Tom Newsom-Davis

Immune Reconstitution Inflammatory Syndrome Associated With Kaposi's Sarcoma

PURPOSEnA proportion of patients with HIV infection who subsequently receive highly active antiretroviral therapy (HAART) exhibit a deterioration in their clinical status, despite control of virologic and immunologic parameters. This clinical response, known as the immune reconstitution inflammatory syndrome (IRIS), occurs secondary to an immune response against previously diagnosed pathogens.nnnPATIENTS AND METHODSnFrom our cohort of 5,832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposis sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively.nnnRESULTSnAfter commencing HAART, ten patients (6.6%) developed progressive KS, which we identify as IRIS-associated KS. In a comparison of these individuals with those whose KS did not progress, we found that IRIS-KS occurred in patients with higher CD4 counts (P = .03), KS-associated edema (P = .01), and therapy with both protease inhibitors and non-nucleosides together (P = .03). Time to treatment failure was similar for both groups, although the CD4 count declined more rapidly at first, in those patients with IRIS-associated KS. Despite this initial decline, in our clinical experience HAART could be successfully continued in those with IRIS-associated KS.nnnCONCLUSIONnWe have identified IRIS-KS in a cohort of HIV patients with KS who start HAART.

HIV-associated anal cancer: has highly active antiretroviral therapy reduced the incidence or improved the outcome?

Background: Highly active antiretroviral therapy (HAART) has reduced the incidence and improved the survival of patients with Kaposi sarcoma and AIDS-related non-Hodgkin lymphoma. We wished to evaluate its effects on incidence and survival in HIV-associated anal cancer. Methods: We measured the incidence and survival of patients with invasive anal cancer from our prospective cohort of 8640 HIV-seropositive individuals. Results: In our cohort of 8640 HIV-seropositive individuals, the incidence of invasive anal cancer (diagnosed in 26 patients) is 60 per 100,000 patient-years. This is 120 times higher than in the age- and gender-matched general population. The incidence of invasive anal cancer in the HIV cohort was 35 (95% confidence interval CI: 15-72) per 100,000 patient-years of follow-up in the pre-HAARTera (1984-1995) and 92 (95% CI: 52-149) per 100,000 patient-years of follow-up in the post-HAARTera (1996-2003) (P > 0.05). These figures are significantly higher than those for the general population (P < 0.001 for both) and give a relative risk of 67 and 176 in the pre- and post-HAART eras, respectively, compared with the general population. The 5-year overall survival is 47% (95% CI: 24%-70%), and the 5-year disease-free survival is 66% (95% CI: 45%-87%). There is no difference in overall survival between the pre- and post-HAART eras (log rank P = 0.19). Conclusions: Unlike other HIV-associated cancers, there has been no significant change in the incidence, clinical features, or overall survival since the introduction of HAART.

A Prognostic Index for Systemic AIDS-Related Non-Hodgkin Lymphoma Treated in the Era of Highly Active Antiretroviral Therapy

