Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Archived Drugs

Stavudine

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.

Resistance

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

Approval
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.

Efficacy
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

Toxicity

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

Mechanism
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.

Pharmacokinetics

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.

Formulations

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

References

1. Haugaard SB, Andersen O, Pedersen SB, et al. Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active antiretroviral therapy. J Med Virol. 2005;77(1):29-38. Available at http://www.ncbi.nlm.nih.gov/pubmed/16032748.
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 http://www.ncbi.nlm.nih.gov/pubmed/16581278.
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 http://www.ncbi.nlm.nih.gov/pubmed/20484736.
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 http://www.ncbi.nlm.nih.gov/pubmed/21494566.
5. Aboulker JP, Babiker A, Chaix ML, et al. Highly active antiretroviral therapy started in infants under 3 months of age: 72-week follow-up for CD4 cell count, viral load and drug resistance outcome. AIDS. 2004;18(2):237-245. Available at http://www.ncbi.nlm.nih.gov/pubmed/15075541.
6. Kline MW, Dunkle LM, Church JA, et al. A phase I/II evaluation of stavudine (d4T) in children with human immunodeficiency virus infection. Pediatrics. 1995;96(2 Pt 1):247-252. Available at http://www.ncbi.nlm.nih.gov/pubmed/7630678.
7. 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(6 Pt 1):886-890. Available at http://www.ncbi.nlm.nih.gov/pubmed/8657531.
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 http://www.ncbi.nlm.nih.gov/pubmed/10224206.
9. 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(7):991-1001. Available at http://www.ncbi.nlm.nih.gov/pubmed/11880966.
10. Nachman SA, Stanley K, Yogev R, et al. Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected children: a randomized controlled trial. Pediatric AIDS Clinical Trials Group 338 Study Team. JAMA. 2000;283(4):492-498. Available at http://www.ncbi.nlm.nih.gov/pubmed/10659875.
11. 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(2):119-125. Available at http://www.ncbi.nlm.nih.gov/pubmed/11840078.
12. Bolton-Moore C, Mubiana-Mbewe M, Cantrell RA, et al. Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia. JAMA. 2007;298(16):1888-1899. Available at http://www.ncbi.nlm.nih.gov/pubmed/17954540.
13. Janssens B, Raleigh B, Soeung S, et al. Effectiveness of highly active antiretroviral therapy in HIV-positive children: evaluation at 12 months in a routine program in Cambodia. Pediatrics. 2007;120(5):e1134-1140. Available at http://www.ncbi.nlm.nih.gov/pubmed/17954553.
14. Kamya MR, Mayanja-Kizza H, Kambugu A, et al. Predictors of long-term viral failure among ugandan children and adults treated with antiretroviral therapy. J Acquir Immune Defic Syndr. 2007;46(2):187-193. Available at http://www.ncbi.nlm.nih.gov/pubmed/17693883.
15. Zhang F, Haberer JE, Zhao Y, et al. Chinese pediatric highly active antiretroviral therapy observational cohort: a 1-year analysis of clinical, immunologic, and virologic outcomes. J Acquir Immune Defic Syndr. 2007;46(5):594-598. Available at http://www.ncbi.nlm.nih.gov/pubmed/18043313.
16. Okechukwu AA, Gambo D, Okechukwu IO. Prevalence of anaemia in HIV-infected children at the University of Abuja Teaching Hospital, Gwagwalada. Niger J Med. 2010;19(1):50-57. Available at http://www.ncbi.nlm.nih.gov/pubmed/20232757.
