Background Latent Tuberculosis Infection (LTBI) remains a major driver of the TB epidemic, and individuals with Human Immuno-deficiency Virus (HIV) are particularly at a heightened risk of developing LTBI. However, LTBI screening among HIV-infected individuals in resource limited setting is largely based on a negative symptom screen, which has low specificity. Methods In a cross sectional diagnostic study, 115 HIV infected participants with a negative symptom screen will be consented and enrolled. They will be requested to donate 5 ml of blood for complete blood count (CBC) and interferon gamma release assay (IGRA) testing. In a nested prospective study, the 115 participants will be initiated on Tuberculosis Preventive Therapy and the CBC testing repeated after 3 months. In the analysis of study finding, the monocyte to lymphocyte ratio (MLR) will be derived from the dividend of the absolute monocyte and lymphocyte counts. The optimal MLR positivity cut-off for elevated or normal MLR will be the highest value of Youden's index, J (sensitivity + specificity-1). The MLR will be cross tabulated with the IGRA status to determine the sensitivity, specificity, negative and positive predictive values of the MLR. The area under the receiver operating characteristic (ROC) curve will be determined to give the overall diagnostic accuracy of MLR. The baseline and 3 month CBC will be used to determine the change in MLR, and a random effect logistic regression will be used to determine factors associated with the change in the MLR. Discussion If positive results are realized from this study, the MLR could become an inexpensive alternative biomarker with potential to improve the specificity of the negative symptom screen in identifying individuals that should be targeted for TB preventive therapy.