Zambian HIV Guidelines:: Efavirenz

	Zambia HIV National Guidelines
	Introduction HIV Counseling and Testing Sexually Transmitted Infections (STIs) General Principles of Antiretroviral Therapy for Chronic HIV Infection in Adults and Adolescents When to Start ARV Therapy for Chronic HIV Infection in Adults and Adolescents Initial Regimen for ARV Therapy Adherence Baseline evaluation and Monitoring Calculations: Ideal Body Weight, Body Mass Index and Creatinine Clearance ARV Therapy for Individuals with Tuberculosis Co-Infection Adverse Effects and Toxicity Immune Reconstitution Inflammatory Syndrome (IRIS) Changing or Stopping ART Treatment Failure Stopping ARV Therapy Post Exposure Prophylaxis Cotrimoxazole Prophylaxis WHO Staging in Adults and Adolescents Nutrition Care and Support Palliative Care in HIV and AIDS
	Guide Editors
	Editor In Chief Joel E. Gallant, MD, MPH Pharmacology Editor Paul Pham, PharmD, BCPS Zambia Guideline Team Peter Mwaba MMed PhD FRCP Alywn Mwinga MMed Isaac Zulu MMed MPH Velepie Mtonga MMed Albert Mwango MBChB Jabbin Mulwanda MMed FCS

Drugs>Antiretrovirals>

Efavirenz

Paul A. Pham, Pharm.D. and John G. Bartlett, M.D.
03-24-2008

Available formulation in Zambia: Capsule: 50 mg; 100 mg; 200 mg; Oral liquid: 150 mg/5 ml; Tablet: 600 mg. EFV 600 mg/TDF 300 mg/FTC 200 mg combination tab.
TDF/FTC plus EFV is now the preferred first line regimen due to long-term efficacy and favorable side effect profile.
EFV is recommended NNRTI to be used with rifampicin.
EFV-based regimen not recommended for the treatment of HIV-2 infection.
To prevent NNRTI resistance with treatment discontinuation, discontinue EFV and continue NRTIs for an additional 10 days.
Contraindicated in 1st trimester of pregnancy. Birth defects occurred in 5 of 188 live births with 1st trimester exposure and in 0 of 13 live births with 2nd or 3rd trimester exposure.

Zambia Information Author: Paul A. Pham, Pharm. D.

INDICATIONS

FDA

Treatment of HIV infection in combination with other antiretrovirals.

FORMS

brand name	generic	Mfg	brand forms	cost*
Sustiva (available in U.S., Canada, and some parts of Europe)	Efavirenz (EFV)	Bristol-Myers Squibb	oral capsule 50 mg	$1.44
			oral tablet 600 mg	$17.31
			oral capsule 200 mg	$5.77
			oral capsule 100 mg	$2.88
Stocrin (brand name available in South Africa, Southeast Asia, and other parts of the world)	Efavirenz (EFV)	Merck	oral capsule 50 mg, 100 mg, 200 mg	variable
			oral tablet 600 mg	variable
			oral solution 30 mg/30 mL (180 mL bottle)	variable
Atripla (available in the U.S.)	EFV/TDF/FTC	Bristol-Myers Squibb & Gilead Sciences	oral tablet EFV 600mg/TDF 300mg/FTC 200mg	$47.95

*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP). AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's information, and the McKesson database.

