CLINICAL PHARMACOLOGY
Mechanism of Action
Efavirenz is an antiviral drug [see Clinical Pharmacology ].
Pharmacokinetics
Absorption
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/high-caloric 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 (2) and Patient Counseling 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 (2) and Patient Counseling Information .
Distribution
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.
Metabolism
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).
Elimination
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.
Special Populations
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.
Drug Interaction Studies
Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9, 2C19, and 3A4 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. The inhibitory effect on CYP3A is expected to be similar between 200-mg, 400-mg, and 600-mg doses of efavirenz. Coadministration of efavirenz with drugs primarily metabolized by 2C9, 2C19, and 3A isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A 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 8 (effect of efavirenz on other drugs) and Table 9 (effect of other drugs on efavirenz). For information regarding clinical recommendations see Contraindications and Drug Interactions .
Table 8: 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) |
|---|
| ↑ 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 x 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. |
| i Relative 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. |
| 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 7-20 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%) |
| Indinavir | 1000 mg q8h x 10 days | 600 mg 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%) |
Lopinavir/
ritonavir | 400/100 mg capsule
q12h x 9 days | 600 mg x 9 days | 11,7c | ↔d | ↓ 19%d
(↓ 36-↑ 3%) | ↓ 39%d
(3-62%) |
| | 600/150 mg tablet
q12h x 10 days with
efavirenz compared to
400/100 mg q12h alone | 600 mg 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 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 x 10 days | 11 | |
| | After AM dose | ↑ 24%
(12-38%) | ↑ 18%
(6-33%) | ↑ 42%
(9-86%)e |
| | After PM dose | ↔ | ↔ | ↑ 24%
(3-50%)e |
Saquinavir
SGCf | 1200 mg q8h x 10 days | 600 mg x 10 days | 12 | ↓ 50%
(28-66%) | ↓ 62%
(45-74%) | ↓ 56%
(16-77%)e |
| Lamivudine | 150 mg q12h x 14 days | 600 mg x 14 days | 9 | ↔ | ↔ | ↑ 265%
(37-873%) |
| Tenofovirg | 300 mg qd | 600 mg x 14 days | 29 | ↔ | ↔ | ↔ |
| Zidovudine | 300 mg q12h x 14 days | 600 mg x 14 days | 9 | ↔ | ↔ | ↑ 225%
(43-640%) |
| Azithromycin | 600 mg single dose | 400 mg x 7 days | 14 | ↑ 22%
(4-42%) | ↔ | NA |
| Clarithromycin | 500 mg q12h x 7 days | 400 mg x 7 days | 11 | ↓ 26%
(15-35%) | ↓ 39%
(30-46%) | ↓ 53%
(42-63%) |
| 14-OH metabolite | | ↑ 49%
(32-69%) | ↑ 34%
(18-53%) | ↑ 26%
(9-45%) |
| Fluconazole | 200 mg x 7 days | 400 mg x 7 days | 10 | ↔ | ↔ | ↔ |
| Itraconazole | 200 mg q12h x 28 days | 600 mg x 14 days | 18 | ↓ 37%
(20-51%) | ↓ 39%
(21-53%) | ↓ 44%
(27-58%) |
| Hydroxy-itraconazole | | ↓ 35%
(12-52%) | ↓ 37%
(14-55%) | ↓ 43%
(18-60%) |
| Rifabutin | 300 mg qd x 14 days | 600 mg 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 x 9 days | NA | ↓ 61%h | ↓ 77%h | NA |
| | 300 mg po q12h days 2‑7 | 300 mg x 7 days | NA | ↓ 36%i
(21-49%) | ↓ 55%i
(45-62%) | NA |
| | 400 mg po q12h days 2‑7 | 300 mg x 7 days | NA | ↑ 23%i
(↓ 1-↑ 53%) | ↓ 7%i
(↓ 23-↑ 13%) | NA |
| Atorvastatin | 10 mg qd x 4 days | 600 mg x 15 days | NA | ↓ 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 x 15 days | 13 | ↓ 32%
(↓ 59-↑ 12%) | ↓ 44%
(26-57%) | ↓ 19%
