Human immunodeficiency virus zidovudine

Human immunodeficiency virus (HIV) is a retrovirus, i.e. its RNA is converted in human cells by the en me reverse transcriptase to DNA which is incorporated into the human genome and is responsible for producing new HIV particles. Zidovudine (azidothymidine, AZT Fig. 5.22F) is a stmctural analogue of thymidine (Fig. 5.22A) and is used to treat AIDS patients. Zidovudine is converted in both infected and uninfected cells to the mono-, di- and eventually triphosphate derivatives. Zidovudine triphosphate, the aetive form, is a potent inhibitor of HIV replication, being mistaken for thymidine by reverse transeriptase. Premature ehain termination of viral DNA ensues. However, AZT is relatively toxic because, as pointed out above, it is converted to the triphosphate by eellular enzymes and is thus also aetivated in uninfected cells. 

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. 

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. 

Peptidases encoded by many viruses play essential roles at various stages of viral replication, including the coordinated assembly and maturation of virons [7a]. Viral peptidases have become important drug targets in the treatment of viral infections. Of note are inhibitors of proteases of the human immunodeficiency virus (HIV), particularly HIV-1 protease (HIV-1 retropepsin, EC 3.4.23.16) and HIV-2 protease [47-50], Drugs in this class, which include indinavir, ritonavir, and saquinavir, are useful in the treatment of AIDS, especially when administered as a cocktail together with one of the drugs that act on the viral retrotranscriptase (e.g., didanosine, stavudine, and zidovudine (AZT)). 

Zidovudine may result in hematologic toxicity (eg, neutropenia, severe anemia), especially in patients with advanced human immunodeficiency virus (HIV). 

Schulman KA, Lynn LA, Glick HA, Eisenberg JM. Cost-effectiveness of low-dose zidovudine therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection. Ann Intern Med 1991 114 798-802. 

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. 

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. 

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

Domsife RE, St. Clair MH, Huang AT, Panella TJ, Koszalka GW, Burns CL, et al. Anti-human immunodeficiency virus synergism by zidovudine (3 -azidothymi... 

Zidovudine is used to suppress the replication of the human immunodeficiency virus (HIV), which is responsible for aquired immune deficiency syndrome, AIDS (Figure 14.12). According to the World Health Organization, by the beginning of 2005 about 40 million people were infected with HIV and about 20 million people around the world had already lost their lives to AIDS. 

Collier AC, Coombs RW, Schoenfeld DA, Bassett RL. et al. 1996. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS clinical trials group. N Engl J Med 334 1011-1017. 

Connor EM, Sperhng RS, Gelber R, Kiselev P, et al. 1994. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS clinical trials group protocol, 076 study group. NEJM. 331 1173-1180. 

Gulick RM, Mellors JW, Havilir D, Eron JJ, et al. 1997. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. NEJM. 337 734-739. 

Sperling RS, Shapirom DE, Coombsm RW, Todd JA, et al. 1996. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. N Engl J Med. 335 1621-1629. 

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. 

Lertora JJ, Rege AB, Greenspan DL, et al. Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus. Clin Pharmacol Ther 1994 56(3) 272-278. 

In 1997, it was estimated that 30 million adults were infected with the human immunodeficiency virus (HIV) worldwide, with increments of five people infected every minute. It is estimated that approximately 7% of the population of sub-Saharan Africa has been infected. The incubation of the disease is 7 to 8 years. Currently available drugs for acquired immunodeficiency syndrome (AIDS) and HIV are zidovudine, didanosine, lamivudine, and stavudine. The causative agent for AIDS is generally an HIV virus, which is transmitted by sexual contact, blood and blood products, the use of contaminated drug needles, and from mother to fetus. 

AZT, the abbreviation for azidodeoxythymidine, is a drug available to treat human immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syndrome (AIDS). Also known by its generic name zidovudine, AZT represents a chemical success to a different challenge synthesizing agents that combat viral infections. 

Sale M, Sheiner LB, Volberding P, Blaschke TF. Zidovudine response relationships in early human immunodeficiency virus infection. Clin Pharmacol Ther 1993 54 556-66. 

Zidovudine is a synthetic nucleoside analog that blocks replication of the human immunodeficiency virus (HIV) by inhibiting reverse transcriptase. The primary indication for zidovudine administration in newborns is the prevention of vertical transmission of HIV. Like chloramphenicol, zidovudine is eliminated in adults primarily by glucuronide conjugation, suggesting that newborns may have a reduced capacity to eliminate zidovudine. However, unlike... 

