Is Kaposi's sarcoma occurring at higher CD4 cell counts over the course of the HIV epidemic?
Crum-Cianflone, Nancy Fa,b; Hullsiek, Katherine Hupplera,c; Ganesan, Anuradhaa,d; Weintrob, Amya,e; Okulicz, Jason Fa,f; Agan, Brian Ka; the Infectious Disease Clinical Research Program HIV Working Group
aInfectious Disease Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
bInfectious Disease Clinic, Naval Medical Center San Diego, San Diego, California, USA
cDivision of Biostatistics, University of Minnesota, Minneapolis, Minnesota, USA
dInfectious Disease Clinic, National Naval Medical Center, Bethesda, Maryland, USA
eInfectious Disease Clinic, Walter Reed Army Medical Center, Washington, District of Columbia, USA
fInfectious Disease Service, San Antonio Military Medical Center, San Antonio, Texas, USA.
Received 25 June, 2010
Revised 12 August, 2010
Accepted 18 August, 2010
Correspondence to Dr Nancy Crum-Cianflone, MD, MPH, Clinical Investigation Department (KCA), Naval Medical Center San Diego, 34800 Bob Wilson Drive, Ste. 5, San Diego, CA 92134-1005, USA. Tel: +1 619 532 6189 40; fax: +1 619 532 8137; e-mail: firstname.lastname@example.org
We evaluated longitudinal rates of Kaposi's sarcoma and trends in CD4 cell counts at the time of Kaposi's sarcoma diagnosis during the HIV epidemic (1985–2008). Although rates of Kaposi's sarcoma have decreased, cases are now occurring at higher CD4 cell counts over time, with more than one-third of cases diagnosed in 2002–2008 occurring at CD4 cell counts of at least 350 cells/μl. These data support future studies evaluating the impact of highly active antiretroviral therapy initiation at higher CD4 cell counts to further reduce Kaposi's sarcoma.
During the HIV epidemic, the types and presentations of cancers have dramatically changed [1–4]. As an AIDS-defining cancer, most Kaposi's sarcoma cases have traditionally occurred at low CD4 cell counts (<200 cells/μl) [5,6]. Although Kaposi's sarcoma rates have decreased , it is unknown whether Kaposi's sarcoma will now be observed at higher CD4 cell counts.
We evaluated Kaposi's sarcoma rates and trends in CD4 cell counts at Kaposi's sarcoma diagnosis among HIV-infected persons using the US Military HIV Natural History Study [3,8]. The diagnosis of Kaposi's sarcoma was based on medical record review using standardized criteria . Rates and rate ratios (overall and for time spent with CD4 cell count <350 and ≥350 cells/μl) with 95% confidence intervals (CI) were calculated with Poisson regression models for four a priori defined calendar periods (1985–1990, 1991–1995, 1996–2001, and 2002–2008). Participants contributed follow-up time to all possible calendar periods from baseline (6 months prior to HIV diagnosis) to the event or censoring time (last study visit). Among those with Kaposi's sarcoma and a proximal CD4 cell count (within 1 year prior to Kaposi's sarcoma diagnosis), participants were compared by proximal CD4 cell count category (<350 versus ≥350 cells/μl) with descriptive statistics (chi-squared and Wilcoxon tests) as appropriate. Medians are presented with interquartile ranges (IQR). We also evaluated factors associated with Kaposi's sarcoma during the highly active antiretroviral therapy (HAART) era (the latest of 1 January 1996 or HIV diagnosis date) with time-updated proportional hazards models.
There were 5067 participants with 39 522 person-years of follow-up between 1985 and 2008. At HIV diagnosis, the median age was 28 (IQR 24–34) years; 92% were men; 45% were African American and 43% were white. Median CD4 cell count was 504 (IQR 350–672) cells/μl) and median HIV RNA level (available for 38% of the cohort) was 4.4 (IQR 3.7–4.9) log10 copies/ml.
Of the 247 Kaposi's sarcoma events during the study period, there were 52, 138, 38, and 19 during the four calendar periods, respectively. The rates of Kaposi's sarcoma decreased over time (Table 1). Compared with 1985–1990, HIV-infected persons in 2002–2008 had a 72% lower rate of Kaposi's sarcoma (relative risk = 0.28, 95% CI 0.16–0.47, P < 0.001). Within each calendar period, the rates were higher for time spent with CD4 cell count of less than 350 versus at least 350 cells/μl, although the rate ratios for those comparisons fell from 9.1 (95% CI 3.7–22.0) in 1985–1990 to 6.2 (95% CI 2.3–16.6) in 2002–2008.
