Optimizing ART for Patients With a History of Treatment Failure and Resistance
A review of treatment modalities for this patient population.
The treatment of HIV infection for newly-diagnosed patients has been simplified in recent years with the advent of highly active antiretroviral therapy and the use of single-tablet regimens (STRs)—tablets that contain 2 or more medications in 1 pill, providing a complete daily regimen. STR data demonstrate excellent efficacy with virologic suppression rates over 90%.1-5 Current guidelines from the International Antiviral Society–USA panel (IAS–USA) and the US Department of Health & Human Services (HHS) guidelines recommend use of an integrase strand transfer inhibitor (INSTI) in combination with 1 to 2 nucleoside reverse transcriptase inhibitors (NRTIs) for initial therapy.6,7 INSTI-based regimens are preferred for treatment-naïve patients because of their advantages over older regimens relating to efficacy, tolerability, and risk of drug-drug interactions.6,7
For patients with HIV treatment failure associated with prior regimens, suboptimal medication adherence, or significant HIV resistance, optimal therapy that leads to an undetectable HIV viral load can be challenging. Patients with prior HIV treatment failure and significant resistance often have regimens involving medications requiring more than once daily dosing, relatively large pill burdens, potential increased risk of drug-drug interactions, and tolerability concerns. The reasons for why patients fail previous regimens are multifactorial but can be placed into 3 broad categories: patient related, HIV related, and regimen related.6, 8-10
Patient-related factors related to adherence are common, especially with those requiring multiple tablets taken several times a day for their HIV regimen. Comorbidities—especially active substance abuse, mental health disorders and other neurocognitive impairment—can lead to missed doses and adherence challenges. Other psychosocial issues such as unstable housing, lack of transportation, and communication difficulties (ie, unpaid phone bills or lack of cell phones) can lead to missed clinic appointments. HIV medication and insurance issues related to formulary restrictions can also be a challenge.
HIV-related factors such as the presence of transmitted or acquired drug resistance, prior treatment failures, innate resistance to certain HIV medications, and high pretreatment viral loads can contribute to virologic failure.
HIV regimen–related factors such as suboptimal pharmacokinetics or viral potency, low barriers to HIV resistance, food requirements, drug-drug interactions, and medication/dispensing errors may lead to virologic failure. When optimizing a patient’s treatment regimen, it is crucial that providers consider all these factors—a new regimen is not going to work in someone unwilling to take it, so open patient and provider communication is encouraged when making a regimen change.
A critical component in successfully optimizing an HIV regimen is to gather and review all previous resistance tests to obtain an accurate, complete assessment of prior HIV resistance. A complete history of prior HIV regimens is also important—use of preprinted charts with medication names and pictures can help the patient remember prior regimens. When resistance tests are compiled and evaluated, print and online databases such as the IAS–USA 2019 HIV Drug Resistance Mutations Update and the Stanford University HIV Drug Resistance Database can assist in selecting the new regimen.11,12 Although the application of these databases to patient care can be complex, they are crucial in making appropriate decisions when selecting the next regimen; expert consultation is recommended with more complex cases and the National Clinician Consultation Center (800-933-3413) can be helpful in making decisions.13 Once resistance testing is reviewed and analyzed, it is typical to construct a new HIV regimen that ideally contains 3 fully active drugs; however, this is not always possible.6 If only 2 active drugs can be used in the new regimen, the HHS guidelines recommend use of at least 1 with a high barrier to resistance—these include a second-generation INSTI such as dolutegravir or bictegravir; or a regimen containing boosted darunavir.6 Regimens that may be selected for patients with significant resistance usually have acceptable pharmacokinetic data (ie, the drugs combined have acceptable blood levels); however, clinical data on their efficacy may be lacking. For example, to minimize pill burden in patients, providers may select an STR and add an additional medication to it to construct a fully active regimen with the smallest pill burden possible. In doing so, providers combine medications for treatment-experienced patients outside of United States Food and Drug Administration (FDA) labeling to provide the smallest pill burden for the patient to maximize success in attaining an undetectable viral load (see Table6 for examples). Print or online databases should also be consulted to ensure drug-drug interactions with the new regimen are evaluated—not just among the new HIV medications but also in combination with other primary care, psychiatric, and recreational therapies or substances the patient may be using. University of Liverpool (www. hiv-druginteractions.org) and the HHS HIV Guidelines Drug-Drug Interaction Tables are excellent recourses.6,14
