12.2 ACYCLOVIR GROUP Acyclovir, famciclovir, valacyclovir, etc., are a group of guanosine analog antivirotics. They enter the cell as inactive substances and are further metabolized into the active drug form. They are first monophosphorylated by viral thymidine kinase and then further di- and tri- phosphorylated by host-cell kinases. In this triphosphorylated form they act as both a substrate and inhibitor of viral DNA polymerase. When the elongating chain incorporates an acyclovir-triphosphate, the chain is terminated due to the lack of a 3’ hydroxyl group. This effectively shuts off the viral mechanism of replication. Two mechanisms of resistance have arisen due to modification of either the DNA polymerase or the thymidine kinase itself. The first is partially overcome by famciclovir or valacyclovir, which (among having an increased half-life) have increased activity in strains with a modified DNA polymerase. The uses for this group are mainly limited to the Herpesviridae family, within which the activity is only in herpes simplex virus (HSV) and varicella zoster virus (VZV). Acyclovir decreases viral shedding in both previously mentioned viruses (especially in cases of herpes simplex meningitis) and reduces symptoms if administered early in chickenpox, or in chicken pox, or zoster complications. Acyclovir can also be used prophylactically in immunocompromised patients, as these patients run the risk of a more serious course. The other members of the Herpesviridae family use a different DNA polymerase and thymidine kinase or even no kinase at all and thus are naturally resistant acyclovir/valacyclovir. The drugs can be administered in topical, oral and IV forms, with acyclovir requiring multiple daily dosings and the others being able to be applied once/twice per day. Adverse Effects The drugs are well tolerated in oral formulations with a slight increase of adverse effects if administered IV. One of the most common ones is obstructive crystalline nephropathy. Adequate hydration will virtually eliminate it and prevent progression to acute renal failure. Another adverse effect is neurotoxicity, which can present as tremor, headache or even confusion.
12.3 GANCICLOVIR Ganciclovir is a drug that is very similar to acyclovir however, because it uses different constituents, has a wider antivirotic cover and different toxicity. Ganciclovir can use the original thymidine kinase like acyclovir to to partly cover HSV and VZV but also has the ability to
be used by phosphotransferase that occurs in cytomegalovirus (CMV; UL97 gene) and similar in related beta-herpesviruses such as HHV-6B and HHV-7. It is also used prophylactically to treat CMV infections such as retinitis, in transplant and AIDS patients. The drug can be injected IV, used topically in the case of beta-herpesvirus retinitis or even as an intravitreal application in the case of VZV acute retinal necrosis. Valganciclovir is a prodrug of ganciclovir and has better oral bioavailability so it can be used in an oral formulation. Adverse Effects Ganciclovir tends to be more toxic than its predecessor acyclovir. It can cause pancytopenia (anemia, leukopenia, and thrombocytopenia) due to bone marrow toxicity. It can also cause neurotoxicity at high doses, which often manifests as seizures. As with acyclovir, ganciclovir can cause crystalline nephropathy unless the patient is properly hydrated. 98
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12.4 FOSCARNET Foscarnet is the answer to ganciclovir and acyclovir resistance. It is not an antimetabolite like ganciclovir/acyclovir and also does not require activation by viral kinases. It works by directly inhibiting viral DNA and RNA polymerase as well as inhibiting HIV reverse transcriptase. Foscarnet is used in CMV retinitis in ganciclovir resistant patients and in acyclovir resistant HSV infections. Foscarnet is used in CMV encephalitis/retinitis, in ganciclovir resistant patients as well as in the HHV-6 encephalitis and in acyclovir resistant HSV/VZV infections. In case or desperate situation, it can be rarely used also as salvage therapy in HIV patients that are not responding to multiple therapies. Adverse Effects The main adverse effect to watch out is nephrotoxicity. This dose-limiting acute tubular necrosis can cause electrolyte imbalances leading to hypocalcaemia, hypokalemia and hypomagnesaemia. Seizures are the most feared complication. Of special note is the coadministration with pentamidine (2nd line in Pneumocystis jirovecii infection), which can exacerbate the hypocalcaemia to very dangerous levels.
