ddC


Mutations associated with drug resistance:	Mutations at positions T69D, 65 (intermediate/high level resistance), 184, 75, 74, 69 (low level resistance), 219, 215, 210, 118, 116, 77, 70, 67, 62, 44 and 41 (contributes to resistance) may all contribute, to some degree, to ddC resistance. T69D confers about 5-10 fold ddC resistance and is the most common RT mutation in patients receiving ddC [Fitzgibbon JE, et al. 1992]. The effects of other mutations at codon 69, including T69N, T69S and T69I are not known, though it is likely that they play a role in drug resistance because they are not naturally occurring polymorphisms [Shafer RW, et al. 1999]. L74V, which occurs more commonly during ddI therapy, also confers about 5- to 10-fold resistance to ddC [St. Clair CM, et al. 1991]. K65R and V75T occur rarely and confer about 5-fold ddC resistance [Zhang D, et al. 1994; Lacey SF, et al. 1994; Gu Z, et al. 1994]. Q151M together with its associated multinucleoside resistance mutations (see AZT and ddI resistance summaries) causes the highest levels of ddC resistance (20- to 30-fold) [Shirasaka T, et al. 1995; Iversen AK, et al. 1996]. The b3-b4 insertion causes 5- to 10-fold levels of ddC resistance, which are increased to higher levels in the presence of AZT-resistance mutations [Winters MA, et al. 1998]. Intermediate levels of ddC resistance (3- to 5-fold) have been documented in the setting of classical AZT resistance mutations together with noncanonical RT mutations [Shafer RW, et al. 1998].
Phenotypic resistance:	Resistance to ddC is easier to detect than resistance to ddI. The dynamic range between wild-type HIV-1 isolates and the most drug-resistant mutant isolates is about 20- to 30-fold.
Cross-resistance:	The mutations causing ddC resistance are nearly identical to those that cause ddI resistance. The main exception is that T69D has been reported more frequently in patients receiving ddC, while L74V and M184V have been reported more frequently in patients receiving ddI. K65R and V75T occur rarely with both. Q151M-mediated multinucleoside resistance, the b3-b4 insertion, and the combination of multiple AZT resistance mutations together with multiple noncanonical mutations are other genetic patterns associated with resistance to both drugs. (See the ddI resistance summary for a review of how resistance to ddI and ddC overlap with other NRTIs.)
Emergence of resistance in vivo:	As noted above, T69D is the most common mutation occurring during monotherapy, but the spectrum of mutations is probably more complex during combination therapy. There are few published complete RT sequences (<10) from patients receiving ddC either alone or in dual NRTI combinations [Shafer RW, et al. 1999]. In general, the clinical use of ddC has declined in recent years, making it difficult to gather additional information on this topic.
Clinical correlates of drug resistance:	Because ddC is a relatively weak NRTI and because it has been seldom used alone, it has been difficult to correlate the development of specific mutations with loss of clinical efficacy.
Additional drug information:	Hivid (zalcitabine) prescribing information available at: http://www.rocheusa.com/products/hivid/pi.html

Bibliography:

Fitzgibbon JE; Howell RM; Haberzettl CA; Sperber SJ; Gocke DJ; Dubin DT. Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine. Antimicrob Agents Chemother. 1992 Jan;36(1):153-7.

Gu Z; Gao Q; Fang H; Salomon H; Parniak MA; Goldberg E; Cameron J; Wainberg MA. Identification of a mutation at codon 65 in the IKKK motif of reverse transcriptase that encodes human immunodeficiency virus resistance to 2',3'-dideoxycytidine and 2',3'-dideoxy-3'-thiacytidine. Antimicrob Agents Chemother. 1994 Feb;38(2):275-81.

Iversen AK; Shafer RW; Wehrly K; Winters MA; Mullins JI; Chesebro B; Merigan TC. Multidrug-resistant human immunodeficiency virus type 1 strains resulting from combination antiretroviral therapy. J Virol. 1996 Feb;70(2):1086-90.

Lacey SF; Larder BA. Novel mutation (V75T) in human immunodeficiency virus type 1 reverse transcriptase confers resistance to 2',3'-didehydro-2',3'-dideoxythymidine in cell culture. Antimicrob Agents Chemother. 1994 Jun;38(6):1428-32.

Shafer RW; Stevenson D; Chan B. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res. 1999;27(1):348-52.

Shafer RW, Winters MA, Palmer S, Merigan TC. Multiple concurrent reverse transcriptase and protease mutations and multidrug resistance of HIV-1 isolates from heavily treated patients. Ann Intern Med. 1998;128:906-11.

Shirasaka T, Kavlick MF, Ueno T, et al. Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. Proc.Natl.Acad.Sci.U.S.A. 1995;92:2398-402.

St Clair MH, Martin JL, Tudor-Williams G, et al. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science. 1991;253:1557-9.

Winters MA, Coolley KL, Girard YA, et al. A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1 confers resistance to multiple nucleoside inhibitors. J Clin Invest. 1998;102:1769-75.

Zhang D; Caliendo AM; Eron JJ; DeVore KM; Kaplan JC; Hirsch MS; D'Aquila RT. Resistance to 2',3'-dideoxycytidine conferred by a mutation in codon 65 of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 1994 Feb;38(2):282-7.

(click titles to view abstracts)

Go to Mutation Matrices: PI, NRTI, NNRTI