Multidrug Resistance in a Patient With HIV

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Summary of Present Illness
A 59-year-old man with HIV (diagnosis, 1995) presents to the clinic for multidrug-resistant (MDR) HIV evaluation. Two months prior to this encounter, emtricitabine (FTC) monotherapy was prescribed secondary to significant antiretroviral (ARV) resistance and multiple complex comorbidities until HIV tropism results were completed to assist with an optimized background therapy (OBT). The patient’s ARV therapy (ART) history in our clinic included FTC/tenofovir disoproxil fumarate or alafenamide (TDF, TAF), doravirine (DOR), efavirenz, etravirine, rilpivirine (RPV), boosted atazanavir or darunavir (DRV), bictegravir (BIC), dolutegravir (DTG), raltegravir (RAL), and fostemsavir (FTR). A compiled genotype included the following resistance mutations: reverse transcriptase (RT) A62V, K103N, V118I, E138K, M184V, T215I, L234I, and F227C; protease I15V, I62V, A71I/T/V, and I93L; and integrase M50I, E138K, S147G, N155H, G163R, S230N, and R263K.

Medical History
The patient’s medical history is significant for hepatitis C with compensated cirrhosis, sustained virological response after direct-acting antiviral treatment, benign prostatic hyperplasia, epididymitis, multiple orthopedic surgeries, hypertension, hyperlipidemia, cerebrovascular accident (CVA), cytomegalovirus retinitis, anal low-grade squamous intraepithelial lesions, and coronary artery disease (CAD) with bypass graft 25 years ago. Repeat coronary catheterization resulted in left internal mammary artery to left anterior descending (LAD) insertion site and distal LAD drug-eluting stents 6 years ago.

Repeat cardiac catheterization 1 year prior demonstrated severe CAD with 90% proximal in-stent restenosis, no new stent deployment, and continuation of medical management including dual antiplatelet therapy (DAPT). The patient’s social history includes past alcohol and illicit drug use (cocaine).

Key Medications
Medications include daily atorvastatin 40 mg, ezetimibe 10 mg, aspirin (ASA) 81 mg, clopidogrel 75 mg, losartan 25 mg, metoprolol succinate 25 mg, famotidine 40 mg, and FTC 200 mg. Twice-daily ticagrelor 90 mg and ranolazine 50 mg extended release are also included.

A medication error was discovered noting triple antiplatelet therapy (prescrib-ed by primary care and cardiology departments) with discontinuation of clopidogrel and DAPT to include ASA with ticagrelor. Notably, the patient has a history of intermittent adherence to medications and appointments.

Epidemiological History
Six years prior to the patient’s recent presentation, an ARV regimen including cobicistat-boosted DRV (DRV/c) with RPV/FTC/TAF maintained HIV virologic suppression (VS) for 3 years. A percutaneous coronary intervention with stent placement of the right posterior descending artery with DAPT (ASA and clopidogrel) necessitated ART adjustments. Clopidogrel is a prodrug converted to its active metabolite via cytochrome P450 (CYP) enzymes. Cobicistat is a potent CYP inhibitor and may decrease active clopidogrel concentrations, increasing stent thrombosis risk.¹ Prasugrel was not an option with the historic CVA. Due to drug-drug interactions (DDIs), FTR 600 mg twice daily was prescribed with RPV/FTC/TAF and DRV discontinuation. Three months after ART substitution, VS was maintained. The patient was then lost to care for 1 year. At the next evaluation, he reported taking RPV/FTC//TAF without FTR with a viral load (VL) of 4520 copies/mL, a CD4 count of 551 cells/µL (18%), and a new RT mutation (E138K), decreasing RPV activity. DOR/lamivudine/TDF with FTR was initiated. VS (< 50 copies/mL) was demonstrated 1 month later. On the same regimen, 5 months later, VL rebound resulted (44,300 copies/mL) with new DOR resistance (RT, F227C and L234I). An infectious disease pharmacy consultation recommended FTC 200 mg daily monotherapy while HIV tropism test results were pending to compose an active ARV regimen (compiled genotype in Summary section).

Physical Exam
The patient presents to the clinic in no acute distress with a torso cast and an immobilized right arm after recent pectoral-to-deltoid muscle transfer surgery.

Laboratory Results
Repeat HIV VL on FTC monotherapy increased to 187,000 copies/mL with a CD4
count of 273 cells/µL (10%). The tropism results showed C-C chemokine receptor type 5 (CCR5) virus, demonstrating maraviroc (MVC) as an ART option.

Clinical Course
A pharmacy consultation was initiated for an MDR HIV ARV regimen, with current medications preventing DRV/c and lenacapavir (LEN) due to similar CYP and P-glycoprotein (P-gP) inhibition DDIs.²

Diagnostic Procedures
See Figure for time course and compiled genotypic mutations.

