Viral, fungal, protozoal and helminthic infections

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Chapter 15 Viral, fungal, protozoal and helminthic infections

Sani Aliyu

Synopsis

• Viruses present a more difficult problem of chemotherapy than do higher organisms, e.g. bacteria, for they are intracellular parasites that use the metabolism of host cells.1 Highly selective toxicity is, therefore, harder to achieve. In the past 15 years, identification of the molecular differences between viral and human metabolism has led to the development of many effective antiviral agents; four were available in 1990, now there are over 40.

• Fungal infections range from inconvenient skin conditions to life-threatening systemic diseases; the latter have become more frequent as opportunistic infections in patients immunocompromised by drugs or AIDS, or in those receiving intensive medical and surgical interventions in intensive care units.

• Protozoal infections. Malaria is the major transmissible parasitic disease in the world. Drug resistance is an increasing problem and differs with geographical location, and species of plasmodium.

• Helminthic infestations cause considerable morbidity. The drugs that are effective against these organisms are summarised.

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
  Etravirine  
  Raltegravir  
  Enfuvirtide  
  Maraviroc  
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

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.

Indications

for aciclovir include:

Herpes simplex virus:

• Skin infections, including initial and recurrent labial and genital herpes, most effective when new lesions are forming; skin and mucous membrane infections (as tablets or oral suspension).

• Ocular keratitis (topical treatment with ophthalmic ointment is standard, oral treatment is also effective).

• Prophylaxis and treatment in the immunocompromised (oral, as tablets or suspension).

• Encephalitis and disseminated disease (i.v.).

Aciclovir-resistant herpes simplex virus has been reported in patients with AIDS but remains rare in immunocompetent patients. Foscarnet (p. 221) and cidofovir (p. 221) have been used in these cases.

Varicella zoster virus:

• Chickenpox, particularly in the immunocompromised (i.v.) or in the immunocompetent with pneumonitis or hepatitis (i.v.).

• Shingles in immunocompetent persons (as tablets or suspension, and best started within 48 h of the appearance of the rash). Immunocompromised persons will often have more severe symptoms and require i.v. administration.

Adverse reactions

are remarkably few. The ophthalmic ointment causes a mild transient stinging sensation and a diffuse superficial punctate keratopathy which clears when the drug is stopped. Oral or i.v. use may cause gastrointestinal symptoms, headache and neuropsychiatric reactions. Extravasation with i.v. use causes severe local inflammation. Crystal-induced acute renal failure is an important complication of i.v. therapy that can be avoided by ensuring good hydration during treatment.

Valaciclovir

is a prodrug (ester) of aciclovir, i.e. after oral administration the parent aciclovir is released. It has an improved bio-availability (about 60%) due to the addition of an ester side chain, thus allowing for a less frequent, 8-hourly, dosing. It is used for treating herpes zoster infections and herpes simplex infections of the skin and mucous membranes.

Famciclovir

(t½ 2 h) is a prodrug of penciclovir, which is similar to aciclovir; it is used for herpes zoster and genital herpes simplex infections, and a single dose is effective at reducing the time to healing of labial herpes simplex. It need be given only 8-hourly. Penciclovir is also available as a cream for treatment of labial herpes simplex.

Idoxuridine

was the first widely used antiviral drug; it is variably effective topically for ocular and cutaneous herpes simplex, with few adverse reactions. It has been superseded by aciclovir.

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.

Table 15.2 Classification and mechanism of antiretrovirals

image

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.

Pharmacokinetics

Zidovudine is well absorbed from the gastrointestinal tract (it is available as capsules and syrup) and is rapidly cleared from the plasma (t½ 1 h); concentrations in cerebrospinal fluid (CSF) are approximately half of those in plasma. Zidovudine is also available i.v. for patients temporarily unable to take oral medications, for neonates and for intrapartum use. The drug is inactivated mainly by glucuronidation in the liver, but 20% is excreted unchanged by the kidney. Zidovudine competitively inhibits the intracellular phosphorylation of stavudine, therefore use in combination with stavudine should be avoided.

Uses

Zidovudine is indicated for the treatment of HIV infection as part of a combination regimen. It is an established choice for the prevention of maternal–fetal transmission, both as part of a combination regimen antenatally in the mother and as monotherapy in the newborn. The enhanced CNS penetration of zidovudine makes it an important option for the treatment of HIV-associated neurocognitive disease (HAND). The drug is available as part of a fixed drug combination with lamivudine (as Combivir), and with abacavir and lamivudine (as Trizivir).

