August 8, 2012
Women living with HIV/AIDS are at higher risk of infection with human papillomavirus (HPV) than women who are HIV uninfected. Moreover, if HIV-infected women contract HPV, they are at higher risk of the infection becoming a malignancy, such as cervical cancer; that malignancy may also be more aggressive and harder to treat.
These realities make answers to questions such as whether the HPV vaccine can benefit HIV-infected women, as well as whether it's safe for them, really important. Six years after the approval of the first HPV vaccine, data are now starting to roll in on these questions, including some presented in two oral poster discussions at the XIX International AIDS Conference.
The first study (abstract, slides), conducted by Jessica Kahn, M.D., and colleagues, looked at whether the quadrivalent HPV vaccine (for HPV strains 6, 11, 16 and 18) was effective and safe for 99 HIV-infected women (79% black, 16% Hispanic, 4% white) ages 16 to 23. Over 48 weeks, the young women received the usual three injections given over the course of six months (vaccinations at day one, week eight and week 24) and were then followed for 24 weeks. To determine how the immune response in the study group compared to HIV-uninfected women, investigators used a historical cohort of 267 women matched by age and similar clinical history.
All the positive participants were infected with HIV after the age of 9. None of them had any opportunistic infections, significant bacterial infections or recent HPV symptoms (e.g., anogenital warts or grade 2/3 cervical intraepithelial neoplasia), though 75% had at least one strain of HPV. In addition, 85% of the group had a CD4+ cell count greater than 350, and 40% had a viral load lower than 400 copies/mL.
In terms of antiretroviral treatment (ART), 69 of the women had either never been on an antiretroviral regimen or hadn't been on any HIV treatment for at least six months, while the other 30 women were on ART for at least six months and had full virologic suppression. Of course, none of the participants were on any treatments that might have modulated the immune system.
The question of the immunogenicity of the vaccine was addressed by measuring, for all four HPV strains, both geometric mean titer (GMT) levels after vaccination as well as seroconversion rates in those who showed no antibodies to each HPV strain or DNA evidence that they were present (so-called "double negatives"). Four weeks after the third vaccination, 100% of all the "double negatives" for each HPV type in the control group, as well as in the group that was on ART, had HPV antibodies, compared to 90% to 96.3% of participants not on ART (HPV-6: 96.3%; HPV-11: 95.5%; HPV-16: 94.6%; HPV-18: 90%). GMT levels at the same time point for each HPV strain were consistently higher in the group on HIV treatment than in the HIV-uninfected control group and consistently lower, though not necessarily significantly so, in the untreated group than in the control group.
Notably, at week 48, 100% of the group on ART retained antibodies to three strains of HPV (-6, -11, -16) and 87.5% had antibodies to HPV-18. Of those untreated for HIV, seroconversion rates were also highest for HPV-6, -11, and -16 (95.8%, 97.4%, 97.1%) and lower for HPV-18 (73.9%).
The vaccine series was well tolerated and very few adverse events were reported, including both clinical symptoms and laboratory abnormalities. The most commonly reported side effect was low-grade post-injection pain (26.3%). No impact on viral load or CD4+ cell count was observed.
While this study does not establish whether the available HPV vaccines effectively protect HIV-infected women from genital warts, cervical cancers and other cancers that result from HPV infection, it demonstrates it is safe to vaccinate young HIV-infected women and that, in women who are negative for both antibodies and DNA presence of HPV, the immune response is robust. Despite a small sample size and the use of historical controls, the authors concluded that the data supports a recommendation to vaccinate all young, HIV-infected women, especially 11-to-12-year-olds.
In a presentation that helped fill in some more blanks about HPV vaccination for women living with HIV/AIDS, the AIDS Clinical Trials Group presented preliminary results (abstract, slides) of a multi-site, racially and ethnically diverse study designed to look at the development of antibody titers to the same four HPV strains (-6, -11, -16, -18) across three CD4 strata in HIV-infected women between the ages of 13 and 45, and to assess the safety and tolerability of the quadrivalent vaccine series.
Michelle Cespedes shared the results of two CD4 strata: 200 to 350 cells/mm3 (127 women) and >350 cells/mm3 (95 women). To assess immune response, Cespedes et al looked at the development of antibody titers in women who had no titers at baseline for each HPV type (HPV-6: 59%; HPV-11: 79%; HPV-16: 65%; HPV-18: 81%).
One month after the third vaccination, 100% of the women who were negative for HPV-6, -11 or -16 had seroconverted. For HPV-18, 91% of the women with a CD4+ cell count greater than 350 had seroconverted compared to 84% of the women with a CD4+ cell count between 200 and 350. Post-vaccine series GMT for each group was highest in those negative at baseline for HPV-16 and lowest for HPV-18. No serious adverse events connected to vaccination were reported.
This study did not look at how durable the immune response was over time, but it showed that, at least in women with a CD4+ cell count above 200 cells/mm3, the response is robust. Given the rather high percentage of women negative for the four HPV types targeted by the quadrivalent vaccine, the study investigators suggested that most HIV-infected women would benefit from vaccination.
These pieces of encouraging data, combined with the greater disease-causing impact of HPV infection on HIV-infected women compared to HIV-uninfected women, begin to beg the question about formal guidance for women living with HIV/AIDS. The need was highlighted by Cindy Firnhaber, a researcher from South Africa, who presented on HPV in the developing world and noted that there really should be separate guidelines for HIV-infected women. "It's not the same disease in my mind," she said.