"The National Institutes of Health has launched a clinical trial to assess the effects of aspirin and cholesterol-lowering drugs, or statins, on preventing cardiovascular disease in people with long-term HIV infections. This group, which includ"...
Mechanism Of Action
Efavirenz is an antiviral drug [see Microbiology].
The effect of SUSTIVA on the QTc interval was evaluated in an open-label, positive and placebo controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between efavirenz concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days [see WARNINGS AND PRECAUTIONS].
Peak efavirenz plasma concentrations of 1.6-9.1 μM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in Cmax and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses.
In HIV-1-infected patients at steady state, mean Cmax, mean Cmin, and mean AUC were dose proportional following 200 mg, 400 mg, and 600 mg daily doses. Time-to-peak plasma concentrations were approximately 3-5 hours and steady-state plasma concentrations were reached in 6-10 days. In 35 patients receiving SUSTIVA 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 μM (mean ± SD), steady-state Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM•h.
Effect Of Food On Oral Absorption
Capsules: Administration of a single 600 mg dose of efavirenz capsules with a high-fat/highcaloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC∞ and a mean increase of 39% and 51% in efavirenz Cmax, respectively, relative to the exposures achieved when given under fasted conditions. [See DOSAGE AND ADMINISTRATION and PATIENT INFORMATION]
Tablets: Administration of a single 600 mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC∞ of efavirenz and a 79% increase in mean Cmax of efavirenz relative to the exposures achieved under fasted conditions. [See DOSAGE AND ADMINISTRATION and PATIENT INFORMATION]
Bioavailability of capsule contents mixed with food vehicles: In healthy adult subjects, the efavirenz AUC when administered as the contents of three 200 mg capsules mixed with 2 teaspoons of certain food vehicles (applesauce, grape jelly or yogurt, or infant formula) met bioequivalency criteria for the AUC of the intact capsule formulation administered under fasted conditions.
Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received SUSTIVA 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma.
Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism.
Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200-400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22-42% lower) and a shorter terminal half-life of 40-55 hours (single dose half-life 52-76 hours).
Efavirenz has a terminal half-life of 52-76 hours after single doses and 40-55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a 14C-labeled dose administered on Day 8. Approximately 14-34% of the radiolabel was recovered in the urine and 16-61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces.
Pediatric: The pharmacokinetic parameters for efavirenz at steady state in pediatric patients were predicted by a population pharmacokinetic model and are summarized in Table 6 by weight ranges that correspond to the recommended doses.
Table 6: Predicted Steady-State Pharmacokinetics of
Recommended Doses of Efavirenz (Capsules/Capsule Sprinkles) in HIV-Infected
|Body Weight||Dose||Mean AUC(0-24) μM•h||Mean Cmax μg/mL||Mean Cmin μg/mL|
|3.5-5 kg||100 mg||220.52||5.81||2.43|
|5-7.5 kg||150 mg||262.62||7.07||2.71|
|7.5-10 kg||200 mg||284.28||7.75||2.87|
|10-15 kg||200 mg||238.14||6.54||2.32|
|15-20 kg||250 mg||233.98||6.47||2.3|
|20-25 kg||300 mg||257.56||7.04||2.55|
|25-32.5 kg||350 mg||262.37||7.12||2.68|
|32.5-40 kg||400 mg||259.79||6.96||2.69|
|> 40 kg||600 mg||254.78||6.57||2.82|
Gender and race: The pharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied.
Renal impairment: The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal.
Hepatic impairment: A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics.
Drug Interaction Studies
Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9 and 2C19 with Ki values (8.5-17 μM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (Ki values 82-160 μM) only at concentrations well above those achieved clinically. Coadministration of efavirenz with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A, or CYP2B6 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.
Drug interaction studies were performed with efavirenz and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. The effects of coadministration of efavirenz on the Cmax, AUC, and Cmin are summarized in Table 7 (effect of efavirenz on other drugs) and Table 8 (effect of other drugs on efavirenz). For information regarding clinical recommendations see DRUG INTERACTIONS.
