Of patients assigned to HAART, 13 (22%) were “HAART treatment failures” and received chemotherapy, 10 between months 2 and 6, and 3 after month 6. Of patients randomized to CXT, 15 (28%) received HAART alone. Thirteen (86%) of these 15 died or were lost to follow-up before receiving chemotherapy. Patients randomized to CXT but not receiving chemotherapy had low baseline CD4 counts (median, 77 cells/μL), compared with those receiving chemotherapy (median, 249 cells/μL). Sixteen patients (31% of chemotherapy administered) received oral etoposide. Among patients receiving chemotherapy, the median number of cycles administered was 6 (interquartile range, 4–6). Five patients (4%) were lost to follow-up (Fig. 1).
Primary outcome was KS response at month 12. In the CXT arm, 9 (17%) had a CR and 26 (49%) had a PR for an ORR of 66%; 18 (34%) failed to respond. In the HAART arm, 4 (7%) had a CR and 19 (32%) had a PR for an ORR of 39%; 36 (61%) failed to respond. The absolute difference in ORR was 27% [95% confidence interval (CI), 9%–43%; Table 2]. Limiting analysis to the 100 subjects with T1 disease, ORR was 64% in the CXT arm and 36% in the HAART arm (P = 0.009, Fisher exact test).
One-year PFS in the CXT arm was 56% versus 31% in the HAART arm [hazard ratio (HR) = 0.52; 95% CI, 0.31–0.88; Fig. 2A]. Results were similar after limiting PFS analysis to T1 patients (HR = 0.54; 95% CI, 0.31–0.93) Furthermore, patients randomized to CXT obtained earlier tumor regression compared with HAART [TTR rate ratio, 2.8 (95% CI, 1.7–4.4); Fig. 2B]. In an as-treated analysis, the proportion of patients receiving HAART alone that achieved PR or better at month 12 month was 38%; for those receiving HAART and at least 1 cycle of chemotherapy, it was 69% (74% for ABV, 56% for oral etoposide) (comparison of HAART to HAART and any chemotherapy, P = 0.001, Fisher exact test).
Despite most patients being poor risk, 12-month OS was 77%, with no significant difference between arms (P = 0.49; Fig. 2C). This remained true after correcting for TIS risk factors (P = 0.33), in a secondary as treated analysis (P = 0.1), and when limiting analysis to T1 subjects (OS = 74%; P = 0.54). Of 26 deaths, 12 died of documented progressive KS (46% of deaths), 10 of these met criteria for KS-IRIS. Nine of the 12 (3 in the HAART arm and 6 in the CXT arm) died before receiving chemotherapy. Two additional patients with pulmonary KS died of respiratory symptoms of unknown etiology. Two died of liver failure, 2 of documented infection, and 8 of other causes. Patient's 12-month OS was evaluated based on the number of ACTG risk features. Multivariate logistic regression including established risk factors effectively risk-stratified patients (P = 0.03), validating the modified ACTG staging system in our population. In this cohort in which 89% had T1 disease, S1 [including history of tuberculosis in 16 (36%) of 44 S1 patients], emerged as the most important TIS predictor of 12-month OS, with borderline statistical significance on multivariate analysis (univariate HR of death, S1 compared with S0 = 2.4, P = 0.02; multivariate analysis, HR = 2.0, P = 0.08). Baseline CD4 count <150 cells per microliter was a less powerful predictor of 12-month OS (univariate HR of death for I1 compared with I0, = 1.9, P = 0.1; multivariate analysis, HR = 1.6, P = 0.24) than using CD4 count <100 cells per microliter as a cutoff (univariate HR of death for CD4 <100 cells/μL compared with ≥100 cells/μL = 2.6, P < 0.01; multivariate analysis, HR = 2.74, P < 0.01; TIS model using I1 = CD4 <100 cells/μL, P < 0.01) (Fig. 2D). Additionally, female sex was an independent risk factor for death in univariate analysis (HR =2.6; P = 0.02), and after correcting for other TIS risk factors (CD4 <100 cells/μL cutoff) and treatment arm (HR = 2.6; P = 0.04).
The commonest severe adverse events (per patient) were abnormal liver function tests (16%), anemia (17%), and infections (22%). There were no statistically significant differences in the number and proportion of severe adverse events between the arms (Table 3). KS-IRIS (for definition of KS-IRIS, see Table 2, Supplemental Digital Content 2, http://links.lww.com/QAI/A308) was diagnosed in 23 patients (21%). Ten of these, including 9 with visceral KS, died. Pulmonary KS-IRIS contributed to 6 of these deaths. Overall, 37% of all deaths occurred in patients who met criteria for KS-IRIS. There were no significant differences between the arms in the occurrence or mortality attributed to KS-IRIS.
