Zidovudine (azidothymidine; AZT) is a deoxythymidine analog that is well absorbed (63%) and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 60–65% of those in serum. Although the serum half-life averages 1 hour, the intracellular half-life of the phosphorylated compound is 3–4 hours, allowing twice-daily dosing. Zidovudine is eliminated primarily by renal excretion following glucuronidation in the liver.
Zidovudine was the first antiretroviral agent to be approved and has been well studied. Studies evaluating the use of zidovudine during pregnancy, labor, and postpartum showed significant reductions in the rate of vertical transmission, and zidovudine remains one of the NRTI agents recommended for use in pregnant women (Table 49–5). Zidovudine is also recommended as an option for postexposure prophylaxis in individuals exposed to HIV.
The most common adverse effects of zidovudine are macrocytic anemia (1–4%) and neutropenia (2–8%). Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy. A symptomatic myopathy may occur with prolonged use. Lipoatrophy appears to be more common in patients receiving zidovudine or other thymidine analogs. High doses can cause anxiety, confusion, and tremulousness.
Induction or inhibition of glucuronidation may alter serum levels of zidovudine when co-administered with atovaquone, lopinavir/ritonavir, probenecid, or valproic acid. Concurrent stavudine is contraindicated due to competitive inhibition of intracellular phosphorylation.
The NNRTIs bind directly to HIV-1 reverse transcriptase (Figure 49–3), resulting in allosteric inhibition of RNAand DNA-dependent DNA polymerase activity. The binding site of NNRTIs is near to but distinct from that of NRTIs. Unlike the NRTI agents, NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active.
The second-generation NNRTIs (etravirine, rilpivirine) have higher potency, longer half-lives and reduced side-effect profiles compared with older NNRTIs (delavirdine, efavirenz, nevirapine).
Baseline genotypic testing is recommended prior to initiating NNRTI treatment because primary resistance rates range from approximately 2% to 8%. NNRTI resistance occurs rapidly with monotherapy and can result from a single mutation. The K103N and Y181C mutations confer resistance to the first-generation NNRTIs, but not to etravirine or rilpivirine. Other mutations (eg, L100I, Y188C, G190A) may also confer cross-resistance among the NNRTI class. However, there is no cross-resistance between the NNRTIs and the NRTIs; in fact, some nucleoside-resistant viruses display hypersusceptibility to NNRTIs.
As a class, NNRTI agents tend to be associated with varying levels of gastrointestinal intolerance and skin rash, the latter of which may infrequently be serious (eg, Stevens-Johnson syndrome). A further limitation to use of NNRTI agents as a component of antiretroviral therapy is their metabolism by the CYP450 system, leading to innumerable potential drug-drug interactions (Tables 49–3 and 49–4). All NNRTI agents are substrates for CYP3A4 and can act as inducers (nevirapine), inhibitors (delavirdine), or mixed inducers and inhibitors (efavirenz, etravirine).
TABLE 49–4 Clinically significant drug-drug interactions pertaining to two-drug antiretroviral combinations.1