Zerit

Generic Name: Stavudine
Class: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
VA Class: AM800
Chemical Name: 2′,3′-Didehydro-3′-deoxythymidine
CAS Number: 3056-17-5

• 
  

  Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported rarely in patients receiving nucleoside reverse transcriptase inhibitors (NRTIs) alone or in conjunction with other antiretrovirals.¹ (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

  
  


• 
  

  Fatal lactic acidosis reported in pregnant women receiving stavudine and didanosine with other antiretrovirals.¹ Stavudine in conjunction with didanosine should be used with caution in pregnant women and only if potential benefits outweigh potential risks.¹ (See Pregnancy under Cautions.)

  
  


• 
  

  Fatal and nonfatal pancreatitis reported in patients receiving stavudine and didanosine with or without hydroxyurea.¹ (See Pancreatitis under Cautions.)

  
  

REMS:

FDA approved a REMS for stavudine to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Antiretroviral; nucleoside reverse transcriptase inhibitor (NRTI).^{1 2 3 4 5 6 7 8 9 10 11 12 16 17 20 21 23 24}

Uses for Zerit

Treatment of HIV Infection

Treatment of HIV-1 infection in conjunction with other antiretrovirals.¹

No longer a preferred or alternative NRTI for initial therapy in adults (increasing reports of toxicity).⁴³

Postexposure Prophylaxis of HIV

Postexposure prophylaxis of HIV infection† in health-care workers and others exposed occupationally via percutaneous injury or mucous membrane or nonintact skin contact with blood, tissues, or other body fluids associated with risk for transmission of the virus.⁶³ Used in conjunction with other antiretrovirals.⁶³

Postexposure prophylaxis of HIV infection† in individuals who have had nonoccupational exposure to blood, genital secretions, or other potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.⁷⁶ Used in conjunction with other antiretrovirals.⁷⁶

Zerit Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.^{1 43}

Reconstitution

Reconstitute powder for oral solution at time of dispensing by adding the amount of purified water specified to provide a solution containing 1 mg/mL.¹

Agitate suspension well prior to administration of each dose.¹

Dosage

Must be given in conjunction with other antiretrovirals.¹

Pediatric Patients

Treatment of HIV Infection

Oral

Birth to 13 days of age: 0.5 mg/kg every 12 hours.^{1 53}

≥14 days of age weighing <30 kg: 1 mg/kg every 12 hours.^{1 53}

≥30 kg to <60 kg: 30 mg twice daily.^{1 53}

≥60 kg: 40 mg twice daily.^{1 53}

Temporarily interrupt stavudine if peripheral neuropathy occurs.¹ If peripheral neuropathy resolves completely, reinitiate using doses 50% of the usually recommended pediatric dose.¹ (See Peripheral Neuropathy under Cautions.)

Adults

Treatment of HIV

Oral

<60 kg: 30 mg twice daily.^{1 43}

≥60 kg: 40 mg twice daily.^{1 43}

Temporarily interrupt stavudine if peripheral neuropathy occurs.¹ If peripheral neuropathy resolves, reinitiate with 15 mg twice daily in those weighing <60 kg and 20 mg twice daily in those weighing ≥60 kg.¹ (See Peripheral Neuropathy under Cautions.)

Postexposure Prophylaxis of HIV†

Occupational Exposure†

Oral

<60 kg: 30 mg twice daily.⁶³

≥60 kg: 40 mg twice daily; if toxicity develops, use 20–30 mg twice daily.⁶³

Initiate postexposure prophylaxis as soon as possible following exposure (within hours rather than days) and continue for 4 weeks, if tolerated.⁶³

Nonoccupational Exposure†

Oral

<60 kg: 30 mg twice daily.⁷⁶

≥60 kg: 40 mg twice daily.⁷⁶

Initiate postexposure prophylaxis as soon as possible following exposure (preferably ≤72 hours after exposure) and continue for 28 days.⁷⁶

