The effect of HAART in 254 consecutive patients with AIDS-related Kaposi's sarcoma
Bower, Marka; Weir, Justinb; Francis, Nicholasb; Newsom-Davis, Toma; Powles, Sama; Crook, Tima; Boffito, Martac; Gazzard, Brianc; Nelson, Markc
aDepartment of Oncology, UK
bDepartment of Histopathology, UK
cDepartment of HIV Medicine, Chelsea and Westminster Hospital, London, UK.
Received 30 January, 2009
Revised 7 April, 2009
Accepted 17 April, 2009
Correspondence to Professor Mark Bower, PhD, FRCP, Department of Oncology, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Tel: +44 208 237 5054; fax: +44 208 746 8863; e-mail: firstname.lastname@example.org
Objective: A prospective cohort study was performed to evaluate the clinical outcomes of patients with histologically confirmed AIDS-related Kaposi's sarcoma diagnosed since the introduction of HAART.
Methods: Two hundred and fifty-four consecutive patients (96% men) diagnosed with Kaposi's sarcoma between 1996 and 2008 are included. Clinicopathological and treatment details were prospectively collected. The median follow-up is over 4 years and maximum 12 years.
Results: The mean age at Kaposi's sarcoma diagnosis was 39 years and average duration of known HIV seropositivity was 4 years. At Kaposi's sarcoma diagnosis, only 19% patients were on HAART and only 7% patients had an undetectable plasma HIV viral load. Seventy-nine (31%) patients had AIDS clinical Trial Group stage T1 disease at Kaposi's sarcoma diagnosis and 122 (48%) had AIDS clinical Trial Group stage I1 disease (CD4 cell count < 150 cells/μl). Nodular grade Kaposi's sarcoma represented 28% of the tumours and was significantly associated with black African ethnicity and AIDS clinical Trial Group T1 stage disease. The overall 5-year survival is 89% (95% confidence interval 84–93). One hundred and sixty-three patients were treated with HAART alone for T0 stage Kaposi's sarcoma; only one died of Kaposi's sarcoma and only 37 (22%) required chemotherapy, giving a systemic treatment-free survival at 5 years of 74% (95% confidence interval 67–82) and the overall survival at 5 years is 91% (95% confidence interval 87–95).
Conclusion: The high success rate of HAART in a large cohort of AIDS–Kaposi's sarcoma patients over a prolonged period of follow-up will reassure patients and clinicians that this is a well tolerated and effective approach to stage T0 Kaposi's sarcoma.
Along with Pneumocystis carinii pneumonia (now renamed Pneumocystis jirovecii), Kaposi's sarcoma heralded the onset of the HIV epidemic [1,2]. Recognized as an AIDS-defining illness for over two decades , Kaposi's sarcoma has always been the most common HIV-associated malignancy and remains an important cause of morbidity and mortality [4,5]. The incidence of Kaposi's sarcoma has declined significantly in HIV-positive populations with access to HAART [6–9]. Moreover, it has been demonstrated that HAART confers protection against Kaposi's sarcoma , increases the time to disease progression in Kaposi's sarcoma , improves prognosis and prolongs survival [5,12,13]. Conversely in the same cohort, HAART appears not to have reduced the incidence of multicentric Castleman's disease, which like Kaposi's sarcoma is associated with human herpesvirus 8 (HHV8) infection .
Numerous case reports and small clinical series have documented the response of Kaposi's sarcoma to HAART alone [15–17], although patients with advanced Kaposi's sarcoma are generally treated with chemotherapy in addition to HAART [18–20]. Indeed, the recently published British HIV Association (BHIVA) guidelines on the management of HIV-associated Kaposi's sarcoma suggest that patients with T1 stage disease [visceral, ulcerating, oedematous or oral disease, according to the AIDS Clinical Trials Group (ACTG) staging classification [21,22], see Table 1] should be treated with liposomal anthracyclines in addition to HAART . Nevertheless, the clinical outcomes for patients with Kaposi's sarcoma diagnosed in the modern era of antiretroviral therapy are largely undescribed. We report the clinical course in 254 consecutive HIV-seropositive patients diagnosed with histologically proven Kaposi's sarcoma since 1996, when HAART became established as routine clinical care in our institution.
