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
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
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.