Treatment and outcome of AIDS-related Kaposi sarcoma in South Africa, Malawi and Zambia: an international comparison

Treatment and outcome of AIDS-related Kaposi sarcoma in South Africa, Malawi and Zambia: an international comparison

Eliane Rohner^1,&, Margaret Kasaro², Susan Citonje Msadabwe-Chikuni³, Kathryn Stinson⁴, Zainab Mohamed⁵, Hannock Tweya⁶, Matthias Egger^1,7, Julia Bohlius¹

 

¹Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland, ²Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia, ³Cancer Diseases Hospital, Lusaka, Zambia, ⁴Khayelitsha ART Program, Médecins Sans Frontières, Cape Town, South Africa, ⁵Radiation Oncology, Groote Schuur Hospital, Cape Town, South Africa, ⁶Lighthouse Trust at Kamuzu Central Hospital, Lilongwe, Malawi, ⁷Centre for Infectious Disease Epidemiology & Research, School of Public Health & Family Medicine, University of Cape Town, Cape Town, South Africa

 

 

^&Corresponding author
Eliane Rohner, Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland

 

 

 

 

Kaposi sarcoma (KS) is a common HIV-related malignancy in sub-Saharan Africa (SSA) [1]. While HIV treatment programs have expanded massively over the past decade, resources for oncological care are still very limited in most SSA countries [1]. A recent Cochrane review [2] suggested that, in general, patients with severe HIV-related KS might benefit from a combination of antiretroviral therapy (ART) and chemotherapy; however, optimal management strategies for AIDS-KS patients in resource-limited settings remain unclear. We compared clinical stage, clinical management and outcomes of adult AIDS-KS patients enrolled in ART programs in Malawi, South Africa, and Zambia.

 

 

In this retrospective cohort study we included adult (aged ≥16 years) AIDS-KS patients diagnosed at three ART programs in South Africa, Malawi and Zambia. Ubuntu Clinic is located in Khayelitsha, a township outside Cape Town. Lighthouse Trust is the largest public ART provider in Malawi, located at the Kamuzu Central Hospital in Lilongwe. The Centre for Infectious Disease Research in Zambia (CIDRZ) is a non-profit organization supporting more than 300 public clinics; we selected three facilities in Lusaka, i.e University Teaching Hospital, Kalinagalinga Clinic, and Kanyama Clinic. All ART programs participate in the International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA-SA), and have local ethics committees and institutional review board approvals to contribute routine data for IeDEA-SA research projects. Additional approvals were obtained from the Human Research Ethics Committee of the University of Cape Town and the Biomedical Research Ethics Committee of the University of Zambia. Per ART program we aimed to include 20 consecutive patients diagnosed with AIDS-KS before ART initiation from 2011 backwards. We reviewed medical charts at HIV clinics and referral oncology clinics (Groote Schuur Hospital, Cape Town, and Cancer Diseases Hospital, Lusaka) and retrieved data from IeDEA-SA databases. Data was captured electronically using an online tool (REDCap). We assessed tumor (T) and systemic illness (S) stage according to the AIDS Clinical Trials Group (ACTG) system [3]. T and S stages were extracted from charts, if available, and otherwise derived from documented information. T0S0, T0S1 and T1S0 were considered good risk and T1S1 poor risk. CD4 cell count at KS diagnosis was the measurement closest to KS diagnosis (-180/+7 days). Patient and tumor characteristics at baseline and treatments received were analyzed descriptively. Results are presented in percentages, medians and interquartile ranges (IQR). We used Kaplan-Meier analyses to estimate survival after KS diagnosis. Patients were defined as lost to follow-up (LTFU) if there was no contact for ≥6 months prior to the data extraction date. Patients LTFU were censored at last contact date. In additional analyses we combined patients who died with those LTFU. Analyses were done in Stata 13.1 (StataCorp LP).

