Immune reconstitution inflammatory syndrome (IRIS) is the name given to a diverse group of symptoms that can occur soon after the initiation of HAART. This can include the first appearance or the recurrence of previously-treated opportunistic infections, like TB, CMV, PCP or MAI, or the flare-up of viral infections that include hepatitis and herpes.
Even though the syndrome has been identified for more than four years, remarkably little is known about why it occurs or how to identify it. Only one study has been published, by an Australian team in 1999, which found that low CD4 counts at HAART initiation were the only independent predictor of IRIS. This finding has led to two schools of thought regarding the cause: either that a greater immune restoration leads to more IRIS events, or that it is caused by a deferred or partial CD4 response after HAART is initiated.
The findings of a team of British reseachers from Kings College Hospital in south east London appear to support the second view, since they found that baseline CD4 counts were not an independent factor in their case review study. In fact, the only difference they found between those people who began HAART and experienced an IRIS-associated adverse event and those who did not, was that IRIS cases were significantly younger by two years (p=0.021), although in univariate analysis a lower CD4 count at 12 weeks (suggesting a partial or deferred rise in CD4 counts) was found to be a predictor of IRIS.
However, these findings are particularly significant because they identify the most common IRIS events, which may be very useful to clinicians who are uncertain as to whether the appearance of certain set of symptoms within six months of starting HAART are due to disease progression or IRIS. This will be of particular relevance in resource-limited settings where virologic or immunologic monitoring is not available.
The study reviewed the case notes of 199 HIV-positive individuals who commenced HAART between January 2000 and August 2002 at Kings College Hospital. The genders were evenly distributed, 59% were African, 29% were white, and 10.5% Caribbean. Median baseline CD4 count was 174 cells/mm3, although 13.6% began HAART with less than 50 cells/mm3 and median viral load was 36,878 copies/ml. The vast majority (83%) were on NNRTI-based HAART.
They found that 44 (22%) had IRIS events, which occurred at a median of 12 weeks (range 3 - 24 weeks) following the initiation of HAART, and that the majority (78%) were due to the occurence - or the more frequent and/or more severe recurrence - of dematological problems: genital herpes simplex (HSV) made up 50% of the cases; genital warts caused by human papilloma virus (HPV), 24%; molluscum contagiosum, 9.5%; and varicella zoster virus, 9.5%.
Non-dermatological manifestations of IRIS were much less common: 2% had TB symptoms, 2% had new liver problems related to hepatitis B (HBV), and there was one case each of KS or PCP symptoms.
A prior history of certain infections appeared to be more likely to recur as part of IRIS. Two thirds of those with genital warts and one third of those with genital herpes simplex had IRIS flare-ups. One quarter had recurrences of hepatitis B-related liver problems, and one fifth had new TB symptoms.
The researchers concluded that although IRIS appears to most commonly manifest as new or more severe or recurrent genital herpes or other dermatological infections, they suggest that those with HSV, HPV, TB and HBV be monitored closely for IRIS when intiating HAART.
Thevarajan I. et al. Epidemiology Of immune reconstitution inflammatory syndrome (IRIS) in an ethnically diverse HIV infected cohort Ninth European AIDS Conference, Warsaw, abstract F4/4, 2003.