Immune Reconstitution Inflammatory Syndrome Associated With Kaposi's Sarcoma
http://www.100md.com
《临床肿瘤学》
the Departments of Oncology and HIV Medicine, Chelsea and Westminster Hospital, London, United Kingdom
ABSTRACT
PURPOSE: A 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.
PATIENTS AND METHODS: From our cohort of 5,832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposi's sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively.
RESULTS: After 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.
CONCLUSION: We have identified IRIS-KS in a cohort of HIV patients with KS who start HAART.
INTRODUCTION
The use of highly active antiretroviral therapy (HAART) in established market economies has resulted in a dramatic reduction in opportunistic infections, AIDS-defining illnesses, and mortality in patients with HIV infection.1-3 A number of studies have demonstrated that starting HAART in the setting of advanced HIV infection may be associated with the reactivation of indolent infections, particularly Mycobacterium tuberculosis, Mycobacterium avium complex, or Cryptococcus neoformans, in a process known as immune reconstitution inflammatory syndrome (IRIS). IRIS may be defined as a progressive deterioration in clinical status as a result of recovery of the immune system, leading to worsening infections despite improvements in surrogate markers of HIV.4-6 IRIS is thought to be the direct result of a reconstituted immune system recognizing pathogens or antigens that were previously present, but clinically asymptomatic. IRIS is associated with a wide range of clinical manifestations generally associated with the specific infection that reactivates.
We have previously described7 three patients treated for AIDS-related systemic non-Hodgkin's lymphoma who developed symptoms and signs consistent with relapsed lymphoma after starting HAART, which we ascribed to IRIS.
Kaposi's sarcoma (KS) remains the most common tumor in individuals infected with HIV and a significant cause of morbidity and mortality.8,9 KS and two rare lymphoproliferations (primary effusion lymphoma and Castleman's disease) is caused by a -herpesvirus, Kaposi's sarcoma–associated herpesvirus (KSHV, also known as Human Herpesvirus-8).10 IRIS is well recognized as a complication of infection with another herpesvirus, cytomegalovirus (CMV),11 whereas retinitis may occur in patients with normal CD4 cell counts,12,13 perhaps due to an immune response against latent CMV antigens.14 HAART decreases the incidence of KS,8 prolongs the time to treatment failure in KS,15,16 leads to resolution of individual lesions,17-20 and also decreases KSHV viral load.21 Thus a number of features of AIDS-associated KS suggest that it is a candidate disease for IRIS and we investigated this possibility in a cohort of HIV-infected individuals with KS. Our findings demonstrate that KS can reactivate during HAART-associated increases in the CD4 count and KS is an IRIS-associated disease. IRIS-KS was associated with a significantly higher CD4 count at the time of KS diagnosis.
PATIENTS AND METHODS
The Chelsea and Westminster HIV cohort (Chelsea and Westminister Hospital, London, United Kingdom) is one of the largest in Europe and we prospectively collect data on the individuals who seek care here. All HIV patients who were admitted to the Chelsea and Westminster since routine prospective data collection commenced in 1983 were identified. This study focused on those patients who were diagnosed for the first time with KS since the HAART era commenced, which we have defined as January 1, 1996, when HAART became routinely available at our institution and many others. We defined HAART in accordance with published guidelines as an antiretroviral therapy consisting of three or more antiretroviral medicines.22 This study identified those patients diagnosed with KS who were started on HAART without other therapy. We compared the characteristics of patients whose KS progressed after receiving HAART with patients whose KS did not progress.
Comparison of univariate variables between groups was by 2 test for nominal variables and Mann Whitney U-test for nonparametric variables. We did not perform multivariate analyses because statistics became unstable due to small numbers. Time to treatment failure was defined as the time from commencing HAART to the time when KS required chemotherapy and/or radiotherapy. The overall time to progression curve was plotted according to the method of Kaplan and Meier,23 and the log-rank method was used to test for the significance between the two progression distributions. We investigated the rate of change of CD4 counts, comparing those individuals with and without IRIS-associated KS. In this case, using all of the available results since the start of HAART, we used repeated measures of analysis of variance allowing for within and between patient variability.