Table 7: Effect of Efavirenz on Coadministered Drug
Plasma Cmax, AUC, and Cmin
|Coadministered Drug||Dose||Efavirenz Dose||Number of Subjects||Coadministered Drug (mean % change)|
|Cmax (90% CI)||AUC (90% CI)||Cmin (90% CI)|
|Atazanavir||400 mg qd with a light meal d 1-20||600 mg qd with a light meal d 7-20||27||↓59% (49-67%)||↓74% (68-78%)||↓93% (90-95%)|
|400 mg qd d 1-6, then 300 mg qd d 720 with ritonavir 100 mg qd and a light meal||600 mg qd 2 h after atazanavir and ritonavir d 7-20||13||↑ 14%a (↓ 17-↑ 58%)||↑39%a (2-88%)||↑48%a (24-76%)|
|300 mg qd/ritonavir 100 mg qd d 1-10 (pm), then 400 mg qd/ritonavir 100 mg qd d 11-24 (pm) (simultaneous with efavirenz)||600 mg qd with a light snack d 11-24 (pm)||14||↑17% (8-27%)||↔||↓42% (31-51%)|
|Indinavir||1000 mg q8h x 10 days||600 mg qd x 10 days||20|
|After morning dose||↔b||↓33%b (26-39%)||↓39%b (24-51%)|
|After afternoon dose||↔b||37%b (26-46%)||52%b (47-57%)|
|After evening dose||↓29%b (11-43%)||46%b (37-54%)||57%b (50-63%)|
|400/100 mg capsule q12h x 9 days||600 mg qd x 9||11,7c||↔d||↓ 19%d (↓ 36-↑ 3%)||↓39%d (3-62%)|
|Lopinavir/ ritonavir||500/125 mg tablet q12h x 10 days with efavirenz compared to 400/100 mg q12h alone||days 600 mg qd x 9 days||19||↑2%d (2-23%)||↔d||↓ 10%d(↓ 22-↑ 4%)|
|600/150 mg tablet q12h x 10 days with efavirenz compared to 400/100 mg q12h alone||600 mg qd x 9 days||23||↑ 36%d (28-44%)||↑ 36%d (28-44%)||↑32%d (21-44%)|
|Nelfinavir||750 mg q8h x 7 days||600 mg qd x 7 days||10||↑21% (10-33%)||↑ 20% (8-34%)||↔|
|Metabolite AG-1402||↓40% (30-48%)||↓ 37% (25-48%)||↓43% (21-59%)|
|Ritonavir||500 mg q12h x 8 days||600 mg qd x 10 days||11|
|After AM dose||↑ 24% (12-38%)||↑ 18% (6-33%)||↔ 42% e (9-86%)|
|After PM dose||↔||↔||↔ 24% e (3-50%)|
|Saquinavir SGCf||1200 mg q8h x 10 days||600 mg qd x 10 days||12||↓ 50% (28-66%)||↓ 62% (45-74%)||↓ 56% e (16-77%)|
|Lamivudine||150 mg q12h x 14 days||600 mg qd x 14 days||9||↔||↔||↑ 265% (37-873%)|
|Tenofovirg||300 mg qd||600 mg qd x 14 days||29||↔||↔||↔|
|Zidovudine||300 mg q12h x 14 days||600 mg qd x 14 days||9||↔||↔||↑225% (43-640%)|
|Maraviroc||100 mg bid||600 mg qd||12||↓51% (37-62%)||↓ 45% (38-51%)||↓ 45% (28-57%)|
|Raltegravir||400 mg single dose||600 mg qd||9||↓36% (2-59%)||↓ 36% (20-48%)||↓ 21% (↓51-↑28%)|
|Boceprevir||800 mg tid x 6 days||600 mg qd x 16 days||NA||↓8% (↓ 22-↑ 8%)||↓ 19% (11-25%)||↓ 44% (26-58%)|
|Simeprevir||150 mg qd x 14 days||600 mg qd x 14 days||23||↓51% (↓ 46-↓56%)||↓ 71% (↓ 67-↓ 74%)||↓91% (↓ 88-↓ 92%)|
|Azithromycin||600 mg single dose||400 mg qd x 7 days||14||↑ 22% (4-42%)||↔||NA|
|Clarithromycin||500 mg q12h x||400 mg qd x 7 days||11||↓26%(15-35%)||↓39%(30-46%)||↓53%(42-63%)|
|14-OH metabolite||7 days||↑ 49% (32-69%)||↑ 34% (18-53%)||↑26% (9-45%)|
