Zambian HIV Guidelines:: Zidovudine

	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>

Zidovudine (AZT)

Paul A. Pham, Pharm.D. and John G. Bartlett, M.D.
06-10-2008

Available formulation in Zambia: Capsule: 100 mg; 250 mg; Oral liquid: 50 mg/5 ml; IV injection: 10 mg/ml in 20-ml vial. Tablet: 300 mg. AZT 300 mg/3TC 150 mg combination tab AZT 300 mg/3TC 150 mg/NVP 200 mg combination tab
AZT /3TC plus EFV or NVP is no longer first line ARV regimen in ARV-naïve patients. TDF/FTC/EFV now preferred first line regimen due to long-term potency, favorable mutation pathway, and lower incidence of anemia.
After TDF/FTC/EFV failure, AZT/3TC or AZT/TDF/FTC plus LPV/r is recommended second line regimen.
Avoid AZT in patients with Hb <10 gm/dl
With severe anemia (Hg <6.5 g/dl), malaria should be ruled out.
Due to the potential for additive bone marrow suppression with AZT co-administration, pyrimethamine, flucytosine, and other bone marrow suppressing agents should be avoided or use with caution.

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*
Retrovir and generic zidovudine	Zidovudine (AZT)	Glaxo and generic manufacturers (Roxane Laboratories, Ranbaxy Laboratories, and Aurobindo Pharma)	oral tablet 100 mg; 300 mg	$2.61 ; $5.22 for Retrovir(100 & 300 mg); $0.95 for generic (300 mg).
			IV vial 10mg/mL (20ml)	$ 28.30
			oral syrup 10mg/mL (8oz)	$62.79
Combivir	AZT/3TC	Glaxo	oral tablet 300 mg AZT/150 mg 3TC	$14.55
Trizivir	AZT/3TC/ABC	Glaxo	oral tablet 300 mg AZT/150 mg 3TC/300 mg ABC	$23.58

*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: 2 per day.

AZT 300 mg PO twice-daily (preferred) or 200 mg PO thrice-daily with or without food (often better tolerated with food).
Combivir (AZT 300 mg + 3TC 150 mg) 1 tab PO twice-daily.
Trizivir (ABC 300 mg + AZT 300 mg + 3TC 150 mg) 1 tab PO twice-daily.
Perinatal transmission protocol (ACTG 076) AZT 300 mg PO twice-daily starting from wk 14 to delivery; intrapartum: AZT IV 2 mg/kg 1st hr, then 1 mg/kg/hr until delivery; postpartum: syrup 2 mg/kg q6h (or 1.5 mg/kg q6h IV) x 6 wks to the infant.

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

300 mg twice-daily

DOSING FOR GLOMERULAR FILTRATION OF 10-50

300 mg twice-daily

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

300mg once-daily

DOSING IN HEMODIALYSIS

300 mg once-daily

DOSING IN PERITONEAL DIALYSIS

300 mg once-daily

DOSING IN HEMOFILTRATION

No data. Usual dose likely.

ADVERSE DRUG REACTIONS

GI intolerance higher than with other NRTIs

COMMON

GI intolerance, headache ( 5-10%)
Insomnia, malaise, myalgia, and asthenia
Bone marrow suppression (ANEMIA-usually seen within 4-6 wks and GRANULOCYTOPENIA-usually seen after 12-24 wks)
Fingernail discoloration/hyperpigmentation
Benign macrocytosis (crude indicator of adherence)

OCCASIONAL

Transaminase elevation with reversible hepatitis
Lipoatrophy

RARE

MYOPATHY (with LDH and CPK elevation with ragged red fibers on muscle biopsy)
Cardiomyopathy
LACTIC ACIDOSIS +/- hepatic steatosis (consider in pts with progressive fatigue, abd. pain, n/v, weight loss, and/or dyspnea)

DRUG INTERACTIONS

Extensive first past liver metabolism to glucoronide AZT. Drugs that induce glucuronidation may decrease AZT plasma concentrations; clinical significance of these potential interactions is unknown since plasma concentrations of AZT do not correlate well with antiviral activity and it is the intracellular triphosphate that exerts anti viral activity.

