respect to STRs and MTRs, side effects are often influenced by the regimen components rather than the number of tablets involved. Thus, the side effects of a particular STR and its equivalent MTR theoretically should be identical. However, in my clinical experience, some patients have reported differences in side effects between STRs and MTRs. Because of these differences, some patients may prefer MTRs over STRs (or STRs over MTRs). For such patients, a risk-benefit discussion is needed during regimen selection.
Pill size can present a challenge for some STRs, particularly among patients with swallowing difficulty. Although liquid formulations offer an alternative approach, they are not available for some regimens. A potential solution involves prescribing these STRs as their component medications, converting them into MTRs. Usually, the components are substantially smaller than the STR formulation, which may be helpful for patients with swallowing difficulty. However, an operational concern affecting MTRs is that pharmacies may only stock some components of an MTR.
Finally, it is important to consider the role of renal function in the context of STR use. The components of an STR may have distinct safety thresholds. For example, consider a patient with HIV taking FTC/TAF/BIC who experiences a clinically significant decline in renal function, leading to a creatinine clearance of 20 mL/minute — this patient would no longer be eligible for the FTC/TAF/BIC regimen.8
Some STRs remain viable options for patients with renal failure, but it is important to determine whether the components require dose adjustments and conversion to an MTR approach. Some STRs, such as dolutegravir/rilpivirine, do not require renal dose adjustment and can be prescribed for patients with renal failure.19 For the above patient previously taking FTC/TAF/BIC, assuming there is no resistance, stable viral suppression, and no proton pump inhibitor use (to avoid interaction with rilpivirine), dolutegravir/rilpivirine may be an appropriate alternative STR.
Can you describe existing barriers to the broader STR uptake among patients with HIV-1 and measures needed to reduce these barriers?
Generally, patients and providers are in agreement regarding STR uptake: patients want STRs and providers prefer to prescribe STRs. Notable barriers to STR access include insurance prescription plans that exclude some STRs, causing patients to navigate multiple copays and manage the increased pill burden associated with MTRs. Some patients with multidrug resistance may only be eligible for an MTR because of the specific patterns of resistance involved in their infection. Such patients often require a tailored MTR. The availability of diverse STR options will help to reduce pill burden for patients with HIV-1, improving their capacity for medication adherence.
This Q&A was edited for clarity and length.
References
1. Choudhary MC, Mellors JW. The transformation of HIV therapy: one pill once a day. Antivir Ther. 2022;27(2):13596535211062396. doi:10.1177/13596535211062396
2. Cohen CJ, Meyers JL, Davis KL. Association between daily antiretroviral pill burden and treatment adherence, hospitalisation risk, and other healthcare utilisation and costs in a US medicaid population with HIV. BMJ Open. 2013;3(8):e003028. doi:10.1136/bmjopen-2013-003028
3. Antiretroviral drug discovery and development. National Institute of Allergy and Infectious Diseases. Updated February 5, 2024. Accessed February 7, 2024. https://www.niaid.nih.gov/diseases-conditions/antiretroviral-drug-development
4. U.S. Food and Drug Administration (FDA) approves ATRIPLA(TM) (efavirenz 600 mg/ emtricitabine 200 mg/ tenofovir disoproxil fumarate 300 mg), the first once-daily single tablet regimen for adults with HIV-1 Infection. News release. Gilead Sciences, Inc. July 12, 2006. Accessed February 8, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2006/7/us-food-and-drug-administration-fda-approves-atriplatm-efavirenz-600-mg-emtricitabine-200-mg-tenofovir-disoproxil-fumarate-300-mg-the-first
5. Freeman R, Gwadz M, Francis K, Hoffeld E. Forgetting to take HIV antiretroviral therapy: a qualitative exploration of medication adherence in the third decade of the HIV epidemic in the United States. SAHARA J. 2021;18(1):113-130. doi:10.1080/17290376.2021.1989021
6. Hocqueloux L, Lefeuvre S, Bois J, et al. Bioavailability of dissolved and crushed single tablets of bictegravir, emtricitabine, tenofovir alafenamide in healthy adults: the SOLUBIC randomized crossover study. J Antimicrob Chemother. 2022;78(1):161-168. doi:10.1093/jac/dkac369
7. Urbina AE, McGowan JP, Fine SM, et al; New York State Department of Health AIDS Institute Medical Care Criteria Committee. Selecting an initial ART regimen. In: Clinical Guidelines Program. Johns Hopkins University; 2022.
8. BIKTARVY®. Prescribing information. Gilead Sciences, Inc; 2022. Accessed February 9, 2024. https://www.gilead.com/~/media/files/pdfs/medicines/hiv/biktarvy/biktarvy_pi.pdf
9. TRIUMEQ. Prescribing information. GlaxoSmithKline, PLC; 2014. Accessed February 9, 2024. www.accessdata.fda.gov/drugsatfda_docs/label/2014/205551s000lbl.pdf
10. Kim HN. Chronic hepatitis B and HIV coinfection: a continuing challenge in the era of antiretroviral therapy. Curr Hepatol Rep. 2020;19(4):345-353. doi:10.1007/s11901-020-00541-x
11. Huhn GD, Eron JJ, Girard PM, et al. Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-experienced, virologically suppressed patients with HIV-1: subgroup analyses of the phase 3 EMERALD study. AIDS Res Ther. 2019;16(1):23. doi:10.1186/s12981-019-0235-1
12. Gardner EM, Burman WJ, Steiner JF, Anderson PL, Bangsberg DR. Antiretroviral medication adherence and the development of class-specific antiretroviral resistance. AIDS. 2009;23(9):1035-1046. doi:10.1097/QAD.0b013e32832ba8ec
13. Gandhi RT, Bedimo R, Hoy JF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2022 recommendations of the International Antiviral Society-USA Panel. JAMA. 2023;329(1):63-84. doi:10.1001/jama.2022.22246
14. Marin RC, Behl T, Negrut N, Bungau S. Management of antiretroviral therapy with boosted protease inhibitors-darunavir/ritonavir or darunavir/cobicistat. Biomedicines. 2021;9(3):313. doi:10.3390/biomedicines9030313
15. Stolbach A, Paziana K, Heverling H, Pham P. A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products. J Med Toxicol. 2015;11(3):326-341. doi:10.1007/s13181-015-0465-0
16. Sax PE, Meyers JL, Mugavero M, Davis KL. Adherence to antiretroviral treatment and correlation with risk of hospitalization among commercially insured HIV patients in the United States. PLoS One. 2012;7(2):e31591. doi:10.1371/journal.pone.0031591
17. Hines DM, Ding Y, Wade RL, Beaubrun A, Cohen JP. Treatment adherence and persistence among HIV-1 patients newly starting treatment. Patient Prefer Adherence. 2019;13:1927-1939. doi:10.2147/PPA.S207908
18. T Tchakoute C, Rhee SY, Hare CB, Shafer RW, Sainani K. Adherence to contemporary antiretroviral treatment regimens and impact on immunological and virologic outcomes in a US healthcare system. PLoS One. 2022;17(2):e0263742. doi:10.1371/journal.pone.0263742
19. Kang J, Kim Y. Use of dolutegravir/rilpivirine in treatment of HIV in PLWH with CKD and ESRD. Open Forum Infect Dis. 2021;8(Suppl 1):S540-S541. doi:10.1093/ofid/ofab466.1094
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Reviewed February 2024
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