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Recent Studies Shed Light on Cancer Among People with HIV

Starting antiretroviral therapy (ART) with a low CD4 count raises the likelihood of certain cancers, but others increase with longer time on therapy, reflecting a rising risk associated with older age, according to a recently published study. Other new research revealed increases in malignancies related to viral infections and a higher risk of Kaposi sarcoma even after immune restoration.

Cancer After ART Initiation

In the first study, described in the September 2013 issue of Clinical Infectious Diseases, Elizabeth Yanik from the University of North Carolina at Chapel Hill and colleagues looked at patterns of cancer incidence and timing after ART initiation.

The analysis included medical records from 11,485 participants in 8 U.S. HIV clinical cohorts who started combination ART between 1996 and 2011. Most (about 80%) were men and they started treatment at a median age of 38 years.

At the time of ART initiation, the median CD4 T-cell count was 202 cells/mm³, indicating substantial immune suppression. Nearly half started a protease inhibitor regimen and about 40% started a NNRTI regimen.

The researchers looked at incidence rates for AIDS-defining cancers -- Kaposi sarcoma (KS), non-Hodgkin lymphoma, and cervical cancer -- and non-AIDS cancers (all others). They separately assessed cancers caused by viruses, such as hepatocellular carcinoma caused by hepatitis B or C, lymphoma related to Epstein–Barr virus, and cervical or anal cancer caused by human papillomavirus (HPV).

Results

• A total of 457 new cases of cancer were reported during 46,318 person-years (PY) of follow-up (average 3 years of follow-up per person), for an incidence rate of 987 cases per 100,000 PY.
• The most common AIDS-defining cancer was KS at 304 cases per 100,000 PY, while the most common non-AIDS cancers were anal cancer for men and breast cancer for women (69 and 128 cases per 100,000 PY, respectively).
• Incidence rates for AIDS-defining and non-AIDS cancers were similar, at 515 and 466 per 100,000 PY, respectively.
• Incidence rates for KS and lymphoma (both non-Hodgkin and Hodgkin) were highest during the first 6 months after ART initiation, then fell steeply during the next 6 months, followed by a more gradual decline.
• The incidence rate for all other cancers combined increased from 416 cases per 100,000 PY at 1 year after ART initiation to 615 per 100,000 PY after 10 years on treatment.
• Rates of non-AIDS cancers rose with longer time on ART, with an average increase of 7% per year.
• Older age was a significant predictor of non-AIDS and non-lymphoma cancers, with risk doubling with each additional 10 years of age.
• Lower CD4 count at the time of ART initiation was associated with greater risk of KS, lymphoma, and HPV-related malignancies.
• Calendar year of ART initiation was not associated with cancer incidence.

"KS and lymphoma rates were highest immediately following ART initiation, particularly among patients with low CD4 cell counts, whereas other cancers increased with time on ART, likely reflecting increased cancer risk with aging," the study authors concluded.

Improvements in ART over time "have not had dramatic effects on cancer incidence," they noted in their discussion, as more people with HIV are now living long enough to develop cancer.

"Our results underscore recommendations for earlier HIV diagnosis followed by prompt ART initiation along with ongoing aggressive cancer screening and prevention efforts throughout the course of HIV care," they advised.

These findings also underline the somewhat arbitrary historical division between "AIDS-defining" and "non-AIDS" cancers. Non-Hodgkin (AIDS-defining) and Hodgkin (non-AIDS) lymphomas followed a similar pattern. Likewise, cervical cancer (AIDS-defining) and anal cancer (non-AIDS) are similar malignancies with the same viral cause and parallel disease progression.

Virus-related Cancers

The second study, published in the September 2013 edition of HIV Medicine, looked at incidence of and risk factors for AIDS-defining and non-AIDS cancers, with the latter divided into virus-related and non-virus-related malignancies.

Investigators with the Brescia HIV Cancer Study Group performed a retrospective cohort analysis of 5090 HIV patients served by the Local Health Authority of Brescia in northern Italy during 1999-2009. Cancer rates among people with HIV were compared to expected rates for the HIV negative general population living in the same area using standardized incidence ratios (SIRs).

Results

• A total of 416 cancers were recorded in 390 HIV positive patients during 32,390 PY of follow-up:

o   200 AIDS-defining cancers (48%);

o   138 non-virus-related non-AIDS cancers (33%);

o   78 virus-related non-AIDS cancers (19%).

• Overall, people with HIV had a 4-fold higher cancer risk than HIV negative individuals (SIR 4.2).
• The excess risk was largest for AIDS-defining cancers (SIR 31.0), but was also significant for virus-related non-AIDS cancers (SIR 12.3).
• The highest SIRs were seen for KS among AIDS-defining cancers and for Hodgkin lymphoma among virus-related non-AIDS cancers.
• In contrast, the overall increased risk for non-virus-related non-AIDS cancers was small (SIR 1.6), with SIRs for many such malignancies being near 1, indicating no difference.
• In a multivariate analysis, older age and CD4 count <50 cells/mm³ were the only independent predictors associated with all cancers.