Special Populations

Renal Impairment

Treatment of HIV Infection

Consider a reduction in the dose and/or an increase in the dosing interval in pediatric patients with renal impairment;^{1 53} data insufficient to recommend a specific dose adjustment.¹

Table 1. Dosage in Adults with Renal Impairment143

Clcr (mL/minute)	Weighing <60 kg	Weighing≥60 kg
≥50	30 mg every 12 hours	40 mg every 12 hours
26–50	15 mg every 12 hours	20 mg every 12 hours
10–25	15 mg every 24 hours	20 mg every 24 hours
Hemodialysis Patients	15 mg every 24 hours given after completion of dialysis and at the same time of day on days that patient does not undergo hemodialysis	20 mg every 24 hours given after completion of dialysis and at the same time of day on days that patient does not undergo hemodialysis

Cautions for Zerit

Contraindications

• 
  

  Known hypersensitivity to stavudine or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving stavudine.¹ Reported most frequently in women; obesity and long-term NRTI therapy also may be risk factors.¹ Has been reported in patients with no known risk factors.¹

Reported in pregnant women receiving stavudine in conjunction with didanosine.¹ (See Pregnancy under Cautions.)

Use with caution in patients with known risk factors for liver disease.¹

Interrupt therapy if there are clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (e.g., hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).¹

Interactions

Concomitant use with didanosine (with or without hydroxyurea) associated with increased risk of hepatotoxicity and pancreatitis.¹ (See Specific Drugs under Interactions.)

Concomitant use with ribavirin and interferon (interferon alfa, peginterferon alfa) associated with increased risk of fatal hepatic decompensation in patients coinfected with HCV and HIV.^{1 80} (See Specific Drugs under Interactions.)

Peripheral Neuropathy

Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, reported; these effects occur more frequently in patients with advanced HIV, a history of neuropathy, or those receiving other neurotoxic drugs, including didanosine.¹

Dosage modification or discontinuance may be necessary.¹ Patients whose symptoms resolve after the drug is discontinued may tolerate a reduced stavudine dosage; if neuropathy recurs, permanent discontinuance should be considered.¹

Other Nervous System Effects

Rapidly ascending neuromuscular weakness, which has been fatal in some cases, reported rarely in patients receiving stavudine in conjunction with other antiretrovirals.^{1 75} Most reported cases of motor weakness occurred in the setting of lactic acidosis.^{1 75}

The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure); symptoms may continue or worsen following discontinuance of antiretroviral therapy.¹ Discontinue stavudine if motor weakness develops.⁷⁵

Pancreatitis

Fatal and nonfatal pancreatitis reported in patients receiving stavudine in conjunction with didanosine in both treatment-naive and previously treated patients, regardless of degree of immunosuppression.^{1 46}

Interrupt treatment with stavudine, didanosine, and any other agent toxic to the pancreas in patients with signs or symptoms of pancreatitis.¹ Reinitiation of stavudine therapy following a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring.¹ If stavudine is reinitiated in these patients, didanosine should not be included in the regimen.¹

General Precautions

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.¹

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.¹

Specific Populations

Pregnancy

Category C.¹ Antiretroviral Pregnancy Registry at 800-258-4263.¹

Some experts state stavudine is an alternative (not a preferred) NRTI for use in multiple-drug antiretroviral regimens in pregnant women.²⁵

Do not use stavudine in conjunction with zidovudine in pregnant women because of potential antagonist antiretroviral effects.²⁵

Fatal lactic acidosis reported in pregnant women receiving stavudine and didanosine with other antiretrovirals.^{1 43} Unclear whether pregnancy potentiates risk of lactic acidosis and severe hepatotoxicity with steatosis that occurs in NRTI-treated individuals.¹ Stavudine in conjunction with didanosine should be used with caution in pregnant women and only if no other options are available.^{1 43}

Clinicians caring for pregnant patients receiving stavudine should be alert for early diagnosis of lactic acidosis and hepatitis steatosis syndrome.¹

