Doravirine: A Return of the NNRTI Class?

Sarah R. Blevins, PharmD1, E. Kelly Hester, PharmD2 ,
Daniel B. Chastain, PharmD3 , and David B. Cluck, PharmD4

Annals of Pharmacotherapy 1–11
© The Author(s) 2019 Article reuse guidelines: DOI: 10.1177/1060028019869641

Objective: To compare and contrast doravirine (DOR) with other agents in the nonnucleoside reverse transcriptase inhibitor (NNRTI) class, review safety and efficacy data from both completed and ongoing clinical trials, and outline the potential place in therapy of DOR. Data Sources: A literature search using the PubMed database (inception to June 2019) was conducted using the search terms HIV, doravirine, non-nucleoside reverse transcriptase inhibitor, NNRTI, and MK-1439. Study Selection and Data Extraction: Clinical data were limited to those published in the English language from phase 2 or 3 clinical trials. Ongoing trials were identified through Data Synthesis: DOR was approved by the US Food and Drug Administration on the strength of 2 phase 3 randomized, double-blind, noninferiority clinical trials with additional studies currently underway examining its utility in other clinical scenarios. Relevance to Patient Care and Clinical Practice: The role of NNRTIs as part of antiretroviral (ARV) therapy has diminished in recent years given the introduction of more tolerable individual ARV agents and regimens. Despite this, new agents are still needed in the therapeutic arena because treatment failure as well as intolerance can still occur with many first-line therapies. The optimal place in therapy of DOR remains to be defined. Conclusions: DOR is a new NNRTI that represents a potential treatment option for treatment-naïve patients, without many of the previously described untoward effects of the NNRTI class.

antiretrovirals, drug interactions, drug trials, HIV/AIDS, infectious disease

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have robust clinical data and real-world experience support- ing their use as part of combination antiretroviral (ARV) regimens. Compared with protease inhibitors (PIs), NNRTIs are at least equipotent regarding immunological recovery and virological suppression.1 Whereas efavirenz (EFV) has the most clinical experience in the class to date, current Department of Health and Human Services (DHHS) and International Antiviral Society—USA guidelines now con- sider use of EFV-based regimens to be alternative in favor of integrase-inhibitor (INSTI)-based regimens.2,3 In addi- tion to being guideline recommended, transition to INSTI- based regimens is predicated on their tolerability and potency compared with PI and NNRTI-based regimens. The demotion of EFV in the DHHS 2015 guidelines represented a significant change in the management of people living with HIV (PLWH) while raising the question of whether EFV represents a viable comparator when examining new agents in clinical trials.
The development of second-generation NNRTIs has focused on improving tolerability, specifically with regard to central nervous system (CNS) adverse effects, and stabil- ity against common mutations, which frequently preclude

the use of first-generation NNRTIs, including EFV and nevirapine. A general overview of the currently available NNRTIs is shown in Table 1. Doravirine (DOR, formerly MK-1439), an NNRTI, seeks to restore the utility of the class as a potential therapeutic option in treatment-naïve patients. This article compares and contrasts DOR with other available agents in the NNRTI class, reviews safety and efficacy data of DOR from clinical trials, describes known resistance patterns, and outlines the potential place in therapy.

Study Selection and Data Extraction
A literature search using the PubMed database (inception to June 2019) and conference abstracts was conducted using

1Chase Brexton Healthcare, Baltimore, MD, USA
2Auburn University Harrison School of Pharmacy, Auburn, AL, USA
3University of Georgia College of Pharmacy, Albany, GA, USA
4East Tennessee State University Gatton College of Pharmacy, Johnson City, TN, USA
Corresponding Author:
David B. Cluck, Department of Pharmacy Practice, East Tennessee State University Gatton College of Pharmacy, Johnson City, TN 37614, USA. Email: [email protected]

2 Annals of Pharmacotherapy 00(0)

Table 1. Comparison of Currently Available Nonnucleoside Reverse Transcriptase Inhibitors.4-9

