HIV integrase inhibitors may increase risk of IRIS

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HIV integrase inhibitors such as dolutegravir and raltegravir may increase the risk of immune reconstitution inflammatory syndrome (IRIS), studies from the Netherlands and France presented last month at the Conference on Retroviruses and Opportunistic Infections (CROI 2017) in Seattle suggest.

Integrase inhibitors are a preferred component of first-line antiretroviral treatment in European and US treatment guidelines, and may soon be added to World Health Organisation guidelines for lower-income countries as low-cost, generic versions of dolutegravir become available.

IRIS occurs when the revival of the immune system due to antiretroviral treatment causes it to react to existing infections, often with severe and paradoxical effects. Inflammatory symptoms such as severely swollen lymph nodes (lymphadenopathy), fever and the worsening of symptoms of opportunistic infections can emerge and may require hospitalisation and/or corticosteroid treatment.

Integrase inhibitors are favoured for first-line treatment, in part, because they reduce viral load very quickly, encouraging more rapid immune reconstitution. But, a very rapid viral load reduction might increase the risk of developing IRIS, due to a more rapid reconstitution of the immune system. To date, despite their widespread use, IRIS has been considered an extremely rare adverse event in people taking any of the integrase inhibitors: dolutegravir (Tivicay, also in Triumeq); elvitegravir (in Genvoya and Stribild) and raltegravir (Isentress).

However, two studies presented at CROI 2017 suggest that early vigilance for IRIS may be especially warranted in people who have low CD4 cell counts – late presenters – who start treatment with an integrase inhibitor. People with low CD4 cell counts are at risk of IRIS during the first three to six months after starting treatment.

The Netherlands study led by Ingeborg Wijting, at the Erasmus University Medical Centre, Rotterdam, looked at all people who started treatment from 2009 onwards with CD4 cell counts below 200 cells/mm3 and who had either an opportunistic infection before or after starting antiretroviral therapy or who were prescribed corticosteroids within 12 months after starting treatment. This sample was designed to capture people at the highest risk of IRIS and to identify all possible cases.

Individuals were classified as having IRIS if they had been diagnosed with IRIS by a clinician or if they fulfilled the French 2004 definition (atypical tumour or opportunistic infection presentation accompanied by viral load decline or CD4 increase).

Of those in the ATHENA cohort, 369 were eligible for the analysis, 69 of whom had taken an integrase inhibitor. Participants in the integrase inhibitor and non-integrase inhibitor treatment groups were well matched.

A total of 73 cases of IRIS were identified in the cohort, comprising 20% of all those treated. 38% of those who started integrase inhibitor treatment and 16% of those starting any other treatment regimen developed IRIS. Recipients of integrase inhibitor treatment were significantly more likely to develop IRIS according to either definition (odds ratio 3.25, 95% CI 1.83-5.80). Use of corticosteroids (23% vs 13%, p = 0.035) and hospitalisation in the year after starting ART (57% vs 45%, p = 0.072) were each more frequent in the integrase inhibitor group, although the difference in the percentage hospitalised was not statistically significant. Of the 369 individuals, 175 were admitted to hospital after initiating antiretroviral therapy.

A diagnosis of mycobacterium avium complex (MAC), cytomegalovirus (CMV) or cryptococcal meningitis was associated with an increased risk of IRIS, independent of antiretroviral treatment regimen.

The French study, led by Marine Dutertre at the Toulouse University Hospital, Toulouse, looked at the risk of developing IRIS in people who started treatment between January 2010 and December 2015, with a CD4 cell count below 200 cells/mm3, and who were admitted to hospital within six months of starting treatment. The study population was drawn from the French Dat’AIDS cohort, a prospective cohort of people receiving treatment at 15 large treatment centres in France.

Of all people in the Dat’AIDS cohort, 2287 qualified for inclusion in this analysis, 12% of whom received an integrase inhibitor. The median CD4 cell count was 34 cells/mm3 in the integrase inhibitor group and 84 cells/mm3 in the non-integrase inhibitor group. Median viral load was 5.3 log10 copies/ml in the integrase inhibitor group and 5.2 log10 copies/ml in the non-integrase group. Viral load fell significantly more in the integrase group than in the non-integrase group (1.7 vs 2.1 log 10 copies/ml, p < 0.001) in the first three months after starting antiretroviral therapy.

In this analysis, an IRIS case was defined as symptoms consistent with an infectious or inflammatory condition according to the AIDS Clinical Trials Group IRIS definition, associated with a viral load reduction of greater than 2 log not explained by a newly acquired infection or the expected clinical course of a previous infection. This definition, together with the requirement for hospitalisation, resulted in a much smaller number of clinical events being classified as IRIS.

The incidence of IRIS was, therefore, much lower than in the Dutch cohort: 3% in the integrase inhibitor group and 1.5% in the non-integrase inhibitor group, a relative risk of 1.99 (95% CI 1.09-3.47). IRIS was most frequently related to tuberculosis, to mycobacterium avium and to progressive multifocal leukoencephalopathy.

Neither research group suggests that integrase inhibitors should be avoided in late presenters at present, but encourage other research groups to confirm their results. French researchers say that “strict clinical monitoring during the 3 to 6-month period usually associated with IRIS occurrence is strongly recommended.”

