Fridae

In May 2009, HTU wrote about cervical cancer in women with HIV (Cervical cancer and you, HTU 186).1 That article quoted recommendations for “aggressive” annual screening for cervical cell changes, because women with HIV were twice as likely to be infected with the human papillomavirus (HPV), the virus that causes the cancer, three to four times more likely to develop pre-cancerous abnormal cells, and twelve times more likely to get invasive cervical cancer if they do.2 If they do get cancer, there is a one in three chance they will be dead of it within ten years.3 But a simple procedure under local anaesthetic can remove pre-cancerous cells if they are identified – and the national screening programme has cut mortality by nearly two-thirds.4 And we now have a vaccine against the two most common cancer-causing varieties of HPV, with a programme to give that vaccine to all teenage girls.

Anal cancer is caused by the same virus and, in the same way as cervical cancer, causes pre-cancerous changes in cells that can be screened for and treated. It’s about 16 times rarer than cervical cancer in the general population. But it’s about 60% more common in women than men and about 50 times more common in gay men with HIV (because anal sex is a risk factor) – which makes it as common in them as cervical cancer is in HIV-positive women and is a huge risk increase: for comparison, lung cancer is ‘only’ 25 times more common in heavy smokers than in non-smokers.5 If you do develop anal cancer, there’s a one-in-three chance you’ll die of it within five years.6,7

But, unlike the regular check-ups for cervical cancer in women, there is no standard screening for anal cancer, or even any agreement about whether it would be a good thing. And although the HPV vaccine has been licensed for use in boys in the US, a licence for this use has not been granted in Europe. 

Why not? Should we be agitating for better screening – especially of gay men with HIV – for anal cancer and for extending the HPV vaccine to boys? 

HPV and anal cancer – the facts 

Cervical and anal cancers are caused almost entirely by a viral infection – HPV – which is not one virus, but a family of about 100 different ones that cause everything from common warts to genital warts to cancers. The majority of sexually active adults eventually acquire at least one variety of HPV and it’s a near-universal infection in people with HIV. For the majority of people HPV has no symptoms. 

Only specific varieties of HPV – the so-called ‘high-risk’ types – cause cancers. HPV 16 is the most common as an infection and is associated with the highest rate of progression to cancer. The second most common and aggressive type in the US and Europe is HPV 18. There are at least twelve other high-risk types, some of which are more common than type 18 in other parts of the world but tend to be less aggressive. Types 16 and 18 between them cause 70% of cervical cancers and 80% of anal cancers worldwide.8

One important fact about HPV is that, in most cases, the body eventually gets rid of the infection. The average length of any single anal HPV infection is five months to a year in HIV-negative people: people with weaker immune systems may take longer to get rid of it.9

Anal cancer differs from cervical cancer in that there is less association between CD4 count and risk, although people with lowered immunity are at greater risk of anal cancer. Most of the increased prevalence is amongst gay men regardless of HIV status.10 This may be due to more frequent infection with a greater variety of types of HPV, largely due to anal intercourse. HIV therapy is not reducing HPV incidence. A recent French study found that 98% of gay men diagnosed with HIV already had evidence of at least one HPV type, 92% a high-risk type and 43% HPV 16; after two years on HIV therapy these percentages were not significantly lower.11 

There are now two HPV vaccines, Merck’s Gardasil and GlaxoSmithKline’s Cervarix. Both vaccines protect against infection with HPV types 16 and 18, and Gardasil against the two most common low-risk genital wart varieties too (HPV 6 and 11). 

Testing and grading 

The high-risk HPV types tend not to cause obvious genital warts but do cause changes to the appearance and function of cells in the anal canal, which can be seen under medical examination. Areas either lose all pigment and look white, or get hyperpigmented and look red. While only a tiny proportion of people with HPV will go on to develop cancer, these changes are very common and can be graded by severity. Two grading categories are used, according to the type of medical test done. 

In a smear test, some cells from the anal region are swabbed off with a sample stick. These cells are suspended in fluid, stained and examined under a microscope, a process called cytology. Cells modified by HPV often have larger or multiple nuclei, thicker walls and a generally ‘denser’ appearance. 

Cells are graded according to their individual appearance into: normal; ‘atypical squamous cells of undetermined significance’ (ASCUS); and low- and high-grade ‘squamous intraepithelial lesion’ (LSIL and HSIL). If they are fully-fledged cancer cells, but there is no invasive cancer, the diagnosis may be adenocarcinoma in situ (AIS). 

