SAFETY AND TOLERABILITY OF EFAVIRENZ + DIDANOSINE + LAMIVUDINE

The study published by Maggiolo et al (Antiviral Therapy, 2002; 6: 249-53), enrolled 75 patients, who received 300 mg didanosine (chewable buffered tablet), lamivudine 300 mg and efavirenz for a period of 1 year. Seven patients stopped therapy because of adverse events. Rash was reported in two patients. Other events (one case each) included: dizziness, hallucinations, gastric discomfort, gastric intolerance to didanosine, and increased alanine aminotransferase and aspartate amoniotransferase in a patient with documented hepatitis C virus coinfection and alcohol abuse. Dizziness was commonly observed in one-third of patients, but it was self-limiting and did not lead to drug discontinuation except in one case cited above. Elevated liver enzyme levels (grade 1 or 2 WHO) were also occasionally observed; this population had a high proportion of HCV co-infected patients. No other adverse event was reported. Moreover, the gastric discomfort and intolerance reported in this trial could be a consequence of the buffered tablet formulation of didanosine which contains antacid. The new enteric-coated formulation is associated with better gastrointestinal tolerability. Overall, the regimen was generally well tolerated, and the reported adverse events were limited to those known to be related to the study drugs.

In the Senegal Study (9th Congress on Retroviruses and Op Inf 2002, Poster 458 W), six patients experienced efavirenz-related CNS symptoms at the beginning of the treatment (first month). No patient reported altered dreams or hallucinations. One patient experienced an allergic reaction with generalized urticaria and fever after 9 days of treatment, which was probably related to efavirenz. Another patient who was treated for pulmonary tuberculosis with isoniazid and rifampin had an isolated elevation of liver enzymes up to 10-fold the upper normal range after 2 weeks on treatment. The liver enzymes normalized at week 8 when the tuberculosis treatment came to an end. No further biological or clinical event was observed in this patient. Side effects attributable to didanosine were as follows: three episodes of diarrhoea at week 2, two episodes of epigastralgia and six cases of peripheral grade 1 neuropathy. Out of these six cases, 5 had been treated earlier for tuberculosis with isoniazid. This study also had used the buffered formulation of didanosine, which may have contributed to the gastrointestinal side effects.

Efavirenz: The most significant adverse events observed in patients treated with efavirenz are nervous system symptoms, psychiatric symptoms and rash. A few cases of pancreatitis have been described, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients. Increases in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving efavirenz.

Lamivudine: Lamivudine is generally well-tolerated. The majority of events are gastrointestinal - nausea, vomiting, abdominal pain or cramps, and diarrhoea. Like all NRTIs, lactic acidosis may occur with lamivudine.

Didanosine: Pancreatitis and peripheral neuropathy are the major toxicities of didanosine.