|Fluconazole||200 mg x 7 days||400 mg qd x 7 days||10||↔||↔||↔|
|Itraconazole||200 mg q12h x 28 days||600 mg qd x 14 days||18||↓37% (20-51%)||↓39% (21-53%)||↓44% (27-58%)|
|Hydroxy- itraconazole||↓35% (12-52%)||↓37% (14-55%)||↓43% (18-60%)|
|Posaconazole||400 mg (oral suspension) bid x 10 and 20 days||400 mg qd x 10 and 20 days||11||↓45% (34-53%)||↓50% (40-57%)||NA|
|Rifabutin||300 mg qd x 14 days||600 mg qd x 14 days||9||↓32% (15-46%)||↓38% (28-47%)||↓45% (31-56%)|
|Voriconazole||400 mg po q12h x 1 day, then 200 mg po q12h x 8 days||400 mg qd x 9 days||NA||↓ 61%h||↓ 77%h||NA|
|300 mg po q12h days 2-7||300 mg qd x 7 days||NA||↓36%i (21-49%)||↓55%i (45-62%)||NA|
|400 mg po q12h days 2-7||300 mg qd x 7 days||NA||↑ 23%i (↓ 1-↑53%)||↑7%i (↓ 23-↑ 13%)||NA|
|Artemether/ lumefantrine Artemether||Artemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over 3 days)||600 mg qd x 26 days||12||↓ 21%||↓ 51%||NA|
|Atorvastatin||10 mg qd x 4 days||600 mg qd x 15 days||14||↓ 14% (1-26%)||↓43% (34-50%)||↓69% (49-81%)|
|Total active (including metabolites)||↓15% (2-26%)||↓32% (21-41%)||↓48% (23-64%)|
|Pravastatin||40 mg qd x 4 days||600 mg qd x 15 days||13||↓ 32% (↓ 59-↑12%)||↓ 44% (26-57%)||↓19% (0-35%)|
|Simvastatin||40 mg qd x 4 days||600 mg qd x 15 days||14||↓72% (63-79%)||↓68% (62-73%)||↓45% (20-62%)|
|Total active (including metabolites)||↓68% (55-78%)||↓ 60% (52-68%)||NAj|
|Carbamazepine Epoxide metabolite||200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 29 days||600 mg qd x 14 days||12||↓20% (15-24%)||↓27% (20-33%)||↓35% (24-44%)|
|↔||↔||↓13% (↓ 30-↑ 7%)|
|Cetirizine||10 mg single dose||600 mg qd x 10 days||11||↓24% (18-30%)||↔||NA|
|Diltiazem||240 mg x 21 days||600 mg qd x 14 days||13||↓ 60% (50-68%)||↓69% (55-79%)||↓63% (44-75%)|
|Desacetyl diltiazem||↓64% (57-69%)||↓75% (59-84%)||↓62% (44-75%)|
|N-monodes-methyl diltiazem||↓ 28% (7-44%)||↓37% (17-52%)||↓37% (17-52%)|
|Ethinyl estradiol/ Norgestimate Ethinyl estradiol Norelgestromin Levonorgestrel||0.035 mg/0.25 mg x 14 days||600 mg qd x 14 days||21||↔||↔||↔|
|21||↓46% (39-52%)||↓ 64% (62-67%)||↓82% (79-85%)|
|6||↓80% (77-83%)||↓ 83% (79-87%)||↓86% (80-90%)|
|Lorazepam||2 mg single dose||600 mg qd x 10 days||12||↑ 16% (2-32%)||↔||NA|
|Methadone||Stable maintenance 35-100 mg daily||600 mg qd x 14-21 days||11||↓45% (25-59%)||↓52% (33-66%)||NA|
|Bupropion Hydroxy- bupropion||150 mg single dose (sustained-release)||600 mg qd x 14 days||13||↓34% (21-47%)||↓55% (48-62%)||NA|
|Paroxetine||20 mg qd x 14 days||600 mg qd x 14 days||16||↔||↔||↔|
|Sertraline||50 mg qd x 14 days||600 mg qd x 14 days||13||↓ 29% (15-40%)||↓ 39% (27-50%)||↓46% (31-58%)|
|↑ Indicates increase
↓ Indicates decrease ↔ Indicates no change or a mean increase or
decrease of < 10%.