Trade Name (Generic Name)
Sustiva (Efavirenz) Viramune (Nevirapine)
Intelence (Etravirine)
Edurant (Rilpivirine)
Pifeltro (Doravirine)
Fixed-dose combination Atripla (TDF/FTC/EFV) Symfi (EFV/3TC/TDF) Symfi Lo (EFV/3TC/TDF) — — Complera (TDF/FTC/ RPV)
Odefsey (TAF/FTC/RPV)
Juluca (DTG/RPV) Delstrigo (DOR/3TC/TDF)
Dosing frequency Once daily Once daily Twice daily Once daily Once daily
Food requirements Recommended to be administered on an empty stomach None Recommended after meals Recommended to be administered with a normal caloric meal (533 kcal) None
Potential for drug- Substrate: CYP3A4 Substrate: CYP3A4 Substrate: CYP3A, Substrate CYP3A4; pH- Substrate: CYP3A4
drug interactions Induces: CYP3A4 and CYP2B6
Inhibits: CYP2C9, CYP2C19, and CYP3A4 and CYP2B6 Induces: CYP3A4 and CYP2B6 CYP2C9, and CYP2C19
Induces: CYP3A4 Inhibits: CYP2C9, CYP2C19, and
P-glycoprotein dependent absorption; caution with drugs that prolong QTc interval and CYP3A5
Dosing in hepatic Not recommended in Not recommended in No dosage adjustment No dosage adjustment No dosage
impairment moderate or severe hepatic impairment (Child-Pugh Class B or C) moderate to severe hepatic impairment (Child-Pugh Class
B or C) is recommended in mild or moderate hepatic impairment (Child-Pugh Class A or B) is required with mild or moderate hepatic impairment (Child- Pugh Class A or B) adjustment in patients with mild or moderate
hepatic impairment (Child-Pugh Class
A or B)
Baseline viral load > Comparable efficacy with Comparable efficacy Comparable efficacy Inferior efficacy Comparable efficacy
100 000 copies/mL comparator therapy with comparator therapy with comparator therapy compared with other fully active regimens with high baseline viral load or CD4 count
<200 cells/mm3 with comparator therapy Effect on lipid panel Increases in total cholesterol, HDL, and triglycerides Neutral effects on lipids Neutral effects on lipids Neutral to minimal impact on lipids Decreases in total cholesterol, LDL, and triglycerides Abbreviations: 3TC, lamivudine; CYP, cytochrome P450; EFV, efavirenz; FTC, emtricitabine; DOR, doravirine; DTG, dolutegravir; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. the search terms HIV, doravirine, non-nucleoside reverse transcriptase inhibitor, NNRTI, and MK-1439. Similar search terms were used to search conference abstracts from the Conference on Retroviruses and Opportunistic Infections, International AIDS Society Conference on HIV Science, and IDWeek. In addition, ongoing trials were identified through Clinical data were limited to those pub- lished in the English language from phase 2 or 3 clinical trials. Reference lists of included articles, abstracts, and posters were also reviewed to identify additional data of rel- evance for inclusion. Chemistry and Pharmacology Structurally, DOR is a 3-chloro-5- [[1-[(4,5-dihydro-4- methyl-5-oxo-1H-1,2,4-triazol-3- yl)methyl]-1,2-dihydro- 2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy] benzonitrile.9 Mechanistically, DOR is similar to other NNRTIs in that it acts as an allosteric inhibitor of the HIV-1 reverse transcrip- tase enzyme, with downstream effects resulting in a decline in viral replication.10 DOR achieves maximal plasma concentrations in approximately 1 to 4 hours.11 Food has a clinically negligible effect on DOR pharmacokinetics.12 Given the predominance of cytochrome P450 (CYP)- mediated metabolism, DOR is minimally excreted in the urine. Moreover, DOR is subject to drug-drug interactions because it is mainly a CYP substrate similar to rilpivirine (RPV). Compared with other agents in the class, DOR is not considered to have appreciable inductive or inhibitory effects on CYP enzymes. Specific drug-drug interactions are outlined in the respective section below. The CYP enzymes that are responsible for the oxidative metabolism are CYP 3A4 and 3A5, with no significant contribution from other CYP enzymes.13 Also characteristic of the NNRTI class, the terminal half-life of DOR is approximately 12-21 hours, facilitating a once-daily dosing strategy.12,13 Efficacy The US Food and Drug Administration approved DOR based on the findings of 2 phase 3 clinical trials, DRIVE- FORWARD and DRIVE-AHEAD, both of which are Blevins et al 3 reviewed here (Table 2).14,15 Ongoing DOR studies include treatment-naïve patients with transmitted NNRTI resistance in DRIVE-BEYOND, as a potential switch strategy in treat- ment-experienced patients in DRIVE-SHIFT and DRIVE- CLEAR, and in combination with islatravir (MK-8591), a novel nucleoside reverse transcriptase translocation inhibi- tor in DRIVE2Simplify.16-19 P007 was a 2-part, randomized, double-blind, phase 2b trial that evaluated DOR versus EFV in combination with single-tablet tenofovir disoproxil fumarate and emtric- itabine (TDF/FTC) in treatment-naïve, HIV-infected patients.20-22 In part 1, a dose-finding study, rates of viro- logical suppression at 24 weeks was similar between DOR 25, 50, 100, and 200 mg once daily and EFV-based regi- mens. At week 24, all patients receiving DOR were switched to 100 mg once daily based on antiviral response and safety profile among the tested doses. This dose was continued through week 48. In the second part of the study, an addi- tional 132 patients were randomized 1:1 to DOR and EFV. The second part of this study was conducted to provide safety data with respect to the selected dose and evaluate the risk of CNS adverse effects. Combined results from part 1 and part 2 showed no significant difference between DOR and EFV in the percentage of patients achieving HIV-1 RNA viral load <40 copies/mL at week 48. DRIVE-FORWARD compared the efficacy and safety of DOR with ritonavir-boosted darunavir (DRV/r) with an investigator-selected nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone of TDF/FTC or abacavir and lamivudine (ABC/3TC) in treatment-naïve patients.14,23 At week 48, DOR was noninferior to DRV/r in the proportion of patients achieving virological suppression, defined as HIV-1 RNA <50 copies/mL.14 Comparable rates of viro- logical suppression were observed in both treatment arms in a subgroup analysis of patients with HIV-1 RNA >100 000 copies/mL and between NRTI backbones in both treatment arms. Virological failure (VF) occurred in 5% of patients in the DOR group and 6.3% in the DRV/r group; however, no DOR-resistance mutations were detected. One patient dis- continued therapy because of noncompliance, and subse- quent resistance testing revealed DOR mutations.
The 96-week results from DRIVE-FORWARD were presented at the International AIDS Conference in 2018.23 A higher percentage of patients achieved virological suppres- sion at 73.1% and 66% in the DOR and DRV/r treatment arms, respectively. Through 96 weeks, an additional patient developed DOR resistance (V106A, P225Y/H).
DRIVE-AHEAD compared the safety and efficacy of DOR as a fixed-dose combination (FDC) with 3TC/TDF (DOR/3TC/TDF) to EFV as a FDC with TDF/FTC in treat- ment-naïve patients.15,24 At week 48, regardless of baseline HIV-1 RNA, similar rates of patients in the DOR and EFV groups achieved virological suppression, satisfying nonin- feriority criteria. More patients in the DOR treatment arm

