Realizing the promise of long-acting antiretroviral treatment strategies for individuals with HIV and adherence challenges: an illustrative case series

Case 1

Ms. X is a 30-year-old African-American female with perinatally-acquired HIV. Her parents were HIV positive, and her mother passed away from complications of AIDS when she was 15 years old. Clinical records from when the patient was 11.8 years old demonstrate persistent fluctuations in her viral load with only brief episodic VS, last at 16.2 years. Combination therapies received in chronological order from the time of ART initiation were (1) stavudine (d4T), efavirenz (EFV), lopinavir/ritonavir (LPV/RTV); (2) atazanavir (ATV), ritonavir (RTV), emtricitabine/tenofovir disoproxil fumarate (FTC/TDF); (3) darunavir (DRV), RTV, FTC/TDF, raltegravir (RAL); (4) ATV, RTV, FTC/TDF, RAL; (5) ATV, RTV, FTC/TDF; (6) ATV, RTV dolutegravir (DTG), FTC/TDF; (7) DTG, FTC/TDF; (8) DTG, FTC/tenofovir alafenamide (TAF); and (9) DTG/RPV, DRV/cobicistat (DRV/c). During the course of treatment, ART regimens were modified based on virologic failure, resistance-associated mutations (RAMs), and for simplification. Her cumulative resistance included: nucleoside reverse transcriptase inhibitor (NRTI) RAMs L210W, T215E/D, K101E, Y181Y/C, and protease inhibitor (PI) RAMs L63P, A71T/A. No INSTI mutations were identified.

Barriers to adherence included cognitive/developmental delay, lack of social support, housing instability, transportation difficulties, poverty, intermittent phone service, lack of childcare, pill burden, medication side effects, and internalized stigma. Various interventions were tried, including simplifying her ART therapy to a once-daily regimen, setting alarm clocks and pillboxes, arranging transportation, assisting with housing, providing adherence counseling, and directly observed therapy (DOT), and connecting her with a patient navigator to help with her outpatient care. Despite these interventions, she remained persistently viremic, even during her two pregnancies, with resultant immune suppression and multiple comorbid opportunistic conditions, including intestinal mycobacterium avium intracellulare (MAI), diffuse molluscum contagiosum, recurrent vaginal infections, and recurrent pneumonia prompting frequent hospitalizations. At 30.6 years of age, she was hospitalized for refractory hypotension in the setting of profuse diarrhea. Her viral load at this time was > 10,000,000 copies/ml. She was re-initiated on her home regimen of DTG/RPV + DRV/c, improving her viral load to 49,800 copies/mL within ten days. Given her longstanding history of poor adherence to an oral regimen, the severe consequences of her advanced immunosuppression, and her proven inability to adhere longitudinally to an oral regimen, the decision was made to switch to monthly intramuscular (IM) injections of CAB/RPV (in clinic), without the OLI, along with biweekly infusions of ibalizumab. Her ibalizumab was initially administered in the clinic and thereafter via home infusion. Her daily oral regimen of DRV/c was continued for additional coverage. Her viral load decreased from 49,800 to 8,110 copies/ml within two weeks. Her most recent viral load was 512 copies/ml four months after initiation of the hybrid regimen (LAI-ART plus oral), her lowest viral load since the age of 16 years ( Fig. 1).

Fig. 1figure 1

Trends in Viral Loads Following LAI-ART Initiation (Time 0 = initiation of LAI-ART). Case #3 not graphed as VL < 20 at LAI-ART initiation and remained suppressed

Given her cognitive delay/limitations, care coordination was essential, including engaging the family members in developing the care plan, and assuring that she was available for transportation pick-up. The outreach specialist enabled daily text message medication reminders, appointment reminders, arranged rideshare transportation to the clinic, and assured navigation around the hospital during medication administration days. With this robust support, she has adhered to her injection visit schedule.

The patient’s medical insurance was Medicaid, which provided coverage for direct to inject (DTI) CAB/RPV through the medical benefit and the state-funded copay assistance program, allowing the medication to be initiated promptly and without financial barriers.

