- Email: [email protected]
Malignancies in HIV: Pre- and Post-Highly Active Antiretroviral Therapy
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Malignancies in HIV: Pre- and Post-Highly Active Antiretroviral Therapy Lavanya Nutankalva, MD; Anthony K. Wutoh, PhD, RPh; John McNeil, MD; Winston R. Frederick, MD; Ramani B. Reddy, MD; Monika Daftary, PharmD; Andrew Gentles, PharmD; and Kwame Addae-Afoakwa, PharmD student
Financial support: This study was partially supported by the Agency for Healthcare Research and Quality grant 1R24HS11673. Objectives: A study was conducted at a large metropolitan tertiary-care teaching hospital to investigate the incidence of cancers among HIV-infected patients over a 13-year period.
© 2008. From College of Medicine (Nutankalva, McNeil, Reddy, assistant professors; Frederick, professor) and School of Pharmacy (Wutoh, professor; Daftary, associate professor; Gentles, pharmacy resident; Addae-Afoakwa, student), Howard University, Washington, DC. Send correspondence and reprint requests for J Natl Med Assoc. 2008;100:817–820 to: Dr. Anthony K. Wutoh, Professor, Howard University School of Pharmacy, 2300 Fourth St. NW, Washington, DC 20059; phone: (202) 806-4209; fax: (202) 806-4478; e-mail: [email protected]
Design: Retrospective cohort study. Methods: A retrospective cohort study was conducted among HIV-infected patients diagnosed with cancer between January 1990 and December 2003 at a large metropolitan teaching hospital. Any HIV-infected patient who also had a confirmed diagnosis of Kaposi’s sarcoma, primary central nervous system lymphoma, invasive cervical cancer or non-Hodgkin’s lymphoma was categorized as having AIDS-defining cancer (ADC) according to the CDC’s initial case definition for AIDS, while patients with other malignancies were classified as having non-ADCs. A clinical database was created consisting of HIV patients diagnosed with cancer at this teaching hospital, and data were abstracted for the current project. Results: A total of 203 HIV-infected patients diagnosed with cancer were identified during the study period. Ninety-three cases occurred before 1995 and 110 after 1996. The median age of patients (at cancer diagnosis) in the era before highly active antiretroviral therapy (HAART) was 37 years and in the post-HAART era was 43 years (p<0.05). Mean CD4 count at cancer diagnosis in the pre-HAART era was 101 cells/mm3, and 183 cells/mm3 in the post-HAART period (p<0.05). Six patients had diagnoses of both ADC and NADC during the study period. Of the 197 remaining cases, 129 (65.4%) were ADCs and 68 (34.6%) were NADCs (p<0.05). The incidence of Kaposi’s sarcoma decreased significantly, while the incidence of lung cancer increased significantly. Conclusions: Of 197 patients with a single diagnosis of either ADC or NADC, there was statistically a larger proportion of NADC cases diagnosed in the post-HAART period compared to the pre-HAART period. The number of ADC diagnoses decreased between the pre- and post-HAART period. Key words: HIV/AIDS n cancer n lung n Kaposi’s sarcoma
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
Background
S
ince the introduction of highly active antiretroviral therapy (HAART), there has been a significant improvement in the clinical response of patients infected with human immunodeficiency virus (HIV) and an overall improvement in quality of life.1 Therapeutic benefits of HAART have long involved the achievement of clinical, virologic and immunologic goals while managing drug toxicity, maintaining treatment goals and facilitating adherence.1,2 However, despite the clinical benefits afforded by HAART, HIV-infected patients may still be at an increased risk of developing certain malignancy in their lifetime. Studies conducted among people living with AIDS indicate a declining risk for AIDS defining cancers such as Kaposi’s sarcoma, non-Hodgkin’s lymphoma and an increase in non-AIDS-defining cancers (NADCs) such as non-Hodgkin’s lymphoma.3-5 These studies were based upon the Centers for Disease Control and Prevention (CDC) case definition of AIDS-defining malignancies, including Kaposi’s sarcoma, primary central nervous system lymphoma, non-Hodgkin’s lymphoma and invasive cervical cancer.4,5 This shift in cancer trends is readily apparent in the HIV/AIDS Cancer Match Study conducted by Engels and colleagues which assessed cancer risk among 375,933 people with AIDS relative to the general population in the United States between 1998– 2002.3 Results of this study indicated that between 1990– 1995 (pre-HAART) and 1996–2002 (post-HAART), the risk declined for Kaposi’s sarcoma [standardized incidence ratio (SIR): 22,100 and 3,640, respectively; P<0.0001] and non-Hodgkin’s lymphoma (SIR: 53.2 and 22.6, respectively; P<0.0001). The risk of cervical VOL. 100, NO. 7, JULY 2008 817
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cancer did not change, while the risk of NADCs, such as Hodgkin’s lymphoma, increased between the period of 1990–2002. Overall, patients with AIDS remained at a higher risk of developing Kaposi’s sarcoma relative to the general population.3 Possible explanations for the variations in cancer incidence may include: HIV-associated immunosuppression may compromise the body’s ability to mount an immune response against proteins encoded by the tumor viruses and potentially against cellular tumor antigens.6 Other mechanisms for tumor development might involve HIV protein Tat, which enhances direct and indirect cytokine and immunological dysregulation. Tat may contribute to the development of a diverse number of tumors through release of proinflammatory cytokines such as interleukin (IL)-6.7,8 This protein has been shown to enhance the infection of endothelial cells in Kaposi’s sarcoma-associated herpesvirus.8 A retrospective cohort study was conducted at a large metropolitan tertiary care teaching hospital to investigate the incidence of cancers among HIV-infected patients over a 13-year period. This study was conducted to assess the variation in cancer diagnosis between the pre-HAART (pre-1995) and post-HAART (post-1996) periods.
