Immune reconstitution syndrome risk highest in those commencing HIV therapy with advanced HIV disease

Individuals who commence antiretroviral therapy (ART) with low CD4 percentages are more likely to experience immune reconstitution inflammatory syndrome (IRIS), according to a case note review of an ethnically diverse group of patients at a South London HIV clinic, published in the February 1^st edition of Clinical infectious Diseases. Since IRIS was observed in just under a quarter of individuals who began ART, those with advanced HIV disease should be screened for occult TB and hepatitis B, and counselled about the potential for IRIS events, say the investigators.

Immune reconstitution inflammatory syndrome (IRIS) is the name given to a diverse group of symptoms that can occur soon after the initiation of ART. 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.

Recent studies have found that IRIS is most likely to occur in individuals who start ART with very advanced immune suppression and that there is a high incidence of IRIS amongst HIV-positive patients with tuberculosis (TB) .

In order to characterise the epidemiology of IRIS amongst a group of patients that more closely represents the current patient experience in sub-Saharan Africa, where TB and hepatitis B is endemic and where individuals are likely to have low CD4 cell counts at baseline, investigators from a South London hospital-based HIV clinic studied a group of patients who were predominantly of African ethnicity and antiretroviral-naive, and who received NNRTI-based regimens.

The study reviewed the case notes of 199 HIV-positive individuals who commenced ART between January 2000 and August 2002 at Kings College Hospital, London. Ethnic and gender characteristics were as follows: 43% black African women; 26% white men; 17% black African men; 7% black Caribbean men; 3% black Caribbean women; 3% white women; and 1% Asian men. The vast majority of black Africans were recent migrants from eastern or south-eastern Africa.

Median baseline CD4 cell count was 174 cells/mm³, although 13.6% began ART with less than 50 cells/mm³ and median viral load was 37,830 copies/ml. The vast majority (83%) were on NNRTI-based ART.

The investigators found that 44 (22%) experienced a total of 51 IRIS events in the six months after initiating anti-HIV therapy, which occurred at a median of twelve weeks (range 4 - 24 weeks), two-thirds of which occurred within three months.

The majority (78%) of all IRIS events were due to the occurrence - or the more frequent and/or more severe recurrence - of dermatological problems: genital herpes simplex (HSV) made up 50% of the cases; genital warts caused by human papilloma virus (HPV), 23%; molluscum contagiosum, 9.1%; and varicella zoster virus, 9.1%.

Non-dermatological manifestations of IRIS were much less common. Five patients (11%) experienced events due to mycobaceterial infections (four with TB and one with MAI); four (9.1%) experienced liver problems related to hepatitis B (HBV), and there was one case each of KS or PCP symptoms.

Of the 51 IRIS events, 49% were new presentations of previously unrecognised infections, and the remaining 51% were either exacerbations (n=9) or recurrent episodes (n=17) of existing infections. Again, all almost all of the new presentations were dematological-related: anogenital herpes (48%), anogenital warts (16%), molluscum contagiosum (16%) and dermatomal zoster (16%). Just one new presentation was due to TB, although TB accounted for four of the ten IRIS event due to an exacerbation of an existing infection.

Lower baseline CD4 percentage (9% vs. 13%; p=0.002) but not absolute CD4 cell count was found to predict IRIS events, as was younger median age (33.7 vs. 35.6; p=0.021). "Older age has been identified as a risk factor for suboptimal CD4 cell response and discordant CD4 cell and virological responses to ART," write the investigators in their discussion. "As as result, younger age at initiation of ART is likely to result in a greater immune restoration and, therefore, an increased risk of developing IRIS."

Multivariate analysis, however, found that the only independent predictors of IRIS were a low baseline CD4 cell percentage and a low CD4%: CD8% ratio. Individuals with a CD4 cell percentage < 10% were almost three-times more likely (OR 2.97; p=0.02) and individuals with a CD4 cell percentage between 10-15% two-and-half-times more likely (OR 2.59; p=0.056) to experience an IRIS event than those with a CD4 percentage >15%. Likewise, individuals with a low CD4%:CD8% ratio of less than 0.15 (OR, 3.45; p=0.016) were more likely to experience and IRIS event than those with a CD4%:CD8% ratio of greater than 0.3.

The investigators conclude by suggesting the following:

• individuals starting anti-HIV therapy for the first time should be counselled about the potential development of IRIS events to avoid being discouraged and inappropriately discontinuing therapy.
• individuals with advanced HIV disease "should be screened to exclude an active or subclinical infection with important opportunistic pathogens", including TB and hepatitis B, both of which are endemic in sub-Saharan Africa.