Lactation

Stavudine distributed into milk in rats; not known whether distributed into human milk.¹

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.¹

Pediatric Use

Use in pediatric patients from birth through adolescence supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients.¹

Adverse effects in pediatric patients generally are similar to those reported in adults.¹

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults, but increased sensitivity cannot be ruled out.¹

Peripheral neuropathy reported in geriatric individuals; monitor these patients for signs and symptoms of peripheral neuropathy.¹

Substantially eliminated by the kidneys; geriatric patients more likely to have decreased renal function; monitor renal function and adjust dosage accordingly.^{1 18}

Hepatic Impairment

Safety and efficacy not established in patients with clinically important hepatic disease.¹

Increased incidence of liver function abnormalities, including potentially fatal hepatic adverse effects, reported in patients with preexisting hepatic impairment.¹

Monitor patients with liver function abnormalities.¹ Interrupt or discontinue therapy if liver disease worsens.¹

Renal Impairment

Dosage adjustments needed based on degree of renal impairment.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Headache, diarrhea, peripheral neurologic symptoms/neuropathy, rash, nausea and vomiting.¹

Interactions for Zerit

Does not inhibit CYP1A2, 2C9, 2C19, 2D6, 3A4.¹

Specific Drugs

Drug	Interaction	Comments
Abacavir	In vitro evidence of additive or synergistic antiretroviral effects1
Clarithromycin	Pharmacokinetic interactions unlikely38
Darunavir	Pharmacokinetic interactions unlikely78
Didanosine	Pharmacokinetic interactions unlikely46 Concomitant use of didanosine and stavudine (with or without hydroxyurea): Possible increased risk of toxicities (pancreatitis, peripheral neuropathy, hyperlactatemia)1 43 In vitro evidence of additive or synergistic antiretroviral effects28 29	Concomitant use of didanosine and stavudine: Avoid concomitant use unless potential benefits outweigh risks43 Avoid concomitant use of didanosine, hydroxyurea, and stavudine1
Doxorubicin	Inhibits stavudine phosphorylation in vitro1	Clinical importance unknown; use concomitantly with caution1
Emtricitabine	Pharmacokinetic interaction unlikely79 In vitro evidence of additive or synergistic antiretroviral effects79
Fluconazole	Pharmacokinetic interactions unlikely38
Ganciclovir	Pharmacokinetic interactions unlikely54
Hydroxyurea	Concomitant use of didanosine and stavudine (with or without hydroxyurea): Potential for increased risk of pancreatitis, peripheral neuropathy, hepatotoxicity1	Avoid concomitant use of hydroxyurea and stavudine1
Interferon (interferon alfa, peginterferon alfa)	Possible increased risk of potentially fatal hepatic decompensation in patients coinfected with HCV and HIV who are receiving interferon alfa, ribavirin, and antiretroviral agents1 80	If stavudine used in patients receiving interferon alfa or peginterferon alfa (with or without ribavirin), closely monitor for toxicities, especially hepatic decompensation; consider discontinuing stavudine as appropriate; if worsening toxicities (e.g., hepatic decompensation Child-Pugh >6) are observed, consider discontinuing or reducing dosage of interferon and/or ribavirin1 80
Lamivudine	Pharmacokinetic interactions unlikely1 In vitro evidence of additive or synergistic antiretroviral effects28 29
Methadone	Decreased stavudine peak plasma concentrations and AUC;31 43 no change in methadone concentrations31	Dosage adjustments not necessary43
Nelfinavir	Pharmacokinetic interactions unlikely33 In vitro evidence of additive or synergistic antiretroviral effects28 32 33 35	Dosage adjustments not needed33
Ribavirin	Ribavirin can reduce phosphorylation of stavudine; no evidence of pharmacokinetic or pharmacodynamic interaction1 Possible increased risk of potentially fatal hepatic decompensation in patients coinfected with HCV and HIV who are receiving interferon alfa or peginterferon alfa, ribavirin, and antiretroviral agents1 80 Possible increase in adverse effects (lactic acidosis, pancreatitis)65 66 68	If stavudine used in patients receiving interferon alfa or peginterferon alfa (with or without ribavirin), closely monitor for toxicities, especially hepatic decompensation; consider discontinuing stavudine as appropriate; if worsening toxicities (e.g., hepatic decompensation Child-Pugh >6) are observed, consider discontinuing or reducing dosage of interferon and/or ribavirin1 80
Rifabutin	Decreased stavudine peak plasma concentrations and AUC38
Saquinavir	In vitro evidence of additive or synergistic antiretroviral effects28 32 33 35
Tipranavir	Pharmacokinetic interaction unlikely77 In vitro evidence of additive antiretroviral effects77
Zidovudine	In vitro evidence of antagonism1 26 40	Concomitant use not recommended1 43