^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

Pill burden: 1 tab per day

EFV 600 mg PO qd. Evening dosing on an empty stomach recommended initially to decrease side effects.
Can be administered as a co-formulated product with TDF/FTC (Atripla) 1 tab PO qd.
Administration with food, especially with high fat meal, may increase CNS side effects: EFV peak levels increased by 40% (caps) and 80% (tabs).
For GI intolerance, consider taking with food after resolution of CNS side effects.
Morning CNS side effects may be decreased if taken several hrs before bedtime. Some pts can tolerate morning dosing after resolution of initial CNS side effects.
With LPV/r: Consider LPV/r 600/150 mg (3 tabs) bid + EFV 600 mg qhs, especially for PI-experienced pts. In PI-naive pts, standard dose of 400/100 (2 tabs) bid may be adequate.
With FPV: FPV 700 mg bid + RTV 100 mg bid OR FPV 1400 mg + RTV 300 mg qd plus EFV 600 mg qhs.
With ATV: ATV 300 mg qd + RTV 100 mg qd + EFV 600 mg qhs. Consider TDM.
With IDV: IDV 800 mg bid + RTV 200 mg bid + EFV 600 mg qhs.
With SQV: SQV 1000 mg bid + RTV 100 mg bid with EFV 600 mg qhs.
With NFV: NFV 1250 mg bid + EFV 600 mg qhs.
With DRV:: Dose not established. Consider DRV/r 600/100 mg bid + EFV 600 mg qhs.
With TPV: TPV/r 500/200 mg bid + EFV 600 mg qhs.
With raltegravir (MK-0518): dose not established.
With maraviroc: MVC 600 mg BID + EFV 600 mg qhs. Note: if PIs (i.e LPV/r or SQV/r) contained in regimen, standard dose MVC recommended.

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

600 mg qhs

DOSING FOR GLOMERULAR FILTRATION OF 10-50

600 mg qhs. Avoid EFV/TDF/FTC co-formulation tab with GFR <50 ml/min.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

600 mg qhs. Avoid EFV/TDF/FTC co-formulation tab with GFR <50 ml/min.

DOSING IN HEMODIALYSIS

600 mg qhs (EFV PK not affected by HD). Avoid EFV/TDF/FTC co-formulation tab with GFR <50 ml/min.

DOSING IN PERITONEAL DIALYSIS

600 mg qhs (limited data). Avoid EFV/TDF/FTC co-formulation tab with GFR <50 ml/min.

DOSING IN HEMOFILTRATION

No data. Consider 600 mg qhs.

ADVERSE DRUG REACTIONS

Generally well tolerated after resolution of CNS side effects (2-4 wks).

COMMON

CNS effects: vivid dreams including nightmares, nocturnal dizziness, morning confusion; depersonalization; usually seen during1st 2-4 wks with gradual resolution in most pts.
Pts experiencing early CNS toxicity should avoid tasks that require concentration, such as driving, especially in the morning.
Pts should be advised of additive effects of alcohol and other psychoactive agents when coadministered with EFV.
Morbilliform rash in up to 26% of pts requiring discontinuation in 1.7% (med. onset 11 days, duration 16 days); incidence and severity lower than NVP. Generally resolves with continued use of EFV.
False-positive urine toxicology screening test for cannabinoids (w/CEDIA DAU Multilevel THC assay only); confirmatory tests negative.

OCCASIONAL

Elevated triglycerides and cholesterol (incidence higher than for NVP).
Elevated transaminases (2-8%; incidence and severity lower compared than for NVP).

RARE

Erythema multiforme and Stevens-Johnson syndrome (0.1%).
Gynecomastia.
Severe psychiatric disorders, primarily depression reported in 2.4%.

DRUG INTERACTIONS

Substrate of CYP3A4 and CYP2B6; inducer of CYP3A4 and CYP2B6; weak inhibitor of CYP3A4, 2B6, 2C9, and 2C19. Inducers of CYP3A4 and CYP2B6 may decrease EFV serum levels. EFV generally decreases serum levels of CYP3A4 and CYP2B6 substrates.

