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People with HIV Have Higher Rates of Non-AIDS Malignancies, Skin Cancer

The incidence of non-AIDS-defining cancers has increased among people with HIV in the era of effective antiretroviral treatment, including malignancies caused by viruses such as human papillomavirus (HPV), and squamous cell non-melanoma skin cancer, according to 2 recently published studies.

Non-AIDS Cancers

As described in the December 28, 2012, advance edition of the Journal of Acquired Immune Deficiency Syndromes, Marco Franzetti from the University of Milan and colleagues retrospectively analyzed new cases of non-AIDS-defining cancer -- that is, malignancies other than Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer -- in a cohort of people with HIV followed between 1985 and 2011.

The analysis included 5924 people who were followed for at least 6 months and who collectively contributed a total of 50,990 person-years of follow-up data. In contrast with some past studies that included mostly men, this one included 1542 women, or about 25% of participants (14,540 total person-years).

The researchers compared incidence rates of non-AIDS cancers before and after the advent of highly active combination antiretroviral therapy (ART) in the mid-1990s, and calculated standardized incidence ratios (SIRs) to compare cancer risks of HIV positive and HIV negative people matched for age and sex in the Milan Cancer Registry.

Results

• 144 new cases of non-AIDS-defining cancer were diagnosed during the follow-up period.

o   22 among men in the pre-ART period (1985-1996);

o   91 among men in the ART era  (1997-2011);

o   3 among women pre-ART;

o   28 among women in the ART era.

• Overall non-AIDS cancer incidence increased from 1.0 cases per 1000 person-years in the pre-ART period to 4.5 cases per 1000 person-years in the ART era:

o   For men: increase from 1.2 to 4.9 cases per 1000 person-years;

o   For women: increase from 0.4 to 3.6 cases per 1000 person-years.

• Hodgkin lymphoma and lung cancer were the most common non-AIDS-defining cancers during both time periods.
• Men had higher than expected rates of anal cancer (SIR 91.5 relative to HIV negative people), Hodgkin lymphoma (SIR 13.0), tonsil cancer (SIR 10.9), lung cancer (SIR 2.1), and liver cancer, mostly hepatocellular carcinoma (SIR 7.1).
• Women had higher than expected rates of vulva cancer (SIR 69.2), Hodgkin lymphoma (SIR 7.5), anal cancer (SIR 41.2), and lung cancer (SIR 4.8).
• Non-AIDS cancer incidence was lower among people with higher current CD4 T-cell counts -- for people both on and off ART -- but the difference did not reach statistically significance.
• However, significantly higher proportions of patients who developed non-AIDS cancer had a previous AIDS diagnosis (43.8% vs42.5%) or a nadir (lowest-ever) CD4 cell count below 200 cells/mm³ (65.3% vs59.7%).

"The spectrum and incidence of non-AIDS-defining cancers in our cohort increased over time," the study authors concluded. "The incidence of non-AIDS-defining cancers, especially virus- and smoking-associated cancers, was significantly higher than expected in HIV-positive men and women."

Cancers with a known or suspected infectious cause, or those related to smoking, accounted for 75% of all non-AIDS cancers observed in this cohort, they elaborated in their discussion.

Like other studies, this analysis revealed increases in malignancies associated with HPV, which causes anal, genital, and -- according to recent evidence -- some mouth/throat cancers. Participants also were at higher risk of Hodgkin lymphoma, associated with Epstein-Barr virus, and liver cancer, which can be caused by hepatitis B or C viruses. Among the 18 patients (all men) diagnosed with liver cancer, 13 had chronic hepatitis C, 2 had chronic hepatitis B, and 1 had both.

This study showed "a relatively modest number of cases of melanoma and did not find any increased risk in comparison with the general population" the authors said.

Noting that nadir CD4 count below 200 cells/mm³ was independently associated with a higher risk of developing non-AIDS cancers, the researchers wrote, "These findings support the hypothesis that immunological recovery in patients with previously severe immunodeficiency may not decrease the risk of non-AIDS-defining cancers, possibly because the recovery is incomplete."

Non-melanoma Skin Cancer

The second study, described in the January 4, 2013, advance edition of the Journal of the National Cancer Institute, looked specifically at incidence of non-melanoma skin cancer -- including basal cell carcinoma and squamous cell carcinoma among people with HIV. 