Methodology
A retrospective cohort study was conducted among HIV-infected patients diagnosed with cancer over a period of 13 years between January 1990 and December 2003 at a large metropolitan teaching hospital. Any HIV-infected patient who also had a confirmed diagnosis of Kaposi’s sarcoma, cervical cancer or non-Hodgkin’s lymphoma was categorized as having AIDS-defining cancer (ADC) according to the CDC’s initial case definition for AIDS, while other malignancies were classified as NADCs. A clinical database was created in SPSS® 15.0, consisting of HIV patients diagnosed with cancer at this teaching hospital, and data were abstracted for the current project. A comparison was conducted to assess variations in the incidence of cancers in the preHAART and post-HAART era (defined as pre- or post1995). Additionally, analyses were conducted to assess variations in cancer incidence by gender. Patient data were collected for age, sex, type of canTable 1. Selected study demographic variables Gender
Male: 159 (80.7%) Female: 38 (19.3%) Ethnicity African American: 193 (98%) Hispanic: 2 (1%) Caucasian: 2 (1%) CD4 count (mean)* ADC: 105 NADC: 219 * P value <0.05
818 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
cer, year of diagnosis of cancer along with clinical markers such as documented HIV infection, CD4 count and clinical outcome. Data was entered, and analyses were conducted using SPSS 15.0 software. Categorical (or nonnormally distributed) variables were assessed using the Chi-squared test (Fisher’s exact test was applied when appropriate), and the Student’s t-test was utilized to assess normally distributed continuous variables.
Results
A total of 203 HIV-infected patients who were diagnosed with cancer were identified during the study period. Ninety-three cases occurred before 1995 and 110 after 1996. The median age of patients (at cancer diagnosis) in the pre-HAART era was 37 years and in the post-HAART era was 43 years (p<0.05) (Table 2). The median CD4 count at cancer diagnosis in the preHAART era was 35 cells/mm3, and 123.5 cells/mm3 in the post-HAART period (p<0.05). Of 203 cases, 134 (55.1%) were ADCs and 83 (40.8%) were NADCs (p<0.05) (six patients were diagnosed with both ADC and NADC cancers at some point in the database; those patients were excluded from further analysis, leaving a total of 197 cases with either ADC or NADC diagnoses). The vast majority of patients in this database were African American (n=193, 98%), with Hispanic and Caucasian patients accounting for 1% each. Nearly 81% (n=159) of the cases were among males, and the remaining 19% (n=38) among females (Table 1). ADCs in pre- and post-HAART were 74 (57%) vs. 55 cases (43%), respectively (Figure 1). NADCs in pre- and postHAART incidence were 18 (26%) vs. 50 (74%), respectively (p<0.05). A total of 97 deaths were noted. Of 72 ADC deaths, 47 occurred before 1995 and 25 after 1995. The total number of NADC deaths was 25, of which nine occurred before 1995 and 16 after 1996 (p<0.05). The relative risk of being diagnosed with a NADCs in post-HAART compared to pre-HAART was 1.54 (CI: 1.25–1.89), reflecting an increase in NADCs in the postHAART period. An assessment of the most frequently diagnosed cancers among all patients during the pre- and post-HAART periods (Table 3) also noted that in the pre-HAART period Kaposi’s sarcoma was the most frequent diagnosis in 57% of the 93 cases. Non-Hodgkin’s lymphoma was the second most frequently diagnosed cancer in this period (17%), and lung cancer was diagnosed in 6.5% of cases. During the post-HAART period, the most frequently diagnosed cancer was non-Hodgkin’s lymphoma (26%), Kaposi’s sarcoma was the second most frequently diagnosed cancer (20%), and lung cancer was diagnosed in 17% of cases. Between the two study periods, there was a statistically significant decrease in the diagnosis of Kaposi’s sarcoma (p<0.0001) and statistically significant increases in the diagnosis of lung cancer (p=0.019) and other cancers (p=0.009). VOL. 100, NO. 7, JULY 2008