Zerit Pharmacokinetics

Absorption

Bioavailability

Well absorbed; peak plasma concentrations attained within 1 hour.¹ Bioavailability is 86%.¹

Stavudine capsules and oral solution are bioequivalent.¹

Food

Food delays time to peak concentrations; no effect on AUC.⁶⁹

Special Populations

Peak plasma concentration and time to peak concentration not altered in patients with renal impairment.¹

Distribution

Extent

Not well characterized.¹ Distributed into semen.⁷⁴

Distributed into CSF in adults and pediatric patients.^{1 70 71}

Not known whether crosses the placenta or is distributed into human milk.¹

Plasma Protein Binding

Negligible.¹

Elimination

Metabolism

Metabolic fate not elucidated.¹

Intracellularly, stavudine is phosphorylated and converted by cellular enzymes to the active 5′-triphosphate metabolite.^{1 2 4 8 17 22}

Elimination Route

Eliminated in the urine (40%) by glomerular filtration and active tubular secretion; remaining 60% presumably eliminated by endogenous pathways.¹

Removed by hemodialysis.^{1 18} Not known whether removed by peritoneal dialysis.¹

Half-life

1.6 hours.¹

Half-life is 0.96 hours in pediatric patients 5 weeks to 15 years of age; 1.59 hours in those 14–28 days of age; 5.27 hours in those 1 day of age.¹

Special Populations

Pharmacokinetics not altered in patients with hepatic impairment (Child-Pugh class B or C).¹

Apparent oral clearance of stavudine decreases and half-life increases as Cl_cr decreases.¹

Stability

Storage

Oral

Capsules

15–30°C in tightly closed containers.¹

Powder for Solution

15–30°C.¹ Following reconstitution with water, oral solution stable for 30 days when refrigerated at 2–8°C.¹ Unused portions of reconstituted oral solution should be discarded after 30 days.¹

Actions and Spectrum

• 
  

  Analog of thymidine, a naturally occurring pyrimidine.^{1 2 3 4 6 8 9 16}

  
  


• 
  

  Pharmacologically related to other NRTIs (e.g., abacavir, didanosine, emtricitabine, lamivudine, zidovudine); differs structurally from these drugs; also differs pharmacologically and structurally from other currently available antiretrovirals.¹

  
  


• 
  

  Active in vitro against HIV-1^{1 2 3 4 9 10 11 12 16 17 20 21 23 24 27 28} and HIV-2.²⁷

  
  


• 
  

  Inhibits replication of HIV by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).^{1 2 3 4 9 12 16 17 21 23}

  
  


• 
  

  Strains of HIV-1 with reduced susceptibility to stavudine have been produced in vitro and have emerged during therapy with the drug.^{1 27}

  
  


• 
  

  Strains of HIV resistant to stavudine may be cross-resistant to some other NRTIs.^{1 27}

  
  


• 
  

  Cross-resistance between stavudine and HIV protease inhibitors (PIs) is highly unlikely since the drugs have different target enzymes.⁴³ Cross-resistance between stavudine and nonnucleoside reverse transcriptase inhibitors (NNRTIs) is considered to be low since the drugs bind at different sites on reverse transcriptase and have different mechanisms of action.⁴³

