Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Archived Drugs


Last Updated: May 22, 2018; Last Reviewed: May 22, 2018

Stavudine (d4T, Zerit)
Stavudine (d4T, Zerit)
For additional information see Drugs@FDA:
Powder for Oral Solution: 1 mg/mL
Capsules: 15 mg, 20 mg, 30 mg, and 40 mg

Generic Formulations
Powder for Oral Solution: 1 mg/mL
Capsules: 15 mg, 20 mg, 30 mg, and 40 mg
Dosing Recommendations Selected Adverse Events
Note: Stavudine is no longer recommended for use in children by the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, because it causes higher rates of adverse effects than other nucleoside reverse transcriptase inhibitors (NRTIs).

Pediatric (Aged ≥14 Days and Weighing <30 kg) Dose:
  • 1 mg/kg per dose twice daily
Adolescent (Weighing ≥30 kg) and Adult Dose:
  • 30 mg per dose twice daily
  • Associated with a higher risk of mitochondrial toxicity than other NRTI drugs
  • Peripheral neuropathy is dose-related and occurs more frequently in patients who have advanced HIV disease or a prior history of peripheral neuropathy, and in patients receiving other drugs associated with neuropathy.
  • Facial/peripheral lipoatrophy
  • Pancreatitis
  • Lactic acidosis/severe hepatomegaly with hepatic steatosis (higher incidence than with other NRTIs). The risk increases when stavudine is used in combination with didanosine.
  • Dyslipidemia
  • Insulin resistance, asymptomatic hyperglycemia
  • Rapidly progressive ascending neuromuscular weakness (rare)
Special Instructions
  • Stavudine can be given without regard to food.
  • Shake stavudine oral solution well before use. Keep refrigerated; the solution is stable for 30 days.
  • Renal excretion 50%. Decrease dose in patients with renal dysfunction.
  • Stavudine is phosphorylated intracellularly to the active metabolite stavudine triphosphate.

Drug Interactions

(See also the Adult and Adolescent Antiretroviral Guidelines and HIV Drug Interaction Checker.)

  • Renal elimination: Drugs that decrease renal function could decrease stavudine clearance.
  • Other nucleoside reverse transcriptase inhibitors (NRTIs): Stavudine should not be administered in combination with zidovudine because of virologic antagonism.
  • Overlapping toxicities: The combination of stavudine and didanosine is not recommended because of overlapping toxicities. Reported toxicities occur more frequently in adults and include serious, even fatal, cases of lactic acidosis with hepatic steatosis with or without pancreatitis in pregnant women.
  • Ribavirin and interferon: Hepatic decompensation (sometimes fatal) has occurred in patients with HIV/hepatitis C virus co-infection who are receiving antiretroviral therapy (ART), interferon, and ribavirin.
  • Doxorubicin: Simultaneous use of doxorubicin and stavudine should be avoided. Doxorubicin may inhibit the phosphorylation of stavudine to its active form.

Major Toxicities

  • More common: Headache, gastrointestinal disturbances, skin rashes, hyperlipidemia, and fat maldistribution.
  • Less common (more severe): Peripheral sensory neuropathy is dose-related. It occurs more frequently in patients with advanced HIV disease, a prior history of peripheral neuropathy, and in patients receiving other drugs associated with neuropathy. Pancreatitis. Lactic acidosis and severe hepatomegaly with hepatic steatosis, including fatal cases, have been reported.1-3 The combination of stavudine and didanosine may result in enhanced toxicity (increased risk of fatal and nonfatal cases of lactic acidosis, pancreatitis, peripheral neuropathy, and hepatotoxicity), particularly in adults, including pregnant women—this combination should not be used. Risk factors found to be associated with lactic acidosis in adults include female sex, obesity, and prolonged nucleoside exposure.4
  • Rare: Increased liver enzymes and hepatic toxicity, which may be severe or fatal. Neurologic symptoms, including rapidly progressive ascending neuromuscular weakness, are most often seen in the setting of lactic acidosis. Noncirrhotic portal hypertension with prolonged exposure.


The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use

Although stavudine is Food and Drug Administration (FDA)-approved for use in infants aged ≥14 days and children, it is no longer recommended for use by the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV because it carries a higher risk of adverse effects associated with mitochondrial toxicity and a higher incidence of lipoatrophy than other NRTIs.

Data from multiple pediatric studies of stavudine administered alone or in combination with other antiretroviral (ARV) agents demonstrate that stavudine is associated with clinical and virologic response.5-11 In resource-limited countries, stavudine is frequently a component of initial ART in children, given with lamivudine and nevirapine. Stavudine is often a component of fixed-dose combinations that are not available in the United States. In this setting, reported outcomes from observational studies are good; data show substantial increases in the CD4 T lymphocyte (CD4) cell count and complete viral suppression in 50% to 80% of treatment-naive children.12-15 In such a setting, where pediatric patients are already predisposed to anemia because of malnutrition, parasitic infestations, or sickle cell anemia, stavudine carries a lower risk of hematologic toxicity than zidovudine, especially in patients receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis.16 Short-term use of stavudine in certain settings where access to other ARVs may be limited remains an important strategy for treating HIV in children.17,18