(0-35%) |
| Simvastatin | 40 mg qd x 4 days | 600 mg 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 | 200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 29 days | 600 mg x 14 days | 12 | ↓ 20%
(15-24%) | ↓ 27%
(20-33%) | ↓ 35%
(24-44%) |
| Epoxide metabolite | | ↔ | ↔ | ↓ 13%
(↓ 30-↑ 7%) |
| Cetirizine | 10 mg single dose | 600 mg x 10 days | 11 | ↓ 24%
(18-30%) | ↔ | NA |
| Diltiazem | 240 mg x 21 days | 600 mg 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-monodesmethyl
diltiazem | | ↓ 28%
(7-44%) | ↓ 37%
(17-52%) | ↓ 37%
(17-52%) |
| Ethinyl estradiol | 50 microgram single dose | 400 mg x 10 days | 13 | ↔ | ↑ 37%
(25-51%) | NA |
| Lorazepam | 2 mg single dose | 600 mg x 10 days | 12 | ↑ 16%
(2-32%) | ↔ | NA |
| Methadone | Stable
maintenance 35-
100 mg daily | 600 mg x 14-21 days | 11 | ↓ 45%
(25-59%) | ↓ 52%
(33-66%) | NA |
| Paroxetine | 20 mg qd x 14 days | 600 mg x 14 days | 16 | ↔ | ↔ | ↔ |
| Sertraline | 50 mg qd x 14 days | 600 mg x 14 days | 13 | ↓ 29%
(15-40%) | ↓ 39%
(27-50%) | ↓ 46%
(31-58%) |
Table 9: Effect of Coadministered Drug on Efavirenz Plasma Cmax, AUC, and Cmin | | Efavirenz
(mean % change) |
|---|
| Coadministered Drug | Dose | Efavirenz Dose | Number of Subjects | Cmax
(90% CI) | AUC
(90% CI) | Cmin
(90% CI) |
|---|
| ↑ 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. |
| Indinavir | 800 mg q8h x 14 days | 200 mg x 14 days | 11 | ↔ | ↔ | ↔ |
Lopinavir/
ritonavir | 400/100 mg q12h x 9 days | 600 mg x 9 days | 11,12a | ↔ | ↓ 16%
(↓ 38-↑ 15%) | ↓ 16%
(↓ 42-↑ 20%) |
| Nelfinavir | 750 mg q8h x 7 days | 600 mg x 7 days | 10 | ↓ 12%
(↓ 32-↑ 13%)b | ↓ 12%
(↓ 35-↑ 18%)b | ↓ 21%
(↓ 53-↑ 33%) |
| Ritonavir | 500 mg q12h x 8 days | 600 mg x 10 days | 9 | ↑ 14%
(4-26%) | ↑ 21%
(10-34%) | ↑ 25%
(7-46%)b |
Saquinavir
SGCc | 1200 mg q8h x 10 days | 600 mg x 10 days | 13 | ↓ 13%
(5-20%) | ↓ 12%
(4-19%) | ↓ 14%
(2-24%)b |
| Tenofovird | 300 mg qd | 600 mg x 14 days | 30 | ↔ | ↔ | ↔ |
| Azithromycin | 600 mg single dose | 400 mg x 7 days | 14 | ↔ | ↔ | ↔ |
| Clarithromycin | 500 mg q12h x 7 days | 400 mg x 7 days | 12 | ↑ 11%
(3-19%) | ↔ | ↔ |
| Fluconazole | 200 mg x 7 days | 400 mg x 7 days | 10 | ↔ | ↑ 16%
(6-26%) | ↑ 22%
(5-41%) |
| Itraconazole | 200 mg q12h x 14 days | 600 mg x 28 days | 16 | ↔ | ↔ | ↔ |
| Rifabutin | 300 mg qd x 14 days | 600 mg x 14 days | 11 | ↔ | ↔ | ↓ 12%
(↓ 24-↑ 1%) |
| Rifampin | 600 mg x 7 days | 600 mg 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 x 9 days | NA | ↑ 38%e | ↑ 44%e | NA |
| | 300 mg po q12h days 2-7 | 300 mg x 7 days | NA | ↓ 14%f
(7-21%) | ↔f | NA |
| | 400 mg po q12h days 2-7 | 300 mg x 7 days | NA | ↔f | ↑ 17%f
(6-29%) | NA |
| Atorvastatin | 10 mg qd x 4 days | 600 mg x 15 days | 14 | ↔ | ↔ | ↔ |
| Pravastatin | 40 mg qd x 4 days | 600 mg x 15 days | 11 | ↔ | ↔ | ↔ |
| Simvastatin | 40 mg qd x 4 days | 600 mg 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 x 35 days | 14 | ↓21%
(15-26%) | ↓36%
(32-40%) | ↓47%
(41-53%) |
| Cetirizine | 10 mg single dose | 600 mg x 10 days | 11 | ↔ | ↔ | ↔ |
| Diltiazem | 240 mg x 14 days | 600 mg x 28 days | 12 | ↑ 16%
(6-26%) | ↑ 11%
(5-18%) | ↑ 13%
(1-26%) |
| Ethinyl estradiol | 50 microgram single dose | 400 mg x 10 days | 13 | ↔ | ↔ | ↔ |
| Famotidine | 40 mg single dose | 400 mg single dose | 17 | ↔ | ↔ | NA |
| Paroxetine | 20 mg qd x 14 days | 600 mg x 14 days | 12 | ↔ | ↔ | ↔ |
| Sertraline | 50 mg qd x 14 days | 600 mg x 14 days | 13 | ↑11%
(6-16%) | ↔ | ↔ |
Microbiology
Mechanism of Action
Efavirenz (EFV) is an NNRTI of HIV-1. EFV activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases α,β, γ, and δ are not inhibited by EFV.
