Nucleoside & Nucleotide Reverse Transcriptase Inhibitors

NUCLEOSIDE & NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS

The NRTIs act by competitive inhibition of HIV-1 reverse tran-scriptase; incorporation into the growing viral DNA chain causes premature chain termination due to inhibition of binding with the incoming nucleotide (Figure 49–4). Each agent requires intra-cytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate form.

Typical resistance mutations include M184V, L74V, D67N, and M41L. Lamivudine or emtricitabine therapy tends to select rapidly for the M184V mutation in regimens that are not fully suppressive. While the M184V mutation confers reduced suscep-tibility to abacavir, didanosine, and zalcitabine, its presence may restore phenotypic susceptibility to zidovudine. The K65R muta-tion is associated with reduced susceptibility to tenofovir, abacavir, lamivudine, and emtricitabine.

All NRTIs may be associated with mitochondrial toxicity, prob-ably 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 thymi-dine analogs zidovudine and stavudine may be particularly associ-ated with dyslipidemia and insulin resistance. Also, some evidence suggests an increased risk of myocardial infarction in patients receiving abacavir or didanosine; this bears further investigation.

ABACAVIR

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 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 once-daily, fixed-dose combination formulation is available. Abacavir is also available in a fixed-dose combination with lamivudine and zidovudine.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 up to 8% of patients receiving abacavir and may be more severe in association with once-daily dosing. Symptoms, which generally occur within the first 6 weeks of therapy, include fever, fatigue, nausea, vomiting, diarrhea, and abdominal pain.

Respiratory symptoms such as dyspnea, pharyngitis, and cough may also be present, and skin rash occurs in about 50% of patients. The laboratory abnormalities of a mildly elevated serum aminotransferase or creatine kinase level may be present but are nonspecific. Although the syndrome tends to resolve quickly with discontinuation of medication, rechallenge with abacavir results in return of symptoms within hours and may be fatal. Testing for the HLA-B5701 allele before initiation of abacavir therapy is recom-mended to identify patients with an increased risk for an abacavir-associated hypersensitivity reaction. Although the positive predictive value of this test is only about 50%, it has a negative predictive value of approximately 100%.

Other potential adverse events are rash, fever, nausea, vomiting, diarrhea, headache, dyspnea, fatigue, and pancreatitis (rare). Abacavir should be used cautiously in patients with existing cardiac risk factors due to a possible increased risk of myocardial events. Since abacavir may lower methadone levels, patients receiving these two agents concurrently should be monitored for signs of opioid withdrawal and may require an increased dose of methadone.

DIDANOSINE

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 neces-sary 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 excretionThe major clinical toxicity associated with didanosine therapy is dose-dependent pancreatitis. Other risk factors for pancreatitis

(eg, alcohol abuse, hypertriglyceridemia) are relative contraindications, and concurrent drugs with the potential to cause pancreatitis, includ-ing zalcitabine, stavudine, ribavirin, and hydroxyurea, should be avoided (Table 49–3). The risk of peripheral distal sensory neuropa-thy, another potential toxicity, may be increased with concurrent use of stavudine, isoniazid, vincristine, or ribavirin. Other reported adverse effects include diarrhea (particularly with the buffered formu-lation), hepatitis, esophageal ulceration, cardiomyopathy, central nervous system toxicity (headache, irritability, insomnia), and hyper-triglyceridemia. Previously asymptomatic hyperuricemia may precipi-tate attacks of gout in susceptible individuals; concurrent use of allopurinol may increase levels of didanosine. Reports of retinal changes and optic neuritis in patients receiving didanosine, particularly in adults receiving high doses and in children, mandate periodic retinal examinations. Lipoatrophy appears to be more common in patients receiving didanosine or other thymidine analogs. As with abacavir, didanosine should be used cautiously in patients with cardiac risk fac-tors due to a possibly increased risk of myocardial infarction.

The buffer in didanosine tablets and powder interferes with absorption of indinavir, delavirdine, atazanavir, dapsone, itracon-azole, and fluoroquinolone agents; therefore, administration should be separated in time. Serum levels of didanosine are increased when co-administered with tenofovir or ganciclovir, and are decreased by atazanavir, delavirdine, ritonavir, tipranavir, and methadone (Table 49–4).