Context The International Prognostic Index (IPI) predicts survival in patients with lymphoma, but its applicability to AIDS-related lymphomas in the era of highly active antiretroviral therapy has not been evaluated. The IPI stratifies patients into risk groups on the basis of age, tumor stage, serum lactate dehydrogenase levels, performance status, and number of extranodal sites. Contribution Among 111 patients with AIDS-related lymphoma diagnosed since 1996, the IPI and CD4 cell count separated patients into 4 strata with 1-year survival rates of 82%, 47%, 20%, and 15%. Implications The IPI and CD4 cell count can help physicians predict the prognosis of patients with AIDS-related lymphoma. The Editors The lymphomas are a diverse group of malignant disorders that vary in their molecular features, genetics, clinical presentation, treatment, and outcome. Major advances in our understanding of the biology of these diseases have been made, leading to new therapies and classifications. Although combination chemotherapy cures intermediate- or high-grade aggressive non-Hodgkin lymphomas in many patients, approximately 50% of patients die of the disease (1). Because Ann Arbor disease staging does not predict outcome (2, 3), the International Prognostic Index was introduced in 1993 to segregate aggressive lymphomas in terms of survival (4). From 2031 patients studied, 4 risk groups were derived on the basis of age, tumor stage, serum lactate dehydrogenase level, performance status, and number of extranodal disease sites. As we enter the third decade of the AIDS epidemic, it is apparent that many cancers are more common in people infected with HIV. Non-Hodgkin lymphoma remains the second most common tumor in such patients (after Kaposi sarcoma), and the rate of death from systemic AIDS-related non-Hodgkin lymphoma remains high (5, 6). The median duration of survival reported with chemotherapy before the availability of highly active antiretroviral therapy (HAART) was 2 to 13 months (7). The outcome of AIDS-related non-Hodgkin lymphoma appears to have improved in the post-HAART era, and phase II studies describe median duration of survival of 15 to 34 months (8-15), an interval similar to that observed among all patients with advanced-stage, high-grade non-Hodgkin lymphoma. It is hypothesized that these improvements are associated with a change in prognostic factors. We sought to develop a new prognostic model for HIV-associated non-Hodgkin lymphoma in the era of HAART, a treatment that has been available in established market economies since 1996. Small prognostic studies of AIDS-related non-Hodgkin lymphoma in patients who presented in the pre-HAART era suggest that application of the International Prognostic Index may be useful in HIV-infected patients (16, 17). We therefore aimed to confirm the validity of the International Prognostic Index, to identify additional prognostic factors for patients with AIDS-related non-Hodgkin lymphoma in the era of HAART, and to devise a new prognostic model for these patients. Methods Patients The Chelsea and Westminster HIV cohort is one of the largest in Europe. Clinical information on 9621 HIV-1 seropositive patients has been accumulated since 1986. All patients in whom lymphoma was diagnosed were identified prospectively; these included 215 patients with AIDS-related non-Hodgkin lymphoma, 60 with primary central nervous system lymphomas, and 26 with Hodgkin disease. We estimated prognostic factors for AIDS-related non-Hodgkin lymphoma in the HAART era in patients receiving HAART. Patients with Hodgkin disease and primary central nervous system lymphomas were excluded. The HAART era is defined as commencing on 1 January 1996, when this treatment became routinely available at our institution and many others. One hundred eleven patients with AIDS-related non-Hodgkin lymphoma received a diagnosis after this date. Highly active antiretroviral therapy is defined as a combination of at least 3 antiretroviral agents, including a nucleoside analogue backbone combined with a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor or both classes of drug, according to generally accepted definitions (18). All patients had histologically confirmed diagnoses of AIDS-related non-Hodgkin lymphoma, and more than 95% had aggressive B-cell disease. All patients had full staging at diagnosis, including examination of bone marrow and cerebrospinal fluid. All patients received a single dose of intrathecal chemoprophylaxis with their staging lumbar puncture. Patients with Burkitt lymphoma or bone marrow, paranasal, or paraspinal involvement received a further 5 doses of intrathecal chemotherapy. Between 1996 and 1998, the patients with AIDS-related non-Hodgkin lymphoma diagnosed in the era of HAART received chemotherapy with bleomycin, etoposide, vincristine, methotrexate, prednisolone/cyclophosphamide, and doxorubicin (18 patients) or cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone (3 patients). A further 21 patients received chemotherapy with cisplatin, vinblastine, and bleomycin (17 patients); radiotherapy alone (3 patients); or best supportive care (1 patient). Since 1999, 59 patients have been treated with infused cyclophosphamide, doxorubicin, and etoposide chemotherapy (13, 19); 2 have received cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone; and 8 (including 3 in whom disease was diagnosed at autopsy) received best supportive care only. The CD4 cell subset analysis was performed by using whole blood stained with murine antihuman monoclonal antibodies to CD4 (TetraOne [Beckman Coulter, High Wycombe, United Kingdom]) on an Epics XL-MCL multiparametric flow cytometer (Beckman Coulter). Statistical Analysis Variables were compared between groups by using the chi-square test for nominal variables and the MannWhitney U test for nonparametric variables. Survival was calculated from the day of diagnosis of AIDS-related non-Hodgkin lymphoma until death or the date of last follow-up. Curves for overall duration of survival were plotted according to the method of Kaplan and Meier (20). The log-rank method was used to test for the significance of differences in survival distributions (21) and univariate Cox proportional hazards regression analysis was used to determine the prognostic significance of clinicopathologic variables at presentation with AIDS-related non-Hodgkin lymphoma. Cox multivariable modeling was used to determine independent variables predictive of survival by entering all variables that were significant in univariate analysis (at a level of P< 0.15). A prognostic model was then constructed from these data by dividing each coefficient in the final multivariable models with significant predictors by the lowest to 2 decimal places. Using these point values, a risk score was assigned to each patient by summing the values for each risk factor present. The prognostic score derived was then grouped into quartiles so that approximately equal numbers of patients were included in each of these categories. The chosen cutoff values for the prognostic risk scores were further investigated by using receiver-operating characteristic methods. Because the performance of prognostic models may be optimistically overestimated when they are determined on the basis of a small sample, a higher apparent performance than that observed in an independent sample of patients not considered in the modeling process may result (22, 23). To formally confirm the validity of the prognostic index based on a small sample, we used the internal empirical distribution function, placing equal probabilities on every original data value, as described elsewhere (24). Nonparametric bootstrapping was used to draw a sample by selecting independent bootstrap values (25-28). Each of these consisted of 111 data points drawn with replacement where each sample unit was replaced in the data set, such that they could be chosen subsequently in random selection. Resampled data were used to generate bootstrap estimates of the hazard ratio, based on the multivariable model presented for the HAART era. These were determined by 2000 iterations of such resampling. Results The overall duration of survival was significantly greater for patients in whom non-Hodgkin lymphoma was diagnosed in the HAART era compared with those in whom the disease was diagnosed in the pre-HAART era (log-rank chi-square, 9.23; P= 0.002) (Figure 1). Among the 215 patients with AIDS-related non-Hodgkin lymphoma, the actuarial overall survival rate, including all causes of death, was 32% at 2 years (95% CI, 25% to 39%) and 26% at 5 years (CI, 19% to 33%). Figure 1. KaplanMeier overall survival curve for 215 patients with systemic AIDS-related non-Hodgkin lymphoma ( NHL ) diagnosed in the era before (104 patients) and after (111 patients) highly active antiretroviral therapy ( HAART ). P Although patients whose disease was diagnosed in the HAART era had significantly higher CD4 cell counts at presentation (median value, 144 106 cells/L vs. 45 106 cells/L; P< 0.001), better Eastern Cooperative Oncology Group performance status (P= 0.003), and fewer previous AIDS-defining illnesses (P< 0.001) than did patients whose disease was diagnosed before the HAART era, the former patients were older (P< 0.001) and had a higher serum lactate dehydrogenase level (P< 0.001) (data not shown). Univariate Cox proportional hazards regression analysis identified many prognostic factors for survival after diagnosis of AIDS-related non-Hodgkin lymphoma in the HAART era, including low CD4 cell count, stage III or IV disease, B-class symptoms, lower Eastern Cooperative Oncology Group performance status, bone marrow and meningeal involvement, and more than 1 extranodal site at presentation (Table 1). Table 1. Clinicopathologic Characteristics of 111 Patients with AIDS-Related Non-Hodgkin Lymphoma Diagnosed in the Era of Highly Active Antiretroviral T

Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease

PURPOSEnTo describe clinical features, treatment outcomes and relapse rates in HIV-associated multicentric Castlemans disease (MCD) in a sizeable mature cohort.nnnMETHODSnFrom a prospective database, we identified 61 HIV-seropositive patients with histologically confirmed MCD (median follow-up, 4.2 years). Since 2003, 49 patients with newly diagnosed MCD have been treated with rituximab with (n = 14) or without (n = 35) etoposide.nnnRESULTSnAt MCD diagnosis, 55 (90%) of 61 patients met proposed clinical criteria defining an attack. Four patients (7%) had histologic evidence of coexisting lymphoma, and one developed lymphoma 2 years after treatment. The incidence of lymphoma is 28 per 1,000 patient years. With rituximab-based treatment, the overall survival was 94% (95% CI, 87% to 100%) at 2 years and was 90% (95% CI, 81% to 100%) at 5 years compared with 42% (95% CI, 14% to 70%) and 33% (95% CI, 6% to 60%) in 12 patients treated before introduction of rituximab (log-rank P < .001). Four of 49 rituximab-treated patients have died; three died as a result of MCD within 10 days of diagnosis, and one died as a result of lymphoma in remission of MCD. Eight of 46 patients who achieved clinical remission suffered symptomatic, histologically confirmed MCD relapse. The median time to relapse was 2 years, and all have been successfully re-treated and are alive in remission. The 2- and 5-year progression-free survival rates for all 49 patients treated with rituximab-based therapy were 85% (95% CI, 74% to 95%) and 61% (95% CI, 40% to 82%), respectively.nnnCONCLUSIONnHIV-associated MCD is a remitting-relapsing disease. The outlook has improved dramatically in recent years with the introduction of rituximab-based therapy and yields high overall survival rates.

The effect of HAART in 254 consecutive patients with AIDS-related Kaposi's sarcoma.

Objective:A prospective cohort study was performed to evaluate the clinical outcomes of patients with histologically confirmed AIDS-related Kaposis sarcoma diagnosed since the introduction of HAART. Methods:Two hundred and fifty-four consecutive patients (96% men) diagnosed with Kaposis 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 Kaposis sarcoma diagnosis was 39 years and average duration of known HIV seropositivity was 4 years. At Kaposis 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 Kaposis sarcoma diagnosis and 122 (48%) had AIDS clinical Trial Group stage I1 disease (CD4 cell count < 150 cells/μl). Nodular grade Kaposis 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 Kaposis sarcoma; only one died of Kaposis 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–Kaposis 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 Kaposis sarcoma.

Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK.

Objectives:To assess the incidence, predictors, and outcomes of Kaposi sarcoma-associated paradoxical immune reconstitution inflammatory syndrome (KS-IRIS) in antiretroviral therapy (ART)-naive HIV-infected patients with Kaposi sarcoma initiating ART in both well resourced and limited-resourced settings. Design:Pooled analysis of three prospective cohorts of ART-naive HIV-infected patients with Kaposi sarcoma from sub-Saharan Africa (SSA) and one from the UK. Methods:KS-IRIS case definition was standardized across sites. Cox regression and Kaplan–Meier survival analysis were used to identify the incidence and predictors of KS-IRIS and Kaposi sarcoma-associated mortality. Results:Fifty-eight of 417 (13.9%) eligible individuals experienced KS-IRIS with an incidence 2.5 times higher in the African vs. European cohorts (Pu200a=u200a0.001). ART alone as initial Kaposi sarcoma treatment (hazard ratio 2.97, 95% confidence interval (CI) 1.02–8.69); T1 Kaposi sarcoma stage (hazard ratio 2.96, 95% CI 1.26–6.94); and plasma HIV-1 RNA more than 5 log10u200acopies/ml (hazard ratio 2.14, 95% CI 1.25–3.67) independently predicted KS-IRIS at baseline. Detectable plasma Kaposi sarcoma-associated herpes virus (KSHV) DNA additionally predicted KS-IRIS among the 259 patients with KSHV DNA assessed (hazard ratio 2.98, 95% CI 1.23–7.19). Nineteen KS-IRIS patients died, all in SSA. Kaposi sarcoma mortality was 3.3-fold higher in Africa, and was predicted by KS-IRIS (hazard ratio 19.24, CI 7.62–48.58), lack of chemotherapy (hazard ratio 2.35, 95% CI 1.09–5.05), pre-ART CD4 cell count less than 200u200acells/&mgr;l (hazard ratio 2.04, 95% CI 0.99–4.2), and detectable baseline KSHV DNA (hazard ratio 2.12, 95% CI 0.94–4.77). Conclusion:KS-IRIS incidence and mortality are higher in SSA than in the UK. This is largely explained by the more advanced Kaposi sarcoma disease and lower chemotherapy availability. KS-IRIS is a major contributor to Kaposi sarcoma-associated mortality in Africa. Our results support the need to increase awareness on KS-IRIS, encourage earlier presentation, referral and diagnosis of Kaposi sarcoma, and advocate on access to systemic chemotherapy in Africa.

