ANTIVIRAL DRUGS DR/AZZA BARAKA

ANTIVIRAL DRUGS

Viruses are obligate intracellular parasites; their replication depends on synthetic processes of the host cell. Because viruses share many of the metabolic processes of the host cell, it is difficult to find drugs that are selective for the pathogen. However, there are some enzymes that are virus-specific and these are potential targets for drugs. Most currently available drugs are only effective while the virus is replicating. Antiviral drugs do not eliminate non replicating viruses. Clinical failure of antiviral therapy may occur with drugsensitive viruses in immunocompromized patients or following emergence of resistant viruses.

ANTIHERPETIC Acyclovir is an acyclic guanosine derivative (guanine nucleoside analogue (that lacks 3 hydroxyl on the side chain. Clinical activity against: HSV1 , HSV2 and against varicellazoster virus and minimal against CMV. Valacyclovir is the L-valyl ester prodrug of acyclovir. Gancyclovir mainly used in treatment of CMV.

ANTIHERPETIC DRUGS

 N.B.

For elongation of DNA chain :The nucleotides are joined together by phosphate-ester bonds between the -OH on carbon #3 of one pentose and the -OH on carbon #5 of the next pentose which is referred to as the 3'-5' phosphate linkage.

Acyclovir is a nucleoside analogue. 1. Acyclovir, therefore, requires three phosphorylation steps for activation. It is converted first to monophosphate derivative by the virus-specified thymidine kinase (VTK) and then to the di and triphosphate compounds by the hosts cellular enzyme. Because it requires the VTK for the initial phosphorylation, it is selectively activated and triphosphate accumulates, only in infected cells. 2. Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms: A- competitive inhibition with deoxy GTP for the viral DNA polymerases with binding to the DNA template as an irreversible complex, and B- chain termination following incorporation into the viral DNA. Acyclovir has affinity for viral DNA polymerases about 300 times more than host cell DNA polymerases and this also accounts for selective toxicity of acyclovir.

Mechanism of Action.

 Remember:

Two viral proteins virus-specified thymidine kinase (VTK) and viral DNA polymerases

Therapeutic Uses
Acyclovir can be used topically , orally and intravenously. 1-Topical acyclovir is used in treatment of: -Very localized herpes simplex. 2-Oral acyclovir is used : a-Prohylactically in: Patients who will receive immunosuppressive drugs and are at risk of herpes virus infection due to reactivation of a latent virus.

b- Therapeutically in: i. Treatment of herpes simplex. ii.Treatment of chicken pox in immunocompromized patients. iii-Treatment of Herpes zoster in immunocompetent patients. Intravenous acyclovir is used in treatment of: a- Viscerally disseminating herpes simplex . b- Herpes zoster in severely immunocompromised patients.

Adverse Effects: 1. GIT: nausea and diarrhea. 2. Renal insufficiency that especially occurs by rapid infusion and can be avoided by good rehydration. 3. Neurotoxicity (especially if patient has renal impairment). 4. Phlebitis if extravasated after I.V. administration).

Gancyclovir
Therapeutic Uses: Treatment of CMV infections Preemptive treatment of CMV: This is an attempt to prevent the progression of asymptomatic infection into CMV disease. Prophylaxis of CMV infection in immunocompromized patients. Side effects: bone marrow supprrssion If resistance to gancyclovir give: foscarnet

II- ANTIRETROVIRAL DRUGS

Approved Antiretroviral agents

A- Nucleoside Reverse transcriptase inhibitors(NRTI (e.g. zidovudine & lamivudine B -Non-nucleoside Reverse transcriptase inhibitors (nNRTIs)e.g. nevirapine C- Protease inhibitors e.g. Indinavir. D-Fusion (Entry) Inhibitors e.g. enfuvirtide (Fuzeon)

HAART
Highly active anti-retroviral therapy HAART is a combination of three antiretroviral drugs belonging to first three groups. This therapy has changed the prognosis of patients infected with HIV.

ZIDOVUDINE Therapeutic Uses

1-Treatment of HIV which results in: 1. Decrease in HIV viral load. 2. Decrease in opportunistic infections because of an increase in CD4 count . 3. Increase in the weight of the patient. 4. Prolongation of survival. N.B. Eradication of HIV infection cannot be

achieved with available antiretroviral regimens

2- Reduce the incidence of vertical transmission of HIV from mother to newborn.

ZIDOVUDINE
Adverse Effects: 1. BM suppression leading to Leucopenia and anaemia. 2. Neurotoxicities. 3. Myopathy 4. Lactic acidosis. (Due to mitochondrial dysfunction with a shift toward anaerobic metabolism leading to lactate overproduction).

When to treat an HIV patient with antiretroviral drugs: If T-cell count is 350 or below, treatment is recommended. Treatment is generally not recommended if T-cell count is above 350. Treatment should be initiated regardless of CD4 count: 1. If very high viral load. 2. If there are symptoms. 3. Patients with the following conditions: pregnancy , HIVassociated nephropathy and hepatitis B virus (HBV) coinfection.

III. ANTIINFLUENZA VIRUS AGENTS

Neuraminidase

inhibitors: e.g. Oseltamivir(Tamiflu) and Zanamivir (Relenza) Both oseltamivir and zanamivir work by inhibiting an enzyme called neuraminidase that the virus needs to replicate, but they act on different parts of the enzyme and resistance to one drug does not confer resistance to the other.