a Compared with atazanavir 400 mg qd alone.
b Comparator dose of indinavir was 800 mg q8h × 10 days.
c Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for lopinavir/ritonavir alone.
d Values are for lopinavir; the pharmacokinetics of ritonavir in this study were unaffected by concurrent efavirenz.
e 95% CI.
f Soft Gelatin Capsule.
g Tenofovir disoproxil fumarate.
h 90% CI not available.
iRelative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days).
j Not available because of insufficient data.
NA = not available.
Table 8: Effect of Coadministered Drug on Efavirenz
Plasma Cmax, AUC, and Cmin
|Coadministered Drug||Dose||Efavirenz Dose||Number of Subjects||Efavirenz (mean % change)|
|C max (90% CI)||AUC (90% CI)||Cmm (90% CI)|
|Indinavir||800 mg q8h x 14 days||200 mg qd x 14 days||11||↔||↔||↔|
|Lopinavir/ritonavir||400/100 mg q12h x 9 days||600 mg qd x 9 days||11,12a||↔||↓ 16% (↓38-↑ 15%)||↓ 16% (↓ 42-↑ 20%)|
|Nelfinavir||750 mg q8h x 7 days||600 mg qd x 7 days||10||↓12% b (↓ 32-↑ 13%)||↓ 12% b (↓ 35-↑ 18%)||↓ 21% (↓53-↑ 33%)|
|Ritonavir||500 mg q12h x 8 days||600 mg qd x 10 days||9||↑14% (4-26%)||↑ 21% (10-34%)||↑ 25% b (7-46%)|
|Saquinavir SGCc||1200 mg q8h x10 days||600 mg qd x10 days||13||↓13%(5-20%)||↓ 12%(4-19%)||↓14%b (2-24%)|
|Tenofovir||300 mg qd||600 mg qd x 14 days||30||↔||↔||↔|
|Boceprevir||800 mg tid x 6 days||600 mg qd x 16 days||NA||↑ 11% (2-20%)||↑ 20% (15-26%)||NA|
|Simeprevir||150 mg qd x 14 days||600 mg qd x 14 days||23||↔||↓ 10% (5-15%)||↓ 13% (7-19%)|
|Azithromycin||600 mg single dose||400 mg qd x 7 days||14||↔||↔||↔|
|Clarithromycin||500 mg q12h x 7 days||400 mg qd x 7 days||12||↑11% (3-19%)||↔||↔|
|Fluconazole||200 mg x 7 days||400 mg qd x 7 days||10||↔||↑ 16% (6-26%)||↑22% (5-41%)|
|Itraconazole||200 mg q12h x 14 days||600 mg qd x 28 days||16||↔||↔||↔|
|Rifabutin||300 mg qd x 14 days||600 mg qd x 14 days||11||↔||↔||↓12% (↓ 24-↑ 1%)|
|Rifampin||600 mg x 7 days||600 mg qd x 7 days||12||↓ 20% (11-28%)||↓ 26% (15-36%)||↓32% (15-46%)|
|Voriconazole||400 mg po q12h x 1 day, then 200 mg po q12h x 8 days||400 mg qd x 9 days||NA||↑ 38%e||↑ 44%e||NA|
|300 mg po q12h days 2-7||300 mg qd x 7 days||NA||↑ 14%f (7-21%)||f||NA|
|400 mg po q12h days 2-7||300 mg qd x 7 days||NA||↔f||↑ 17%f (6-29%)||NA|
|Artemether/ Lumefantrine||Artemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over 3 days)||600 mg qd x 26 days||12||↔||↓ 17%||NA|
|Atorvastatin||10 mg qd x 4 days||600 mg qd x 15 days||14||↔||↔||↔|
|Pravastatin||40 mg qd x 4 days||600 mg qd x 15 days||11||↔||↔||↔|
|Simvastatin||40 mg qd x 4 days||600 mg qd x 15 days||14||↓ 12% (↓28-↑ 8%)||↔||↓12% (↓25-↑ 3%)|
|Aluminum hydroxide 400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg||30 mL single dose||400 mg single dose||17||↔||↔||NA|
|Carbamazepine||200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 15 days||600 mg qd x 35 days||14||↓21% (15-26%)||↓36% (32-40%)||↓ 47% (41-53%)|