Drug-to-Drug Interactions

Drug-to-Drug Interaction

Drug	Effect of Interaction	Recommendations/Comments
Amphotericin B	Possible additive anemia.	With coadministration, monitor for anemia.
Clarithromycin	AZT: No significant change in AUC.	Not clinically significant. Use standard dose.
Stavudine (d4T)	In vitro and in vivo antagonism.	Do not co-administer. Switch to an alternative NRTI.
Dapsone	Possible additive anemia	With co-administration, monitor for anemia.
Fluconazole	Slight increase in AZT half-life. No change in fluconazole PK.	Not clinically significant. Use standard dose.
Flucytosine	Possible additive bone marrow suppression.	With co-administration, monitor for bone marrow suppression, esp. neutropenia.
Ganciclovir	Additive bone marrow suppression.	Close monitoring of CBC recommended. Switch to alternative ART or use concomitant G-CSF if neutropenia is severe. In vitro antagonism; clinical significance unknown.
Pyrimethamine	Possible additive bone marrow suppression.	With co-administration, monitor for bone marrow suppression.
Rifampin	AZT AUC decreased	Clinical significance unknown; consider switching to rifabutin.
Sulfadiazine	Possible additive bone marrow suppression.	With co-administration, monitor for bone marrow suppression esp. anemia.
Trimethoprim + Sulfamethoxazole	Possible additive bone marrow suppression.	With co-administration, monitor for bone marrow suppression.
Tipranavir	AZT AUC decreased by approx. 42% with TPV/r 250/200 mg twice-daily co-admin.	Clinical significance unknown. AZT intracellular triphosphate levels not measured.
Adriamycin	Possible additive bone marrow suppression.	With co-administration, monitor for bone marrow suppression (esp. neutropenia).
APAP (acetaminophen)	Theoretical concern of competing hepatic metabolism (glucuronidation) that has not been demonstrated in vivo.	Not clinically significant. Intermittent use of acetaminophen is considered safe. Adverse effects not consistently reported.
Atovaquone	AZT: AUC increased by 31%.	Clinical significance unknown.Use standard dose.
Buprenorphine	No change in AZT AUC.	No significant interaction. Use standard dose.
ddC (Zalcitabine)	Modest antiviral effect due to poor activity of ddC.	Do not co-administer. Switch to an alternative NRTI.
Fatty food	AZT AUC decreased by 57% with a liquid fat meal. Intracellular AZT triphosphate was not measured.	Clinical significance of fatty meal unknown. Administer AZT with food since it improves GI tolerance.
Hydroxyurea	Possible additive bone marrow suppression.	With co-administration, monitor for bone marrow suppression.
Interferon	Possible additive bone marrow suppression.	With co-administration, monitor for bone marrow suppression.
Probenecid	May increase AZT levels by inhibiting renal tubular secretion of AZT.	High incidence of probenecid rash with co-administration.
Ribavirin	In vitro antagonism but not in vivo.	Antagonism not observed in vivo, however, pts should be closely monitored for severe anemia.
Vinca alkaloids (Vincristine, Vinblastine)	Possible additive bone marrow suppression.	With co-administration, monitor for bone marrow suppression.

RESISTANCE

TAMs: selected by AZT and d4T. Resistance (including NRTI cross-resistance) increases with number of TAMs. Greater resistance with 41L/L210W/T215Y pathway than with D67N/K70R/K219 pathway.
E44D, V118I: accessory mutations that increase AZT resistance when combined with TAMs (especially M41L/L210W/T215Y).
Q151M or T69 insertion: high-level AZT resistance and NRTI cross-resistance. Selected by AZT/ddI and ddI/d4T combinations.
M184V: increases AZT susceptibility, partially reversing effect of TAMs, but cannot overcome effect of multiple TAMs.
K65R and L74V: increase susceptibility to AZT (clinical significance unknown).

PHARMACOLOGY

Pharmacology

COMMENTS

Pros: Availability of generics; extensive long-term data and clinical experience; documented efficacy in preventing perinatal and occupational transmission; effective in treating thrombocytopenia. High-level resistance requires multiple mutations:failure of AZT/3TC-containing combinations results in gradual accumulation of TAMs.When AZT used in a TDF- or ABC-containing regimen, K65R or L74Vunlikely to occur.
Cons: twice-daily dosing; GI intolerance (especially nausea), headaches, fatigue, asthenia, anemia, neutropenia; mitochondrial toxicity, including lipoatrophy, lactic acidosis, hepatic steatosis; high-level resistance with multiple TAMs leads to broad NRTI cross-resistance. AZT/3TC less effective than TDF/FTC at 48 wks, primarily because of greater drop-out due to anemia and other side effects.

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