experienced VF compared with the EFV group, whereas more EFV patients discontinued treatment for reasons other than VF (drug rash and CNS-related events). A total of 23 patients receiving DOR or EFV-based regimens underwent ARV resistance testing. A total of 7 patients had DOR- associated resistance mutations. In contrast, 11 patients who received EFV displayed both genotypic and phenotypic resistance to EFV. Notably, 2 of these isolates displayed phenotypic resistance to DOR.
Week 96 results of DRIVE-AHEAD presented at IDWeek 2018 showed comparable rates of virological sup- pression in the DOR and EFV groups, regardless of baseline HIV-1 RNA.24 Two additional patients in the EFV arm developed resistance to EFV between weeks 48 and 96.
DRIVE-FORWARD and DRIVE-AHEAD have several limitations pertaining to generalizability.14,15,25 Perhaps most noteworthy is the predominance of males in the study populations (greater than 80% in both studies), with few patients being of older age (<1% >65 years old), an increasingly important demographic given the current life expectancy of PLWH today. The percentage of patients who achieved virological suppression on DOR-containing regi- mens (84%) was also considerably lower when compared with second-generation INSTI-based regimens (88%-90% with dolutegravir and 89%-93% with bictegravir at week 48).26 This finding could influence how this drug is utilized in clinical practice.
DRIVE-BEYOND evaluated the safety and efficacy of DOR/3TC/TDF as a FDC in treatment-naïve patients with transmitted NNRTI resistance.16 Although the study did not reach the target enrollment of 60 patients, the investigators did follow the 10 enrolled patients through week 48. The study design permitted any one of the following reverse transcriptase mutations: K103N, Y181C, and G190A. Eight of the 10 enrolled patients had a K103N mutation, and 2 patients had a G190A. One of the patients with a G190A experienced VF at week 24 because of nonadherence, whereas 1 patient with a K103N was lost to follow-up. Virological suppression was observed in all patients remain- ing in the study at week 48. Treatment-emergent resistance mutations were not identified in any patient.
In DRIVE-SHIFT, virologically suppressed patients on stable antiretroviral therapy (ART) for at least 6 months were switched to DOR/3TC/TDF immediately after study enrollment (immediate switch group [ISG]) or at week 24 (delayed switch group [DSG]).17 The primary end point was the proportion of patients maintaining virological suppres- sion, defined as HIV-1 RNA <50 copies/mL, receiving DOR at week 48 (ISG) compared with those continuing baseline ART at week 24 (DSG). At week 24, rates of viro- logical suppression were similar between ISG and DSG patients. Virological suppression was noninferior between ISG at week 48 compared with DSG at week 24. Among ISG through 48 weeks and DSG from 24 to 48 weeks, VF Table 2. Overview of Doravirine Clinical Trials. Study Population Design Treatment Groups Efficacy End Points Adverse Effects P00720-22 ART-naïve, baseline HIV-1 RNA ≥ 1000 copies/mL, CD4 ≥ 100 cells/mm3 DRIVE-FORWARD14,23 ART-naïve, baseline HIV-1 RNA ≥ 1000 copies/mL, CD4 ≥ 100 cells/mm3 with no NRTI, NNRTI, or PI resistance mutations Phase 2b, 2-part, randomized, double-blind study Phase 3, randomized, double-blind, multicenter noninferiority trial Part 1 – Dose-ranging – DOR 25, 50, 100, and 200 mg qd (n = 40-43 per treatment group) vs EFV 600 mg QHS (n = 42) plus TDF/FTC ×48 weeks Part 2 – Randomized 1:1 to DOR 100 mg qd (n = 108) or EFV 600 mg QHS (n = 108) plus TDF/FTC ×48 weeksa DOR 100 mg qd (n = 385) or DRV/r 800 mg/100 mg qd (n = 384) plus TDF/FTC or 3TC/ABC ×48 weeks 48 Weeks VL < 40 copies/mL (primary): – Part 1 ○ DOR: 76% ○ EFV: 71% – Part 2 ○ DOR: 77.8% ○ EFV: 78.7% (95% CI = −12.2, 10.0) VL < 200 copies/mL (secondary): – Part 1 ○ DOR: 83% ○ EFV: 79% – Part 2 ○ DOR: 85.2% ○ EFV: 84.3% (95% CI -8.9, 10.8) 48 Weeks VL < 50 copies/mL (primary): – DOR: 84% – DRV/r: 80% (95% CI = −1.6, 9.4) – NI margin: −10% VL < 50 copies/mL in patients with baseline VL > 100 000 copies/mL:
– DOR: 81%
– DRV/r: 76.4%
VL < 50 copies/mL in patients with baseline CD4 ≤ 200 copies/mm3: – DOR: 82.9% – DRV/r: 72.1 VF: – DOR: 5% – DRV/r: 6.3% Discontinuation without VF: – DOR: 10.4% – DRV/r: 13.9% Abnormal dreams – DOR: 5.6% – EFV: 14.8% Insomnia – DOR: 6.5% – EFV: 2.8% Sleep disorder – DOR: 4.6% – EFV: 6.5% Diarrhea – DOR: 0.9% – EFV: 6.5% Headache – DOR: 2.8% – EFV: 5.6% Nausea – DOR: 7% – DRV/r: 8% Diarrhea – DOR: 5% – DRV/r: 13% Headache – DOR: 6% – DRV/r: 3% Rash – DOR: 2% – DRV/r: 3% Neuropsychiatric – DOR: 6% – DRV/r: 5% (continued) Table 2. (continued) Study Population Design Treatment Groups Efficacy End Points Adverse Effects DRIVE-AHEAD15,24 ART-naïve, baseline HIV RNA ≥ 1000 copies/mL with no resistance mutations to DOR, EFV, or NRTIs Phase 3, randomized, double-blind, multicenter noninferiority trial DOR 100 mg qd (n = 383) or DRV/r 800 mg/100 mg qd (n = 383) plus TDF/FTC or 3TC/ABC continued through 96 weeks DOR/3TC/TDF qd (n=364) or EFV/FTC/TDF (n=364) ×48 weeks 96 Weeks VL < 50 copies/mL (primary): – DOR: 73.1% – DRV/r: 66% (95% CI = 0.5, 13.7) VL < 50 copies/mL in patients with baseline VL > 100 000 copies/mL:
– DOR: 65.4%
– DRV/r: 65.2%
VL < 50 copies/mL in patients with baseline CD4 >50 and ≤200 copies/mm3:
– DOR: 71%
– DRV/r: 65.8%
– DOR: 9%
– DRV/r: 11%
Discontinuation without VF:
– DOR: 16%
– DRV/r: 19%
48 Weeks:
VL < 50 copies/mL (primary): – DOR: 84% – EFV: 81% (95% CI −2.0, 9.0) – NI margin: −10% VL < 50 copies/mL in patients with baseline VL > 100 000 copies/mL:
– DOR: 81.2%
– EFV: 80.8%
– DOR: 6%
– EFV: 3.8%
Discontinuation without VF:
– DOR: 9.6%
– EFV: 13.7%

