FIGURE 49–3 Life cycle of HIV. Binding of viral glycoproteins to host cell CD4 and chemokine receptors leads to fusion of the viral and host cell membranes via gp41 and entry of the virion into the cell. After uncoating, reverse transcription copies the single-stranded HIV RNA genome into double-stranded DNA, which is integrated into the host cell genome. Gene transcription by host cell enzymes produces messenger RNA, which is translated into proteins that assemble into immature noninfectious virions that bud from the host cell membrane. Maturation into fully infectious virions is through proteolytic cleavage. NNRTIs, nonnucleoside reverse transcriptase inhibitors; NRTIs, nucleoside/nucleotide reverse transcriptase inhibitors.
The drug is eliminated by both cellular metabolism and renal excretion. Didanosine (ddI) is a synthetic analog of deoxyadenosine. Oral The major clinical toxicities associated with didanosine therapy bioavailability is approximately 40%. Buffered or enteric-coated are peripheral distal sensory neuropathy and dose-dependent pan-formulations are necessary to prevent inactivation by gastric acid. creatitis. Therefore, co-administration with drugs or conditions that Cerebrospinal fluid concentrations of the drug are approximately increase the risk of either (eg, alcohol abuse, hypertriglyceridemia, 20% of serum concentrations. Serum half-life is 1.5 hours, but the pregnancy, zalcitabine, stavudine, isoniazid, vincristine, ribavirin, intracellular half-life of the activated compound is 20–24 hours. and hydroxyurea), should be avoided. Other reported adverse effects include diarrhea (particularly with the buffered formulation), hepatitis, esophageal ulceration, cardiomyopathy, central nervous system toxicity (headache, irritability, insomnia), and hypertriglyceridemia. Concurrent stavudine increases the risk of lactic acidosis. Reports of retinal changes and optic neuritis in patients receiving didanosine, particularly in adults receiving high doses and in children, mandate periodic retinal examinations.
Increased levels of didanosine when administered with tenofovir necessitate dose reduction. Concurrent allopurinol or ribavirin is contraindicated. The buffer in didanosine tablets interferes with the absorption of delavirdine and nelfinavir, necessitating separation in time. The chewable tablets contain phenylalanine, which can be harmful to patients with phenylketonuria.
Emtricitabine (FTC) is a fluorinated analog of lamivudine with a long intracellular half-life (>24 hours), allowing for once-daily dosing. 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.
Emtricitabine is one of the NRTI agents recommended for use in pregnancy (Table 49–5). The combination of tenofovir and emtricitabine is recommended as pre-exposure prophylaxis to reduce HIV acquisition in high-risk persons.
Both emtricitabine and lamivudine may select for the M184V/I mutation and therefore should not be used together.
The most common adverse effects observed in patients receiving emtricitabine are headache, diarrhea, nausea, and rash. Hyperpigmentation of the palms or soles may be observed (~ 3%), particularly in African Americans (up to 13%). Clinically significant drug-drug interactions involving emtricitabine have not been identified. Due to its activity against HBV, exacerbation of HBV may occur if therapy is interrupted or discontinued in patients co-infected with HIV.