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A gender-based assessment finds that among the male patients (81%, n=159), the most prevalent cancers in the pre-HAART period were Kaposi’s sarcoma (n=52) and non-Hodgkin’s lymphoma (n=13). In the post-HAART period, the frequency of Kaposi’s sarcoma among men decreased to 22, but non-Hodgkin’s lymphoma increased to 24 cases. Additionally among males, lung cancer also increased from five cases pre-HAART to 11 cases postHAART. Among females cases (19%, n=38), the most prevalent cancer in the pre-HAART period was cervical cancer, with five cases pre-HAART and the same number of cases in the post-HAART period. Non-Hodgkin’s lymphoma increased from three cases pre-HAART to five cases post-HAART. Again, among females, the incidence of lung cancer increased dramatically from one in the preHAART period, to eight in the post-HAART period.
Discussion
A retrospective cohort study was conducted at a large metropolitan tertiary care teaching hospital to investigate the incidence of cancers among HIV-infected patients over a 13-year period. The patients in this database were almost exclusively African American (n=98%). The results of this study demonstrate that in the period 1990– 2003, a total of 203 cases of cancer were identified in this institution. Of 197 patients with a single diagnosis of either an ADC or NADC, there were statistically a larger proportion of NADC cases diagnosed in the postHAART period compared to the pre-HAART period. While the number of ADC diagnoses decreased between the pre- and post-HAART period. These results are consistent with the findings of Bedimo and colleagues, who reported a decline in ADC and a corresponding increase in NADC in a similar pre-HAART and post-HAART study period.9 In the Bedimo study of 2,800 patients, there were a total of 178 new cases of ADC and 60 new cases of NADCs, including Hodgkin’s lymphoma, skin cancer, invasive anal cancer, colon cancer, lung cancer, breast cancer, kidney cancer, and head and neck cancer. Bedimo further noted that comparison studies between pre-HAART (1989–1996) and post-HAART (1997–2002) periods indicated the rate of AIDS-defining malignancies decreased from 40 to 11.33 cases per 1,000 patient years between the two periods, while the
incidence of NADCs increased from 3.27 to 10.87 cases per 1,000 patient years.9 The current study notes that there was a statistically significant difference in mean CD4 count based upon ADC or NADC diagnosis. This also supports Bedimo’s findings, which suggest that patients with a history of severe immunosuppression may no longer be at increased risk of developing ADC, provided they experience a positive immunologic response to HAART. Another interesting finding in the current study is the increase in the diagnosis of lung cancer in this patient population. Lung cancer was diagnosed in 6.5% of cases in the pre-HAART period, and increased to 17% of cases in the post-HAART period, a statistically significant increase (p=0.019). However, the reason for this increase is unclear, though it may be related to the increased age of patients in the post-HAART period, and smoking behavior. There was also a statistically significant decrease in the diagnosis of Kaposi’s sarcoma. Figure 1. AIDS-defining cancer (ADC) versus non-ADC cancers
ADC or NADC Cancer 80
ADC
NADC
70 60 50 40 30 20 10 0
Pre-HAART
Post-HAART
Pre-HAART (1995 & before) or Post-HAART (after 1996) HAART: Highly active antiretroviral therapy
Table 2. Comparison of variables in the pre-HAART versus post-HAART period
N Age (mean)* Age (median)* Mean CD4 count (at cancer diagnosis)* ADC* Non-ADC*
Pre-HAART 93 38 37 101 (n=69 74 18
Post-HAART 110 45 43 183 (n=90) 55 50
P Value <0.0001 <0.0001 0.002 <0.0001 <0.0001
* P value <0.05
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Table 3. Most frequent cancer diagnoses during the study period
Cancer Kaposi’s sarcoma Non-Hodgkin’s lymphoma+ Lung cancer+ Cervical cancer++ Anal cancer++ Others Subtotal
+
Pre-HAART Period
Post-HAART Period
Cases
Percentage
Cases
Percentage
P Value
53 16
57% 17.2%
22 29
20% 26%
<0.0001* 0.117
6 5 2 11 93%
6.5% 5.4% 2.2% 11.8% 100%
19 5 6 29 110
17.3% 4.5% 5.5% 26.4% 100
0.019* 0.785 0.228 0.009*
* P values < 0.05; + Pearson’s Chi-squared test; ++ Fisher’s exact test
