Background: The HIV epidemic remains a major public health concern, particularly among youths living with HIV. While the availability of antiretroviral therapy has significantly improved the health outcomes of people living with HIV, there is growing evidence that youths living with HIV may be at increased risk of cardiovascular disease. However, the underlying mechanisms linking HIV and cardiovascular disease among youths living with HIV remain poorly understood. One potential explanation is that HIV-related biomarkers, including detectable viral load (VL) and low cluster of differentiation 4 (CD4) lymphocyte counts, may contribute to increased cardiovascular risk. Despite the potential importance of these biomarkers, the relationship between HIV-related biomarkers and cardiovascular risk among youths living with HIV has been understudied., Objective: To address this gap, we examined whether detectable VL and low CD4 lymphocyte counts, both of which are indications of unsuppressed HIV, were associated with cardiovascular risk among youths living with HIV., Methods: We analyzed electronic health record data from 7 adolescent HIV clinics in the United States (813 youths living with HIV). We used multivariable linear regression to examine the relationship between detectable VL and CD4 lymphocyte counts of ≤200 and cardiovascular risk scores, which were adapted from the gender-specific Framingham algorithm., Results: In our study, nearly half of the participants (366/766, 47.8%) had detectable VL, indicating unsuppressed HIV, while 8.6% (51/593) of them had CD4 lymphocyte counts of ≤200, suggesting weakened immune function. We found that those with CD4 lymphocyte counts of ≤200 had significantly higher cardiovascular risk, as assessed by Cardiac Risk Score2, than those with CD4 lymphocyte counts of >200 (P=.002). After adjusting for demographic and clinical factors, we found that for every 1000-point increase in VL copies/mL, the probability of having cardiovascular risk (Cardiac Risk Score2) increased by 38%. When measuring the strength of this connection, we observed a minor effect of VL on increased cardiovascular risk (β=.134, SE 0.014; P=.006). We obtained similar results with Cardiac Risk Score1, but the effect of CD4 lymphocyte counts of ≤200 was no longer significant. Overall, our findings suggest that detectable VL is associated with increased cardiovascular risk among youths living with HIV, and that CD4 lymphocyte counts may play a role in this relationship as well., Conclusions: Our study highlights a significant association between unsuppressed HIV, indicated by detectable VL, and increased cardiovascular risk in youths living with HIV. These findings emphasize the importance of implementing interventions that address both VL suppression and cardiovascular risk reduction in this population. By tailoring interventions to meet the unique needs of youths, we can promote overall well-being throughout the HIV care continuum and across the life span. Ultimately, these efforts have the potential to improve the health outcomes and quality of life of youths living with HIV., International Registered Report Identifier (irrid): RR2-10.2196/11185., (©Sitaji Gurung, Kit N Simpson, Christian Grov, H Jonathon Rendina, Terry T K Huang, Henna Budhwani, Stephen Scott Jones, Tyra Dark, Sylvie Naar. Originally published in the Interactive Journal of Medical Research (https://www.i-jmr.org/), 16.08.2023.)