  
  

Advice to Patients

• 
  

  Critical nature of compliance with HIV therapy.¹ Importance of using stavudine in conjunction with other antiretrovirals—not for monotherapy.¹

  
  


• 
  

  Antiretroviral therapy is not a cure for HIV infection, and opportunistic infections still may occur.¹ HIV transmission via sexual contact or sharing needles is not prevented by antiretrovirals.¹

  
  


• 
  

  Possibility of lactic acidosis; patients who experience symptoms of lactic acidosis (abdominal discomfort, nausea, vomiting, fatigue, dyspnea, motor weakness) should seek immediate medical attention.¹ Discontinuation of the drug may be required.¹

  
  


• 
  

  Possibility of peripheral neuropathy; manifestations include numbness, tingling, or pain in hands or feet.¹ Advise patient to report these symptoms to their clinician.¹ Dosage modification or discontinuance may be needed.¹

  
  


• 
  

  Possibility of pancreatitis, including fatal pancreatitis if used with didanosine.¹

  
  


• 
  

  Importance of patient reading the patient package insert from manufacturer.¹

  
  


• 
  

  Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.¹

  
  


• 
  

  Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of advising patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Stavudine

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	15 mg*	Stavudine Capsules
			Zerit	Bristol-Myers Squibb
		20 mg*	Stavudine Capsules
			Zerit	Bristol-Myers Squibb
		30 mg*	Stavudine Capsules
			Zerit	Bristol-Myers Squibb
		40 mg*	Stavudine Capsules
			Zerit	Bristol-Myers Squibb
	For solution	1 mg/mL*	Stavudine for Oral Solution
			Zerit	Bristol-Myers Squibb

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Stavudine 40MG Capsules (CAMBER PHARMACEUTICALS): 60/$129.99 or 180/$369.97

Zerit 1MG/ML Solution (B-M SQUIBB ONCOLOGY/IMMUNOLOGY): 200/$87.99 or 600/$255.97

Zerit 15MG Capsules (B-M SQUIBB ONCOLOGY/IMMUNOLOGY): 60/$363.99 or 180/$1,050.34

Zerit 20MG Capsules (B-M SQUIBB ONCOLOGY/IMMUNOLOGY): 60/$388.98 or 180/$1,126.01

Zerit 30MG Capsules (B-M SQUIBB ONCOLOGY/IMMUNOLOGY): 60/$416.98 or 180/$1,197.99

Zerit 40MG Capsules (B-M SQUIBB ONCOLOGY/IMMUNOLOGY): 60/$426.97 or 180/$1,225.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Bristol-Myers Squibb. Zerit (stavudine) capsules and powder for oral solution prescribing information. Princeton, NJ; 2008 Nov.

2. Ho HT. Cellular pharmacology of 2′,3′-dideoxy-2′, 3′-didehydrothymidine, a nucleoside analog active against human immunodeficiency virus. Antimicrob Agents Chemother. 1989; 33:844-9. [PubMed 2764535]

3. Yarchoan R, Mitsuya H. Clinical and basic advances in the antiretroviral therapy of human immunodeficiency virus infection. Am J Med. 1989; 87:191-200. [IDIS 261900] [PubMed 2474251]

4. Hitchcock MJM. 2′3′-Didehydro-2′,3′-dideoxythymidine (D4T), an anti-HIV agent. Antiviral Chem. 1991; 2:125-32.

5. August EM, Birks EM. 3′-Deoxythymidin-2′-ene permeation of human lymphocyte H9 cells by nonfacilitated diffusion. Mol Pharmacol. 1991; 39:246-9. [PubMed 1847498]

6. Martin JC, Hitchcock MJM, Fridland A et al. Comparative studies of 2′3′-didehydro-2′,3′-dideoxythymidine (D4T) with other pyrimidine nucleoside analogues. Ann NY Acad Sci. 1990; 616:22-8. [PubMed 1964029]

