As of 2010, Kaposi sarcoma (KS) accounted for 12% of cancer diagnoses in people living with HIV or AIDS in the United States, and the condition is not uncommon among those with relatively high CD4 cell counts, sustained suppression of HIV replication with ART, or both. However, the independent associations between CD4 cell count, HIV RNA viral load, and ART with KS risk are not well defined.

 

Shedding Light on KS Risk

For a study published in the Journal of Acquired Immune Deficiency Syndromes, Robert Dubrow, MD, PhD, and colleagues set out to answer three questions:

  1. Over the course of HIV infection, when is CD4 cell count most predictive of KS risk? In particular, is low recent CD4 cell count (regardless of the previous CD4 count history) versus a long duration of low CD4 cell count a better predictor of increased KS risk?
  2. Is the association between HIV RNA viral load level and KS risk independent of CD4 cell count, and if so, which measure of viral load is the best predictor? In particular, is high recent viral load (regardless of the previous viral load history) versus a long duration of high viral load a better predictor of increased KS risk?
  3. Is the known protective effect of ART on KS risk entirely mediated by its effects on CD4 cell count and HIV RNA viral load level? If not, then ART may have direct anti-KS activity.

The researchers analyzed data on approximately 78,000 adults in the US and Canada who were followed from 1996 to 2009. During this period, nearly 400 cases of KS occurred among participants. Among them, “we used fairly sophisticated statistical models to examine relationships between CD4 cell count, viral load, ART use, and KS risk,” explains Dr. Dubrow.

The study found that low recent (180 days previously) CD4 cell count was most predictive of high KS risk, when compared with CD4 cell count 540, 900, and 1,260 days previously (Table). “Low recent CD4 cell count was also more predictive than low cumulative count, essentially a low average count over the previous 3 years,” adds Dr. Dubrow. “That said, we found both high recent HIV RNA viral load and high cumulative HIV RNA viral load to be the best independent viral load predictors of elevated KS risk. The association between KS and high cumulative HIV RNA provides a possible explanation for the elevated KS risk among HIV-infected persons on ART, suggests that it is important to control HIV replication promptly after HIV diagnosis in order to prevent KS, and was our most important and novel finding. Controlling HIV replication promptly is consistent with current ART recommendations and with the Strategic Timing of Antiretroviral Treatment trial in which KS incidence was significantly lower in persons with CD4 cell counts greater than 500 cells/µL who initiated ART immediately when compared with those who deferred initiation.”

Dr. Dubrow notes that the protective effect of ART on KS risk was entirely mediated by its effects on CD4 cell count and viral load. “Thus, we found no evidence for direct anti-KS activity of ART, independent of its effect of controlling viral replication, which results in increased CD4 cell count,” he adds.

 

Looking Ahead

The study results suggest a multifactorial etiology for KS, with early and late phases of development, according to Dr. Dubrow. “While recent CD4 cell count and viral load effects suggest that HIV and immunosuppression are involved in late phases of KS development, the cumulative viral load effect suggests that ongoing HIV exposure may promote earlier phases of development,” he says. “The independent association between cumulative viral load and KS risk requires confirmation and further characterization, including how long the cumulative viral load effect lasts after viral suppression with ART.”

 

References

Dubrow R, Qin L, Lin H, et al. Association of CD4+ T-cell count, HIV-1 RNA viral load, and antiretroviral therapy with kaposi sarcoma risk among HIV-infected persons in the United States and Canada. J Acquir Immune Defic Syndr. 2017;75:382-390.  Available at
http://journals.lww.com/jaids/Abstract/2017/08010/Association_of_CD4__T_cell_Count,_HIV_1_RNA_Viral.2.aspx.

Semeere A, Busakhala N, Martin J. Impact of antiretroviral therapy on the incidence of Kaposi’s sarcoma in resource-rich and resource-limited settings. Curr Opin Oncol. 2012;24:522-530.

Robbins H, Shiels M, Pfeiffer R, et al. Epidemiologic contributions to recent cancer trends among HIV-infected people in the United States. AIDS. 2014;28:881-890.

Park L, Tate J, Sigel K, et al. Time trends in cancer incidence in persons living with HIV/AIDS in the antiretroviral therapy era: 1997–2012. AIDS. 2016;30:1795-1806.