– DOR: 12%
– DRV/r: 14%
– DOR: 17%
– DRV/r: 24%
– DOR: 15%
– DRV/r: 12%
– DOR: 5%
– DRV/r: 6%
– DOR: 9.4%
– DRV/r: 9.7%
– DOR: 15.7%
– DRV/r: 18.8%

– DOR: 11%
– EFV: 13%
– DOR: 13%
– EFV: 12%
– DOR: 5%
– EFV: 9%
Abnormal dreams
– DOR: 5%
– EFV: 12%
– DOR: 5%
– EFV: 12%
– DOR: 24%
– EFV: 57%


Table 2. (continued)
Study Population Design Treatment Groups Efficacy End Points Adverse Effects

DRIVE-BEYOND16 ART-naïve, baseline HIV RNA
≥ 1000 copies/mL, CD4 ≥ 100 cells/mm3 with a single NNRTI resistance mutation but no genotypic resistance to DOR, 3TC, or TDF
DRIVE-SHIFT17 Virologically suppressed patients on stable ART consisting of 2 NRTIs plus bPI, EVG, or NNRTI × ≥6
months with no history of VF or resistance to DOR, 3TC, or TDF

Phase 2, multicenter, open-label, single- arm trial

Phase 3, open-label, active-controlled, noninferiority trial

DOR/3TC/TDF qd (n = 364) or EFV/FTC/TDF (n = 364)
continued through 96 weeks

DOR/3TC/TDF qd (n = 10)
×48 weeks

Randomized 2:1 to switch to DOR/3TC/TDF qd on day 1 (ISG [n = 447]) or continue baseline ART and switch after 24 weeks (DSG [n = 223])

