Enteral Administration of Twice-Daily Dolutegravir and Rilpivirine as a Part of a Triple-Therapy Regimen in a Critically Ill Patient with HIV

Introduction

When HIV-infected patients are hospitalized and require enteral nutrition, antiretroviral therapy (ART) administration is challenging. ^{1 –6} Alternative routes of medication administration (eg, naso- or orogastric-feeding tubes) are often necessary in critically ill patients in the intensive care unit (secondary to nil per os orders and/or mechanical ventilation) as only 2 antiretroviral (ARV) drugs are available parenterally (zidovudine [ZDV]/enfuvirtide) and are not commonly utilized. ⁷ Limited pharmacokinetic data comparing intact and crushed ARV formulations administered with enteral nutrition are available. ² Crushing oral dosage forms may alter medication exposure and bioavailability, creating the potential for subtherapeutic ARV concentrations, with potential for viral rebound and genotypic resistance. ^{1 –6}

Two ARV drugs (dolutegravir and rilpivirine) have unique absorption issues with regard to concurrent oral supplements and food with minimal enteral administration data available. ^1,3,4,6 Dolutegravir may be taken without regard to food, although increases in the area under the concentration time curve and maximum concentration of 66% and 67%, result, respectively, when administered with a high-fat meal. ^8,9 When dolutegravir is concurrently administered with cation-containing supplements (aluminum/magnesium) or multivitamin preparations (iron/calcium) decreased dolutegravir minimum concentrations result by 74% and 32%, respectively. ¹⁰ Separating dolutegravir administration from cations/multivitamins by 2 hours improves the pharmacokinetic profile. ¹⁰ The dolutegravir pharmacokinetic parameters are additionally maintained when ingested with calcium and iron if given simultaneously with food. ^8,9 Rilpivirine must be administered with food (400-533 kcals) for adequate absorption, as exposure to rilpivirine may be 40% lower when taken in a fasted state. ^{11 –13} As such, optimal dolutegravir and rilpivirine administration may be challenging, particularly in the setting of continuous enteral nutrition.

This case report describes the enteral administration of crushed dolutegravir and rilpivirine in a critically ill patient with lymphoma while maintaining virologic suppression.

Case

A 27-year-old male with stage IV Hodgkins lymphoma and HIV for 4 years (baseline at malignancy diagnosis: CD4 count = 198 [22%] cells/mm³ and HIV viral load [VL] = 5 630 000 copies/mL])was admitted to the medical intensive care unit with acute respiratory failure in the setting of recurrent pneumonia. The patient contracted HIV from his perinatally infected wife (patient’s current genotype: K103N with prior exposure to fixed dose efavirenz/emtricitabine/tenofovir disoproxil fumarate; wife’s genotype: M184V, K103N, Y181C, 221Y) and was presumed to have multidrug-resistant virus due to his wife’s extensive prior ARV drug experience. Antiretroviral therapy and opportunistic infection prophylaxis were initiated 8 months prior to this admission, with twice-daily darunavir 600 mg, ritonavir (RTV) 100 mg, dolutegravir 50 mg with daily fixed dose combination (FDC) of tenofovir (TDF)/emtricitabine and sulfamethoxazole-trimethoprim 400/80 mg, respectively. Four weeks later (VL = 1790 copies/mL), chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]) was initiated, and ART was altered to avoid severe bone marrow suppression from concurrent protease-inhibitor drug–drug interactions to the following: twice-daily dolutegravir 50 mg (100 mg total daily dose to enhance the genetic barrier) and daily FDC abacavir (ABC)-lamivudine (3TC) with rilpivirine 25 mg with continuation of sulfamethoxazole-trimethoprim 800/160 mg for Pneumocystis jiroveci prophylaxis. ^14,15 At the time of the current hospital admission, the patient was virologically suppressed (<20 copies/mL) with a CD4 count of 76 (38%) cells/mm³ having completed 6 cycles of ABVD.

On hospital day 17, the patient was intubated for worsening hypoxemia, and on day 18, continuous orogastric tube feeding was initiated. Both ABC and 3TC solutions were administered enterally. Dolutegravir and rilpivirine oral tablets were crushed, mixed with 10 mL of water, and flushed down the tube at separate administration times. Enteral feedings were held twice daily for 2 hours before and after dolutegravir administration. Rilpivirine was administered once daily concurrently with a 240-mL bolus of an enteral (2 kcal/mL) formula.