Epidemiologic studies have also documented the risk of cancer among HIV-infected persons in sub-Saharan Africa.10 An AIDS Cancer Match Study conducted by Mbulaiteye and colleagues assessed the cancer risk among persons with HIV/AIDS in Uganda between 1988–2002.10 The SIR was used to identify increased cancer risks in three different periods: early, late or combined. Of 12,607 infected patients, they reported an increased risk of ADCs such Kaposi’s sarcoma (SIR: 6.4, 95% CI: 4.8–8.4), non-Hodgkin’s lymphoma (SIR: 6.7, 95% CI: 1.8–17) and cervical carcinoma (SIR: 2.4, 95% CI: 1.1–4.4). The risk of five NADCs were increased in the combined periods: non-Hodgkin’s lymphoma (SIR: 5.7, 95% CI: 1.2–17), cancers of the conjunctiva (SIR: 4.0, 95% CI: 1.5–8.7), kidney (SIR: 16, 95% CI: 1.8– 58), thyroid (SIR: 5.7, 95% CI: 1.1–16) and uterus (SIR: 5.5, 95% CI: 1.5–14).10 Various potential explanations of the increase in NADC include: improved diagnosis of these conditions among clinicians, damage caused by the HIV virus, potential that NADCs may be due to side effects of prolonged HAART therapy, increased susceptibility to NADC due to changes in the patients immune system post-HAART restoration or some other explanation.6,7,9,11 Decreases in ADC signal success in the ability of HAART to decrease the likelihood of diagnosis due to Kaposi’s sarcoma and non-Hodgkin’s lymphoma. In our study, the incidence of NADC and its mortality has increased in the postHAART era. These increases may possibly be explained by the overall improved survival period due to HAART and early detection with improved screening procedures, but no change in patients’ lifestyles. This study was limited due to the relatively small size of the study population, which also limited the analyses that could be conducted. Additionally, a prospective study design would be better suited to assess variations in the development of ADC and NADC cancers. Further, changes in the definition of AIDS over the study period should be considered in the interpretation of the results. Despite these limitations, this study provides 820 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
an important assessment of variations in the diagnosis of cancers among a largely African-American group of HIV-infected patients at a large metropolitan teaching hospital. Considerations should be made regarding the increase in NADC over the study period, as well as the impact that this increase may have on patient survival.
References
1. May MT, Sterne JA, Costagliola D, et al. HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis. Lancet. 2006; 368(9534):451458. 2. Bartlett J, Gallant J. (2004, May). 2004 Medical Management of HIV infection. John Hopkins University Medicine Health Publishing Business Group. 3. Engels E, Pfeiffer R, Goedert J, et al. Trends in cancer risk among people with AIDS in the United States 1980–2002. AIDS. 2006;20(12):1645-1654. 4. Centers for Disease Control. Update on acquired immune deficiency syndrome (AIDS)-United States. MMWR Morb Mortal Wkly Rep. 1987;36:1S-15S. 5. Centers for Disease Control. 1993 revised classification for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep. 1992;41:961-962. 6. Aoki Y, Yarchoan R, Braun J, et al. Viral and cellular cytokines in AIDS related malignant lymphomatous effusions. Blood. 2000;96:1599-1601. 7. Yarchoan R, Tosato G, Little RF. Therapy Insight: AIDS-Related Malignancies-The Influence of Antiviral Therapy on Pathogenesis and Management. Nat Clin Pract Oncol. 2005;2:406-415. 8. Aoki Y and Tosato G. HIV-1 Tat enhances Kaposi’s sarcoma-associated herpesvirus (KSHV) infectivity. Blood. 2004;104:810-814. 9. Bedimo R, Chen R, Accortt N et al. Trends in AIDS-defining and Non-AIDS defining malignancies among HIV-infected patients. 1989-2002. Clin Infect Dis. 2004;39:1380-1384. 10. Mbulaiteye S, Katabira E, Wabinga H, et al. Spectrum of cancers among HIV-infected persons in Africa: the Uganda AIDS-Cancer Registry Match Study. Int J Cancer. 2006;118(4):985-990. 11. Rabkin CS. AIDS and cancer in the era of highly active antiretroviral therapy (HAART). Eur J Cancer. 2001;37:1316-1319. n
We Welcome Your Comments The Journal of the National Medical Association welcomes your Letters to the Editor about articles that appear in the JNMA or issues relevant to minority healthcare. Address correspondence to [email protected].