EMTRICITABINE

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 contraindi-cated in young children, pregnant women, patients with renal or hepatic failure, and those using metronidazole or disulfiram. Also, because of its activity against HBV, patients co-infected with HIV and HBV should be closely monitored if treatment with emtricitabine is interrupted or discontinued, owing to the likelihood of hepatitis flare.

Emtricitabine is often co-administered with tenofovir, and a once-daily, fixed-dose combination formulation is available, both alone and in combination with efavirenz. In a recent placebo-controlled study, use of emtricitabine and tenofovir was effective as preexposure prophylaxis, reducing HIV acquisition in men who have sex with men.

Like lamivudine, the M184V/I mutation is most frequently associated with emtricitabine use and may emerge rapidly in patients receiving regimens that are not fully suppressive. Because of their similar mechanisms of action and resistance profiles, the com-bination of lamivudine and emtricitabine is not recommended.

The most common adverse effects observed in patients receiv-ing emtricitabine are headache, diarrhea, nausea, and rash. In addition, hyperpigmentation of the palms or soles may be observed (∼ 3%), particularly in African-Americans (up to 13%). No drug-drug interactions of note have been reported to date.

LAMIVUDINE

Lamivudine (3TC) is a cytosine analog (Figure 49–2) with in vitro activity against HIV-1 that is synergistic with a variety of antiret-roviral nucleoside analogs—including zidovudine and stavudine— against both zidovudine-sensitive and zidovudine-resistant HIV-1 strains. As with emtricitabine, lamivudine has activity against HBV; therefore, discontinuation in patients that are co-infected with HIV and HBV may be associated with a flare of hepatitis.

Oral bioavailability exceeds 80% and is not food-dependent. In children, the average 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 the drug is eliminated unchanged in the urine.

Lamivudine is often co-administered with abacavir, and a once-daily, fixed-dose combination formulation is available. Lamivudine is also available in a fixed-dose combination with zidovudine, either alone or in combination with abacavir.

Lamivudine therapy rapidly selects for the M184V mutation in regimens that are not fully suppressive.Potential adverse effects are headache, dizziness, insomnia, fatigue, dry mouth, and gastrointestinal discomfort, although these are typically mild and infrequent. Lamivudine’s bioavail-ability 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.

STAVUDINE

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. Excretion is by active tubular secretion and glomerular filtration.

The major 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, zalcitabine, vincristine, isoniazid, or ribavirin, or in patients with advanced immunosuppression. Symptoms typically resolve upon discontinuation of stavudine; in such cases, a reduced dosage may be cautiously restarted. Other potential adverse effects are pancreatitis, arthralgias, and elevation in serum aminotransferases. Lactic acidosis with hepatic steatosis, as well as lipodystrophy, appear to occur more frequently in patients receiv-ing stavudine than in those receiving other NRTI agents. Moreover, because the co-administration of stavudine and didanos-ine 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. A rare adverse effect is a rapidly progressive ascending neuromuscu-lar weakness. Since zidovudine may reduce the phosphorylation of stavudine, these two drugs should not be used together. There is no evidence of human teratogenicity in those taking stavudine.

TENOFOVIR

Tenofovir is an acyclic nucleoside phosphonate (ie, nucleotide) analog of adenosine (Figure 49–2). 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 is also approved for the treatment of patients with HBV infection.

Tenofovir disoproxil fumarate 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 once-daily, fixed-dose combination formulation is available, either alone or in combination with efavirenz. A recent placebo-controlled study found that use of emtricitabine and tenofovir was effective as preexposure prophylaxis, reducing HIV acquisi-tion in men who have sex with men. In another placebo-con-trolled study, use of the experimental 1% tenofovir gel as a vaginal microbicide was effective in decreasing the incidence of heterosexual HIV acquisition.

