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HPV vaccination to prevent recurrence of Anal Intraepithelial Neoplasia in HIV+ MSM - a randomised, placebo-controlled multicentre trial
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AIDS May 5 2021
"We now provided evidence that qHPV vaccination as secondary prevention for HGAIN recurrence in HIV+ MSM is ineffective."
"We found no difference (p = 0·38) in cumulative HGAIN recurrence rates between the qHPV (44/64, 68.8%) and placebo group (38/62, 61.3%) in the intention-to-treat analysis (absolute risk reduction -7.5 (95%CI -24.1–9.2)). This was similar in the per-protocol analysis.”

In HIV+ MSM successfully treated for intra-anal HGAIN, vaccination with the prophylactic qHPV vaccine does not prevent short-term recurrence of HGAIN. This finding appeared consistent across all subgroups, accounting for the stratification factors. We could confirm that the qHPV vaccine is immunogenic and safe in HIV+ MSM.[16] Vaccination with qHPV induced a significant increase in concentrations of type-specific antibodies against all vaccine types and the non-vaccine types 31 and 45, but two-thirds of participants were already seropositive for vaccine types HPV16 and 18 at baseline. A similar proportion of recurrent HGAIN lesions in both groups were caused by vaccine types, supporting non-efficacy. Additionally, we did not observe significant effects of qHPV vaccination on the secondary outcomes prevention of LGAIN and anogenital condylomata.
Vaccination with qHPV for primary prevention of anal HPV infections and HGAIN has been proven ineffective in PLWH (aged >26 years)[24] and HIV+ MSM.[25] This in spite of the induction of adequate antibody responses by the qHPV vaccine in PLWH. Efficacy as secondary prevention, i.e. preventing new infections or lesions in patients with ongoing or previous HPV infection and/or resulting premalignant lesions, has been questioned.[26-28] A recent meta-analysis indicates efficacy (RR=0.41) of qHPV vaccination as a treatment adjuvant to prevent recurrence of HGCIN.[14] However, considerable heterogeneity between studies was noted (different age of patients (mostly younger), timing of vaccination before or after treatment and duration of follow-up), and only one included study was a randomised trial specifically designed to assess prevention of recurrent HGCIN after treatment. However, this study was neither placebo-controlled nor blinded.[29] A recent RCT could not confirm prevention of recurrent HGCIN by HPV vaccination in HIV+ women.[15] The only study in MSM evaluating qHPV as treatment adjuvant to prevent HGAIN recurrence claimed a significant reduction (HR=0.50) of HGAIN recurrence 2 years after qHPV vaccination, but this was a non-randomised, non-concurrent cohort study of HIV-negative MSM, who were on average slightly younger than our study cohort.[13] We now provided evidence that qHPV vaccination as secondary prevention for HGAIN recurrence in HIV+ MSM is ineffective.
How the secondary prevention efficacy of qHPV as treatment adjuvant observed in aforementioned studies should be explained remains to be elucidated.[13, 14, 29] One hypothesis that has been posed in the literature suggests a ‘therapeutic’ effect of the vaccine.[30] This hypothesis seems somewhat counterintuitive, since a combination of innate and adaptive (including T-cell-mediated) immune responses is required to actively clear (residual) AIN lesions, whereas the mode of action of prophylactic (L1 VLP) qHPV vaccination relies predominantly on potent neutralising antibodies. Although the interplay with the immune system is not fully unravelled, vaccination does also induces a L1-specific CD8 T-cell response, however basal keratinocytes at the site of infection do not express L1 and it has been suggested that they may therefore escape the immune system.[31]
Another hypothesis in literature proposes a specific ‘prophylactic’ effect by preventing new lesions caused by HPV types to which patients were not previously exposed.[30] In general antibody responses adequately correlate with the efficacy of this vaccine. Our and previous observations of non-efficacy of qHPV in PLWH, in spite of adequate antibody responses, show this is not the case for PLWH.[24, 25] We hypothesise that the HIV-infection, the MSM risk group, or the combination is likely to be the cause of this non-efficacy. If this hypothesis would hold true, younger patients could still benefit, as their probability of being previously exposed to these HPV types is generally lower, especially in MSM who often harbour many hrHPV types and anal HPV prevalence does not decrease at older age.[32] We found no significant effect in our analysis for the ‘younger’ age group (<44 years), although our population still consisted mainly of middle-aged (median age 49 years) HIV+ MSM. At baseline two-thirds of participants were already seropositive for vaccine HPV types 16 and 18, showing previous exposure to these types. We cannot rule out that young (HIV+) MSM, possibly naïve for at least some HPV types, would benefit from post-treatment vaccination, given results in women in which cohorts were generally younger. However, screening for anal cancer in HIV+ MSM, and thus treatment of HGAIN, is generally not started before the age of 30-35 years.
Deshmukh et al. modelled cost-effectiveness and concluded that post-treatment adjuvant qHPV vaccination for HIV-negative MSM aged 27 years and older is cost-effective,[33] and likewise in HIV+ MSM.[9] Based on our findings, post-treatment vaccination is unlikely to be universally cost-effective in HIV+ MSM.
This trial is, to our knowledge, the first RCT designed to investigate in HIV+ MSM the efficacy of qHPV vaccination as post-treatment adjuvant to prevent HGAIN recurrence, confirmed by determining causal HPV types in recurrent HGAIN lesions and assessing immunogenicity with HPV type-specific antibody response. We decided to investigate the clinically relevant outcome of overall HGAIN recurrence, irrespective of possible anal HPV infections at baseline, rather than HPV type-specific efficacy.
Our study has several limitations. First, although participants were thoroughly screened by two experienced high-resolution anoscopists at enrolment and all suspected lesions were biopsied, we cannot rule out that microscopical lesions remained undetected or were misdiagnosed, although this would be equally distributed by randomisation. Anal cytology in case of a negative HRA at enrolment could have slightly lowered this risk, although the diagnostic yield of additional cytology at FU18 turned out to be low. Second, as we did an ITT analysis, starting at first vaccination, a number of participants already had their recurrence at the time of third vaccination (6 months). However, also during the ensuing year we observed no difference in recurrence rates between the two study arms. We acknowledge that the follow-up of 12 months after last vaccination is short. However, in a previous study in HIV-negative MSM, the strongest significant effect was already observed within the first year after last vaccination.[13] Moreover, during our follow-up period we already observed recurrence rates that approximate current literature.[6-8] Previous follow-up studies after HGAIN treatment have shown recurrence rates levelling off three years after treatment.[7] Hypothetically, vaccination with qHPV could have long-term effects by reaching this plateau phase earlier, lowering the total number of recurrences, and/or result in less treatment-resistant recurrent lesions. For this reason extended follow-up is planned for the study participants. Third, we were unable to determine causative HPV types in all recurrent HGAIN lesions, precluding a definite conclusion on prevention of vaccine-type recurrences. Fourth, our study does not give a decisive answer whether the nonavalent HPV vaccine, which has a wider coverage of HPV types but was not licensed yet during the preparation of this trial, would be efficacious to prevent recurrent HGAIN in HIV+ MSM, although this is not supported by the cross-reactivity we observed for HPV31 and 45. Finally, follow-up was discontinued when the primary endpoint was reached, while ideally follow-up should have been continued to assess secondary endpoints LGAIN and anogenital condylomata. Although we included a worst- and best-case scenario, the results for these endpoints should therefore be interpreted with caution, as is expressed by the wide CIs.
The anal cancer precursor HGAIN is highly prevalent in HIV+ MSM and screening for premalignant lesions is advocated for this group. However, treatment is frustrated by high recurrence rates. In search of a strategy to reduce recurrence of HGAIN, vaccination with qHPV has been suggested. We have now provided evidence from an RCT that there is insufficient scientific rationale to support qHPV vaccination as treatment adjuvant to prevent short-term HGAIN recurrences in HIV+ MSM.