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Malignancies in HIV: Pre- and Post-Highly Active Antiretroviral Therapy Lavanya Nutankalva, MD; Anthony K. Wutoh, PhD, RPh; John McNeil, MD; Winston R. Frederick, MD; Ramani B. Reddy, MD; Monika Daftary, PharmD; Andrew Gentles, PharmD; and Kwame Addae-Afoakwa, PharmD student
Financial support: This study was partially supported by the Agency for Healthcare Research and Quality grant 1R24HS11673. Objectives: A study was conducted at a large metropolitan tertiary-care teaching hospital to investigate the incidence of cancers among HIV-infected patients over a 13-year period.
© 2008. From College of Medicine (Nutankalva, McNeil, Reddy, assistant professors; Frederick, professor) and School of Pharmacy (Wutoh, professor; Daftary, associate professor; Gentles, pharmacy resident; Addae-Afoakwa, student), Howard University, Washington, DC. Send correspondence and reprint requests for J Natl Med Assoc. 2008;100:817–820 to: Dr. Anthony K. Wutoh, Professor, Howard University School of Pharmacy, 2300 Fourth St. NW, Washington, DC 20059; phone: (202) 806-4209; fax: (202) 806-4478; e-mail: [email protected]
Design: Retrospective cohort study. Methods: A retrospective cohort study was conducted among HIV-infected patients diagnosed with cancer between January 1990 and December 2003 at a large metropolitan teaching hospital. Any HIV-infected patient who also had a confirmed diagnosis of Kaposi’s sarcoma, primary central nervous system lymphoma, invasive cervical cancer or non-Hodgkin’s lymphoma was categorized as having AIDS-defining cancer (ADC) according to the CDC’s initial case definition for AIDS, while patients with other malignancies were classified as having non-ADCs. A clinical database was created consisting of HIV patients diagnosed with cancer at this teaching hospital, and data were abstracted for the current project. Results: A total of 203 HIV-infected patients diagnosed with cancer were identified during the study period. Ninety-three cases occurred before 1995 and 110 after 1996. The median age of patients (at cancer diagnosis) in the era before highly active antiretroviral therapy (HAART) was 37 years and in the post-HAART era was 43 years (p<0.05). Mean CD4 count at cancer diagnosis in the pre-HAART era was 101 cells/mm3, and 183 cells/mm3 in the post-HAART period (p<0.05). Six patients had diagnoses of both ADC and NADC during the study period. Of the 197 remaining cases, 129 (65.4%) were ADCs and 68 (34.6%) were NADCs (p<0.05). The incidence of Kaposi’s sarcoma decreased significantly, while the incidence of lung cancer increased significantly. Conclusions: Of 197 patients with a single diagnosis of either ADC or NADC, there was statistically a larger proportion of NADC cases diagnosed in the post-HAART period compared to the pre-HAART period. The number of ADC diagnoses decreased between the pre- and post-HAART period. Key words: HIV/AIDS n cancer n lung n Kaposi’s sarcoma
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
Background
S
ince the introduction of highly active antiretroviral therapy (HAART), there has been a significant improvement in the clinical response of patients infected with human immunodeficiency virus (HIV) and an overall improvement in quality of life.1 Therapeutic benefits of HAART have long involved the achievement of clinical, virologic and immunologic goals while managing drug toxicity, maintaining treatment goals and facilitating adherence.1,2 However, despite the clinical benefits afforded by HAART, HIV-infected patients may still be at an increased risk of developing certain malignancy in their lifetime. Studies conducted among people living with AIDS indicate a declining risk for AIDS defining cancers such as Kaposi’s sarcoma, non-Hodgkin’s lymphoma and an increase in non-AIDS-defining cancers (NADCs) such as non-Hodgkin’s lymphoma.3-5 These studies were based upon the Centers for Disease Control and Prevention (CDC) case definition of AIDS-defining malignancies, including Kaposi’s sarcoma, primary central nervous system lymphoma, non-Hodgkin’s lymphoma and invasive cervical cancer.4,5 This shift in cancer trends is readily apparent in the HIV/AIDS Cancer Match Study conducted by Engels and colleagues which assessed cancer risk among 375,933 people with AIDS relative to the general population in the United States between 1998– 2002.3 Results of this study indicated that between 1990– 1995 (pre-HAART) and 1996–2002 (post-HAART), the risk declined for Kaposi’s sarcoma [standardized incidence ratio (SIR): 22,100 and 3,640, respectively; P<0.0001] and non-Hodgkin’s lymphoma (SIR: 53.2 and 22.6, respectively; P<0.0001). The risk of cervical VOL. 100, NO. 7, JULY 2008 817
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cancer did not change, while the risk of NADCs, such as Hodgkin’s lymphoma, increased between the period of 1990–2002. Overall, patients with AIDS remained at a higher risk of developing Kaposi’s sarcoma relative to the general population.3 Possible explanations for the variations in cancer incidence may include: HIV-associated immunosuppression may compromise the body’s ability to mount an immune response against proteins encoded by the tumor viruses and potentially against cellular tumor antigens.6 Other mechanisms for tumor development might involve HIV protein Tat, which enhances direct and indirect cytokine and immunological dysregulation. Tat may contribute to the development of a diverse number of tumors through release of proinflammatory cytokines such as interleukin (IL)-6.7,8 This protein has been shown to enhance the infection of endothelial cells in Kaposi’s sarcoma-associated herpesvirus.8 A retrospective cohort study was conducted at a large metropolitan tertiary care teaching hospital to investigate the incidence of cancers among HIV-infected patients over a 13-year period. This study was conducted to assess the variation in cancer diagnosis between the pre-HAART (pre-1995) and post-HAART (post-1996) periods.
