Cidofovir
Cidofovir is an acyclic nucleoside phosphonate with a broad-spectrum activity against DNA viruses. It competitively inhibits the incorporation of deoxycytidine triphosphate into viral DNA by viral DNA polymerase, causing a disruption in chain elongation95. Cidofovir’s mechanism of action and its selectivity for HPV-transformed cells is dependent on their inability to respond to DNA damage, rather than having a direct anti-HPV effect. Viral oncoproteins E6 and E7, in HPV infected cells cause deregulation of cell cycle control, making these cells are more susceptible to DNA damage than normal keratinocytes 96. Treatment with Cidofovir causes cell death by apoptosis. Induction of apoptosis in HPV infected cells by Cidofovir was associated with accumulation of the tumour suppressor proteins p53 and pRb and the cyclin-dependent kinase inhibitor p21/WAF-1 97.
Systemic exposure of Cidofovir after vaginal application is low. This was observed in a trial of nine women with CIN2+ treated with 3 g of 2% Cidofovir gel administered in a cervical cap and applied directly to the cervix, once per week for five or ten hours, over a period of three weeks. Very low plasma concentrations were reached when compared with intravenous administration, at the approved dose 98indicating that the drug stays at the desired site of action on the cervix and works locally with limited systemic absorption and thereby minimizing the risk of unwanted systemic side effects. In another study, 48 women with biopsy-proven CIN2+ were treated with either three applications of 3 ml of 2% Cidofovir gel in a cervical cap or a placebo for four hours, six weeks before conization. Biopsy results from the excised cones showed resolution of CIN in 60.8% in the Cidofovir group compared to 20% in the placebo group. In addition, there were no systemic toxicity or cervico-vaginal side effects of Cidofovir compared to the placebo. However, Cidofovir failed to eradicate HPV infection52. Contrastingly, in a separate study by Snoeck et al., 15 women had 3 g of 1% Cidofovir gel applied on the cervix three times on alternate days by a gynaecologist using colposcopy for an average of 17 days. The results from the cone biopsies taken after more prolonged treatment with Cidofovir showed a complete response in seven of the 15 patients and in four of these seven patients, PCR results showed resolution of HPV infection. Once again there was no toxicity observed in the normal tissue and the treatment was well tolerated99. These studies support selectivity of Cidofovir against HPV induced epithelial proliferation compared to normal epithelium. In five of the 15 patients there was a limited response in the superficial epithelial layers, two patients did not respond, and one patient downgraded from CIN3 to CIN1. The partial response is likely due to poor bioavailability of the drug at the deeper epithelial layers indicating the need to modify the dosage or formulation of the drug in order to reach the deeper layers 99