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Soaring anal cancer incidence in the combination ART era.

Abstract: People with HIV infection have strikingly higher anal cancer incidence and prevalence than people the same age in the general population. From the dawn of the HIV epidemic through the early combination antiretroviral therapy (cART) era, researchers calculate that HIV-positive women had more than a 14 times higher incidence of invasive anal cancer than similarly aged women without HIV, HIV-positive men had a 35 times higher invasive anal cancer incidence, and HIV-positive men who have sex with men (MSM) had a 52 times higher incidence. Most anal cancer research in HIV populations involves MSM, but numerous studies show that 20% to almost 50% of HIV-positive women have receptive anal sex, and HIV-positive women have a higher risk of anal intraepithelial neoplasia--an anal cancer precursor--than women without HIV. Anal cancer incidence in HIV-positive people did not drop after the arrival of cART, and in some cohorts incidence rose substantially. But recent multicohort studies and other research suggest that anal cancer rates in the cART epoch may have peaked or even begun falling. One study found an association between longer cART-induced HIV control and lower odds of incident anal cancer.

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When combination antiretroviral therapy (cART) arrived in the mid-1990s, things changed. ART halted runaway HIV epidemics in many countries with high HIV prevalence, like Botswana, which had 71% fewer AIDS deaths in 2011 than in 2005. (1) In many countries, people who respond well to ART and don't inject drugs live as long as anyone else. (2) In the United States, 5-year cumulative incidence of the three AIDS cancers plunged from 18% in 1980-1989 to 4.2% in 1996-2006. (3)

But cART didn't change everything. For example, as fewer and fewer people got diagnosed with AIDS cancers after cART prescribing began, more and more got diagnosed with certain non-AIDS cancers, notably anal cancer. The same population-based US analysis of 472,378 people with AIDS that charted a dwindling of AIDS cancers found that 5-year cumulative incidence of anal cancer jumped from 0.02% in 1980-1989 to 0.07% in 1990-1995 and up to 0.09% in 1996-2006, the first cART decade. (3)

AIDS cancers remain substantially more common than non-AIDS cancers in people with HIV. But besides the just-noted reversal in incidence, AIDS and non-AIDS cancers emerge at strikingly different rates after ART begins. Among 11,485 HIV-positive people starting cART between 1996 and 2011 in eight US cohorts, incidence of the AIDS cancers Kaposi sarcoma and non-Hodgkin lymphoma peaked in the first 6 months of therapy at 1342 cases per 100,000 person-years than plummeted to 164 cases per 100,000 from 6 months through 10 years of therapy. (4) Although anal cancer incidence remained much lower than AIDS cancer incidence in the overall study period, the anal cancer rate changed hardly at all from 72 per 100,000 in the first 6 months of cART to 69 per 100,000 in the following 9.5 years of therapy.

A 2012 meta-analysis of anal cancer incidence (the new-diagnosis rate) in men who have sex with men (MSM), figured an incidence of 21.8 cases per 100,000 person-years in the pre-cART period, (5) a rate almost 15 times higher than anal cancer incidence in the general population of US men. (6) But studies of anal cancer incidence in MSM in the cART era reckoned an incidence of 77.8 per 100,000 person-years, (5) more than triple the already high rate among MSM in the pre-cART era.

Why has anal cancer become such an intransigent menace to people with HIV, even those responding well to cART? Which HIV-positive people run a particularly high risk of anal cancer? How should people with HIV be screened for anal cancer? How much can HPV vaccination help? This issue of RITA! addresses those questions and many more in four review articles and an interview with Joel Palefsky (University of California, San Francisco), long a leader in HPV-related cancer research and care in people with HIV. The box "Anal cancer basics" offers a quick refresher on key points.