Methodology
A retrospective cohort study was conducted among HIV-infected patients diagnosed with cancer over a period of 13 years between January 1990 and December 2003 at a large metropolitan teaching hospital. Any HIV-infected patient who also had a confirmed diagnosis of Kaposi’s sarcoma, cervical cancer or non-Hodgkin’s lymphoma was categorized as having AIDS-defining cancer (ADC) according to the CDC’s initial case definition for AIDS, while other malignancies were classified as NADCs. A clinical database was created in SPSS® 15.0, consisting of HIV patients diagnosed with cancer at this teaching hospital, and data were abstracted for the current project. A comparison was conducted to assess variations in the incidence of cancers in the preHAART and post-HAART era (defined as pre- or post1995). Additionally, analyses were conducted to assess variations in cancer incidence by gender. Patient data were collected for age, sex, type of canTable 1. Selected study demographic variables Gender
Male: 159 (80.7%) Female: 38 (19.3%) Ethnicity African American: 193 (98%) Hispanic: 2 (1%) Caucasian: 2 (1%) CD4 count (mean)* ADC: 105 NADC: 219 * P value <0.05
818 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
cer, year of diagnosis of cancer along with clinical markers such as documented HIV infection, CD4 count and clinical outcome. Data was entered, and analyses were conducted using SPSS 15.0 software. Categorical (or nonnormally distributed) variables were assessed using the Chi-squared test (Fisher’s exact test was applied when appropriate), and the Student’s t-test was utilized to assess normally distributed continuous variables.
Results
A total of 203 HIV-infected patients who were diagnosed with cancer were identified during the study period. Ninety-three cases occurred before 1995 and 110 after 1996. The median age of patients (at cancer diagnosis) in the pre-HAART era was 37 years and in the post-HAART era was 43 years (p<0.05) (Table 2). The median CD4 count at cancer diagnosis in the preHAART era was 35 cells/mm3, and 123.5 cells/mm3 in the post-HAART period (p<0.05). Of 203 cases, 134 (55.1%) were ADCs and 83 (40.8%) were NADCs (p<0.05) (six patients were diagnosed with both ADC and NADC cancers at some point in the database; those patients were excluded from further analysis, leaving a total of 197 cases with either ADC or NADC diagnoses). The vast majority of patients in this database were African American (n=193, 98%), with Hispanic and Caucasian patients accounting for 1% each. Nearly 81% (n=159) of the cases were among males, and the remaining 19% (n=38) among females (Table 1). ADCs in pre- and post-HAART were 74 (57%) vs. 55 cases (43%), respectively (Figure 1). NADCs in pre- and postHAART incidence were 18 (26%) vs. 50 (74%), respectively (p<0.05). A total of 97 deaths were noted. Of 72 ADC deaths, 47 occurred before 1995 and 25 after 1995. The total number of NADC deaths was 25, of which nine occurred before 1995 and 16 after 1996 (p<0.05). The relative risk of being diagnosed with a NADCs in post-HAART compared to pre-HAART was 1.54 (CI: 1.25–1.89), reflecting an increase in NADCs in the postHAART period. An assessment of the most frequently diagnosed cancers among all patients during the pre- and post-HAART periods (Table 3) also noted that in the pre-HAART period Kaposi’s sarcoma was the most frequent diagnosis in 57% of the 93 cases. Non-Hodgkin’s lymphoma was the second most frequently diagnosed cancer in this period (17%), and lung cancer was diagnosed in 6.5% of cases. During the post-HAART period, the most frequently diagnosed cancer was non-Hodgkin’s lymphoma (26%), Kaposi’s sarcoma was the second most frequently diagnosed cancer (20%), and lung cancer was diagnosed in 17% of cases. Between the two study periods, there was a statistically significant decrease in the diagnosis of Kaposi’s sarcoma (p<0.0001) and statistically significant increases in the diagnosis of lung cancer (p=0.019) and other cancers (p=0.009). VOL. 100, NO. 7, JULY 2008