Total lymphocyte and subset analysis was performed using whole blood stained with murine antihuman monoclonal antibodies to CD4 (T helper cells), CD8 (a cytotoxic T cell marker), CD19 (B cells), and CD16/56 (natural-killer cells; tetraONE, Beckman Coulter, High Wycombe, United Kingdom) and were evaluated on an Epics XL-MCL multiparametric four-color flow cytometer (Beckman Coulter). Appropriate institutional review board approval was obtained.
RESULTS
Between 1996 and 2004, a total of 5,832 HIV-1–positive patients were eligible for analysis, representing 34,133 patient-years of follow-up at our unit. From these 5,832 patients, 300 patients (5%) were diagnosed for the first time with KS, the majority (96%) of whom were men, reflective of the entire cohort. For 237 (79%) of these 300 patients, KS was their first AIDS-defining illness. Of the 300 patients diagnosed for the first time with KS, 242 patients (81%) are alive and on follow-up after a median of 3.1 years from their initial diagnosis of KS. These patients have a median of 6.7 years from diagnosis of HIV-1 infection.
At the time of diagnosis of KS, 61 patients (20%) had been prescribed HAART for at least 3 months, but only 38% of these patients had an undetectable HIV viral load. A total of 239 patients (of whom 229 were men) diagnosed with KS were HAART-naive, although 40 patients had received prior antiretroviral therapy with single or dual nucleoside reverse transcriptase inhibitor therapy, which does not constitute HAART. The median CD4 cell count at the time of KS diagnosis for these 40 patients was 110 cells/mm3 (interquartile range, 214 cells/mm3).
The initial treatment for 150 of 239 patients was HAART alone. The clinicopathologic characteristics of these patients is listed in Table 1; these patients are the denominators of this study. Importantly, ten of the 150 HAART-naive patients who started HAART alone as therapy for HIV infection with KS developed rapid clinical progression of KS within 2 months of starting HAART. All ten patients developed new KS lesions and progression of established lesions during the first 2 months following the start of HAART. It was documented that the rate of progression of KS accelerated during this time period, compared with the weeks and months before starting HAART.
We observed no differences in demographic or virologic parameters in patients who developed IRIS-KS, compared with patients who did not. A significantly higher CD4 count at KS diagnosis was observed in those patients who developed IRIS-KS (P = .028, examining CD4 count alone; P = .045 for KS immunologic stage24). The site of KS was not significant, although KS-associated edema was more likely to be observed in patients with IRIS-KS (P = .013). Specific classes of HAART were not associated with the development of IRIS-KS, although using both major HAART classes together, protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) in a single regimen, was found to be significant (P = .033).
Comparing the time to treatment failure for the IRIS-KS and KS groups, we observed no significant differences (Fig 1; log-rank P = .0735). Importantly, HAART was continued in patients with IRIS-KS, although five of 10 patients required chemotherapy and/or radiotherapy within 1 year.
Following the start of HAART, we followed immunologic parameters in terms of CD4 count (T helper), CD8 count (cytotoxic T cells), CD3 count (total T cells), CD16/56 count (natural-killer cells), CD19 count (B cells), and HIV viral load (data not shown). No significant conclusions could be drawn from these data; the median viral load was suppressed to less than 50 copies/mL in both groups, and the CD8, CD3, CD19, and CD16/56 counts were generally unchanged over a period of 1 year. The rate of increase of CD4 count relative to baseline in patients with IRIS-KS versus patients without IRIS-KS suggested that those patients without IRIS-KS demonstrated an increase in their CD4 counts over time, whereas there was no sustained improvement in CD4 counts in patients with IRIS-KS (Fig 2).
DISCUSSION
HAART improves immune function by suppressing HIV viral replication and increasing CD4 cell counts.2,25,26 In this article, we describe 10 cases of IRIS-KS. The only variables that were significantly associated with the development of IRIS among patients with KS after starting HAART, compared with a larger cohort of those patients who did not develop IRIS, were a higher CD4 cell count both when expressed as a continuous variable and when included as part of KS immune (I) staging24 and the presence of tumor-associated edema reflective of the inflammatory component of this disease. Commencing HAART with a regimen containing both a PI and NNRTI was also associated with the development of IRIS, perhaps related to the increased potency of the HAART regimen versus other single PI-based or NNRTI-based regimens. HAART was continued in both of the groups that we compared, although a trend toward more rapid treatment failure was observed in the small number of patients with IRIS-KS (Fig 1).