The primary mutation associated with resistance to tenofovir is K65R. Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, flatulence) are the most common adverse effects but rarely require discontinuation of therapy. Since tenofovir is formulated with lactose, these may occur more frequently in patients with lactose intolerance. Other potential adverse effects include headache and asthenia. Tenofovir-associated proximal renal tubulopathy causes excessive renal phosphate and calcium losses and 1-hydroxylation defects of vitamin D, and preclinical studies in several animal spe-cies have demonstrated bone toxicity (eg, osteomalacia). Monitoring of bone mineral density should be considered with long-term use in those with risk factors for or with known osteoporosis, as well as in children. Reduction of renal function over time, as well as cases of acute renal failure and Fanconi’s syndrome, have been reported in patients receiving tenofovir alone or in combination with emtricit-abine. For this reason, tenofovir should be used with caution in patients at risk for renal dysfunction. Tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir. Concurrent use of atazanavir or lopinavir/ ritonavir may increase serum levels of tenofovir (Table 49–4).

Tenofovir is associated with decreased fetal growth and reduc-tion in fetal bone porosity in monkeys. There is significant placental passage in humans.

ZALCITABINE

Zalcitabine (ddC) is a cytosine analog with high oral bioavailabil-ity (87%) and a serum half-life of 1–2 hours (Figure 49–2). An intracellular half-life of 2.6 hours necessitates thrice-daily dosing, which limits its usefulness. Plasma levels decrease by 25–39% when the drug is administered with food or antacids. The drug is excreted renally. Cerebrospinal fluid concentrations are approxi-mately 20% of those in the plasma.

Although a variety of mutations associated with in vitro resis-tance to zalcitabine have been described, phenotypic resistance appears to be rare.

Zalcitabine therapy is associated with a dose-dependent periph-eral neuropathy that can be treatment-limiting in 10–20% of patients but appears to be slowly reversible if treatment is stopped promptly. The potential for causing peripheral neuropathy consti-tutes a relative contraindication to use with other drugs that may cause neuropathy, including stavudine, didanosine, isoniazid, vincristine, and ribavirin. Decreased creatinine clearance or concur-rent use of potential nephrotoxins (eg, amphotericin B, foscarnet, and aminoglycosides) may increase the risk of zalcitabine neuropa-thy, as does more advanced immunosuppression. The other major reported toxicity is oral and esophageal ulceration. 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. Headache, nausea, rash, and arthralgias may occur but tend to be mild or to resolve during therapy. Zalcitabine causes thymic lymphoma in rodents, as well as hydrocephalus at high doses; clinical relevance is unclear. 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

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 serumhalf-life averages 1 hour, the intracellular half-life of the phospho-rylated compound is 3–4 hours, allowing twice-daily dosing. Zidovudine is eliminated primarily by renal excretion following glucuronidation in the liver.

Zidovudine is available in a fixed-dose combination formulation with lamivudine, either alone or in combination with abacavir.Zidovudine was the first antiretroviral agent to be approved and has been well studied. The drug has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals. Efficacy has also been demonstrated in the treatment of HIV-associated dementia and thrombocytope-nia. 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%.

High-level zidovudine resistance is generally seen in strains with three or more of the five most common mutations: M41L, D67N, K70R, T215F, and K219Q. However, the emergence of certain mutations that confer decreased susceptibility to one drug (eg, L74V for didanosine and M184V for lamivudine) may enhance zidovudine susceptibility in previously zidovudine-resistant strains. Withdrawal of zidovudine may permit the rever-sion of zidovudine-resistant HIV-1 isolates to the susceptible wild-type phenotype.The most common adverse effect of zidovudine is myelosup-pression, resulting in macrocytic anemia (1–4%) or neutropenia (2–8%). Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy. Lipoatrophy appears to be more common in patients receiving zidovudine or other thymidine analogs. Less common toxicities include throm-bocytopenia, hyperpigmentation of the nails, and myopathy. High doses can cause anxiety, confusion, and tremulousness. Zidovudine causes vaginal neoplasms in mice; however, no human cases of genital neoplasms have been reported to date. Short-term safety has been demonstrated for both mother and infant.

Increased serum levels of zidovudine may occur with concomi-tant administration of probenecid, phenytoin, methadone, flucon-azole, atovaquone, valproic acid, and lamivudine, either through inhibition of first-pass metabolism or through decreased clearance. Zidovudine may decrease phenytoin levels. Hematologic toxicity may be increased during co-administration of other myelosuppres-sive drugs such as ganciclovir, ribavirin, and cytotoxic agents. Combination regimens containing zidovudine and stavudine should be avoided due to in vitro antagonism.