Treatment and Follow-Up
Due to the patient's complex ARV history and MDR HIV on the compiled genotype, daily FTC/TAF, MVC 300 mg twice daily, and ibalizumab-uiyk (IBA) infusions (loading/maintenance dose of 2000 mg/800 mg) were prescribed.^3,4 A medication organizer was filled by a mail-order pharmacy to assist with adherence.

Discussion
There are approximately 1.2 million people living with HIV (PLWH) in the United States.^5,6 Recent data suggest for every 100 PLWH, 75% have received some form of care, 54% have been retained in care, and 66% have achieved VS.^5,6 Notable advances in ARV regimens have decreased toxicities and pill burden, but challenges remain with maintaining VS and preventing resistance.

HIV resistance develops from various risk factors. HIV is prone to high replication rates with numerous mutations, resulting in resistance evolution. Historical ARV classes including nucleoside RT inhibitors (NRTIs), non-NRTIs, and first-generation integrase strand transfer inhibitors (INSTIs; elvitegravir and RAL) conferred low resistance barriers. Newer INSTIs (BIC and DTG) and protease inhibitors (boosted DRV) have higher resistance barriers.

Pharmacokinetic factors, including altered gastrointestinal absorption or reduced plasma ARV concentrations due to DDIs, may additionally result in resistance. Medication adherence, poor access to care, and pill burden impact the ability to achieve VS. ART options for MDR PLWH should include 2 drugs with high resistance barriers or 3 fully active agents.^5,7,8 There are currently 4 medications for MDR HIV with unique mechanisms of action: FTR, MVC, IBA, and LEN. FTR is a prodrug of temsavir and functions as a gP120 attachment inhibitor, preventing conformation changes necessary for HIV host cell attachment. In 371 PLWH with MDR HIV, FTR 600 mg twice daily with OBT achieved VS (< 40 copies/mL) in 54% and 60% of patients at week 48 and 96, respectively.^9,10 A median CD4 increase of 175 cells/μL (IQR, 89-299) at week 96 resulted, including a median increase of 212 cells/μL (IQR, 105-306) in patients with baseline CD4 counts of less than 20 cells/μL.^9,10 MVC is a CCR5 coreceptor antagonist inhibiting binding on the CD4 cell surface.⁵ A trofile test is required to determine CCR5 presence.⁵ MVC is not recommended for CXCR4-positive or dual-tropism HIV. MVC was studied in 1070 MDR PLWH with CCR5 tropic virus. Investigators evaluated the safety and efficacy of MVC 300 mg daily and MVC 300 mg twice daily, respectively, dosed with an OBT. Both twice-daily (56%) and daily (52%) regimens resulted in statistically significant VS rates (VL, < 50 copies/mL) compared with placebo (22%) with higher increases in CD4 counts (124 cells/uL and 116 cells/uL, respectively, vs 61 cells/uL with placebo).¹¹ IBA is a monoclonal antibody inhibiting HIV entry by binding to the CD4 extracellular domain. IBA is an intravenous ARV provided as an initial loading dose of 2000 mg followed by a maintenance dose of 800 mg every 14 days. IBA was evaluated in 40 MDR PLWH as functional monotherapy for 7 days, followed by the addition of oral OBT on day 14.

The OBT had to include 1 fully active ARV with IBA for a complete regimen. Study patients were on average 53 years old, White, and male, with a mean VL of 31,623 copies/mL and a CD4 count of 150 cells/μL, with 73% having 2-drug class resistance at baseline. In 17 participants, the OBT included investigational FTR. By week 25, 43% of IBA-treated patients achieved VS ( < 50 copies/mL) with mean CD4 increases of 62 cells/μL. Among patients with CD4 counts greater than 50 cells/μL, 61% achieved VS compared with 18% with values below 50 cells/μL. Investigators noted virologic failure in 10 patients, with 9 having reduced IBA susceptibility.¹² LEN is a first-in-class HIV capsid inhibitor. It inhibits early and late stages of viral replication by preventing nuclear transport, capsid formation, and virus assembly. There are 2 initial dosing schematics involving oral lead-in followed by 927-mg maintenance subcutaneous (SQ) injections every 6 months.^2,13 In a phase 2/3 trial with 72 treatment-experienced patients, 2 cohorts were enrolled: cohort 1 randomly assigned PLWH to oral LEN or placebo with existing ART until day 15. The LEN group transitioned to SQ injections, and patients receiving placebo initiated oral LEN for 14 days followed by SQ injections. Cohort 2 were not randomly assigned and began an OBT regimen with concurrent LEN (oral followed by SQ on day 15). By week 52, 83% and 72% of patients had achieved VS ( < 50 copies/ mL) in cohort 1 and 2, respectively. An immunologic response resulted in both cohorts with CD4 increases of 82 cells/μL and 113 cells/μL, respectively.¹⁴