In an anoscopy, the physician will visually examine the anal region in more detail using a proctoscope, and take biopsies: small snips of whole tissue. These will then be examined under the microscope in a process called histology, which looks at changes in the whole tissue and how it is organised, rather than at individual cells: for instance, what proportion of cells in the biopsy have become atypical and whether the lesion just affects the epithelium – the surface membrane of the anal tissue – or has penetrated to deeper areas. Any lesions are then graded into anal intraepithelial neoplasia (AIN), grades 1, 2 or 3. 

Cytology is sensitive – it is good at picking up signs of pre-cancerous changes in cells – but HPV specialists at the Chelsea and Westminster Hospital found that it only correctly predicted the AIN grade in 40% of cases.12 This is in contrast to cervical cytology in screening, which is over 90% specific.13 So, while a smear test may be the cheapest and most convenient way of screening for possible anal cancer, an anoscopy is the only way to decide if changes warrant treatment. For the types of treatment people can be given, see below.

Screening

Given the comparative rarity of anal cancer, screening the general public is not considered necessary. But for those at higher risk (gay men with HIV, possibly all gay men and women who have anal sex), cervical screening is a good precedent for the value of anal screening. In the UK, cervical screening is offered to women aged 25 to 65. The death rate due to cervical cancer in women under 45 went down by nearly two-thirds between 1988, when screening was introduced, and 2002, despite there being an increase in genital wart diagnoses at the same time.14

So surely we should be trying to do the same for anal cancer? 

Professor Mark Bower is a consultant at London’s Chelsea and Westminster Hospital, specialising in HIV-related cancers. Though in favour of people with HIV having regular anal screening, he says that the case for it being routine is surprisingly hard to make. 

That’s partly because it’s still relatively rare. In the Chelsea and Westminster cohort, they have seen 60 cases in 11,112 patients (one per 188 patients) throughout the clinic’s history, but this includes patients coming to the hospital specifically to see HPV and anal cancer specialists. In patients attending the Chelsea and Westminster’s general HIV clinic, they see fewer than one new case a year. 

This may seem odd, given that rates of AIN are very high. For instance, one study of HIV-positive men found that despite AIN grades 2 or 3 being found at least once in 133 of the 247 patients in the study (54%), there were only two cases of anal cancer in three years.15 

We don’t know exactly why some anal (or cervical) lesions turn into an invasive cancer, and others don’t. Bower has evaluated the cases of nearly 1000 HIV-positive men who have sex with men seen over the last ten years at the Chelsea and Westminster. 

“These guys’ AIN grade goes up and down and up again,” he says. “A lot of them have been coming here for ten years and show no signs of progressing.” 

This is partly due to the natural history of HPV and the fact that infections regress as often as they recur. Most AIN grade 1 lesions simply disappear and only a minority progress to higher grades. We don’t even know the rate at which high-grade AIN lesions change into anal cancer: estimates vary hugely from 0.2 to 12.5% a year (the consensus is between 1 and 5%). The thing that keeps lesions coming back in gay men is not persistent HPV infection but reinfection; in HIV-positive gay men, persistent infection adds to the risk. 

Or incidence of anal cancer may be lower than expected because, in many patient cohorts, gay men with HIV are already being screened regularly. Even in cervical cancer, it has been difficult to calculate the benefit of national screening because so much ad hoc screening was being done before the national programme began. 

“Maybe it’s because of our excellent interventions,” says Bower, “or maybe it’s because progression to cancer just doesn’t happen in most people with AIN.” There has never actually been a randomised controlled trial of cervical cancer screening, and there couldn’t ethically be one of an HPV-associated cancer now: would you allow your doctor to ignore pre-cancerous cell changes to see if they turned into cancer?

Another problem is cost-effectiveness. 

There have been two studies in the US, showing that screening would be relatively cost-effective in both HIV-negative and HIV-positive gay men. In the cost-effectiveness study in HIV-positive gay men, the cost per quality-adjusted life-year (QALY) saved was $16,000 with annual screening and $13,000 if done every two years.16 In HIV-negative gay men, the cost was considerably greater if you screened annually ($34,800) but comparable if done biennially ($15,100).17 

However, a UK cost-effectiveness model found that national screening of gay men (with or without HIV) was unlikely to be cost-effective, with an average cost per QALY gained of £39,405, which is way beyond the usually quoted NICE (National Institute for Health and Clinical Excellence) threshold of £30,000.18 It was actually more cost-effective to screen all gay men in this study, rather than just the HIV-positive ones. 

This model, however, contained a number of different assumptions from the US models. In the US, it was assumed that annual rate of transition from high-grade AIN to anal cancer was high: from 3.6 to 5% a year. Actual surveys suggest a lower rate of progression. The UK study assumed a much lower rate: about one case of anal cancer per 500 cases on untreated AIN grades 2 or 3 (0.2%), or one case per 2500 treated cases. This is probably on the low side, and there have been a number of other criticisms levelled at the UK paper, such as the assumption of a high rate of regression from AIN 1 to asymptomatic. 