After commencing HAART, the recovery of CD4 counts observed normally in HIV-positive patients, for example in those patients without IRIS-KS (Fig 2), is thought to occur in two phases. The first phase (redistribution) is associated with an increase in circulating memory T-cells redistributing from lymphoid tissue, the gut in particular.27 The second phase (repopulation) occurs some months later and is characterized by the production of naive T-cells, resulting in an improvement of the immune repertoire.28,29 During early immune restoration, the ability to mount an inflammatory response to a variety of previously indolent antigens is restored,25 and it appears that such reactivation of immune response to indolent pathogens can result in clinical signs of active disease, known as IRIS.
The clinical manifestations depend on the particular antigen, however, the disease has an excellent prognosis with antimicrobial treatment.6 More than 100 cases of IRIS have been described in the literature,30-32 involving a wide range of pathogens including M tuberculosis, M avium, Cryptococcus neoformans, CMV, Pneumocystits carinii pneumonia, and viral hepatitis. IRIS has also been described as the reactivation of autoimmune diseases including Graves' disease and sarcoidosis.6,33-35 Treatment for this disorder includes continuation of primary therapy against the offending pathogen (presumably to decrease the antigenic load), continuation of effective HAART, and judicious use of anti-inflammatory agents, usually steroids. Although the clinical manifestations of IRIS are sometimes dramatic, and result in substantial morbidity, the fact that affected patients are capable of generating an inflammatory response allows many of them to ultimately discontinue secondary prophylaxis for the offending pathogen. Interestingly, unlike for the other IRIS-associated conditions, we successfully continued treatment without use of concomitant steroids.
In this article, we describe a series of 10 patients with IRIS-related progression of KS from a cohort of 150 antiretroviral-naive patients with KS who started HAART. Previously,36-38 three patients have been described in separate reports with similar findings suggestive of IRIS-associated KS. The major factors supporting these previous descriptions of IRIS-associated KS are the temporal relationship between rapid clinical progression of KS and the initiation of HAART, as we observed in our cohort. We also observed a temporal relationship and have identified factors that were significantly more likely to be observed associated with IRIS-KS, despite similar clinical outcomes (Fig 1).
This case series of IRIS-KS, the first of its kind, demonstrates that IRIS-KS occurs frequently in HAART-naive individuals with AIDS-related KS. Those with a higher CD4 count appear more susceptible but have a decreased subsequent rate of increase in their CD4 count. This is reflected by KS progression following the start of HAART.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Autran B, Carcelain G, Li TS, et al: Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277:112-116, 1997
Palella FJ Jr, Delaney KM, Moorman AC, et al: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection: HIV Outpatient Study Investigators. N Engl J Med 338:853-860, 1998
Portsmouth S, Stebbing J, Gazzard B: Current treatment of HIV infection. Curr Top Med Chem 3:1458-1466, 2003
Autran B, Carcelain G: AIDS. Boosting immunity to HIV: Can the virus help? Science 290:946-949, 2000
Autran B, Carcelain G, Debre P: Immune reconstitution after highly active anti-retroviral treatment of HIV infection. Adv Exp Med Biol 495:205-212, 2001
Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, et al: Immune reconstitution inflammatory syndrome: Emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore) 81:213-227, 2002
Powles T, Thirlwell C, Nelson M, et al: Immune reconstitution inflammatory syndrome mimicking relapse of AIDS related lymphoma in patients with HIV 1 infection. Leuk Lymphoma 44:1417-1419, 2003
Portsmouth S, Stebbing J, Gill J, et al: A comparison of regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi's sarcoma. AIDS 17:17-22, 2003
Stebbing J, Bower M, Srivastava P: Kaposi's sarcoma as a model for cancer immunotherapy. Trends Mol Med 10:187-193, 2004
Stebbing J, Portsmouth S, Bower M: Insights into the molecular biology and sero-epidemiology of Kaposi's sarcoma. Curr Opin Infect Dis 16:25-31, 2003