7. Zhu Z, Hitchcock MJM. Metabolism and DNA interaction of 2′3′-didehydro-2′,3′-dideoxythymidine in human bone marrow cells. Mol Pharmacol. 1991; 40:838-45. [PubMed 1658614]

8. August EM, Marongiu ME, Lin T-S et al. Initial studies on the cellular pharmacology of 3′-deoxythymidin-2′-ene (d4T): a potent and selective inhibitor of human immunodeficiency virus. Biochem Pharmacol. 1988; 37:4419-22. [PubMed 2849444]

9. Yarchoan R, Mitsuya H, Myers CE et al. Clinical pharmacology of 3′-azido-2′,3′-dideoxythymidine (zidovudine) and related dideoxynucleosides. N Engl J Med. 1989; 321:726-38. [IDIS 258616] [PubMed 2671731]

10. Browne MJ, Mayer KH, Chafee SBD et al. 2′,3′-Didehydro-3′-deoxythymidine (d4T) in patients with AIDS or AIDS-related complex: a phase I trial. J Infect Dis. 1993; 167:21-9. [IDIS 306938] [PubMed 8093363]

11. De Clercq E. HIV inhibitors targeted at reverse transcriptase. AIDS Res Hum Retroviruses. 1992; 8:119-34. [PubMed 1371690]

12. Yarchoan R. Anti-retroviral therapy of AIDS and related disorders: general principles and specific development of dideoxynucleosides. Pharmacol Ther. 1989; 40:329-48. [PubMed 2646649]

13. Funk MB, Linde R, Wintergerst U et al. Preliminary experiences with triple therapy including nelfinavir and two reverse transcriptase inhibitors in previously untreated HIV-infected children. AIDS. 1999; 13:1653-8. [PubMed 10509566]

14. Krogstad P, Lee S, Johnson G et al. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1. Clin Infect Dis. 2002; 34:991-1001. [IDIS 480417] [PubMed 11880966]

15. Yogev R, Lee S, Wiznia A et al. Stavudine, nevirapine and ritonavir in stable antiretroviral therapy-experienced children with human immunodeficiency virus infection. Pediatr Infect Dis J. 2002; 21:119-25. [IDIS 477734] [PubMed 11840078]

16. Mansuri MM, Hitchcock MJM, Buroker RA et al. Comparison of in vitro biological properties and mouse toxicities of three thymidine analogs active against human immunodeficiency virus. Antimicrob Agents Chemother. 1990; 34:637-41. [PubMed 1693057]

17. Balzarini J, Herdewijn P. Differential patterns of intracellular metabolism of 2′,3′-didehydro-2′,3′-dideoxythymidine and 3′-azido-2′,3′-dideoxythymidine, two potent anti-human immunodeficiency virus compounds. J Biol Chem. 1989; 264:6127-33. [PubMed 2539371]

18. Eron JJ, Murphy RL, Peterson D et al. A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START II). AIDS. 2000; 14:1601-10. [PubMed 10983647]

19. Seminari E, Maggiolo F, Villani P et al. Efavirenz, nelfinavir, and stavudine rescue combination therapy in HIV-1-positive patients heavily pretreated with nucleoside analogues and protease inhibitors. J Acquir Immune Defic Syndr. 1999; 22:453-60. [IDIS 441272] [PubMed 10961606]

20. Hamamoto Y, Nakashima H, Matsui T et al. Inhibitory effect of 2′,3′-didehydro-2′,3′-dideoxynucleosides on infectivity, cytopathic effects, and replication of human immunodeficiency virus. Antimicrob Agents Chemother. 1987; 31:907-10. [PubMed 3039911]

21. Mansuri MM, Starrett Jr JE, Ghazzouli I et al. 1-(2,3-Dideoxy-beta-D-glycero-pent-2-enofuranosyl)thymine. A highly potent and selective anti-HIV agent. J Med Chem. 1989; 32:461-6. [PubMed 2536441]