Anal cancer and HIV: first hints and harbingers

HIV can affect every inch of the body, from the cerebral cortex to the toes. The inch-and-a-half-long anal canal is no exception. A 2009 study of 473 randomly selected HIV-positive outpatients in a Paris clinic found that 208 of them (44%) had visible anal lesions, including HPV-related lesions in 23%, hemorrhoidal disease in 14%, and anal fissures in 11% (Figure 1). (9) And MSM did not account for all these lesions. The study group included 200 MSM, 123 heterosexual men, and 150 women. Respective proportions with at least one anal lesion were 53.5%, 41.5%, and 33.3%.

Findings like these are nothing new among MSM. The first PubMed citation linking anal carcinoma and homosexuality, originating in Brooklyn, appeared more than 15 years before anyone noticed AIDS in an article on "proctologic lesions" in MSM. (10) A dozen years later--and still a half-decade before the first AIDS cases emerged--a group of New York City proctologists described what they called "gay bowel syndrome" in 260 MSM who made up 10% of their practice. (11) Although these clinicians later endured censure for using this term to describe a melange of maladies not specifically gay, limited to the bowels, or syndromic, they offered the first early warning that men who have anal sex with other men often suffer from anal warts, anal fissures, viral hepatitis, and a swarm of other insults that abet passage of sexually transmitted infections (STIs) and--it turned out--heightened the risk of anal cancer.

In 1979 researchers at Philadelphia's Fox Chase Cancer Center reported four cases of cloacogenic anal cancer (see "Anal cancer basics" on page 6) in four men who "engaged in longstanding receptive anal intercourse." (12) Because the anorectal transitional zone where cloacogenic tumors arise shares an embryologic origin with the uterine cervix, a site of cancers related to sexual intercourse, the Fox Chase team posed "the serious question of the etiologic potential of receptive anal intercourse in the development of cloacogenic carcinoma."

In 1982, only a few months after three New England Journal articles detailed the first cases of AIDS late in 1981, researchers in Washington state found that 47 men with anal cancer diagnosed from 1974 through 1979 were more likely to have a positive syphilis test and to be single than men with cancer at other sites. (13) "Because in men, but not in women, having had syphilis and being single are associated with the practice of anal intercourse," the investigators proposed, "our data suggest that anal intercourse may be a risk factor for anal cancer."

In 1984, researchers at New York's Beth Israel Medical Center published four cases of anal carcinoma in situ in 7 MSM with anal warts. (14) Lesions in all these men had morphology consistent with papillomavirus infection. Because 4 of the 7 men had histories "suspicious for or diagnostic of the acquired immunodeficiency syndrome," the Beth Israel team urged colleagues to consider AIDS in MSM with persistent or recurrent perianal lesions.

Two years after that, researchers in Melbourne offered the first study linking HPV, HIV, and anal cancer in MSM. (15) Examining anorectal mucosal cells from 61 MSM, they found cytological evidence of dysplasia and HPV in 24 men and evidence of HPV without dysplasia in 26 men. Four factors made dysplasia more likely: history of anal warts, frequent receptive anal intercourse, antibody to HIV, and immune dysfunction signaled by a low CD4/GD8 ratio. The link between HIV antibodies and long-lasting dysplasia was independent of the association with immune dysfunction.

A boom In anal cancer burden

In the general US population, anal cancer remains rare. SEER Stat Fact Sheets from the National Cancer Institute list an annual incidence of 1.5 cases per 100,000 men and 1.9 per 100,000 women. (6) In contrast, annual colorectal cancer incidence is 52.2 per 100,000 men and 39.3 per 100,000 women. Respective lung cancer rates are 74.3 and 51.9 per 100,000. But anal cancer incidence was much lower decades ago. In Connecticut, for example, invasive anal cancer incidence doubled from 0.14 per 100,000 in 1940-1959 to 0.27 per 100,000 in 1980-1988. (16) Across the United States from 1973 through 1989, the SEER cancer registry showed a 24% to 34% jump in anal cancer incidence among men and a 10% to 13% jump among women. (16) Among white men in the San Francisco area, anal cancer incidence vaulted more than 100% from 0.5 per 100,000 in 1973-1975 to 1.2 per 100,000 in 1988-1989.

