Antiviral Drugs

ANTIVIRAL  DRUGS

Most of the antibacterial and antifungal agents described earlier in this chapter have little or no activity against viruses because they target structures or enzyme systems that are only found in bacterial and fungal cells. In contrast to other microorganisms, viruses do not possess the enzymes necessary for their own replication. After entry into the host cell, the virus uses the enzymes already present, or induces the formation of new ones, in order to synthesize the individual components of the virus particle which are then assembled and released from the host cell. Because viruses literally ‘take over’ the machinery of an infected human cell, there are very few unique features of viral replication that can be exploited for the purposes of achieving selective toxicity, i.e. creating antiviral agents that inhibit or kill the virus without harming the human host.

Prior to the identification of the HIV virus in 1983 there was a very limited range of effective synthetic antiviral agents; the fourth edition of this book, published in 1987, described only nine. The HIV/AIDS pandemic provided a major stimulus for fundamental research into the structure and reproduction of viruses in general and retroviruses in particular, and this, together with (1) better understanding of the role played by some viruses in the development of specific cancers, (2) more sophisticated diagnostic methods, and (3) elucidation of the genomes of several viruses, has led to a wealth of new antiviral drugs; Table 11.9 lists 21, and a further 20 that are used largely or exclusively for the treatment of HIV are shown in Table 11.10. Although these new drugs may be categorized on the basis of their chemical structure (Figure 11.14) or mode of action, most of them are licensed for use against a limited number of viruses, and often just a single one, so the most convenient and useful way of considering antivirals is on the basis of the infections they are intended to treat.

HIV

There is a large and progressively increasing variety of antiretroviral agents available to treat HIV, and their use requires specialist knowledge. A detailed account of the characteristics of each individual drug is beyond the scope of this chapter, but it is possible to gain a good understanding of the principles of HIV chemotherapy by considering the life cycle of the virus (Figure 11.13) in relation to the modes of action of the drugs in current use.

The virus particle initially binds to a CD4 protein receptor and one of two co-receptors on the surface of a T-lymphocyte. Maraviroc, an antagonist of the CCR5 co-receptor, is licensed in the UK for the treatment of patients exclusively infected with CCR5-tropic HIV. The bound virus then fuses with the host cell membrane and the viral RNA is released into the cell. This step is targeted by enfuvirtide, a fusion inhibitor, that is used for managing infection that has failed to respond to a regimen of other anti-retroviral drugs. The single-stranded viral RNA is used as a template from which a complementary DNA strand is manufactured by viral reverse transcriptase; there are several nucleoside analogue inhibitors of this enzyme (Table 11.10), together with a smaller number of non-nucleoside inhibitors (e.g. efavirenz, etravirine, and nevirapine). The DNA is duplicated, and in its double-stranded form it enters the cell nucleus where an HIV enzyme integrates it into the host DNA to create what is termed a provirus. The integrase enzyme can be inhibited by raltegravir, a drug which again is largely reserved for the treatment of HIV infection resistant to multiple anti-retrovirals.

The provirus may remain latent (dormant) within the cell nucleus for a period of time varying from 2 weeks to 20 years; it is then activated by regulatory proteins termed transcription initiators which cause the viral DNA to be transcribed into viral mRNA and several long protein molecules. It is the latent provirus that represents the major hurdle to complete eradication of HIV, and recent research interest has focused on the transcription initiators as alternative potential targets for anti-retroviral drug action. The long proteins only become functional after being split into smaller molecules by viral protease enzymes and there are now many protease inhibitor drugs available for the treatment of HIV (Table 11.10).

HIV infection cannot be cured, but strict adherence to a regimen of anti-retroviral drugs can substantially extend survival. However, there are several problems that may arise during therapy, of which one of the most significant is the risk of the virus becoming resistant. This risk may be minimized by using combinations of three or more drugs with different mechanisms of action in regimens that have become known as highly active anti-retroviral therapy (HAART). Treatment is normally initiated with two nucleoside reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor; the regimens currently recommended in the UK contain either tenofovir, emtricitabine and efavirenz, or abacavir, lamivudine, and efavirenz. Retinovir, used in low concentrations at which it has no intrinsic antiviral activity, has been shown to increase the duration of effective blood concentrations of almost all the other protease inhibitors listed in Table 11.10, and these synergistic combinations have given rise to the term boosted protease inhibitor; a combination product of retinovir and lopinavir is commercially available. Regimens containing two nucleoside reverse transcriptase inhibitors and a boosted protease inhibitor are reserved for patients with resistance to firstline treatment. Synergy is often observed between anti-retroviral drugs, both between agents having the same, and different, modes of action.

