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Nursing Pharmacology: Antiviral Drugs
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Antiretroviral Drugs Used in Treating HIV Infection
→Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (continued):
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Stavudine (d4T, Zerit) |
Stavudine (Zerit, d4T) is another example of a pyrimidine nucleoside analog.
Stavudine is an "prodrug" in that it must undergo conversion to the triphosphate form which is required for activity against HIV-1.4
Stavudine, as the triphosphate, inhibits reverse transcriptase enzyme activity both in HIV -1 and in HIV-2 based on in vitro assays.1
Comparable to zidovudine, stavudine exhibits highest potency in activated cells.
Mutations and Stavudine Resistance:
As described for zidovudine, the mutational pattern at reverse transcriptase codons conferring stavudine drug resistance has been described at numerous codons:1,9,11
Mutational resistance clusters appears to account for about 40% % of patients failing to respond to stavudine.1
Stavudine resistance mutations develop and accumulate slowly and cross-resistance to several nucleoside analogues is noted with prolonged treatment.
Stavudine, following oral administration, is well absorbed with bioavailability averaging between 82% and 100% in clinical studies.13
Stavudine may be administered with or without food.
Generally, stavudine doses may not require adjustment for total patient body weight, for patients weighing between 40 and 100 kg.
Dosage
change may also be appropriate in those patients with renal insufficiency.1,14
The basis for dosage adjustment is that about 40% of the dose is excreted without change in the urine.
Patients with renal failure may be more likely to experience peripheral neuropathy, a side effect occurring in about 15% to 21% of stavudine-treated patients who do not have kidney dysfunction.14
The most
frequently observed and serious stavudine toxic effect is peripheral
neuropathy.1
With a dosage of 40 mg twice a day, neuropathy incidence is about 10%.
Factors that predispose to peripheral neuropathy following stavudine include higher stavudine doses and the presence of stavudine-independent HIV-related neuropathy.
Increased risk of stavudine-mediated peripheral neuropathy may occur in patients receiving other neurotoxic drugs, including didanosine, vincristine, isoniazid or ribavirin.1,7
Stavudine may also be associated with a progressive motor neuropathy that may ultimately include respiratory failure.1,15
This disorder has been described as similar to Guillain-Barré syndrome.
Considering the nucleoside analogues, stavudine administration is the drug most associated with lipoatrophy (Fat wasting).1
The underlying mechanism of action remains to be determined; however mitochondrial toxicity may be involved.
Stavudine side
effects such as lipoatrophy, lipodystrophy, peripheral neuropathy and less
frequently lactic acidosis and hepatitis have been sufficient to reduce the
use of stavudine unless an alternative is unavailable.17
Patients receiving stavudine may be prescribed as an alternative abacavir or tenofovir.
Acute pancreatitis is not a major side effect with stavudine; however, pancreatitis is more likely when stavudine is administered along with didanosine.1,18
Pancreatitis is more commonly observed in patient receiving didanosine (ddI) and outcomes of ddI continued administration in the presence of pancreatitis tend to worsen.
Combination
of didanosine and stavuding increases risk and severity of peripheral
neuropathy and life-threatening pancreatitis.
Accordingly, these agents should not be used together.1,18
Stavudine and zidovudine also compete for intracellular, drug-activating phosphorylation and therefore should not be co-administered.1
Compared to zidovudine, stavudine delayed HIV disease progression and reduced plasma HIV RNA by 70%-90%.1
The long-term virologic stavudine response was enhanced by lamivudine coadministration.
Significant and
long-lasting viremia suppression along with sustained CD4 + T
cell count elevation have been confirmed when stavudine is combined with
other nucleoside analogues plus nonnucleoside reverse transcriptase
inhibitors (NNRTIs) or protease inhibitors.
As noted earlier, stavudine, as a consequence of toxicities, is used much less frequently in the developed world.
However, in
"resource-poor" settings due to availability of relatively inexpensive
generic forms and co-formulated with nevirapine and lamivudine, stavudine
continues to be widely administered.1
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