Kaposi sarcoma (KS) is one of the commonest AIDS-defining malignancies. KS incidence decreased in the West with the availability of highly active antiretroviral therapy (HAART),
but it has increased in sub-Saharan Africa 1 due to high rates of HIV-1 and human herpes virus-8 coinfection, overburdening already frail health care systems. HIV-associated KS (HIV-KS) can cause substantial morbidity and mortality, which may be improved by chemotherapy. Most studies of chemotherapy for HIV-KS have been evaluated in the United States and Europe. 2 PEGylated liposomal doxorubicin and paclitaxel have response rates ranging from 46% to 76% in the HAART era, but they are not considered World Health Organization (WHO) essential drugs 3–8 and are unavailable in many resource-poor settings. 9 In industrialized countries, HAART is usually combined with chemotherapy for advanced HIV-KS. However, prospective evaluation of HAART alone for the treatment of HIV-KS has been limited, 3 and its efficacy in advanced HIV-KS is unknown. 7
Before the availability of HAART in sub-Saharan Africa, HIV-KS mortality was high. In a prospective study in Zimbabwe in the 1990s comparing palliative chemotherapy, radiation, and supportive care in 470 HIV-KS patients in the absence of the available HAART, the 12-month overall survival (OS) was only 30%–40%.
Similar outcomes were seen in KwaZulu-Natal (KZN), 10 South Africa. In countries where HAART became widely available in 1996, OS of HIV-KS patients dramatically improved, 11 and HAART has become essential in HIV-KS management. With the availability of HAART in the public sector of 12 South Africa in 2003, we sought to more fully define the outcomes achieved with HAART in African patients with this common AIDS-defining malignancy, including those with advanced disease. Additionally, we hypothesized that chemotherapy started soon after the initiation of HAART may further improve KS-specific outcomes with manageable toxicities. METHODS
Participants and Study Design
The Kaposi sarcoma AIDS AntiRetroviral Therapy (KAART) Trial is a prospective, single-center, randomized, open-labeled trial comparing HAART with HAART combined with early chemotherapy (CXT) for HIV-KS. Treatment-naive patients (no prior KS or HIV therapy) were recruited and enrolled from Dermatology Clinic at the King Edward VIII Hospital, Durban, a public sector tertiary referral center for approximately 10.3 million people in KZN,
South Africa. Enrolled patients had proven HIV and histologically confirmed KS. Exclusion criteria included KS requiring urgent chemotherapy (ie, symptomatic visceral disease or fungating lesions), peripheral neuropathy, clinical congestive heart disease or ejection fraction <50%, neutrophil count of <1000 units per liter, hemoglobin < 9.0 gm/dL, platelet count of <75 × 10 9 per liter, serum creatinine >114.4 μmol/L, direct serum bilirubin >85 μmol/L, aspartate aminotransferase or alanine aminotransferase >2.5 times the normal range, and intensive phase of tuberculosis therapy. Patients were staged according to modified AIDS Clinical Trials Group (ACTG) criteria into “Good” and “Poor” risk groups, then randomized to HAART or CXT by 4-digit computer generated code. “Poor” risk subjects had any tumor, immune, or symptom (TIS) ACTG staging feature associated with poor survival in HIV-KS. These included high-risk tumor features (T 1) (visceral disease, tumor-associated edema, or ulceration), advanced immune suppression (I 1) (CD4 <150 cells/μL), or systemic features of AIDS (S 1) (history of opportunistic infections, wasting, fevers, night sweats, poor performance status) (for ACTG Staging of KS, see Table 1, Supplemental Digital Content 1, ). https://links.lww.com/QAI/A307 13,14
The study was done in accordance with principles of the Declaration of Helsinki and in compliance with Good Clinical Practice guidelines, with ethical approval from the Nelson R. Mandela School of Medicine institutional review board. All subjects provided written informed consent. This protocol was registered at clinicaltrials.gov (NCT00380770).