Adverse reactions

early in treatment may include anorexia, nausea, vomiting, headache, dizziness, malaise and myalgia, but tolerance develops to these and usually the dose does not need to be altered. More serious are anaemia and neutropenia, which develop more commonly when the dose is high, with advanced disease, and in combination with ganciclovir, interferon-α and other marrow suppressive agents. A toxic myopathy (not easily distinguishable from HIV-associated myopathy) may develop with long-term use. Rarely, a syndrome of hepatic necrosis with lactic acidosis may occur with zidovudine (and with other reverse transcriptase inhibitors).

Didanosine

Didanosine (ddI) is a thymidine analogue with similar activity to zidovudine. It has a short plasma half-life (t½ 1 h) but a much longer intracellular duration than zidovudine, and thus prolonged antiretroviral activity. Didanosine is rapidly but incompletely absorbed from the gastrointestinal tract (30–40%) and is widely distributed in body water; 30–65% is recovered unchanged in the urine. Drug absorption is affected by food and therefore it has to be taken on an empty stomach or at least 2 h after a meal. Didanosine may cause pancreatitis, lactic acidosis, hepatomegaly with steatosis and peripheral neuropathy. Other adverse effects include hyperuricaemia and diarrhoea, any of which may give reason to reduce the dose or discontinue the drug. Retinal changes and optic neuritis have also been reported. The combination of stavudine and didanosine is associated with a high risk of toxicity and should be avoided. Dose adjustment of didanosine is required when used in combination with tenofovir and in patients with renal insufficiency.

Lamivudine and emtricitabine

Lamivudine (3TC) is a reverse transcriptase inhibitor with a relatively long intracellular half-life (14 h; plasma t½ 6 h). Lamivudine is the most common nucleoside analogue used in HAART regimens due to its excellent tolerance profile. A nucleoside backbone of lamivudine with zidovudine (Combivir), abacavir (Kivexa) or emtricitabine and tenofovir (Truvada) as fixed drug combinations, appears to reduce viral load effectively and to be well tolerated. The drug is well absorbed from the gastrointestinal tract (86%) and excreted mainly by the kidney with minimal metabolism; dose modification is necessary in renal impairment.

Lamivudine was the first nucleoside analogue to be licensed for therapy of chronic hepatitis B infection, for which it should be used in combination with tenofovir (as part of a HAART regimen) in HIV co-infected patients. Emergence of resistant mutants of hepatitis B is troublesome (due to mutations of the viral reverse transcriptase/DNA polymerase), occurring in up to about 30% of patients after 1 year and 70% after 5 years of therapy.

The most common unwanted effects include headache and gastrointestinal upset. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. A higher dose of lamivudine is required for the treatment of HIV than for hepatitis B infection; patients with co-infection should receive doses appropriate for treatment of HIV.

Emtricitabine

Emtricitabine has a similar structure, tolerability, efficacy and resistance profile. It should not be used in combination with lamivudine, as it contains the same active constituent.

Abacavir

Abacavir (t½ 2 h) has high therapeutic efficacy; it is usually well tolerated, but adverse effects include hypersensitivity reactions especially during the first 6 weeks of therapy, affecting about 8% of patients; the drug must be stopped immediately and avoided in future if hypersensitivity is suspected. The presence of the HLA-B*5701 allele predicts increased risk of hypersensitivity reaction in the Caucasian population; patients should be tested for the presence of this allele prior to starting therapy.

Tenofovir

Tenofovir (t½ 17 h), administered orally as the prodrug tenofovir disoproxil fumarate, is also effective against hepatitis B virus. Some 80% is excreted renally and dose adjustment is recommended in patients with a creatinine clearance of less than 50 mL/min. Monitor closely for signs of new onset or acute renal impairment, electrolyte and renal tubular disturbance (Fanconi syndrome); avoid concomitant nephrotoxic drugs while on tenofovir.

Tenofovir competes with didanosine for renal tubular excretion, raising didanosine plasma concentrations with associated risk of pancreatitis, peripheral neuropathy and lactic acidosis. Severe acute exacerbation of hepatitis has been described following cessation of therapy for hepatitis B infection.

Stavudine

Stavudine (d4T) inhibits reverse transcriptase by competing with the natural substrate deoxythymidine triphosphate, and additionally is incorporated into viral DNA, causing termination of chain elongation (t½ 1.5 h). Troublesome lipoatrophy has limited its use by most authorities outside the developing world. Hepatic toxicity and pancreatitis are reported, and a dose-related peripheral neuropathy may occur, all probably related to mitochondrial toxicity. Stavudine is more frequently associated with lactic acidosis than other nucleoside analogues.

