National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Sydney NSW 2010, Australia
There has been a great deal of methodological debate about studies linking acquired immunodeficiency syndrome (AIDS) and cancer, especially about whether the pre-AIDS period can be used in calculating rates. We were in a unique position to address this issue using real data because of the existence of both human immunodeficiency virus (HIV) and AIDS registries in Australia. Overall, our results suggest that pre-AIDS linkage data can be used (1).
Regarding the specific issues expressed by Engels et al. (2), we share their concern that estimating risks during the pre-AIDS period in AIDScancer registry linkage studies may be biased downward by the increased mortality of people diagnosed with cancer before AIDS. This bias can be accounted for by adjusting for cancer survival rates in the linkage population, as we did in our study (1) and a previous one (3). We did not present estimates of survival-adjusted relative risks in our most recent report (4) but referenced the current report demonstrating that adjustment did not materially affect the results (1). Investigators who do not have access to HIV-cancer linkage will not be able to perform this comparison. As Engels et al. acknowledge, estimated risks may also be biased upward by potential increased rates of progression to AIDS among people diagnosed with cancer. However, because of a lack of information on the magnitude of any such association in HIV-positive people, it is not possible to adjust for this bias. For this reason, in our paper we concluded the following: "We would recommend that in publications both adjusted and unadjusted analyses are presented" (1, p. 155).
We did not conclude (1), as stated by Engels et al. (2), that survival adjustment is unnecessary. Rather, our belief that both adjusted and unadjusted data be presented allows for the possibility of bias in either direction. Engels et al. are almost certainly correct in their supposition that, for rapidly fatal tumors, such as lung cancer, downward bias is likely to dominate. However, for many other tumors that occur commonly at this age and that have been hypothesized to be related to HIV-associated immunodeficiency, such as testicular cancer, Hodgkins disease, and anal cancer, survival is much better, and successful therapy for these conditions, or the diagnostic work-up for these conditions, may lead to substantial upward bias; thus, the association between Hodgkins disease and immunodeficiency may have been understated because of this potential bias.
Of course, other important biases may affect the use of pre-AIDS data in AIDScancer registration linkage studies. A major potential bias for data on cancer occurrence since the mid-1990s is that, as a result of the use of effective antiretroviral therapy, people with AIDS now constitute an increasing minority of people who have HIV. People diagnosed with AIDS are increasingly unlikely to represent people with HIV. Factors that influence access to therapy, particularly in countries without universal health care such as the United States, are likely to be important in this selection.
In this new era of effective HIV therapy, AIDScancer registry linkage studies are increasingly unrepresentative of the total population of HIV-infected persons. Although our HIV-cancer linkage study (1) showed that the relative risks of cancer in the 5 years prior to AIDS diagnosis could reliably estimate cancer risk in HIV-infected persons, this finding may change as an increasingly smaller proportion of persons with HIV are diagnosed with AIDS. In the future, studies of cancer risk among HIV-infected populations at all stages of immunodeficiency will be needed to define prospectively the risk of cancer associated with HIV-related immunodeficiency.
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