Study does not support routine HPV quadrivalent vaccination to protect against anal cancer in older people living with HIV

The quadrivalent HPV vaccine Gardasil does not protect older adults with HIV against persistent anal infection with human papillomavirus (HPV) 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 HPV 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 HSIL – high-grade squamous intraepithelial lesions (pre-cancerous lesions) and, potentially, to the development of anal cancer.

There is a high prevalence of HSIL 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 types of HPV, is the most effective strategy for the prevention of cervical and anal cancers.

The original Gardasil vaccine, offers protection against the two most common HPV types associated with the development of cervical and anal cancer – HPV types 16, and 18 – as well as HPV 6 and 11 which cause genital warts. The vaccine is routinely offered to girls and boys aged 11-12 and is recommended for young women up to age 26 and young men up to age 21 in the United States, as well as young gay or HIV-positive men age 13-26 who were not vaccinated when they were younger. A newer version of Gardasil protects against 9 HPV types.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. 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 had 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 study 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 (FDA) 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.