Viral, fungal, protozoal and helminthic infections

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Chapter 15 Viral, fungal, protozoal and helminthic infections

Viral infections

Antiviral agents are most active when viruses are replicating. The earlier that treatment is given, therefore, the better the result. Apart from primary infection, viral illness is often the consequence of reactivation of latent virus in the body. Patients whose immune systems are compromised may suffer particularly severe illness. Viruses are capable of developing resistance to antimicrobial drugs, with similar implications for the individual patient, for the community and for drug development. An overview of drugs that have proved effective against virus diseases appears in Table 15.1.

Table 15.1 Drugs of choice for virus infections

Organism Drug of choice Alternative
Varicella zoster    
    chickenpox Aciclovir Valaciclovir or famciclovir
    zoster Aciclovir or famciclovir Valaciclovir
Herpes simplex    
    keratitis Aciclovir (topical)  
    labial Aciclovir (topical and/or oral) Valaciclovir or famciclovir
    genital Aciclovir (topical and/or oral) Valaciclovir
  Famciclovir (oral) Penciclovir
    encephalitis Aciclovir  
    disseminated Aciclovir Foscarnet
Human immunodeficiency virus (HIV) Lamivudine/emtricitabine Abacavir
  Tenofovir Didanoside
  Zidovudine Stavudine
  Lopinavir/ritonavir Saquinavir
  Atazanavir Darunavir
  Fosamprenavir Tipranavir
  Efavirenz Nevirapine
Hepatitis B Pegylated interferon α-2a and interferon 2b, lamivudine Adefovir, tenofovir, entecavir, telbivudine
Hepatitis C Pegylated interferon α-2a or interferon 2b plus ribavirin  
Hepatitis D Interferon-α Pegylated interferon α-2a and interferon 2b
Influenza A Zanamivir, oseltamivir Amantadine
Cytomegalovirus (CMV) Valganciclovir, ganciclovir Foscarnet, cidofovir
Respiratory syncytial virus Ribavirin Palivizumab
Papillomavirus (genital warts) Imiquimod  
Molluscum contagiosum Imiquimod Cidofovir

Herpes simplex and varicella zoster


Aciclovir (t½ 3 h) is a nucleoside analogue that is selectively phosphorylated by virus-specific thymidine kinase. Phosphorylated aciclovir inhibits viral replication by acting as a substrate for viral DNA polymerase, thus accounting for its high therapeutic index. It is effective against susceptible herpes viruses if started early in the course of infection, but it does not eradicate persistent infection because viral DNA is integrated in the host genome. About 20% is absorbed from the gut, but this is sufficient for oral systemic treatment of some infections. It distributes widely in the body; the concentration in CSF is approximately half that of plasma, and the brain concentration may be even lower. These differences are taken into account in dosing for viral encephalitis (for which aciclovir must be given i.v.). Dose adjustment is required for patients with impaired renal function, as the drug is predominantly excreted in the urine. For oral and topical use the drug is given five times daily. It can be given twice daily orally for suppressive therapy.

Human immunodeficiency virus (HIV)

According to World Health Organization data, 33 million people worldwide were living with human immunodeficiency virus (HIV) in 2008, with close to 3 million new infections yearly; almost 10 million were in need of antiretroviral therapy but more than half of these had no access to treatment.

General comments

The aims of antiretroviral therapy are to delay disease progression and prolong survival by suppressing the replication of the virus. Optimal suppression also prevents the emergence of drug resistance and reduces the risks of onward transmission to sexual partners and the unborn children of HIV-infected mothers. Virological failure may be defined as primary where there is inability to reduce plasma HIV viral load to fewer than 50 copies per microlitre despite 6 months of antiretroviral therapy, or secondary if there is failure to maintain viral load suppression at less than 50 copies per microlitre.

No current antiviral agents or combinations eliminate HIV infection, but the most effective combinations (so-called ‘highly active antiretroviral therapy’, HAART) produce profound suppression of viral replication in many patients and allow useful reconstitution of the immune system, measured by a fall in the plasma viral load and an increase in the numbers of cytotoxic T cells (CD4 count). Rates of opportunistic infections such as Pneumocystis carinii pneumonia and cytomegalovirus (CMV) retinitis are reduced when CD4 counts are restored, and life expectancy is markedly increased.