Adefovir

Adefovir dipivoxil is a nucleoside analogue used for chronic hepatitis B infection, including against lamivudine-resistant strains. It is administered as the oral prodrug (plasma t½ 8 h, intracellular t½ of active metabolite 17 h). Adverse effects are uncommon, but include headache, abdominal pain and diarrhoea. Resistance emerges over time (30% after 5 years), but much less commonly than with lamivudine therapy, possibly due to the flexibility of the adefovir molecule, which allows it to conform to mutated binding sites. Dose adjustment is required for patients with renal impairment. Adefovir should not be co-prescribed with tenofovir. The recommended adefovir dose for hepatitis B therapy will not suppress HIV infection; HIV status should therefore be confirmed prior to commencing adefovir for hepatitis B infection, as unrecognised co-infection may lead to the emergence of HIV resistance.

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:

• amprenavir, atazanavir, fosamprenavir (a prodrug of amprenavir), lopinavir, ritonavir, saquinavir, tipranavir, indinavir and darunavir.

Adverse effects

include gastrointestinal disturbance, headache, dizziness, sleep disturbance, raised liver enzymes, neutropenia, pancreatitis and rashes. Unique side-effects include asymptomatic reversible unconjugated hyperbilirubinaemia with atazanavir and nephrolithiasis with indinavir.

Interactions

Involvement with the cytochrome P450 system provides scope for numerous drug–drug interactions. Agents that induce P450 enzymes, e.g. rifampicin, St John’s wort, accelerate their metabolism, reducing plasma concentration and therapeutic efficacy; enzyme inhibitors, e.g. ketoconazole, cimetidine, raise their plasma concentration with risk of toxicity.

The powerful inhibiting effect of ritonavir on CYP 3A4 and CYP 2D6 is harnessed usefully by its combination in low (subtherapeutic) dose with other protease inhibitors; the result is to decrease the metabolism and increase the therapeutic efficacy of the concurrently administered protease inhibitors (called ritonavir ‘boosting’ or ‘potentiation’), i.e. a beneficial drug–drug interaction. Ritonavir boosting is particularly advantageous in patients infected with low-level resistant virus where the high drug levels help improve efficacy, but this may be at the detriment of increased gastrointestinal side-effects and metabolic disturbances. Ritonavir boosting is now a recommended treatment standard for all protease inhibitor containing regimens.

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.

Efavirenz

is taken once per day (t½ 52 h). Rash is relatively common during the first 2 weeks of therapy, but resolution usually occurs within a further 2 weeks; the drug should be stopped if the rash is severe or if there is blistering, desquamation, mucosal involvement or fever. Neurological adverse reactions occur in about 50% of patients, usually insomnia, depression and abnormal dreams; this may be reduced by taking the drug before retiring at night; gastrointestinal side-effects and occasional hepatitis and pancreatitis have also been reported. Efavirenz is teratogenic, so should be avoided in pregnancy. Resistance is associated with mutations at codon 103 and 181, which also confers cross-resistance to nevirapine.

Nevirapine

is used in combination with at least two other antiretroviral drugs. It is commonly prescribed in the developing world and is relatively safe in pregnancy. It penetrates the CSF well, and undergoes hepatic metabolism (t½ 28 h); it induces its own metabolism and the dose should be increased gradually. Nevirapine is initially commenced as a once-daily regimen, with a 2-week lead-in period to twice daily if tolerated. Rash (including Stevens–Johnson syndrome) is seen in up to 20% of patients and, occasionally, fatal hepatitis. The risk of an adverse drug event is closely related to the CD4 count; nevirapine is contraindicated in females with CD4 counts above 250 per microlitre and males with CD4 counts above 400 per microlitre.

Etravirine

(t½ 41 h) is administered twice daily after meals; rash is the commonest adverse effect, generally appearing within the first 6 weeks of therapy, and peripheral neuropathy. Etravirine has activity againt NNRTI-resistant HIV strains and should be used in combination with other antiretroviral agents. Due to potentially significant drug interactions, etravirine should not be co-administered with other NNRTIs, unboosted protease inhibitors and ritonavir-boosted tipranavir, fosamprenavir and atazanavir.