Screening gay men for anal cancer and its precursors has not been recommended in UK guidelines. The British HIV Association’s cancer guidelines of 2008 state: “there is little evidence for routine [screening] as the early detection of lesions still poses substantial difficulties and single biopsies may miss areas of AIN, with histology and cytology yielding some discordant results.”19 

In complete contrast, US guidelines – such as those from New York State20 – recommend “anal cytology at baseline and annually”, especially for men with HPV or anal warts, and the European AIDS Clinical Society (EACS) guidelines recommend a rectal examination and/or smear every one to three years for gay men.21 Anoscopy would be reserved for people with abnormal cytology results, and the New York guidelines estimate that this would be less than 30% of the screened population. 

Treatment 

One of the reasons screening is not nationally adopted in the UK is because, to quote the BHIVA guidelines, “Treatment options for AIN are limited by morbidity and high recurrence rates.” That probably isn’t as true as it was. The becoming-standard treatment for AIN is infrared coagulation therapy (ICT) which involves burning off the affected areas with a heat gun. That sounds very painful, but can be carried out under local anaesthetic, causing only a couple of days’ discomfort. High recurrence rates are still a problem: after one treatment, 50% of HIV-negative gay men and 65% of HIV-positive ones had recurrent lesions within ten months. Until we get more data, we don’t know if these treatments are preventing progression to cancer – or just subjecting people to unnecessary discomfort. 

If you are one of the unlucky few who get anal cancer, it’s not the end of the world. With a survival rate of 65% at five years, anal cancer looks bad compared to testicular cancer (97% alive at five years), but very good compared to advanced lung cancer (5% alive at five years). Surgery is not necessary for the majority of people if anal cancer is diagnosed before it becomes invasive. The standard treatment is radiotherapy, plus the anti-cancer drugs mitomycin C and capecitabine, or cisplatin – the kind of drugs that are much more tolerable these days, thanks to anti-emetic drugs. 

Less easy to get on with is the radiotherapy, which involves a daily visit to the clinic for six weeks, and causes proctitis (anal and rectal inflammation and pain) for another six weeks or so after that. After these treatments it’s the usual watchful wait to see if it’s really gone or if it recurs. 

About that vaccine... 

What about getting yourself vaccinated? And should we be vaccinating adolescent boys as well as girls anyway, in case they get HPV 16 or 18? 

In January this year, the US Food and Drug Administration approved the use of Gardasil to prevent anal cancer in people (of both sexes) between the ages of 9 and 26. So far, the European Medicines Agency (EMA) has not followed suit. In the decentralised healthcare system of the US, this is by no means a guarantee that your healthcare system will agree to pay for Gardasil, but it does mean that people who fall within the age criteria have a fighting chance. In a system like the UK’s NHS, EMA approval would only be the first step anyway, as medicines then have to undergo the eagle-eye scrutiny of our health technology assessment agency NICE, before the NHS will agree to provide it for free (and, for reasons of cost, the NHS approved Cervarix for vaccinating adolescent girls, not Gardasil). 

The US approval followed a study22 that found that Gardasil had 65% efficacy in preventing anal lesions caused by the four types it immunises against in young men aged 19 to 26. That was for all the men who entered the study – and some who were already infected with HPV 16 or 18. The efficacy in men not already infected when they entered the study was 90%. 

However, this tells us nothing about whether Gardasil really prevents anal cancer or even AIN – because nearly all the anal lesions seen were anal warts caused by types 6 and 11. 

If you’re older and gay, surely it’s too late to vaccinate? Well... not necessarily, because the body can get rid of HPV infections, remember. There is very little research in this area, but a 2009 study largely of gay, HIV-positive, male US Army veterans found that 43% did not have antibodies to HPV types 16 or 18.23 This could mean they’d just been infected and not yet developed an antibody response, but it could also mean they’d never been infected or had got rid of their infection. An HPV DNA test would tell. 

So might you benefit from getting the vaccine? Only if you can find out which HPV types you have and if you’ve never had type 16 or 18. In theory the HPV vaccine could protect you from reinfection but we don’t know whether it actually does. The vaccine has no effect on current infections. You’ll only get it done privately at present and, at £480 for a three-shot course of Gardasil (Cervarix costs about £315 privately) I is not cheap, and that’s not counting the costs of consultation and testing. 

