Reasons for gender-related differences in the risk of AIDS-related Kaposi sarcoma (AIDS-KS) are unknown. Four hundred thirty-eight male and 166 female AIDS-KS patients were evaluated in Harare, Zimbabwe. Female patients were younger than male patients in this study (median of 33 vs. 38 years; P < 0.001), mirroring the epidemiology of AIDS in Zimbabwe. In a multivariate model adjusted for CD4 T-cell count, age, prior radiation treatment, and chemotherapy, women were more likely to report fever, diaphoresis, or weight loss (odds ratio = 1.7, 95% confidence interval: 1.1 to 2.7; P = 0.009). These findings suggest an increased severity of KS or other unidentified infections among women with AIDS-KS in Zimbabwe.
From the *Division of Infectious Diseases, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO; †Department of Medicine, University of Zimbabwe School of Medicine, Harare, Zimbabwe; and ‡Department of Preventive Medicine Biometrics, University of Colorado Health Sciences Center, Denver, CO.
Received for publication June 3, 2006; accepted October 20, 2006.
Supported by grants from the National Institutes of Health (TW0123 and CA79389); the Colorado Center for AIDS Research (AI054907); the Departments of Medicine and Medical Laboratory Sciences, University of Zimbabwe; and the Michael Gelfand Medical Research Foundation.
This study followed the US Department of Health and Human Services guidelines for human experimentation and was approved by the Colorado Multiple Institutional Review Board and the Institutional Review Board of the University of Zimbabwe (BRTI - Biomedical Research and Training Institute).
Reprints: Thomas B. Campbell, MD, Division of Infectious Diseases, University of Colorado Health Sciences Center, PO Box B168, 4200 East Ninth Avenue, Campus Box B168, Denver, CO 80262 (e-mail: email@example.com).
The risk of AIDS-related Kaposi sarcoma (AIDS-KS) is greater in HIV-1-infected men, compared with women, in North America1 and Europe.2 The predilection of AIDS-KS for North American and European men is easily explained by the epidemiology of HIV-1 and KS sarcoma herpesvirus (KSHV) in these populations. In sub-Saharan Africa, however, where KSHV and HIV-1 seroprevalence are similar in men and women,3 the incidence of AIDS-KS is greater in men. For instance, in Zimbabwe, the age-adjusted incidence of KS per 100,000 population was 2.3 in men and 0.3 in women before the AIDS epidemic, and it was 48 and 18, respectively, during the AIDS epidemic.4 Available data suggest that AIDS-KS in women is associated with more extensive disease and worse outcome.5 AIDS-KS is uncommon in women outside sub-Saharan Africa, however, and most existing information on KS pathogenesis comes from studies of HIV-infected men. Because the reasons for gender-related differences in AIDS-KS are unknown and little information about the characteristics of AIDS-KS in African women is available, we tested the hypothesis that clinical, immunologic, and virologic markers of AIDS-KS are different in women and men in Harare, Zimbabwe.
The Institutional Review Boards of the University of Colorado Health Sciences Center and the University of Zimbabwe School of Medicine approved this study, and informed consent was obtained from all participants. All men and women who were diagnosed with AIDS-KS at the Parirenyatwa Hospital KS Clinic in Harare, Zimbabwe between 1998 and 2001 were eligible to participate.
Each participant was asked whether or not he or she had weight loss, fever, or night sweats and received a complete physical examination. Liver function tests, a complete blood cell count, chest radiography, and HIV serology were performed for all subjects. Most participants had a CD4 lymphocyte count. All subjects had KS confirmed by biopsy of a suspected lesion. A single investigator determined the KS clinical stage on the basis of the following criteria according to Krigel et al6: stage I, locally indolent cutaneous lesion; stage II, locally aggressive cutaneous lesion with or without regional lymph node involvement; stage III, multiple cutaneous lesions or generalized lymph node involvement, including lymphedema, without palatal KS or radiographic evidence of pulmonary KS; and stage IV, palatal or radiographic evidence of pulmonary KS. Stage IV KS determined by these criteria is an independent marker of decreased length of survival of patients with AIDS-KS in Zimbabwe.7
Peripheral Blood Kaposi Sarcoma Herpesvirus Load
The amount of KSHV DNA present in DNA preparations obtained from peripheral blood mononuclear cells (PBMCs) or plasma was determined by real-time polymerase chain reaction (PCR) amplification of a conserved region of the ORF 26 minor capsid gene as reported previously.8 In all assays, there was a linear relation between the value of the threshold cycle (CT) for the standards and the logarithm of minor capsid DNA copy number (r2 = 0.98 for each assay). If the measured KSHV DNA was greater than or equal to 1 copy, the PCR reaction was considered positive. Negative controls included 2 PCR reactions that contained 2 μg of carrier DNA and 4 reactions that contained no DNA. In all assays, the measured fluorescence of the 6 negative controls did not exceed the threshold after 40 PCR cycles.
All analyses assumed a 2-sided test of hypothesis with an overall significance level of 0.05. Analyses were conducted using SAS (SAS Institute, Cary, NC) and Splus (Insightful Corporation, Seattle, WA) software. Because of nonnormal distributions and truncation, nonparametric tests were used where appropriate. Continuous characteristics were compared using Wilcoxon rank sum tests in Splus. Log transformations were used to normalize the continuous variables CD4+ T-cell count and age, as appropriate. Odds ratios (ORs) were estimated using the logistic procedure in SAS, with corresponding P values obtained via a likelihood ratio test. Age-adjusted comparisons of continuous outcome data were conducted using ordinary least squares regression.