22. Marongiu ME, August EM. Effect of 3′-deoxythymidin-2′-ene (d4T) on nucleoside metabolism in H9 cells. Biochem Pharmacol. 1990; 39:1523-8. [PubMed 2159760]

23. Lin TS, Schinazi RF. Potent and selective in vitro activity of 3′-deoxythymidin-2′-ene (3′-deoxy-2′,3′-didehydrothymidine) against human immunodeficiency virus. Biochem Pharmacol. 1987; 36:2713-8. [PubMed 2443141]

24. Baba M, Pauwels R, Herdewijn P et al. Both 2′,3′-dideoxythymidine and its 2′,3′-unsaturated derivative (2′,3′-dideoxythymidinene) are potent and selective inhibitors of human immunodeficiency virus replication in vitro. Biochem Biophys Res Commun. 1987; 142:128-34. [PubMed 3028398]

25. Perinatal HIV Guidelines Working Group. US Public Health Service Task Force recommendations for use of antiretroviral drugs in pregnant HIV-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States (April 29, 2009). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

26. Havlir DV, Tierney C, Friedland GH et al. In vivo antagonism with zidovudine plus stavudine combination therapy. J Infect Dis. 2000; 182:321-5. [IDIS 450347] [PubMed 10882616]

27. Lea AP. Stavudine: a review of its pharmacodynamic and pharmacokinetic properties and clinical potential in HIV infection. Drugs. 1996; 51:846-64. [PubMed 8861550]

28. Merrill DP, Moonis M, Chou TC et al. Lamivudine or stavudine in two- and three-drug combinations against human immunodeficiency virus type 1 replication in vitro. J Infect Dis. 1996; 173:355-64. [IDIS 362747] [PubMed 8568296]

29. Deminie CA, Bechtold CM, Stock D et al. Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication. Antimicrob Agents Chemother. 1996; 40:1346-51. [PubMed 8725999]

30. Zhu QY, Scarborough A, Polsky B et al. Drug combinations and effect parameters of zidovudine, stavudine, and nevirapine in standardized drug-sensitive and resistant HIV type 1 strains. AIDS Res Hum Retroviruses. 1996; 12:507-17. [PubMed 8679306]

31. Rainey PM, Friedland G, McCance-Katz EF et al. Interaction of methadone with didanosine and stavudine. J Acquir Immune Defic Syndr. 2000; 24:241-8. [IDIS 452905] [PubMed 10969348]

32. Patick AK, Boritzki TJ, Bloom LA. Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro. Antimicrob Agents Chemother. 1997; 41:2159-64. [PubMed 9333041]

33. Agouron Pharmaceuticals. Viracept (nelfinavir mesylate) prescribing information. La Jolla, CA; 2003 Jul 31.

34. AIDS Clinical Trials Information Service (ACTIS). AIDSTRIALS Database. Nov 29, 1999.

35. Roche Pharmaceuticals. Fortovase (saquinavir) soft gelatin capsules prescribing information. Nutley, NJ; 2002 Jul.

36. Peterson EA, Ramirez-Ronda CH, Hardy WD et al. Dose-related activity of stavudine in patients infected with human immunodeficiency virus. J Infect Dis. 1995; 171(Suppl 2):S131-9. [IDIS 343074] [PubMed 7861018]

37. Hammer SM, Saag MS, Schechter M et al. Treatment of adult HIV infection: 2006 recommendations of the International AIDS Society–USA panel. JAMA. 2006; 296:827-43. [PubMed 16905788]

38. Piscitelli SC, Kelly G, Walker RE et al. A multiple drug interaction study of stavudine with agents for opportunistic infections in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 1999; 43:647-50. [IDIS 424139] [PubMed 10049281]

39. Kline MW, Fletcher CV, Federici ME et al. Combination therapy with stavudine and didanosine in children with advanced human immunodeficiency virus infection: pharmacokinetic properties, safety, and immunologic and virologic effects. Pediatrics. 1996; 97:886-90. [IDIS 368236] [PubMed 8657531]

40. GlaxoSmithKline. Retrovir (zidovudine) tablets, capsules, syrup prescribing information. Research Triangle Park, NC; 2003 Apr.

