Back HIV-Related Conditions Cancer CROI 2016: Study Does Not Support Routine HPV Vaccination to Prevent Anal Cancer in People with HIV

CROI 2016: Study Does Not Support Routine HPV Vaccination to Prevent Anal Cancer in People with HIV


The quadrivalent HPV vaccine Gardasil does not protect older adults with HIV against persistent anal infection with human papillomavirus or the development of high-grade anal lesions (HSIL), but the ACTG A5298 study showed some evidence that it may protect against persistent oral HPV infection, Timothy Wilkin of Weill Cornell Medical College reported at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) last week in Boston.

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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 2 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 age 11-12 and is recommended for young women up to age 26 and young men up to age 21 in the U.S., as well as young gay or HIV-positive men age 13-26 who were not vaccinated when they were younger. 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 U.S. cohort study which followed men for at least 2 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 already been exposed to cancer-causing HPV types in the past.

ACTG A5298 was a randomized 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 3 years.

The study recruited 575 participants with a median age of 47 years. 80% were male, 46% were non-Hispanic white, 34% were non-Hispanic black, and 20% were 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. 60% 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 randomized to receive the quadrivalent vaccine or placebo injections 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 6 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 2 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 [HR] 0.75, 95% CI 0.45-1.26), nor 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, again not a significant difference (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).

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 series 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 age 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 2 types of HPV most commonly associated with cancer, but since this trial began, the U.S. Food and Drug Administration has approved a vaccine to protect against 9 types (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.



TJ Wilkin, H Chen, M Cespedes, et al. ACTG A5298: A Phase 3 Trial of the Quadrivalent HPV Vaccine in Older HIV+ Adults. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 161.