A study of cancer incidence in 15,565 MSM in New York City and San Francisco from 1978 through 1990 charted an overall standardized incidence ratio (SIR) of 1.6, meaning the observed overall cancer rate was 60% higher than the expected cancer rate in the general population after statistical adjustment for age. (17) In contrast, the SIR comparing MSM with the general population was 2.5 for Hodgkin lymphoma and 24.4 for anal cancer. In other words, MSM tracked from the cusp of the US HIV epidemic through 1990 got diagnosed with anal cancer at a rate 24 times higher than expected for men their age. Three quarters of the San Francisco men tested positive for HIV, but anal cancer incidence did not correlate with HIV status, a finding indicating that all MSM in this urban center ran a skyscraping risk of anal cancer.

A more recent anal cancer incidence study involved 499,230 US patients diagnosed with AIDS from 1980 through 2004. (18) Focusing on HPV-related cancers, a National Cancer Institute team calculated that these people with AIDS had a 60% higher than expected rate of invasive oropharyngeal cancer compared with the general population (SIR 1.6), women with AIDS had more than a 5 times higher rate of cervical cancer (SIR 5.6), women with AIDS had more than a 14 times higher rate of anal cancer (SIR 14.5), men with AIDS had almost a 35 times higher rate of anal cancer (SIR 34.6), and MSM with AIDS had a 52 times higher rate of anal cancer (SIR 51.8). Among men, every 100-cell lower CD4 count at AIDS onset raised the risk of invasive anal cancer almost 60% (relative risk per 100-cell lower CD4 count 1.59, 95% confidence interval [CI] 1.09 to 2.34, P = 0.016).

Meta-analyses of studies published through November 1, 2011 found a pooled anal cancer incidence of 5.1 per 100,000 HIV-negative MSM, (5) more than triple the 1.5 per 100,000 men in the general US population (Figure 2). (6) Still, the authors believe the 5.1 incidence may be an underestimate because it rests on only two studies with only three incident cases of anal cancer.

Among HIV-positive MSM, this meta-analysis reckoned an anal cancer incidence of 45.9 per 100,000 men) more than 30 times the US general population rate. When the researchers divided the HIV population into the pre-cART era (four studies before 1996) and the cART era (four studies from 1996 onward), they charted an anal cancer incidence of 21.8 per 100,000 MSM pre-cART and 77.8 per 100,000 with cART. Although the reasons for this jump remain unclear, the authors speculate that "the immune restoration related to [cART] may not be sufficient to clear persistent long standing HPV infection and the improved survival associated with [cART] may allow for sufficient time for chronically HPV infected men to develop invasive anal cancer" (5) (see "Complex impact of CART on anal cancer incidence" below).

Comparing incidence of non-AIDS malignancies in 33,420 US veterans with HIV and 66,840 without HIV, researchers found a 60% higher incidence of all non-AIDS cancers in the HIV group (incidence rate ratio 1.6) after adjustment for age, race, and gender. (19) For individual cancers assessed, the incidence difference between HIV-positive and negative veterans was greatest for anal cancer, at an incidence rate ratio of 14.9 (111.2 versus 7.4 cases per 100,000 person-years). The next greatest incidence difference among non-AIDS malignancies involved Hodgkin lymphoma, at an incidence rate ratio 4.9. The observation period for this study lay entirely in the HAART era (1997 through 2004), and an estimated 80% of veterans in this cohort took antiretroviral therapy.

Sifting numbers in 15 linked HIV and cancer registries in the United States, National Cancer Institute investigators estimate that from 1991-1995 to 2001-2005, the number of AIDS cancers in people with AIDS swooned more than 3-fold from 34,587 to 10,325 (P < 0.001) (Figure 3). (20) Over the same two periods, the number of non-AIDS cancers in people with AIDS rose 3-fold from 3192 to 10,059 and the number of anal cancers in AIDS patients rocketed more than 7.5-fold from 206 to 1564. In comparison, the number of lung cancers in people with AIDS rose just over 2-fold and the number of liver cancers jumped 5-fold.