Adherence and HIV-Related Outcomes
Seven-day recall was performed on 1070 (91%) of 1175 total visits. In the HAART arm, patients reported 100% adherence in 92.4% of visits versus 89.5% of visits in the CXT arm (P = 0.8, Fisher exact test). Seven patients (12%) in the HAART arm and 5 (9%) in the CXT arm changed HAART due to toxicity or virologic failure. Two in the HAART arm changed HAART regimen on 2 occasions. HIV virologic control was very good, with 82% of patients with HIV <50 copies per milliliter at month 12 and no difference between the arms (P = 1.0). CD4 reconstitution was seen in most patients. In patients completing 12 months of follow-up, median increase from baseline to month 12 was 129 cells per microliter (range, −185 to +860) with no difference between the arms (P = 0.73) (median CD4 count and interquartile range: baseline, month 6, month 12, by arm; see Figure 1, Supplemental Digital Content 3, http://links.lww.com/QAI/A309).
QUALITY OF LIFE
QOL improved significantly from baseline to month 12 on HAART. In the entire cohort, median global health score (perfect score = 100) was 50 at baseline and 67 at month 12 (P < 0.001). CR or PR by month 12 was associated with increased global health score (P < 0.001). Across subjects, improvements in emotional (P < 0.001), social (P = 0.003), and cognitive functioning (P < 0.001) were noted. Symptom scales demonstrating statistically significant improvements (P < 0.01) were fatigue, appetite loss, pain, dyspnea, insomnia, constipation, diarrhea, and financial problems. Comparing arms, a trend toward improved role functioning (perfect score = 100) favored the CXT arm (median change HAART = 0, CXT = +17; P = 0.011). Improvement in pain (perfect score = 0, median change HAART = -16.7, CXT = -33.3; P = 0.1) and overall QOL (median change HAART = 12.5; CXT = 16.7; P = 0.08) were also greater in the CXT arm. Comparisons between the arms were not statistically significant.
This is the first randomized controlled trial using HAART in African patients with HIV-KS. We compared HAART alone with HAART combined with chemotherapy for KS efficacy, OS, safety, control of HIV, adherence, and QOL improvement. Patients were treatment naive, 89% had advanced (but not immediately life threatening) KS, and 58% had CD4 <200 cells per microliter. This is the population most likely to be in need of therapy for both diseases in Africa. Randomization to CXT improved 12-month ORR (66% in CXT arm versus 39% HAART arm). Seventy-seven percent of patients were alive at 12 months, and patients randomized to HAART alone had similar OS compared with those randomized to HAART and chemotherapy.
The KAART study provides much-needed, randomized, controlled trial evidence regarding therapy for HIV-KS in sub-Saharan Africa. Thirty-nine percent responded to HAART alone, providing the best estimate of efficacy of HAART alone in the treatment of HIV-KS treatment-naive patients with advanced KS. ORR with HAART alone compares favorably with that seen in a Spanish study (ORR = 20%), despite a high proportion of T1 patients in the KAART study (T1 15% in the Spanish study versus 89% in KAART),7 perhaps reflective of differences in HIV resistance profiles, other unmeasured KS associated factors, and adherence. The ORR seen in the CXT arm (66%) is superior to a large Zimbabwean study, which administered ABV without the benefit of HAART (49%).10
Importantly, we demonstrated excellent 12-month OS (77%) in this high-risk cohort, comparing favorably with the <40% 12-month OS noted in the Zimbabwean study10 and in line with OS estimates across a range of HIV-KS stages in industrialized countries (24-month OS, 58%–84%)8,12,21,22 after the broad availability of HAART. In Africa, modified ACTG staging remains useful for prognosis in HIV-KS (P = 0.03). Systemic illness is a significant prognostic factor of OS. History of tuberculosis was the commonest comorbidity (36%), and management of concurrent KS and tuberculosis remains a particularly important challenge in sub-Saharan Africa. Active screening and therapy for tuberculosis are important steps to reduce morbidity and mortality of HIV-KS patients. HIV-KS patients with CD4 <100 cells per microliter are also at an increased risk of dying in the first 12 months of therapy and may require extra attention to supportive care.
Although KAART demonstrates that HAART with or without chemotherapy improves 12-month OS in South African treatment-naive patients with HIV-KS (77% versus 30%–40% historical controls), additional studies are needed. KS-IRIS developed in 23 patients and contributed to mortality in 10. Improved understanding of the risk factors and underlying pathophysiology of KS-IRIS,23,24 improved recognition and earlier use of chemotherapy, and novel treatment strategies could lead to further improvements in survival for these high-risk patients.