 

 

We extracted data for 60 AIDS-KS patients. Three Malawian patients were ineligible; 57 patients were included in the analysis. All patients were diagnosed with AIDS-KS before initiating ART at the HIV clinic. Two KS cases (10%) in South Africa and none in Malawi and Zambia were histologically confirmed. In Malawi and Zambia, most AIDS-KS patients were male; in South Africa, 60% (N = 12) were female (Table 1). Median age at KS diagnosis was 35 years (IQR 24-42 years) and similar across sites. Median CD4 cell count at KS diagnosis was lowest in Zambia (66 cells/µL), followed by Malawi (137 cells/µL) and South Africa (174 cells/µL); the percentage of missing values ranged from 10% to 44% per site. The percentage of patients with poor risk AIDS-KS (T1S1) was higher in Zambia (45%) than in South Africa (25%) and Malawi (24%). Tumors were often located on lower extremities (67%, N = 38) and in the oral cavity (35%, N = 20). Tumor-associated edema was documented in 44% of patients (N = 25). KS lesions on head/neck, trunk, and upper extremities were noted in most South African patients, but rarely in patients from Malawi and Zambia (Table 1). In Zambia, 13 patients (75%) received protease-inhibitors (PI) but none of the first-line ART regimens in South Africa or Malawi included PIs. In South Africa, 18 patients (90%) were referred to an oncology department; in Malawi all treatments were administered at the HIV clinic. In Zambia, only one patient (5%) was referred to the oncology clinic but never appeared there. Most patients in South Africa and Malawi but only one patient in Zambia received chemotherapy (Table 1). In South Africa, all chemotherapy regimens given included ≥2 drugs; most commonly vincristine/bleomycin (60%, N = 12). In Malawi, most patients received vincristine monotherapy (65%, N = 11). Six patients from South Africa (30%), but none from Malawi or Zambia, received radiotherapy. The probability of surviving one year after KS diagnosis was 89% (95% confidence interval (CI) 62%-97%) in South Africa, 84% (50%-96%) in Zambia and 66% (36%-84%) in Malawi (Figure 1, Figure 2). When we included LTFU as a failure event, one-year survival probabilities dropped to 75% (95% CI 50%-89%) in South Africa, 50% (95% CI 27%-69%) in Zambia, and 47% (95% CI 23%-68%) in Malawi.

 

 

For this international comparison, we deliberately identified patients at HIV clinics and followed their path through the health care system. We extracted data from charts of HIV clinics and oncology departments. The retrospective design ensured that we captured routine conditions, and that our study had no effect on clinical management. Clinical management of AIDS-KS patients varied across sites and countries in SSA. While South Africa offered combination chemotherapy at specialized oncology departments, Malawi and Zambia usually managed AIDS-KS patients at the ART programs. One year after KS diagnosis 75% of patients in South Africa and less than 50% of patients in Malawi and Zambia were alive and in care. Some limitations need to be addressed. Several patients were LTFU early after KS diagnosis, and generally, patients LTFU are more likely to have died than patients who remained in care [4]. To assess the impact of differential LTFU on the survival probabilities we performed sensitivity analyses including LTFU as a failure event. The extent of data recorded in medical charts varied between sites and relevant study data was often not available. For example, we could not assess KS response to treatment because location, number and extent of KS lesions were not documented in detail. In general, KS-specific documentation was more comprehensive in oncology departments than at HIV clinics, which might have caused us to underestimate clinical KS stage in patients not referred to oncology departments. The AIDS-KS patient load and calendar periods covered varied between sites, and this reduced comparability across sites. As patient populations and treatment approaches differ between ART programs, our findings are unlikely to be representative of all ART programs in Malawi, South Africa, and Zambia. Many patients were diagnosed in advanced AIDS-KS stage; in line with results from other studies in the region [5, 6]. In Malawi, all patients received chemotherapy, as described in a previous Lighthouse Trust study [7].

 

We found that 90% of patients from Khayelitsha (Cape Town) received chemotherapy, while an earlier study reported that only 29% received chemotherapy [5]. This difference is likely due to improved service delivery over time. To our knowledge, published data on routine KS treatment at ART programs in Zambia are not available. Our one-year survival estimate from Lighthouse Trust was lower than a recent estimate from a specialized KS clinic in Malawi [6], perhaps because different chemotherapy regimens were used, and perhaps because more specialized oncological care was available at the KS clinic. Our survival estimate for South Africa was in line with a previous study [8]. Another study from Khayelitsha [5], which recruited patients earlier than we did (2001-2007 vs. 2005-2011), had shown a lower survival estimate at one year (60%). This might be explained by the higher proportion of patients in our study who received ART and chemotherapy, but also by temporal survival improvements in AIDS-KS patients. When ART coverage was low in SSA, most AIDS-KS patients were diagnosed in advanced KS stage and died a few months later. Since 2004, ART availability has increased substantially in Southern Africa, and efforts have been made to improve HIV testing and linkage to care. AIDS-KS patients should now be diagnosed in earlier KS stage. However, our and other studies have shown that in SAA, patients are still diagnosed in advanced KS stages [5,6]. In addition to HIV treatment, KS patients are likely to benefit from specialized oncology care. However, data from SSA are scarce and findings from high-income countries cannot be extrapolated to African settings. Survival after KS diagnosis is an essential measure to assess and compare treatment outcomes in AIDS-KS patients. However, survival data are prone to bias if LTFU is substantial [9]. AIDS-KS patients are more likely to be LTFU than HIV-positive patients without KS [10], so these patients might require dedicated tracking efforts to obtain reliable survival estimates.

