Zidovudine resistance

The most common adverse effect produced by didanosine is diarrhea. Abdominal pain, nausea, vomiting, anorexia, and dose-related peripheral neuropathy may occur. Pancreatitis occurs rarely, as do hyperuricemia, bone marrow suppression, retinal depigmentation, and optical neuritis. Resistance to didanosine appears to result from mutations different from those responsible for zidovudine resistance. 

Richman DD, Rosenthal AS, Skoog M, Echner RJ, Chou T-C, Sabo JP, et al. BIRG-587 is active against zidovudine-resistant human immunodeficiency virus type 1 and synergistic with zidovudine. Antimicrob Agents Chemother 1991 35 305-308. 

Larder BA, Coates KE, Kemp SD. Zidovudine-resistant human immunodeficiency virus selected by passage in cell culture. J Virol 1991 65 5232-5236. 

Didanosine is a synthetic purine nucleoside analog that inhibits the activity of reverse transcriptase in HIV-1, HIV-2, other retroviruses and zidovudine-resistant strains. A nucleobase carrier helps transport it into the cell where it needs to be phosphorylated by 5 -nucleoiidase and inosine 5 -monophosphate phosphotransferase to didanosine S -monophosphate. Adenylosuccinate synthetase and adenylosuccinate lyase then convert didanosine 5 -monophosphate to dideoxyadenosine S -monophosphate, followed by its conversion to diphosphate by adenylate kinase and phosphoribosyl pyrophosphate synthetase, which is then phosphorylated by creatine kinase and phosphoribosyl pyrophosphate synthetase to dideoxyadenosine S -triphosphate, the active reverse transcriptase inhibitor. Dideoxyadenosine triphosphate inhibits the activity of HIV reverse transcriptase by competing with the natural substrate, deoxyadenosine triphosphate, and its incorporation into viral DNA causes termination of viral DNA chain elongation. It is 10-100-fold less potent than zidovudine in its antiviral activity, but is more active than zidovudine in nondividing and quiescent cells. At clinically relevant doses, it is not toxic to hematopoietic precursor cells or lymphocytes, and the resistance to the drug results from site-directed mutagenesis at codons 65 and 74 of viral reverse transcriptase. 

Zalcitabine (ddC) is a cytosine analog (Figure 49-4) that has synergistic anti-HIV-1 activity with a variety of antiretroviral agents against both zidovudine-sensitive and zidovudine-resistant strains of HIV-1. 

Pellegrin, I. Garrigue, I. Caumont, A. Pellegrin, J. L. Merel, R Schrive, M. H. Bonot, R Pleury, H. Persistence of zidovudine-resistance mutations in HIV-1 isolates from... 

Larder, B. A., Kellam, P and Kemp, S. D. (1991) Zidovudine resistance predicted by direct detection of mutations in DNA from HIV-infected lymphocytes. AIDS 5,137-144. 

C) Point mutations in the gene for reverse transcriptase lead to zidovudine resistance... 

Ikarashi Y, Ohno K, Momma J, et al. (1994) Assessment of contact sensitivity of four thiourea accelerators comparison of two mouse lymph node assays with the guinea pig maximization test. Food Chem Toxicol 32 1067-1072 Ippolito B, Del Poggio P, Arid C, et al. (1994) Transmission of zidovudine-resistant HIV during a bloody fight. JAMA... 

Larder BA, Kemp SD. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science 1989 246 1155-1158. 

Kellam P, Boucher CAB, Larder BA. Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. Proc Natl Acad Sci USA 1992 89 1934-1938. 

Currently, amantadine, vidarabine, trifluridine, idoxuridine, sciclovir, ribavirin, and zidovudine are used as antiviral drugs. An analysis of the mechanisms of action of existing and used viral drugs permits the conclusion to be made that they can increase resistance of... 

Zidovudine was the first drug of the class. It is a dideoxythymidine analog. It has to be phos-phorylated to the active triphosphate. This triphosphate is a competitive inhibitor of HIV reverse transcriptase. By incorporation into viral DNA it also acts as a chain-terminator of DNA synthesis. Mutations in viral reverse transcriptase are responsible for rapidly occurring resistance. Zidovudine slows disease progression and the occurrence of complications in AIDS patients. It is readily absorbed. However, first pass metabolism reduces its oral bioavailability with some 40%. It readily crosses the blood-brain barrier. Plasma protein binding is about 30%. Zidovudine is glucuronidated in the liver to an inactive metabolite. Its elimination half-life is 1 hour. 

Didanosine (2 3 -dideoxyinosine or ddl) is a dideoxynucleoside purine analogue. Its mechanism of action is identical to that of zidovudine and resistance to didanosine is known to occur rapidly in patients who were already treated with zidovudine. Didanosine shows in vitro synergy with zidovudine while their toxicity profiles are different. Oral absorption is decreased by food and didanoside penetrates into the brain to a limited extend. Pancreatitis is the most serious complication. Other adverse reactions include peripheral neuropathy, diarrhoea and other gastrointestinal disturbances. 

One large randomised controlled trial demonstrates that nevirapine given to mothers as a single dose at the onset of labour and to babies as a single dose within 72 hours of birth is more effective than an intrapartum and post-partum regimen of zidovudine. However this regimen can cause NNRTI resistant virus in mother and child. 

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. 

Lamivudine is the best-tolerated NRTI. Its most common adverse effects include headache, malaise, fatigue, and insomnia. Pancreatitis is rare. Gastrointestinal complaints are common with lamivudine-zidovudine therapy but are probably mainly due to the zidovudine component. Lamivudine resistance sometimes occurs early in treatment. Cross-resistance to zal-citabine, didanosine, and abacavir can occur simultaneously. Withdrawal of lamivudine in patients infected with both hepatitis B virus and HIV can cause a flare-up of hepatitis symptoms. 

Abacavir is associated with side effects such as anorexia, nausea, vomiting, malaise, headache, and insomnia. A potentially fatal hypersensitivity reaction develops in approximately 5% of patients, usually early in the course of treatment. Fever and rash are the most common symptoms of this reaction malaise, respiratory symptoms, and gastrointestinal complaints may also occur. Resistance to abacavir may be associated with resistance to zidovudine, didanosine, and lamivudine. 

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,... 

Shafer RW, Kozal MI, Winters M, Iversen AKN, Katenstein DA, Ragni MV, et al. Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations. J Infect Dis 1994 169 722-729. 

Demeter L, Resnick L, Nawaz T, Timpone JG Jr., Batts D, Reichman RC. Phenotypic and genotypic analysis of ateviridine (ATV) susceptibility of HIV-1 isolates obtained from patients receiving ATV monotherapy in a phase I clinical trial (ACTG 187) comparison to patients receiving combination therapy with ATV and zidovudine. In Third Workshop on Viral Resistance. Gaithersburg, Maryland, 1993. 

After oral administration, lamivudine is rapidly absorbed, and its bioavailability is about 86%. Food slows down its absorption, and it is excreted unchanged in the urine. The drug crosses the placenta, and the transfer to placenta does not appear to be altered by zidovudine. Its concentrations are higher in the male genital tract in comparison with the circulation. In combination with other antiretroviral therapy, lamivudine is recommended for the treatment of HIV infection. It inhibits plasma HIV-1 RNA concentrations but resistance develops rapidly when used as monotherapy. 

Resistance to didanosine, due typically to mutation at codon 74 (L74V), may partially restore susceptibility to zidovudine but may confer cross-resistance to abacavir, zalcitabine, and lamivudine. High-level resistance (> 100-fold decreased susceptibility) has not been reported to date. 

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