Antiretroviral Agents

Antiretroviral Agents

These drugs are used mainly in the treatment of AIDS and T-cell leukaemias. They have a similar mechanism of action i.e. they are first converted by cellular kinases into their active triphosphate form, which inhibits viral reverse transcriptase, thereby terminating viral DNA chain formation.

Zidovudine (AZT, ZDV)

Zidovudine (azidothymidine) was the first drug approved for use in the treatment of HIV infection, and has been around since 1987. It is usually given orally, but can also be administered as an intravenous infusion.

Adverse effects include serious anaemia, leucopenia, nausea, headache, myalgia, vomiting, diarrhoea, taste perver-sion, sweating, vertigo, dyspnoea, chest pain, and increased urinary frequency. Nausea and vomiting are common side effects of zidovudine therapy, occurring in 66 of 145 (46%) of AIDS patients during clinical trials. Dark blue or brownish transverse fingernail and toenail discolouration may occur after weeks of zidovudine therapy.

Several cases of acute overdose with zidovudine have been reported in the literature with minimal effects. Following acute overdoses of up to 50 grams in both adults and children, with no fatalities, some patients experienced non-specific CNS symptoms. Acute overdose may cause seizures, nystagmus, ataxia, nausea, and headache. Based on the adverse drug reac-tion profile, bone marrow suppression might be expected to occur after overdosage.

Chronic effects of zidovudine therapy may include a syndrome of fatal lactic acidosis and hepatic failure. Granulocytopenia has been the most frequently reported adverse effect following thera-peutic use, and is directly related to dose and duration of therapy. Anaemia has been the second most common adverse reaction during therapy. Polymyositis-like syndrome has been reported in several patients on months of therapy.

Treatment involves symptomatic and supportive measures. Complete blood counts (CBC’s) should be monitored inten-sively in patients who overdose on zidovudine. Arterial blood gases and hepatic function should be monitored in symptomatic patients. Intensive monitoring for bone marrow suppression is recommended following overdosage. In the presence of bone marrow suppression, transfusions and protective measures for granulocytopenia may be needed until recovery of bone marrow function.

Severe metabolic acidosis (arterial pH less than 7.1) should be corrected with IV sodium bicarbonate (a reasonable starting dose is 1 to 2 mEq/kg). Monitor blood gases to guide bicarbo-nate therapy. Monitor serum sodium to avoid overload. Some investigators suggest that there could be a riboflavin deficiency in AIDS patients taking these drugs, resulting in lactic acidosis and hepatic steatosis. These authors have treated patients with this syndrome with riboflavin 50 mg and reported clinical recovery and return of serum lactate levels to normal.

Haemodialysis and haemoperfusion do not appear to be beneficial.

Didanosine (Dideoxynosine, DDI)

Didanosine is a purine nucleoside which is recommended for the treatment of zidovudine-resistant/intolerant cases of HIV infection. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5-triphos-phate (ddATP). The active metabolite inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5-triphosphate (dATP), and by its incorporation into viral DNA. Viral DNA growth is terminated. It can be administered orally (though food decreases absorption significantly), or intravenously.

Adverse effects include painful peripheral neuropathy and pancreatitis. Painful distal symmetrical peripheral neuropathy is a major dose -limiting toxicity of didanosine. It often progresses to severe, opioid-requiring pain. It generally has an abrupt onset and rapid progression. Histologically, axonal degeneration is evident. The frequency is related to didanosine dose and stage of disease. The painful neuropathic syndrome consists of tingling, burning, or aching in the lower extremities, particularly at night-time but gradually progressing to interfere with walking, sleep, and routine daily activities. There are no associated neurologic deficits except for occasional diminished vibratory sensation and decreased ankle reflexes.

The major toxicity of didanosine is pancreatitis, which has been fatal in some cases, and has been posted as a warning in the product insert. Pancreatitis is often accompanied by severe lactic acidosis. Frequency of pancreatitis is dose-related, with an incidence in phase 3 adult studies ranging from 1 to 10%, and in paediatric studies up to 13%. Other nucleoside reverse transcriptase inhibitors have been reported to cause pancrea-titis, however, it appears most often following didanosine or stavudine therapy.

Less common effects comprise rhinitis, epistaxis, rhinor-rhoea, sinusitis, pharyngitis, abdominal pain, diarrhoea, rash, heart failure, hepatitis and hepatic failure, CNS disturbances (convulsions), and retinal depigmentation and optic neuritis (in children). Hepatomegaly with steatosis, which may be fatal, has been reported with the therapeutic use of didanosine, especially in women. Arrhythmias were reported in 6% of paediatric patients in phase I trials. Dermatologic effects include the development of skin rashes, eczema, impetigo, pruritus, exco-riation, sweating, erythema, and Stevens-Johnson syndrome.

