eCase - First-line ART

Key Principles and Recommended Regimens for First-line Antiretroviral Therapy

Released: May 22, 2019

Expiration: May 20, 2020

Joseph J. Eron, Jr., MD

Daniel R. Kuritzkes, 医学博士

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Introduction ARV Treatment Guidelines for First-line Therapy in Adult Patients Pretherapy ARV Resistance Testing Choosing Among the Integrase Inhibitors for First-line Therapy Selection of the NRTI Pair Choosing Other Than INSTI-Based Initial Therapy Clinical Trials of NNRTI-Based vs INSTI-Based Therapy Clinical Trials of INSTI-Based vs Boosted PI-Based Therapy Clinical Trials of NNRTI-Based vs PI-Based Therapy Choosing Among the NNRTIs for First-line Therapy Choosing Among the Boosted PIs for First-line Therapy NRTI-Limiting Approaches in Initial Therapy Recommendations for Special Situations Primary Care Essentials References

There are several choices for boosted PI–based therapy, with the following listed as either recommended or alternative initial therapies for patients with HIV: atazanavir plus ritonavir, atazanavir/cobicistat, darunavir plus ritonavir, and cobicistat/darunavir.^1,2,4 Fosamprenavir plus ritonavir, saquinavir plus ritonavir, and lopinavir/ritonavir are no longer included as recommended initial or alternative/secondary initial regimens in US or European guidelines.⁴

Ritonavir and cobicistat are both potent inhibitors of CYP3A liver enzymes, and as such slow the metabolism of drugs metabolized by the enzyme. As PIs are almost exclusively metabolized through CYP3A4 (other than nelfinavir), coadministration of low-dose ritonavir (100 or 200 mg daily) or cobicistat (150 mg daily, with atazanavir or darunavir only) with PIs increases plasma levels of that the particular PI and may allow for less frequent dosing and higher trough concentrations. This pharmacokinetic boosting likely accounts for the enhanced antiviral effect of boosted PI vs unboosted PI regimens, particularly in the presence of some PI-resistant viruses.

Of note, in Europe and in the United States, cobicistat has been approved for use as a boosting agent with darunavir 800 mg once daily or atazanavir 300 mg once daily.^118,119 Cobicistat is available as a PI booster in the United States in the once-daily fixed-dose combinations, atazanavir/cobicistat 300 mg/150 mg, cobicistat/darunavir 150 mg/800 mg (also available in Europe), and cobicistat/darunavir/emtricitabine/tenofovir AF 150 mg/800 mg/200 mg/10 mg (complete single-tablet regimen FDA approved in July 2018; also available in Europe).^120-122

Boosted Atazanavir-Based Initial Therapy

Atazanavir Plus Ritonavir Initial Therapy. Atazanavir plus ritonavir is included as part of alternative regimens in the European AIDS Clinical Society guidelines⁴ and as one of the “First-line Regimens to be Used in Certain Clinical Situations” in the DHHS guidelines.¹ These recommendations are based on the results of several prospective comparative clinical trials. In the phase III CASTLE study, the safety and efficacy of atazanavir plus ritonavir 300/100 mg once daily were compared with those of lopinavir/ritonavir twice daily, each combined with emtricitabine/tenofovir DF, in 883 treatment-naive patients.⁴¹ Lopinavir/ritonavir was administered twice daily in capsule formulation to Week 48 and in tablet formulation, where available, thereafter. At Week 48, the efficacy of atazanavir plus ritonavir was noninferior to that of lopinavir/ritonavir, with 78% vs 76% achieving HIV-1 RNA < 50 copies/mL, respectively, by intent-to-treat analysis. The risk of grade 2-4 hyperbilirubinemia was higher with use of atazanavir plus ritonavir, whereas grade 2-4 diarrhea was more frequent in the lopinavir/ritonavir arm. Mean changes in total cholesterol, non–high density lipoprotein cholesterol, and triglycerides were statistically significantly lower in the atazanavir plus ritonavir arm, and more patients in the lopinavir/ritonavir arm initiated lipid-lowering therapy during the study (8% vs 2%). In post hoc subgroup analyses, the study regimens demonstrated similar activity among patients who had high baseline HIV-1 RNA (≥ 100,000 copies/mL), but patients with lower baseline CD4+ cell counts appeared to have inferior responses to lopinavir/ritonavir vs those with CD4+ cell counts ≥ 200 cells/mm³, a difference that was not apparent with atazanavir plus ritonavir.

