Vaccine and Infectious Disease Division
Clinical studies to compare treatment timing in patients with HIV-associated malignancies (HIVAMs) that are naïve to antiretroviral therapy (ART) would afford investigators the opportunity to determine the best time to begin HIV treatment in persons with comorbid cancers. Authors from Fred Hutchinson Cancer Research Center, Linda Oseso and Dr. Rachel Bender Ignacio, and Baylor College of Medicine outlined this recommendation in a commentary published alongside the first edition of the NCCN Guidelines for Cancer in People Living with HIV, also in the Journal of the National Comprehensive Cancer Network (NCCN) on August 10, 2018.
The authors propose that a future clinical trial take place in a low-resource setting, such as sub-Saharan Africa, where the burden of HIVAM is increasing, and where limited treatment options exist for many cancers. Early initiation of ART, regardless of CD4+ T-cell count (a marker of immune system robustness), is in keeping with the World Health Organization’s (WHO) guidelines on when to start ART in persons living with HIV (PLWH). Not specifically addressed in the WHO’s ART guidelines are clinical standards for when to initiate ART in the presence of certain serious conditions, such as HIVAMs, that may make the short-term delay of ART initiation appropriate.
HIVAMs are diverse, and include AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs), which include all other tumors, and vary with respect to risk factors that may influence the ideal time to initiate ART. The practice of delaying ART in patients with HIVAMs is often attributed to the possibility of complex drug-drug interactions (DDIs) as well as health systems challenges associated with co-treatment of diseases. In addition, concern about the risk of immune reconstitution inflammatory syndrome (IRIS), a condition wherein the immune system could create a profound inflammatory response to the cancer itself after ART initiation, leading to additional morbidity and mortality, further leads to lack of a clear practice standard of starting ART early.
In this first NCCN guideline dedicated to cancer in PLWH, early ART initiation is strongly recommended by the panel for all ART-naïve persons presenting with HIVAM, although these recommendations are based on best available observational data, inference from care for the general population of PLWH, and expert opinion.
The commentary authors therefore report on a global survey, which they administered electronically to diverse and experienced clinicians who treat HIVAM approximately 2 years prior to the generation of these new guidelines, and which revealed that more than half of these experts (range 64%-84%, depending on cancer type) would initiate ART either concurrently or before chemotherapy in patients with HIVAMs. The authors found that preferred ART start time differed somewhat depending the cancer type in question, but that the most notable differences were between infectious disease clinicians, who generally expedite ART, and oncologists, who more frequently reported staggering the initiation of ART and chemotherapy. US-based clinicians also tended to expedite ART more than colleagues practicing in Africa.
Considerations of DDIs and IRIS contribute to differences in the perceived risks of untreated HIV versus complexity and toxicities of administering ART with chemotherapy by clinicians, in the authors’ opinions. The authors also reported that CD4 T-cell count infrequently governed decision-making about ART initiation in scenarios of different HIVAMs presented to clinicians, who overall endorsed that providing ART was ultimately important for all PLWH and cancer.
“Data from clinical trials on timing of antiretroviral therapy initiation in tuberculosis and HIV co-infection have drastically changed WHO recommendations, and subsequently global practice surrounding initiation of ART in TB/HIV co-infection. We hope that gathering further data on how and when to initiate ART in HIVAMs will show similar benefits on care delivery and clinical outcomes in HIVAM, which is only growing in global impact,” said Rachel A. Bender Ignacio, MD, MPH, associate in the Vaccine and Infectious Diseases Division, at Fred Hutch.
The authors suggest there is a need for future clinical trials in low-resource settings with ART-naïve patients diagnosed with HIVAMs, in which ART would be started immediately or briefly delayed until up to two cycles of chemotherapy were completed. To avoid delaying ART for persons with extraordinary immunosuppression, they suggest a study design that would limit enrollment to patients without significant damage to their immune systems. Until such a trial could be completed, the authors strongly endorse implementation of early ART, as outlined in the new NCCN Guidelines for Cancer in People Living with HIV, across both resourced and lower-resourced settings.
“We hope that the use of the NCCN clinical practice guidelines and the pursuit of further data, as we have proposed in our commentary, will assist clinicians to initiate and continue ART during HIVAM treatment,” said Linda N. Oseso, MPH, project manager at Fred Hutch.