The gravity of anal cancer in people with HIV lies not merely in its vertiginously higher incidence and prevalence compared with the general population but in the age at which it strikes. This message resolved into crystalline focus in a canny study by National Cancer Institute researchers. (21) Previous research suggested that many cancers in people with HIV developed up to two decades before they did in HIV-negative populations. But this capacious gap turned out to reflect a consistent flaw in calculations. Studies were reckoning age at diagnosis in HIV populations that had much larger proportions of middle-aged people than the comparison general populations--for the very good reason that many fewer HIV-positive people survived into their 60s and 70s than did people without HIV. When the National Cancer Institute team corrected their statistical machinations for this cohort make-up difference, the age-at-diagnosis difference between HIV and non-HIV groups vanished for most cancers--except anal cancer and a few others.

The study involved 212,055 people with AIDS enrolled in the US/AIDS Cancer Match Study from 1996 to 2007, entirely within the cART era. (21) People 65 and older in the general population contributed 12.5% of follow-up time to the analysis. In contrast, age 65 and older people with AIDS contributed only 1.5% of follow-up time to the analysis. Before statistical correction for this imbalance, median ages at cancer diagnosis in the AIDS population and the general population were, for example, 52 and 73 for colon cancer, 46 and 60 for melanoma, 58.5 and 68 for prostate cancer, 50 and 70 for lung cancer, and 42 and 62 for anal cancer. After correction for the imbalance, median expected ages at diagnosis in the general population plunged from 73 to 52 for colon cancer, from 60 to 45 for melanoma, from 68 to 58 for prostate cancer, from 70 to 54 for lung cancer, and from 62 to 45 for anal cancer (Figure 4). With these adjustments for these five cancers, only the AIDS/ general population age differences for lung cancer (50/54 years, P < 0.001) and anal cancer (42/45 years, P < 0.001) remained statistically significant.

For HIV providers and people in their care, the bottom line is that anal cancer in this AIDS population developed at a remarkably young median age--and at an age 3 years younger than in the general population.

Anal HPV and dysplasia in women with HIV

Most research on anal dysplasia and cancer in people with HIV has focused on MSM, but HIV-positive women also face a heightened risk of anal dysplasia. In the US general population, anal cancer incidence is higher in women than in men (1.9 versus 1.5 per 100,000 person-years), although that distribution flips among African Americans (1.6 in women versus 1.9 in men). (6)

HIV-positive women are no strangers to anal intercourse, an anal cancer risk factor, according to two analyses of the SUN Study cohort (Figure 5). (22,23) One study involved 142 HIV-positive women seen at seven clinics in four cities--Denver, Minneapolis, Providence, and St. Louis. (22) Just over half (57%) were African American, 30% were non-Hispanic white, and 10% Hispanic. Fifty-seven of these 142 women (40%) reported receptive anal intercourse. A separate analysis of 120 women in the same cohort found that 43 (36%) ever had receptive anal intercourse and 12 (10%) had receptive anal sex in the past 6 months. (23) From 20% to 47% of HIV-positive women in two other HIV cohorts, reviewed below, (24-26) also reported having receptive anal sex.

One of the SUN Study analyses (22) and two other studies (24,25) found an independent association between receptive anal intercourse and abnormal anal cytology or AIN in women. Three of these studies found higher rates of AIN or abnormal anal cells in HIV-positive women than in women without HIV. (24-26)

The first SUN Study assessment of AIN involved 170 women seen in 2004-2006. (22) Median age at first evaluation was 39, and 40% of women reported receptive anal intercourse. While 15% of women had atypical squamous cells, 17% had low-grade AIN and 3% high high-grade AIN. Having receptive anal intercourse in the past 6 months more than tripled the odds of abnormal anal cytology (aOR 3.46, 95% CI 1.10 to 12.1, P = 0.038), while infection with more high-risk HPV types upped the odds 22% (aOR 1.22, 95% CI 1.03 to 1.46, P = 0.022).