Abstract 1
Immunocompromised HIV-infected patients frequently initiate ART based on integrase inhibitors (INSTI). Together with a low CD4 T cell count and a high likelihood of opportunistic infection, the sharp control of viral replication associated with INSTI-based ART might synergize the risk of immune reconstitution inflammatory syndrome (IRIS). Our aim was to determine the incidence of IRIS in exposed patients who initiated ART with or without INSTI as a third agent.
We selected from the Dat’AIDS cohort patients with a CD4 T cell count < 200/mm3 starting from 01/01/2010 to 01/01/2015 ART based on 2 NRTIs associated with a bPI, a NNRTI or an INSTI, and admitted to hospital within 6 months. IRIS events were defined as symptoms consistent with an infectious or inflammatory condition associated with a drop of > 2 log10 copies/mL of HIV viral load, not explained by a newly acquired infection, the expected clinical course of a previous infection, or side-effects. Three physicians blinded to the ART regimen evaluated files and determined the classification by consensus. Characteristics associated with IRIS were analyzed in uni-and multivariate analysis.
The study population included 2287 patients from 15 centers in France. Median age was 45 years (IQ25-75 37-53), and 63% were men. The third agent was bPI in 65%, NNTI in 12%, and INSTI in 12%. At ART initiation, the median HIV viral load and CD4 T cell count were 5.2 log10 copies/mL (4,8-5,7) and 83/mm3 (31-146). IRIS occurred in 41 patients (1.8%) and was associated with tuberculosis (12 cases), atypical mycobacteria (10), JC virus (6), CMV (5), HHV-8 (4), Toxoplasma (2), Cryptococcus (1) and HBV (1). Patients receiving INSTI-based ART did not differ from those without INSTI regarding pre-ART HIV viral load and CD4 T cell count (table). IRIS occurred in 12/398 (3%) patients receiving INSTI-based ART, compared to 29/1889 (1.5%) patients without INSTI (OR 1.99 (1.1-3.5), p=0.04). Repartition of opportunistic infections did not differ according to ART regimen.
Starting ART based on INSTI in exposed patients is associated with a higher risk of IRIS. The homogenous repartition of opportunistic infections among regimen groups argued against a bias of indication linked to mycobacterial infection and co-medication used, although we cannot preclude it formally. While effective control of HIV replication is key, initiation of ART not based on INSTI might be wise in selected patients at high risk of IRIS, deserving further studies.

Marine Dutertre, Lise Cuzin, Pascal Puglièse, Veronique Joly, Marc-Antoine Valantin, Laurent Cotte, Thomas Huleux, Pierre Delobe, Guillaume Martin-Blondel

Abstract 2
Integrase inhibitors(II) are associated with an accelerated HIV-RNA decline and enhanced CD4 recovery. In late-presenters, these factors are associated with the immune reconstitution inflammatory syndrome (IRIS), a pathological immune reaction against antigens of opportunistic infections (OI). Whether the use of II containing cART is a risk factor for IRIS is unknown as phase-III trials of licensed II included few late presenters.
Observational study within the ATHENA cohort. Case finding by full chart review was done in all treatment-naïve patients initiating cART from 2009 onwards who were at increased risk for IRIS: those with CD4 ≤200cells/mm3, who were diagnosed with PCP, toxoplasmosis, Kaposi’s sarcoma, CMV disease, cryptococcosis, mycobacterial disease or PML and/or initiated corticosteroids ≤12months after cART-initiation and/or died ≤12months after cART-initiation. 2 definitions of IRIS were used: IRIS criteria by French (=French IRIS) and IRIS diagnosed by the treating physician(=clinical IRIS). Patient charts were reviewed for both definitions using a standardized CRF. The 2 primary outcomes were French IRIS and combined clinical or French IRIS. Cox regression was used to compare the risk of IRIS in II and non-II users, while controlling for potential confounders. Patients were censored when switching from INI to non-INI or vice versa.
369 of 3250 patients initiating first-line cART fulfilled in- and exclusion criteria for chart review with a mean viral load and CD4 count of 275423c/ml and 38cells/mm3. Most prevalent OI were PCP (N=172), Candidiasis (N=143), Mycobacterial infections (N=51) and Kaposi’s sarcoma (N=38). Any form of IRIS was observed in 26/69 (38%) of II-users compared to 47/300 (16%) in the non-II users (OR 3.2, 95%CI 1.8-5.8) (Table). Cox regression showed that use of II was independently associated with French as well as any form of IRIS (HR 2.6, 95%CI 1.3-5.1, p=0.004 and HR 2.6, 95%CI 1.6-4.4, p=0.0001).
Patients diagnosed with an OI and a CD4-count ≤200cells/mm3 initiating II-based cART had a more than doubled incidence of IRIS. If confirmed in future studies, initiating II-based cART in late-presenters with OI may have to be revisited, especially in resource limited-settings.

Ingeborg Wijting, Casper Rokx, Ferdinand Wit, Anneloes Postma, Andy Hoepelman, Ineke van der Ende, Peter Reiss, Bart Rijnders

Aidsmap material
CROI 2017 abstract 732
CROI 2017 abstract 731

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