The Chelsea and Westminster HIV cohort is one of the largest single-centre cohorts in Europe, and we prospectively collect routine data on individuals who attend. HIV-positive patients are seen at regular intervals for clinical assessment, trial follow-up and immunologic assessments. This study focuses on a cohort of individuals who have been diagnosed for the first time with biopsy-proven Kaposi's sarcoma since the HAART era commenced, which we have defined as 1 January 1996 when HAART became routinely available at our institution and many others.
Comparison of variables between groups was done by χ2 test for nominal variables and by Kruskal–Wallis test for nonparametric continuous variables; all P values presented are two sided. Overall survival (OS) was calculated from the day of Kaposi's sarcoma diagnosis until death or the date of last follow-up. OS duration curves were plotted according to the method of Kaplan and Meier . The log rank method was used to test the significance of differences in survival distributions . For Kaposi's sarcoma patients treated with HAART alone, disease-free survival was plotted using the same methods with disease-free survival being calculated as time from Kaposi's sarcoma diagnosis to date of first additional systemic treatment for Kaposi's sarcoma or date of last follow-up.
We identified 254 consecutive patients with biopsy-proven Kaposi's sarcoma diagnosed since 1996. Ten (4%) were women and the median age at Kaposi's sarcoma diagnosis was 38.6 years (range 16–71 years). Thirty-eight (15%) were of black African ethnicity, and 30 (12%) had an AIDS-defining illness prior to diagnosis of Kaposi's sarcoma. The median interval between known HIV diagnosis and Kaposi's sarcoma diagnosis was 4.3 years (range 0–20 years). At the time of Kaposi's sarcoma diagnosis, the median CD4 cell count was 185 cells/μl (range 1–971 cells), and 122 patients (48%) had ACTG stage I1 disease (CD4 cell count < 150 cells/μl) at Kaposi's sarcoma diagnosis. Plasma HIV viral load measurement was introduced into routine clinical practice in 1999 and values are available at the time of Kaposi's sarcoma diagnosis for 214 patients. The median plasma HIV-1 viral load was 74 644 copies/ml (range 0–>500 000 copies) and 18 out of 214 patients (8%) had undetectable HIV viral load at time of Kaposi's sarcoma diagnosis, including 12 patients who had CD4 cell counts above 300 cells/μl. Forty-eight patients (19%) were receiving HAART for at least 3 months at the time of Kaposi's sarcoma diagnosis. However, only 18 of these 48 patients had an undetectable plasma HIV viral load at the time of Kaposi's sarcoma diagnosis.
Seventy-nine patients (31%) had ACTG stage T1 disease at Kaposi's sarcoma diagnosis, including 31 (12%) with extensive oral disease, 33 (13%) with tumour-associated oedema, 24 (9%) with pulmonary Kaposi's sarcoma and 15 (6%) with gastrointestinal Kaposi's sarcoma. All 254 patients had histological confirmation of the diagnosis and the biopsies were reviewed by two pathologists (J.W. and N.F.) and graded into patch, plaque and nodular histological types. Sixty-six patients (26%) had patch grade Kaposi's sarcoma, 118 (46%) had plaque grade Kaposi's sarcoma and 70 (28%) had nodular grade Kaposi's sarcoma. Nodular grade Kaposi's sarcoma was associated with black African ethnicity, extensive oral and gastrointestinal disease and T1 stage (see Table 2).
Among the 175 patients with T0 disease, 158 were treated with HAART alone, 10 with HAART and local radiotherapy for cosmetically significant lesions, five patients with HAART and systemic chemotherapy and two with surgical excision alone. The five patients treated with HAART and systemic chemotherapy for T0 disease included three who received chemotherapy for simultaneously diagnosed non-Hodgkin lymphoma or multicentric Castleman's disease, one patient treated in early 1996 and one patient who was treated with chemotherapy for rapidly progressing facial Kaposi's sarcoma diagnosed when he had been on HAART for 17 months and had an undetectable HIV viral load but a CD4 cell count of 128 cells/μl. The two patients, treated with complete surgical excision only of single cutaneous stage T0I0S0 Kaposi's sarcoma lesions, declined starting HAART. At the time of Kaposi's sarcoma diagnoses, their CD4 cell counts were 431 and 339 cells/μl and HIV plasma loads 14 449 and 28 974 copies/ml, respectively. They remain free from Kaposi's sarcoma 2.5 and 6.5 years later.