A study reported in 2001 involved 251 HIV-positive and 68 HIV-negative women in a San Francisco contingent of the Women's Interagency HIV Study (WIHS), an ongoing study of HIV-positive women and HIV-negative women with similar sociodemographics. (24) About 60% of women with and without HIV were African American, and median age at the baseline visit was 40 years (range 20 to 61).

Among women with anal cytologic results, 26% with HIV versus 8% without HIV had some abnormality (atypical squamous cells of undetermined significance or low- or high-grade AIN). (24) High-grade AIN could be detected in 6% of HIV-positive women and 2% of HIV-negative women. Compared with HIV-negative women, those with HIV had a tripled risk of abnormal anal cells (relative risk [RR] 3.2, 95% CI 1.3 to 7.5). In women with HIV, lower CD4 count (P < 0.001) and higher viral load (P = 0.02) made anal cell abnormalities more likely. Four factors raised the risk of abnormal anal cytology in women with HIV: abnormal cervical cytology (RR 1.5, 95% CI 0.97 to 2.2), genital warts (RR 1.4, 95% CI 0.98 to 2.1), anal intercourse (RR 2.0, 95% CI 1.3 to 3.1), and diarrhea for more than 1 month (RR 1.8, 95% CI 1.2 to 2.7).

In a study involving 470 HIV-positive and 185 HIV-negative women in the San Francisco, Chicago, and Brooklyn units of the Women's Interagency HIV Study, about two thirds of women were African American and 47% ever had anal sex. (25) Rates of low-grade AIN in women with and without HIV were 12% and 5%, while rates of high-grade AIN were 9% and 1%,. Overall AIN prevalence was 16% in women with HIV. Any receptive anal intercourse tripled the odds of low-grade AIN (adjusted OR 3.2, 95% CI 1.5 to 6.8%), while anal HPV infection raised chances of high-grade AIN more than 7 times (aOR 7.6, 95% CI 1.5 to 38).

A multisite analysis of the Reaching for Excellence in Adolescent Care and Health (REACH) Project involved 238 behaviorally HIV-infected adolescent girls between 12 and 18 years old and 139 girls without HIV. (26) Almost three quarters of the HIV group (73%) were black, as were 63% of the HIV-negative group. A slightly lower proportion of HIV-positive than HIV-negative girls reported receptive anal intercourse (20% versus 28%, P = 0.08). Only 58% of girls with HIV had ever taken antiretroviral therapy.

Compared with HIV-negative girls, HIV-positive girls had a higher incidence of any anal HPV infection (30 versus 14 per 100 person-years, P = 0.002), high-risk anal HPV (12 versus 5.3 per 100 person-years, P = 0.04), anogenital warts (6.7 versus 1.6 per 100 person-years, P = 0.002), and anal dysplasia (12 versus 5.7 per 100 person-years, P = 0.05). (26) Late versus early CDC disease stage boosted the risk of anal dysplasia 7 times (adjusted hazard ratio [aHR] 7.02, 95% CI 2.18 to 22.59), while ever having high-risk anal HPV infection almost quadrupled the risk (aHR 3.72, 95% CI 1.52 to 1.92). Smoking in this teenage group independently tripled chances of infection with high-risk HPV (aHR 3.46, 95% CI 1.21 to 9.89).

Complex impact of cART on anal cancer incidence

Because a weakened immune system cannot muster enough robust cancer-fighting cells, you would expect HIV-positive people with depleted CD4 cells to succumb more readily to cancer, perhaps especially virus-related cancers like anal cancer. The converse expectation might be that people who replenish their CD4 squad when responding to cART would stand a better chance of warding off anal cancer. But that hasn't happened.

Analysis of 263 people with histologically confirmed anal cancer in the French Hospital Database on HIV determined that incidence has remained intractably high since the introduction of cART. (27) The French team figured SIRs to compare incidence in HIV-positive people with incidence in the general population across four periods: 1992-1996 (pre-cART period), 1997-2000 (early cART period), and 2001-2004 and 2005-2008 (recent cART periods). Risk of anal cancer in the three ART periods more than doubled risk in the pre-cART period (hazard ratio 2.5, 95% CI 1.28 to 4.98), with no difference from one cART period to the next.