17. Kenny J, Musiime V, Judd A, Gibb D. Recent advances in pharmacovigilance of antiretroviral therapy in HIV-infected and exposed children. Curr Opin HIV AIDS. 2012;7(4):305-316. Available at http://www.ncbi.nlm.nih.gov/pubmed/22678488.
18. Palmer M, Chersich M, Moultrie H, Kuhn L, Fairlie L, Meyers T. Frequency of stavudine substitution due to toxicity in children receiving antiretroviral treatment in sub-Saharan Africa. AIDS. 2013;27(5):781-785. Available at http://www.ncbi.nlm.nih.gov/pubmed/23169331.
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 http://www.ncbi.nlm.nih.gov/pubmed/14668455.
20. Van Dyke RB, Wang L, Williams PL, Pediatric ACTGCT. Toxicities associated with dual nucleoside reverse-transcriptase inhibitor regimens in HIV-infected children. J Infect Dis. 2008;198(11):1599-1608. Available at http://www.ncbi.nlm.nih.gov/pubmed/19000014.
21. Joly V, Flandre P, Meiffredy V, et al. Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: results of a substudy from a comparative trial. AIDS. 2002;16(18):2447-2454. Available at http://www.ncbi.nlm.nih.gov/pubmed/12461419.
22. European Paediatric Lipodystrophy Group. Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected children in Europe. AIDS. 2004;18(10):1443-1451. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15199321&query_hl=60.
23. Ene L, Goetghebuer T, Hainaut M, Peltier A, Toppet V, Levy J. Prevalence of lipodystrophy in HIV-infected children: a cross-sectional study. Eur J Pediatr. 2007;166(1):13-21. Available at http://www.ncbi.nlm.nih.gov/pubmed/16896646.
24. Haubrich RH, Riddler SA, DiRienzo AG, et al. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS. 2009;23(9):1109-1118. Available at http://www.ncbi.nlm.nih.gov/pubmed/19417580.
25. Jacobson DL, Patel K, Siberry GK, et al. Body fat distribution in perinatally HIV-infected and HIV-exposed but uninfected children in the era of highly active antiretroviral therapy: outcomes from the Pediatric HIV/AIDS Cohort Study. Am J Clin Nutr. 2011;94(6):1485-1495. Available at http://www.ncbi.nlm.nih.gov/pubmed/22049166.
26. Dapena M, Jimenez B, Noguera-Julian A, et al. Metabolic disorders in vertically HIV-infected children: future adults at risk for cardiovascular disease. J Ped Endocrin Metab. 2012;25(5-6):529-535. Available at http://www.ncbi.nlm.nih.gov/pubmed/22876550.
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 http://www.ncbi.nlm.nih.gov/pubmed/22205436.
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 http://www.ncbi.nlm.nih.gov/pubmed/23038217.
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 http://www.ncbi.nlm.nih.gov/pubmed/22814353.
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.
31. Innes SEV, van Niekerk M, Rabie H, et al. Prevalence and risk factors for lipoatrophy among pre-pubertal African children on HAART, Abstract #CDB430. Presented at: 6th IAS Conference on HIV Pathogensesis, Treatment and Prevention. 2011. Rome, Italy.
32. Cohen S, Innes S, Geelen SP, et al. Long-term changes of subcutaneous fat mass in HIV-infected children on antiretroviral therapy: a retrospective analysis of longitudinal data from two pediatric HIV-cohorts. PLoS One. 2015;10(7):e0120927. Available at http://www.ncbi.nlm.nih.gov/pubmed/26148119.
33. Fortuin-de Smidt M, de Waal R, Cohen K, et al. First-line antiretroviral drug discontinuations in children. PLoS One. 2017;12(2):e0169762. Available at https://www.ncbi.nlm.nih.gov/pubmed/28192529.
34. Sawawiboon N, Wittawatmongkol O, Phongsamart W, Prasitsuebsai W, Lapphra K, Chokephaibulkit K. Lipodystrophy and reversal of facial lipoatrophy in perinatally HIV-infected children and adolescents after discontinuation of stavudine. Int J STD AIDS. 2012;23(7):497-501. Available at http://www.ncbi.nlm.nih.gov/pubmed/22844004.
