A. RESPIRATORY VIRUS INFECTIONS
1. Amantadine (Symmetrel) and rimantadine (Flumadine) act on RNA viruses by inhibiting the uncoating of viral nucleic acids, which reduces viral replication.
a. Amantadine and rimantadine block the M2 ion channel in the viral membrane, which is required for fusion of the viral membrane with the host cell membrane.
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b. Resistance occurs due to mutation of the viral M2 protein.
c. These drugs are used primarily for the prophylaxis of type A influenza viral infections. (Amantadine is also used as an anti-Parkinson drug.)
d. They can be administered as a supplement to the flu vaccine.
e. Treatment with either of these drugs is effective if initiated within 48 hours after the initial appearance of symptoms.
2. Neuraminidase inhibitors include oseltamivir (Tamiflu) and zanamivir (Relenza).
a. They are sialic acid analogs that inhibit the viral neuraminidase enzyme and prevent spread of virus to other cells.
b. Neuraminidase is inserted into the host cell membrane to allow the release of new virions. In the presence of neuraminidase inhibitors, virions accumulate at the infected cell’s internal surface and cannot be released.
c. These drugs are most effective if given prophylactically or within the first 48 hours after infection. They are effective for both type A and type B influenza viral infections.
3. Ribavirin (Virazole) is a guanosine analog that is effective against a broad spec-trum of viruses. It is used to treat respiratory syncytial virus (RSV) and chronic hepatitis C (in combination with interferon αα).
a. Ribavirin inhibits guanine nucleotide formation, prevents mRNA capping, and blocks RNA-dependent RNA polymerase.
b. Rhinoviruses and enteroviruses contain preformed mRNA and are therefore resistant to ribavirin.
B. HEPATIC VIRUS INFECTIONS
1. There are currently five hepatitis viruses (A-E), with B and C being the most com-mon causes of chronic liver complications. Hepatitis A infection is acute.
a. Hepatitis B is treated with interferon αα (Roferon) or lamivudine (Epivir).
b. Chronic hepatitis C is treated with a combination of interferon αα and ribavirin.
2. Interferonαα (Roferon) is a naturally occurring, inducible glycoprotein that inter-feres with the ability of viruses to infect new cells.
a. It is thought to induce host cell enzymes that inhibit viral translation.
b. Interferon α causes flu-like symptoms and interferes with hepatic drug metabolism.
3. Nucleoside and nucleotide analogs interfere with viral replication.
a. Lamivudine (Epivir) is a cytosine analog that selectively inhibits the DNA polymerase of hepatitis B. It also inhibits human immunodeficiency (HIV) reverse transcriptase.
b. Adefovir dipivoxil (Hepsera) is a nucleotide analog that is incorporated into hepatitis B viral DNA and causes chain termination.
c. Entecavir (Baraclude) is a guanosine analog used against hepatitis B.
C. Drugs against herpes virus infections are only active during the acute and not the latent phases of the virus’s life cycle.
1. Acyclovir (Zovirax) is a guanine analog that is a relatively safe antiviral drug.
a. It has two sites of selective toxicity (Figure 10-1).
i. Viral kinases preferentially phosphorylate acyclovir to acyclovir monophosphate.
ii. Acyclovir triphosphate is active against viral DNA polymerases.
b. Clinical indications include:
i. Genital and labial herpes simplex virus (HSV) types 1 or 2. There is no effect on the latent forms.
ii. Herpes encephalitis and keratitis.
iii. Varicella-zoster virus.
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140 CHAPTER 10
c. Valacyclovir (Valtrex) is an orally bioavailable prodrug of acyclovir.
d. Resistance can occur due to alteration or loss of viral thymidine kinase.
2. Ganciclovir (Cytovene) is an analog of acyclovir that is used for cytomegalovirus (CMV) and Epstein–Barr virus infections.
a. CMV does not have a thymidine kinase; thus, it is intrinsically resistant to acyclovir.
b. Valganciclovir (Valcyte), a prodrug version of ganciclovir, is orally bioavailable.
3. Cidofovir (Vistide) is a cytosine analog that is used to treat CMV infections in HIV-positive patients. Such infections are now less common with the widespread use of highly active antiretroviral therapy (HAART). The antisense oligonucleotide fomivirsen (Vitravene) is used for the same purpose.
4. Penciclovir (Denavir) and famciclovir (Famvir) are acyclic guanosine analogs used against HSV-1, HSV-2, and varicella.
5. Vidarabine (Vira-A) is an adenosine analog used for herpetic and vaccinial eye infec-tions in immunocompromised patients. It is less HSV-specific compared to acyclovir.