Case 2

Ms. H is a 33-year-old woman with cognitive limitations due to childhood lead poisoning who acquired HIV at 22 years of age when she was sexually assaulted during pregnancy. She initiated LPV/RTV, lamivudine (3TC), and zidovudine (AZT) during pregnancy in 2011 but had to undergo a Cesarean section secondary to rising HIV viral load despite reported medication adherence. She was enrolled in the PROMISE study of ART in pregnancy and assigned to the no-treatment post-partum arm, leading to the temporary discontinuation of ART after delivery. She resumed ART a year later. All combination therapies received in chronological order from the time of ART initiation were (1) LPV/RTV, 3TC, AZT; (2) DRV, RTV, DTG, TDF/FTC; and (3) bictegravir (BIC)/TAF/FTC. During the course of treatment, changes were made to ART regimens based on virologic failure, resistance panels, and for simplification. Her cumulative resistance included: NRTI RAMs M184V and INSTI accessory resistance mutation G163R. Her viral load trajectory took a downward turn, precipitated by various life events, and exacerbated by depression, anxiety, panic attacks, and nausea and vomiting with medications unrelieved by prescribed antiemetics. Her viral load remained elevated despite intensive case management, including DOT and medication reminders. With her persistent viremia (8930 copies/ml), immune decline (CD4 278 cells/mm3), and growing concerns that the patient’s continued intermittent adherence to her oral ART would lead to INSTI resistance and preclude her from the use of currently approved LAI-ART, the decision was made to initiate LAI-ART (CAB/RPV) without OLI plus liquid DRV and RTV. Her viral load became undetectable (< 20 copies/ml) within two months of treatment initiation and has remained undetectable since then (Fig. 1). She has adhered to her injection visit schedule.

Critical care coordination included familial involvement, daily treatment reminders, appointment reminders, transportation, and care navigation. She had Medicaid insurance, which provided DTI CAB/RPV coverage through the medical benefit and the state-funded copay assistance program, allowing her to expeditiously begin therapy. The team pharmacist secured prior authorization and financial coverage and developed a therapeutic plan in coordination/conjunction with the medical team.

Case 3

Miss Y. is a 37-year-old woman with perinatally-acquired HIV, initially diagnosed at five years of age when her mother died of HIV. She has had chronic challenges with nonadherence, which she attributes to limited support systems during her youth as well as currently with competing responsibilities (i.e., employment, childcare), medication side effects (e.g., nausea and grogginess), and internalized stigma and pill aversion when having to take her medication. Her HIV regimen history included (1) monotherapy zidovudine (AZT), (2) nelfinavir, stavudine, and lamivudine (NFV, D4T, 3TC), (3) AZT, abacavir, lamivudine (AZT, ABC, 3TC), (4) atazanavir, ritonavir, tenofovir, emtricitabine (ATV, RTV, TDF/FTC), (5) efavirenz tenofovir, emtricitabine (EFV, TDF/FTC), (6) darunavir, ritonavir, tenofovir, emtricitabine (DRV, RTV, TDF/FTC), and ultimately bictegravir, tenofovir, emtricitabine (BIC/TAF/FTC), all of which she took variably, with persistent intermittent nonadherence. During the course of treatment, ART regimens were modified based on virologic failure, resistance panels, and for simplification. Her cumulative resistance included: NRTI RAMs D67N, T69D, and NNRTI RAMs A98G. No INSTI mutations were identified. Given her nonadherence, she had longstanding immunosuppression with CD4 < 200 cells/mm3 for > 5 years with a nadir of 29 cells/mm3, with persistent oral mucocutaneous candidiasis and onychomycosis, and various infections, including varicella, pneumonia, and pyelonephritis. Her complaints included decreased energy and appetite with an inability to gain weight. She was first offered LAI-ART in 2019 as part of a study that would require her to adhere to an oral regimen for six months before being randomized to either continue oral ART or to receive LAI-ART; she declined due to a lack of a guarantee that she would receive the LAI-ART. She then continued oral ART, guided by discussions with her provider that LAI-ART would be available clinically by early 2020 if she could attain and maintain a suppressed viral load. Working with her care team, she was transparent about when she was not adherent, and viral loads were not checked at those visits. She was able to suppress viral loads over a 6-month period, and in August 2020, she discontinued her oral ART, received the 1-month OLI of cabotegravir/rilpivirine, followed by the injectable loading dose. She has since adhered to all her monthly dosing appointments, sustained VS, and transitioned to a bi-monthly injection schedule. Regarding care coordination, she received daily medication reminders from the outreach specialist and appointment reminders for adherence to her oral ART regimen and OLI. She had monthly appointments (in-person or telehealth) for check-ins and assessment of adherence with adherence counseling. She too had Medicaid, which provided coverage for LAI CAB/RPV through the medical benefit and the state-funded copay assistance program. The patient was expeditiously started on the regimen as soon as the clinic had an available appointment.

Immune reconstitution inflammatory syndrome (IRIS) was not observed in any of the patients.

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