41. Shafer RW, Iversen AKN, Winters MA et al. Drug resistance and heterogeneous long-term virologic responses of human immunodeficiency virus type 1-infected subjects to zidovudine and didanosine combination therapy. J Infect Dis. 1995; 172:70-8. [IDIS 350663] [PubMed 7541064]

42. Centers for Disease Control and Prevention. Report of the NIH panel to define principles of therapy of HIV infection. MMWR Recomm Rep. 1998; 47(No. RR-5):1-42.

43. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (November 3, 2008). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

44. Gazzard B, for the BHIVA Guidelines Writing Committee. British HIV association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2005). HIV Med. 2005; 6(Suppl 2):1-61.

45. Melvin AJ, Mohan KM, Arcuino LA et al. Clinical and virologic and immunologic responses of children with advanced human immunodeficiency virus type 1 disease treated with protease inhibitors. Pediatr Infect Dis J. 1997; 16:968-74. [IDIS 394571] [PubMed 9380474]

46. Bristol-Myers Squibb. Videx (didanosine) chewable/dispersible buffered tablets, buffered powder for oral solution, pediatric powder for oral solution prescribing information. Princeton, NJ; 2003 Feb.

47. Spruance SL, Pavia AT, Mellors JW et al. Clinical efficacy of monotherapy with stavudine compared with zidovudine in HIV-infected, zidovudine-experienced patients. A randomized, double-blind, controlled trial. Ann Intern Med. 1997; 126:355-63. [IDIS 380434] [PubMed 9054279]

48. Kline MW, Fletcher CV. A pilot study of combination therapy with indinavir, stavudine (d4T), and didanosine (ddI) in children infected with human immunodeficiency virus. J Pediatr. 1998; 132:543-6. [IDIS 404504] [PubMed 9544920]

49. Smyth AC. Bristol-Myers Squibb. Dear healthcare provider letter regarding fatal lactic acidosis in pregnant women treated throughout gestation with the combination of stavudine and didanosine 2001 Jan 5. From FDA web site.

50. Chene G, Angelini E, Cotte L et al. Role of long-term nucleoside-analogue therapy in lipodystrophy and metabolic disorders in human immunodeficiency virus-infected patients. Clin Infect Dis. 2002; 34:649-57. [IDIS 476867] [PubMed 11810598]

51. Hurst M, Noble S. Stavudine: an update of its use in the treatment of HIV infection. Drugs. 1999; 58:919-49. [PubMed 10595868]

52. Rouleau D, Conway B, Raboud J et al. Stavudine plus lamivudine in advanced human immunodeficiency virus disease: a short-term pilot study. J Infect Dis. 1997; 176:1156-60. [IDIS 396352] [PubMed 9359713]

53. Working Group on Antiretroviral Therapy and Medical Management of HIV-infected Children of the National Resource Center at the François-Xavier Bagnoud Center, Health Resources and Services Administration (HRSA), and National Institutes of Health (NIH). Guidelines for the use of antiretroviral agents in pediatric HIV infection (February 23, 2009). From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website.

54. Jung D, AbdelHameed MH, Teitelbaum P et al. The pharmacokinetics and safety profile of oral ganciclovir combined with zalcitabine or stavudine in asymptomatic HIV- and CMV-seropositive patients J Clin Pharmacol. 1999; 39:505-12.

55. Wintergerst U, Hoffmann F, Solder B et al. Comparison of two antiretroviral triple combinations including the protease inhibitor indinavir in children infected with human immunodeficiency virus. Pediatr Infect Dis J. 1998; 17:495-9. [IDIS 408835] [PubMed 9655541]

56. GlaxoSmithKline. Ziagen (abacavir sulfate) t