A new therapeutic vaccine for human papillomavirus (HPV), a sexually transmitted virus that can cause anal and genital cancer, appears safe and stimulates an immune response in HIV-positive people, according to a poster presented Monday at the Fourth International AIDS Society Conference on HIV Treatment, Pathogenesis and Prevention in Sydney.
Although two HPV preventive vaccines have now been approved in Europe, it is unclear if those vaccines will have any impact on the incidence of anal or cervical cancer in HIV-positive people already infected with HPV.
An analysis of the FUTURE 1 study of the approved Gardasil HPV vaccine found a 73% efficacy rate against the development of anogenital warts or pre-cancerous or cancerous cell changes in the anus in women during four years of follow-up. However the investigators stressed that the study did not include HIV-positive people, and the protective effect of the vaccine in people with HIV remains unclear.
A therapeutic vaccine against cancer-causing HPV type 16 is being developed by the Australian company CSL. It is designed to prevent the development of neoplasia (pre-cancerous cell changes) by stimulating cellular immune responses to this type of HPV.
The manufacturer chose to test the vaccine in HIV-positive people in order to determine whether it would induce immune responses to HPV in people with moderate immune suppression.
The study enrolled 35 HIV-positive men who have sex with men in Melbourne and Sydney into a dose-ranging study of the safety and tolerability of the vaccine. Secondary objectives of the study were to examine the evolution of immunological responses to HPV after vaccination, including antibody and T-cell-mediated immunity, as well as anal HPV clearance and related pathology (such as anal neoplasia and anal warts).
Participants were randomly assigned to receive either placebo injections or the HPV-16 E6E7 vaccine plus the “Iscomatrix” adjuvant at one of three doses (25mg, 70mg or 240mg). Three groups received three injections at days 0, 28, and 84, while a fourth group received injections on an accelerated schedule at days 0, 14 and 70.
At study entry, the median age was 47 years and the median CD4 cell count was 627 cells/mm3. Participants had experienced fairly serious immune suppression in the past, with a median nadir (lowest-ever) CD4 cell count of 154 cells/mm3. Almost all (94%) were taking antiretroviral therapy during the study.
One of the questions about HIV treatment is whether a low nadir CD4 count limits the degree of immune restoration and the breadth of immune response an individual can expect to achieve after a few years of successful antiretroviral therapy, and whether this in turn might alter the long-term risk of certain types of cancer.
All participants were infected with high-risk (cancer-causing) HPV types. More than half (59%) had HPV-16, 32% had HPV-18 and 17% to 41% had nine other high-risk types; many were infected with multiple types. Most participants (80%) had some degree of abnormal cells in the anus detectable by Pap smear, including 31% with low-grade and 14% with high-grade anal intraepithelial neoplasia.
After 36 weeks of follow-up, the vaccine was generally well tolerated. Although there were no severe adverse reactions, most participants reported moderate to severe injection site pain and swelling and systemic symptoms including headache, muscles aches and fatigue. CD4 cell counts remained stable in all participants, but five experienced HIV viral load blips.
Immunological responses were good. Nearly three-quarters of participants (71%) experienced at least a three-fold increase in interferon-gamma responses to the E6-E7 peptides in the vaccine as measured by the Quantiferon assay. Further, almost all participants (96%) experienced at least a four-fold increase in IgG antibodies specific to these peptides.
However, there were no clear trends in HPV detectability or anal cell changes when comparing the different vaccine doses and placebo. Two participants receiving the vaccine cleared HPV-16 – compared with none in the placebo group -- but three others who started with other HPV types acquired HPV-16.
Whilst four of six participants who started with high-grade anal neoplasia experienced resolution, others developed new high-grade neoplasia during follow-up. Overall, a majority of participants experienced either a slight improvement or no change in anal lesions.
The researchers concluded that the HPV-16 therapeutic vaccine appeared safe and well-tolerated in HIV-positive people, producing strong and persistent antibody and T-cell-mediated immune responses, despite the fact that the study participants had considerable immune impairment in the past as indicated by low nadir CD4 cell counts,
Lead author Jonathan Anderson told aidsmap that the current study was too small to determine the efficacy of the vaccine, but the researchers were encouraged by the good immune response and plan to conduct further studies.
Anderson J et al. A randomised, placebo-controlled, dose escalation study to determine the safety, tolerability and immunogenicity of an HPV therapeutic vaccine in HIV-positive participants with oncogenic HPV infection of the anus. Fourth International AIDS Society Conference on HIV Treatment, Pathogenesis and Prevention, Sydney, abstract MOPEB089, 2007.