HAART was fixed-dose combination of stavudine (40 mg), lamivudine (150 mg), and nevirapine 200 mg (Triomune; Cipla-Medpro, Capetown,
South Africa). This regimen was determined by the availability to investigators through a donation from CIPLA during a period when antiretrovirals were unavailable in the public sector in South Africa and was the first available public sector HAART regimen in KZN. Patients who developed resistance or drug toxicity received a second-line HAART regimen. Chemotherapy consisted of doxorubicin (20 mg/m 2 intravenously), bleomycin (10 U/m 2 intravenously), and vincristine (1.4 mg/m 2 intravenously, capped at 2 mg) (ABV) every 3 weeks, started within the first month of initiation of HAART, with the goal of continuing chemotherapy for 2 cycles beyond maximal response. This relatively low-cost regimen consists of agents on the WHO essential drug list. 15 Patients randomized to CXT were referred to public sector Oncology Clinic for chemotherapy administration. Patients in the HAART arm with inadequate KS response by month 6 or progressive KS requiring chemotherapy before month 6 were considered “HAART treatment failures” and offered chemotherapy based on both clinician judgment and the evaluation of KS response using ACTG response criteria. Although planned protocol chemotherapy was ABV, oral etoposide (50–100 mg for 1–21 days of a 28-day cycle) 9 was used as alternative therapy in the event of difficulties with chemotherapy drug supply or intravenous administration during the protocol. Dose modifications of HAART or chemotherapy were performed for toxicity or changes in renal function. Etoposide was started at 50 mg daily but could be escalated to 100 mg in patients in subsequent cycles with inadequate KS tumor regression and no limiting toxicities. 16 Monitoring and Response Evaluation
At baseline, KS was evaluated by physical examination, chest radiograph, and upper endoscopy. If indicated, bronchoscopy was performed. Endoscopy and chest radiography were repeated at 6 months in those with baseline visceral KS. Investigators in the Dermatology Clinic assessed the clinical response every 3 months through month 12. Response evaluations included lesion counts, measurement of the sum product of the diameters of 5 marker lesions, and assessment of nodularity. KS responses were graded as complete, partial, stable disease, and progressive disease using previously described ACTG criteria (for ACTG KS Response Criteria, see
Table 2, Supplemental Digital Content 2, ). https://links.lww.com/QAI/A308 Partial response (PR) required at least 50% decrease in the number of lesions and/or sum product of the diameters of marker lesions and/or nodularity of lesions and no new lesions, whereas complete response (CR) required clinical resolution of all lesions and tumor-associated phenomenon. CR and PR were combined to determine the overall response rate (ORR). 13,14
Monitoring included history and physical examination, complete blood count, serum chemistry, CD4 count, and HIV-1 viral load (HIV-VL) performed at baseline, week 2, week 4, and then monthly for 12 months. HIV-VL was measured by RNA polymerase chain reaction (HIV-1 QT kit; Roche Diagnostics, Rotkreuz, Switzerland), and CD4 counts were performed by EpicsXL Flow Cytometer and tetraOne System (Beckman Coulter, Brea, CA). Toxicities were graded using Division of AIDS (DAIDS) toxicity scale. Adherence was assessed by a 7-day recall questionnaire,
at week 2, week 4, and then monthly. 17,18
Previously validated quality-of-life (QOL) questionnaires (EORTC QOL-30),
available in English and isiZulu, were completed at baseline and trimonthly. The questionnaire measures 6 functioning scales: physical, role, cognitive, emotional, social, and global QOL; and 9 symptom scales and/or items: fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact. 19,20 Differences greater than 10 points in QOL scores were considered to be clinically important. 20 21 Primary and Secondary Outcomes
Primary outcome was comparison between arms of the proportion of patients with a KS PR or better at month 12 compared with baseline. Secondary outcomes included comparisons between arms of progression-free survival (PFS; time from randomization to progressive disease or death), time to response (TTR; time from randomization to achievement of PR or better), OS, adverse events (including the immune reconstitution inflammatory syndrome [IRIS]), immunological and virologic parameters, adherence, QOL, and evaluation of modified ACTG prognostic criteria.
Detection of 30% absolute improvement in ORR from 0.3 to 0.6 at month 12 with the addition of chemotherapy (2-sided α = 0.05, β = 0.8) required 49 patients per arm. Assuming modest loss to follow-up, accrual goal was 120. Comparisons were based on intention-to-treat (ITT) analysis. Between arms, 12-month ORR, incidence of per-patient specific serious adverse events, and proportion of patients with undetectable HIV at month 12 were compared using Fisher exact test. TTR was compared between arms using the Mantel–Haenszel rate ratio. PFS and OS were evaluated using Kaplan–Meier methodology with log–rank test to compare arms. Multivariate analysis of ACTG TIS risk factors employed Cox regression. Difference in CD4 reconstitution between arms was evaluated with the Mann–Whitney test. We evaluated intragroup changes in QOL scores between baseline and month 12 (Wilcoxon signed-rank test), changes between baseline and month 12 QOL scores between the 2 groups (Mann–Whitney test), and the relationship between clinical responses and global QOL (Kruskal–Wallis test). Given multiple comparisons in QOL analysis,
P < 0.01 was considered statistically significant, whereas 0.01 < P < 0.05 represented important trends. In addition to ITT analyses, secondary planned as treated analysis was performed for 12-month ORR and OS. Role of the Funding Sources
Study planning, design, implementation, analysis, and write-up were performed entirely by the investigators. Funders had no role in conceptualization, planning, design, analysis, or writing of this manuscript.