Trough concentrations (Ct) of rilpivirine and dolutegravir were drawn immediately prior to the dose after 8 and 9 days of orogastric administration, respectively (Table 1). Therapeutic drug monitoring (TDM) analysis was conducted by the University of Florida Infectious Diseases Pharmacokinetics Laboratory (UF IDPL). Virologic suppression (<20 copies/mL; hospital day 29) was maintained after ART enteral administration. The patient died on hospital day 31 after multiple complications.

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Table 1.

Laboratory Responses with ART Enteral Administration.

		Time after Starting Therapy via Orogastric Tube
Variable	Baseline Value	Resultant Value	Daysa
HIV viral load, copies/mL	<20	<20	10
CD4 Count, cells/mm3 (% lymphocytes)	76 (38)	–	–
Dolutegravir	–	820 ng/mLb	9
Rilpivirine	–	30 ng/mLc	8

Abbreviation: ART, antiretroviral therapy.

^aNumber of days after administration of crushed ART.

^bSteady-state trough concentration = 830 ng/mL (University of Florida Infectious Diseases Pharmacokinetics Laboratory reference for 50 mg once daily).

^cRange = 40 to120 ng/mL (University of Florida Infectious Diseases Pharmacokinetics Laboratory reference).

Discussion

This case report demonstrates the successful maintenance of virologic suppression with enteral administration of crushed dolutegravir/rilpivirine with liquid ABC and 3TC in a critically ill patient. Due to significant drug–drug interactions with the patient’s chemotherapy regimen, cytochrome P450 3A4 inhibitors (protease inhibitors) and inducers (etravirine) were avoided. ^14,15 As such, dolutegravir was dosed for treatment resistance to allow for a high genetic barrier. Although rilpivirine failure may result due to high HIV VLs (>100 000 copies/mL) and low CD4 counts (<200 cells/mm³), an additional agent was necessary to allow standard triple therapy due to the concern for a suppressed M184V mutation leading to lamivudine resistance. ^7,11 Dolutegravir and rilpivirine enteral administration has not been previously reported.^1,6 Optimal enteral administration of rilpivirine and dolutegravir may be challenging due to necessary caloric requirements and avoidance of electrolytes, multivitamin preparations, and acid suppressive agents. ^{8 –12} In this report, dolutegravir was separated from enteral nutrition to avoid possible cation binding within the feed itself, while enteral formula boluses were administered with rilpivirine to provide the 400 to 533 kcals necessary for optimal absorption. Complex administration of enteral feeding requires excellent communication between members of the multidisciplinary patient care team, and in the case of this patient, it resulted in detectable ARV concentrations.

Antiretroviral TDM is controversial especially during acute illness as alteration in alpha-1-acid glycoprotein concentrations may result and affect the unbound ARV fraction. ¹⁶ However, TDM is recommended in specific clinical scenarios (eg, altered gastrointestinal absorption) to avoid subtherapeutic concentrations with subsequent virologic rebound. ^7,16 In the present case, the dolutegravir Ct was below laboratory reference ranges (UF IDPL) when compared to patients administered 100 mg total daily dose in the integrase strand transfer inhibitor treatment experienced trials. ¹⁷ Although continued HIV VL suppression resulted in this case report, these authors would recommend consideration of dolutegravir dose titration (150-200 mg total daily dose) to achieve optimal dolutegravir Ct via the enteral route, especially in the integrase-experienced patient necessitating higher dolutegravir concentrations. The rilpivirine Ct was also decreased below laboratory reference ranges (UF IDPL) when administered with an enteral bolus, which may also suggest a benefit of increasing rilpivirine dosing to 50 mg daily, similar to the recommendations with strong cytochrome P450 inducers (rifabutin). ¹¹ Additional pharmacokinetic data are necessary for the successful enteral administration of rilpivirine and dolutegravir and to determine optimal ARV dosing regimens.

Conclusion

Enteral administration of dolutegravir and rilpivirine in conjunction with optimal coordination of tube feeding may provide adequate drug concentrations and maintain virologic suppression in critically ill patients.