Lopinavir/Ritonavir for the Treatment of COVID-19 Positive Patients With Cancer and Immune Suppression in the Last Year

Inclusion Criteria: * Ability to understand and the willingness to sign a written informed consent document * Participants with a diagnostically proven COVID-19 positive nasal swab test result within 14 days * Participants must have a diagnosis of cancer * Participants must be considered immune suppressed either due to their cancer diagnosis or due to treatment of their cancer. Participants must meet at least one of the following criteria: * Have received immune suppressing anti-cancer therapy in the past year (i.e., therapy that suppresses white blood cells and/or has been shown to be associated with infection, as stipulated in the drug package insert) * Have received intravenous immunoglobulin (IVIG) in the past year for treatment and/or prevention of recurrent infections * Are within one year of an autologous bone marrow transplant or chimeric antigen receptor (CAR) T-cell therapy, or within five years of an allogeneic bone marrow transplant * Have been treated for three or more infections within the past 6 months * Have an absolute neutrophil count at or below 1,500 cells/mcL at some point within two months of the time of consent. This can be due therapy and/or due to cancer suppressing marrow function * Have a history of neutropenic fever in the past year * Presence of a chronic infection, e.g. tuberculosis (TB) or osteomyelitis, or within 3 months of treatment for such. Topical fungal infections of the skin are not included in this category * Participants with mild symptoms, must have had mild symptoms for no more than 2 weeks * Participants with moderate symptoms, must have had moderate symptoms for no more than 1 week * Pregnant or women of child-bearing potential may be treated if they have no documented lopinavir-associated resistance substitutions * Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x upper limit of normal (ULN) * Total bilirubin =\< 2 x ULN (individuals with higher values felt to be consistent with inborn errors of metabolism will be considered on a case-by-case basis) * Creatinine =\< 2 x ULN * Participants with abnormal blood counts (white blood cell \[WBC\], platelet, hemoglobin \[Hg\]) will not be excluded Exclusion Criteria: * Participants who do not develop mild to moderate symptoms within 28 days of test results * Participants with rapid clinical deterioration, in the opinion of the investigator * Participants experiencing severe symptoms according to COVID-19 Symptom Grading Tool * History of being human immunodeficiency virus (HIV) positive; by history only; participants do not need to confirm by testing * Participant has any other concurrent severe and/or uncontrolled medical conditions that would, in the investigator's judgment, may cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol * Participants receiving any contraindicated medication that in the opinion of the investigator cannot be continued while receiving study drug and cannot be held for the duration of the 14-day study treatment period safely * History of unstable cardiac disease in the past 6 months * History of prolonged QT interval, or on other cardiac medications known to prolong the QT interval * Use of strong inhibitors and inducers of CYP3A4 is prohibited. Lopinavir/ritonavir (L/R) is primarily metabolized by CYP3A4. Therefore, concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nelfinavir and saquinavir), and inducers of CYP3A (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort) are not permitted. The use of other herbals will be reviewed on a case-by-case basis. If they are deemed to be strong modulators of CYP3A4, patients will be excluded if they are unable or unwilling to stop taking them * Women who plan to breast feed while on this study are not eligible for participation due to the potential for unnecessary adverse event risks to a child