In the most recent cART period, 2005-2008, HIV-positive MSM had more than a 100 times higher anal cancer incidence than the general population (SIR 109.8, 95% CI 84.6 to 140.3), other HIV-positive men had almost a 50 times higher incidence (SIR 49.2, 95% CI 33.2 to 70.3), and HIV-positive women had a 13 times higher incidence (SIR 13.1, 95% CI 6.8 to 22.2). Even people who reached a CD4 above 500 cell/[mm.sup.3] had extraordinarily higher anal cancer incidence than the general population--with an SIR of 67.5 when the CD4 nadir lay below 200 cells/[mm.sup.3] and an SIR of 24.5 when the nadir lay above 200 cells/[mm.sup.3]. Combination ART, the French team concluded, "appears to have no preventive effect on anal cancer, particularly in MSM." (27)

Parallel evidence comes from London, where researchers at Chelsea and Westminster Hospital analyzed pre-cART and cART era anal cancer incidence in their cohort of 8640 HIV-positive people. (28) They counted 26 people with invasive anal cancer for an incidence of 60 per 100,000 person-years, a rate 120 times higher than in the age- and gender-matched general population. Incidence of invasive anal cancer stood at 35 per 100,000 in the pre-cART era and 92 per 100,000 in the cART era, rates 67 and 176 times higher than in the general population. Five-year disease-free survival stood at 66% and did not differ between the two treatment periods.

Studies from San Diego County, (29) San Francisco, (30) the US Multicenter AIDS Cohort Study (MACS), (31,32) and a US military cohort (33) also yielded evidence that anal cancer incidence rose after cART arrived.

Why did anal cancer incidence seem to swell with cART's advent instead of dropping, as incidence of AIDS cancers did? There's no easy answer but lots of suggestions that, together, probably explain this vexing epidemiology, cART helps HIV-positive people live longer, and prolonged survival allows HPV-induced cellular abnormalities to bud into cancers--especially since screening for high-grade AIN (an anal cancer precursor) is far from routine.

HPV infection is the most common STI in the United States, and people with HIV--another STI--tend to pick up HPV and high-risk (cancer-causing) HPV genotypes more often than HIV-negative people with relatively sedate sex lives. (34) HPV infection often regresses without treatment, and that helps explain why the billions of HPV-infected people in the world don't end up with anal or cervical cancer. But people with HIV--even those who respond to cART--have a maimed immune system that lets HPV's toehold turn into a foothold then into dysplasia. Anal cancer expert Joel Palefsky suggests that the CD4s added with cART "may reflect only partial restoration of the immune response to HPV antigens, or a limited role of this immune response in clearing [high-grade] AIN lesions once they have passed a certain point in their development." (35)

Two statistical wrinkles could contribute to higher anal cancer incidence after people with HIV started taking cART--competing risks and ascertainment bias. Competing risks is a fancy term that explains why surviving longer with HIV could make one more vulnerable to cancers that develop as we age. For example, an HIV group being assessed for incident anal cancer may die first from an AIDS disease like non-Hodgkin lymphoma (the competing risk). But if that HIV group starts cART and cART cuts chances of non-Hodgkin lymphoma (as it does), they could survive long enough to succumb to a slowly developing anal cancer. As a result, it looks like anal cancer incidence is lower in pre-cART days when people were dying of competing risks before they could get anal cancer. Ascertainment bias means that clinicians started screening HIV-positive people for anal abnormalities as reports of anal dysplasia and cancer proliferated in the cART era, and this heightened ascertainment makes it look like more HIV-positive people have anal cancer in more recent years.

Has the anal cancer bounce leveled off?