Among the 247 Kaposi's sarcoma patients, 179 (72%) had a proximal CD4 cell count available. For the four calendar periods, the proximal CD4 cell count at Kaposi's sarcoma diagnosis was at least 350 cells/μl for 18, 7, 14, and 35%, respectively (P = 0.01, Fig. 1). Participants with proximal CD4 cell count of less than 350 compared with at least 350 cells/μl at Kaposi's sarcoma diagnosis were more likely to have a prior non-Kaposi's sarcoma AIDS event (47 versus 9%, P < 0.001), diagnosed with HIV in the pre-HAART era (97 versus 83%, P = 0.001), and spent a smaller percentage of time on antiretroviral therapy (median of 49 versus 62%, P = 0.09); the two groups did not differ by demographics or HIV duration at the time of Kaposi's sarcoma diagnosis.
Among the 3422 participants with 20 263 person-years of follow-up since availability of HAART in 1996, 45 had Kaposi's sarcoma and a proximal CD4 cell count. From a proportional hazards model considering only time-updated CD4 cell count, each incremental increase of 50 cells/μl decreased the risk of Kaposi's sarcoma by 30% (hazard ratio 0.70, 95% CI 0.64–0.76, P < 0.001). In a model with both CD4 cell count category and HAART use as time-updated covariates, compared with those with CD4 cell count of at least 350 cells/μl and on HAART, those with CD4 cell count of at least 350 cells/μl but not on HAART had an increased risk of Kaposi's sarcoma (hazard ratio 2.0, 95% CI 0.7–6.30, P = 0.22) that did not reach statistical significance, whereas those with CD4 cell count of less than 350 cells/μl (regardless of HAART use) had an increased risk (hazard ratio 8.3, 95% CI 3.4–20.2, P < 0.001).
Our study demonstrates that although the Kaposi's sarcoma rates have declined during the HAART era and lower CD4 cell counts remain an important risk factor, a greater proportion of Kaposi's sarcoma cases are now occurring at higher CD4 cell counts. During the late HAART period, over one-third of Kaposi's sarcoma cases occurred at CD4 cell counts of at least 350 cells/μl. Clinicians should be aware of these trends and watchful for the occurrence of Kaposi's sarcoma despite robust CD4 cell counts.
The occurrence of Kaposi's sarcoma at higher than expected CD4 cell counts has been previously reported [9–13]. However, our study is unique in that we describe the changing trends of CD4 cell counts at Kaposi's sarcoma diagnosis over the entire HIV epidemic and demonstrate a rising proportion of cases at higher CD4 cell counts. To our knowledge, only one other study examined CD4 cell count trends at Kaposi's sarcoma diagnosis over time, but found no change in CD4 cell counts between the pre-HAART and post-HAART eras; however, their population had high rates of drug use and poor antiretroviral adherence , whereas our population had free medical care, excellent reported medication adherence, and low rates of drug use (<1%) .
Similar to other studies in the HAART era [9,10,15], 35% of our cases were on HAART and 9% had an HIV RNA level of less than 400 copies/ml at Kaposi's sarcoma diagnosis. Such cases are somewhat surprising because HAART has reduced the number of Kaposi's sarcoma cases by its effects on HIV suppression and potential antiangiogenic effects [10,16]. Some Kaposi's sarcoma cases in the setting of HAART may be related to the immune reconstitution inflammatory syndrome [17,18]; however, most of our cases were not associated with the introduction of HAART.
Given these trends, determining whether HAART use at higher CD4 cell counts will reduce the impact of Kaposi's sarcoma is of clinical importance. We found a suggestion of increased risk of Kaposi's sarcoma among those not on HAART compared with those on HAART with CD4 cell counts of at least 350 cells/μl. Prior studies have shown that Kaposi's sarcoma in the setting of HAART results in less aggressive and more localized disease .
In summary, Kaposi's sarcoma remains an important disease among HIV-infected persons, despite achievement of higher CD4 cell counts. Among patients with access to HAART, the proportion of Kaposi's sarcoma cases occurring at high CD4 cell counts appears to be rising. Future studies are needed to determine whether earlier HAART initiation will further decrease the burden of Kaposi's sarcoma among HIV-infected persons.
Support for this work (IDCRP-000-04) was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), under Inter-Agency Agreement Y1-AI-5072. The content of this publication is the sole responsibility of the authors and does not necessarily reflect the views or policies of the NIH or the Department of Health and Human Services, the DoD, the Departments of the Army, Navy or Air Force, nor the US Government. Mention of trade names, commercial products, or organizations does not imply endorsement by the US Government. The authors acknowledge that the research protocol (‘Incidence and Risk Factors for AIDS-Defining and Non-AIDS-Defining Cancers in an HIV-Infected Cohort’) received applicable Institutional Board review and approval.
Part of these data will be presented at the 48th Annual Meeting of the Infectious Disease Society of America; 21–24 October 2010; Vancouver, Canada.
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