Michael Silverberg and colleagues from Kaiser Permanente and the National Cancer Institute compared skin cancer rates among 6560 HIV positive and 36,821 HIV negative white adults in the Kaiser Permanente Northern California health plan followed between 1996 and 2008.

Results

• Incidence rates of non-melanoma skin cancer were 1426 per 100,000 person-years for HIV positive people vs 766 per 100,000 person-years for HIV negative people (divide by 1000 for rates comparable to the Italian study above).
• The adjusted rate ratio for all non-melanoma skin cancers was 2.1, or about twice the risk for HIV positive vs HIV negative participants.
• Adjusted rate ratios for were 2.6 for squamous cell carcinomas and 2.1 for basal cell carcinomas.
• There was a significant trend of higher rate ratios associated with lower recent CD4 cell counts among HIV positive people for squamous cell carcinoma, though not for basal cell carcinoma.
• There was 1 case of squamous cell carcinoma to every 2 cases of basal cell carcinoma among HIV positive people with low CD4 counts, but among those with high CD4 levels the ratio was similar to the 1-to-4 ratio seen in the HIV negative general population.

"HIV [positive] subjects had a two-fold higher incidence rate of non-melanoma skin cancers compared with HIV [negative] subjects," the researchers concluded. "Squamous cell carcinomas but not basal cell carcinomas were associated with immunodeficiency."

The authors noted that prior studies have shown higher rates of virus-associated cancers both among people with HIV and among organ transplant recipients who take immunosuppressive drugs. Studies have also found elevated rates of non-melanoma skin cancers -- up to 50-fold higher -- among transplant patients. Analyses of people with HIV have yielded conflicting data, and most cancer registries do not include basal and squamous cell carcinomas.

"Here, we provide evidence with an internal control group that squamous cell carcinomas and basal cell carcinomas are both increased approximately two-fold among HIV [positive] subjects and that the observed association with immunodeficiency appears to be specific to squamous cell carcinoma and not basal cell carcinoma," they wrote.

"It is noteworthy that the observed increased incidence rate here for squamous cell carcinomas among HIV [positive] subjects is much lower than the more than 50-fold higher rates observed among transplant populations," they continued. "Furthermore, squamous cell carcinomas among transplant recipients tend to be very aggressive; by contrast, we noted similar clinical presentation for non-melanoma skin cancers by HIV status with respect to invasiveness, differentiation, and location. These observations suggest that immunosuppressive transplant medications may have direct oncogenic properties, whereas HIV-induced immunosuppression likely plays a clinically significant but reduced role in the etiology of squamous cell carcinomas."

"The association between immunodeficiency and squamous cell carcinoma in HIV [positive] subjects suggests that the pathogenesis of cutaneous squamous cell carcinomas may involve an infectious agent, such as a virus, because most cancers linked to immunodeficiency have known viral etiologies," they suggested. "In this regard, it is interesting that an association between HPV infection and squamous cell carcinomas has been noted in several recent studies."

However, "[f]or basal cell carcinomas, we did not find evidence of an association with immunodeficiency, ART, or other HIV-specific factors," they wrote. "Instead, the increased incidence rate for basal cell carcinoma was observed only for men, particularly [men who have sex with men]...Together, these results suggest that unmeasured confounders possibly related to sex, sexual orientation, and income might have contributed to the higher incidence of basal cell carcinomas among HIV [positive] subjects."

"Given the increasing longevity for HIV-positive individuals, the burden of many age-related, non-AIDS-defining cancers, including non-melanoma skin cancers, will only continue to increase," Silverberg stated in a press release issued by Kaiser Permanente. "Based on our studies, non-melanoma skin cancers are by far the most common cancer this population experiences."

2/12/13

References

M Franzetti, F Adorni, C Parravicini, et al. Trends and Predictors of Non AIDS-Defining Cancers in Men and Women With HIV-Infection. A Single-Institution Retrospective Study Before and After the Introduction of HAART. Journal of Acquired Immune Deficiency Syndromes. December 28, 2012 (Epub ahead of print).

MJ Silverberg, W Leyden, EM Wharton, et al. HIV Infection Status, Immunodeficiency, and the Incidence of Non-Melanoma Skin Cancer. Journal of the National Cancer Institute. January 4, 2013 (Epub ahead of print).

Other Source

Kaiser Permanente. Kaiser Permanente Study Reveals Two-Fold Higher Incidence of Non-Melanoma Skin Cancers for Individuals with HIV. Press release. January 29, 2013