Studies showing climbing anal cancer incidence since cART came of age (27-33) paint only part of the picture. Two recent megacohort inquests in North America and other studies suggest that anal cancer rates in the cART epoch may have topped out or even begun falling. (4,36-38) A 13-cohort North American analysis involving 34,189 people with HIV (55% MSM, 19% other men, and 26% women) carved cART time into three slices: 1996-1999, 2000-2003, and 2004-2007. (36) Taking the middle period as the reference era, these investigators determined that people diagnosed with anal cancer in 1996-1999 had a 50% lower rate of anal cancer (adjusted rate ratio 0.5, 95% CI 0.3 to 0.9) while people diagnosed in 2004-2007 had nearly the same anal cancer rate as those diagnosed in 2000-2003 (adjusted rate ratio 0.9, 95% CI 0.6 to 1.2). Anal cancer rates rose after the early CART era, these investigators conclude, then plateaued.

A study of eight US HIV cohorts examined AIDS and non-AIDS cancer incidence in 11,485 cART-treated people over a longer period, 1996 through 2011. (4) Gauging anal cancer incidence from the time cohort members started CART, these researchers found that incidence stayed flat for a decade--measuring 72 per 100,000 person-years in the first 6 months of treatment and 69 per 100,000 in the following 9.5 years. Overall, these researchers found, the year when cART began did not affect cancer incidence.

A case-control comparison of 20,277 HIV-positive and 202,313 HIV-negative people in the Kaiser Permanente Northern California system charted a non-significant drop in anal cancer incidence through three cART periods. (37) Poisson regression models adjusted for HIV status, age, gender, calendar period, and HIV status/calendar period interaction tracked a gradual dwindling of the anal cancer rate ratio comparing HIV-positive with negative people as the cART era evolved: 159.9 in 1996-1999, 122.9 in 2000-2003 and 94.0 in 2004-2007 (P = 0.83).

Rather than scrutinizing anal cancer risk year-byyear or cART era-by-era, a Houston team analyzed anal cancer incidence according to time spent on cART with an undetectable viral load (Figure 6). (38) This study involved male veterans with follow-up over some period from 1985 through 2009. Age-adjusted anal cancer incidence was similar in men who ever received cART and never received cART (146.8 and 134.3 per 100,000 person-years).

Focusing on cART-treated veterans, an analysis adjusted for demographics, nadir CD4 count, and most recent CD4 count determined that men with an undetectable viral load during 81% to 100% of follow-up time had 45% lower odds of incident anal cancer (adjusted odds ratio 0.55, P = 0.0004) when compared with men who had an undetectable load less than 20% of the time. And veterans with an undetectable load 60% to 80% of the time had almost the same decrease in anal cancer odds when compared with the under-20% group (adjusted odds ratio 0.56, P = 0.04). These investigators propose that "optimizing cART adherence and HIV viral load control may decrease the risk of subsequent squamous cell cancer of the anus." (38)

In an editorial on these issues, Joel Palefsky observes that today's cART combinations are much stronger and easier to take than those of the past, and that should lead to "more pronounced and sustained HIV viral load suppression" in people starting a contemporary cART regimen. (35) It's too early to tell whether better HIV control will decrease anal cancer incidence, Palefsky writes. "What is clear," he adds, "is that the problem of anal cancer, a potentially preventable disease, will not be going away soon." (35)

Anal cancer basics: from condyloma to invasive cancer (7,8)

Squamous cell (epidermoid) carcinomas, which include cloacogenic (basaloid transitional cell) tumors, account for most anal cancers, with adenocarcinoma accounting for the rest.

Condylomas (warts) develop just outside the anus and in the lower anal canal. Anal cancer is more likely in people with anal condyloma.

Human papillomavirus (HPV), a DNA virus, causes both condyloma and anal cancer. HPV is the most common sexually transmitted infection in the United States and many other countries.

Dysplasia is a cluster of abnormal anal cells in the membrane lining the anal canal.

Anal Intraepithellal neopiasia (AIN) and anal squamous Intraepithelial lesions (SILs) are names for the lesions caused by dysplasia.

Depending on how the anal membrane cells look, AIN and anal SIL can be divided into low-grade lesions and high-grade lesions. High-grade AIN is less likely to go away without treatment and more likely to develop into anal cancer.

