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Stavudine (d4T), sold under the brand name Zerit among others, is an antiretroviral medication used to prevent and treat HIV/AIDS.
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Common side effects include headache, diarrhea, vomiting, rash, and peripheral nerve problems. It is available as a generic medication. Stavudine can also reduce the risk of developing HIV-1 infection after coming into contact with the virus either at work (e.g., needlestick) or through exposure to infected blood or other bodily fluids. It is always used in combination with other HIV medications for the better control of the infection and a reduction in HIV complications.
Pregnancy and breastfeeding
Stavudine has been demonstrated to affect the fetus in animal studies but no data are available from human studies.
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, in order to avoid the risk of HIV transmission through breast milk. There is also evidence that stavudine gets into animal breast milk, although no data are available for human breast milk.
Adverse effects
Common side effects
It is still used as a first choice in first line therapy in resource poor settings such as in India. Only in the case of development of peripheral neuropathy or pregnancy is treatment changed to the next choice, zidovudine. The safety and effectiveness of dosage titration was not reported in treatment naive patients. It was only reported in those patients with sustained virologic suppression. These findings are not generalized to stavudine used in ART naive patients who have high viral loads.
In November 2009, the World Health Organization (WHO) stated that "[The WHO] recommends that countries phase out the use of stavudine, or d4T, because of its long-term, irreversible side-effects. Stavudine is still widely used in first-line therapy in developing countries due to its low cost and widespread availability. Zidovudine (AZT) or tenofovir (TDF) are recommended as less toxic and equally effective alternatives."
Mechanism of action
Stavudine is a nucleoside analog of thymidine. It is phosphorylated by cellular kinases into an active triphosphate. Stavudine triphosphate inhibits HIV's reverse transcriptase by competing with the natural substrate, thymidine triphosphate. Reverse transcriptase is the enzyme the virus uses to make a DNA copy of its RNA in order to insert its genetic material into the host's DNA. Upon incorporation into the DNA strand, stavudine triphosphate causes termination of DNA replication.
Pharmacokinetics
Absorption: Stavudine has rapid absorption and good oral bioavailability (F = 0.86).
History
Stavudine was first created by Jerome Horwitz in the 1960s and was originally named D4T. When the AIDS epidemic occurred in the 1980s, William Prusoff and others at Yale University discovered the anti-HIV properties of stavudine.
In 1990, Yale patented the use of the drug stavudine (d4T) to treat HIV and granted an exclusive license to Bristol-Myers Squibb to manufacture the drug under the brand name Zerit.
Stavudine was the first drug to be granted parallel track status in 1992, by the US Food and Drug Administration (FDA), which allowed the agency to make Stavudine available to patients before being approved. Stavudine was submitted under the FDA's accelerated approval process. Through this process, Stavudine's effectiveness was measured by its effect on the surrogate marker, CD4, instead of clinical endpoints. The FDA concluded that an increase in CD4 cell counts was an indicator of how effective the drug would be against AIDS and HIV infection. Stavudine was the fourth drug to be approved for the treatment of AIDS and HIV infection by the FDA on 27 June 1994. Even after approval, studies were continued to evaluate the clinical benefit of the drug. If there is no indication of clinical benefits, the accelerated approval may be withdrawn.
In 2018, Mylan Pharmaceuticals discontinued manufacturing stavudine 20 mg, 30 mg, and 40 mg capsules.