Lamivudine or emtricitabine therapy tends to select rapidly for the M184V mutation in regimens that are not fully suppressive; however, although this mutation confers reduced susceptibility to abacavir, didanosine, and zalcitabine, its presence may restore phenotypic susceptibility to zidovudine. The K65R mutation is associated with reduced susceptibility to tenofovir, abacavir, lamivudine, and emtricitabine.
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, recent evidence suggests an increased risk of myocardial infarction in patients receiving abacavir or didanosine; this bears further investigation.
Abacavir is a guanosine analog (Figure 49–2) that is well absorbed following oral administration (83%) and is unaffected by food. The serum half-life is 1.5 hours; the intracellular half-life of 3.3 hours necessitates twice-daily dosing. The drug undergoes hepatic glucuronidation and carboxylation. Cerebrospinal fluid levels are approximately one third those of plasma.
Abacavir is often co-administered with lamivudine, and a combination formulation is available.
High-level resistance to abacavir appears to require at least two or three concomitant mutations and thus tends to develop slowly.
Hypersensitivity reactions, occasionally fatal, have been reported in 3–5% of patients receiving abacavir. Symptoms, which generally occur within the first 6 weeks of therapy, include fever, malaise, nausea, vomiting, diarrhea, and anorexia. Respiratory symptoms such as dyspnea, pharyngitis, and cough may also be present, and skin rash occurs in about 50% of patients. Abacavir should be used cautiously in patients with existing cardiac risk factors due to a possible increased risk of myocardial events.
Didanosine (ddI) is a synthetic analog of deoxyadenosine (Figure 49–2). Oral bioavailability is approximately 40%; dosing on an empty stomach is optimal, but buffered formulations are necessary to prevent inactivation by gastric acid (Table 49–3). Cerebrospinal fluid concentrations of the drug are approximately 20% of serum concentrations. Serum half-life is 1.5 hours, but the intracellular half-life of the activated compound is as long as 20–24 hours. The drug is eliminated by both cellular metabolism and renal excretion.
The major clinical toxicity associated with didanosine therapy is dose-dependent pancreatitis. Other risk factors for pancreatitis (eg, alcoholism, hypertriglyceridemia) are relative contraindications, and other drugs with the potential to cause pancreatitis, including zalcitabine, stavudine, and hydroxyurea, should be avoided (Table 49–3). Other reported adverse effects include peripheral distal sensory neuropathy, diarrhea (particularly with the buffered formulation), hepatitis, esophageal ulceration, cardiomyopathy, central nervous system toxicity (headache, irritability, insomnia), and hypertriglyceridemia. Asymptomatic hyperuricemia may precipitate attacks of gout in susceptible individuals.
Emtricitabine (FTC) is a fluorinated analog of lamivudine with a long intracellular half-life (> 24 hours), allowing for once-daily dosing (Figure 49–2). Oral bioavailability of the capsules is 93% and is unaffected by food, but penetration into the cerebrospinal fluid is low. Elimination is by both glomerular filtration and active tubular secretion. The serum half-life is about 10 hours.
The oral solution, which contains propylene glycol, is contraindicated in young children, pregnant women, patients with renal or hepatic failure, and those using metronidazole or disulfiram. The most common adverse effects observed in patients receiving emtricitabine are headache, diarrhea, nausea, and asthenia. In addition, hyperpigmentation of the palms and/or soles may be observed (~ 3%), particularly in blacks (up to 13%). No drug-drug interactions of note have been reported to date.
Lamivudine (3TC) is a cytosine analog (Figure 49–2) with in vitro activity against HIV-1 that is synergistic with a variety of antiretroviral nucleoside analogs—including zidovudine and stavudine—against both zidovudine-sensitive and zidovudine-resistant HIV-1 strains. Oral bioavailability exceeds 80% and is not food-dependent. In children, the mean cerebrospinal fluid:plasma ratio of lamivudine was 0.2. Serum half-life is 2.5 hours, whereas the intracellular half-life of the triphosphorylated compound is 11–14 hours. Most of lamivudine is eliminated unchanged in the urine.
Potential adverse effects are headache, dizziness, insomnia, fatigue, and gastrointestinal discomfort, although these are typically mild. Lamivudine's bioavailability increases when it is co-administered with trimethoprim-sulfamethoxazole. Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another; therefore, their concurrent use should be avoided if possible. Short-term safety of lamivudine has been demonstrated for both mother and infant.
The thymidine analog stavudine (d4T) (Figure 49–2) has high oral bioavailability (86%) that is not food-dependent. The serum half-life is 1.1 hours, the intracellular half-life is 3.0–3.5 hours, and mean cerebrospinal fluid concentrations are 55% of those of plasma
The major dose-limiting toxicity is a dose-related peripheral sensory neuropathy. The incidence of neuropathy may be increased when stavudine is administered with other neuropathy-inducing drugs such as didanosine and zalcitabine, or in patients with advanced immunosuppression. Lactic acidosis with hepatic steatosis, as well as lipoatrophy, appear to occur more frequently in patients receiving stavudine than in those receiving other NRTI agents. Moreover, because the co-administration of stavudine and didanosine may increase the incidence of lactic acidosis and pancreatitis, concurrent use should be avoided. This combination has been implicated in several deaths in HIV-infected pregnant women
TEnofoviR: Like the nucleoside analogs, tenofovir competitively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA. However, only two rather than three intracellular phosphorylations are required for active inhibition of DNA synthesis.
Tenofovir disopoxilfumarate is a water-soluble prodrug of active tenofovir. The oral bioavailability in fasted patients is approximately 25% and increases to 39% after a high-fat meal. The prolonged serum (12–17 hours) and intracellular half-lives allow once-daily dosing. Elimination occurs by both glomerular filtration and active tubular secretion.
Tenofovir is often co-administered with emtricitabine, and a combination formulation is available. Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, flatulence) are the most common adverse effects but rarely require discontinuation of therapy. Tenofovir-associated proximal renal tubulopathy causes excessive renal phosphate and calcium losses and 1-hydroxylation defects of vitamin D. Tenofovir is associated with decreased fetal growth and reduction in fetal bone porosity in monkeys. There is significant placental passage in humans.
Zalcitabine (ddC) is a cytosine analog with high oral bioavailability (87%) and a serum half-life of 1–2 hours. Intracellular half-life of 2.6 hours necessitates thrice-daily dosing, which limits its usefulness (Figure 49–2). Plasma levels decrease by 25–39% when the drug is administered with food or antacids. The drug is excreted renally. Cerebrospinal fluid concentrations are approximately 20% of those in the plasma.
Zalcitabine therapy is associated with a dose-dependent peripheral neuropathy that can be treatment-limiting in 10–20% of patients but appears to be slowly reversible if treatment is stopped promptly. The other major reported toxicity consists of oral and esophageal ulcerations. Pancreatitis occurs less frequently than with didanosine administration, but co-administration of other drugs that cause pancreatitis may increase the frequency of this adverse effect. The AUC of zalcitabine increases when co-administered with probenecid or cimetidine, and bioavailability decreases with concurrent antacids or metoclopramide. Lamivudine inhibits the phosphorylation of zalcitabine in vitro, potentially interfering with its efficacy
Zidovudine (azidothymidine; AZT) is a deoxythymidine analog (Figure 49–2) 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 1.1 hours, 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.
In pregnancy (Table 49–5), a regimen of oral zidovudine beginning between 14 and 34 weeks of gestation, intravenous zidovudine during labor, and zidovudine syrup to the neonate from birth through 6 weeks of age has been shown to reduce the rate of vertical (mother-to-newborn) transmission of HIV by up to 23%
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