Carcinoma in situ is the term used to describe cells on the anal lining that look like cancer calls but have not grown into deeper layers of the anus.

Invasive anal cancer is the term used to describe growth of cancer cells beyond the surface of the anus into deeper layers.

For terms related to anal cancer screening, see the box "Screening for anal cell abnormalities and cancer" in the article "Anal cancer screening approach awaits more data and clinical expertise."

Sources: National Cancer Institute. Anal cancer treatment (PDQ). Cellular classification of anal cancer. http://www.cancer.gov/cancertopics/pdq/treatment/anal/HealthProfessional/page2;

American Cancer Society. Anal cancer. What is anal cancer? http://www.cancer.org/cancer/analcancer/detailedguide/anal-cancer-what-is-anal-cancer

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Figure 1. A random sample of 473
HIV-positive patients in Paris found
that almost half had one or more
macroscopic anal lesions, including
one quarter who had HPV-related lesions
and 11% who had anal fissures.
(Source: Abramowitz L, et al. 2009. (9))

Anal lesions In a random sample of 473 people with HIV

1 or more lesions   44%
HPV lesions         23%
Hemorrhoids         14%
Anal fissure        11%
Other anal lesions   9%

Note: Table made from bar graph.

Figure 2. Meta-analyses of anal cancer
incidence in MSM with or without
HIV calculated a rate of 5.1 per
100,000 person-years in HIV-negative
men, more than triple the rate
of 1.5 per 100,000 in the US general
population of men. Anal cancer
incidence was higher still in HIV-positive
MSM, especially since the
advent of combination antiretroviral
therapy (cART). (Source: Machalek
DA, et al. (5))

Meta-analysis of anal cancer Incidence In NSM
with and without HIV

HIV- MSM         5.1
HIV+ MSM        45.9
HIV+ pre-cART   21.8
HIV+ cART       77.8

Note: Table made from bar graph.

Figure 4. After statistical correction
for the imbalanced age composition of
US groups with AIDS and the general
population, median age at cancer diagnosis
in AIDS patients did not differ
from the expected age in the general
population for colon cancer, melanoma,
or prostate cancer. But after adjustment
median age at diagnosis was
significantly lower in the AIDS group
for anal cancer (P < 0.001) * and lung
cancer (P < 0.001). * (Source: Shiels
MS, et al. (21))

Median age at cancer diagnosis for
five non-AIDS cancers

           With AIDS   General pop

Colon        52           52
Melanoma     46           45
Prostate     58.5         58
Anal *       42           45
Lung *       50           54

Note: Table made from bar graph.

Figure 5. Four studies of US women
with HIV found that 20% to 47% reported
ever having receptive anal intercourse,
including 221 of 470 (47%)
in WIHS, (25) 57 of 142 (40%) in the SUN
Study, (22) 43 of 120 (36%) in a separate
SUN Study analysis, (23) and 47 of 238
(20%) in REACH. (26)

Receptive anal intercourse rates in
US women with HIV

WIHS 2009    47%
SUN 2010     40%
SUN 2011     36%
REACH 2013   20%

Note: Table made from bar graph.

Figure 6. US veterans who had an
undetectable HIV load during 81% to
100% of follow-up time had 45% lower
odds of incident anal cancer than veterans
with an undetectable HIV load
during less than 20% of follow-up time.
Veterans with an HIV load undetectable
during 60% to 80% of follow-up
time had 44% lower odds of incident
anal cancer. (Source: Chiao EY, et al. (38))

Time with undetectable HIV load and
risk of anal cancer

Lowered risk of
incident anal cancer
compared with
undetectable
<20% of time

Undetectable 81-100% of time   45%[down arrow]
Undetectable 60-80% of time    44%[down arrow]
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Title Annotation:Perspective
Author:Mascolini, Mark
Publication:Research Initiative/Treatment Action!
Article Type:Report
Date:Dec 22, 2013
Words:6739
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