A randomized controlled trial of highly active antiretroviral therapy versus highly active antiretroviral therapy and chemotherapy in therapy-naive patients with HIV-associated Kaposi sarcoma in South Africa

Abstract

Background: The optimal approach to HIV-associated Kaposi sarcoma (HIV-KS) in sub-Saharan Africa is unknown. With large-scale rollout of highly active antiretroviral therapy (HAART) in South Africa, we hypothesized that survival in HIV-KS would improve and administration of chemotherapy in addition to HAART would be feasible and improve KS-specific outcomes.

Methods: We conducted a randomized, controlled, open-label trial with intention-to-treat analysis. Treatment-naive patients from King Edward VIII Hospital, Durban, South Africa, a public-sector tertiary referral center, with HIV-KS, but no symptomatic visceral disease or fungating lesions requiring urgent chemotherapy, were randomized to HAART alone or HAART and chemotherapy (CXT). HAART arm received stavudine, lamivudine, and nevirapine (Triomune; CXT arm received Triomune plus bleomycin, doxorubicin, and vincristine every 3 weeks. When bleomycin, doxorubicin, and vincristine were not available, oral etoposide (50-100 mg for 1-21 days of a 28-day cycle) was substituted. Primary outcome was overall KS response using AIDS Clinical Trial Group criteria 12 months after HAART initiation. Secondary comparisons included time to response, progression-free survival, overall survival, adverse events, HIV control, CD4 reconstitution, adherence, and quality of life.

Results: Fifty-nine subjects were randomized to HAART and 53 to CXT; 12-month overall KS response was 39% in the HAART arm and 66% in the CXT arm (difference, 27%; 95% confidence interval, 9%-43%; P = 0.005). At 12 months, 77% were alive (no survival difference between arms; P = 0.49), 82% had HIV viral load <50 copies per milliliter without difference between the arms (P = 0.47); CD4 counts and quality-of-life measures improved in all patients.

Conclusions: HAART with chemotherapy produced higher overall KS response over 12 months, whereas HAART alone provided similar improvement in survival and select measures of morbidity. In Africa, with high prevalence of HIV and human herpes virus-8 and limited resources, HAART alone provides important benefit in patients with HIV-KS.

Figure 1. Patient Flow Chart: screening, randomization, follow-up events, and analysis

Figure 2. Progression-free Survival, Time to Response, and Overall Survival

a) Progression-free survival: Kaplan-Meier analysis, hazard ratio for progression in HAART plus chemotherapy (CXT) arm compared to HAART alone arm = 0.52 (95% CI = 0.31, 0.88, log-rank test). b) Time to partial or complete response: based on three-monthly evaluations, patients censored (hatch marks) at time of death or loss to follow-up. Time to response rate ratio HAART arm compared to HAART plus chemotherapy (CXT) arm 2.8 (95% CI 1.7, 4.4, Mantel-Haenszel rate ratio) c) Overall survival by arm: Kaplan-Meier analysis, CXT = HAART plus chemotherapy Difference between arms not significant (p=0.49, log-rank test), also not significant after correcting for TIS risk factors (p=0.33, Cox regression). d) Overall survival by number (0-3) of modified ACTG TIS risk factors, (I₁ = CD4 less than 100 cells/mL): Kaplan-Meier analysis, multivariate Cox regression including modified ACTG risk factors effectively risk-stratified patients (p<0.01).