Jacobson NG, Szabo SJ, Guler ML, et al: Regulation of interleukin-12 signalling during T helper phenotype development. Adv Exp Med Biol 409:61-73, 1996
Whitcup SM, Fortin E, Nussenblatt RB, et al: Therapeutic effect of combination antiretroviral therapy on cytomegalovirus retinitis. JAMA 277:1519-1520, 1997
Whitcup SM: Cytomegalovirus retinitis in the era of highly active antiretroviral therapy. JAMA 283:653-657, 2000
Elkington R, Walker S, Crough T, et al: Ex vivo profiling of CD8+-T-cell responses to human cytomegalovirus reveals broad and multispecific reactivities in healthy virus carriers. J Virol 77:5226-5240, 2003
Bower M, Fox P, Fife K, et al: Highly active anti-retroviral therapy (HAART) prolongs time to treatment failure in Kaposi's sarcoma. AIDS 13:2105-2111, 1999
Stebbing J, Portsmouth S, Gazzard B: How does HAART lead to the resolution of Kaposi's sarcoma? J Antimicrob Chemother 51:1095-1098, 2003
Diz Dios P, Ocampo Hermida A, Miralles Alvarez C, et al: Regression of AIDS-related Kaposi's sarcoma following ritonavir therapy. Oral Oncol 34:236-238, 1998
Martinelli C, Zazzi M, Ambu S, et al: Complete regression of AIDS-related Kaposi's sarcoma-associated human herpesvirus-8 during therapy with indinavir. AIDS 12:1717-1719, 1998
Paparizos VA, Kyriakis KP, Papastamopoulos V, et al: Response of AIDS-associated Kaposi sarcoma to highly active antiretroviral therapy alone. J Acquir Immune Defic Syndr 30:257-258, 2002
Winceslaus J: Regression of AIDS-related pleural effusion with HAART: Highly active antiretroviral therapy. Int J STD AIDS 9:368-370, 1998
Quinlivan EB, Zhang C, Stewart PW, et al: Elevated virus loads of Kaposi's sarcoma-associated human herpesvirus 8 predict Kaposi's sarcoma disease progression, but elevated levels of human immunodeficiency virus type 1 do not. J Infect Dis 185:1736-1744, 2002
Yeni PG, Hammer SM, Hirsch MS, et al: Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel. JAMA 292:251-265, 2004
Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958
Krown SE, Testa MA, Huang J: AIDS-related Kaposi's sarcoma: Prospective validation of the AIDS Clinical Trials Group staging classification: AIDS Clinical Trials Group Oncology Committee. J Clin Oncol 15:3085-3092, 1997
Lederman M: Immune restoration and CD4+ T-cell function with antiretroviral therapies. AIDS 15:S11-S15, 2001 (suppl 2)
Douek DC, Picker LJ, Koup RA: T cell dynamics in HIV-1 infection. Annu Rev Immunol 21:265-304, 2003
Stebbing J, Gazzard B, Douek DC: Where does HIV live? N Engl J Med 350:1872-1880, 2004
Carcelain G, Debre P, Autran B: Reconstitution of CD4+ T lymphocytes in HIV-infected individuals following antiretroviral therapy. Curr Opin Immunol 13:483-488, 2001
Carcelain G, Tubiana R, Samri A, et al: Transient mobilization of human immunodeficiency virus (HIV)-specific CD4 T-helper cells fails to control virus rebounds during intermittent antiretroviral therapy in chronic HIV type 1 infection. J Virol 75:234-241, 2001
Watson J: Pneumocystis carinii: Where are we now? J HIV Ther 7:8-12, 2002
Robinson MR, Csaky KG, Lee SS, et al: Fibrovascular changes misdiagnosed as cytomegalovirus retinitis reactivation in a patient with immune recovery. Clin Infect Dis 38:139-141, 2004
Stebbing J, Atkins M, Nelson M, et al: Hepatitis B reactivation during combination chemotherapy for AIDS-related lymphoma is uncommon and does not adversely affect outcome. Blood 103:2431-2432, 2004
Narita M, Kellman M, Franchini DL, et al: Short-course rifamycin and pyrazinamide treatment for latent tuberculosis infection in patients with HIV infection: The 2-year experience of a comprehensive community-based program in Broward County, Florida. Chest 122:1292-1298, 2002
Cabie A, Abel S, Brebion A, et al: Mycobacterial lymphadenitis after initiation of highly active antiretroviral therapy. Eur J Clin Microbiol Infect Dis 17:812-813, 1998
Li SD, Yong S, Srinivas D, et al: Reactivation of sarcoidosis during interferon therapy. J Gastroenterol 37:50-54, 2002
Weir A, Wansbrough-Jones M: Mucosal Kaposi's sarcoma following protease inhibitor therapy in an HIV-infected patient. AIDS 11:1895-1896, 1997
Connick E, Kane MA, White IE, et al: Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma during potent antiretroviral therapy. Clin Infect Dis 39:1852-1855, 2004
Leidner R, Aboulafia D: Flare of AIDS-associated Kaposi's sarcoma (KS) following HAART: A manifestation of immune reconstitution syndrome. Presented at the 8th International Conference on Malignancies in AIDS and other immunodeficiencies, Bethesda, MD, April 29-30, 2004(M. Bower, M. Nelson, A.M.)