At Week 96, the rate of virologic suppression to HIV-1 RNA < 50 copies/mL was statistically significantly higher in the atazanavir plus ritonavir arm (74% vs 68% by intent-to-treat analysis¹²³; 75% vs 68% by snapshot analysis⁹²) primarily because of a higher rate of treatment discontinuations in the lopinavir/ritonavir arm. Adverse events were the most common reason for discontinuation in the lopinavir/ritonavir arm, whereas lack of efficacy was the most frequent reason for discontinuation in the atazanavir plus ritonavir arm.

An additional favorable feature of atazanavir plus ritonavir is that it, along with darunavir plus ritonavir, is associated with less effect on plasma lipids than lopinavir/ritonavir or efavirenz.⁴⁷ In the D:A:D study, atazanavir was not associated with increased risk of myocardial infarction; among the boosted PIs, atazanavir is the only drug not to have this association.⁶⁰Furthermore, an observational study of the Veterans Administration HIV Cohort (N = 9500) found that initial treatment with atazanavir-containing regimens was associated with a reduced risk of cardiovascular events, including myocardial infarction and stroke, compared with starting other PI-based, NNRTI-based, or INSTI-based regimens.⁹⁷ In ACTG 5257, randomization to atazanavir plus ritonavir led to slower progression of carotid intima media thickness than either darunavir plus ritonavir or raltegravir.⁹⁶It has been postulated that the beneficial cardiovascular effects of atazanavir are mediated by indirect hyperbilirubinemia, which is a potent antioxidant. Certain population-based studies have demonstrated a lower risk of cardiovascular disease in individuals with Gilbert syndrome, a genetic condition that similarly causes indirect hyperbilirubinemia.¹²⁴

The most common adverse event is indirect hyperbilirubinemia; in the CASTLE study, symptomatic jaundice was experienced by 4% of atazanavir plus ritonavir patients vs 0% for lopinavir/ritonavir.⁴¹ In clinical practice, jaundice may rarely become severe enough to cause cosmetic concerns for the patient, and if so, an alternative regimen may be chosen. In addition, atazanavir therapy has been associated with nephrolithiasis; sometimes kidney stone analysis will demonstrate atazanavir as a component of the stone.¹²⁵An analysis of the EUROSIDAcohort demonstrated increased risk of chronic kidney disease with cumulative exposure to atazanavir (incident rate ratio IRR: 1.21; 95% CI: 1.09-1.34; P = .0003), indinavir (IRR: 1.12, 95% CI: 1.06-1.18; P < .0001), lopinavir/ritonavir (IRR: 1.08; 95% CI: 1.01-1.16; P = .030), and tenofovir DF (IRR: 1.16; 95% CI: 1.06-1.25; P < .0001),after adjusting for other variables.⁵² A similar analysis of the ANRS Aquitaine Cohort found an increased risk of chronic kidney disease in patients who had received tenofovir DF or a PI for more than 6 months, with the greatest increase in risk among those receiving concomitant therapy with tenofovir DF and a PI (of whom 41% had received atazanavir plus ritonavir and 35% had received lopinavir/ritonavir).⁵³ Patients should be informed that gallstones have been reported with atazanavir use.⁹²

Coadministration of atazanavir with tenofovir DF significantly reduces atazanavir concentrations. As a result, ritonavir boosting of atazanaviris required whenever atazanavir and tenofovir DF are coadministered. In addition, stomach acidity is required for optimal atazanavir absorption. Although H₂-blockers and proton pump inhibitors may be used in certain situations with atazanavir, clinicians should be aware of acceptable dosing strategies. In general, it is advisable for patients to avoid use of acid-reducing therapies when receiving atazanavir-based therapy; if such treatment is required (such as for therapy of acid reflux disease), an alternative boosted PI (such as darunavir plus ritonavir, or other agents such as efavirenz, elvitegravir/cobicistat, or dolutegravir, should be considered.

