Released: May 22, 2019
Expiration: May 20, 2020
When discussing choices for NNRTI-based first-line therapy, the real choice presently is among efavirenz, rilpivirine, and doravirine. Although other NNRTIs are FDA approved for first-line ART, current guidelines do not recommend them or include them as alternative options (eg, nevirapine and delavirdine). Etravirine is approved for treatment-experienced patients only.
Efavirenz-Based Initial Therapy
The NNRTIs currently approved by the FDA for initial therapy are efavirenz, nevirapine, delavirdine, rilpivirine, and doravirine. During the past several years, NNRTIs have been removed from lists of recommended first-line regimens in US and European ART guidelines due to a higher rate of adverse events during the first months of efavirenz use and its lower threshold for resistance at virologic failure relative to other options.1,2,4 Efavirenz, however, remains a component of alternative first-line regimens based on the abundant data from comparative clinical trials (summarized above) supporting its potent antiviral activity, the simplicity of dosing (including a 1-pill, once-daily coformulation with emtricitabine/tenofovir DF), and its overall favorable safety and tolerability profile. Rilpivirine is also considered an alternative agent for first-line therapy in US and European guidelines (and in fact is part of recommended first-line regimens in the EACS guidelines, paired with either emtricitabine/tenofovir DF or emtricitabine/tenofovir AF) but only for patients with baseline HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm3.4 Doravirine was approved by the FDA in August 2018 and is recommended as an initial regimen in certain clinical situations in the DHHS guidelines.1 Notably, delavirdine is not recommended by any guidelines in any circumstances.
It is important to note that not all patients are appropriate candidates for efavirenz-based therapy. Patients who have acquired NNRTI-resistant virus would require an alternative choice, typically a boosted PI or INSTI. Furthermore, efavirenz treatment is associated with CNS adverse events in more than one half of the patients who begin the drug.101 Since dizziness and drowsiness are particularly common, especially in the first 2 weeks of therapy, most patients prefer to take the medication at bedtime; taking this medication on an empty stomach is recommended since this reduces the severity of these adverse events. For the vast majority of patients, these CNS symptoms either resolve completely or substantially diminish after 1-2 weeks, with residual vivid dreams being the most common complaint among long-term efavirenz-treated patients.79 However, a small minority of patients continue to be highly troubled by efavirenz CNS adverse events, which may be manifested as a mood disorder (predominantly depression). An analysis of ACTG clinical trials showed an increased risk of suicidality in patients randomized to efavirenz-containing regimens.80 Similarly, results from the START trial showed a higher rate of suicidal behavior in patients randomized to receive immediate efavirenz-based regimens compared to ART-naive controls.102 For that reason, clinicians should select alternatives to efavirenz in patients with active psychiatric disease, in particular depression. In more recent clinical trials, particularly those comparing efavirenz with the NNRTI rilpivirine103 or the INSTI dolutegravir,17 the rate of discontinuation of efavirenz due to adverse events has been an important factor in the outcome of the trial.
In the past, US perinatal HIV guidelines have recommended against the use of efavirenz in pregnant women before 8 weeks’ gestational age. As a result, efavirenz was also not considered to be an appropriate choice for sexually active women of childbearing potential who were not using reliable contraception. These recommendations were based on data demonstrating an association between efavirenz use early in pregnancy and fetal CNS abnormalities in animal reproductive studies involving nonhuman primates along with isolated case reports of human infant neural tube defects when efavirenz was used in the first trimester of pregnancy.104 However, current DHHS perinatal HIV guidelines no longer include this restriction, noting that available data indicate that the risk of neural tube defects with first trimester efavirenz exposure is similar to that of the general population.105 This guidance is consistent with recommendations from both the World Health Organization106 and the British HIV Association (BHIVA) guidelines for initiating ART in pregnant women.107 The BHIVA guidelines also cite the numerous reports of first-trimester exposure without signal of risk of teratogenicity over that seen in the general population.108 Reassuring data were also provided by a retrospective study of nearly 10,000 women in Botswana.109 Among these women, 170 were receiving efavirenz/emtricitabine/tenofovir DF at the time of conception and an additional 1468 started this regimen during pregnancy. There was no difference in preterm delivery or stillbirth rates among these women vs those starting zidovudine prophylaxis or another 3-drug ARV regimen, and there were fewer small for gestational age infants among infants of mothers on efavirenz/emtricitabine/tenofovir DF vs other 3-drug ARV regimens. Of note, the FDA prescribing information for efavirenz continues to advise against the use of efavirenz during the first trimester of pregnancy.101
An additional issue to consider with efavirenz is the emergence of resistance to efavirenz at virologic failure, which is usually associated with a single mutation. In most clinical trials of efavirenz virologic failure is uncommon, but resistance to NNRTIs has occurred in a high percentage of these patients and is accompanied by resistance to the NRTI component of the regimen in a smaller number of patients.17,47,98 This difference in incidence of resistance at virologic failure between NNRTI and boosted PI–based regimens has also been reported in observational studies.110 Such data suggest that patients with suboptimal medication adherence receiving efavirenz-containing regimens are at relatively high risk for resistance development. Regimens using either dolutegravir or boosted PIs would be preferable in these cases.