Drug-to-Drug Interactions

Drug-to-Drug Interaction

Drug	Effect of Interaction	Recommendations/Comments
Amodiaquine	Amodiaquine AUC increased with co-administration.	Co-administration of EFV with artesunate plus amodiaquine may result in significant LFT elevations. With EFV co-administration, significant increase in amodiaquine AUC (114% and 302%) reported in 2 pts.
ATV	ATV AUC: decreased 74%; Cmin: decreased 93% (without RTV co-administration) ATV AUC: increased 241%; Cmin: increased 671% (with RTV co-administration).	Recommended dosing: ATV 300 mg + RTV 100 mg qd + EFV 600 mg qhs (consider ATV TDM esp. in PI-experienced patients). Unboosted ATV (without RTV) not recommended with EFV.
Azithromycin	Azithromycin AUC unchanged	No significant interaction. Use standard dose.
Clarithromycin	Clarithromycin AUC: decreased 39%; 14-hydroxyclarithromycin AUC: increased 34%.	Clinical significance unknown. High incidence of rash seen in healthy volunteer receiving this combination. Consider alternative macrolide (azithromycin).
Fluconazole	Fluconazole AUC increased 16%.	No significant interaction. Use standard dose.
FPV	APV Cmin decreased by 36% (dose used FPV 1400 mg qd plus RTV 200 mg qd). APV Cmin decreased by 17% (dose used FPV 700 mg bid + RTV100 mg bid).	Recommended dosing: FPV 1400 mg + RTV 300 mg qd(in PI-naive pts only) or FPV 700 mg bid + RTV 100 mg bid + EFV 600 mg qhs.
IDV	IDV AUC: decreased 19%; Cmin: decreased 48%.	Clinically significant: Recommended dose: IDV 1000 mg q8h + EFV 600 mg qhs OR IDV 800 mg bid + RTV 200 mg bid + EFV 600 mg qhs.
LPV/r	LPV AUC decreased (non-significant); Cmin decreased 39%.	Clinically significant: Consider LPV/r 600/150 mg (3 tabs) bid + EFV 600 mg qhs, especially in PI-experienced pts. Standard dose of 400/100 mg bid may be adequate in PI-naive pts.
NFV	NFV AUC: increased 20%. M8 AUC: decreased 37%.	No significant interaction. Use standard dose: NFV 1250 mg bid + EFV 600 mg qhs.
NVP	EFV AUC: decreased 22%; Cmin: decreased 36%.	Co-administration not recommended due to overlapping resistance profile. With co-administration consider increasing EFV to 800 mg qd.
Rifampin	EFV AUC: decreased 26%; no change in rifampin AUC.	Recommended dosing: EFV 800 mg/d with rifampin 600 mg qd (monitor for EFV CNS side effects). May decrease to EFV 600 mg/d if 800 mg dose not easily tolerated.
RTV	RTV AUC: increased 18% EFV AUC: increased 21%.	No significant interaction. Use standard dose of RTV and EFV.
SQV	SQV/r AUC: decreased 62% (with unboosted SQV) SQV Cmin: decreased 10% (w/ boosted SQV 400 mg/RTV 400 mg); RTV Cmin: no significant change EFV: no significant change.	Do not coadminister unboosted SQV with EFV. Recommended dose: SQV 1000 mg + RTV 100 mg bid + EFV 600 mg qhs.
Darunavir	DRV Cmin decreased by 31%. EFV AUC and Cmin increased 21% and 17%, respectively (studied with DRV/r 300/100 mg bid).	Dose not established. Consider DRV 600/100 mg bid with EFV 600 mg qhs.
Tipranavir	No significant change in TPV and EFV PK parameters with higher TPV/r dose (750mg/200mg BID)	Consider TPV/r 500/200 mg bid + EFV 600mg QD.
Artemether (artemisinin)	May decrease serum level of artemether	Close monitoring of artemether therapeutic efficacy (i.e parasite count on blood smear and clinical signs and symptoms of clinical improvement). Co-administration of EFV with artesunate plus amodiaquine may result in significant LFT elevations.
Astemizole	May significantly increase astemizole serum level	Contraindicated due to the potential for cardiac arrhythmias. Recommended alternative antihistamine: loratadine, fexofenadine, desloratidine, or cetirizine.
Atorvastatin	Atorvastatin: AUC decreased by 43%.	May require atorvastatin dose increase with close monitoring of LFTs and CPK.
Azathioprine	Interaction unlikely	Applies to all PIs and NNRTIs: Use standard dose.
Buprenorphine	Buprenorphine AUC and Cmin decreased by 50%. EFV not affected.	No withdrawal symptoms noted when buprenorphine Cmin decreased from 0.85 ng/ml to 0.42 ng/ml. It should be noted that withdrawal symptoms may not be seen until a decrease to 0.23 ng/ml. Use standard dose buprenorphine with titration to therapeutic effect.
Bupropion	May increase bupropion serum level slightly	Not likely to be clinically significant. Start with lowest possible dose of bupropion with co-administration. In a small case series no seizures reported with co-administration.