96 Weeks
VL < 50 copies/mL (primary): – DOR: 77.5% – DRV/r: 73.6% (95% CI = −2.4, 10.0) VL < 50 copies/mL in patients with baseline VL > 100 000 copies/mL:
– DOR: 71%
– EFV: 79.7%
VL < 50 copies/mL in patients with baseline CD4 ≤ 200 copies/mm3: – DOR: 65% – EFV: 82.1% VF: – DOR: 9% – EFV: 8% Discontinuation without VF: – DOR: 11% – EFV: 17% 48 Weeks VL < 50 copies/mL (primary): 100% VL < 50 copies/mL (primary): – ISG at 48 weeks: 90.8% – DSG at 24 weeks: 94.6% (95% CI = −7.9, 0.3) – NI margin: −8% VL < 50 copies/mL: – ISG at 24 weeks: 93.7% – DSG at 24 weeks: 94.6% (95% CI = −4.7, 3.0) Dizziness – DOR: 10% – EFV: 38% Sleep disorders/disturbances – DOR: 14% – EFV: 28% Altered sensorium – DOR: 5% – EFV: 9% Rash – DOR: 6% – EFV: 12% Depression/suicide/self-injury: – DOR: 4% – EFV: 7% Psychotic disorders: – DOR: 0.3% – EFV: 1.1% Drug-related adverse events: 60% Drug-related adverse events at week 48 – ISG: 5.6% – DSG: 13.9% Discontinued because of drug- related adverse events: – ISG: 0.9% – DSG: 1.9% VF: – ISG at 48 weeks: 1.3% – DSG at 24 weeks: 0.4% – DSG at 48 weeks: 0.5 Discontinuation without VF: – ISG at 48 weeks: 7.6% – DSG at 24 weeks: 5.8% – DSG at 48 weeks: 2.9% Abbreviations: 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; bPI, boosted protease inhibitor; DOR, doravirine; DRV/r, darunavir/ritonavir; DSG, delayed switch group; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; ISG, immediate switch group; NI, noninferiority; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; QD, daily; QHS, daily at bedtime; TDF, tenofovir disoproxil fumarate; VF, virological failure; VL, viral load. aAll patients on DOR were switched to DOR 100 mg daily. Blevins et al 7 Table 3. Mean Changes in Lipid Levels From Baseline at 48 and 96 Weeks. DRIVE-FORWARD, 48 Weeks DRIVE-FORWARD, 96 Weeks DRIVE-AHEAD, 48 Weeks DRIVE-AHEAD, 96 Weeks DOR + 2 NRTIs DRV/r + 2 NRTIs DOR + 2 NRTIs DRV/r + 2 NRTIs DOR/3TC/ TDF EFV/FTC/ TDF DOR/3TC/ TDF EFV/FTC/ TDF LDL cholesterola −4.5 mg/dL 9.9 mg/dL −0.44 mg/dL 14 mg/dL −1.6 mg/dL 8.7 mg/dL −0.62 mg/dL 10.8 mg/dL Non-HDL cholesterola −5.3 mg/dL 13.8 mg/dL −0.48 mg/dL 17.7 mg/dL −3.8 mg/dL 13.3 mg/dL −2.1 mg/dL 14.9 mg/dL Total cholesterolb −1.4 mg/dL 17.9 mg/dL −2.0 mg/dL 21.8 mg/dL Triglyceridesb −3.1 mg/dL 22.0 mg/dL −12.4 mg/dL 22.0 mg/dL HDL cholesterolb 3.9 mg/dL 4.2 mg/dL 1.9 mg/dL 8.5 mg/dL Abbreviations: 3TC, lamivudine; DOR, doravirine; DRV/r, darunavir/ritonavir; EFV, efavirenz; FTC, emtricitabine; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. aP < 0.001. bStatistical analysis not prespecified. occurred in 8 patients, whereas 40 discontinued treatment for reasons other than VF, including adverse events, patients lost to follow-up, and withdrawal of consent. Of the patients who experienced VF or discontinued therapy, the only mutation that was discovered was an M184M/I conferring resistance to FTC. DRIVE-CLEAR is an ongoing double-blind, multicenter, randomized trial evaluating the CNS effects of switching patients who are virologically suppressed on EFV/FTC/TDF to DOR/3TC/TDF.18 DRIVE2Simplify is also an ongoing randomized, double-blind, active-comparator-controlled, dose-ranging study designed to assess the activity, pharma- cokinetics, tolerability, and safety of islatravir in combina- tion with DOR and 3TC in treatment-naïve patients.19 Safety In the DRIVE-FORWARD study, the overall incidence of treatment-related adverse effects were comparable at 31% and 32% in the DOR and DRV/r arms, respectively.14 The most commonly reported adverse effects in the DOR and DRV/r arms were nausea, diarrhea, headache, and neuro- psychiatric events (Table 2). The study defined neuropsy- chiatric events as any of the following: disturbances in attention, dizziness, somnolence, abnormal dreams, confu- sion, depressed mood, depression, insomnia, nightmares, and psychotic disorder. In this study, no discontinuations were attributed to neuropsychiatric changes in either treat- ment arm. Two patients receiving DOR and 1 patient receiving DRV/r had to discontinue treatment because of rash. The overall rates of discontinuation resulting from adverse effects were 1% and 3% in the DOR and DRV/r arms, respectively. In