Five important things to know about the newly approved doravirine

By: 

• Elizabeth Sherman, PharmD, AAHIVP
  South Florida, Southeast AIDS Education and Training Center
  College of Pharmacy, Nova Southeastern University
• Sarah Khan, PharmD Candidate
  College of Pharmacy, Nova Southeastern University
• Adrianna Oller, PharmD Candidate
  College of Pharmacy, Nova Southeastern University

On August 30, 2018, the US Food and Drug Administration (FDA) approved Pifeltro® (doravirine, DOR), a new non-nucleoside reverse transcriptase inhibitor (NNRTI) to be administered in combination with other antiretroviral medications for the treatment of HIV-1 infection in adults with no prior antiretroviral treatment history. The FDA simultaneously approved Delstrigo®, a single tablet regimen containing doravirine, tenofovir disoproxil fumarate (TDF), and lamivudine (3TC). This article provides a review of 5 important facts about doravirine for clinicians.

1. DOR is available by itself (Pifeltro®) and also co-formulated in a single tablet regimen with 2 NRTIs (Delstrigo®). However, Desltrigo contains the NRTIs TDF and 3TC which may limit its use.

DOR is available in 100 mg tablets (Pifeltro®) and is to be dosed orally once daily with or without food. It is also available co-formulated in a three-drug, single-tablet once-daily antiretroviral (ARV) regimen Delstrigo® (DOR/TDF/3TC). Both tablets are indicated for the treatment of HIV in treatment-naïve patients. Even though Delstrigo® is considered a complete regimen for the treatment of HIV-1 infection, the use of TDF its co-formulation limits its use since TDF is associated with higher rates of bone loss, mineralization defects, and new onset or worsening renal impairment as compared to tenofovir alafenamide (TAF). The use of TDF and 3TC in Delstrigo were likely due to their availability in generic formulation. Currently, most providers in the US avoid patient exposure to TDF if other options are available. Providers desiring use of TAF with a DOR-containing ARV regimen out of safety concerns will need to prescribe DOR separately with TAF-emtricitabine (FTC), resulting in an ARV pill burden of two pills per day.

2. In clinical trials, DOR was as effective as efavirenz and darunavir/ritonavir and was better tolerated than efavirenz when used as initial therapy; it was also effectively used as a switch in virologically suppressed patients. DOR has not been studied head-to-head with an integrase inhibitor nor has it been studied in patients with treatment experience who have failed a previous NNRTI-based regimen.

FDA approval of Pifeltro® and Delstrigo® was based on two phase 3 trials (DRIVE-FORWARD and DRIVE-AHEAD), which evaluated their safety and efficacy in treatment-naive HIV-1 infected patients. In the DRIVE-FORWARD clinical trial, patients were randomized to receive either DOR once daily or darunavir 800 mg plus ritonavir 100 mg (DRV/r) once daily, each in combination with TDF/FTC or abacavir (ABC)/3TC. By week 48, 84% of patients in the DOR group and 80% of the patients in the DRV/r group achieved virologic suppression (HIV-1 RNA <50 copies/mL); the difference was not statistically significant. Patients treated with DOR also showed statistically significant superior lipid profiles as measured by changes from baseline in LDL-cholesterol and non-HDL cholesterol. In addition, the patients in the DOR group presented with fewer adverse events than patients treated with DRV/r.

In the DRIVE-AHEAD clinical trial, patients were randomized to receive either DOR/TDF/3TC or efavirenz/TDF/FTC once daily. By week 48, 84.3% of patients in the DOR group and 80.8% of patients in the EFV group achieved virologic suppression (HIV-1 RNA <50 copies/mL); the difference was not statistically significant. A statistically significant lower number of patients treated with DOR compared to patients treated with EFV reported neuropsychiatric events such as dizziness, sleep disorders and disturbances, and altered sensorium.

The DRIVE-SHIFT trial evaluated a switch from a stable ARV regimen to DOR/TDF/3TC in virologically suppressed adults with HIV-1. Patients had no history of prior virologic failure or known resistance to any component of Delstrigo®. At week 48, 90.8% of patients in the switch group remained undetectable (HIV RNA < 50 copies/mL).

Delstrigo® is currently under investigation in treatment-naïve patients with NNRTI transmitted resistance with one of the following NNRTI mutations: K103N, Y181C, or G190A (DRIVE BEYOND). Results from this study are not yet available.

