Integrase inhibitors may increase risk of IRIS in late presenters for HIV treatment

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 United States treatment guidelines, and may soon be added to World Health Organization 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 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. Thirty-eight per cent 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 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.”