HIV Viremia and HIV-Associated Lymphoma Mortality
Objective: To examine the association between early HIV viremia and mortality after HIV-associated lymphoma.
Design: Multicenter observational cohort study.
Setting: Center for AIDS Research Network of Integrated Clinical Systems cohort.
Participants: HIV-infected patients with lymphoma diagnosed between 1996 and 2011, who were alive 6 months after lymphoma diagnosis and with at least two HIV RNA values during the 6 months after lymphoma diagnosis.
Exposure: Cumulative HIV viremia during the 6 months after lymphoma diagnosis, expressed as viremia copy-6-months.
Main outcome measure: All-cause mortality between 6 months and 5 years after lymphoma diagnosis.
Results: Of 224 included patients, 183 (82%) had non-Hodgkin lymphoma (NHL) and 41 (18%) had Hodgkin lymphoma. At lymphoma diagnosis, 105 (47%) patients were on antiretroviral therapy (ART), median CD4 cell count was 148 cells/μl (interquartile range 54–322), and 33% had suppressed HIV RNA (<400 copies/ml). In adjusted analyses, mortality was associated with older age [adjusted hazard ratio (AHR) 1.37 per decade increase, 95% CI 1.03–1.83], lymphoma occurrence on ART (AHR 1.63, 95% CI 1.02–2.63), lower CD4 cell count (AHR 0.75 per 100 cells/μl increase, 95% CI 0.64–0.89), and higher early cumulative viremia (AHR 1.35 per log10copies × 6-months/ml, 95% CI 1.11–1.65). The detrimental effect of early cumulative viremia was consistent across patient groups defined by ART status, CD4 cell count, and histology.
Conclusion: Exposure to each additional 1-unit log10 in HIV RNA throughout the 6 months after lymphoma diagnosis was associated with a 35% increase in subsequent mortality. These results suggest that early and effective ART during chemotherapy may improve survival.
In resource-rich settings, cancer is the leading cause of death among HIV-infected persons in the modern antiretroviral therapy (ART) era, and lymphoma the most frequent cancer-related cause.
Effects of ART early after HIV-associated lymphoma diagnosis remain uncertain. Chemotherapy clinical trials conducted by the National Cancer Institute (NCI) and AIDS Malignancy Consortium (AMC) have employed various strategies with respect to ART without directly comparing approaches. Strategies have included concurrent ART during chemotherapy, ART suspension until chemotherapy completion, or ART left to physicians' discretion. Potential negative effects of concurrent ART during chemotherapy include overlapping toxicities, medication interactions, antiapoptotic ART effects, and HIV resistance from ART interruption.
Similar concerns previously existed regarding ART during treatment for opportunistic infections, including toxicities and interactions, ART discontinuity and HIV resistance, and risk of the immune reconstitution inflammatory syndrome (IRIS). However, multiple randomized clinical trials have demonstrated that deferring ART by even several weeks worsens outcomes for patients with opportunistic infections, particularly when severely immunosuppressed, with cryptococcal and tuberculous meningitis being possible exceptions. A similar detrimental effect of deferred ART is possible for HIV-associated lymphoma patients, who present with significant immunosuppression even in the ART era. Additionally, Epstein–Barr virus (EBV) is present in approximately 40% of tumors with marked variation by histologic subtype. For EBV-associated lymphomas, early immune reconstitution may improve outcomes, analogous to EBV-associated posttransplant lymphoproliferative disease (PTLD), for which prompt reduction of immunosuppression may obviate need for chemoimmunotherapy.
Reflecting these controversies, consensus guidelines make no strong recommendation for or against concurrent ART during chemotherapy. We studied a large United States cohort of HIV-infected lymphoma patients who survived at least 6 months after lymphoma diagnosis, to examine effects of early HIV viremia, as a marker of early and effective ART, on all-cause mortality.
Abstract and Introduction
Abstract
Objective: To examine the association between early HIV viremia and mortality after HIV-associated lymphoma.
Design: Multicenter observational cohort study.
Setting: Center for AIDS Research Network of Integrated Clinical Systems cohort.
Participants: HIV-infected patients with lymphoma diagnosed between 1996 and 2011, who were alive 6 months after lymphoma diagnosis and with at least two HIV RNA values during the 6 months after lymphoma diagnosis.
Exposure: Cumulative HIV viremia during the 6 months after lymphoma diagnosis, expressed as viremia copy-6-months.
Main outcome measure: All-cause mortality between 6 months and 5 years after lymphoma diagnosis.
Results: Of 224 included patients, 183 (82%) had non-Hodgkin lymphoma (NHL) and 41 (18%) had Hodgkin lymphoma. At lymphoma diagnosis, 105 (47%) patients were on antiretroviral therapy (ART), median CD4 cell count was 148 cells/μl (interquartile range 54–322), and 33% had suppressed HIV RNA (<400 copies/ml). In adjusted analyses, mortality was associated with older age [adjusted hazard ratio (AHR) 1.37 per decade increase, 95% CI 1.03–1.83], lymphoma occurrence on ART (AHR 1.63, 95% CI 1.02–2.63), lower CD4 cell count (AHR 0.75 per 100 cells/μl increase, 95% CI 0.64–0.89), and higher early cumulative viremia (AHR 1.35 per log10copies × 6-months/ml, 95% CI 1.11–1.65). The detrimental effect of early cumulative viremia was consistent across patient groups defined by ART status, CD4 cell count, and histology.
Conclusion: Exposure to each additional 1-unit log10 in HIV RNA throughout the 6 months after lymphoma diagnosis was associated with a 35% increase in subsequent mortality. These results suggest that early and effective ART during chemotherapy may improve survival.
Introduction
In resource-rich settings, cancer is the leading cause of death among HIV-infected persons in the modern antiretroviral therapy (ART) era, and lymphoma the most frequent cancer-related cause.
Effects of ART early after HIV-associated lymphoma diagnosis remain uncertain. Chemotherapy clinical trials conducted by the National Cancer Institute (NCI) and AIDS Malignancy Consortium (AMC) have employed various strategies with respect to ART without directly comparing approaches. Strategies have included concurrent ART during chemotherapy, ART suspension until chemotherapy completion, or ART left to physicians' discretion. Potential negative effects of concurrent ART during chemotherapy include overlapping toxicities, medication interactions, antiapoptotic ART effects, and HIV resistance from ART interruption.
Similar concerns previously existed regarding ART during treatment for opportunistic infections, including toxicities and interactions, ART discontinuity and HIV resistance, and risk of the immune reconstitution inflammatory syndrome (IRIS). However, multiple randomized clinical trials have demonstrated that deferring ART by even several weeks worsens outcomes for patients with opportunistic infections, particularly when severely immunosuppressed, with cryptococcal and tuberculous meningitis being possible exceptions. A similar detrimental effect of deferred ART is possible for HIV-associated lymphoma patients, who present with significant immunosuppression even in the ART era. Additionally, Epstein–Barr virus (EBV) is present in approximately 40% of tumors with marked variation by histologic subtype. For EBV-associated lymphomas, early immune reconstitution may improve outcomes, analogous to EBV-associated posttransplant lymphoproliferative disease (PTLD), for which prompt reduction of immunosuppression may obviate need for chemoimmunotherapy.
Reflecting these controversies, consensus guidelines make no strong recommendation for or against concurrent ART during chemotherapy. We studied a large United States cohort of HIV-infected lymphoma patients who survived at least 6 months after lymphoma diagnosis, to examine effects of early HIV viremia, as a marker of early and effective ART, on all-cause mortality.
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