Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents With HIV

What to Start

Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens

Summary

Four non-nucleoside reverse transcriptase inhibitors (NNRTIs)—doravirine (DOR), efavirenz (EFV), nevirapine (NVP), and rilpivirine (RPV)—are currently approved by the U.S. Food and Drug Administration (FDA) for the initial treatment of HIV when used in combination with other antiretroviral (ARV) drugs. A fifth NNRTI, etravirine (ETR), is approved only for people who are ART-experienced.

NNRTI-based regimens have demonstrated virologic potency and durability. The major disadvantages of currently available NNRTIs (especially EFV and RPV) include the prevalence of NNRTI-resistant viral strains in people without prior antiretroviral therapy (ART),¹ a low barrier for the development of resistance, and potential for drug–drug interactions, although drug–drug interactions are less common with DOR. Resistance testing should be performed before initiation of an NNRTI-based regimen in people without prior ART. High-level resistance to all NNRTIs (except ETR or DOR) may occur with a single mutation. In people treated with RPV, the presence of RPV resistance mutations at virologic failure may confer cross-resistance to other NNRTIs, including ETR.^2,3 DOR-based regimens and one of the RPV-based regimens are now categorized as recommended Other Initial Antiretroviral Regimens for Certain Clinical Situations. More details about these NNRTIs are provided below.

This section of the guidelines focuses on DOR and RPV, the two NNRTIs recommended by the Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) as part of an initial ART regimen for people with HIV in certain clinical scenarios (see Table 6b in the Initial Combination Antiretroviral Regimens for People With HIV section and Table 7). There is no clinical trial comparing the efficacy of these two NNRTIs as initial ARV regimens. The Panel no longer recommends EFV as initial therapy because of the high incidence of serious toxicities, including neuropsychiatric effects and suicidality. NVP is no longer commonly used in clinical practice in the United States due to a relatively high potential for adverse effects compared to other NNRTIs.

Doravirine

Efficacy in Clinical Trials

The efficacy of DOR-based therapy as initial ART was demonstrated in two randomized, double-blind, placebo-controlled trials.

Doravirine-Based Regimen Versus Efavirenz-Based Regimen

• In the DRIVE-AHEAD trial, 734 participants received either DOR/tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) or EFV/TDF/emtricitabine (FTC), both as a daily fixed-dose combination (FDC) tablet.⁴
• At 96 weeks, DOR/TDF/3TC was noninferior to EFV/TDF/FTC, with 77.5% of participants who received DOR/TDF/3TC and 73.6% of those who received EFV/TDF/FTC achieving HIV RNA <50 copies/mL. Although virologic responses to ART overall were lower in participants with pre-treatment HIV RNA >100,000 copies/mL or pre-treatment CD4 T lymphocyte (CD4) cell counts of ≤200 cells/mm³, there was no difference between the DOR-treated and EFV-treated participants.
• Virologic rebound and virologic nonresponse were similar in the DOR/TDF/3TC (9.3%) and EFV/TDF/FTC (7.7%) treatment groups. At 96 weeks, genotype resistance results were reported for 21 participants with protocol-defined virologic failure in the DOR arm and 15 participants in the EFV arm. For the DOR arm, 7 of 21 (33.3%) participants had NNRTI resistance and 6 of 21 (28.6%) had NRTI resistance. For EFV, 10 of 15 (66.7%) participants had NNRTI resistance and 5 of 15 (33.3%) had NRTI resistance.
• More participants in the EFV arm discontinued their assigned ART due to adverse events than in the DOR arm (6.6% vs. 3.0%). Neuropsychiatric side effects and rash were more common in the EFV arm.

