Viral infections

Severe mucocutaneous and systemic infections with herpes simplex virus are best treated with aciclovir. Prophylaxis is used after severe infection and in patients with increasing severity and frequency of recurrences.

Varicella zoster virus infections are usually treated with high-dose aciclovir given by mouth. However, dissemination of infection from dermatomal zoster is unusual even without treatment.

Valaciclovir is a pro-drug of aciclovir which is used in the treatment of herpes zoster and herpes simplex infections of skin and mucous membranes. Valaciclovir is a L-valine ester of aciclovir that is rapidly converted to aciclovir after oral administration. The antiviral spectrum and mode of action is therefore the same as aciclovir. Aciclovir has, however, a low oral bioavailability (about 15—20%). Valaciclovir has three or four times the oral bioavailability of aciclovir.

Famciclovir is a diacetyl ester of 6-deoxy penciclovir which has been used in the treatment of herpes zoster and genital herpes infections. Famciclovir is metabolised to penciclovir in the intestinal wall and liver. Penciclovir and aciclovir have similar antiviral spectrum.

Aciclovir resistant herpes simplex infections can occur, particularly in patients with advanced disease and severe immunosuppression. Alternative agents to treat resistant infections include foscarnet and cidofovir.

Reactivation of cytomegalovirus with viraemia and end­organ disease tends to occur when CD4 cell counts are persistently below 50 ? 10⁶∕l. Ganciclovir (an acyclic analogue of deoxyguanosine), foscarnet phosphonoformate (a pyrophosphate analogue, which inhibits polymerase enzymes) and cidofovir (a nucleoside analogue with potent in vitro activity against viruses) are used for the treatment of cytomegalovirus retinopathy, gastrointestinal and neurological disease.

The detection of mutations in the CMV UL97 gene is associated with an increase in CMV DNA levels in blood and clinical progression of CMV retinitis during ganciclovir therapy. High-level resistance to ganciclovir results in cross-resistance to cidofovir. Resistance to foscarnet can occur but the mechanism is different.

Cidofovir has been shown to be effective however in delaying progression and time to relapse in patients who have experienced therapy failure on ganciclovir and foscarnet. The dosing schedule of cidovofir is convenient and more suitable to outpatient care than with either intravenous ganciclovir or foscarnet. It is given once weekly (5mg∕kg) for two weeks as induction therapy and then at the same dose every two weeks thereafter as maintenance therapy. The main side-effect is

Box 9.3 Management of CMV disease: key points

• Population at highest risk of clinical disease: CD4 < 50 ? 10⁶∕l

positive CMV viraemia

• Diagnostic criteria: combination or clinical presentation +/ — histopathology +/— virus isolation (culture or antigen detection)

• Choice of first line therapy dependent upon renal function, haematological indices and risk of toxicity

• Where possible all patients should be started on an effective HAART regimen to increase the CD4 count to above 100 ? 10⁶∕l

• Secondary prophylaxis maybe discontinued once the CD4 count has risen and remains above 100 ? 10⁶∕l

Table 9.3 Opportunistic infections: recommendations for initiation of primary prophylaxis