Carbamazepine	Efavirenz AUC decreased by 34% and carbamazepine AUC decreased by 27%.	Avoid co-administration. Consider alternative anticonvulsant (e.g., valproic acid, lamotrigine, levetiracetam, or topiramate). With coadministration, monitor carbamazepine levels and consider efavirenz TDM.
Caspofungin	May decrease caspofungin serum level.	Monitor for caspofungin therapeutic failure, may need to increase dose to 70 mg/d.
Cetirizine	EFV: no significant change cetirizine: no change	No significant interaction. Use standard dose of both drugs.
Cisapride	May increase cisapride serum level.	Contraindicated due to potential for cardiac arrhythmias. Recommended alternative: metoclopramide.
Cocaine	May theoretically increase serum level of hepatotoxic metabolite.	Avoid illicit drugs for obvious reasons.
Cyclophosphamide	May decrease serum level of cyclophosphamide.	No data. Monitor for chemotherapeutic response. Cyclophosphamide dose may need to be increased.
Cyclosporine	May significantly decrease serum level of cyclosporine.	Monitor serum level of cyclosporine closely with co-administration. Cyclosporin dose may need to be increased.
Diltiazem	Diltiazem AUC decreased by 69% with co-administration. EFV AUC increased by 11%.	Titrate diltiazem dose to effect. Higher diltiazem and other Ca channel blocker doses may be needed.
Docetaxel	May decrease serum level of docetaxel.	No data. Docetaxel dose may need to be increased.
Echinacea	May decrease EFV serum level. Echinacea decreased CYP3A4 substrate (midazolam) by 23%.	Clinical significance unknown but should avoided until the safety of this combination is further evaluated.
Ergot derivatives	May significantly increase serum level of ergotamine resulting in acute ergot toxicity.	Contraindicated. Consider alternative agent for migraine such as sumatriptan but not eletriptan, since it is a CYP3A4 substrate and significant drug-drug interaction occurred with CYP3A4 inhibitor.
Ethinyl Estradiol	Ethinyl estradiol AUC increased 37%.	Clinical significance unknown. No data on progesterone component of oral contraceptive available. Alternative form of birth control should be recommended.
Etoposide	May decrease serum level of etoposide.	No data. Etoposide dose may need to be increased.
Famotidine	No significant interaction.	Use standard dose.
Fatty meal (54% fat) or low fat meal (4%)	EFV AUC increased by 50% and 22% with high fat and low fat meal, respectively. Fatty meal increased EFV tabs Cmax by 79% and EFV caps Cmax by 51%.	Manufacturer recommends taking EFV on an empty stomach due to the potential for increased CNS side effect from high EFV Cmax. May not be necessary after initial side effects have resolved.
Fluoxetine	EFV AUC not significantly affected by SSRI (population PK).	No significant interaction. Use standard dose.
Garlic supplement	No data.	Reduction on SQV serum level. No data with EFV. Avoid co-administration.
Heroin (Diamorphine)	Drug interactions unlikely.	Interaction unlikely but illicit drug use should be avoided for obvious reasons.
Ifosphamide	May decrease serum level of ifosphamide.	Applies to EFV and NVP: No data. Ifosphamide dose may need to be increased.
Itraconazole	Itraconazole AUC decreased by 39%. EFV AUC not affected.	For invasive fungal infections, monitor itraconazole serum levels with co-administration. Consider alternative antifungal (i.e. fluconazole: no significant interaction).
Ketoconazole	May decrease ketoconazole serum levels.	May need to increase ketoconazole dose (i.e. fluconazole: no significant interaction).
Lorazepam	No significant change.	Use standard dose.
Maraviroc	Maraviroc AUC decreased by 45%.	Maraviroc 600 mg BID + EFV 600 mg qhs. If PIs (i.e LPV/r or SQV/r) are included in regimen, standard dose MVC recommended.
Medroxyprogesterone (DMPA)	No significant drug interaction. EFV AUC was not significantly affected. DMPA concentrations were not reported.	Efficacy of DMPA was not affected by EFV co-administration. Use standard dose of both drugs. Counsel patient on the potential for teratogenicity of EFV.
Mefloquine	May decrease serum level of mefloquine.	If available consider mefloquine serum level monitoring. Close monitoring of mefloquine therapeutic efficacy (i.e. parasite count on blood smear and clinical signs and sx of clinical improvement).
Methadone	Methadone AUC: decreased 57%.	Monitor for opiate withdrawal. May need to increase the maintenance dose of methadone.
