Pediatric patients. In pediatric clinical trials, 14% of children on monotherapy and 15% of those on combination therapy with lamivudine developed pancreatitis.
Mucocutaneous manifestations. When mucocutaneous manifestations are seen with Combivir, there appears to be an equal chance that zidovudine or lamivudine may be responsible.
Lamivudine resistance. One of the concerns of lamivudine use for the treatment of chonic hepatitis B is the emergence of a variety of genotypes for lamivudine resistance, particularly in HIV-1/HBV-coinfected patients (97-99).
Abacavir (ABC) is a second-generation NRTI given accelerated FDA approval for use in multi-drug cocktails. It is a synthetic carboxycyclic nucleoside with a 6-cyclopropylamino modification. The structure, brand names, and approved usage are shown in Fig. 2.8. Abacavir is the most powerful nucleoside analogue and one of the most powerful antiretroviral drugs currently available. Its use results in reduction in viral loads and increases in CD4 counts which are unparalleled by any other nucleoside analogue and are similar to most potent PIs (100). Abacavir is normally administered as 300-mg doses twice daily although there is some indication that a 600-mg dose once daily is equally effective (101). In one study, abacavir plus zidovudine and lamivudine raised CD4 counts and lowered plasma HIV RNA to undetectable levels in two-thirds of previously untreated patients (102). In addition, abacavir plus a PI lowered HIV viral loads in the majority of previously
untreated patients to undetectable levels (103,104). However, it should be noted that resistance to zidovudine and lamivu-dine gives cross-resistance to abacavir (105). In patients with lipoatrophy caused by stavudine or zidovudine sensitivity, aba-cavir results in modest increases in limb fat over 24 weeks (73). In patients who have previously been heavily treated with other nucleoside analogues, the addition of abacavir would be ineffective. Abacavir combined with zidovudine and lamivu-dine is now marketed as Trizivir for HAART therapy.
Hypersensitivity reactions. A serious and potentially lethal hypersensitivity reaction to abacavir is seen in 2-5% of patients (106-110). Clinical presentation includes fever to 39-40°C, macules, papules, and urticaria, fatigue, malaise, nausea, vomiting, diarrhea, abdominal pain, arthralgias, cough, and/or dyspnea. These clinical presentations may be associated with increased creatine phosphokinase (CPK), elevated liver function tests, and lymphopenia. These findings usually occur within the first six weeks of therapy. The hypersensitivity reaction usually resolves with cessation of abacavir, but a rechallenge of the drug after this reaction can be fatal. All physicians and patients should be aware of this potentially serous side effect. Therefore, patients taking ABC who develop a skin eruption associated with fever, gastrointestinal symptoms, cough, dyspnea, and constitutional symptoms should be instructed to promptly contact their physician or, if severe, go to the nearest emergency room. Prednisolone may not be effective in treating hypersensitivity from drug toxicity (111).
Vertigo. Many HIV-positive patients report symptoms and signs of inner ear disease. Vertigo can cause significant morbidity and prevent patients from living a normal life. The appearance of vertigo with the introduction and removal of abacavir therapy implies that it may be a causative agent, with mitochondrial toxicity being the suspected mechanism (112).
Agranulocytosis after rash resolution. Several weeks after resolution of a slight rash, one patient developed a fever, sore throat, ulcerated lips, diarrhea, and abdominal pain, probably the result of drug-related antibodies (113).
Hypersensitivity. Hypersensitivity includes not only rash, as described earlier, but anaphylactic shock (114-116). Many severe reactions seem to occur when abacavir is reintroduced after a previous cessation of treatment for hypersensitivity.
Emtricitabine (Emtriva, Coviracil, FTC)
Emtricitabine is a deoxycytidine nucleoside approved for use in combination with other antiretroviral agents (Fig. 2.9). It was tested in combination with didanosine and efavirenz against a stavudine, didanosine, and efavirenz combination. After 24 and 48 weeks, patients receiving the emtricitabine had significantly higher rates of virologic suppression and elevated CD4 levels than the combination recipients. The dosage recommendation at this printing is one daily dose of 200 mg.
Mirochondrial toxicity. Mitochondrial toxicity is often associated with the use of NRTIs. To manage the tissue and drug-related toxicities (i.e., myopathy, peripheral neuropathy, lactic acidosis), interruption of NRTI
therapy with a better-tolerated substitute should be considered (117).
The most common side effects during combination therapy involving emitricitabine include:
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