Study Subjects, Randomization, and Follow-up Events
From 2003 to 2009, 310 patients were screened; 112 were eligible, consented, and randomized (59 to HAART and 53 to CXT) and followed for up to 12 months (
Fig. 1). Table 1 illustrates baseline demographic characteristics. Notably, 110 of 112 were black, 55% were women, 69% were from the urban area of Durban, and 31% were rural residents of KZN. Ninety-three percent were on poor risk based on modified ACTG criteria: 89% had advanced disease with a high tumor burden (T 1), 54% had a CD4 count <150 cells per microliter (I 1) (58% had CD4 <200 cells/μL), and 42% had inflammatory “B” symptoms or a history of opportunistic infection (S 1), including a history of treated tuberculosis in 16 subjects. FIGURE 1:
Patient flow chart: screening, randomization, follow-up events, and analysis.
Baseline Patient Characteristics
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). KS Outcomes
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 T 1 disease, ORR was 64% in the CXT arm and 36% in the HAART arm ( P = 0.009, Fisher exact test). TABLE 2:
Twelve-Month KS Response, Compared With Baseline by AIDS Clinical Trial Group Response Criteria
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 T 1 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). FIGURE 2:
Progression-free survival, time to response, and OS. A, Progression-free survival: Kaplan–Meier analysis, HR for progression in HAART plus chemotherapy (CXT) arm compared with HAART alone arm was 0.52 (95% CI, 0.31–0.88, log-rank test). B, Time to partial or CR based on trimonthly evaluations, patients censored (hatch marks) at time of death or loss to follow-up. Time to response rate ratio of HAART arm compared with HAART plus chemotherapy (CXT) arm was 2.8 (95% CI, 1.7–4.4, Mantel–Haenszel rate ratio). C, OS by arm: Kaplan–Meier analysis, CXT = HAART plus chemotherapy Difference between the arms was not significant (
P = 0.49, log-rank test) also not significant after correcting for TIS risk factors ( P = 0.33, Cox regression). D, OS by number (0–3) of modified ACTG TIS risk factors (I 1 = CD4 <100 cells/mL): Kaplan–Meier analysis, multivariate Cox regression including modified ACTG risk factors effectively risk-stratified patients ( P < 0.01). Overall Survival
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 T 1 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 T 1 disease, S 1 [including history of tuberculosis in 16 (36%) of 44 S 1 patients], emerged as the most important TIS predictor of 12-month OS, with borderline statistical significance on multivariate analysis (univariate HR of death, S 1 compared with S 0 = 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 I 1 compared with I 0, = 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 I 1 = 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). Adverse Events
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, ) 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. https://links.lww.com/QAI/A308 TABLE 3:
Serious Adverse Events: DAIDS Grades 3–5 Toxicities and Immune Reconstitution Syndrome; Intention to Treat, Worst Grade per Patient
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, ). https://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. DISCUSSION
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 T
1 patients in the KAART study (T 1 15% in the Spanish study versus 89% in KAART), 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%). 7 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 study
and in line with OS estimates across a range of HIV-KS stages in industrialized countries (24-month OS, 58%–84%) 10 after the broad availability of HAART. In Africa, modified ACTG staging remains useful for prognosis in HIV-KS ( 8,12,21,22 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,
improved recognition and earlier use of chemotherapy, and novel treatment strategies could lead to further improvements in survival for these high-risk patients. 23,24
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 men and is the first prospective study demonstrating inferior outcomes in women despite comparable therapy. 25–27
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 HIV viremia and allowing for immune reconstitution 28 are the primary goals in using HAART to treat HIV-KS, 29 evaluation of additional anti–human herpes virus-8 effects of specific antiretroviral agents remains an area of active research. 30–32 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.
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 T 1 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. ACKNOWLEDGMENTS
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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