Based on these findings, the study authors concluded, "Among HIV-infected people there was an excess of [AIDS-defining cancers] and also of [non-AIDS-defining cancers], particularly those related to viral infections. Ageing and severe immunodeficiency were the strongest predictors."

Another analysis of the same cohort, described in the August 2013 issue of AIDS Research and Human Retroviruses, found that SIRs for non-virus-related non-AIDS cancers increased over time. After stratifying by sex, however, only HIV positive men had an excess risk for these types of cancer, with an SIR of 1.9, or nearly twice the risk. A similar pattern was not seen for HIV positive women.

People with HIV had higher rates of lung cancer (SIR 3.6) and testicular cancer (SIR 3.1), but rates of prostate cancer (SIR 1.1) and breast cancer (SIR 0.9) were similar to those of the general population.

The only independent predictors of non-virus-related non-AIDS cancers were older age and shorter duration or not using of ART, with CD4 count not reaching significance in a multivariate analysis.

"HIV-infected men showed a 2-fold increased risk of non-virus-related [non-AIDS-defining cancers] compared to the general population," the researchers concluded. "However, the use of combination ART appeared to be beneficial in protecting against the development of these malignancies."

ART and AIDS-defining Cancers

Finally, Mira Hleyhel fromINSERM and fellow investigators with the FHDH-ANRS CO4 Cohort study team also examined trends in the incidence of AIDS-defining cancers among people with HIV relative to the general population, looking at the effect of controlled viral load and restored immunity after starting combination ART, which became widely available in the mid-1990s.

As described in the July 29, 2013, advance edition of Clinical Infectious Diseases, the researchers estimated age- and sex-standardized cancer incidence rates among patients enrolled in the French Hospital Database on HIV and in the general French population during 4 calendar periods: 1992-1996, 1997-2000, 2001-2004, and 2005-2009. The median CD4 count rose over time -- from 259 cells/mm³ during the pre-ART era to 413 cells/mm³ during the late ART period -- as ART coverage reached 86%.

SIRs were calculated for all periods, and separately for patients on combination ART, those with CD4 counts >500/mm³ for at least 2 years, and those with viral load suppressed to <500 copies/mL.

Although the incidence of AIDS-defining cancers fell significantly across the calendar periods, the risk remained consistently higher for people with HIV compared with the general population.

Among HIV patients with restored immune function, the relative risk of KS remained significantly elevated (SIR 35.4). The risk of non-Hodgkin lymphoma was similar to that of the general population (SIR 1.0), but was diagnosed at a significantly younger age among people with HIV (about 11 years sooner).

"The incidence of all [AIDS-defining cancers] continued to fall, including cervical cancer, in the combination ART period, but the risk remained higher than in the general population in 2005-2009," the researchers concluded. "In patients with stably restored immunity, KS remained significantly more frequent than in the general population."                

"Age at KS and cervical cancer diagnosis was only slightly different between HIV-infected and general populations (-2 and -3 years respectively), while the difference was more marked for non-Hodgkin lymphoma (-11 years)," they elaborated in their discussion. "Our results do not favor the hypothesis of premature aging in HIV patients for KS and cervical cancer."

The rise in CD4 count as ART use increased over time "is likely to account in large part for the decrease in the burden of the 3 [AIDS-defining cancers]," they added. "However, the magnitude of the fall differed according to the cancer, gender, and HIV transmission group. The reason for this heterogeneity is unclear, but it might involve differences in the relation between immunodeficiency and cancer risk, or differences in the proportion of persons coinfected with the relevant oncogenic virus."

Treated patients who achieved virological suppression and good immunological recovery did not have an increased risk of non-Hodgkin lymphoma, leading the authors to suggest that ART "would be most beneficial to prevent the risk of cancer in HIV-infected patients if it restores or maintains CD4 count above 500 [cells/mm³], thereby indicating the need for an earlier diagnosis of HIV infection and an earlier treatment initiation."

9/3/13

References

EL Yanick, S Napravnik, SR Cole, JJ Eron, et al. Incidence and Timing of Cancer in HIV-Infected Individuals Following Initiation of Combination Antiretroviral Therapy. Clinical Infectious Diseases 57(5):756-764. September 30, 2013.

A Calabresi, A Ferraresi, A Festa, et al (Brescia HIV Cancer Study Group). Incidence of AIDS-defining cancers and virus-related and non-virus-related non-AIDS-defining cancers among HIV-infected patients compared with the general population in a large health district of northern Italy, 1999-2009. HIV Medicine 14(8):481-490. September 2013.

L Albini, A Calabresi, D Gotti, et al. Burden of Non-AIDS-Defining and Non-Virus-Related Cancers Among HIV-Infected Patients in the Combined Antiretroviral Therapy Era. AIDS Research and Human Retroviruses 29(8):1097-1104. August 2013.

M Hleyhel, A Belot, AM Bouvier, et al. Risk of AIDS-defining cancers among HIV1-infected patients in France between 1992 and 2009: Results from the FHDH-ANRS CO4 cohort. Clinical Infectious Diseases. July 29, 2013 (Epub ahead of print).