Antiviral chemotherapy- Control of Viruses

CONTROL OF VIRUSES

ANTIVIRAL CHEMOTHERAPY

A number of antivirals are in use in the UK ( British National Formulary, 2009) for a range of viral infections, including HIV, herpesvirus infections, viral hepatitis, influenza and respiratory syncytial virus. Antiviral treatments are particularly important for persons at high risk, notably immunocompromised patients. Most antivirals are prodrugs that need to be activated within the cell, usually by a kinase, and other cellular enzymes.

Antivirals can act at different stages of the viral replication cycle, with the most effective treatments targeting unique viral enzymes, such as proteases, polymerases and the reverse transcriptase (Table 5.4). A number of targets are being investigated to prevent viral attachment to the host cell: competition for CD4 receptors using a pentapeptide identical in sequence to the terminal amino acids of HIV gp120; inhibition of herpes simplex virus (HSV) ribonucleotide reductase; competition for the cell receptor using a hexapeptide fusion sequence at the N terminus of the influenza haemagglutinin viral receptor. Proteases are particularly important for the uncoating process preventing the release of viral nucleocapsid and for the cleavage of viral polypeptide gene products (e.g. indinavir sulphate). The replication of viral DNA is also a wellexploited target with the use of nucleoside analogues (e.g. idoxiuridine is incorporated into viral and cellular DNA instead of thymidine), nonnucleoside analogues (e.g. nevirapine and foscarnet) and oligonucleotides (Table 5.5). These nucleic acid oligomers with base sequence complementary to conserved regions of proviral DNA have been successful use in the prevention of viral mRNA function. The inhibition of HIV reverse transcriptase has led to the synthesis of many successful antivirals (Table 5.4). The release of the mature virions after the multiplication process can also be blocked. This is the case of neuraminidase inhibitors (e.g. zanamivir and ozaltamivir) preventing the shedding of virions.

Unfortunately, antiviral chemotherapy is associated with a number of problems. Many viral diseases only become apparent after extensive viral multiplication and tissue damage have occurred, delaying treatments. Many antivirals are toxic (e.g. nucleoside analogues) since viral replication often depends on the use of host cell enzymes. There is also scope for improving the pharmacokinetic properties of antivirals, providing a better penetration and retarding drug degradation. The use of prodrugs has improved drug adsorption. Finally, antiviral monotherapy often leads to the development of virus resistance. Emerging HIV resistance has been well documented and current treatments are based on a triple therapy.

HIV

There is no cure for HIV infections as yet. The role of antivirals is to slow or halt disease progression. Since their discovery and use, these drugs (Table 5.4), called antiretrovirals, have considerably prolonged the life expectancy of patients, although not without some important side effects. Antiretroviral treatments aim to reduce HIV plasma levels for as much and as long as possible. Several antiretroviral drugs are usually given together to avoid emerging viral resistance. Initiation of HIV treatment (HAART) is therefore complex and involves two nucleoside reverse transcriptase inhibitors and two nonnucleoside reverse transcriptase inhibitors. Alternative regimens are possible following treatment failure and deterioration of a patient’s condition. The use of antiretrovirals for prophylaxis after exposure is also possible, where a patient has been exposed to HIVcontaminated materials (e.g. needle injury). Such use follows guidelines available locally (e.g. hospital) or nationally (e.g. Department of Health, British Association for Sexual Health and HIV).

The immune reconstitution syndrome and the lipodystrophy syndrome have been associated with antiretroviral treatments. The latter includes fat redistribution, insulin resistance, hyperglycaemia and dyslipidaemia. In addition, these antivirals can be damaging to liver function and have been associated with osteonecrosis following longterm combination treatments. A number of side effects are commonly associated with the use of antiretrovirals: gastrointestinal disturbance, anorexia, pancreatitis, liver damage, dyspnoea, cough, headache, insomnia, dizziness, fatigue, blood disorders, myalgia, arthralgia, rash, urticaria and fever. Protease inhibitors are metabolized by cytochrome P450 and therefore have a significant potential for drug interactions. Nonnucleoside reverse transcriptase inhibitors have been shown to interact with a number of drugs metabolized in the liver. They have been associated with a number of side effects such as rash, psychiatric and central nervous system disturbances, and even fatal hepatitis.

Herpesvirus infections

Herpesviridae is a family of viruses that include the herpes simplex virus, chickenpox (varicella), shingles (herpes zoster) and cytomegalovirus. Mild herpes simplex virus infections in healthy individuals are treated with a topical antiviral drug (e.g. treatment of cold sores). However, for primary herpetic gingivostomatitis a change of diet and analgesics are recommended. For severe infections (e.g. neonatal herpes infection, infection in immunocompromised patients) a systemic antiviral drug is used (Table 5.4). Antiviral treatments for chickenpox are recommended in patients at risk and in neonates to reduce risks of severe diseases. In healthy adults, treatment taken with 24 hours of the appearance of a rash may decrease the duration and severity of symptoms. Systemic antivirals are used to decrease the severity and duration of shingles when taken within 72 hours of the onset of rash. Antivirals for herpes are also associated with a number of side effects which vary depending on the drug, but may include nausea, vomiting, stomach pain, headache, fatigue, rash, and increase in serum and urine uric acid. Antivirals for the treatment of cytomegalovirus are usually given to immunocompromised patients and they tend to be more toxic with notable nephrotoxicity (e.g. cidofovir) and a number of documented side effects (e.g. ganciclovir, foscarnet)

Viral hepatitis

Hepatitis B and C are major causes of viral chronic hepatitis. The initial treatment for acute hepatitis B is with interferons (peginterferon alfa 2a) which may reduce the risk of chronic infection. However, the use of interferon is limited by a poor response rate in patients and frequent relapse. A number of antivirals are licensed for the treatment of chronic hepatitis B (Table 5.4). The choice of antivirals depends upon the initial response to peginterferon alfa, emerging viral resistance, and co  infection with HIV. For the treatment of chronic hepatitis C, a combination of ribavarin and peginterferonalfa is recommended, although the choice and duration of treatment depends upon the viral genotypes and viral load. These antivirals are also associated with a number of side effects including nausea, vomiting, abdominal pain and diarrhoea.

Influenza

Two antivirals are recommended for the treatment of influenza according to the National Institute of Health and Clinical Excellence (NICE) guidelines (Table 5.4). Oseltamivir was extensively used for the prevention and control of the swine flu outbreak in the UK in 2009. Following an intensive use, at least two major limitations in the usefulness of the drug have been identified. First, the drug needs to be taken within a few hours of the onset of symptoms, which proved very difficult with a number of symptoms from mild ‘cold-like’ to severe ‘flulike’ symptoms reported. Second, the side effects, especially in young children and adolescents, have been very severe, prompting many parents to stop the medication, decreasing the willingness to give the antivirals to children who have been possibly exposed to the virus.

Respiratory syncytial virus

Respiratory syncytial virus (RSV) is responsible for severe bronchiolitis notably in infants. A monoclonal antibody (palivizumab) or an antiviral drug (ribavirin) is indicated for the treatment of RSV (Table 5.4). The antiviral is associated with a number of severe side effects.