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A gender-based assessment finds that among the male patients (81%, n=159), the most prevalent cancers in the pre-HAART period were Kaposi’s sarcoma (n=52) and non-Hodgkin’s lymphoma (n=13). In the post-HAART period, the frequency of Kaposi’s sarcoma among men decreased to 22, but non-Hodgkin’s lymphoma increased to 24 cases. Additionally among males, lung cancer also increased from five cases pre-HAART to 11 cases postHAART. Among females cases (19%, n=38), the most prevalent cancer in the pre-HAART period was cervical cancer, with five cases pre-HAART and the same number of cases in the post-HAART period. Non-Hodgkin’s lymphoma increased from three cases pre-HAART to five cases post-HAART. Again, among females, the incidence of lung cancer increased dramatically from one in the preHAART period, to eight in the post-HAART period.
Discussion
A retrospective cohort study was conducted at a large metropolitan tertiary care teaching hospital to investigate the incidence of cancers among HIV-infected patients over a 13-year period. The patients in this database were almost exclusively African American (n=98%). The results of this study demonstrate that in the period 1990– 2003, a total of 203 cases of cancer were identified in this institution. Of 197 patients with a single diagnosis of either an ADC or NADC, there were statistically a larger proportion of NADC cases diagnosed in the postHAART period compared to the pre-HAART period. While the number of ADC diagnoses decreased between the pre- and post-HAART period. These results are consistent with the findings of Bedimo and colleagues, who reported a decline in ADC and a corresponding increase in NADC in a similar pre-HAART and post-HAART study period.9 In the Bedimo study of 2,800 patients, there were a total of 178 new cases of ADC and 60 new cases of NADCs, including Hodgkin’s lymphoma, skin cancer, invasive anal cancer, colon cancer, lung cancer, breast cancer, kidney cancer, and head and neck cancer. Bedimo further noted that comparison studies between pre-HAART (1989–1996) and post-HAART (1997–2002) periods indicated the rate of AIDS-defining malignancies decreased from 40 to 11.33 cases per 1,000 patient years between the two periods, while the
incidence of NADCs increased from 3.27 to 10.87 cases per 1,000 patient years.9 The current study notes that there was a statistically significant difference in mean CD4 count based upon ADC or NADC diagnosis. This also supports Bedimo’s findings, which suggest that patients with a history of severe immunosuppression may no longer be at increased risk of developing ADC, provided they experience a positive immunologic response to HAART. Another interesting finding in the current study is the increase in the diagnosis of lung cancer in this patient population. Lung cancer was diagnosed in 6.5% of cases in the pre-HAART period, and increased to 17% of cases in the post-HAART period, a statistically significant increase (p=0.019). However, the reason for this increase is unclear, though it may be related to the increased age of patients in the post-HAART period, and smoking behavior. There was also a statistically significant decrease in the diagnosis of Kaposi’s sarcoma. Figure 1. AIDS-defining cancer (ADC) versus non-ADC cancers
ADC or NADC Cancer 80
ADC
NADC
70 60 50 40 30 20 10 0
Pre-HAART
Post-HAART
Pre-HAART (1995 & before) or Post-HAART (after 1996) HAART: Highly active antiretroviral therapy
Table 2. Comparison of variables in the pre-HAART versus post-HAART period
N Age (mean)* Age (median)* Mean CD4 count (at cancer diagnosis)* ADC* Non-ADC*
Pre-HAART 93 38 37 101 (n=69 74 18
Post-HAART 110 45 43 183 (n=90) 55 50
P Value <0.0001 <0.0001 0.002 <0.0001 <0.0001
* P value <0.05
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Malignancies in HIV
Table 3. Most frequent cancer diagnoses during the study period
Cancer Kaposi’s sarcoma Non-Hodgkin’s lymphoma+ Lung cancer+ Cervical cancer++ Anal cancer++ Others Subtotal
+
Pre-HAART Period
Post-HAART Period
Cases
Percentage
Cases
Percentage
P Value
53 16
57% 17.2%
22 29
20% 26%
<0.0001* 0.117
6 5 2 11 93%
6.5% 5.4% 2.2% 11.8% 100%
19 5 6 29 110
17.3% 4.5% 5.5% 26.4% 100
0.019* 0.785 0.228 0.009*
* P values < 0.05; + Pearson’s Chi-squared test; ++ Fisher’s exact test
