Jo

ch2oh

FIGURE 50-2 Structures and mechanism of nucleoside and nucleotide reverse transcriptase inhibitors.

harbor HIV. Nucleoside and nucleotide analogs must enter cells and undergo phosphorylation to generate synthetic substrates for the enzyme (Figure 50-3). The fully phosphorylated analogs block replication of the viral genome both by competitively inhibiting incorporation of native nucleotide and by terminating elongation of nascent proviral DNA because they lack a 3'-hydroxyl group.

All but one of the drugs in this class is a nucleoside that must be triphosphorylated at the 5'-hydroxyl to exert activity. The sole exception, tenofovir, is a nucleoside monophosphate analog that requires two phosphates for full activity. These compounds inhibit both HIV-1 and HIV-2 and several have broad-spectrum activity against other retroviruses; some are also active against hepatitis B virus (HBV) or the herpesviruses.

Although many of the drugs in this class induce only a modest decrease in HIV RNA when used as monotherapy, several have favorable safety and tolerability profiles that make them a valuable component of combination regimens.

Table 50-2

Pharmacokinetic Properties of Nucleoside and Nucleotide Reverse Transcriptase Inhibitors*

Parameter

Zidovudine

Lamivudine

Stavudine^

Didanosine*

Abacavir

Zalcitabine

Tenofovir

Emtricitabine

Oral bioavailability, %

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