On the other hand, efavirenz has been demonstrated to be highly effective in treatment-naive patients regardless of baseline CD4+ cell count or HIV-1 RNA level, an advantage over rilpivirine.111
Rilpivirine-Based Initial Therapy
Rilpivirine was approved for first-line therapy based on the results of the phase III ECHO and THRIVE trials in which rilpivirine demonstrated noninferior virologic activity to efavirenz.112,113 In the ECHO trial, each was paired with emtricitabine/tenofovir DF and in the THRIVE trial, the investigator chose the NRTI pair. Overall, rilpivirine-based therapy was noninferior to efavirenz-based therapy in each trial. However, there were several differences between the agents noted in the trials: among patients with a baseline HIV-1 RNA > 100,000 copies/mL, more patients taking efavirenz achieved undetectable HIV-1 RNA. More patients experienced treatment failure with rilpivirine based on virologic nonsuppression whereas more patients taking efavirenz failed due to adverse events. Of note, rilpivirine was associated with a lower incidence of CNS adverse events. More patients receiving rilpivirine exhibited viral resistance mutations to NRTIs and NNRTIs at failure. The primary NNRTI resistance mutation in those taking rilpivirine was E138K, which is associated with cross-resistance to all current NNRTIs including etravirine.
Rilpivirine is no longer included as a component of recommended first-line regimens in US guidelines, but it is listed as an option for patients who cannot receive generally recommended first-line regimens and who have baseline HIV-1 RNA < 100,000 copies/mL and baseline CD4+ cell count > 200 cells/mm3 in the IAS-USA guidelines2 and as a component of regimens to be used in certain clinical situations in the DHHS guidelines for patients with HIV-1 RNA < 100,000 copies/mL and baseline CD4+ cell count > 200 cells/mm3.1 However, emtricitabine/rilpivirine/tenofovir DF and emtricitabine/rilpivirine/tenofovir AF are both recommended by the EACS guidelines panel as first-line regimens but only in patients with baseline HIV-1 RNA < 100,000 copies/mL and baseline CD4+ cell count > 200 cells/mm3.4 The recommendation to include emtricitabine/rilpivirine/tenofovir AF is based on bioequivalent pharmacokinetic data with emtricitabine/rilpivirine/tenofovir DF.114
The noninferiority of emtricitabine/rilpivirine/tenofovir DF to efavirenz/emtricitabine/tenofovir DF as coformulated single-tablet regimens was evidenced in the open-label phase III STaR trial.115 At Week 48, 86% of patients receiving the rilpivirine regimen achieved HIV-1 RNA levels < 50 copies/mL based on the FDA snapshot algorithm compared with 82% of those receiving the efavirenz regimen. In this trial, a significantly higher percentage of patients receiving rilpivirine with baseline HIV-1 RNA ≤ 100,000 copies/mL achieved viral suppression to < 50 copies/mL (89% of rilpivirine-treated patients vs 82% of efavirenz-treated patients; 95% CI for the difference: 1.1% to 13.4%). Also, among patients with baseline HIV-1 RNA > 100,000 copies/mL, a similar number of patients treated with rilpivirine as with efavirenz achieved viral suppression (80% vs 82%, respectively; 95% CI for the difference: -11.1% to 7.5%). As seen in ECHO and THRIVE, virologic failure was more common among rilpivirine-treated than efavirenz-treated study subjects with baseline HIV-1 RNA > 100,000 copies/mL. NNRTI resistance mutations were also more common in rilpivirine-treated patients, especially in those baseline HIV-1 RNA > 100,000 copies/mL. Rash and lipid abnormalities were less common with rilpivirine than with efavirenz.