Combination therapy reduces the risks of emergence of resistance to antiretroviral drugs, which is increasing in incidence even in patients newly diagnosed with HIV. Mutations in the viral genome either prevent binding of the drug to the active site of the protease or reverse transcriptase enzymes, or lead to removal of the drug from the reverse transcriptase active site. The potential for rapid development of resistance is immense because untreated HIV replicates rapidly (50% of circulating virus is replaced daily), the spontaneous mutation rate is high, the genome is small, the virus will develop single mutations at every codon every day, and for many antiretroviral agents a single mutation will render the virus fully resistant.

The decision to begin antiretroviral therapy is based primarily on the CD4 cell count (most current recommendations are to start in patients with counts below 350 cells per microlitre). Early initiation of antiretroviral therapy should also be considered for patients with CD4 cell count above 350 cells per microlitre but a low CD4 percentage (e.g < 14%), those with an AIDS diagnosis (e.g. Kaposi sarcoma), hepatitis B and HIV co-infection where treatment is indicated, and in conditions where achieving a suppressed viral load is desired in order to prevent transmission (e.g. in pregnancy).

There are currently more than 20 approved antiretroviral agents in four classes, plus various fixed drug combinations (Table 15.2).

Current HAART regimens use a combination of drugs that act at different phases of the viral life cycle. The most frequently used combinations employ a backbone of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (rPI). The choice for the individual patient is best made after reference to contemporary, expert advice (see the websites listed in the Guide to further reading).

Alternative combinations are used if these variables deteriorate or unwanted drug effects occur. Antiretroviral resistance testing, both genetic (by searching viral RNA for sequences coding for resistance) and phenotypic (by testing antiretroviral agents against the patient’s virus in cell culture), also guide the choice of drug regimen, especially after virological failure.

Pregnancy and breast feeding pose special problems. The objectives of therapy are to minimise drug toxicity to the fetus while reducing the maternal viral load and the catastrophic results of HIV transmission to the neonate. Prevention of maternal–fetal and maternal–infant spread is the most cost-effective way of using antiretroviral drugs in less developed countries. Maternal–fetal transmission rates are related to maternal viral load, with rates of 0.1% reported when maternal viral load is less than 50 copies per microlitre while on HAART. Where resources permit, access to safe alternatives to breast feeding should be provided to infected mothers.

Combination antiretroviral therapy, especially the thymidine nucleoside analogue reverse transcriptase inhibitors zidovudine and stavudine, causes redistribution of body fat in some patients – the ‘lipodystrophy syndrome’. Protease inhibitors can disturb lipid and glucose metabolism to a degree that warrants a change to drugs with limited effects on lipid metabolism, e.g. ritonavir-boosted atazanavir, and the introduction of lipid-lowering agents.

Impaired cell-mediated immunity leaves the host prey to opportunistic infections including: candidiasis, coccidioidomycosis, cryptosporidiosis, CMV disease, herpes simplex, histoplasmosis, Pneumocystis carinii pneumonia, toxoplasmosis and tuberculosis (often with multiply resistant organisms). Treatment of these conditions is referred to elsewhere in this text.2

Improvement in immune function as a result of antiretroviral treatment may provoke an inflammatory reaction against residual opportunistic organisms (immune reconstitution inflammatory syndrome, IRIS). Although infrequent, this may present with development of new infections or worsening opportunistic infections, e.g. tuberculosis and cryptococcal disease.

Antiretroviral drugs may also be used in combination to reduce the risks of infection with HIV from injuries, e.g. from HIV-contaminated needles and following sexual exposure to a high-risk partner. The decision to offer such post-exposure prophylaxis (PEP), and the optimal combination of drugs used, is a matter for experts; administration must begin within a few hours of exposure and continue for 28 days.

Some drugs described here have found additional indications, or are used only, for therapy of non-HIV infections, e.g. adefovir for chronic hepatitis B infection.

Nucleoside and nucleotide reverse transcriptase inhibitors

The HIV replicates by converting its single-stranded RNA into double-stranded DNA, which is incorporated into host DNA; this crucial conversion, the reverse of the normal cellular transcription of nucleic acids, is accomplished by the enzyme reverse transcriptase. Nucleoside reverse transcriptase inhibitors have a high affinity for the reverse transcriptase enzyme and are integrated by it into the viral DNA chain, causing premature chain termination. While all nucleoside reverse transcriptase inhibitors require activation by host enzymes to triphosphates prior to incorporation into the DNA chain, tenofovir (as the only nucleotide analogue) is unique in requiring only two phosphorylations for activation.

