Stavudine NRTIs

At present there are seven NRTIs, which have been formally approved for the treatment of AIDS 3 -azido-2, 3 -dideoxythymidine (AZT, zidovudine), 2, 3 -dideoxyinosine (ddl, didanosine), 2, 3 -dideoxycytidine (ddC, zalcitabine), 2, 3 -didehydro-2, 3 -dideoxythymidine (d4T, stavudine), (—)-L-3 -thia-2, 3 -dideoxycytidine (3TC, lamivudine), cyclopentenyl V -cyclopropylaminopurine (abacavir, ABC), and (—)-L-5-fluoro-3 -thia-2, 3 -dideoxycytidine ((—)FTC, emtricitabine) (De Clercq 2004a) (Fig. 3). 

There are currently six major antiretroviral drug families (Table 5). Nucleoside reverse transcriptase inhibitors (NRTI) are nucleoside analogs (discussed in more detail in chapter by De Clercq and Neyts, this volume) and were the first approved antiretroviral agents. They include drugs such as AZT, didanosine (ddl), stavudine (d4T), abacavir (ABC), and lamivudine (3TC), the latest used at doses of 300 mg daily as anti-HIV agent (lOOmg/day is the dosing approved for treatment of HBV... 

TC, lamivudine ABC, abacavir APV, amprenavir AST, aspartate aminotransferase ALT, alanine aminotransferase ATV, atazanavir CBC, complete blood cell count D/C, discontinue ddl, didano-sine d4T, stavudine EFV, efavirenz FTC, emtricitabine P1BV, hepatitis B virus F1CV, hepatitis C vims HIV, human immunodeficiency virus IDV, indinavir IV, intravenous LFT, liver function tests LPV/r, lopinavir + ritonavir NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor PT, prothrombin time T.bili, total bilirubin TDF, tenofovir disoproxiI fumarate TPV, tipranavir ULN, upper limit of normal ZDV, zidovudine. 

Drugs that may be affected by peginterferon alfa-2a include theophylline, methadone, and NRTIs (eg, didanosine, zidovudine, stavudine). 

Zidovudine (ZDV or AZT) is a nucleoside reverse transcriptase inhibitor (NRTI) and it was the first anti-HIV agent to be introduced. Other NRTIs include stavudine (d4T), lamivudine (3TC), didano-sine (ddl), abacavir (ABC) and zalcitabine (ddC). Recent additions to this class are emtricitabine (FTC) which has a molecular structure similar to 3TC and tenofovir (TDF) a nucleotide reverse transcriptase inhibitor. 

As a class effect NRTIs are associated with lactic acidosis and hepatic steatosis, conditions which may occur more frequently in pregnant women. The individual NRTIs have their own adverse reactions. Pancreatitis is seen with lamivudine, stavudine, di-danosine and rarely with zalcitabine while the latter three agents can also induce peripheral neuropathy. 

The adverse effects with which stavudine is most frequently associated are headache, diarrhea, skin rash, nausea, vomiting, insomnia, anorexia, myalgia, and weakness. Peripheral neuropathy consisting of numbness, tingling, or pain in the hands or feet is also common with higher doses of the drug. Significant elevation of hepatic enzymes may be seen in approximately 10 to 15% of patients. Lactic acidosis occurs more frequently with stavudine than with other NRTIs. Viral resistance to stavudine may develop, and cross-resistance to zidovudine and didanosine may occur. 

A. The NRTIs can produce a potentially fatal syndrome of lactic acidosis and severe hepatomegaly with hepatic steatosis. Risk factors associated with the development of this syndrome include female sex, obesity, alcoholism, and prolonged exposure to NRTIs. Peripheral neuropathy is a common side effect of some NRTIs (e.g., stavudine., didanosine, and zalcitabine) but not associated with these risk factors. Stevens-Johnson syndrome is rarely associated with NNRTIs, such as nevirapine, and not with these risk factors. Hyperuricemia is not associated with these risk factors. Hypersensitivity reaction may oc-... 

NRTIs) abacavir sulfate didanosine (ddl) lamivudine (3TC) stavudine (d4T) zalcitabine (ddC) zidovudine (AZT)... 

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

In the HIV infected population, further evidence suggested that visceral fat accumulation, dyslipidemia, and insulin resistance are closely linked and associated with antiretroviral treatment, most pronounced with the use of protease inhibitors. In contrast, subcutaneous fat wasting is primarily determined by the choice of nucleoside reverse transcriptase inhibitor (NRTI). Switching studies have supported this notion, since substitution of stavudine has been associated with improvement in fat wasting, while switching a protease inhibitor had no beneficial effect in more than 30 clinical trials (142). 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

Nevirapine = Viramune] (dipyridodiazepinone) [NRTIs in clinical use Abacavir (ABC) Adefovir dipivoxil (9-[2-Phosphonomethoxy)ethyl] -adenine PMEA) AZT Didanosine (= 2, 3 -Dideoxyinosine) Lamivudine Stavudine Zalcitabine (2, 3 -Dideoxycytidine]... 

