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