Plasma HHV8 DNA predicts relapse in individuals with HIV-associated multicentric Castleman disease.

HIV-associated multicentric Castleman disease (HIV-MCD) is a rare lymphoproliferative disorder caused by infection with human herpesvirus-8. The disease follows a relapsing and remitting clinical course, with marked systemic symptoms during an active attack, which can prove fatal. Its incidence is rising, and new data indicate the utility of the anti-CD20 monoclonal antibody rituximab at inducing remissions in both first- and second-line settings, although biomarkers associated with relapse have not been previously identified. In 52 individuals with a histologic diagnosis of HIV-MCD, we performed univariate and multivariate analyses to predict factors associated with an HIV-MCD attack. Although a younger age (< 50 years) was associated with an attack, the strongest association was observed with plasma levels of human herpesvirus-8 DNA. Rising levels predicted an attack (hazard ratio = 2.9; 95% confidence interval, 1.3-6.7), and maintenance therapy with rituximab should be considered in these individuals.

Resolution of AIDS-related Castleman's disease with anti-CD20 monoclonal antibodies is associated with declining IL-6 and TNF-α levels

A 32-year-old HIV-1 positive man was diagnosed with Castlemans disease following a long history of constitutional symptoms. Primary therapy with single agent rituximab was associated with a near complete response. During this time, his KSHV (Kaposis sarcoma-associated herpesvirus) viral load decreased and we also observed immediate, large and sustained decreases in interleukin-6 (IL-6) and tumor necrosis factor-alpha levels (TNF-alpha). This highlights the close association between circulating cytokines such as IL-6 and virally-induced malignancy.

Pulmonary Kaposi sarcoma in the era of highly active antiretroviral therapy.

Since the introduction of highly active antiretroviral therapy (HAART) there has been a dramatic reduction in the incidence of Kaposi sarcoma (KS) and an improvement in survival. We wished to examine whether the outcome in pulmonary KS (pKS) has also altered.

Nadir B cell counts are significantly correlated with the risk of Kaposi's sarcoma

Infection with HIV‐1 is known to impair B cell function. To further elucidate the role of B cells during infection and tumorigenesis, we studied their numbers in cases of AIDS‐related Kaposis sarcoma (KS) during the HAART era. Patients with AIDS‐related KS were identified from a database of 4,480 HIV‐1 positive individuals and the incidence of KS and rate ratio was stratified according to nadir number of B cells, measured as the CD19 count. In an unadjusted model, we observed that lower B cell counts were associated with a statistically significant increased risk of KS development (p < 0.001). We also observed a trend toward increased counts during KS resolution. When adjusted for nadir CD4 count in a multi‐variable model, higher B cell counts were protective against KS development (p = 0.015). These data highlight a potential role for B cells and therefore the humoral immune system in KS aetiopathogenesis.