KS-associated IRIS common among people starting HIV therapy in Africa

Over 13% of people with HIV-related Kaposi’s sarcoma experience a worsening of disease after starting antiretroviral therapy, an international team of investigators report in the online edition of AIDS. This paradoxical worsening of disease was attributed to immune reconstitution inflammatory syndrome (IRIS) and was significantly more likely to occur among patients in southern Africa compared to those in the UK.

The authors believe their findings have important implications for HIV treatment strategies in southern Africa and also highlight the need for improvements in KS awareness among both clinicians and patients in resource-limited settings.

Kaposi’s sarcoma (KS) is the most common HIV-related cancer and is an important cause of illnesses and death in sub-Saharan Africa.

The introduction of effective HIV therapy in the late 1990s was accompanied by a substantial fall in KS incidence among people with HIV in the UK and similar countries. Moreover, treatment with antiretroviral drugs alone has been associated with complete or partial resolution of KS in up to 80% of patients.

However, there have been case reports of KS disease actually worsening in some patients after they started HIV therapy. Such deterioration is probably due to IRIS.

Investigators wanted to establish a clearer understanding of the incidence and risk factors for KS-associated IRIS among people with baseline KS at the time they started antiretrovirals.

They therefore examined the results from four observational cohorts involving a total of 436 people with HIV-related KS at the time they started antiretroviral therapy. Three of the cohorts were in sub-Saharan Africa (South Africa, Zimbabwe and Mozambique) and contributed 49% of participants. The remaining 51% were enrolled in the fourth cohort, which involved participants from London.

Common criteria were used to diagnose KS-IRIS across all four cohort studies. Two investigators had to agree the diagnosis and a separate investigator reviewed all cases.

There were significant differences between the participants enrolled in the African and the UK cohorts. Participants in the UK cohort were more likely to be male (95 vs 45%, p <0.001) and were older at the time of KS diagnosis (39 vs 35 years, p < 0.001). The participants in London also had less severe disease (T1, poor prognosis = 62 vs 87%, p < 0.001) and were also less likely to have detectable KS viral load (58 vs 76%, p = 0.004). All the participants from the sub-Saharan African cohorts were of African ethnicity, as were 16% of participants who received care in London.

Median CD4 cell count at the time HIV therapy started was 196 cells/mm³ for the UK cohort and 138 cells/mm³ for the African cohorts (p < 0.001).

Treatment strategies differed between sub-Saharan Africa and the UK. Treatment consisted of antiretroviral therapy alone for all the participants in the African cohorts. Just over a third (34%) of the participants in London received chemotherapy in conjunction with HIV treatment.

Some 19 participants were lost to follow-up before completing three months of antiretroviral therapy. The remaining 417 individuals contributed a total of 104 person-years of follow-up.

Overall, 58 participants (14%) developed a paradoxical KS-IRIS. The rate was 20% for participants in the African cohorts and 9% for participants in London.

Incidence was 7 cases per 100 person-months for patients in Africa compared to an incidence of 3 cases per 100 person-months for the UK patients. The investigators therefore calculated that incidence was 2.5 times higher in Africa compared to the UK.

Risk factors for the development of a KS-IRIS were initial treatment with antiretroviral therapy alone (p = 0.047), more advanced KS disease stage (p = 0.013), a HIV viral load above 100,000 copies/ml (p = 0.005) and detectable KS viral load (p = 0.015).

After the development of KS-IRIS, some 55% of participants received treatment with a combination of antiretroviral therapy and chemotherapy. The remaining participants received HIV treatment only.

Some 7% of patients had a complete response to treatment; 40% had a partial response; KS disease remained stable in 12% and 36% of individuals experienced disease progression, including 33% of patients who died.

All the participants in London had a complete or partial response compared to 23% of participants in sub-Saharan Africa.

The mortality rate was significantly higher among KS-IRIS patients compared to patients who did not have this paradoxical reaction (33 vs 11%, p < 0.001).

“Our results...highlight the relevance of KS-IRIS to mortality in SSA [sub-Saharan Africa], which is remarkably higher than for any other paradoxical IRIS event associated with major OIs [opportunistic infections], such as Cryptococcus or TB,” comment the authors.

Mortality risk factors were KS-IRIS (p < 0.001), not receiving chemotherapy (p = 0.029), a baseline CD4 cell count below 200 cells/mm³ (p = 0.05) and a detectable KS viral load at baseline (p = 0.069).

The investigators believe their findings have a number of “clinical and programmatic implications”. These include the continued scale-up of antiretroviral treatment in resource-limited settings and the initiation of treatment at a CD4 threshold of 350 cells/mm³.

The authors also believe that education surrounding KS needs to be improved in resource-limited settings and that there is an “urgent need” for global guidance on the management of KS and KS-IRIS.