Zambian HIV Guidelines:: Stavudine

	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>

Stavudine

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

Coformulation: d4T (30 mg) + 3TC (150 mg) + NVP (200 mg); Dose: 1 tab twice daily.
40 mg twice daily dosing no longer recommended due to increased risk of mitochondrial toxicity.
Co-administration with ddI, INH, phenytoin, and vincristine may increase the risk of peripheral neuropathy.
Contraindicated with AZT due to in vitro and in vivo antagonism.

REFERENCES

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*
Zerit	Stavudine (d4T)	Bristol-Myers Squibb	oral capsule 15 mg; 20 mg; 30 mg; 40 mg	$7.11/40 mg tab
			oral liquid 1 mg/mL (200 mL bottle)	$79.38/bottle

*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

Wt >60 kg: 40 mg PO twice-daily (some data supporting 30 mg PO twice-daily, less toxic but limited efficacy data).
Wt <60kg: 30 mg PO twice-daily.
Package insert recommends dose reduction (wt >60 kg: 20 mg twice-daily, wt <60 kg 15 mg twice-daily) for peripheral neuropathy; however, treatment with alternate agent preferred due to limited efficacy data with lower doses and potential for irreversible neuropathy with continued use d4T.

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

Wt >60 kg dose: 40 mg twice-daily (consider 30 mg twice-daily), wt <60 kg dose: 30 mg twice-daily

DOSING FOR GLOMERULAR FILTRATION OF 10-50

Wt >60 kg Cr clearance 26-50 mL: 20 mg twice-daily, wt >60 kg Cr clearance 10-25 mL/min: 20 mg once-daily ; wt <60 kg Cr clearance 26-50 mL/min:15mg twice-daily, wt <60 kg Cr clearance 10-25 mL/min:15 mg once-daily.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

Wt >60 kg: 20 mg q24h, wt <60 kg: 15mg q24h.

DOSING IN HEMODIALYSIS

Wt >60 kg dose: 20 mg q24h, wt <60 kg dose: 15 mg q24h, on days of dialysis dose post-dialysis.

DOSING IN PERITONEAL DIALYSIS

Wt >60 kg dose: 20 mg q24h. Wt <60 kg dose: 15 mg q24h, on days of dialysis dose post-dialysis.

DOSING IN HEMOFILTRATION

No data: Consider ½ of standard dose.

ADVERSE DRUG REACTIONS

COMMON

Peripheral neuropathy (5-24%). Onset is usually 2 to 6 mos. Reversible with early discontinuation.
Macrocytosis (inconsequential).
Lipoatrophy: caused by mitochondrial toxicity; d4T most common cause; dose dependent--may be less common or severe with 30 mg twice-daily.

OCCASIONAL

GI intolerance with diarrhea.
Lactic Acidosis and/or Hepatic Steatosis caused by mitochondrial toxicity. Potentially life-threatening: d4T most common cause.
Hyperlipidemia

RARE

HIV-associated neuromuscular weakness syndrome (HANWS): ascending motor weakness, generally accompanied by lactic acidosis.
Esophageal ulcer (association unclear).

DRUG INTERACTIONS

Few pharmacokinetic drug interactions.

AZT: co-administration with AZT contraindicated due to in vitro and in vivo antagonism.
ddI: avoid co-administration due to increased rate of lactic acidosis and peripheral neuropathy.
Use with caution with any drug capable of causing peripheral neuropathy.

Drug-to-Drug Interactions

Drug-to-Drug Interaction

Drug	Effect of Interaction	Recommendations/Comments
AZT	In vitro and invivo antagonism.	Do not co-administer.
Fluconazole	d4T AUC: no significant change.	No significant interaction.
IDV	d4T AUC: increased by 25%.	Unlikely to be significant. Use standard dose.
Isoniazid	May increase risk of peripheral neuropathy.	Give INH with pyridoxine to decrease the risk of neuropathy. Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
ddI (EC and buffered)	Additive toxicity (peripheral neuropathy, lactic acidosis, and pancreatitis).	Do not co-administer, especially in pregnancy.
Metronidazole (long term)	May increase risk of peripheral neuropathy (rare).	Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
Cisplatin	May increase risk of peripheral neuropathy.	Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
Disulfiram	May increase risk of peripheral neuropathy.	Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
Gold compounds	May increase risk of peripheral neuropathy.	Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
Hydralazine	May increase risk of peripheral neuropathy	Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
Methadone	d4T AUC: decreased by 23%; Methadone: no change.	Unlikely to be significant. Use standard dose.
Pyridoxine (vitamin B6) high-dose	May increase risk of peripheral neuropathy.	Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
Ribavirin	In vitro antagonism but not in vivo.	Not clinically significant. No in vivo antagonism observed.
Rifabutin	d4T AUC: no significant change.	No significant interaction. Use standard dose.
Thalidomide	May increase risk of peripheral neuropathy.	Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
Vincristine	May increase risk of peripheral neuropathy.	Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.

RESISTANCE

TAMs (41L, 67N, 70R, 210W, 215Y/F, 219 Q/E): selected by d4T and AZT; increasing d4T resistance (and NRTI cross-resistance) with increasing number of TAMs.
151M complex and 69S insertion confer high-level resistance to d4T, in the setting of multi-NRTI resistance.
184V: as with AZT, 184V mutation (associated with 3TC resistance) may increase susceptibility or delay resistance to d4T

PHARMACOLOGY

Pharmacology

COMMENTS

d4T has fallen out of favor in recent years due to concern over long-term toxicity, including potentially fatal lactic acidosis, peripheral neuropathy, and lipoatrophy. Nevertheless it remains a potent agent for pts who need a thymidine analog but cannot tolerate AZT. ddI + d4T should be avoided, especially in pregnant pts.

Pros: well studied NRTI. Well tolerated in short term; gradual emergence of TAM-medicated resistance.
Cons: NRTI most commonly associated with mitochondrial toxicity; ddI+d4T+EFV inferior to AZT+3TC+EFV in ACTG 384; d4T+3TC+EFV non-inferior to TDF+3TC+EFV in GS903, but with greater toxicity (neuropathy, lipoatrophy, hyperlipidemia). Important to refrigerate (10C or lower) oral liquid formulation since significant loss of stability was observed after 4 weeks at 25C.

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