|Cetirizine||10 mg single dose||600 mg qd x 10 days||11||↔||↔||↔|
|Diltiazem||240 mg x 14 days||600 mg qd x 28 days||12||↑ 16% (6-26%)||↑ 11% (5-18%)||↑ 13% (1-26%)|
|Famotidine||40 mg single dose||400 mg single dose||17||↔||↔||NA|
|Paroxetine||20 mg qd x 14 days||600 mg qd x 14 days||12||↔||↔||↔|
|Sertraline||50 mg qd x 14 days||600 mg qd x 14 days||13||↑ 11% (6-16%)||↔||↔|
|↑ Indicates increase ↓ Indicates decrease
↔ Indicates no change or a mean increase or decrease of < 10%.
a Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for efavirenz alone.
b 95% CI.
c Soft Gelatin Capsule.
d Tenofovir disoproxil fumarate.
e 90% CI not available.
f Relative to steady-state administration of efavirenz (600 mg once daily for 9 days).
NA = not available.
Mechanism Of Action
Efavirenz is an NNRTI of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 reverse transcriptase and human cellular DNA polymerases α, β, γ, and δ are not inhibited by efavirenz.
Antiviral Activity In Cell Culture
The concentration of efavirenz inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90-95% (EC90-95) ranged from 1.7 to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs), and macrophage/monocyte cultures. Efavirenz demonstrated antiviral activity against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, N), but had reduced antiviral activity against group O viruses. Efavirenz demonstrated additive antiviral activity without cytotoxicity against HIV-1 in cell culture when combined with the NNRTIs delavirdine and nevirapine, NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz was not antagonistic with adefovir, used for the treatment of hepatitis B virus infection, or ribavirin, used in combination with interferon for the treatment of hepatitis C virus infection.
In Cell Culture
In cell culture, HIV-1 isolates with reduced susceptibility to efavirenz ( > 380-fold increase in EC90 value) emerged rapidly in the presence of drug. Genotypic characterization of these viruses identified single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in reverse transcriptase.
Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. One or more substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 in reverse transcriptase were observed in patients failing treatment with efavirenz in combination with indinavir, or with zidovudine plus lamivudine. The K103N substitution was the most frequently observed. Long-term resistance surveillance (average 52 weeks, range 4-106 weeks) analyzed 28 matching baseline and virologic failure isolates. Sixty-one percent (17/28) of these failure isolates had decreased efavirenz susceptibility in cell culture with a median 88-fold change in efavirenz susceptibility (EC50 value) from reference. The most frequent NNRTI substitution to develop in these patient isolates was K103N (54%). Other NNRTI substitutions that developed included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%).