NEW TREATMENT OPTIONS
Recent approval of medications designed for patients with treatment experience also provides new options that offer new tools to attain virologic suppression. Fostemsavir is a newer medication in a novel class of medications known as attachment inhibitors. A prodrug of temsavir, fostemsavir is approved by the FDA for use in combination with other antiretrovirals for treatment-experienced adults with resistant HIV who are failing their current antiretroviral regimen. Data supporting its approval were from the BRIGHTE study (NCT02362503) demonstrating that in patients with extensive prior HIV treatment (some with zero fully active medications), 60% of subjects who received fostemsavir with other medications attained an undetectable viral load through 96 weeks of treatment.15,16
Increases in CD4 count were also significant; subjects with initial CD4 counts of less than 20 cells/mm3 gained on average 240 additional T cells through 96 weeks.15,16 Fostemsavir was also found to be well tolerated with nausea being the most common adverse event. Although drug interactions are minimal with fostemsavir, concurrent use of cytochrome P450 3A4 inducers may decrease fostemsavir levels. Therefore, medications such as carbamazepine, phenytoin, St John’s wort (Hypericum perforatum), and rifampin should be avoided.6 HMG-CoA reductase inhibitors (statins) may be increased so lowest statin dose should be used. Please consult additional references for more extensive drug interaction information on fostemsavir.6,14 Based on its metabolism, fostemsavir can be combined with common HIV medications such as darunavir/cobicistat; dolutegravir and bictegravir; rilpivirine and doravirine; and tenofovir-containing regimens (Table6).
Ibalizumab, a CD4-directed postattachment HIV-1 inhibitor, is also indicated for use in heavily treatment-experienced patients with multidrug-resistant HIV. Ibalizumab is administered via intravenous infusion, dosed as a 2000-mg load and followed by a maintenance dose of 800 mg every 2 weeks.17 Some patients may experience infusion-related reactions during the infusion, although this is rare. It also is important that patients not miss their maintenance dose beyond 3 days; when this occurs, it requires reloading with the 2000-mg dose and may require insurance approval. Data supporting the approval of ibalizumab came from the TMB-301 trial (NCT02475629) in which heavily pretreated patients were given ibalizumab combined with an optimized background regimen. At 25 weeks, 43% of patients attained an undetectable viral load. Although ibalizumab can be useful in this patient population, the need for a monitored infusion and medication costs are factors that may hinder its use. The average wholesale acquisition cost is approximately $9900 per month, which requires prior authorization with insurance for coverage.6 Despite these challenges, ibalizumab can play an important role for patients with minimal options when optimizing therapy and trying to configure a regimen with active medications.
In addition to the FDA-approved options, an additional promising treatment for heavily pretreated patients is lenacapavir, one of a novel class of medications known as capsid inhibitors. Recent data from the CAPELLA study (NCT04150068) were presented demonstrating its efficacy in highly treatment-experienced patients. At study entry, patients had to have HIV resistance to at least 2 drugs from 3 of 4 commonly used drug classes (NRTIs, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and INSTIs) with no more than 2 fully active agents from any of those 4 classes.18 After adding lenacapavir to an optimized background regimen, 81% of subjects attained a viral load below 50 copies/mL and 89% were below 400 copies/mL at 26 weeks. In addition to its efficacy, lenacapavir is unique in that it is given as a long-acting subcutaneous injection that lasts 6 months.18 Although injection site reactions such as redness, swelling, and pain can occur, these reactions had resolved within 2 weeks in the study for most subjects.
Optimizing HIV treatment in heavily pretreated patients can be challenging and complex. Despite excellent efficacy of newer medications in treating HIV, success rates in more complex cases are not as robust. Despite these challenges, attaining and maintaining an undetectable HIV viral load and improving CD4 cell counts are still our goals of therapy. The use of HIV resistance tests is critical to constructing an appropriate regimen, and the use of the Stanford database and other resources can be helpful. Use of newer medications such as fostemsavir and ibalizumab (and potentially lenacapavir, if granted FDA approval) provides novel mechanisms of action to combine with older medications to construct regimens sufficient to provide a virologic response. Providers are encouraged to work closely with patients to ensure that the optimized HIV regimen is one they are open to taking, especially if it involves infusion or injectable medications.