Entry inhibitors

Enfuvirtide

is the first antiretroviral agent to target the host cell attachment/entry stage in the HIV replication cycle; the linear 36-amino acid synthetic peptide inhibits fusion of the cellular and viral membranes. It is given by subcutaneous injection (t½ 4 h). The drug seems most effective when combined with several antiretroviral agents to which the virus is susceptible and is licensed for use in treatment-experienced patients with extensive drug resistance. Enfuvirtide does not inhibit cytochrome P450 enzymes and therefore has limited drug interactions.

Adverse effects are usually limited to mild injection-site reactions, although hypersensitivity, peripheral neuropathy and other adverse reactions are reported rarely. HIV isolates with decreased susceptibility have been recovered from enfuvirtide-treated patients; these exhibit mutations in the gp41 outer envelope glycoprotein of the virus (which plays a key role in infection of CD4 cells by fusing the HIV envelope with the host cell membrane).

Maraviroc

is an entry inhibitor that specifically targets and blocks the chemokine co-receptor CCR5, which is used by HIV for fusion and cell entry. Maraviroc has no activity against HIV virions that preferentially bind to another surface chemokine co-receptor (CXCR4), found in about 60% of antiretroviral experienced patients. Hence a ‘Trofile assay’ is required to determine if a susceptible (CCR5 tropic) strain is present as the dominant quasispecies in a patient prior to commencing maraviroc therapy. It is recommended as part of a combination regimen in treatment-experienced patients with multidrug-resistant strains.

Integrase inhibitors

Raltegravir

(t½ 41 h) targets the HIV integrase enzyme, which is essential in integrating viral genetic material into the DNA of the host target cell. It is generally well tolerated and metabolised by glucuronidation. It has a low genetic barrier to resistance (arising from mutations in the integrase gene) and should be used with caution in patients at increased risk of myopathy or rhabdomyolysis.

Fixed-dose combinations of antiretroviral drugs

are convenient, help to lessen pill burden and may improve compliance, but the components of the combination may differ in their dependence on metabolic inactivation or renal excretion; particular attention to these is necessary when use in patients with renal or hepatic impairment is proposed.

Fixed-dose combination antiretrovirals

Combivir zidovudine and lamivudine
Kivexa (Europe), Epzicom (USA) abacavir and lamivudine
Truvada tenofovir and emtricitabine
Trizivir zidovudine and lamivudine and abacavir
Atripla tenofovir and emtricitabine and efavirenz
Kaletra lopinavir and ritonavir

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.

Amantadine

Amantadine is effective only against influenza A; it acts by interfering with the uncoating and release of viral genome into the host cell. It is well absorbed from the gastrointestinal tract and is eliminated in the urine (t½ 3 h). Following the emergence of the 2009 influenza A (H1N1) virus as the predominant circulating strain, resistance to amantadine is now almost universal; for this reason amantidine is no longer recommended for the treatment of influenza.

Adverse reactions

include dizziness, nervousness, lightheadedness and insomnia. Drowsiness, hallucinations, delirium and coma may occur in patients with impaired renal function. Convulsions may be induced, and amantadine should be avoided in epileptic patients.

Amantadine for Parkinson’s disease: see page 365.

Zanamivir (Relenza)

Zanamivir is a viral neuraminidase inhibitor that blocks both entry of influenza A and B viruses to target cells and the release of their progeny. It is administered as a dry powder twice daily in a 5-day course by a special inhaler. The limited bio-availability (2%) of zanamivir has made it the preferred antiviral in pregnancy. The duration of symptoms is reduced from about 6 to 5 days, with a smaller reduction in the mean time taken to return to normal activities. In high-risk groups the reduction in duration of symptoms is a little greater, and fewer patients need antibiotics. It is also effective for prophylaxis given as a once-daily inhalation.

The UK National Institute for Health and Clinical Excellence (NICE) recommends that zanamivir be reserved for:

• At-risk patients (those with chronic respiratory or cardiovascular disease, immunosuppression or diabetes mellitus, or over the age of 65 years).

• When virological surveillance in the community indicates that influenza virus is circulating.

• Only those presenting within 48 h of the onset of influenza-like symptoms.

Zanamivir retains activity against amantadine-resistant and some oseltamivir-resistant strains.

Unwanted effects

are uncommon, but bronchospasm may be precipitated in asthmatics, and gastrointestinal disturbance and rash are occasionally seen.

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.

Unwanted effects

are uncommon; some people experience gastrointestinal symptoms that are reduced by taking the drug with food.

Resistance to oseltamivir emerged in late 2007 among seasonal influenza A H1N1 viruses as a result of a spontaneous mutation at position 274 (His274Tyr) in the neuraminidase enzyme. So far, this mutation appears to be confined mostly to seasonal influenza A H1N1 strains, with the majority of 2009 influenza A (H1N1) viruses still susceptible to oseltamivir; the mutation also does not appear to confer resistance to zanamivir.