Other problems of HIV therapy are drug toxicity and patient adherence to their prescribed medication, and these two are often linked. The variety and severity of the side effects, particularly those relating to redistribution of body fat, make it more difficult for patients to achieve the adherence and persistence required for effective treatment. All the common drugs used in therapy are orally active because any drug that required lifelong daily injections would so predispose to non-adherence as to prejudice its commercial viability. Several of the anti-retroviral drugs listed in Table 11.10, particularly those with unique mechanisms of action, are used in such restricted circumstances that they are extremely expensive.

HERPES AND CYTOMEGALOVIRUS INFECTIONS

There are eight herpes viruses capable of causing human infection, but of these the most important are:

·                                        the two herpes simplex viruses, HSV-1 and HSV-2, which, respectively, cause cold sores on the face and lips, and genital herpes

·        the varicella zoster virus causing chickenpox and shingles

·        the Epstein–Barr virus responsible for infectious mononucleosis (glandular fever)

·        the cytomegalovirus (CMV) which may cause retinitis (inflammation of the retina) and, infrequently, similar symptoms to infectious mononucleosis.

The first four of the drugs listed in Table 11.9 for the treatment of herpes infections are the most important. Inosine pranobex is an orally active immuno-modulator the effectiveness of which has not been proven, and idoxuridine, a pyrimidine analogue used as a solution in dimethyl-sulphoxide for the treatment of cutaneous herpes, has largely been superseded by aciclovir.

Many antiviral drugs are nucleoside analogues, and aciclovir together with its prodrug valaciclovir, and penicyclovir and its prodrug famciclovir, are important examples of this group. Aciclovir and peniciclovir are structurally very similar and they act in the same way both to inhibit viral DNA polymerase and to cause premature termination of DNA synthesis. Both drugs are only effective when they have been phosphorylated in the cell, and selective toxicity arises because phosphorylation is achieved much more efficiently by virus-encoded thymidine kinase than by the corresponding mammalian enzyme, so human cell DNA synthesis is little affected. All four drugs are used primarily to treat herpes simplex and varicella zoster infections; CMV is normally resistant to them and Epstein–Barr virus shows intermediate sensitivity. Aciclovir is available as an intravenous injection, tablets and a cream, but the last two of these need to be administered five times daily in order to maintain effective levels. Its prodrug valaciclovir has a much longer half-life and the dose frequency is correspondingly reduced to 2–3 times a day. Peniciclovir has little oral activity and is used topically, primarily for cold sores, but it is applied every 2 hours during waking hours. The orally active famciclovir is taken between one and three times daily for the treatment of genital herpes and shingles.

Because CMV does not produce thymidine kinase it is not normally susceptible to aciclovir and peniciclovir, so a different group of drugs is used to treat it. Ganciclovir has a similar structure to aciclovir but it is phosphorylated more effectively in infected cells than healthy ones, albeit by a host cell enzyme. It is injected intravenously for the treatment of life-threatening or sight-threatening CMV infections in immuno-compromised patients only, or for the prevention of CMV infection following organ transplants. Valganciclovir is an expensive, orally active, valine ester prodrug of ganciclovir which is used in similar circumstances. Both drugs are toxic, and the latter carries a specific warning in the UK British National Formulary about potential teratogenic and carcinogenic activity. Cidofovir is a cytosine analogue that is active against most herpesviruses, and is used by injection in AIDS patients to treat CMV retinitis that is unresponsive to other drugs. Foscarnet, too, is given for CMV retinitis when ganciclovir cannot be used; it has a relatively simple phosphonoformic acid structure capable of chelating metal ions, which is thought to be the basis of its inhibitory action on polymerase enzymes.