The study population was 604 individuals with AIDS-KS who were antiretroviral naive. These AIDS-KS cases included 450 participants who were reported previously8 and 154 individuals who have not been reported previously. In a univariate analysis, female AIDS-KS patients were younger than male patients (Table 1; median of 33 vs. 38 years; P < 0.001) and were more likely to have systemic symptoms (fever, diaphoresis, or weight loss; OR = 1.8; 95% confidence interval [CI]: 1.3 to 2.6; P = 0.001). The KS disease stage, history of prior or current treatment with chemotherapy or radiation therapy, median CD4+ lymphocyte count, CD4 count <200 cells/mm3, peripheral blood KSHV load, and presence of KSHV in peripheral blood were not different in women compared with men (see Table 1).
The finding that women were significantly younger than men at the time they presented for treatment of AIDS-KS in Zimbabwe could indicate that women are infected with HIV-1 at an earlier age9,10 or that immunosuppression from HIV-1 infection and KS pathogenesis progresses more rapidly in women. To account for differences in age, a continuous regression model adjusting for age was used and demonstrated that there was no significant difference in CD4+ lymphocyte count between women and men (P = 0.4). In addition, a multivariate model, which adjusted for CD4+ T-cell count <200 cells/mm3 and log age, demonstrated that the presence of KSHV DNA in the plasma or PBMCs (OR = 1.4, 95% CI: 0.86 to 2.4; P = 0.2); CD4+ lymphocytes <200 mm3 (OR = 0.88, 95% CI: 0.57 to 1.4; P = 0.6, age adjusted only); KS disease stage 1, 2, or 3 versus KS disease stage 4 (OR = 0.94, 95% CI: 0.61 to 1.4; P = 0.8); and history of prior treatment (OR = 0.90, 95% CI: 0.58 to 1.4; P = 0.6) were not associated with gender but that women were still more likely to have systemic symptoms (OR = 1.8, 95% CI: 1.2 to 2.7; P = 0.008). In univariate analysis, systemic symptoms were reported in 36% (62 of 172) of AIDS-KS patients who had received prior or current radiation treatment or chemotherapy compared with 44% (187 of 424) of untreated subjects (P = 0.08). After adjustment of the multivariate model for prior treatment history, women remained more likely to have systemic symptoms (OR = 1.7, 95% CI: 1.1 to 2.7; P = 0.009) compared with men.
This study provides the first systematic description of the characteristics of AIDS-KS in African women and the first comparison of the viral and immunologic markers of HIV-1 and KS disease in women and men. The proportion of men and women (3:1 ratio) in our study was similar to the ratio of male-to-female AIDS-KS patients reported by the Zimbabwe Cancer Registry4 and by other studies of African populations.3 It seems unlikely that the unequal proportion of men and women in our study was the result of decreased access to health care for women compared with men. Although this inequity has been demonstrated in other African populations,11 differential access to health care would have biased toward women presenting with lower CD4+ lymphocyte counts and more advanced KS stage. This was not observed in our study. Because men and women in our study had similar CD4+ lymphocyte counts and peripheral blood KSHV loads even after adjusting for age, our study did not detect any immunologic or virologic differences between men and women that would explain a lower risk of AIDS-KS in African women. Although gender-related differences in the risk of AIDS-KS could result from difference in the prevalence of infection with KSHV, previous studies have demonstrated an equal prevalence of KSHV infection in African men and women.3,10,12
The finding that women with AIDS-KS were more symptomatic than men has not been reported previously. Because Zimbabwean women and men had similar KS disease stage and CD4+ lymphocyte counts, the reasons for the increased frequency of systemic symptoms among women with AIDS-KS in our study are not obvious. Although we cannot exclude a difference in symptom reporting by men and women,13 our study was designed to minimize reporting bias. Our study did not rely on passive reporting of symptoms; rather, men and women were questioned about symptoms during an interview conducted in their native language by trained research personnel. The finding that women are more likely to have symptoms of fever, diaphoresis, or weight loss suggests underlying differences in the biology and pathogenesis of KS disease and/or HIV-1 disease in women compared with men or gender differences in the incidence of other coinfections. These differences could be attributable to a greater burden of KS disease or to the increased levels of inflammatory cytokines associated with additional subclinical coinfections in women compared with men. Because our study did not measure the prevalence or incidence of other coinfections, we are not able to evaluate these possibilities.
Our observations provide additional evidence that the biology of AIDS-KS differs in men and women and are consistent with the increased risk of KS disease progression observed in 2 previous studies.5,14 Because AIDS-KS is a major cause of morbidity and mortality in men and women in Africa, additional studies of the potential mechanisms for gender-related differences in AIDS-KS are needed to evaluate the roles of gender-specific factors such as parity, menstrual status, and female sex hormones in AIDS-KS pathogenesis.
Real-time PCR assays were performed by Uma Pugazenthi in the Quantitative PCR Core Laboratory of the University of Colorado Cancer Center.
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