35. Blanco F, Garcia-Benayas T, Jose de la Cruz J, Gonzalez-Lahoz J, Soriano V. First-line therapy and mitochondrial damage: different nucleosides, different findings. HIV Clin Trials. 2003;4(1):11-19. Available at http://www.ncbi.nlm.nih.gov/pubmed/12577192.
36. Cherry CL, Gahan ME, McArthur JC, et al. Exposure to dideoxynucleosides is reflected in lowered mitochondrial DNA in subcutaneous fat. J Acquir Immune Defic Syndr. 2002;30(3):271-277. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12131563.
37. Sanchez-Conde M, de Mendoza C, Jimenez-Nacher I, Barreiro P, Gonzalez-Lahoz J, Soriano V. Reductions in stavudine dose might ameliorate mitochondrial-associated complications without compromising antiviral activity. HIV Clin Trials. 2005;6(4):197-202. Available at http://www.ncbi.nlm.nih.gov/pubmed/16214736.
38. Crain MJ, Chernoff MC, Oleske JM, et al. Possible mitochondrial dysfunction and its association with antiretroviral therapy use in children perinatally infected with HIV. J Infect Dis. 2010;202(2):291-301. Available at http://www.ncbi.nlm.nih.gov/pubmed/20533872.
39. World Health Organization. Toxicity of reduced and standard doses of d4T. 2009. Available at https://iris.who.int/handle/10665/107280.
40. World Health Organization. Rapid advice. Antiretroviral therapy for HIV infection in adults and adolescents. 2009. Available at https://iris.who.int/handle/10665/107280.
41. Pahuja M, Glesby M, Grobler A, et al. Effects of a reduced dose of stavudine (d4T) on the incidence and severity of peripheral neuropathy in PLHIV in South Africa. Abstract #WEPE0149. Presented at: IAS-AIDS. 2010.
42. Hoffmann CJ, Charalambous S, Fielding KL, et al. HIV suppression with stavudine 30 mg versus 40 mg in adults over 60 kg on antiretroviral therapy in South Africa. AIDS. 2009;23(13):1784-1786. Available at http://www.ncbi.nlm.nih.gov/pubmed/19491652.
43. Pujades-Rodriguez M, Dantony E, Pinoges L, et al. Toxicity associated with stavudine dose reduction from 40 to 30 mg in first-line antiretroviral therapy. PLoS One. 2011;6(11):e28112. Available at http://www.ncbi.nlm.nih.gov/pubmed/22132226.
44. Brennan A, Maskew M, Sanne I, Fox M. The effect of 30 vs. 40 mg of stavudine vs. tenofovir on treatment outcomes amongst HIV+ patients: Johannesburg, South Africa. Abstract # 1098. Presented at: Conference on Retroviruses and Opportunistic Infections. 2013. Atlanta, GA.
45. Maskew M, Westreich D, Fox MP, Maotoe T, Sanne IM. Effectiveness and safety of 30 mg versus 40 mg stavudine regimens: a cohort study among HIV-infected adults initiating HAART in South Africa. J Int AIDS Soc. 2012;15(1):13. Available at http://www.ncbi.nlm.nih.gov/pubmed/22410312.
46. Kaul S, Kline MW, Church JA, Dunkle LM. Determination of dosing guidelines for stavudine (2',3'-didehydro-3'-deoxythymidine) in children with human immunodeficiency virus infection. Antimicrob Agents Chemother. 2001;45(3):758-763. Available at http://www.ncbi.nlm.nih.gov/pubmed/11181356.
47. Sy SK, Innes S, Derendorf H, Cotton MF, Rosenkranz B. Estimation of intracellular concentration of stavudine triphosphate in HIV-infected children given a reduced dose of 0.5 milligrams per kilogram twice daily. Antimicrob Agents Chemother. 2014;58(2):1084-1091. Available at http://www.ncbi.nlm.nih.gov/pubmed/24295968.
48. Sy SK, Malmberg R, Matsushima A, et al. Effect of reducing the paediatric stavudine dose by half: a physiologically-based pharmacokinetic model. Int J Antimicrob Agents. 2015;45(4):413-419. Available at http://www.ncbi.nlm.nih.gov/pubmed/25697412.
49. Innes S, Norman J, Smith P, et al. Bioequivalence of dispersed stavudine: opened versus closed capsule dosing. Antivir Ther. 2011;16(7):1131-1134. Available at http://www.ncbi.nlm.nih.gov/pubmed/22024529.