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

Abstract

Background Kaposi sarcoma (KS) remains common among HIV-infected persons. To better understand KS etiology and to help target prevention efforts, we comprehensively examined a variety of CD4+ T-cell count and HIV-1 RNA viral load (VL) measures, as well as antiretroviral therapy (ART) use, to determine independent predictors of KS risk. Setting North American AIDS Cohort Collaboration on Research and Design. Methods We followed HIV-infected persons during 1996-2009 from 18 cohorts. We used time-updated Cox regression to model relationships between KS risk and recent, lagged, trajectory, and cumulative CD4 count or VL measures, as well as ART use. We used Akaike's information criterion and global p-values to derive a final model. Results In separate models, the relationship between each measure and KS risk was highly significant (p<0.0001). Our final mutually-adjusted model included recent CD4 count (hazard ratio [HR] for <50 vs. ≥500 cells/μL = 12.4; 95% confidence interval [CI]: 6.5-23.8), recent VL (HR for ≥100,000 vs. ≤500 copies/mL = 3.8; 95% CI: 2.0-7.3), and cumulative (time-weighted mean) VL (HR for ≥100,000 vs. ≤500 copies/mL = 2.5; 95% CI: 1.0-5.9). Each p-trend was <0.0001. After adjusting for these measures, we did not detect an independent association between ART use and KS risk. Conclusions Our results suggested a multifactorial etiology for KS, with early and late phases of development. The cumulative VL effect suggested that controlling HIV replication promptly after HIV diagnosis is important for KS prevention. We observed no evidence for direct anti-KS activity of ART, independent of CD4 count and VL.

HIV‐1, HAART and cancer: A complex relationship

“…Ritonavir‐based, indinavir†‐based or nelfinavir*‐based therapy confers no advantages compared to other PI‐ or NNRTI‐based regimens in the prevention of ADCs . This is in line with the fact that the HAART impact on the decrease of ADCs is mainly connected with improvement in immune function and viral load . At the same time, some studies showed potential advantages of PI‐based HAART in ADCs prevention over other regimens.…”

“…The protective effect of HAART is mainly explained by virus inhibition and immune restoration. Although at first it was thought that HAART had an additional protective effect independent of CD4 cell count and viral load, the latter studies did not detect any independent effect of HAART on Kaposi sarcoma incidence after adjusting for more variables and in a larger cohort …”

“…However, the risks for developing all ADCs are still largely elevated in HIV‐infected people; this risk is proportional to the HIV load and inversely proportional to the CD4 cell count (Fig. ) . Immunosuppression is a strong predictor for ADCs.…”

“…1). 19,20 Immunosuppression is a strong predictor for ADCs. For Burkitt's lymphoma, albeit, immune reconstitution is supposed to be, at certain CD4 cell counts, a risk factor for the development of lymphoma, indicating a more complex relationship with the immune status.…”

“…Although at first it was thought that HAART had an additional protective effect independent of CD4 cell count and viral load, 19,98-100 the latter studies did not detect any independent effect of HAART on Kaposi sarcoma incidence after adjusting for more variables and in a larger cohort. 20,101 HAART was first reported to be protective for NADCs, 102 or to have no effect 6 ; nowadays, the use of HAART is associated with a higher rate of NADCs over no treatment and long cumulative exposure to HAART is a predictor of NADCs risk. 33,96,97,100 This effect is mainly driven by virus-related cancers, as their incidence was significantly higher in people treated with antiretrovirals compared to no antiretroviral treatment, while there was no change in virus-unrelated cancer rates between HIV-infected people with or without antiretroviral therapy.…”