Professor of HIV
Queen Mary, University of London
Lead for HIV Research
Barts Health NHS Trust
The Royal London Hospital
London, United Kingdom
Chloe Orkin, MBChB, FRCP, MD, has disclosed that she has participated on speaker bureaus for, received consulting fees from, and received funds for research support from Gilead Sciences, Janssen, MSD, and ViiV Healthcare.
The 2018 Conference on Retroviruses and Opportunistic Infections (CROI) held in Boston, Massachusetts, showcased the latest research across many relevant clinical topics. Although we did not see many phase III ART clinical trials presented at CROI 2018, I was greatly interested in the studies focusing on the role of INSTIs in immune reconstitution inflammatory syndrome (IRIS). Below I summarize the clinical challenge presented by IRIS and highlight several important presentations and their clinical implications for this challenging condition.
Clinical Challenge: IRIS and the Risk of Mortality
Globally, substantial proportions of patients still present for treatment with advanced HIV disease (defined as CD4+ cell counts < 200 cells/mm3 and/or AIDS-defining illnesses). Despite advances in ART, there remains a high mortality rate in patients with advanced disease shortly after starting ART. There are multiple risk factors for mortality, and IRIS is thought to be a substantial contributor. Furthermore, the risk for IRIS correlates with a faster decline in HIV-1 RNA. INSTIs—which are now the preferred option in first-line ART—lower HIV-1 RNA very quickly. Two previously reported cohort studies described an increased incidence of IRIS with INSTIs, but analyses of randomized studies were generally lacking until CROI 2018.
IRIS and Risk of Mortality: Analyses of Randomized Trials
Three important studies on this issue were presented at CROI 2018. The first was the large randomized controlled REALITY trial, which was conducted in sub-Saharan Africa in patients with CD4+ cell counts < 100 cells/mm3 and assessed the effects on 24-week mortality of adding an INSTI to a standard 3-drug regimen (2 NRTIs + NNRTI) for 12 weeks. IRIS event endpoints were adjudicated by a blinded expert panel. REALITY showed that despite a faster HIV-1 RNA decline in the raltegravir-intensified group, the 24-week and 48-week mortality rates were similar and there was no effect on fatal or non-fatal IRIS events.
The second report was a post hoc analysis of the randomized phase III OPTIMAL trial, which evaluated the impact of first-line INSTIs on IRIS events. This study enrolled patients with CD4+ cell counts < 200 cells/mm3. The analysis found no significant difference in IRIS rates between those who received INSTIs vs those who did not.
The third was an interim analysis of the open-label, randomized phase IIIa INSPIRING study, which compared the use of single-agent dolutegravir vs efavirenz when combined with rifampicin-based tuberculosis therapy. The authors reported on the rate of IRIS, a secondary endpoint. They found no difference in incidence of tuberculosis-associated IRIS or other IRIS between treatment arms.
These data collectively give us more confidence that using INSTIs in patients with very low CD4+ cell counts is unlikely to lead to IRIS-related mortality. I find these data reassuring, given the move toward INSTI-based first-line regimens.
Would you intensify ART with an INSTI for patients with low CD4+ cell counts? Please join the conversation and share your experiences in the comments box below.