6. Foscarnet (Foscavir) is used to treat mucocutaneous HSV and CMV.
a. It is a phosphonoformate that inhibits viral DNA and RNA polymerase at the pyrophosphate binding site and terminates chain elongation.
b. Foscarnet has broad antiviral activity against CMV, acyclovir-resistant HSV, and herpes zoster.
c. Resistance develops due to mutation of the viral polymerases.
D. DRUGS AGAINST HIV
1. Principles of treating HIV infection
a. HIV is a retrovirus. Its RNA genome is converted in the host cell to DNA using the viral enzyme reverse transcriptase (RT).
b. Because HIV-RT does not have a proofreading function, frequent mutation of the virus leads to rapid development of resistance to anti-HIV drugs.
c. In order to delay the development of resistance, HIV treatment is typically given in three-drug combinations, a strategy called HAART.
i. Typically, a HAART drug “cocktail” consists of two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor, or else two NTRIs and one nonnucleoside reverse transcriptase inhibitor (NNRTI).
ii. HAART therapy is highly effective at managing HIV infection. Failure is often due to poor patient compliance with the demanding drug regimens.
iii. These regimens can dramatically reduce the symptoms of AIDS; however, no regimen can eliminate HIV.
Acyclovir
Acyclovir monophosphate
Acyclovir triphosphate
*Viral thymidine kinase
* Viral DNA polymerase
Figure 10-1 Mechanisms of selective toxicity (*) for acyclovir.
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2. The first HIV drugs were nucleoside and nucleotide analogs with a preference for viral reverse transcriptase (RT) over host DNA polymerases. These nucleoside reverse transcriptase inhibitors (NRTIs) lack the 3⬘-hydroxyl group.
a. Their incorporation into viral DNA terminates viral DNA synthesis.
i. NRTIs have significant adverse effects, which could be due to inhibition of mitochondrial DNA polymerases.
ii. NRTIs with overlapping toxicities should not be coadministered.
b. Zidovudine (Retrovir), formerly called azidothymidine (AZT), is a thymidine analog that is converted to the triphosphate form. It is the prototype NRTI.
i. Zidovudine is used:
(a) In the treatment of HIV-positive and AIDS patients
(b) In pregnant women with HIV to reduce the transmission of HIV to the newborn
(c) To reduce the incidence of HIV in health-care workers exposed to the virus via needlestick
ii. Bone marrow depression may occur. Toxicity is potentiated if AZT is coadministered with other drugs that are also glucuronylated (e.g., ribavirin, stavudine, acetaminophen).
iii. Stavudine (Zerit) is another thymidine analog that can cause peripheral neuropathy. It should not be given with AZT.
c. Zalcitabine (Hivid) and lamivudine (Epivir) are deoxycytosine analogs.
i. Both can be coadministered with AZT in HAART.
ii. Both drugs cause peripheral neuropathy and should not be coadministered with one another.
d. Abacavir (Ziagen) is a deoxyguanosine analog.
e. Didanosine (Videx) is an adenosine analog and can also cause peripheral neu-ropathy. It should not be coadministered with zalcitabine.
f. Tenofovir (Viread) is the first nucleotide analog (most other NRTIs are nucle-oside analogs). It is an adenosine-5’-monophosphate analog.
3. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of HIV-RT.
a. Thus, there is no cross resistance between NRTIs and NNRTIs.
b. The three NNRTIs currently in use are efavirenz (Sustiva), nevirapine (Viramune), and delavirdine (Rescriptor).
4. Protease inhibitors were introduced in 1995 and have greatly reduced deaths due to HIV infection. They act by inhibiting the protease that cleaves viral pro-tein precursors.
a. Protease inhibitors can cause a characteristic “buffalo hump” deposit of fat on the upper back. They inhibit cytochrome P450 enzymes, leading to accumula-tion of some drugs.
b. Most protease inhibitors are peptidomimetics or peptides.
i. Ritonavir (Norvir) is used in combination with drugs such as AZT and didanosine for the treatment of HIV. It can also be used to increase the bioavailability of other protease inhibitors.
ii. Atazanavir (Reyataz) can be given once daily instead of requiring multiple doses like the other protease inhibitors do.
iii. Lopinavir/ritonavir (Kaletra) is a coformulation of two protease inhibitors.
iv. Others common protease inhibitors include saquinavir (Invirase), indi-navir (Crixivan), and nelfiindi-navir (Viracept).
5. Enfuvirtide (Fuzeon) is the first viral fusion inhibitor. It is a peptide that binds to gp41 and prevents fusion of viral and host cell membranes. Its biggest draw-back is its high cost.
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