As-Needed Vs Immediate Etoposide Chemotherapy in Combination With Antiretroviral Therapy for Mild-to-Moderate AIDS-Associated Kaposi Sarcoma in Resource-Limited Settings: A5264/AMC-067 Randomized Clinical Trial

Abstract

Background: Mild-to-moderate AIDS-associated Kaposi sarcoma (KS) often responds to antiretroviral therapy (ART) alone; the role of chemotherapy is unclear. We assessed the impact of immediate vs as-needed oral etoposide (ET) among human immunodeficiency virus (HIV)-infected individuals with mild-to-moderate KS initiating ART.

Methods: Chemotherapy-naive, HIV type 1-infected adults with mild-to-moderate KS initiating ART in Africa and South America were randomized to ART (tenofovir/emtricitabine/efavirenz) alone (chemotherapy "as-needed" arm) vs ART plus up to 8 cycles of oral ET (immediate arm). Participants with KS progression on ART alone received ET as part of the as-needed strategy. Primary outcome was ordinal as follows: failure, stable, and response at 48 weeks. Secondary outcomes included time to initial KS progression, KS-associated immune reconstitution inflammatory syndrome (KS-IRIS), and KS response.

Results: Of 190 randomized participants (as-needed = 94, immediate = 96), the majority were men (71%) and African (93%). Failure (53.8% vs 56.6%), stable (16.3% vs 10.8%), and response (30% vs 32.5%) did not differ between arms (as-needed vs immediate) among those with week 48 data potential (N = 163, P = .91). Time to KS progression (P = .021), KS-IRIS (P = .003), and KS response (P = .003) favored the immediate arm. Twenty-five participants died (13%). Mortality, adverse events, CD4+ T-cell changes, and HIV RNA suppression were similar at 48 weeks.

Conclusions: Among HIV-infected adults with mild-to-moderate KS, immediate ET provided early, nondurable clinical benefits. By 48 weeks, no clinical benefit was observed compared to use of ET as needed. Mortality was high and tumor response was low.

Clinical trials registration: NCT01352117.

Figures

Figure 1.

A5264 study Consort diagram. Abbreviation: ART, antiretroviral therapy.

Figure 2.

Kaplan-Meier plots with 95% confidence limits on (A) time to Failure, (B) time to initial KS progression, (C) time to suspected KS-IRIS, (D) time to initial KS response. In (A), Failure is defined as KS progression, death or initiation of alternate KS treatment, and Failure time is the time of the earliest of these events. P-values are from log-rank test and log-rank test stratified by the screening CD4 count. In (B) and (D), p-values are from Gray’s test and Gray’s test stratified by the screening CD4 count, with death and initiation of alternate KS treatment as competing risks. In (D), delayed ET initiation in as-needed was also modeled as competing risk and reflects response on ART alone. In (C), the p-value is from Gray’s test, and the time of suspected KS-IRIS is the time of initial KS progression meeting additional criteria for KS-IRIS. Abbreviations: KS, Kaposi sarcoma; KS-IRIS, KS–associated immune reconstitution inflammatory syndrome.