In the HAART era, the incidence of non-ADMs is significantly higher among HIV-infected than age-, race-, and gender-matched HIV-uninfected patients. After a median follow-up time of over 5 years, the IRR of all non-ADM among HIV-infected patients was 1.6 (95% CI: 1.5–1.7). This 60% higher rate of non-ADM among HIV-infected patients was consistent for two time-periods representing early and more recent HAART eras (1996–1997 to 2002–2003, respectively). Further, cancers other than those strongly asssociated with HCV infection (hepatoma) or men who have sex with men (anal cancer) demonstrated significantly increased IRR when HIV infected patients were compared with demographically similar uninfected patients.
Patients with non-ADMs tend to have somewhat lower CD4 counts than non-cancer patients. This effect appears to be largely driven by anal cancers which not only have a significantly higher IRR (in HIV-infected vs. HIV-uninfected patients), but appear to be significantly associated with immunosuppression in our cohort, whith the median CD4 count of anal cancer patients being only 58% of that of non-cancer patients. Both the very high IRR and the association of immunosuppression make the epidemiology of this malignancy more similar to that of ADM than non-ADM . Indeed, the biology of anal cancer – with its strong association with Human Papilloma Virus (HPV) infection – is very similar to that of cervical cancer, which is included among ADMs. Prostate cancer patients had higher median CD4 count than non-cancer patients with HIV infection. This result, consistent with previous observations of a high mean CD4 count in HIV patients with prostate cancer,18
is intriguing, but it should also be noted that prostate cancer was equally common among HIV infected and uninfected subjects.
Congruent to our findings, a previously published analysis of linked population-based AIDS and cancer registry data from 11 geographically diverse areas in the United States 7
concluded that selected non-ADM, including Hodgkin’s disease, lung cancer, soft tissue malignancies, lip and testicular cancer were potentially associated with immunosuppression. Consistent with this observation, an interesting study has recently been published comparing cancer incidence in population-based cohort studies of people with HIV/AIDS and solid organ transplantation (another immunosuppressed population in which epidemiologic studies have also found a wide range of cancers) 19. The authors interpreted their finding of similar spectra and a similar pattern of increased risk of cancer in the two populations as strongly suggesting that immune deficiency is the likely underlying cause.
However, with the exception of anal cancer and Hodgkin’s disease, an association has not been consistently found between advancing immunosuppression and the development of non-ADM () among HIV infected patients4, 5, 7, 20
. Indeed, even if patients with non-ADMs tend to have slightly lower CD4 counts than non-cancer patients in some cohorts, these malignancies do not appear to share the same association with degree of immunosuppression as the AIDS-defining malignancies 4, 7
. One possible explanation of the increased risk is that, despite improved immune function on HAART, cancer immune surveillance is still inadequate in patients with HIV.
It is possible that despite the matching, the current findings reflect an overrepresentation of traditional cancer risk factors among the HIV-infected patients, especially viral co-infections (HCV and HPV) and smoking status. Several studies have described an increased prevalence and recurrence of both cervical HPV infection and invasive cervical cancer among HIV-1 positive women compared to HIV-1 negative patients, especially among those with low CD4 cell counts21, 22
. The prevalence of oral, anal, and cervical HPV infection in HIV-positive individuals compared with HIV-negative individuals increases with progressively lower CD4+ levels, as does incident high-grade intraepithelial neoplasia (CIN) 22–25
. While we do not have the rates of HPV infection among HIV-infected and uninfected patients in the VACS Virtual Cohort, it could be inferred by the proportion of men who have sex with men in both groups in the VACS Ongoing Study Cohort, (47.5% and 6.4% respectively) that the HPV infection rates would be higher in HIV-infected patients.
An excess risk of traditionally smoking-related cancers is seen in HIV-infected patients 3, 4, 6, 7
. Importantly, Crothers et al., 26
found (through a self-administered questionnaire) nearly equivalent rates of current or past smoking history in 1,014 HIV-infected and 713 HIV-uninfected veterans enrolled in the Veterans Aging Cohort 5 Site Study in 2001 and 2002 (75% vs. 76%). Regardless, after controlling for smoking, rates of lung cancer are higher in HIV-infected than uninfected patients 27
. Consistent with a prior analysis of by McGinnis et al.17
, we find that rates of alcohol abuse and dependence are similar in among HIV-infected and uninfected patients in the VACS Virtual Cohort (21% and 20% respectively), but HCV co-infection is more common among HIV-infected than uninfected patients (36% vs. 12%).
A possible limitation to our study is that our findings may be explained by ascertainment bias. Specifically, the HIV-infected patients were seen more often than uninfected patients and therefore may have had more opportunity to be have a diagnosis of cancer made and recorded resulting in the HIV infected patients appearing to have higher rates of cancer when the rates were not truly different. We think this is unlikely. First, if ascertainment bias explained our results, we would have expected a more uniform effect across cancers. Instead only a handful of cancers were more common and, among HIV infected individuals, these cancers were more common among more immunosuppressed individuals. Second, cancer rates among the uninfected comparators in our cohort are higher than those reported by SEER for the general population 16, 17
. This suggests that, if anything, our estimate of rates among the controls may be upwardly biased. Specifically, controls had to have a reason to seek medical care—one of which might be symptoms of cancer. Thus, our estimate of relative rates comparing HIV infected individuals to HIV uninfected demographic controls receiving care in the VA may instead be a conservative estimate of the true difference in rates. Finally, others have also found increased rates of specific non-ADMs among those with HIV infection 4, 6, 12
. There remains the strong possibility that HIV itself and/or HAART use have an oncogenic potential, which would be likely to be more evident as survival of HIV patients lengthens, and treatment duration is prolonged 28 29
There was an increase in IRR of non-ADM over time in our cohort, with the highest rates being recorded in the later years of the follow-up period. All patients were observed exclusively in the HAART era (1997 through 2004), and HAART use among participants of the VACS is estimated at 80% 26, 30
. Data on use of HAART by individual patients in the cohort is not included in this analysis, and the potential impact of HAART on the incidence of malignancies was not evaluated. However, other studies have shown significantly higher incidence of non-ADMs in the HAART era, compared to the pre-HAART era 4, 8, 11, 27, 31
. We have shown that all studies that failed to show an increase in non-ADM rates in the HAART era had an average follow-up time of less than 1 year per patient in the HAART era. When follow-up time in the HAART era was greater than 1 year per patient, an increase in rates was oberved (author reply to Dal Maso et al 32
The strengths of our study include a thorough description of the VACS cohort, including ascertainment of the rates of several cancer risk factors, including smoking, substance abuse and HCV co-infection, which cannot be ascertained in population-based comparison groups 3, 7, 12 3, 4, 6
; matching, and a long median follow-up time, compared to some previous studies which allows more lag time for detection of cancer incidences 3, 6, 32
. In addition, for ascertainment of patient diagnoses (HIV and malignancy diagnoses) we used a validated method requiring at least 2 outpatient and one inpatient diagnostic codes, which maximizes the positive predictive value of the identification algorithm 15
. Our major limitations include the uneven distribution of some cancer risk factors (such as HCV infection) within the two groups and the overrepresentation of males making it difficult to adequately evaluate rates of female-specific cancers.
In conclusion, after adjusting for age, race and gender, the incidence of non-ADMs is significantly higher among HIV-infected than HIV-uninfected patients in the HAART era. This pattern is consistent throughout the observation period and is not only true of cancers associated with HCV infection or homosexual orientation. 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.