Our study found that both the clinical presentation of KS and clinical outcomes differ between men and women in Uganda. Women presented with lower CD4 T-cell counts at diagnosis, had frequent orofacial KS, and were less likely to have tumor-associated edema or nodular lesions than men. Women were also less likely to demonstrate clinical improvement than men.
Women in our study had significantly lower CD4 counts at KS diagnosis than men, as has been reported by others 
. The frequency of this finding across several studies suggests that greater immunosuppression may be an intrinsic part of the pathophysiology of KS in women. More severe immunosuppression due to HIV may be needed in women for KS to overcome gender-related factors, including hormonal, environmental, or genetic factors, which normally protect women against the disease. Human chorionic gonadotrophin (hCG) has been hypothesized to be a protective factor in KS development based on its inhibition of the growth KS cell lines in vitro 
. However, therapeutic trials of intralesional hCG have been inconclusive and pregnancy does not affect the risk of developing KS, suggesting factors other than hCG are important 
. Gender-based differences in immune responses, as evidenced epidemiologically by differences in rates of autoimmune disease or vaccine response in men and women 
, could also contribute to differences in KS presentation and response. Control of HHV-8, the etiologic agent of KS, may also differ in men and women, as evidenced by a cohort study of persons with HIV and KS in Uganda showing that men have higher rates of HHV-8 replication in mucosa and peripheral blood than women 
. HHV-8 replication is in turn an essential step in the development of KS 
. However, in US 
and Ugandan 
cohorts, lower CD4 counts were not associated with poorer control of HHV-8 replication. Thus the interaction between immunosuppression, HHV-8 replication and development of KS in women needs to be further investigated.
We also observed that the location of KS lesions differed between men and women. Our finding that women had frequent oral KS lesions is in agreement with previous studies 
. Notably, the presence of lesions on the hard palate was also associated with a greater hazard of improvement. It is unclear why palatal lesions would be associated with improvement, particularly since palatal KS has been identified as a marker of pulmonary KS in Uganda 
. It is possible that persons with more severe disease offer a greater opportunity for clinicians to observe a clinical response, though we did not find an association between burden of disease as measured by number of lesions or lesion locations and response. The trend that men are more likely to present with lower extremity lesions and associated edema mirrors the typical presentation of non-HIV-associated KS, which is predominantly a disease of men. The higher likelihood of lower extremity involvement in men supports the notion that there may be gender differences in KS pathophysiology.
Male gender was significantly associated with the probability of clinical improvement. Importantly, this association remained after adjusting for KS clinical presentation, suggesting that the lower likelihood of clinical improvement in women may in part be attributed to additional factors beyond the more severe disease presentation and greater immunosuppression at KS diagnosis observed among women in our cohort. Of note, we did not identify any cases of KS immune reconstitution inflammatory syndrome (IRIS) in our cohort, and we are not aware of gender differences in IRIS risk that could account for the lower rate of KS improvement in women. A factor not evaluated in our study that could impact our findings is the type of therapy received by men and women. KS treatment usually involves administration of antiretroviral therapy and chemotherapy, but the treatment provided to men and women in our cohort may have differed due to clinical or socioeconomic factors. However, if the pathology of KS differs in men and women, it is also possible that equivalent KS treatment regimens are not equally effective in women. Future studies of KS in women should include evaluation of treatment to measure the effect of treatment on response and to determine if current therapies are equally efficacious in both genders.
Health care utilization and health-seeking behaviors may have also differed among men and women. For example, men may have been more likely to have money to pay for chemotherapy than women, perhaps contributing to the higher rate of clinical improvement we observed in men. Additionally, women tend to have greater exposure to HIV testing as routine counseling and testing has been applied to perinatal settings, and this may have allowed for both a greater number of KS cases and perhaps earlier stage disease to be identified among women. The frequency of clinic attendance after KS diagnosis could also influence the likelihood of receiving treatment or observing an “improved” response, but we found no difference in follow-up time between men and women in our cohort. Future prospective studies should also capture detailed data on health care utilization patterns to carefully evaluate their impact on KS outcomes in men and women.
Our study has several important limitations. As a retrospective chart review, our study is subject to incomplete data which may have led to misclassification of presentation or response variables, and consequently limited our ability to observe important associations. In particular, complete ACTG staging was not available for patients and there was limited assessment of visceral KS involvement in this cohort. Our classification of “improvement” relied on clinician documentation in charts, and it is possible that changes in lesion size, lesion number, or edema were not consistently documented in the medical record. Underestimating “improvement” should lead to a conservative misclassification, however, and would diminish the apparent difference in clinical improvement between men and women. Further, we could not reliably determine other important outcome measures, including mortality, because we were unable to ascertain if loss to follow up was due to death or another factor. Clinical improvement as defined by any lesion regression may not correspond to survival benefit, so it will be important to evaluate survival in future studies.
Despite these limitations, our study supports the hypothesis that gender affects the pathophysiology of HIV-associated KS. Our findings suggest that it may be possible to prevent many cases of KS in HIV-infected women if they are able to initiate ART at higher CD4 T-cell counts, as recommended by international guidelines 
, and that clinicians caring for HIV-infected women in KS-endemic areas should carefully examine the hard palate for earlier detection of KS. Prospective studies are needed to identify predictors of response and to evaluate response to treatment in women with KS, particularly in Africa where the disease burden is greatest. Such studies will not only address potential gender disparities in KS management, but will also provide an unprecedented opportunity to gain insight into the basic pathophysiology of KS by exploring gender differences in a disease that, prior to the AIDS epidemic, was almost exclusively found in men.