3. There are some clinically significant drug-drug interactions with DOR about which clinicians must be aware before prescribing, such as with anticonvulsants and rifamycins.

DOR is metabolized primarily by cytochrome P450 (CYP) 3A and is contraindicated when coadministered with drugs that are strong cytochrome CYP3A enzyme inducers. If DOR is taken along with a potent CYP3A enzyme inducer, it will cause a significant decrease in DOR plasma concentrations reducing its antiretroviral effect in the body. Examples of strong CYP3A inducers include, but are not limited to: the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin; the androgen receptor inhibitor enzalutamide, the cytotoxic agent mitotane, antimycobacterials such as rifampin and rifapentine, and the herbal  supplement St. John’s Wort. Not only is the co-administration of these agents contraindicated with DOR, but additionally a cessation period of at least 4 weeks with any of these medications is recommended prior to DOR initiation to prevent any potential drug interactions.

Importantly, there is one specific drug interaction necessitating a DOR dose adjustment. Rifabutin is a commonly used medication, often replaced for rifampin, in patients co-infected with both HIV and tuberculosis because of its favorable drug interaction profile with antiretroviral medications. In pharmacokinetic studies, the area under the curve of DOR was lowered by 50% when co-administered with rifabutin. Therefore, the dose of DOR needs to be increased when prescribed concomitantly with rifabutin; prescribing recommendations are to increase Pifeltro® dosage to one 100 mg tablet by mouth twice daily. In addition, the recommended dosing for Delstrigo® is to take one 100 mg tablet of Pifeltro® approximately 12 hours after the dose of Delstrigo®. This special dosing regimen requires a patient to have a prescription for both the single and combined formulation of DOR.

Pharmacokinetic studies have shown that DOR is safe to use with the antiretrovirals TDF, 3TC, dolutegravir, or ritonavir as there are no clinically significant changes in drug concentration when co-administered with DOR. DOR should not be prescribed with the antiretrovirals EFV, etravirine, or nevirapine because concurrent administration results in decreased DOR levels.

4. DOR can be used safely in patients with any level of renal impairment and in patients with mild to moderate hepatic impairment.

The renal and hepatic dosing recommendations for Pifeltro® and Delstrigo® differ slightly due to the coformulation in each specific tablet. Pifeltro® possesses an advantage to patients who have mild, moderate, or severe renal impairment as no dosage adjustments are necessary with any level of renal impairment. However, DOR has not been sufficiently studied in patients who have end stage renal disease and has not been studied in patients on dialysis. In addition, no hepatic dosage adjustments for Pifeltro® are required in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment. DOR has not been studied in patients with severe (Child Pugh Class C) hepatic impairment.

Delstrigo®, on the other hand, requires renal dosing adjustments due to its fixed dose combination with 3TC and TDF which are primarily excreted by the kidney. Both 3TC and TDF require a renal dose adjustment in patients with a creatinine clearance below 50 ml/min. As a result, Delstrigo® is not recommended in patients with an estimated creatinine clearance of <50 mL/min. It is also suggested that Delstrigo® should be avoided with concurrent use of other nephrotoxic agents such as high dose non-steroidal anti-inflammatory drugs as this could  exacerbate renal adverse effects. No hepatic dose adjustments for Delstrigo® are required in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment. Delstrigo® has not been studied in patients with severe (Child Pugh Class C) hepatic impairment.

5. In vitro, DOR retains activity against HIV with a K103N or Y181C mutations.

Resistance to DOR is associated with the selection of 1 or more resistance mutations, but the resistance profile of DOR has not been fully elucidated. In the clinical trials noted above, a number of reverse transcriptase mutations emerged with DOR failure: V106I/A/M/T, A98G, V108I, E138G/K, Y188L, H221Y, F227C/I/R, and Y318F. Phenotypic analysis has shown that resistance to DOR generally causes cross-resistance to EFV and rilpivirine; etravirine remains sensitive against viruses with certain combinations of mutations. To date, no clinical studies have evaluated the effects of DOR resistance on virologic outcomes of second-line ARV regimens. Resistance mutations selected by other NNRTIs, including any of the mutations listed above, would be expected to contribute to DOR resistance. In vitro, DOR retains activity against K103N and Y181C mutations, but not viruses with Y188L or some combinations that include V106A or E138K. Clinical data are needed to define the effect of resistance mutations on the activity of DOR.