Atazanavir/Cobicistat-Based Initial Therapy. The atazanavir plus cobicistat regimen is available as individual single pills or in the fixed-dose combination atazanavir/cobicistat. In both cases, the dose of atazanavir is 300 mg when boosted with cobicistat 150 mg and should be taken once daily with food. This regimen is indicated for use in combination with other ARV agents.^118,120

Atazanavir/cobicistat is included as part of alternative regimens in the EACS guidelines⁴and as part of one of the “First-line Regimens to be Used in Certain Clinical Situations” in the DHHS guidelines.¹

The atazanavir/cobicistat combination was approved based on a clinical trial of 692 treatment-naive patients with HIV infection randomized to receive either atazanavir/cobicistat or atazanavir boosted with ritonavir in combination with emtricitabine/tenofovir DF.¹²⁶ At Week 48, a similar proportion of patients receiving cobicistat experienced virologic success as those receiving ritonavir (85% and 87%, respectively) including among patients with high baseline HIV-1 RNA levels (> 100,000 copies/mL) (both 86%). Safety and tolerability of cobicistat also appeared to be similar to ritonavir as rates of serious adverse events were comparable (10% vs 7%, respectively) and 7% of patients in both arms discontinued treatment due to an adverse event. At the Week 144 analysis, the proportion of patients experiencing virologic success remained comparable between cobicistat- and ritonavir-boosted regimens (72% and 74%, respectively), and development of resistance was generally infrequent (emtricitabine resistance detected in 3 patients taking cobicistat and 1 patient taking ritonavir; no documented resistance to either PI or tenofovir DF).¹²⁷ OS at Week 144 was consistent with that reported at Week 48. Virologic success also was not significantly different among subgroups except for women in which atazanavir/cobicistat was favored over atazanavir plus ritonavir (OR 2.36 at Week 144).¹²⁷ Notably, there were more discontinuations in women receiving atazanavir plus ritonavir due to consent withdrawal and pregnancy. These results demonstrated that cobicistat is noninferior to ritonavir when used in combination with atazanavir plus emtricitabine/tenofovir DF.

Boosted Darunavir-Based Initial Therapy

Darunavir/Ritonavir Initial Therapy. Darunavir plus ritonavir is a recommended boosted PI for first-line therapy in the EACS guidelines.⁴

It is one of the boosted PIs included in “First-line Regimens to be Used in Certain Clinical Situations” in the DHHS guidelines¹and is included among the regimens recommended only for patients for whom “generally recommended regimens are not available or not an option” in the IAS-USA guidelines.²

Ritonavir-boosted darunavir 800/100 mg once daily has been compared with lopinavir/ritonavir for the treatment of ARV-naive patients, and as a result of this comparison, darunavir plus ritonavir is one of the recommended options for initial therapy. In the phase III ARTEMIS study, 689 patients were randomized to receive darunavir plus ritonavir once daily or lopinavir/ritonavir once or twice daily, each combined with emtricitabine/tenofovir DF.⁴² Patients were permitted to use the tablet formulation of lopinavir/ritonavir if available locally; 83% of lopinavir/ritonavir patients switched from the capsule to the tablet formulation during the study. At Week 48, the virologic efficacy of darunavir plus ritonavir was noninferior to that of lopinavir/ritonavir; the proportion of patients achieving HIV-1 RNA < 50 copies/mL was 84% on darunavir plus ritonavir and 78% on lopinavir/ritonavir (P < .001). Among patients with baseline HIV-1 RNA ≥ 100,000 copies/mL, rates of virologic suppression were statistically significantly higher with darunavir plus ritonavir (79% vs 67%; P < .05). Grade 2-4 gastrointestinal events, grade 2-4 elevations in total cholesterol and triglycerides, moderate to severe diarrhea, and toxicity-related discontinuations were all significantly less frequent with use of darunavir plus ritonavir.

