Three Studies Look at Elevated Risk of Non-AIDS-Related Cancer in People with HIV

Three Studies Look at Elevated Risk of Non-AIDS-related Cancer in People with HIV

SUMMARY: People with HIV are more likely than HIV negative individuals to develop various non-AIDS-defining cancers, according to 3 recently published studies. This increase is especially pronounced for malignancies with infectious causes, such as anal cancer due to human papillomavirus (HPV), and occurs even among individuals with relatively high CD4 cell counts. Taken together, these studies underscore the need for regular cancer screening and changing modifiable risk factors such as smoking.

By Liz Highleyman

Since the advent of highly active antiretroviral therapy (HAART), rates of AIDS-defining malignancies -- Kaposi's sarcoma, non-Hodgkin lymphoma, and invasive cervical cancer -- have declined. However, as people with HIV live longer due to effective treatment, they have more time to develop non-AIDS cancers.

Study 1

In the first study, reported in the October 2009 Journal of Acquired Immune Deficiency Syndromes, Roger Bedimo and colleagues explored whether the incidence of non-AIDS-defining malignancies is significantly higher in HIV positive compared with HIV negative individuals.

Using data from the U.S. Veterans Affairs Healthcare System, the researchers calculated incidence rates of malignancies from 1997 through 2004 for a cohort of 33,420 HIV positive veterans (followed for a median 5.1 years) and for 66,840 HIV uninfected patients matched according to sex, age, and race (followed for a median 6.4 years).

Most participants (about 98%) were men, the mean age was 46 years, 43% were African-American, 32% were white, and 8% were Hispanic (17% other or unknown). About 20% in both groups were heavy alcohol users, but more HIV positive than HIV negative participants were coinfected with hepatitis C virus (36% vs 12%).

Incidence rate ratios (IRRs) were calculated to compare cancer rates among HIV positive versus HIV negative patients. Within the HIV positive group, CD4 counts closest to the first observation date were compared between those with and without cancer.

Results

	A total of 2128 non-AIDS-defining malignancies were diagnosed among HIV positive patients, compared with 3142 in the HIV negative group.
	The overall rates of non-AIDS-defining malignancies in the 2 groups were 1260 vs 841 cases per 100,000 person-years, respectively, for an IRR of 1.6 (that is, 60% higher for HIV positive patients).
	HIV positive veterans were more likely to have anal cancer, lung cancer, melanoma skin cancer, Hodgkin's lymphoma, and liver cancer.
	The IRR was highest for anal cancer, at 14.9.
	The likelihood of prostate cancer was similar in the HIV positive and negative groups, with an IRR of 1.0.
	Among the HIV positive patients, median CD4 counts were significantly lower for those with all non-AIDS-defining malignancies (249 cells/mm3 vs 270 cells/mm3 for HIV patients without cancer), anal cancer (156 vs 270 cells/mm3), and Hodgkin's lymphoma (217 vs 269 cells/mm3).
	Prostate cancer, in contrast, was associated with a higher CD4 count (311 vs 266).
	For all other non-AIDS-defining malignancies, there was no statistically significant difference between CD4 counts of patients with and without cancer.
	The rate of non-AIDS-defining malignancies declined among HIV negative individuals from 1998-1999 to 2000-2001, but remained stable over time in the HIV positive group.

"In the highly active antiretroviral therapy era, the incidence of non-AIDS-defining malignancies is higher among HIV-infected than HIV-uninfected patients, adjusting for age, race, and gender," the study authors concluded. "Some non-AIDS-defining malignancies do not seem to be associated with significantly lower CD4 counts."

"This 60% higher rate of non-AIDS-defining malignancies among HIV-infected patients was consistent for 2 periods representing early and more recent HAART eras (from 1996-1997 to 2002-2003, respectively)," they elaborated in their discussion.

"These trends warrant a high index of suspicion for malignancies among HIV providers and a renewed focus on understanding the mechanisms underlying the increased rates," they recommended.

Department of Medicine, Veterans Affairs North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas, TX; Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA; Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX; Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, Houston, TX; Department of Medicine, VA Connecticut Healthcare System and Yale University School of Medicine and Public Health, West Haven, CT.

Study 2

In the second study, Meredith Shiels and colleagues performed a meta-analysis to estimate summary standardized incidence ratios (SIRs) of non-AIDS cancers among HIV positive individuals compared with general population rates overall, and stratified by sex, AIDS diagnosis, and use of HAART. Results were reported in the December 2009 Journal of Acquired Immune Deficiency Syndromes.

A total of 42 potential studies were identified; 13 were included in the overall meta-analysis, and an additional 5 that were excluded from the overall analysis were included in stratified analyses for sex, AIDS status, and HAART era.

Results

In all the included studies combined, a total of 4796 non-AIDS cancers occurred among 625,716 HIV positive individuals.

Overall, HIV positive individuals had twice the risk of non-AIDS malignancies compared with the general population.

SIRs for all non-AIDS cancers were greater among men than women, and among people AIDS versus without AIDS.

SIRs were elevated for several specific cancers, indicating higher rates in people with HIV.