Epidemiologic studies have also documented the risk of cancer among HIV-infected persons in sub-Saharan Africa.10 An AIDS Cancer Match Study conducted by Mbulaiteye and colleagues assessed the cancer risk among persons with HIV/AIDS in Uganda between 1988–2002.10 The SIR was used to identify increased cancer risks in three different periods: early, late or combined. Of 12,607 infected patients, they reported an increased risk of ADCs such Kaposi’s sarcoma (SIR: 6.4, 95% CI: 4.8–8.4), non-Hodgkin’s lymphoma (SIR: 6.7, 95% CI: 1.8–17) and cervical carcinoma (SIR: 2.4, 95% CI: 1.1–4.4). The risk of five NADCs were increased in the combined periods: non-Hodgkin’s lymphoma (SIR: 5.7, 95% CI: 1.2–17), cancers of the conjunctiva (SIR: 4.0, 95% CI: 1.5–8.7), kidney (SIR: 16, 95% CI: 1.8– 58), thyroid (SIR: 5.7, 95% CI: 1.1–16) and uterus (SIR: 5.5, 95% CI: 1.5–14).10 Various potential explanations of the increase in NADC include: improved diagnosis of these conditions among clinicians, damage caused by the HIV virus, potential that NADCs may be due to side effects of prolonged HAART therapy, increased susceptibility to NADC due to changes in the patients immune system post-HAART restoration or some other explanation.6,7,9,11 Decreases in ADC signal success in the ability of HAART to decrease the likelihood of diagnosis due to Kaposi’s sarcoma and non-Hodgkin’s lymphoma. In our study, the incidence of NADC and its mortality has increased in the postHAART era. These increases may possibly be explained by the overall improved survival period due to HAART and early detection with improved screening procedures, but no change in patients’ lifestyles. This study was limited due to the relatively small size of the study population, which also limited the analyses that could be conducted. Additionally, a prospective study design would be better suited to assess variations in the development of ADC and NADC cancers. Further, changes in the definition of AIDS over the study period should be considered in the interpretation of the results. Despite these limitations, this study provides 820 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
an important assessment of variations in the diagnosis of cancers among a largely African-American group of HIV-infected patients at a large metropolitan teaching hospital. Considerations should be made regarding the increase in NADC over the study period, as well as the impact that this increase may have on patient survival.
References
1. May MT, Sterne JA, Costagliola D, et al. HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis. Lancet. 2006; 368(9534):451458. 2. Bartlett J, Gallant J. (2004, May). 2004 Medical Management of HIV infection. John Hopkins University Medicine Health Publishing Business Group. 3. Engels E, Pfeiffer R, Goedert J, et al. Trends in cancer risk among people with AIDS in the United States 1980–2002. AIDS. 2006;20(12):1645-1654. 4. Centers for Disease Control. Update on acquired immune deficiency syndrome (AIDS)-United States. MMWR Morb Mortal Wkly Rep. 1987;36:1S-15S. 5. Centers for Disease Control. 1993 revised classification for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep. 1992;41:961-962. 6. Aoki Y, Yarchoan R, Braun J, et al. Viral and cellular cytokines in AIDS related malignant lymphomatous effusions. Blood. 2000;96:1599-1601. 7. Yarchoan R, Tosato G, Little RF. Therapy Insight: AIDS-Related Malignancies-The Influence of Antiviral Therapy on Pathogenesis and Management. Nat Clin Pract Oncol. 2005;2:406-415. 8. Aoki Y and Tosato G. HIV-1 Tat enhances Kaposi’s sarcoma-associated herpesvirus (KSHV) infectivity. Blood. 2004;104:810-814. 9. Bedimo R, Chen R, Accortt N et al. Trends in AIDS-defining and Non-AIDS defining malignancies among HIV-infected patients. 1989-2002. Clin Infect Dis. 2004;39:1380-1384. 10. Mbulaiteye S, Katabira E, Wabinga H, et al. Spectrum of cancers among HIV-infected persons in Africa: the Uganda AIDS-Cancer Registry Match Study. Int J Cancer. 2006;118(4):985-990. 11. Rabkin CS. AIDS and cancer in the era of highly active antiretroviral therapy (HAART). Eur J Cancer. 2001;37:1316-1319. n
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VOL. 100, NO. 7, JULY 2008