this study, no discontinuations were attributed to neuropsychiatric changes in either treatment arm. At 96 weeks, the most common adverse effects remained diarrhea, nausea, and headache in the DOR and DRV/r arms.23 In the DRIVE-AHEAD study, the incidence of treat- ment-related adverse effects in the DOR arm (31%) was approximately half that compared with the EFV arm (63%).14,15 The most commonly reported adverse effects in the DOR and EFV arms, respectively, were abnormal dreams, dizziness, nausea, and rash (Table 2). At 96 weeks, discontinuation rates for treatment-related adverse events were lower in the DOR group compared with the EFV group (3% vs 7%).24 CNS-related adverse events were reported as the reason for discontinuation for approxi- mately half of those discontinuing treatment in both arms. in all 10 patients receiving EFV discontinued therapy because of rash compared with none in the DOR treatment arm. At 96 weeks, there were significantly fewer prespeci- fied neuropsychiatric adverse events in the DOR arm com- pared with the EFV arm, including dizziness (10% and 38%), sleep disorders (14% and 28%), and altered senso- rium (5% and 9%). Fewer patients in the DOR group reported depression and suicide/self-injury, and psychosis and psychotic disorders. The effect of DOR on fasting lipids levels was evaluated in both the DRIVE-FORWARD and DRIVE-AHEAD stud- ies and is shown in Table 3.14,15 In both studies, treatment with DOR resulted in reduction in mean low-density lipo- protein (LDL) cholesterol, non–high-density lipoprotein (HDL) cholesterol, total cholesterol, and triglycerides com- pared with increases in the comparator arms. Mean LDL cholesterol was significantly lower in DOR-treated patients compared with the DRV/r group and the EFV group, dem- onstrating DOR superiority. Similarly, mean differences in non–HDL cholesterol were also statistically significant. Although statistical testing was not prespecified for total cholesterol and triglycerides, numerical differences between DOR and comparator groups were notably lower. HDL cho- lesterol elevation was similar between DOR and DRV/r treatment arms, but DOR showed a lower percentage increase compared with EFV treatment arms. Reduction in 8 Annals of Pharmacotherapy 00(0) LDL and non-HDL cholesterol was maintained through 96 weeks in patients treated with DOR, whereas LDL and HDL remained elevated in EFV or DRV/r. Few grade 3 to 4 laboratory abnormalities were observed in both studies. In the DRIVE-FORWARD study, grade 3 elevations in LDL cholesterol were reported in <1% and 3% with DOR and DRV/r, respectively.14 Grade 3 serum creatinine elevations were reported in 1% and 3% of these patients. However, changes from baseline were minimal and comparable between DOR and DRV/r (0.04-0.07 and 0.05-0.06 mg/dL, respectively). Serum creatinine eleva- tions in the DRIVE-AHEAD study were uncommon and similar between DOR and EFV arms.15 There are insufficient pharmacokinetic and safety data to recommend DOR in either pregnant or pediatric patient populations. Patients with hepatitis B coinfection should be monitored carefully because hepatitis flares may occur with abrupt withdrawal of either 3TC or TDF. Dosing Recommendations DOR is available as both a FDC and a single tablet, allow- ing it to be used with other NRTI combinations. The avail- ability of a single tablet is important in regard to its clinical utility because the FDC contains TDF, a tenofovir formula- tion that has been largely replaced by tenofovir alafenamide because of diminished systemic toxicity. The recommended adult dosage for adults is 1 tablet once daily with or without food either as a single tablet or FDC.9 Patients with severe renal impairment have higher DOR trough concentrations and a longer half-life, but this does not necessitate dosage adjustment.9,27 DOR has not been studied in peritoneal dial- ysis or hemodialysis to determine the need for supplemental dosing. A small pharmacokinetic comparison study in HIV- uninfected patients demonstrated that DOR plasma concen- trations and half-lives were similar in both healthy patients and those with moderate hepatic impairment (Child-Pugh scores 7-9).9,28 