Antiviral Activity in Cell Culture
The concentration of EFV 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. EFV 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. EFV demonstrated additive antiviral activity without cytotoxicity against HIV-1 in cell culture when combined with the NNRTIs delavirdine (DLV) and nevirapine (NVP), NRTIs (abacavir, didanosine, emtricitabine, lamivudine [LAM], stavudine, tenofovir, zalcitabine, zidovudine [ZDV]), PIs (amprenavir, indinavir [IDV], lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide. EFV demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. EFV 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.
Resistance
In cell culture
In cell culture, HIV-1 isolates with reduced susceptibility to EFV (>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 RT.
Clinical studies
Clinical isolates with reduced susceptibility in cell culture to EFV have been obtained. One or more RT substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 were observed in patients failing treatment with EFV in combination with IDV, or with ZDV plus LAM. The mutation K103N 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 EFV susceptibility in cell culture with a median 88-fold change in EFV 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
Cross-resistance among NNRTIs has been observed. Clinical isolates previously characterized as EFV-resistant were also phenotypically resistant in cell culture to DLV and NVP compared to baseline. DLV- and/or NVP-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 EFV in cell culture. Greater than 90% of NRTI-resistant clinical isolates tested in cell culture retained susceptibility to EFV.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. In studies in which rats were administered efavirenz at doses of 0, 25, 50, or 100 mg/kg/day for 2 years, no increases in tumor incidence above background were observed. The systemic exposure (based on AUCs) in mice was approximately 1.7-fold that in humans receiving the 600-mg/day dose. The exposure in rats was lower than that in humans. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, efavirenz showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. Given the lack of genotoxic activity of efavirenz, the relevance to humans of neoplasms in efavirenz-treated mice is not known.
Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. As a result of the rapid clearance of efavirenz in rats, systemic drug exposures achieved in these studies were equivalent to or below those achieved in humans given therapeutic doses of efavirenz.
Animal Toxicology
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 ].
|
CLINICAL STUDIES
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 10. 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 non-clade B virus.
Table 10: Outcomes of Randomized Treatment Through 48 and 168 Weeks, Study 006 | | SUSTIVA + ZDV
+ LAM
n=422 | SUSTIVA + IDV
n=429 | IDV + ZDV + LAM
n=415 |
|---|
| Outcome | Week 48 | Week 168 | Week 48 | Week 168 | Week 48 | Week 168 |
|---|
| 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. |
| Respondera | 69% | 48% | 57% | 40% | 50% | 29% |
| Virologic failureb | 6% | 12% | 15% | 20% | 13% | 19% |
| 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 |
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 (efavirenz) (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/mm 3 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 11. Plasma HIV RNA levels were quantified with the AMPLICOR HIV-1 MONITOR assay using a lower limit of quantification of 500 copies/mL.
Table 11: Outcomes of Randomized Treatment Through 48 Weeks, Study ACTG 364* | Outcome | SUSTIVA + NFV +
NRTIs
n=65 | SUSTIVA + NRTIs
n=65 | NFV + NRTIs
n=66 |
|---|
| * 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. |
| 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% |
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.
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