This was especially true for cancers associated with infectious causes:

	Anal cancer: SIR 28;
	Liver cancer: SIR 5.6;
	Hodgkin's lymphoma: SIR 11.

HIV positive people also had higher rates of cancers related to smoking:

	Lung cancer: SIR 2.6;
	Kidney cancer: SIR 1.7;
	Laryngeal cancer: SIR 1.5.

Having an AIDS diagnosis was associated with greater SIRs for Hodgkin's lymphoma, leukemia, lung cancer, brain cancer, and all non-AIDS cancers combined.

Incidences of breast cancer and prostate cancer were lower among HIV positive women and men, respectively, compared with the general population.

Based on these findings, the study authors concluded, "HIV-infected individuals may be at an increased risk of developing non-AIDS cancers, particularly those associated with infections and smoking. An association with advanced immune suppression was suggested for certain cancers."

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Study 3

Finally, as described in the November 13, 2009 issue of AIDS, Michael Silverberg and colleagues evaluated the risk of cancers with and without a known infectious cause in people with and without HIV.

This analysis included 20,277 adult HIV patients and 202,313 HIV negative members of the Kaiser Permanente health system followed between 1996 and 2007. Again, most participants (90%) were men and the mean age was 41 years.

The researchers looked for newly occurring cases of AIDS-defining cancers, infection-related non-AIDS-defining cancers -- anal squamous cell cancer, vagina/vulva cancer, penis cancer, HPV-related mouth and throat cancer, stomach cancer (associated with Helicobacter pylori), and Hodgkin's lymphoma (linked to Epstein-Barr virus) -- and all other non-AIDS malignancies not known to be related to infectious causes.

Results

HIV positive patients developed 552 cases of AIDS-defining cancers, compared with 179 cases among HIV negative individuals.

For infection-related non-AIDS cancers, the corresponding figures were 221 and 284 cases, respectively.

For other non-AIDS malignancies, the numbers were 388 and 3418, respectively.

Infection-related cancers (both AIDS-defining and non-AIDS) accounted for 67% of all cancers among people with HIV, compared with 12% among HIV negative people of similar sex and age.

The incidence rate ratios comparing HIV positive to HIV negative participants were:

	37.7 for AIDS-defining cancers, with decreases in the rate ratio over time (P < 0.001).
	9.2 for infection-related non-AIDS cancers, also with decreases over time (P < 0.001).
	1.3 for non-infectious non-AIDS malignancies, with no change over time (P = 0.44).

The difference in rates of infection-related non-AIDS cancer were largely attributable to anal cancer (IRR 101.6) and Hodgkin's lymphoma (IRR 19.4).

Stomach cancer was the only infection-related non-AIDS cancers not significantly associated with HIV status.

Looking at specific non-infectious non-AIDS malignancies, rates of other types of anal cancer (IRR 35.3), non-melanoma skin cancer (IRR 10.6), lung cancer, melanoma, and non-HPV head and neck cancer were higher among HIV positive people.

The rate of prostate cancer, however, was lower among HIV positive patients (IRR 0.7).

"In comparison with those without HIV infection, HIV-infected persons are at particular risk for cancers with a known infectious cause, although the higher risk has decreased in the antiretroviral therapy era," the investigators concluded. "Cancers without a known infectious cause are modestly increased in HIV-infected persons compared with HIV-uninfected persons."

"These results have implications for prevention of cancers in HIV-infected persons," they wrote in their discussion. "First, we found little evidence for the need for a different screening approach compared with general guidelines for breast, prostate, or colorectal cancer among HIV-infected persons."

"Prevention efforts in HIV-infected persons, however, should continue to focus on infection-related cancers, including the evaluation of more routine vaccinations for infections such as hepatitis B, and possibly the extension of the recently approved HPV vaccine to adolescent boys," they continued. "For anal squamous cell cancer, universal screening guidelines for the detection of early lesions m ay also greatly benefit this population. Finally, our study supports the concept of earlier initiation of ART, as the burden of infection-related cancers may be reduced further with improved immune function."

Division of Research, Kaiser Permanente Northern California, Oakland, CA; Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA; Kaiser Permanente Northern California, Hayward Medical Center, Hayward, CA; Kaiser Permanente Southern California, Los Angeles Medical Center, Los Angeles, CA; Hematology-Oncology Division, San Francisco General Hospital and University of California San Francisco, San Francisco, CA.

12/08/09

References

R Bedimo, K McGinnis, M Dunlap, and others. Incidence of Non-AIDS-Defining Malignancies in HIV-Infected Versus Noninfected Patients in the HAART Era: Impact of Immunosuppression. Journal of Acquired Immune Deficiency Syndromes 52(2): 203-208 (Abstract). October 2009.

M Shiels, S Cole, G Kirk, and C Poole. A Meta-Analysis of the Incidence of Non-AIDS Cancers in HIV-Infected Individuals. 52(5): 611-622 (Abstract). December 2009.

M Silverberg, C Chao, W Leyden, and others. HIV Infection and the Risk of Cancers with and without a Known Infectious Cause. AIDS 23(17): 2337-2345 (Abstract). November 13, 2009.