Anal cancer precursor lesions high-grade anal intraepithelial neoplasia (HGAIN) are highly prevalent among HIV+ men-who-have-sex-with-men (MSM). Treatment of HGAIN is frustrated by high recurrence rates. We investigated the efficacy of the quadrivalent human papillomavirus (qHPV) vaccine as post-treatment adjuvant in preventing HGAIN recurrence in HIV+MSM.
Randomised, double-blind, placebo-controlled, multicentre trial.
Three HIV outpatient clinics in Amsterdam, the Netherlands.
HIV+MSM with CD4 count >350 cells/μl, biopsy-proven intra-anal HGAIN successfully treated in the past year, and lesions still in remission at enrolment, as assessed by high-resolution anoscopy (HRA).
Participants were randomised to three doses of qHPV (Gardasil-4®, MSD) or placebo with vaccinations at 0, 2, and 6 months. HRA was repeated at 6, 12 and 18 months.
Main outcome measure:
The primary outcome was cumulative, biopsy-proven HGAIN recurrence rate at 18 months, evaluated in an intention-to-treat (received all vaccinations) and per-protocol analysis (all vaccinations and complete follow-up).
We randomised 126 participants of which 64 (50.8%) received qHPV and 62 (49.2%) placebo. All participants received three vaccinations and in both groups for two participants follow-up was incomplete. We found no difference (p = 0·38) in cumulative HGAIN recurrence rates between the qHPV (44/64, 68.8%) and placebo group (38/62, 61.3%) in the intention-to-treat analysis (absolute risk reduction -7.5 (95%CI -24.1–9.2)). This was similar in the per-protocol analysis.

Despite adequate serological responses to qHPV vaccination, short-term recurrence of HGAIN was not prevented. These findings do not support qHPV vaccination as a treatment adjuvant to prevent HGAIN recurrence in HIV+MSM.
Preliminary results were previously presented at (abstracts included in submission):
• International Anal Neoplasia Society Scientific Meeting in Amsterdam, The Netherlands, November 1-3, 2019 (oral presentation)
• Dutch HIV Treating Physicians Scientific Meeting Amsterdam, The Netherlands, January 17, 2020 (oral presentation)
• International Papillomavirus Society Conference (digital) July 20-24, 2020 (poster)

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