Stavudine is associated with a higher rate of adverse events than zidovudine in adults and children receiving ART.19,20 In a large pediatric natural history study (PACTG 219C), stavudine-containing regimens had a modest—but significantly higher—rate of clinical and laboratory toxicities than regimens containing zidovudine, with pancreatitis, peripheral neuropathy, and lipodystrophy/lipoatrophy (fat maldistribution) associated more often with stavudine use.20

Lipodystrophy and Metabolic Abnormalities
Lipodystrophy syndrome (LS), and specifically lipoatrophy (loss of subcutaneous fat), are toxicities associated with NRTIs, particularly stavudine, in adults and children.21-24 Stavudine use has consistently been associated with a higher risk of lipodystrophy and other metabolic abnormalities (e.g., insulin resistance) in multiple pediatric studies involving children.25-33 Improvements in (or resolution of) lipodystrophy were reported in 22.9% to 73% of cases after discontinuation of stavudine in two separate studies.30,34

Lactic acidosis with hepatic steatosis, including fatal cases, has been reported with use of nucleoside analogues, including stavudine, alone or in combination with didanosine.1-3

Many of the stavudine-related adverse events are believed to be due to mitochondrial toxicity resulting from inhibition of mitochondrial DNA polymerase gamma, with depletion of mitochondrial DNA in fat, muscle, peripheral blood mononuclear cells, and other tissues.1,35-37 In a recent analysis involving a large cohort of pediatric patients (PACTG protocols 219 and 219C), possible mitochondrial dysfunction was associated with NRTI use, especially in children receiving stavudine and/or lamivudine.38

World Health Organization Recommendations
The World Health Organization (WHO) cautions against using doses of stavudine that exceed 30 mg twice daily. This is in contrast to the FDA-recommended dose of 40 mg twice daily in patients weighing 60 kg or more.39,40 Studies comparing the efficacy and toxicity of the two doses have consistently shown that both doses have similar efficacy. However, while the 30-mg dose shows lower toxicity than the 40-mg dose, the overall incidence of toxicity with the 30-mg dose is considered to be unacceptably high.41-45 WHO recommends that stavudine be phased out of use in all patients because of concerns about unacceptable toxicity, even at the lower dose. Safer alternative agents can be prescribed.


Current pediatric dosing recommendations are based on early pharmacokinetic (PK) studies designed to achieve exposure (area under the curve) in children similar to that found in adults receiving a dose with proven efficacy.46 Although WHO has recommended using a reduced dose in adults, a similar dose reduction has not been suggested in children. A reduced pediatric dose has been proposed based on PK modeling, but clinical data on intracellular concentrations of the active stavudine triphosphate are lacking.47,48 Intracellular stavudine triphosphate concentrations have not been measured in neonates.


The pediatric formulation for stavudine oral solution requires refrigeration and has limited stability once reconstituted. As an alternative dosing method for children, capsules can be opened and dispersed in a small amount of water, with the appropriate dose drawn up into an oral syringe and administered immediately. Because plasma exposure of stavudine is equivalent whether the drug is administered in an intact or a dispersed capsule, dosing with the dispersal method can be used as an alternative to the oral solution.49


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  2. Koh MT. Unrecognized near-fatal hyperlactatemia in an HIV-infected infant exposed to nucleoside reverse transcriptase inhibitors. Int J Infect Dis. 2007;11(1):85-86. Available at
  3. Hernandez Perez E, Dawood H. Stavudine-induced hyperlactatemia/lactic acidosis at a tertiary communicable diseases clinic in South Africa. J Int Assoc Physicians AIDS Care (Chic). 2010;9(2):109-112. Available at
  4. Matthews LT, Giddy J, Ghebremichael M, et al. A risk-factor guided approach to reducing lactic acidosis and hyperlactatemia in patients on antiretroviral therapy. PLoS One. 2011;6(4):e18736. Available at
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  8. Kline MW, Van Dyke RB, Lindsey JC, et al. Combination therapy with stavudine (d4T) plus didanosine (ddI) in children with human immunodeficiency virus infection. The Pediatric AIDS Clinical Trials Group 327 Team. Pediatrics. 1999;103(5):e62. Available at
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  19. Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med. 2003;349(24):2293-2303. Available at
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  27. Alam N, Cortina-Borja M, Goetghebuer T, et al. Body fat abnormality in HIV-infected children and adolescents living in Europe: prevalence and risk factors. J Acquir Immune Defic Syndr. 2012;59(3):314-324. Available at
  28. Kinabo GD, Sprengers M, Msuya LJ, et al. Prevalence of lipodystrophy in HIV-infected children in Tanzania on highly active antiretroviral therapy. Pediatr Infect Dis J. 2013;32(1):39-44. Available at
  29. Piloya T, Bakeera-Kitaka S, Kekitiinwa A, Kamya MR. Lipodystrophy among HIV-infected children and adolescents on highly active antiretroviral therapy in Uganda: a cross sectional study. J Int AIDS Soc. 2012;15(2):17427. Available at
  30. Aurpibul L, Puthanakit T, Taejaroenkul S, et al. Improvement of lipodystropy in children after substitution of stavudine with zidovudine in NNRTI-based antiretroviral therapy, Abstract #CDB437. Presented at: 6th IAS Conference on HIV Pathogenesis Treatment and Prevention. 2011. Rome, Italy.
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