Preferred Pl-based regimens are lopinavir/ritonavir plus lamivudine or emtricitabine plus another NRTI, usually zidovudine, stavudine or abacavir. Alternative combinations include other Pis with or without ritonavir, and two NRTIs. The combination of a protease inhibitor with ritonavir provides inhibition of cytochrome p450 enzymes and permits less frequent dosing of amprenavir, indinavir, lopinavir and saquinavir. Use of ritonavir in this setting is also known as boosting. ... 

Zidovudine monotherapy was the only available treatment for HIV disease before the 1990s, and was used until 1992. Zidovudine monotherapy has been proven to be efficacious for both the treatment of HAD as well as for HIV-associated minor cognitive/motor disorder (MCMD) (Arendt et al., 1992 Sidtis et al., 1993 Tozzi et al., 1993). Unfortunately, the beneficial effect of zidovudine was transient and an addition of a second NRTI such as dideoxyinosine (ddl), lamivudine (3TC), or dideoxycytidine (ddC), may not further improve psychomotor performance. Stavudine was shown to improve motor performance even after pretreatment with zidovndine (Arendt et al., 2001). A study in 1998, using abacavir versns placebo showed no nenrologic deterioration in the abacavir group as compared with the placebo group (Lanier et al., 2001). However, there was no benefit when abacavir was added to a stable ART, despite good proven CNS penetration. 

There have been reports of HIV-associated nenromnscnlar weakness, probably associated with symptomatic lactic acidosis (Estanislao et al., 2004). Lethal cases have been reported in association with stavudine. Usually the cases have occurred after several months of use of the medication and have been associated with sensory motor neuropathy and elevated serum lactate levels. It is tempting to include this condition as another manifestation of mitochondrial damage indnced by NRTIs. 

Two HIV-1-positive women, both of whom had taken regimens containing stavudine and didanosine for at least 2 years, presented in the third trimester of pregnancy, one with acute lactic acidosis and one with acute pancreatitis and lactic acidosis (32). In the first case both mother and baby died. It is not known whether pregnancy is a risk factor for NRTI-induced lactic acidosis, perhaps in combination with riboflavin deficiency or a metabolic defect in the fetus, or whether NRTIs independently cause lactic acidosis through mitochondrial toxicity. 

Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of medications approved for the management of HIV infection. They are structural analogues of nucleic acids. They undergo intracellular phosphorylation to a triphosphate metabolite and it is this metabolite that is pharmacologically active against reverse transcriptase. Drugs in this class include abacavir, adefovir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine. 

There are currently a variety of nucleoside analogs (i.e., AZT [zidovudine] [3], DDC [zalcitabine] [4], DDI [didanosine] [4], D4T [stavudine] [5], and 3TC [lamivudine] [6] [also designated NRTIs or nucleoside RT inhibitors]) and two nonnucleoside RT inhibitors (i.e., nevirapine [viramune] and BHAP [delavirdine] [also designated NNRTIs] [7,8]) officially approved for treatment of HIV-infected individuals. It should be noted that the NNRTIs are uniquely active against HIV-1, but not HIV-2 RT, whereas the NRTIs inhibit both HIV-1 and HIV-2 RTs. In addition, several other structural classes of... 

Mechanisms Stavudine is a thymidine analog. Depending on specific sites of mutation on the reverse transcriptase gene, resistance may emerge to stavudine alone, or cross-resistance between other NRTIs may occur. 

Antiviral nucleoside inhibitor of HIV reverse transcriptase (NRTI). Used in combination regimens. Tox peripheral neuropathy, pancreatitis. Other NRTIs latnivudine (3TC), stavudine (d4T), zalcitabine (ddC), and the prototype, zidovudine (see below). 

NRTIs are faulty version reverse transcriptase. Reproduction of HIV is stalled when HIV uses NRTI instead of the normal reverse transcriptase. Dmgs within this category include Abacavir (Ziagen, ABC), Abacavir, Lamivudine (Epzicom), Abacavir, Lamivudine, Zidovudine (Trizivir), Didanosine (Videx, ddl, Videx EC), Emtricitabine (Emtriva, FTC, Coviracil), Emtricitabine, Tenofovir DF (Truvada), Lamivudine (Epivir, 3TC), Lamivudine, Zidovudine (Combivir), Stavudine (Zerit, d4T), Tenofovir DF (Viread, TDF), Zalcitabine (Hivid, ddC), and Zidovudine (Retrovir, AZT, AZV). 

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