At Week 96, darunavir plus ritonavir met the predetermined criteria for superiority to lopinavir/ritonavir regarding the proportion of patients attaining HIV-1 RNA < 50 copies/mL in the overall study population (79% vs 71%, respectively, by intent-to-treat analysis).¹²⁸ However, the snapshot analysis of these data in the 96-week window (90-102 weeks) yielded a smaller difference: 78% of those receiving darunavir plus ritonavir and 74% of those receiving lopinavir/ritonavir had HIV-1 RNA < 50 copies/mL.¹²⁹Analyses suggested that lopinavir/ritonavir was associated with both a higher risk of virologic failure and a higher rate of discontinuation because of adverse events. The difference was particularly striking among patients with suboptimal medication adherence, who did significantly better on darunavir plus ritonavir than on lopinavir/ritonavir, perhaps reflecting the superior pharmacokinetic properties of the former.¹³⁰

One potential concern about using darunavir plus ritonavir as initial therapy is that this PI has a central role in treatment-experienced patients, especially those with PI resistance.^131-134 However, in the ARTEMIS study (as with other studies of initial boosted PI therapy), patients who experienced virologic failure did not develop primary PI mutations in either the darunavir plus ritonavir or lopinavir/ritonavir treatment arms. This suggests that patients who experience virologic failure in first-line therapy with darunavir plus ritonavir could still use it in later lines.

Darunavir levels are not affected by coadministration of acid-reducing agents. One comparative clinical trial found that the metabolic changes between darunavir plus ritonavir and atazanavir plus ritonavir were approximately similar.¹³⁵ Likewise, the ACTG A5257 trial found similar fasting low-density lipoprotein cholesterol and triglyceride levels among patients in the darunavir plus ritonavir and atazanavir plus ritonavir treatment arms, which were higher than those of patients receiving raltegravir (P ≤ .001). Overall, this trial determined superior tolerability of darunavir plus ritonavir and raltegravir over atazanavir plus ritonavir mainly due to hyperbilirubinemia and gastrointestinal toxicity.⁸⁵However, a more recent substudy of ACTG 5257 showed that carotid intima media thickness progressed slower with atazanavir plus ritonavir than with either darunavir plus ritonavir or raltegravir.⁹⁶

A recent reanalysis of 35,711 HIV-infected patients in the D:A:D cohort followed for a median of 7 years found a 59% increase in the risk of cardiovascular disease with 5-year cumulative exposure to darunavir plus ritonavir whereas no increased risk was found for atazanavir plus ritonavir exposure (Capsule Summary).⁹⁵ Investigators suggest that further study into mechanisms underlying darunavir plus ritonavir exposure and cardiovascular disease risk is warranted.

Darunavir plus ritonavir has also been investigated as part of NRTI-sparing regimens, both for treatment-naive patients and as switch regimens for persons with HIV with virologic suppression. In the DHHS guidelines, 2 darunavir plus ritonavir-based regimens are included as part of nontraditional 2-drug regimens for persons who require first-line therapy and tenofovir DF, tenofovir AF, and abacavir cannot be used: darunavir plus ritonavir with twice-daily raltegravir (for persons with baseline HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm³)and darunavir plus ritonavir plus lamivudine.¹ The EACS guidelines recommend the alternative regimen darunavir plus ritonavir plus raltegravir.⁴ Data supporting these approaches will be discussed in more detail in the section on NRTI-sparing strategies for first-line therapy.¹³⁶

Darunavir/Cobicistat-Based Initial Therapy. The darunavir plus cobicistat regimen is available as individual single pills, in the fixed-dose combination, cobicistat/darunavir, or in the fixed-dose single-tablet regimen, cobicistat/darunavir/emtricitabine/tenofovir AF. Of note, the FDA approval of fixed-dose cobicistat/darunavir/emtricitabine/tenofovir AF in July 2018 provides patients and clinicians with the first-ever PI-based single-tablet ART regimen. This combination is approved for use in treatment-naive patients as well as for use as a switch regimen in patients with virologic suppression on their current ART regimen who do not have known darunavir or tenofovir resistance. The dose of darunavir is 800 mg when boosted with cobicistat 150 mg, and should be taken once daily with food.^118,121 The approval of cobicistat/darunavir was based on pharmacokinetic equivalency to the darunavir plus ritonavir combination. Darunavir/cobicistat plus 2 NRTIs is now included as a recommended first-line regimen in the European AIDS Clinical Society guidelines.⁴It is one of the boosted PIs included in “First-line Regimens to be Used in Certain Clinical Situations” in the DHHS guidelines¹and is included among the regimens recommended only for patients for whom “generally recommended regimens are not available or not an option” in the IAS-USA guidelines.²Finally, cobicistat/darunavir plus raltegravir is included as an NRTI-sparing regimen in the EACS guidelines.⁴

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