Conclusion

So what’s a boy to do who is worried about HPV and anal cancer, possibly because he’s had anal warts? “You should get screened annually and if you’re diagnosed with any lesions, you should ask for a referral to a specialist centre like ours,” is Mark Bower’s conclusion. The same would also apply if you are an HIV-positive woman who has anal sex. There’s an inevitable contradiction here: while UK cost-effectiveness modellers still come out against anal screening as standard for people with HIV, on an individual level, it is wise to talk to your doctor about getting yourself checked out with a smear test. 

You may also want to do a regular self-examination of your anus, although in most cases the lesions caused by high-risk HPV strains tend to be flat and you won’t be able to feel anything. But if you do feel anything lumpy, you should certainly have it seen by a doctor as soon as possible. Other symptoms to report promptly are abnormal discharge or bleeding from the anus, itching, pain or pressure around the anus, and anal sores that do not heal. (These symptoms can also be caused by other, more common, problems.) 

In a world where HIV therapy is relatively standardised, the mess of contradictory evidence and recommendations around anal cancer thrusts us back to the time when HIV treatment itself was experimental and controversial, and you had to hunt for a hospital that agreed that viral load tests were cost-effective. Keeping yourself safe from anal cancer is one area where patient power makes a difference, and it pays to demand the best service. Get your rear end checked out regularly, and don’t die of embarrassment.

This article was first published by NAM/Aidsmap.com and is republished with permission.

References

See www.aidsmap.com/Cervical-cancer-and-you/page/1439443/

Massad LS et al. Evolution of cervical abnormalities among women with HIV-1: evidence from surveillance cytology in the Women’s Interagency HIV Study. J Acquir Immune Defic Syndr 25(5):432-442, 2001.

See www.cancerhelp.org.uk/type/cervical-cancer/about/cervical-cancer-risks-and-causes

Peto J et al. The cervical cancer epidemic that screening has prevented in the UK. The Lancet 364:249-56, 2004.

See http://info.cancerresearchuk.org/cancerstats/causes/lifestyle/tobacco/

See www.cancerhelp.org.uk/type/anal-cancer/treatment/statistics-and-outlook-for-cancer-of-the-anus

Grulich AE et al. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. The Lancet 370: 59-67, 2007.

Kim JJ et al. Cost effectiveness analysis of including boys in a human papillomavirus vaccination programme in the United States. BMJ 339:b3884, 2009.

Shvetsov YB et al. Duration and Clearance of Anal Human Papillomavirus (HPV) Infection among Women: The Hawaii HPV Cohort Study. Clin Infect Dis. 48(5):536-546, 2009.

Daling JR et al. Correlates of homosexual behaviour and the incidence of anal cancer. JAMA 247:1988-1990, 1982.

Piketty C et al. 24 months of cART is not associated with a reduction of anal HPV infection in HIV+ MSM. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 871, 2011.

Fox PA et al. The value of anal cytology and human papillomavirus typing in the detection of anal intraepithelial neoplasia: a review of cases from an anoscopy clinic. Sexually Transmitted Infections 81:142-146, 2005.

Coste J et al. Cross sectional study of conventional cervical smear, monolayer cytology, and human papillomavirus DNA testing for cervical cancer screening. BMJ 326(7392):733, 2003.

Peto J et al. op. cit.

de Pokomandy A et al. HAART and progression to high-grade anal intraepithelial neoplasia in men who have sex with men and are infected with HIV. Clin Infect Dis, online edition, doi: 10.1093/cid/cir064, 2011.

Goldie S et al. The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. JAMA 281(19):1822-1829, 1999.

Goldie S et al. Cost-effectiveness of screening for anal squamous intraepithelial lesions and anal cancer in human immunodeficiency virus-negative homosexual and bisexual men. Am J Med 108(8):634-41, 2000.

Karnon J et al. Cost-utility analysis of screening high-risk groups for anal cancer. Journal of Public Health 30(3):293-304, 2008.

Bower M et al. British HIV Association guidelines for HIV-associated malignancies 2008. HIV Medicine 9:336-388, 2008. See www.bhiva.org/Malignancies2008.aspx

New York State Public Health Department Guidelines Neoplastic Complications Of HIV Infection. 2007. See http://bit.ly/jQvR3v

Lundgren JD et al. European AIDS Clinical Society Guidelines: Prevention and Management of Non-Infectious Co-Morbidities in HIV. 2009. See www.europeanaidsclinicalsociety.org

Giuliano AR et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. NEJM 364(5):401-411, 2011.

Berman S et al. Seroprevalence of antibodies to HPV-16 and HPV-18, and correlation with the presence of HPV DNA and anorectal cytologic abnormalities in a cohort of HIV-positive men involved in a study of HIV-positive males receiving the quadrivalent HPV vaccine, Gardasil. 5th IAS Conference on HIV Treatment, Pathogenesis and Prevention, Cape Town, abstract WeB102, 2009.