Use of an integrase inhibitor, which can bring down viral load rapidly, was not associated with an increased risk of immune reconstitution inflammatory syndrome (IRIS) in people who started antiretroviral treatment with very low CD4 cell counts, according to a presentation at the 25th Conference on Retroviruses and Opportunistic Infections (CROI 2018) in Boston.
IRIS can occur when antiretroviral therapy (ART) stops HIV replication and allows the immune system to recover enough to respond to pre-existing infections. This can lead to inflammatory symptoms such as swollen lymph nodes (lymphadenopathy) and fever and the apparent worsening of symptoms of opportunistic infections (OIs).
Research presented at last year's CROI suggested that HIV integrase inhibitors such as raltegravir (Isentress) and dolutegravir (Tivicay) may increase the risk of IRIS in people who start treatment late, after they have already sustained serious immune system damage.
To further explore this association, Diana Gibb of the MRC Clinical Trials Unit at University College London and colleagues did a retrospective analysis of IRIS rates in the REALITY trial, which enrolled adults and children in sub-Saharan Africa who started ART with a CD4 T-cell count below 100 cells/mm3.
REALITY included 1805 treatment-naive adults, adolescents and children age 5 and older in Kenya, Malawi, Uganda and Zimbabwe. Just over half were men and the median age was 36 years (4% were age 4 to 17). The median CD4 count was 38 cells/mm3, but a third had 0 to 24 cells, indicating very advanced immune suppression.
Participants were randomly assigned to start treatment using either a standard ART regimen of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and a non-nucleoside reverse transcriptase inhibitor (NNRTI), or else the standard regimen plus raltegravir for 12 weeks. In addition, the REALITY trial also evaluated the benefits of supplementary food and enhanced prophylaxis against infections commonly associated with death in people with advanced HIV disease.
The primary endpoint of the study was mortality at 24 weeks. As previously reported, there was no significant difference in mortality between the raltegravir-intensified and standard treatment arms (about 10% in each), although the enhanced prophylaxis package did result in a significant reduction in the risk of death and Aids-related events.
At CROI, Gibb reported that the addition of raltegravir led to faster declines in viral load measured in stored plasma samples. In the raltegravir arm, 41.0% of people had HIV RNA below 50 copies/ml at 4 weeks and 71.9% did so at 12 weeks, compared with 13.4% and 51.7%, respectively, in the standard therapy arm. By week 24, three-quarters of participants in both groups had undetectable viral load, rising to about 80% by week 48.
Despite this faster viral load decline, the incidence of fatal IRIS events – defined as atypical or exaggerated presentation of an opportunistic infection or cancer soon after ART initiation – was similar in the raltegravir intensification arm and the standard therapy arm: 4.0% vs 3.4%, not a statistically significant difference. These events occurred a median of 4.4 weeks after starting therapy. The most common fatal IRIS event in both groups was tuberculosis (TB) exacerbation (2.2% and 2.3, respectively), followed by cryptococcal IRIS (0.9% and 0.6%).
Looking at fatal and non-fatal IRIS events combined, the incidence rates were 9.9% in the raltegravir intensification arm and 9.5% in the standard therapy arm, again not a significant difference. TB and cryptococcal IRIS were again most common. Other types of IRIS events were rare, including Kaposi sarcoma flares (occurring in 8 and 4 people, respectively), viral hepatitis (1 and 3 people, respectively) and cytomegalovirus (2 and 1 people, respectively).
Factors that independently predicted fatal and non-fatal IRIS events included older age and having current TB at the time of ART initiation. Having a higher CD4 count and receiving enhanced infection prophylaxis significantly reduced the risk of IRIS.
"Our data provide reassurance that the current move to first-line integrase inhibitor-based ART will not increase IRIS," the researchers concluded. Gibb said these findings based on raltegravir can likely be applied to other integrase inhibitors including dolutegravir.
Gibb added that CD4 counts should be measured before starting ART to identify individuals with low numbers who are at high risk of IRIS and death, for whom the enhanced prophylaxis package would be especially beneficial.
Abstract
Among HIV-infected adults/children with CD4<100 cells/ul initiating ART in sub-Saharan Africa, the REALITY trial (ISRCTN43622374) showed that 12-week raltegravir (RAL)-intensified quadruple therapy resulted in significantly faster VL declines through 24 weeks, but did not reduce overall mortality or WHO 3/4 events compared to standard triple-drug ART. Integrase inhibitors may replace NNRTIs in first-line ART; there is concern that more rapid VL declines may lead to higher rates of serious IRIS in severely immunocompromised individuals starting ART.
ART-naïve HIV-infected adults/children ≥5y with CD4<100 cells/ul were randomized to initiate ART (2NRTI+NNRTI) with 12 weeks RAL (Std+RAL) or without (Std). Events, causes of death, and compatibility with IRIS were adjudicated by an endpoint review committee blind to randomization. Predictors of time to first fatal/non-fatal IRIS-compatible event were identified using backwards elimination treating death from other causes as a competing risk.
1805 patients with median baseline CD4 37 cells/ul and VL 249770 c/ml (74.0%≥100,000c/ml) were randomized to Std+RAL (n=902) vs Std (n=903). Mean change in log10 VL at week 4 was –3.4(SE 0.03) in Std+RAL vs -2.7(0.03) in Std (p<0.001; 42.8% vs 14.5% <50 c/ml respectively). In total 67(29.8%) of 225 deaths were adjudicated as IRIS-compatible, occurring a median 4.4(IQR2.6-9.4) weeks after ART initiation; a further 113 non-fatal IRIS-compatible events occurred after median 3.4(2.0-6.3) weeks on ART (figure). Fatal/non-fatal IRIS-compatible events occurred in 89(9.9%) Std+RAL vs 86(9.5%) Std patients (p=0.79). TB-IRIS occurred in 53(5.9%) vs 54(6.0%) respectively (p=1.00), cryptococcal-IRIS in 15(1.7%) vs 16(1.8%) (p=1.00), other IRIS events of known aetiology in 17(1.9%) vs 14(1.6%) (p=0.59) (Kaposi's sarcoma (8 vs 4), viral hepatitis (1 vs 3), CNS event unknown pathogen (3 vs 1), CMV (2 vs 1), toxoplasmosis (1 vs 1), PCP (0 vs 2), lung event unknown pathogen (0 vs 2), and other (3 vs 0)), and IRIS events of unknown aetiology in 4(0.4%) vs 2(0.2%) respectively. Risks of non-fatal/fatal IRIS were independently higher in those with lower pre-ART CD4 (p<0.001), older individuals (p=0.004) and those with TB at ART initiation (p=0.01).
Despite significantly more rapid declines in HIV VL, there was no evidence that 12 weeks' RAL intensification impacted incidence or case-fatality of IRIS in severely immunocompromised individuals initiating ART.
Authors
Diana Gibb, Alexander J Szubert, Ennie Chidziva, Abbas Lugemwa, Shalton Mwaringa, Abraham Siika, Jane E Mallewa, Mutsa Bwakura-Dangarembizi, Sheila Kabahenda, Andrew Reid, Keith Baleeta, Sarah Walker, Sarah Pett
[link url="http://www.aidsmap.com/Integrase-inhibitors-do-not-raise-risk-of-IRIS-in-severely-immunocompromised-people/page/3251870/"]Aidsmap material[/link]
[link url="http://www.croiconference.org/sessions/impact-raltegravir-intensification-first-line-art-iris-reality-trial"]CROI 2018 abstract[/link]