Cross-resistance among NNRTIs has been observed. Clinical isolates previously characterized as efavirenz-resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine-and/or nevirapine-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to efavirenz in cell culture. Greater than 90% of NRTI-resistant clinical isolates tested in cell culture retained susceptibility to efavirenz.
Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4-to 13-fold greater than those in humans given the recommended dose [see WARNINGS AND PRECAUTIONS].
Study 006, a randomized, open-label trial, compared SUSTIVA (600 mg once daily) + zidovudine (ZDV, 300 mg q12h) + lamivudine (LAM, 150 mg q12h) or SUSTIVA (600 mg once daily) + indinavir (IDV, 1000 mg q8h) with indinavir (800 mg q8h) + zidovudine (300 mg q12h) + lamivudine (150 mg q12h). Twelve hundred sixty-six patients (mean age 36.5 years [range 18-81], 60% Caucasian, 83% male) were enrolled. All patients were efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The median baseline CD4+ cell count was 320 cells/mm³ and the median baseline HIV-1 RNA level was 4.8 log10 copies/mL. Treatment outcomes with standard assay (assay limit 400 copies/mL) through 48 and 168 weeks are shown in Table 9. Plasma HIV RNA levels were quantified with standard (assay limit 400 copies/mL) and ultrasensitive (assay limit 50 copies/mL) versions of the AMPLICOR HIV-1 MONITOR assay. During the study, version 1.5 of the assay was introduced in Europe to enhance detection of nonclade B virus.
Table 9: Outcomes of Randomized Treatment Through 48
and 168 Weeks, Study 006
|Outcome||SUSTIVA + ZDV+ LAM
|SUSTIVA + IDV
|IDV + ZDV + LAM
|Week 48||Week 168||Week 48||Week 168||Week 48||Week 168|
|Discontinued for adverse events||7%||8%||6%||8%||16%||20%|
|Discontinued for other reasonsc||17%||31%||22%||32%||21%||32%|
|CD4+ cell count (cells/mm³)|
|Observed subjects (n)||(279)||(205)||(256)||(158)||(228)||(129)|
|Mean change from baseline||190||329||191||319||180||329|
|a Patients achieved and maintained confirmed
HIV-1 RNA < 400 copies/mL through Week 48 or Week 168.
b Includes patients who rebounded, patients who were on study at Week 48 and failed to achieve confirmed HIV-1 RNA < 400 copies/mL at time of discontinuation, and patients who discontinued due to lack of efficacy.
c Includes consent withdrawn, lost to follow-up, noncompliance, never treated, missing data, protocol violation, death, and other reasons. Patients with HIV-1 RNA levels < 400 copies/mL who chose not to continue in the voluntary extension phases of the study were censored at date of last dose of study medication.
For patients treated with SUSTIVA + zidovudine + lamivudine, SUSTIVA + indinavir, or indinavir + zidovudine + lamivudine, the percentage of responders with HIV-1 RNA < 50 copies/mL was 65%, 50%, and 45%, respectively, through 48 weeks, and 43%, 31%, and 23%, respectively, through 168 weeks. A Kaplan-Meier analysis of time to loss of virologic response (HIV RNA < 400 copies/mL) suggests that both the trends of virologic response and differences in response continue through 4 years.
ACTG 364 is a randomized, double-blind, placebo-controlled, 48-week study in NRTI-experienced patients who had completed two prior ACTG studies. One-hundred ninety-six patients (mean age 41 years [range 18-76], 74% Caucasian, 88% male) received NRTIs in combination with SUSTIVA (600 mg once daily), or nelfinavir (NFV, 750 mg three times daily), or SUSTIVA (600 mg once daily) + nelfinavir in a randomized, double-blinded manner. The mean baseline CD4+ cell count was 389 cells/mm³ and mean baseline HIV-1 RNA level was 8130 copies/mL. Upon entry into the study, all patients were assigned a new open-label NRTI regimen, which was dependent on their previous NRTI treatment experience. There was no significant difference in the mean CD4+ cell count among treatment groups; the overall mean increase was approximately 100 cells at 48 weeks among patients who continued on study regimens. Treatment outcomes are shown in Table 10. Plasma HIV RNA levels were quantified with the AMPLICOR HIV-1 MONITOR assay using a lower limit of quantification of 500 copies/mL.