Midazolam	May increase midazolam level.	Do not co-administer. Consider lorazepam (not significantly affected by EFV), oxazepam, or temazepam.
Milk thistle	No data.	Data limited to interaction study with milk thistle and IDV. IDV AUC unchanged; IDV Cmin decreased by 47%. Clinical significance unknown. Avoid co-administration.
Mycophenolate	Interaction unlikely. No significant interaction observed with NVP.	No significant interaction observed with NVP. Use standard dose.
Paclitaxel	May decrease serum level of paclitaxel.	Applies to EFV and NVP: No data. Monitor for chemotherapeutic response. Paclitaxel dose may need to be increased.
Paroxetine	Paroxetine AUC not affected.	No significant interaction. Use standard dose.
Phenobarbital	EFV and anticonvulsants levels may be decreased.	Consider alternative anticonvulsants (i.e. valproic acid, lamotrigine, levetiracetam, or topiramate). With co-administration, monitor anticonvulsants level and consider EFV TDM.
Phenytoin	EFV and anticonvulsants levels may be decreased.	Consider alternative anticonvulsants (i.e. valproic acid, lamotrigine, levetiracetam, or topiramate). With co-administration, monitor anticonvulsants level and consider EFV TDM.
Pravastatin	Pravastatin AUC decreased 44%.	Clinical significance unknown. May need to increase dose of pravastatin.
Raltegravir (MK-0518)	Raltegravir AUC decreased by 36%.	Dose not established.
Rifabutin	Rifabutin AUC: decreased 38% No change in EFV AUC.	Recommended dosing: Increase rifabutin to 450 mg/d or 600 mg 3x/wk with EFV 600 mg qhs.
Rifapentine	EFV serum levels may be significantly decreased.	Avoid co-administration. Consider using rifabutin with dose adjustment.
Rosiglitazone	EFV Cmin decreased by 6% (non-significant) (n=10).	Use standard dose.
Rosuvastatin	Other CYP3A4 inhibitor (i.e erythromycin) did not affect rosuvastatin serum level.	Rosuvastatin AUC and Cmax unexpectedly increased 2.1 and 4.7-fold at steady state with LPV/r co-administration. Despite increased rosuvastatin exposure, the LDL-lowering effects were attenuated with LPV/r co-administration. Close monitoring recommended due to limited clinical data.
Sertraline	Sertraline AUC decreased 39%.	Titrate sertraline to effect.
Simvastatin	Simvastatin: AUC decreased by 68%.	May require simvastatin dose increase with close monitoring of LFTs and CPK.
Sirolimus	May significantly decrease serum level of sirolimus.	Applies to EFV and NVP: dose sirolimus based on serum level. May need to increase sirolimus dose.
St. John's wort	Not studied, may decrease EFV levels.	Contraindicated. Use an alternative (more effective) antidepressant.
Tacrolimus	May significantly decrease serum level of tacrolimus.	Dose tacrolimus based on serum level. May need to increase tacrolimus dose.
Tamoxifen	May decrease serum level of tamoxifen.	No data. Monitor for chemotherapeutic response. Tamoxifen dose may need to be increased.
Teniposide	May decrease serum level of teniposide.	No data. Monitor for chemotherapeutic response. Teniposide dose may need to be increased.
Terfenadine	May significantly increase terfenadine serum level.	Contraindicated due to the potential for cardiac arrhythmias. Recommended alternative antihistamine: loratadine, fexofenadine, desloratidine, or cetirizine.
THC	Based on data with NFV and IDV interactions are unlikely.	Applies to PIs and NNRTIs: Interactions are unlikely but illicit drug use should be avoided for obvious reasons.
Triazolam	May increase triazolam serum level.	Contraindicated. Consider lorazepam (not significantly affected by EFV), oxazepam, or temazepam.
Vinblastine	May decrease serum level of vinblastine.	Applies to EFV and NVP: No data. Monitor for chemotherapeutic response. Vinblastine dose may need to be increased.
Vincristine	May decrease serum level of vincristine.	Applies to EFV and NVP: No data. Monitor for chemotherapeutic response. Vincristine dose may need to be increased.
Voriconazole	EFV (400 mg PO qd) decreased steady state voriconazole (200 mg q12h) AUC by 77%. EFV AUC was increased by 44%. No significant change in voriconazole and EFV AUC with voriconazole 400 mg q12h plus EFV 300 mg qhs.	EFV should not be co-administered with voriconazole at the standard doses. .
Warfarin	Not studied; may increase or decrease warfarin effects; monitor INR and adjust warfarin as indicated.	Monitor INR and adjust warfarin as indicated.