Adverse effects: 1-Nausea, vomiting, diarrhea and abdominal pain are the most frequent adverse effect 2-Headache, vertigo and insomnia. 3-Bronchospasm and a decline in lung function have been reported after usage of zanamivir in patients with underlying pulmonary conditions such as asthma. Because of the risk of these respiratory adverse events, zanamivir is not generally recommended for the treatment of patients with underlying airways disease

IV- ANTIHEPATITIS DRUGS

Antihepatitis C

Antihepatitis B

HCV Lifecycle
Receptor binding and endocytosis Fusion and uncoating (+) RNA
ER lumen
LD

Transport and release

LD

Virion assembly

Translation and protease polyprotein processing

LD

Membranous web ER lumen

polymerase RNA replication

Goals of treatment of chronic hepatitis B

The goals of treatment of chronic hepatitis B are (i) Decrease viral load, to slow the progression of fibrosis to cirrhosis; (ii) to prevent hepatic failure; and (iii)to prevent the development of hepatocellular carcinoma (HCC). There is no cure for hepatitis B. HBV is maintained in a replicative form in the hepatocyte nuclei termed covalently closed circular DNA (cccDNA) which serves as a template for viral transcription. Current therapies have little or no direct effect on cccDNA. Hence, viral relapse occurs once antiviral medications are discontinued.

II-i-Anti hepatitis B

Approved therapies include 1. Standard and pegylated interferon-alfa. 2. Nucleoside reverse transcriptase inhibitors: lamivudine, adefovir and entecavir. Lamivudine, but neither adefovir nor entecavir, are approved for children. HBV has a very curious way of replicating itself since, although it is a DNA virus, it uses an RNA proviral intermediate that has to be copied back to DNA. For the purpose of copying RNA to DNA, HBV like retroviruses, has a virally-encoded DNA polymerase (P) called reverse transcriptase.

 The

main side effect of lamivudine is pancreatitis & lactic acidosis , of adefovir is nephrotoxicity & lactic acidosis. Current therapies do not eradicate HBV so long-term treatment is usually required. Even with successful therapy, patients remain at risk for reactivation of viral replication and require lifelong monitoring

Anti-HCV
The ultimate goals of antiviral therapy in HCV are 1. Eliminate HCV, 2. Improve or normalize the biochemical and histological parameters. 3. Prevent progression to cirrhosis and liver cancer. 4. Improve symptoms. 5. Prolong survival. Approved therapies include: 1. Standard and pegylated interferon-alfa 2. Standard and pegylated interferon-alfa + Ribavirin

There are three types of interferon: IFN-alpha , IFN-beta , and IFN-gamma . IFN has antiviral, antiproliferative and immunomodulatory effects. Therapeutic Uses: CHB, CHC. Interferon-alpha is given subcutaneously or intramuscularly.

INTERFERONS (IFNS)

The important parameters that affect response to IFN treatment are: Viral genotype: e.g. HCV genotype 1 is the most difficult to treat, whereas genotypes 2 and 3 are the most susceptible to interferon therapy Pre-treatment HCV RNA levels (viral load). A low baseline serum viral load (<2 million copies/mL or 800 000 IU/mL) is associated with a significantly higher probability of achieving SVR following interferon-based therapy.

Other important factors associated with SVR, include: shorter disease duration, age <40 years, lower body weight, absence of cirrhosis, low hepatic iron concentration, gender (women responding better than men) and levels of liver enzymes.

As a general rule, the success of treatment is determined at two time points: 1. Just as the course of treatment is completed, referred to as the end-of-treatment response (ETR); and 2. Six months after treatment is completed, referred to as the sustained virological response (SVR). The tests that are most important at these time points are the liver enzyme tests and the HCV viral load. If a person's liver enzyme levels are back to normal and HCV viral load is undetectable at the end of treatment, the person is said to have an effective ETR. If a person's liver enzyme levels remain normal and the HCV viral load is still undetectable six months after completing treatment, he or she is said to have an effective SVR.

Pegylated Interferons Peginterferon alphas differ from the older, unmodified interferon alphas in:
1.

2. 3. 4.

5.

A polyethylene glycol molecule, an inert compound that slows the elimination from the body, is attached to the interferon molecule. As a result its elimination from the body is slowed and higher. More constant blood levels of interferon alpha are achieved with less frequent dosing. In contrast to unmodified interferon alpha, which must be injected three times a week to treat chronic hepatitis C, peginterferon alpha needs to be injected only once a week. This results in enhanced compliance and clinically superior anti-viral activity( SVR).

Albuferon
A form of interferon alfa genetically fused to albumin. Possible advantages compared to other forms of interferon are its very long half-life. Thus, the lower dosing frequency (every two to four weeks rather than every week).

1.

Influenza like syndrome: fever, headache, nausea, vomiting, diarrhea, myalgia and arthralgia. (As a rule,

INTERFERONS Adverse Effects

everyday symptoms people experience as a result of HCV infection will grow worse during treatment).
2.

3.
4. 5.

6.
7.

Bone marrow suppression. Neurotoxicity (Depression). Nephrotoxicity. Thyroid dysfunction (Autoimmne). Teratogenicity. Inhibition of cytochrome P450 liver enzymes.

Contraindications to IFN
1.
2. 3. 4. 5.

Decompensated cirrhosis. Pregnancy. Uncontrolled depression Severe cytopenias. Autoimmune diseases.

Ribavirin

it helps in decreasing viral load and increasing SVR. It is not used alone in treatment of HCV.
The drug is effective ( in combination with IFN) against: HCV where

Therapeutic Uses: The addition of oral ribavirin to interferon alpha is superior to interferon alpha alone in the treatment of chronic hepatitis C Adverse effects: 1. Hemolytic anemia because it is concentrated in RBCs resulting in their lysis. Symptoms include: bleeding gums, blood in urine or stools. 2. Anemia, which can make heart disease worse. 3. Chest pain.
Viramadine, is a prodrug of ribavirin less likely to cause hemolytic

Contraindications To RIBAVIRIN

Absolute contraindication in pregnancy, necessitating reliable birth control during treatment with this drug and for 6 months after this medication has been stopped .