Immune reconstitution syndrome may affect 10% of patients starting antiretroviral treatment in Africa, according to the results of a prospective South African study published in AIDS. The syndrome was most common in those who began treatment at the lowest CD4 cell counts.
Immune reconstitution inflammatory syndrome, or IRIS, is a condition sometimes seen in HIV-positive people who have recently started antiretroviral therapy.
During IRIS, underlying infections suddenly flare up and produce symptoms (sometimes severe) which were not seen before treatment started. The seemingly paradoxical effects of IRIS are thought to result from the increased immune response to the underlying infections. Studies have found varying rates - up to 32% - of IRIS in people beginning antiretroviral therapy. Few studies have been prospective, and few have studied IRIS in Africa, where the rates of infections frequently seen with this syndrome (such as tuberculosis) are high.
No single "gold standard" definition of IRIS exists. For this study, cases were classified by three a priori definitions: "suspected" if there were new symptoms of an infectious or inflammatory condition with no objective evidence of immune reconstitution, "probable" if there was also an increase in CD4 cell count or a ≥ 1 log10 viral load drop at six months post- antiretroviral therapy, and "confirmed" if there was also a confirmed ≥ 1 log10 viral load drop at the time of the IRIS diagnosis.
IRIS diagnoses were excluded due to any of the following: observed virologic failure (10 viral load drop during the six months), continued CD4 cell decline, documented ART non-compliance, or – in the case of suspected tuberculosis (TB)-related IRIS – a known diagnosis of multidrug-resistant TB.
In this study, American and South African researchers followed a prospective cohort of antiretroviral therapy -naïve patients at a large HIV clinic at Johannesburg Hospital. All antiretroviral therapy -naïve adult patients (>18 years old) beginning therapy between January 6 and July 7, 2006, were considered (those who had received single-dose nevirapine for prevention of mother-to-child transmission were eligible). Treatment initiation was in accordance with national guidelines, which include people with CD4 cell counts ≤ 200 cells/mm3 or at WHO disease stage IV.
Of the 546 in total who began treatment during this time, 423 were eligible and enrolled into the study cohort. Participants were almost exclusively black (99%) and largely female (70%, of whom 22% were pregnant), with a median age of 34 years and median CD4 count of 115 cells/mm3. Most (77%) were initiated on d4T, 3TC, and efavirenz; 20% were already receiving TB treatment when they started antiretroviral therapy.
Clinical data from these participants was followed for a period of six months, for a total of 181 person-years of follow-up. During this time there was one suspected case of IRIS, 21 probable cases, and 22 confirmed – a total of 44 (10.4%), for an overall incidence rate of 25.1 cases per 100 person-years of antiretroviral therapy.
The median onset time was 48 days, with 75% of the cases occurring within 90 days of antiretroviral therapy introduction. The most common clinical diagnosis was tuberculosis (41%), with other diagnoses including folliculitis and other dermatological conditions (18%), varicella zoster (14%), herpes simplex (9%), cryptococcal meningitis (7%), molluscum contagiosum (7%) and Kaposi's sarcoma (4.5%).
There were three deaths among the 44 IRIS cases, two of which were directly attributable to IRIS: one case of severe cryptococcal meningitis, and one case of disseminated tuberculosis. Twelve patients (27%) required hospitalisation related to the IRIS event; the great majority (93%) were able to continue on antiretroviral therapy without interruption.
In a nested case-control study, the 44 IRIS cases were matched to control subjects according to the length of time on antiretroviral therapy, within two weeks. In multivariate analysis, only baseline CD4 cell count independently predicted IRIS. Higher baseline CD4 cell counts were associated with a lower risk of IRIS with a hazard ratio of 0.72 (95% confidence interval, 0.52-0.98) for each 50 cell/mm3 increase.
The researchers note that the 10.4% incidence rate observed in this cohort was lower than the rates of 17% to 25% reported in retrospective cohorts; this difference was thought to reflect "the prospective application of strict case definitions and thus [represent] a more accurate estimate of the true IRIS incidence in [this] population." Consistent with many previous reports, the majority of cases were due to TB. Overall mortality was "low" (1.9%), "but in agreement with post-ART mortality rates reported in similar South African cohorts"; IRIS-related mortality was also "relatively low" at 4.5%.
Reference:
Murdoch DM et al. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS 22: 601-610, 2008.