- Cahn P, Madero JS, Arribas JR, et al. Durable efficacy of dolutegravir plus lamivudine in antiretroviral treatment-naive adults with HIV-1 infection: 96-week results from the GEMINI-1 and GEMINI-2 randomized clinical trials. J Acquir Immune Defic Syndr. 2020;83(3):310-318. doi:10.1097/QAI.0000000000002275
- Stellbrink HJ, Arribas JR, Stephens JL, et al. Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet HIV. 2019;6(6):e364-e372. doi:10.1016/S2352-3018(19)30080-3
- Wohl DA, Yazdanpanah Y, Baumgarten A, et al. Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet HIV. 2019;6(6):e355-e363. doi:10.1016/S2352-3018(19)30077-3
- Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1–infected patients at week 48. AIDS. 2008;22(12):1389-1397. doi:10.1097/QAD.0b013e32830285fb
- Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1–infected treatment-naive patients in the ARTEMIS trial. HIV Med. 2013;14(1):49-59. doi:10.1111/j.1468-1293.2012.01060.x
- Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Office of AIDS Research. Updated August 16, 2021. Accessed January 11, 2022. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv
- Saag MS, Gandhi RT, Hoy JF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2020 recommendations of the International Antiviral Society–USA Panel. JAMA. 2020;324(16):1651–1669. doi:10.1001/jama.2020.17025
- d’Arminio Monforte A, Lepri AC, Rezza G, et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naïve patients. I.CO.N.A. Study Group. Italian Cohort of Antiretroviral-Naïve Patients. AIDS. 2000;14(5):499-507. doi:10.1097/00002030-200003310-00005
- Mocroft A, Youle M, Moore A, et al. Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre. AIDS. 2001;15(2):185-194. doi:10.1097/00002030-200101260-00007
- Paredes R, Lalama CM, Ribaudo HJ, et al; AIDS Clinical Trial Group (ACTG) A5095 Study Team. Pre-existing minority drug-resistant HIV-1 variants, adherence, and risk of antiretroviral treatment failure. J Infect Dis. 2010;201(5):662-671. doi:10.1086/650543
- Wensing AM, Calvez V, Ceccherini-Silberstein F, et al. 2019 update of the drug resistance mutations in HIV-1. Top Antivir Med. 2019;27(3):111-121.
- Stanford University HIV Drug Resistance Database. Stanford University. Updated November 22, 2021. Accessed January 6, 2022. https://hivdb.stanford.edu/
- National Clinician Consultation Center. University of California, San Francisco. Accessed January 6, 2022. www.nccc.ucsf.edu
- HIV drug interactions. University of Liverpool. Updated January 12, 2022. Accessed January 6, 2022. www.hiv-druginteractions.org
- Lataillade M, Ackerman P, Schoofs T, Clark A, Kozal M. Fostemsavir in heavily treatment-experienced individuals living with HIV-1: insights from the phase 3 BRIGHTE study. J AIDS HIV Treat. 2021;3(2):31-36.
- Kozal M, Aberg J, Pialoux G, et al; BRIGHTE Trial Team. Fostemsavir in adults with multidrug-resistant HIV-1 infection. N Engl J Med. 2020;382:1232-1243. doi:10.1056/NEJMoa1902493
- Emu B, Fessel J, Schrader S, et al. Phase 3 study of ibalizumab for multidrug-resistant HIV-1. N Engl J Med. 2018;379(7):645-654. doi:10.1056/NEJMoa1711460
- Molina JM, Segal-Maurer S, Stellbrink HJ, et al. Efficacy and safety of long-acting subcutaneous lenacapavir in phase 2/3 in heavily treatment-experienced people with HIV: week 26 results (Capella study). Abstract OALA0101. Presented at: 11th IAS Conference on HIV Science; July 18-21, 2021; virtual. https://onlinelibrary.wiley.com/doi/full/10.1002/jia2.25755. Accessed 1.13.2022