Balls F, Pizzo P, Eddy J, Wilfert C, McKinney R, Scott G, Murphy RF, Jaronsinski PF, Falloon J, Poplack DG. Pharmacokinetics of zidovudine administered intravenously and orally in children with human immunodeficiency virus infection. J Pediatr 1989 114 880Hl. 

Mirochnick M, Capparelli E, Dankner W, Sperling RS, vanDyke R, Spec tor SA. Zidovudine pharmacokinetics in premature infants exposed to human immunodeficiency virus. Antimicrob Agents Chemother 1998 42 808-12. 

Boucher FD, Modlin JF, Weller S, Ruff AA, Mirochnick M, Pelton SP, Wilfert C, McKinney R Jr, Crain MJ, Elkins MM, Blum MR, Prober CG. Phase 1 evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus. J Pediatr 1993 122 137-44. 

O Sullivan MJ, Boyer PJ, Scott GB, Parks PW, Weller S, Blum R, Balsley J, Bryson YJ. The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants Phase I Acquired Immunodeficiency Syndrome Clinical Trial Group Study (protocol 082) Zidovudine Collaborative Working Group. Am J Obstet Gynecol 1993 168 1510-6. 

The human immunodeficiency virus replicates by converting its single-standed RNA into double-stranded DNA which is incorporated into host DNA this crucial conversion, the reverse of the normal cellular transcription of nucleic acids, is accomplished by the enzyme reverse transcriptase. Zidovudine, as the triphosphate, was the first anti-HIV drug to be introduced and has a high affinity for reverse transcriptase. It is integrated by it into the viral DNA chain, causing premature chain termination. The drug must be present continuously to prevent viral alteration of the host DNA, which is permanent once it occurs. 

Henry K, Wallace RJ, Belhnan PC, Norris D, Fisher RL, Ross LL, Liao Q, Shaefer MS TARGET Study Team. Twice-daily triple nucleoside intensification treatment with lamivudine-zidovudine plus abacavir sustains suppression of human immunodeficiency virus type 1 results of the TARGET Study. J Infect Dis 2001 183(4) 571-8. 

Yarchoan R, Perno CF, Thomas RV, Klecker RW, AUain JP, Wills RJ, McAtee N, Fischl MA, Dubinsky R, McNeely MC, et al Phase I studies of 2 3 -dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet 1988 1(8577) 76-81. 

Domanski MJ, Sloas MM, Folhnann DA, ScaUse PP 3rd, Tucker EE, Egan D, Pizzo PA. Effect of zidovudine and didanosine treatment on heart function in children infected with human immunodeficiency virus. J Pediatr 1995 127(l) 137-46. 

Lee BL, Safrin S, Makrides V, Gambertogho JG. Zidovudine, trimethoprim, and dapsone pharmacokinetic interactions in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother 1996 40(5) 1231-6. 

Chen SC, Barker SM, Mitchell DH, Stevens SM, O Neill P, Cunningham AL. Concurrent zidovudine-induced myopathy and hepa-totoxicity in patients treated for human immunodeficiency virus (HIV) infection. Pathology 1992 24 109-111. 

Larder, B. A., Chesebro, B., and Richman, D. D. (1990) Susceptibilities of zidovudine-susceptible and -resistant human immunodeficiency virus isolates to antiviral agents determined by using a quantitative plaque reduction assay. Antimicrob. Agents Chemother. 34,436 141. 

Kaye, S., Loveday, C., and Tedder R. S. (1992) A microtitre format point mutaion assay Application to the detection of drug resistance in human immunodeficiency virus type-1 infected patients treadted with zidovudine. J. Med. Virol. 37,241-246. 

The human immunodeficiency virus type 1 (HIV-1) belongs to the family of positive-stranded, enveloped RNA viruses with a DNA intermediate step (retroviruses). Because of the lack of fidelity of the reverse transcriptase (RT), the replication is error-prone, and the infection is characterized by its quasispecies nature. Antiretroviral treatment with such compounds as zidovudine (AZT), zalcitabine (ddC), didanosine (ddl), stavudine (d4T), and lamivudine (3TC) select for quasispecies variants that are resistant to these compounds (1). The detection of these variants is clinically important because they may affect the outcome of the treatment (2). 

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