Doravirine-Based Regimen Versus Darunavir/Ritonavir-Based Regimen

• In the DRIVE-FORWARD trial, 769 participants received DOR or darunavir/ritonavir (DRV/r) once daily along with two investigator-selected nucleoside reverse transcriptase inhibitors (NRTIs), either abacavir (ABC)/3TC or TDF/FTC.⁵
• At 48 weeks, DOR was noninferior to DRV/r with 84% of study participants who received DOR versus 80% of those who received DRV/r achieving HIV RNA <50 copies/mL. Participants who received DOR plus ABC/3TC (n = 48) and those who received DOR plus TDF/FTC (n = 316) had similar virologic responses.
• At 96 weeks, DOR was superior to DRV/r in terms of virologic suppression (73% vs. 66%).⁵
• Protocol-defined virologic failure was similar in the DOR and DRV/r groups (9% vs. 11%) by Week 96. Genotype resistance results were reported for 11 and 14 participants with virologic failure in the DOR and DRV/r arms, respectively. Treatment-emergent resistance to any study drug occurred in 2 of 11 participants in the DOR group and 1 of 14 participants in the DRV/r group.
• Treatment-related diarrhea was more frequently reported in the DRV/r arm. Greater increases in fasting low-density lipoprotein cholesterol, triglycerides, non–high-density lipoprotein cholesterol, and total cholesterol were seen in the participants who received DRV/r than in those who received DOR.
• In a pooled analysis of DRIVE-AHEAD and DRIVE-FORWARD participants who entered an open-label extension phase following the initial 96 weeks of randomized treatment, 550 participants continued their DOR-based regimen and 502 participants switched to a DOR-based regimen from the control arms. At 192 weeks, 83% percent of participants who continued on DOR and 81% of participants in the switch arm maintained viral suppression. Discontinuation due to drug-related adverse events was <1% overall and similar between the two arms, with no discontinuations due to renal adverse events.⁶

Other Factors and Considerations

• DOR is available as a single-drug 100-mg tablet⁷ and as part of a single-tablet regimen (STR) that contains DOR/TDF/3TC 100 mg/300 mg/300 mg⁸ and is dosed once daily, with or without food.
• DOR-based regimens have not been directly compared to integrase strand transfer inhibitor (INSTI)–based regimens in clinical trials and have not been studied with tenofovir alafenamide (TAF) in clinical trials.
• A post hoc analysis of three randomized controlled trials examined weight gain among ART-naive participants receiving DOR versus DRV/r or EFV. At week 96, mean weight gain was similar in the DOR group (2.4 kg), DRV/r group (1.8 kg), and EFV group (1.6 kg). No significant differences between treatment groups were found in the proportion of participants whose body mass index classification increased to overweight or obese at Week 48 or Week 96.⁹
• DOR is primarily metabolized by the CYP3A4 enzyme and should not be coadministered with strong CYP3A4 inducers. DOR concentration may increase in the presence of a CYP3A4 inhibitor (see Table 24b). DOR is not a CYP3A4 inducer or inhibitor; thus, it is not expected to affect the concentrations of concomitant CYP3A4 substrates.
• Treatment-emergent resistance mutations to DOR may confer cross-resistance to certain other NNRTIs. Most isolates with DOR mutations remain susceptible to ETR.¹⁰
• There are currently no data on the safety of DOR use during pregnancy.
• There are limited clinical trial data with the combination of DOR + ABC/3TC, so the Panel is less certain about the efficacy of this regimen.

The Panel’s Recommendations

• Based on the clinical trial data discussed above, the Panel classifies DOR/TDF/3TC (BI) and DOR plus two NRTIs (BI for TDF/FTC and BIII for TAF/FTC) as Other Initial Antiretroviral Regimens for Certain Clinical Scenarios.

Rilpivirine

Oral RPV is approved for use in combination with two NRTIs as initial ART for people with HIV who have pre-treatment viral loads <100,000 copies/mL. RPV is also approved as an extended-release injectable suspension as part of a long-acting (LA) injectable complete ARV regimen when used with cabotegravir (CAB), an INSTI. This regimen is approved to replace oral ART in people with virologic suppression and no history of resistance to RPV or INSTIs (see Optimizing Antiretroviral Therapy in the Setting of Viral Suppression for discussion of LA CAB/RPV).