VIRAL HEPATITIS

Hepatitis, inflammation of the liver, can be caused by various drugs and toxins, but hepatitis due to viral infection is more common. The viruses most frequently responsible are the hepatitis viruses A–E (which are not all related), but about 5% of cases of viral hepatitis are due to other viruses, e.g. herpesvirus, CMV, Epstein–Barr virus, etc. Hepatitis virus A (formerly known as infectious hepatitis) is a self-limiting, rarely fatal, food-borne infection that does not result in permanent liver damage and is not normally treated with antiviral drugs. Hepatitis E is similarly self-limiting and relatively uncommon, and hepatitis D can only arise as a co-infection with the hepatitis B virus, so it is hepatitis viruses B and C (HBV and HCV respectively) that are the most problematic and which require antiviral therapy.

It has been estimated that approximately one third of the world’s population are infected with HBV and just over one tenth of that number with HCV. The two infections have several features in common, although the viruses are not of the same family. In both cases the disease may be acute or chronic and in the latter case there may be progression to liver damage and a higher risk of contracting liver cancer. Acute HBV cases do not normally receive antiviral drugs, and that was formerly the case for HCV also, but recent evidence suggests that early treatment of HCV has a higher success rate and shorter treatment time than that required for chronic disease, so this practice is now more common.

HBV is unusual in that it is not a retrovirus like HIV but it does use reverse transcriptase in its replication process. For this reason two of the drugs used to treat HIV infection, lamivudine and tenofovir, are also effective for HBV; in addition, adefovirdipivoxil, entecavir and telbivudine are also used, typically for 6 months or more for all five drugs. In patients with decompensated liver disease (liver cirrhosis with fluid accumulation in the abdomen) lamivudine or adefovir are recommended. Adefovir is effective in lamivudine-resistant HBV infection, but telbivudine should not be used because cross-resistance may arise. Entecavir is effective in patients not previously treated with nucleoside analogues, but resistance can occur in patients who have received lamivudine. Again, all of these antivirals are available as relatively expensive, oral products.

There are several genotypes of HCV which exhibit different drug sensitivities, so the genotype should be determined before drug selection. Interferon-α is used together with ribovirin for the treatment of chronic infection by both HCV and HBV. Interferons are low molecular weight proteins produced by virus-infected cells that themselves induce the formation of a second protein inhibiting the transcription of viral mRNA. Interferon-α needs to be injected on a daily basis or at least three times weekly, but in its polyethylene glycol- derivatized form (peginterferon-α2a) it is much longer acting and requires less frequent dosing. The combination of ribavirin and interferon-α is less effective against HCV than the combination of peginterferon-α2a and ribavirin. Peginterferon-α2a alone should be used if ribavirin is contraindicated or not tolerated, but ribavirin alone is ineffective.

INFLUENZA AND RESPIRATORY SYNCYTIAL VIRUS

There are three related influenza viruses, A, B and C, of which C is relatively rare and causes only mild infections. All three reproduce in the same way and possess the enzyme neuraminidase which is responsible for liberating the newly formed virus particles from the host cell. There are two neuraminidase inhibitors available, oseltamivir which is formulated as an ethyl ester prodrug for oral administration, and zanamivir which is administered by inhalation. Neither drug has activity against other viruses.

Both oseltamivir and zanamivir are most effective if taken within 48 hours of the onset of symptoms, when they may reduce the duration of the symptoms by about 1–1.5 days; they may also reduce the risk of complications in elderly patients or those with chronic diseases. They are useful too for postexposure prophylaxis of influenza, but again need to be administered within a few hours of exposure. Mutant strains of influenza viruses have developed resistance to oseltamivir but currently these are uncommon, and no such resistance has so far been observed with zanamivir.

Amantadine is a drug that inhibits an ion-channel protein in influenza A but not influenza B virus (which does not possess the target molecule). Again, it is effective if given soon after the onset of symptoms, but resistance has now become widespread so the drug, although still available, is no longer recommended in the UK.

Respiratory syncytial virus (RSV) is a commonly occurring virus related to those causing measles and mumps. It infects most infants by the age of 2 years, but unfortunately there is no long-lasting immunity following infection and no vaccine available. Ribavirin (Section 13.3) is one of the few antiviral agents used in the treatment of RSV, but its value is very much in doubt. Palivizumab is a monoclonal antibody used for preventing serious lower respiratory tract disease caused by RSV in children at high risk of the disease.