Peramivir

is an experimental neuraminidase inhibitor formulated for intravenous use and currently undergoing phase III trials. The drug was granted temporary emergency use authorisation by the US Food and Drug Administration (FDA) during the 2009 influenza A (H1N1) pandemic for hospitalised patients with severe suspected or confirmed influenza A (H1N1) infection where oseltamivir or zanamivir therapy has failed or the inhalational or oral routes are considered unreliable.

Cytomegalovirus

Ganciclovir

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.

Valganciclovir

is an oral prodrug of ganciclovir that provides systemic concentrations almost as high as those following i.v. therapy. It is used for treatment of CMV retinitis (acute treatment of peripheral retinal lesions and maintenance suppressive therapy) in patients with AIDS, and to prevent CMV disease in patients receiving immunosuppressive therapy following organ transplantation (especially liver transplants). A combined approach of ganciclovir-releasing intraocular implant plus oral valganciclovir is sometimes considered in patients with immediate sight-threatening CMV retinitis.

Ganciclovir-resistant CMV isolates have been reported, and require treatment with foscarnet or cidofovir.

Adverse reactions

include neutropenia and thrombocytopenia, which are usually but not always reversible. Concomitant use of potential marrow-depressant drugs, e.g. co-trimoxazole, amphotericin B, azathioprine, zidovudine, should be avoided, and co-administration of granulocyte colony-stimulating factor may ameliorate the myelosuppressive effects. Other reactions are fever, rash, gastrointestinal symptoms, confusion and seizure (the last especially when imipenem is co-administered).

Foscarnet

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.

Cidofovir

Cidofovir

is given by i.v. infusion (usually every 1–2 weeks) for CMV retinitis in patients with AIDS when other drugs are unsuitable or resistance is a problem. It has also been used i.v. and topically to produce resolution of molluscum contagiosum skin lesions in immunosuppressed patients, and it may be effective in other poxvirus infections. Nephrotoxicity is common with i.v. use, but is reduced by hydration with i.v. fluids before each dose and co-administration with probenecid. Other unwanted effects include bone marrow suppression, nausea and vomiting, and iritis and uveitis, and cause about 25% of patients to discontinue therapy.

Fomivirsen

Fomivirsen, an antisense oligonucleotide, is available in some countries as an intravitreal injection for CMV retinitis in HIV-infected patients who cannot tolerate or who have failed treatment with other drugs.

Respiratory syncytial virus (RSV)

Ribavirin

is a synthetic nucleoside used for RSV bronchiolitis in infants and children, inhaled by a special ventilator. As therapeutic efficacy for this indication is controversial, it is usually reserved for the most severe cases and those with coexisting illnesses, such as immunosuppression. Systemic absorption by the inhalational route is negligible.

Ribavirin is effective by mouth (t½ 45 h) for reducing mortality from Lassa fever and hantavirus infection (possibly also other viral haemorrhagic fevers and West Nile virus) and, when combined with interferon α-2b or peg-interferon, for chronic hepatitis C infection (see below). It does not cross the blood–brain barrier, so is unlikely to be effective in viral encephalitides. Systemic ribavirin is an important teratogen, and it may cause cardiac, gastrointestinal and neurological adverse effects. It may also cause haemolytic anaemia, for which close monitoring is required.

Palivizumab

is a humanised monoclonal antibody directed against the F glycoprotein on the surface of RSV. It is given by monthly i.m. injection in the winter and early spring to infants and children less than 2 years old at high risk of RSV infection. Transient fever and local injection site reactions are seen and rarely, gastrointestinal disturbance, rash, leucopenia or disturbed liver function occur. Anaphylaxis has occurred rarely (1 in 10 000).

Drugs that modulate the host immune system

Interferons

Virus infection stimulates the production of protective glycoproteins (interferons) which act:

• directly on uninfected cells to induce enzymes that degrade viral RNA

• indirectly by stimulating the immune system

• to modify cell regulatory mechanisms and inhibit neoplastic growth.

Interferons are classified as α, β or γ according to their antigenic and physical properties. α-Interferons (subclassified -2a, -2b and -N1) are effective against conditions that include hairy cell leukaemia, chronic myelogenous leukaemia, recurrent or metastatic renal cell carcinoma, Kaposi’s sarcoma in patients with AIDS (an effect that may be due partly to its activity against HIV) and condylomata acuminata (genital warts).

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