Efficacy in Clinical Trials

• Two Phase 3 randomized, double-blind clinical trials—ECHO and THRIVE—compared RPV and EFV, each combined with two NRTIs.¹¹ At 96 weeks, the following findings were reported:
• RPV was noninferior to EFV overall.
• Among participants with pre-ART viral loads >100,000 copies/mL, more RPV-treated participants experienced virologic failure than EFV-treated participants. NNRTI and NRTI resistance were more frequently found in RPV-treated participants with virologic failure.
• Among the RPV-treated participants, the rate of virologic failure was greater in those with pre-treatment CD4 counts <200 cells/mm³ than in those with CD4 counts ≥200 cells/mm³.
• STaR, a Phase 3b, open-label study, compared two STRs—RPV/TDF/FTC and EFV/TDF/FTC—as initial ART in 786 people with HIV. The results at 96 weeks¹² were similar to those reported at 48 weeks.¹³
• RPV was noninferior to EFV overall.
• RPV was superior to EFV in participants with pre-ART viral loads ≤100,000 copies/mL and noninferior in those with pre-ART viral loads >100,000 copies/mL. Among participants with pre-ART viral loads >500,000 copies/mL, virologic failure was more common in RPV-treated than in EFV-treated participants.
• At Week 96, there were more participants with emergent resistance in the RPV/FTC/TDF arm than in the EFV/FTC/TDF arm (5.3% vs. 1.0%, respectively).
• The STR of RPV/TAF/FTC was approved by the FDA based on results from a bioequivalence study. In this study, plasma concentrations of RPV, FTC, and TAF 25 mg in participants taking the coformulated drug were similar to those seen in participants who received RPV as the single-drug tablet and TAF/FTC as part of the STR of EVG/c/TAF 10 mg/FTC.¹⁴

Adverse Effects

• RPV is generally well tolerated. In the ECHO, THRIVE, and STaR trials, fewer instances of CNS adverse events (e.g., abnormal dreams, dizziness, psychiatric side effects), skin rash, and dyslipidemia were reported in the RPV arms than in the EFV arms, and fewer people in the RPV arms discontinued therapy due to adverse events. However, up to 9% of clinical trial participants experienced depressive disorders, including approximately 1% of participants who had suicidal thoughts or who attempted suicide. People receiving RPV who have severe depressive symptoms should be evaluated to assess whether the symptoms may be due to RPV and if the risks of continuing the same regimen outweigh the benefits.

Other Factors and Considerations

• Oral RPV is formulated both as a single-drug tablet and in STRs with TAF/FTC, with TDF/FTC, and with DTG. Among available STRs, RPV/TDF/FTC is no longer recommended by the Panel for initial therapy.
• RPV is also available as part of an LA injectable ARV regimen for use in combination with LA CAB in people with HIV who are virologically suppressed and do not have resistance to these drugs (see Optimizing Antiretroviral Therapy in the Setting of Viral Suppression).
• The STR of RPV/TAF/FTC is given once daily and must be administered with a meal (containing at least 390 kcal).
• RPV is also coformulated as a once-daily FDC tablet with DTG that is used as continuation therapy for people with HIV who have achieved viral suppression.¹⁵ However, this combination has not been studied in people with HIV and no prior ART, and it is not recommended for initial therapy (see Optimizing Antiretroviral Therapy in the Setting of Viral Suppression).
• The oral drug absorption of RPV can be significantly reduced in the presence of acid-reducing agents. RPV is contraindicated in people who are receiving proton pump inhibitors and should be used with caution in those receiving H2 antagonists or antacids (see Drug–Drug Interactions for dosing recommendations).
• RPV is primarily metabolized in the liver by the CYP3A enzyme; its plasma concentration may be affected in the presence of CYP3A inhibitors or inducers (see Drug–Drug Interactions).
• At doses above the approved dose of 25 mg, RPV may cause QTc interval prolongation. RPV should be used with caution when coadministered with a drug known to increase the risk of Torsades de Pointes.

The Panel’s Recommendations

• Given the availability of other effective regimens that do not have virologic and immunologic prerequisites to initiate treatment, substantial drug–drug interactions, and a low genetic barrier to resistance, RPV is not recommended for initial therapy in most persons with HIV. RPV/TDF/FTC is no longer recommended as part of Other Initial Antiretroviral Regimens for Certain Clinical Scenarios, largely due to the limitations of RPV and the availability of DOR/TDF/3TC, which has fewer drug–drug interactions and no virologic and immunologic prerequisites. The Panel continues to recommend RPV/TAF/FTC as part of Other Initial Antiretroviral Regimens for Certain Clinical Scenarios (see Table 6b in the Initial Combination Antiretroviral Regimens for People With HIV section), largely to retain an STR option containing an NNRTI and TAF.
• Use of RPV with TAF/FTC (BII) should be limited to persons with pre-treatment viral loads <100,000 copies/mL and CD4 counts >200 cells/mm³.
• Data on RPV plus ABC/3TC are insufficient to consider recommending this regimen.

References

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