RESISTANCE

K103N: Most common mutation selected by EFV, resulting in high-level resistance to EFV, NVP, DLV.
Y181 mutations: 181C/I: resistance to NPV, DLV, low-level resistance to EFV (minimal clinical data on use of EFV with 181C/I). 181C can partially reverse TAM-mediated AZT, TDF resistance to V108I
Y188 mutations: 188L high-level resistance to NVP, EFV, intermediate resistance to DLV; 188C: high-level resistance to NVP, low-level resistance to EFV, DLV; 188H: low-level resistance to NVP, EFV, DLV.
G190 mutations: 190A: high-level resistance to NVP, intermediate resistance to EFV; 190S: high-level resistance to NPV, EFV; both cause hypersusceptibility to DLV (unknown clinical significance).
L100I: intermediate resistance to EFV, DLV; low-level resistance to NVP; can partially reverse TAM-mediated AZT, TDF resistance.
V106 mutations: 106A: low-level EFV resistance, high-level NPV resistance, intermediate DLV resistance; 106M: high-level resistance to EFV, NPV, intermediate resistance to DLV; 106I: not associated with resistance .
P225H: increases EFV resistance when combined with other NNRTI mutations.
V108I: low-level resistance to EFV and other NNRTIs. Clinically insignificant when present as sole mutation.

PHARMACOLOGY

Pharmacology

COMMENTS

Pros: Multiple studies demonstrating potency and durability, including in pts with high VL and/or low CD4; convenient (1 pill qd), including co-formulation with TDF and FTC (Atripla); generally well tolerated; minimal long-term toxicity; less hepatotoxicity and less severe rash than with NVP; long half-life (forgiving of delayed or missed doses); a preferred agent in DHHS guidelines with more rapid 1st phase virologic decay and superior virologic efficacy compared to LPV/r containing regimen in ACTG 5142;
Cons: Early CNS side effects common and require pt education/counseling; more hyperlipidemia than with NVP (though less than with most PIs); low genetic barrier (single point mutation) to resistance; long-half life may increase risk of resistance in pts who interrupt therapy. Lower CD4 increase and more lipoatrophy than with LPV/r in ACTG 5142. (Lipoatrophy difference probably applies only to d4T- or AZT-containing regimens.)

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Abbreviations