Zidovudine (AZT, Retrovir)

Zidovudine, a thymidine analogue, is the first antiretroviral licensed for the treatment of HIV-1. Resistance develops rapidly when used as monotherapy through the sequential accumulation of thymidine analogue mutations (TAMs) at codon 41, 67, 70, 215 and 219; conversely, point mutations at codon 184 selected by lamivudine and emtricitabine therapy enhance susceptibility to zidovudine (and stavudine) by delaying the emergence of TAMs.

Protease inhibitors

In its process of replication, HIV produces precursor proteins, which are subsequently cleaved by the protease enzyme into component parts and reassembled into virus particles; protease inhibitors disrupt this essential process.

Protease inhibitors reduce viral RNA concentration (‘viral load’), increase the CD4 count and improve survival when used in combination with other agents. They are metabolised extensively by isoenzymes of the cytochrome P450 system, notably by CYP 3A4, and most protease inhibitors inhibit these enzymes. They have a plasma t½ of 2–4 h, except for fosamprenavir (8 h) and atazanavir (7 h with food). The drugs have broadly similar therapeutic effects. Members of the group include:

Non-nucleoside reverse transcriptase inhibitors

This group is structurally different from the reverse transcriptase inhibitors; members are active against the subtype HIV-1 but not HIV-2, a subtype encountered mainly in West Africa. Non-nucleoside reverse transcriptase inhibitors are metabolised by CYP 450 enzymes and hence the potential for significant drug–drug interactions. The drugs have considerably longer half-lives when compared to nucleoside reverse transcriptase inhibitors.

Entry inhibitors

Influenza A

Neuraminidase inhibitors are highlighted by the emergence of avian influenza viruses with the potential for mutation to cause pandemic spread in the human population, although their clinical effectiveness is not high. The two antiviral drugs oseltamivir and zanamivir were widely used for the public health control of the 2009 influenza A (H1N1) pandemic.

Oseltamivir (Tamiflu)

Oseltamivir is an oral prodrug of a viral neuraminidase inhibitor. It reduces the severity and duration of symptoms caused by influenza A or B in adults and children if commenced within 36 h of the onset of symptoms. More specifically, the risk of respiratory complications such as secondary pneumonia, antibiotic use and hospital admission are reduced. It is effective for post-exposure prophylaxis, where it should be started within 48 h of contact with the index case and continued daily for 10 days, a usage that might be appropriate for health-care workers and those especially likely to suffer serious complications from pre-existing illness. Prophylaxis may be given for 2 weeks after influenza immunisation while protective antibodies are being produced.

Oseltamivir is one option for treatment and prophylaxis of avian H5N1 and 2009 influenza A (H1N1) virus. In the event of a pandemic, treatment for 5 days and prophylactic use for up to 6 weeks (or until 48 h after last exposure) are suggested.



Ganciclovir resembles aciclovir in its mode of action, but is much more toxic. An acyclic analogue of guanosine, the drug is converted to a triphosphate form which competitively inhibits virion DNA polymerase, leading to chain termination. It is given i.v. and is eliminated in the urine, mainly unchanged (t½ 4 h). Ganciclovir is active against several types of virus but toxicity limits its i.v. use to life- and sight-threatening CMV infection in immunocompromised patients, including CMV retinitis, pneumonitis, colitis and disseminated disease.


Foscarnet finds use i.v. for CMV retinitis in patients with HIV infection when ganciclovir is contraindicated, and for aciclovir-resistant herpes simplex virus infection (see p. 213). It is generally less well tolerated than ganciclovir; adverse effects include renal toxicity (usually reversible), nausea and vomiting, neurological reactions and marrow suppression. Hypocalcaemia is seen especially when foscarnet is given with pentamidine, e.g. during treatment of multiple infections in patients with AIDS. Renal toxicity can be minimised with good hydration and dose modification. Foscarnet causes a contact dermatitis which can lead to unpleasant genital ulcerations due to high urine drug concentrations; this is potentially preventable with good urinary hygiene.