KAART had a female preponderance, reflecting the HIV and HIV-KS epidemics in South Africa. Women had poorer 12-month survival not explained by ACTG prognostic factors or treatment arm. This finding builds on retrospective observations that women with HIV-KS have more aggressive disease and inferior outcomes than men25–27 and is the first prospective study demonstrating inferior outcomes in women despite comparable therapy.
Notably, HIV and HIV-KS outcomes observed in KAART were obtained using a nonnucleoside reverse transcriptase inhibitor–based regimen. Additional HAART regimens, including protease inhibitor–based regimens, are now available in the public sector in South Africa. Although controlling HIV28 viremia and allowing for immune reconstitution29 are the primary goals in using HAART to treat HIV-KS,30–32 evaluation of additional anti–human herpes virus-8 effects of specific antiretroviral agents remains an area of active research.33,34
KAART is the first study to document the influence of HAART, with or without chemotherapy, on QOL in patients with HIV-KS. Patients benefited significantly in overall global health status, functioning, and symptom scales. Most dramatic improvements were reported for pain, fatigue, insomnia, constipation, and financial problems. There were no statistically significant differences in QOL measures between the arms; however, obtaining PR or better was associated with improvement in global QOL, validating tumor regression as an important palliative goal in advanced HIV-KS.10,35
A related question is whether addition of chemotherapy to HAART causes unnecessary toxicity or otherwise compromises HIV-directed care. Overall, the adverse event profile was manageable in both arms and not statistically different. The commonest adverse events experienced were hepatitis, paresthesias, anemia, diarrhea, vomiting, and pneumonia. The majority were grade 1–2 toxicities; severe toxicity rates did not differ significantly between the arms. Given cross over between arms and the use of 2 separate chemotherapeutic regimens, the lack of difference of severe toxicities between the arms should not be strictly interpreted. Patients receiving chemotherapy in addition to HAART for HIV-KS require monitoring for known chemotherapy-specific adverse events. Larger studies are required to further define the toxicity profile of patients eceiving chemotherapy for HIV-KS in sub-Saharan Africa. HAART regimen changes due to drug toxicity were noted in 8 (7%) of 112 patients, the commonest being nevirapine hepatitis (4 of 122). Less common were peripheral neuropathy and anemia. Chemotherapy did not significantly worsen adherence. This is crucial, as high pill burden is an important issue in HIV care in resource-limited settings. Patients likely benefited from frequent support to achieve and maintain adherence. CD4 increase and HIV-VL decay were comparable between the arms.
A limitation of the study was that some patients randomized to CXT did not receive the intended ABV due to a variety of common problems with chemotherapy administration in sub-Saharan Africa. Despite this introduced heterogeneity, which would be expected to weaken findings in ITT analysis, being randomized to CXT had benefits with respect to tumor response. The number needed to treat with chemotherapy in addition to HAART to obtain a PR or better by 12 months was 3.7 (95% CI, 2.2–11.9). The number needed to treat to prevent one patient from disease progression at 6 months was 3.3 (95% CI, 2.3–5.8). Importantly, findings from the KAART study may not be generalizable to HIV-KS patients with symptomatic visceral disease or fungating lesions. Furthermore, the KAART study was not designed to evaluate optimal chemotherapy in patients with HIV-KS. To address this, another randomized controlled trial of several chemotherapeutic regimens for African patients with advanced HIV-KS is planned (NCT01435018).
HAART is essential in improving survival in patients with HIV-KS in South Africa, whereas chemotherapy improves KS-specific responses. HAART controls HIV and may be sufficient in managing KS in a sizable proportion of treatment naive HIV-KS patients, even those with T1 disease. This is of particular importance given the current unavailability of chemotherapy in many African settings, where KS remains the commonest malignancy. Effective therapy for KS remains an important goal for decreasing the morbidity in African patients with HIV-KS. Chemotherapy has a beneficial role in some HIV-KS patients, and the addition of chemotherapy to HAART results in an improved ORR, TTR, and PFS in HIV-KS. Further studies of HAART combined with additional KS therapies are warranted for African patients with advanced HIV-KS as is more widespread availability and the use of established chemotherapy for patients with symptomatic disease.
The authors acknowledge G. Ganyile, K. Hoosen, U. Bodasing and H. Dawood for their invaluable assistance; Qurraisha and Slim Abdool Karim for their advice, expertise, and support and Irene van Middelkoop for managing the database.
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
Kaposi sarcoma; AIDS; HIV; highly active antiretroviral therapy; South Africa