Overdose experience is limited. The major toxicity of didanosine is pancreatitis. Possible effects of overdose (based on extrapolation from adverse effects) include pancreatitis, convulsions, peripheral neuropathy, diarrhoea, hyperuri-caemia, hepatic dysfunction, and lactic acidosis. Treatment is mainly supportive. Monitor the following laboratory tests in symptomatic patients after an overdose: cardiac monitoring, aminotransferases, complete blood count, and levels of elec-trolytes, platelets, creatine kinase, and amylase, acid base status. Convulsions may rarely occur and should be treated aggressively. Cardiac failure, pancreatitis, hepatic dysfunction, and peripheral neuropathy must be anticipated, and treated on conventional lines as and when they arise. Haemodialysis may be beneficial.

Stavudine

Stavudine is a thymidine nucleoside analogue which is used in HIV patients who are intolerant to other drugs. It is well absorbed on oral administration, and is metabolised in the liver, and probably also via degradation and salvage by other pyrimidine pathways which may contribute to its elimination.

The main adverse effect is painful sensory neuropathy. The most serious presentation of nucleoside analogue toxicity with chronic therapeutic administration is mitochondrial toxicity leading to lactic acidosis, with or without hepatic microsteatosis. Pancreatitis, neuropathy and myopathy often accompany the syndrome. Lactic acidosis has been reported in patients receiving both single and dual nucleoside analogue (NRTI) regimens for HIV infection and may lead to multiorgan failure. This most commonly occurs in persons on prolonged (> 6 months) therapy. The manufacturers of lamivudine and stavudine have issued warnings concerning lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, with the therapeutic use of these drugs. The syndrome of lactic acidosis and hepatic steatosis, a complication of nucleoside reverse-transcriptase inhibitors, may be associated with ribo-flavin deficiency in these patients.

Peripheral lipoatrophy or lipomata, histologically seen as apoptosis, has been reported in up to 50% of NRTI treated patients, with stavudine causing more reported cases than the other NRTIs.

Overdose experience is limited. Based on toxicities seen with chronic (therapeutic) administration, acute overdose may be associated with peripheral neuropathies and hepa-totoxicity.

Treatment is mostly supportive. Complete blood counts (CBCs) should be monitored frequently in patients who overdose on nucleoside analogs. Monitor serum electrolytes, renal and liver function tests, pancreatic enzymes and CPK.

Convulsions may occur and should be treated aggressively. Cardiac failure has been reported and cardiac monitoring is recommended. Hepatic failure may occur and liver function should be monitored. Peripheral neuropathies, which are gener-ally reversible on drug withdrawal, may occur and should be treated with pain management as needed.

Zalcitabine

It is a cytosine nucleoside analogue which has a potency similar to zidovudine, but suffers from the same adverse effect (painful sensory neuropathy) as didanosine and stavudine. Severe peripheral neuropathy necessitating discontinuation of therapy occurs in about 10% of patients. After stopping zalcitabine, some patients experience a period of symptom intensification, referred to as “coasting”, lasting for several weeks to months. Pancreatitis has also been reported. Lactic acidosis, with or without hepatic microsteatosis can also occur. Ototoxicity, mouth ulcers, oesophageal ulceration, hepatomegaly, cardiac arrhythmias, neutropenia, cutaneous eruptions, arthralgia, dizziness, confusion, amnesia, and depression are the other adverse effects reported.

Overdose experience is limited. Based on toxicities seen with chronic (therapeutic) administration, acute overdoses may be expected to result in peripheral neuropathies, hepatic dysfunction, gastrointestinal effects, elevated pancreatic enzymes, and possibly convulsions.

Treatment is on the same lines as for stavudine (vide supra).

Lamivudine

It is a nucleoside analogue in which the 3/ carbon of the ribose of zalcitabine has been replaced by sulfur, and shows promise as a new anti-AIDS drug with relatively low toxicity. However, diarrhoea, which does not appear to be dose-dependant, may be severe enough to necessitate discontinuance of medication, and may be accompanied by nausea and vomiting. Skin rashes and/ or pruritus, hair loss, oral ulcerations/lesions, anaemia, throm-bocytopenia, and neutropenia have also occurred. Drowsiness and convulsions are a rare occurrence but have been reported following therapy with lamivudine. Based on toxicities seen with chronic (therapeutic) administration, acute overdoses may be expected to result in bone marrow suppression, peripheral neuropathies and gastrointestinal effects.