Additional studies are needed in patients with severe hepatic impairment. Drug Interactions DOR drug-drug interactions have been extensively evalu- ated, with the most frequently implicated drugs being indif- ferent to the presence of DOR, including statins, oral contraceptives, methadone, midazolam, or hepatitis C antivi- rals (elbasvir/grazoprevir and ledipasvir/sofosbuvir).11,29-32 Coadministration with antacids or pantoprazole had no clini- cally relevant effect on the pharmacokinetics of DOR.33 Concurrent use of strong CYP inducers or inhibitors such as rifampin and ritonavir should be avoided because these are expected to result in reduced or increased concentrations, respectively. Rifampin is contraindicated with DOR because of the extensive CYP3A4 induction effects on DOR (C24 Table 4. Doravirine-Associated Resistance Mutations.a L100I K101E V106A V106I V106M V108I E138K Y188L G190A G190S H221Y P225H F227C F227L F227V M230I M230L L234I P236L Y318F aMajor mutations in bold. concentrations reduced 97%).34 A pharmacokinetic study demonstrated that increasing the dose of DOR to 100 mg twice daily will maintain adequate trough concentrations when taken with rifabutin.35 Phenytoin, carbamazepine, oxcarbazepine, enzalutamide, and mitotane cannot be con- comitantly administered with DOR because coadministration may result in a subtherapeutic DOR concentration. A phar- macokinetic study also examined the expected impact of transitioning from EFV to DOR-based regimens. EFV, a pre- dominant CYP enzyme inducer, does lower DOR concentra- tions, but this is not expected to require an adjustment in DOR dose.36 No clinically significant concentration changes or safety concerns were observed with coadministration of dolutegravir and DOR.37 Resistance Profile Greater than 90% of NNRTI resistance is associated with the K103N, Y181C, and G190A mutations.38 An NNRTI that is able to maintain appreciable activity against these mutations would prove useful as part of a therapeutic regimen. Early in development, DOR maintained in vitro activity against HIV isolates with K103N and Y181C mutations.38,39 Feng et al38 demonstrated that DOR was 30-fold more potent than EFV against a K103N in vitro. They also showed that DOR was 9-fold and 4-fold more potent against Y181C than etravirine (ETR) and RPV, respectively.38 Investigators discovered that viral breakthrough in the presence of DOR was mainly asso- ciated with a V106A mutation, which is thought to result in an approximate 10-fold decrease in susceptibilty.38 Other major mutations resulting in viral breakthrough included F227L and L234I. Multiple substitutions can confer up to a 150-fold decrease in susceptibility to DOR. Additionally, investigators found that these mutations generally developed in 1 of 2 orders: (1) V108I  V106A  L234I or (2) L234I  V108I  V106A.39 This information may be useful when monitoring genotypes of poorly adherent patients. A list of DOR-associated resistance mutations is listed in Table 4. In vitro findings are consistent with resistance testing from phase 3 clinical trials. In the DRIVE-FORWARD trial, 19 patients receiving DOR had VF.14 Resistance data were available for 7 of these, but no DOR-associated resistance mutations were identified; however, resistance data were also available for 1 DOR patient who withdrew from the study because of noncompliance.14 This patient developed 3 Blevins et al 9 DOR-associated mutations, including V106I, H221Y, and F227C, resulting in a nearly 100-fold increase in the IC50 for DOR.14 In the DRIVE-AHEAD study, genotype data were available for 13 of 22 patients receiving DOR who experienced VF. Additionally, genotype data were available from 9 patients who discontinued therapy.15 Six patients who received DOR displayed both genotypic and pheno- typic resistance to DOR and EFV, whereas only 1 patient displayed genotypic resistance to DOR. Four of these patients had resistance exclusively associated with a substi- tution at V106.15 The remaining 3 had a V106 substitution in combination with other mutations. Of note, 5 of these 7 patients had 3TC-associated resistance mutations as well. Soulie et al40 investigated the presence of baseline