The median follow-up for the entire cohort of 254 patients is 4.1 years (maximum 12.9 years), and 32 patients have died. The causes of death include Kaposi's sarcoma (12), other malignancies (nine), opportunistic infections (eight), chronic pancreatitis (one), ischaemic heart disease (one) and unknown (one). The actuarial OS at 5 years is 89% [95% confidence interval (CI) 84–93] and at 10 years is 81% (95% CI 74–89) (see Fig. 1). Patients with T1 stage Kaposi's sarcoma had a significantly worse OS (log rank P = 0.0011), as did patients with I1 stage Kaposi's sarcoma (log rank P = 0.0010).
The initial treatment for 163 patients was HAART alone, for 73 patients was HAART and systemic liposomal anthracycline chemotherapy and for 15 patients was HAART and radiotherapy. Two patients had complete surgical excision only of single cutaneous stage T0I0S0 Kaposi's sarcoma lesions and declined starting HAART. One patient with advance disseminated pulmonary stage T1I1S1 Kaposi's sarcoma and concurrent pulmonary tuberculosis was treated with palliative care alone in accordance with his wishes.
One hundred and sixty-three patients were treated with HAART alone as initial therapy for Kaposi's sarcoma of whom 80% were antiretroviral naive. Thirty-two of these 163 patients were on HAART at the time of Kaposi's sarcoma diagnosis but only 11 had undetectable plasma HIV viral loads at the time of Kaposi's sarcoma diagnosis. Overall 37 out of 163 patients (22%) subsequently failed requiring systemic therapy for Kaposi's sarcoma. Approximately, two-third of these 37 patients failed to respond to HAART alone that occurred within the first year of starting HAART. The actuarial systemic treatment-free survival at 5 years is 74% (95% CI 67–82) and at 10 years is 73% (95% CI 64–81) (see Fig. 2). The initial classes of HAART therapy were nonnucleoside reverse transcriptase inhibitor (NNRTI) based for 100 patients (61%), protease inhibitor based for 56 patients (34%), triple nucleosides based for five patients (3%) and both protease inhibitor and NNRTI based for two patients (1%). There was no difference in Kaposi's sarcoma-free survival between the classes of HAART (log rank P = 0.22) or between those treated with or without a protease inhibitor (log rank P = 0.097) (see Fig. 3). The histological grades of these 163 patients were plaque grade for 77 (47%), patch grade for 53 (33%) and nodular grade for 33 (20%). There was no difference in Kaposi's sarcoma-free survival between the tumour grades (log rank P = 0.73). The ACTG I stages of these patients were I0 for 87 (53%) and I1 for 76 (47%). There was no difference in Kaposi's sarcoma-free survival between patients with stage I0 and stage I1 Kaposi's sarcoma (log rank P = 0.39). Similarly, there was no difference in Kaposi's sarcoma-free survival between patients using the higher CD4 cell count cutoff of 300 cells/μl (log rank P = 0.71). Finally, ethnicity also had no influence on Kaposi's sarcoma-free survival, comparing patients of black African origin with other ethnicities (log rank P = 0.12).
This large single-institution cohort included 254 patients with histologically confirmed Kaposi's sarcoma who have been treated in a uniform fashion and followed up for a median of over 4 years and a maximum of 12 years. Many studies [7,26–29] have reported the declining incidence of Kaposi's sarcoma in the era of HAART amongst cohorts of patients with access to these medicines. In this study, 81% of patients were not receiving HAART at the time Kaposi's sarcoma was diagnosed and nearly two-thirds (30/48) of the patients who were on HAART at the time of Kaposi's sarcoma diagnosis had detectable HIV viral load, suggesting failure of HAART due to drug resistance or adherence problems. In all, only 18 patients (7% of the cohort) were diagnosed with Kaposi's sarcoma while on a fully suppressive HAART regimen. These 18 patients were generally older (mean age 43 years, range 25–66 years) and had a higher CD4 cell count at Kaposi's sarcoma diagnosis (median 277 cells/μl, range 49–732 cells). These patients had been HIV positive for a mean of 7.7 years and on HAART for a mean of 31 months when the Kaposi's sarcoma was diagnosed. Similar patients on HAART with undetectable HIV viraemia and high CD4 cell counts who developed Kaposi's sarcoma have been described [30–32], and indeed one group of authors has suggested that these patients represent a new disease process, although this is highly controversial .