 

 

Despite increasing ART availability, many patients are still diagnosed in advanced AIDS-KS stage in SSA. Management of AIDS-KS patients varied considerably across sites in Malawi, South Africa, and Zambia, and it is unclear which treatment procedures and clinical paths should be adopted in which setting. Better survival data is needed to reliably assess outcomes across different standards of care.

 

 

The authors declare no competing interests.

 

 

Julia Bohlius, Matthias Egger and Eliane Rohner designed the study Margaret Kasaro, Susan Citonje Msadabwe-Chikuni, Kathryn Stinson, Zainab Mohamed and Hannock Tweya were involved in compiling and extracting the data; Eliane Rohner analyzed the data; Eliane Rohner and Julia Bohlius wrote the first draft of the paper; all authors discussed the results, gave input and approved the final version of the manuscript.

 

 

We thank Bett Wilson for extracting data at the Lighthouse Trust and Kali Tal for her editorial suggestions. This study was done on behalf of the International epidemiology Database to Evaluate AIDS (IeDEA). Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health [award number U01AI069924] and also supported by the National Cancer Institute [grant number 5U01A1069924-05]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional funding was received from the Swiss National Science Foundation [Ambizione-PROSPER PZ00P3_136620 to J.B.]. IeDEA-SA site investigators and cohorts: Gary Maartens, Aid for AIDS, South Africa; Michael Vinikoor, Centre for Infectious Disease Research in Zambia (CIDRZ), Zambia; Monique van Lettow, Dignitas, Malawi; Robin Wood, Gugulethu ART Programme, South Africa; Nosisa Sipambo, Harriet Shezi Clinic, South Africa; Frank Tanser, Africa Centre for Health & Population Studies (Hlabisa), South Africa; Andrew Boulle, Khayelitsha ART Programme, South Africa; Geoffrey Fatti, Kheth'Impilo, South Africa; Sam Phiri, Lighthouse Clinic, Malawi; Cleophas Chimbetete, Newlands Clinic, Zimbabwe; Karl Technau, Rahima Moosa Mother and Child Hospital, South Africa; Brian Eley, Red Cross Children's Hospital, South Africa; Josephine Muhairwe, SolidarMed Lesotho; Anna Jores, SolidarMed Mozambique; Kamelia Kamenova, SolidarMed Zimbabwe, Matthew P Fox, Themba Lethu Clinic, South Africa; Hans Prozesky, Tygerberg Academic Hospital, South Africa. IeDEA-SA data centers: Nina Anderegg, Marie Ballif, Julia Bohlius, Cam Ha Dao Ostinelli, Frédérique Chammartin, Matthias Egger, Lukas Fenner, Per von Groote, Andreas Haas, Taghavi Katayoun, Eliane Rohner, Adrian Spörri, Gilles Wandeler, Elizabeth Zaniewski, Kathrin Zürcher, Institute of Social and Preventive Medicine, University of Bern, Switzerland; Andrew Boulle, Morna Cornell, Mary-Ann Davies, Nicola Maxwell, Leigh Johnson, Mmamapudi Kubjane, Patience Nyakato, Gem Patten, Michael Schomaker, Priscilla Tsondai, Victoria Iyun, Tshabakwane Nembandona, Ernest Mokotoane, School of Public Health and Family Medicine, University of Cape Town, South Africa.

 

 

Table 1: demographics, disease characteristics and treatment of included AIDS-KS patients

Figure 1: Kaplan-Meier estimates of cumulative survival after KS diagnosis in Malawi, South Africa and Zambia, not including (A) and including (B) loss to follow-up as a failure event

Figure 2: Kaplan-Meier estimates of cumulative survival after Kaposi sarcoma (KS) diagnosis in Malawi, South Africa, and Zambia, including loss to follow-up as a failure

 

 

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