DOR- associated resistance mutations in treatment-naïve HIV patients. Genotype data from more than 9000 treatment- naïve patients were reviewed for presence of DOR-associated mutations. The number of genotypes with 1, 2, 3, and 4 DOR mutations was 127 (1.3%), 8 (0.1%), 1 (0.01%), and 1 (0.01%), respectively. The most commonly identified muta- tions were Y108I, Y188L, H221Y, and Y318F.40 Substitutions at V106, which appears to the major cause of viral break- through, were very rare (n = 8; 0.1%). Other common NNRTI-associated mutations were more prevalent: K103N (n = 201; 2.1%) and E138A/G/K/Q/R (n = 637; 6.5%).40 The available data for DOR show that it has a unique resistance pattern compared with other available NNRTIs. It maintains activity against common NNRTI resistance mutations, including those that are commonly transferred.38 DOR could potentially be used to treat NNRTI-experienced patients, including those with baseline NNRTI resistance; however, as evidenced in phase 3 and in vitro studies, devel- opment of DOR resistance is possible and could result in treatment failure.14,15,38,39 Data from a cross-sectional analy- sis of a large Italian database examined the prevalence of predicted DOR resistance based on NNRTI exposure his- tory. The study concluded that DOR resistance is uncom- mon in NNRTI-experienced patients, but prior exposure to EFV or ETR could increase risk of DOR resistance.41 More real-world data are also needed to draw a definitive conclu- sion concerning the genetic barrier of DOR and its ability to withstand poor patient adherence. In contrast, the preva- lence of DOR mutations at baseline is exceedingly rare.40 Although not recommended in current guidelines as a first- line therapy, there are no data that suggest that DOR should be avoided in treatment-naïve patients because of concern for resistance. Relevance to Patient Care and Clinical Practice Unlike many other agents in the NNRTI class, DOR does not have obvious therapeutic limitations such as food require- ments, adverse effects resulting in decreased tolerability, or a greater propensity for drug-drug interactions. Despite dis- playing noninferiority to EFV and DRV/r, the use of DOR- containing regimens must be carefully balanced given the current dearth of clinical experience, lack of study generaliz- ability, and adverse effects associated with long-term use of TDF such as nephrotoxicity and decreased bone mineral density. DOR represents a welcome addition to available ARV therapeutic options, but the patient population deriving the most benefit remains to be defined. Given the stability to many NNRTI mutations, DOR may have a role in treatment- experienced patients as well. At present, clinical trials are ongoing; thus, using DOR in this patient population should be done with caution. Because of its genetic barrier, DOR may be an attractive option for patients with previous NNRTI exposure who are unable to tolerate INSTIs. It is worth not- ing that there are currently no head-to-head trials with INSTIs; however, a head-to-head comparison or clinician- reported real-world experience could result in another major change to the guidelines. Conclusion The most current DHHS guidelines recommend DOR- containing regimens for use in special clinical situations because of lack of clinical experience. As clinical experi- ence accrues, provided that patient outcomes are positive, DOR could reintroduce the NNRTI class as a first-line treat- ment option. The reemergence of this class could also come as a consequence of accumulating concerns regarding birth defects and CNS adverse effects associated with the use of INSTI-based regimens.26 Until newer data emerge, DOR- based regimens should continue to be reserved for special situations. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The authors received no financial support for the research, author- ship, and/or publication of this article. ORCID iDs E. Kelly Hester Daniel B. Chastain David B. Cluck References 1. Riddler SA, Haubrich R, DiRienzo AG, et al; AIDS Clinical Trials Group Study A5142 Team. Class-sparing regimens for initial treatment of HIV-1 infection. 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