Doravirine-Based Initial Therapy
The FDA approved doravirine for first-line ART based on results of the phase III DRIVE-AHEAD and DRIVE-FORWARD trials in which doravirine demonstrated noninferiority to efavirenz and ritonavir-boosted darunavir, respectively. In DRIVE-AHEAD, a double-blind noninferiority trial, 734 treatment-naive adults were randomized to either doravirine plus lamivudine and tenofovir DF with placebo for the efavirenz regimen or to efavirenz/emtricitabine/tenofovir DF plus placebo for the doravirine regimen.116 Doravirine was noninferior to efavirenz at the 48-week primary efficacy analysis, with 84.3% vs 80.8% of patients, respectively, achieving HIV-1 RNA levels < 50 copies/mL based on the FDA snapshot analysis (treatment difference: 3.5%; 95% CI: -2.0% to 9.0%). Virologic response rates were consistent across most patient subgroups with the exception of age, where response rates were lower with doravirine vs efavirenz among individuals aged 31 years or younger and response rates were higher with doravirine vs efavirenz among individuals older than 31 years of age. The PDVF rate was slightly higher with doravirine compared with efavirenz (6.0% vs 3.8%, respectively). Among those who received doravirine and experienced PDVF, 7 out of 13 patients evaluated had mutations associated with doravirine resistance and 6 of those displayed phenotypic resistance to doravirine; of these 7 patients, 5 also had genotypic resistance to lamivudine. Among the efavirenz-treated patients who experienced PDVF or who discontinued early without PDVF, 12 out of 23 patients assessed had mutations associated with efavirenz resistance, 11 of these also had phenotypic resistance to efavirenz, and 5 also had genotypic resistance to emtricitabine. The doravirine arm exhibited lower rates of adverse events, drug-related adverse events, and discontinuations due to adverse events compared with the efavirenz arm. Notably, the proportion of patients experiencing prespecified neuropsychiatric events by Week 48 was significantly lower in the doravirine arm vs the efavirenz arm for the categories of dizziness (8.8% vs 37.1%, respectively; P ≤ .001); sleep disorders/disturbances (12.1% vs 25.2%, respectively; P ≤ .001); and altered sensorium (4.4% vs 8.2%, respectively; P = .033). Patients receiving doravirine also experienced minimal changes or decreases in mean lipid levels from baseline to Week 48 whereas patients in the efavirenz arm experienced increases, which were significantly greater than those in the doravirine arm for low density lipoprotein cholesterol and non–high density lipoprotein cholesterol (both P < .0001).
Doravirine is now included in the DHHS guidelines as a component of first-line regimens to be used in certain clinical situations (Table 2).1
Considerations for Choosing a First-line NNRTI
When choosing among efavirenz, doravirine, and rilpivirine, the latter would be a reasonable option in patients with baseline HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm³, where the better tolerability of rilpivirine is not offset by excess risk of virologic failure. Additional considerations for the use of rilpivirine include the requirement for taking the drug with a meal and that concomitant proton pump inhibitor administration is contraindicated; by contrast, doravirine has no food requirements and no known interactions with the proton pump inhibitor pantoprazole.74 In patients with higher HIV-1 RNA, efavirenz or doravirine may be preferable due to better antiviral efficacy and lower risk of resistance on virologic failure. Doravirine has shown noninferiority to efavirenz in terms of virologic efficacy, which was maintained across subgroups of patients with high baseline HIV-1 RNA levels and low CD4+ cell counts.116 Doravirine also exhibited significantly lower rates of neuropsychiatric events and an improved lipid profile compared with efavirenz. In vitro analyses suggested that viruses with resistance mutations selected by doravirine remain susceptible to efavirenz and rilpivirine (eg, V106A) and that mutations selected by efavirenz and rilpivirine remain susceptible to doravirine (eg, K103N, Y181C).117 However, in clinical trials, treatment-emergent doravirine-resistant variants demonstrated cross-resistance to efavirenz, nevirapine, and rilpivirine and partial resistance to etravirine by phenotypic resistance testing.72
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