Key Terms: RT: reverse transcriptase inhibitor, PI: protease inhibitors, INSTI: integrase strand transferase inhibitors, VL: viral load, PCI: percutaneous coronary intervention, BIC: bictegravir, FTC: emtricitabine, TAF: tenofovir alafenamide, DRV/c: darunavir/cobicistat, RPV: rilpivirine, FTR: fostemsavir, DOR: doravirine, 3TC: lamivudine, TDF: tenofovir disoproxil fumarate, IBA: ibalizumab, MVC: maraviroc, PJP: pneumocytisi jirovecci pneumonia

In our patient, DOR resistance occurred with combination FTR. Secondary to FTR nonadherence, and as there is no commercially available gP120 resistance testing to ensure susceptibility, a new MDR ARV regimen was necessary.⁵ LEN is a CYP 3A4 and P-gP inhibitor conferring DDIs with ticagrelor and ranolazine and was not a safe option. The tropism returned with a CCR5-positive result and his resistance profile showed TAF susceptibility. An ARV regimen of IBA infusions with oral MVC twice daily and FTC/TAF once daily was prescribed.

MVC/FTC/TAF initiation occurred 2 weeks prior to the first IBA loading dose secondary to health insurance barriers. No adverse effects were reported after initial doses with a resultant 3-log reduction at week 6. MDR HIV is challenging to manage, but novel oral and parenteral options exist. As PLWH age, complex comorbidities and polypharmacy limit choices secondary to DDIs and the necessity to prevent further resistance if suboptimal treatment is prescribed. New therapies provide options for patients but medication and patient specific factors must be taken into consideration.

References

1.Marsousi N, Daali Y,Fontana P, et al.Impact ofboosted antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites. Clin Pharmacokinet. 2018;57(10):1347-1354. doi:10.1007/s40262- 018-0637-6

2.Sunlenca.Package insert. Gilead Sciences; 2022.

3.Wensing AM, Calvez V, Ceccherini-Silberstein F, et al. 2022 update of the drug resistance mutations in HIV-1. Top Antivir Med. 2022;30(4):559-574.

4.HIV Drug Resistance Database. Stanford University. Accessed May 21, 2024. https://hivdb.stanford.edu/

5. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Clinical info. Updated February 27, 2024. AccessedApril 7, 2024. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv

6. US Statistics. HIV.gov. Updated December 7, 2023. Accessed May 29, 2024. https://www.hiv.gov/hiv-basics/overview/data-and-trends/statistics

7.Sax PE, Garcia-Diaz J. Managing HIV multidrug resistance: a persistent challenge.CMEZone.com. December 31, 2022. Accessed May 29, 2024. https://www.cmezone.com/Activities/4552/pdf/CU213_WM.pdf

8.Capetti A, Rizzardini G.Choosing appropriate pharmacotherapyfor drug- resistant HIV. Expert Opin Pharmacother. 2019;20(6):667-678. doi:10.1080/14656566.2019.1570131

9.KozalM,AbergJ,PialouxG,etal; BRIGHTE Trial Team. Fostemsavir in adults with multidrug-resistant HIV-1 infection. N Engl J Med. 2020;382(13):1232-1243. doi:10.1056/NEJMoa1902493

10.Lataillade M, Lalezari JP, Kozal M, et al. Safety and efficacyof the HIV-1 attachment inhibitor pro drug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study. Lancet HIV. 2020;7(11):e740-e751. doi:10.1016/S2352-3018(20)30240-X

11.Gulick RM,LalezariJ,GoodrichJ,etal; MOTIVATE Study Teams.Maravirocfor previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008;359(14):1429-1441. doi:10.1056/NEJMoa0803152

12.EmuB,FesselJ, Schrader S,etal.Phase3studyofibalizumabformultidrug- resistant HIV-1. N Engl J Med. 2018;379(7):645-654. doi:10.1056/NEJMoa1711460

13.Segal-Maurer S,DeJesus E,Stellbrink HJ, et al; CAPELLA Study Investigators.Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection. N Engl J Med. 2022;386(19):1793-1803. doi:10.1056/NEJMoa2115542

14.Ogbuagu O, Segal-Maurer S, RatanasuwanW, etal; GS-US-200-4625 Investigators. Efficacy and safety of the novel capsid inhibitor lenacapavir to treat multidrug-resistant HIV: week 52 results of a phase 2/3 trial