Table 10: Outcomes of Randomized Treatment Through 48
Weeks, Study ACTG 364*
|Outcome||SUSTIVA + NFV + NRTIs
|SUSTIVA + NRTIs
|NFV + NRTIs
|HIV-1 RNA < 500 copies/mLa||71%||63%||41%|
|HIV-1 RNA ≥ 500 copies/mLb||17%||34%||54%|
|CDC Category C Event||2%||0%||0%|
|Discontinuations for adverse eventsc||3%||3%||5%|
|Discontinuations for other reasonsd||8%||0%||0%|
|* For some patients, Week 56
data were used to confirm the status at Week 48.
a Subjects achieved virologic response (two consecutive viral loads < 500 copies/mL) and maintained it through Week 48.
b Includes viral rebound and failure to achieve confirmed < 500 copies/mL by Week 48.
c See ADVERSE REACTIONS for a safety profile of these regimens.
d Includes loss to follow-up, consent withdrawn, noncompliance.
A Kaplan-Meier analysis of time to treatment failure through 72 weeks demonstrates a longer duration of virologic suppression (HIV RNA < 500 copies/mL) in the SUSTIVA-containing treatment arms.
Study AI266922 is an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of SUSTIVA in combination with didanosine and emtricitabine in antiretroviral-naive and -experienced pediatric patients. Thirty-seven patients 3 months to 6 years of age (median 0.7 years) were treated with SUSTIVA. At baseline, median plasma HIV-1 RNA was 5.88 log10 copies/mL, median CD4+ cell count was 1144 cells/mm³, and median CD4+ percentage was 25%. The median time on study therapy was 60 weeks; 27% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA < 400 copies/mL and < 50 copies/mL at Week 48 were 57% (21/37) and 46% (17/37), respectively. The median increase from baseline in CD4+ count at 48 weeks was 196 cells/mm³ and the median increase in CD4+ percentage was 6%.
Study PACTG 1021 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of SUSTIVA in combination with didanosine and emtricitabine in pediatric patients who were antiretroviral therapy naive. Forty-three patients 3 months to 21 years of age (median 9.6 years) were dosed with SUSTIVA. At baseline, median plasma HIV-1 RNA was 4.8 log10 copies/mL, median CD4+ cell count was 367 cells/mm³, and median CD4+ percentage was 18%. The median time on study therapy was 181 weeks; 16% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA < 400 copies/mL and < 50 copies/mL at Week 48 were 77% (33/43) and 70% (30/43), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 238 cells/mm³ and the median increase in CD4+ percentage was 13%.
Study PACTG 382 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of SUSTIVA in combination with nelfinavir and an NRTI in antiretroviralnaive and NRTI-experienced pediatric patients. One hundred two patients 3 months to 16 years of age (median 5.7 years) were treated with SUSTIVA. Eighty-seven percent of patients had received prior antiretroviral therapy. At baseline, median plasma HIV-1 RNA was 4.57 log10 copies/mL, median CD4+ cell count was 755 cells/mm³ , and median CD4+ percentage was 30%. The median time on study therapy was 118 weeks; 25% of patients discontinued before Week 48. Using an ITT analysis, the overall proportion of patients with HIV RNA < 400 copies/mL and < 50 copies/mL at Week 48 were 57% (58/102) and 43% (44/102), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 128 cells/mm³ and the median increase in CD4+ percentage was 5%.
Last reviewed on RxList: 2/6/2017
This monograph has been modified to include the generic and brand name in many instances.
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