The histological classification of these biopsy-confirmed Kaposi's sarcoma lesions fell into the three most commonly recognized groups, reflecting the progression from patch to plaque and finally nodular grades [34,35]. Nodular grade Kaposi's sarcoma represented 28% of the Kaposi's sarcoma diagnosed and this grade of histology was significantly associated with black African ethnicity and ACTG T1 stage disease. In particular, nodular histology was significantly associated with extensive oral and gastrointestinal involvement. These findings would support the hypothesis that nodular grade histology represents a more aggressive disorder. In contrast, nodular grade Kaposi's sarcoma was not associated with more advanced immunodeficiency as there were no significant differences in CD4 cell counts or plasma HIV viral load, nor in the proportion of patients on HAART at the time of their Kaposi's sarcoma diagnosis. The OS from Kaposi's sarcoma diagnosis was inferior (log rank P = 0.026) for patients with nodular grade histology (5-year survival rate 79%, 95% CI 68–90) compared with patch grade (5-year survival rate 91%, 95% CI 84–98) or plaque grade (5-year survival rate 92%, 95% CI 86–98). However, the majority of this difference is attributable to the greater proportion of patients with T1 stage disease amongst those with nodular grade histology. The treatment-free survival for patients with T0 disease treated with HAART alone in contrast reveals no significant difference in outcomes by histological grading (log rank P = 0.73). These findings suggest that the histological grading of the Kaposi's sarcoma has far less influence on outcome than the staging of the disease and that histological grading should not influence treatment strategies.
Previously, small series [36–40] have attempted to report the Kaposi's sarcoma resolution rates in patients treated with HAART, all with chemotherapy in selected patients. The reported response rates are 44–77%, but it is often uncertain whether these responses are attributable to chemotherapy or HAART, and the results may be influenced by the duration of follow-up and how thorough a clinical examination is undertaken at each visit in patients in routine clinical practice rather than a clinical trial. We studied a subgroup of 163 patients who were treated with HAART only for Kaposi's sarcoma and show that after 5 years only a quarter of the patients have required systemic anti-Kaposi's sarcoma therapy. We have deliberately not included localized treatment with either radiotherapy or intralesional chemotherapy in this analysis because these essentially cosmetic treatments tend to be offered in our clinical practice to patients on the basis of the visibility of the lesions rather than the extent or severity. Nonetheless, it is striking that so few of the patients who were treated with HAART alone required further therapy for Kaposi's sarcoma over a prolonged period of follow-up.
The protease inhibitor class of antiretrovirals have been shown to possess antiangiogenic and antiproliferative properties in-vitro and in experimental animal models , leading many clinicians to advocate their use in HIV-associated Kaposi's sarcoma. However, the incidence of Kaposi's sarcoma was significantly lower in HIV-seropositive patients receiving an NNRTI-based regimen than those receiving a protease inhibitor-based regimen in a cohort of 8640 . Moreover, NNRTI-based HAART is as effective as protease inhibitor-based HAART in prolonging time to treatment failure in Kaposi's sarcoma , and in a small cohort of naive patients, protease inhibitor-based regimens were as likely to induce remission of Kaposi's sarcoma as protease inhibitor-sparing regimens . This study again confirms the efficacy of protease inhibitor-sparing regimens and also supports the view that the effects of HAART are mediated by immune restoration rather than a direct antiangiogenic or antitumour effect of the antiretrovirals.
This large cohort confirms the previous reports of an improved survival following a diagnosis of Kaposi's sarcoma in the era of HAART [12,13,36,44]. The actuarial 5-year OS in this cohort of 254 patients is 89% and it is striking that the deaths of only 12 patients were attributed to Kaposi's sarcoma, whereas nine patients died of other malignancies. Amongst the 163 patients who were treated with HAART alone for their Kaposi's sarcoma, the 5-year OS is 91% (95% CI 87–95) and in this group only a single death was attributed to Kaposi's sarcoma. The high success rate of HAART in a large cohort of antiretroviral-naive patients over a prolonged period of follow-up will reassure patients and clinicians that this is a well tolerated and effective approach to stage T0 Kaposi's sarcoma and supports published guidelines.
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