12.5 CIDOFOVIR Cidofovir is a similar agent to foscarnet. It acts by preferentially inhibiting viral DNA polymerase and like foscarnet does not require activation by viral kinases. It is mainly used in CMV retinitis patients that are also immunocompromised and in acyclovir-resistant HSV,
moreover, cidofovir is also active against more DNA viruses such as adenoviruses, papillomaviruses or polyomaviruses. Therefore cidofovir can be used in particular situation for treatment of these viral infections as well. It is regarded as an excellent agent as its long half-life allows for infrequent dosing which increases compliance to therapy. However, the long half-life is also the reason for severe toxicity. Adverse Effects Cidofovir is also nephrotoxic like foscarnet. Adequate hydration is of paramount importance and should be always as such it is often co-administered with probenecid (to decrease secretion into proximal convoluted tubules) and IV saline. Novel virostatic drugs – in the last couple of years, there are new virostatic compounds introduced on the market active against DNA viruses – such as letermovir (inhibitor of CMV terminase), brincidofovir (per oral prodrug of cidofovir) or maribavir (CMV UL97 inhibitor).
12.6 INFLUENZA DRUGS Influenza is a severe disease with possible serious sequelae, especially in the elderly. Oseltamivir and zanamivir are two drugs used today that are collectively known as second generation of neuraminidase inhibitors. Neuraminidase causes the release of the progeny virus and as such these drugs prevent that from happening. The infected cell is not preserved but neuraminidase inhibitors prevent further spread of the virus. The drugs need to be taken within 99
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48 hours of onset of symptoms and they both have two different formulations. Oseltamivir is taken orally while zanamivir is given intranasally in the form of a spray and i.v. formula. Nausea and vomiting tend to be common side effects but more serious ones like liver inflammation and subsequent elevation of liver enzymes tend to be far rarer. Of interesting note, is the now defunct amantadine usage in the treatment of influenza. In a textbook case of resistance development, the site of action of amantadine (M2 protein to aid in activation of viral RNA transcriptase) underwent a change in the wild-type virus. This resistance is so strong that in many areas more than 90% of wild-type influenza A is fully resistant to the drug.
12.7 HEPATITIS B DRUGS Tenofovir has established itself as a primary treatment in hepatitis B virus (HBV) infection in recent years. It is very potent and capable of suppressing lamivudine, telbivudine and entecavir resistant strains. It also has a very low chance to develop resistance in HBV strains. Tenofovir acts by inserting itself into a growing DNA chain (a feature that also allows its use in HIV patients). It does this by lacking a 3’ OH group and thus not allowing the addition of further nucleotides. Adverse effects include renal insufficiency, bone marrow suppression (G-CSF and EPO can be used to compensate) and decreased bone density. Lamivudine is another agent in the arsenal against HBV. It also acts by inhibiting DNA polymerase, by adding itself to the growing chain but, unlike tenofovir, it is a nucleoside and thus must be phosphorylated inside the cell. This gives rise to the possibility of resistance formation (which is unfortunately becoming very common), in which case the treatment is often switched to tenofovir. Adverse effects tend to be milder than with tenofovir but with the increased risk for lactic acidosis and pancreatitis (especially in HIV patients). Interferon alpha is a great modality in treating HBV. It can be used as an adjunct therapy (as is often the case with hepatitis C virus (HCV)) or solo therapy in the case of HBV. Interferon has a wide and varied mechanism of action, the majority of which is beyond the scope of this book. In simplified terms, it can activate translation inhibitory peptide, which decreases the protein synthesis necessary to propagate the synthesis of virions and it can also further inhibit protein synthesis by activating protein kinase R, which inactivates eIF-2. Resistance to interferon is slow to develop, if it develops at all, thus it is an excellent choice in HBV therapy. The true advantage is the relatively short duration of the therapy in compensated patients and as such it is a very popular option, especially in young adults. The biggest drawbacks by far are the adverse side effects. Neutropenia and myopathy are very common but it is the mental confusion and severe depression that are the truly feared adverse effects of this therapy.
12.8 HEPATITIS C DRUGS PEGylated IFN-alpha alongside ribavirin has been the only alternative in the HCV treatment. However, during last couple of years a modern treatment based on combination of new compounds aiming different parts of the HCV living cycle – called DAA-direct acting antivirals. Due to the specificity of such different drugs, genotyping of the virus became 100
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