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Study does not support routine HPV quadrivalent vaccination to protect against anal cancer in older people living with HIV
Keith Alcorn, 2016-02-29 13:30:00
The quadrivalent HPV vaccine Gardasil does not protect older adults
with HIV against persistent anal infection with human papillomavirus or the
development of HSIL, but the ACTG A5298 study showed some evidence that it may
protect against persistent oral infection, Timothy Wilkin of Weill Cornell
Medical College told the Conference on Retroviruses and Opportunistic
Infections (CROI 2016) in Boston on Thursday.
Anal cancer caused by human papillomavirus is one of the
most common cancers with an infectious cause in people living with HIV.
Persistent HPV infection with a cancer-causing virus type may lead to the
development of high-grade squamous intraepithelial lesions
(pre-cancerous lesions) and, potentially, to the development of anal cancer.
There is a high prevalence of high-grade
squamous intraepithelial lesions in people with HIV, although there is also
evidence that lesions frequently
resolve without treatment.
Vaccination before becoming sexually active, or before
acquisition of cancer-associated HPV, is the most effective strategy for the
prevention of cervical and anal cancers.
A vaccine (Gardasil)
which offers protection against the four most common HPV types associated with
the development of cervical and anal cancer – HPV types 6, 11, 16 and 18 – is
routinely offered to girls and is recommended for young gay men aged 13-26 in
the United States. The vaccine has also been recommended for use in England for
men who have sex with men under the age of 45 attending sexual health clinics.
The incidence of anal HPV is high among sexually active gay
men: a US cohort study which followed men for at least two years found an
annual incidence of 13%.
However, evidence is lacking regarding the efficacy of the HPV
vaccine in older people living with HIV, who are more likely to have been
exposed to cancer-causing HPV types in the past.
ACTG A5298 was a randomised placebo-controlled study of the
quadrivalent HPV vaccine in people living with HIV over the age of 26. The
study was designed to test the efficacy of the quadrivalent vaccine in
preventing persistent HPV infection and HSIL in adults with no evidence of
infection with HPV types 6, 11, 16 and 18 at pre-trial screening. Participants
were followed for three years.
The study recruited 575 participants with a median age of 47
years, 80% male, 46% white non-Hispanic, 20% Hispanic and 34% Black
non-Hispanic. The median baseline CD4 cell count was 602 cells/mm3 and
90% had undetectable viral load (<200 copies/ml). The study excluded
participants with anal cancer.
The study population had a high prevalence of anal
cytological abnormalities. At baseline 64% had abnormal anal cytology and 33%
had HSIL. Sixty per cent were infected with one or more of the HPV types
covered by the quadrivalent vaccine, most commonly HPV 16 (32%), and 11% had
oral infection with one or more HPV
types covered by the vaccine.
Study participants were randomised to receive quadrivalent
vaccine or placebo at baseline, and at weeks 8 and 24. They were tested for HPV
DNA in anal and oral tissue and underwent histological screening for HSIL at
baseline and every six months thereafter.
Inadequate or non-existent antibody response to HPV
infection leads to persistent infection, increasing the risk of pre-cancerous
lesions and the development of anal cancer. The efficacy of the vaccine to
stimulate antibody responses in people with compromised immunity is therefore
critical. The vaccine was highly immunogenic: 99% of participants who received
the vaccine had antibodies to HPV 16 at week 24 compared to 48% at baseline.
There was no change in HPV 16 seropositivity in the placebo group. No grade 3
or 4 serious adverse events were reported during the study.
After 130 weeks of follow up there was no significant
difference between the two arms in the number of participants with detectable
HPV at any single visit (26 in the vaccine arm vs 33 in the placebo arm, hazard
ratio 0. 75, 95% CI 0.45 – 1.26), nor a significant difference in the number of
participants with persistently detectable anal HPV (13 vs 17, HR 0.73, 95% CI
0.69-1.44). Although persistent HPV 16 infection declined in the vaccine group
by week 130 and returned to above baseline levels in the placebo group, this
difference was not statistically significant.
Anal HSIL was detectable after week 52 in 46 of the vaccine
recipients and 47 of the placebo recipients (HR 1.0, 95% CI 0.69-1.44). There
was no difference in abnormal anal cytology at weeks 52, 104 or 156.
Although there was no significant difference in detection of
oral HPV infection at any single visit (7 vs 10, HR 0.68, 95% CI 0.26 – 1.80),
the study found a significantly reduced risk of persistent oral HPV infection
in the vaccinated group (1 vs 8, HR 0.12, 95% CI 0.02-0.98, p=0.019).
Why did the vaccine not protect against anal HPV infection
or HSIL development? Poor immunogenicity was not the reason, and early
infections prior to completion of the full vaccination schedule cannot be
blamed, because similar results were found when infections detected prior to
week 28 were excluded from the analysis. Instead, say investigators,
vaccination likely failed to show a benefit because some prior infections were
not detected by anal HPV DNA testing, and because the vaccine does not
stimulate cellular immunity to clear pre-existing infections.
The investigators concluded that the study results do not
support routine HPV vaccination of adults aged 27 and over for prevention of
HPV infection or improvement of HSIL, but do consider the findings regarding
prevention of persistent oral HPV infection to justify further investigation of
vaccination in people living with HIV for prevention of oral cancers. HPV
vaccination has been shown to protect against oral HPV infection in women aged
18 to 25.
One question not addressed in post-presentation discussion
was the breadth of the vaccine. The quadrivalent vaccine protects against four
types of HPV most commonly associated with cancer, but since this trial began
vaccinating participants, the US Food and Drug Administration has approved a
vaccine to protect against nine subtypes (Gardasil
9) – those included in the previous Gardasil vaccine, plus types 31, 33,
45, 52 and 58. Whether greater vaccine breadth would have altered the risk of HSIL
in this study is unclear.