ABSTRACT
PURPOSE: A 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.
PATIENTS AND METHODS: From our cohort of 5,832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposi's sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively.
RESULTS: After 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.
CONCLUSION: We have identified IRIS-KS in a cohort of HIV patients with KS who start HAART.
INTRODUCTION
The use of highly active antiretroviral therapy (HAART) in established market economies has resulted in a dramatic reduction in opportunistic infections, AIDS-defining illnesses, and mortality in patients with HIV infection.1-3 A number of studies have demonstrated that starting HAART in the setting of advanced HIV infection may be associated with the reactivation of indolent infections, particularly Mycobacterium tuberculosis, Mycobacterium avium complex, or Cryptococcus neoformans, in a process known as immune reconstitution inflammatory syndrome (IRIS). IRIS may be defined as a progressive deterioration in clinical status as a result of recovery of the immune system, leading to worsening infections despite improvements in surrogate markers of HIV.4-6 IRIS is thought to be the direct result of a reconstituted immune system recognizing pathogens or antigens that were previously present, but clinically asymptomatic. IRIS is associated with a wide range of clinical manifestations generally associated with the specific infection that reactivates.
We have previously described7 three patients treated for AIDS-related systemic non-Hodgkin's lymphoma who developed symptoms and signs consistent with relapsed lymphoma after starting HAART, which we ascribed to IRIS.
Kaposi's sarcoma (KS) remains the most common tumor in individuals infected with HIV and a significant cause of morbidity and mortality.8,9 KS and two rare lymphoproliferations (primary effusion lymphoma and Castleman's disease) is caused by a -herpesvirus, Kaposi's sarcoma–associated herpesvirus (KSHV, also known as Human Herpesvirus-8).10 IRIS is well recognized as a complication of infection with another herpesvirus, cytomegalovirus (CMV),11 whereas retinitis may occur in patients with normal CD4 cell counts,12,13 perhaps due to an immune response against latent CMV antigens.14 HAART decreases the incidence of KS,8 prolongs the time to treatment failure in KS,15,16 leads to resolution of individual lesions,17-20 and also decreases KSHV viral load.21 Thus a number of features of AIDS-associated KS suggest that it is a candidate disease for IRIS and we investigated this possibility in a cohort of HIV-infected individuals with KS. Our findings demonstrate that KS can reactivate during HAART-associated increases in the CD4 count and KS is an IRIS-associated disease. IRIS-KS was associated with a significantly higher CD4 count at the time of KS diagnosis.
PATIENTS AND METHODS
The Chelsea and Westminster HIV cohort (Chelsea and Westminister Hospital, London, United Kingdom) is one of the largest in Europe and we prospectively collect data on the individuals who seek care here. All HIV patients who were admitted to the Chelsea and Westminster since routine prospective data collection commenced in 1983 were identified. This study focused on those patients who were diagnosed for the first time with KS since the HAART era commenced, which we have defined as January 1, 1996, when HAART became routinely available at our institution and many others. We defined HAART in accordance with published guidelines as an antiretroviral therapy consisting of three or more antiretroviral medicines.22 This study identified those patients diagnosed with KS who were started on HAART without other therapy. We compared the characteristics of patients whose KS progressed after receiving HAART with patients whose KS did not progress.
Comparison of univariate variables between groups was by 2 test for nominal variables and Mann Whitney U-test for nonparametric variables. We did not perform multivariate analyses because statistics became unstable due to small numbers. Time to treatment failure was defined as the time from commencing HAART to the time when KS required chemotherapy and/or radiotherapy. The overall time to progression curve was plotted according to the method of Kaplan and Meier,23 and the log-rank method was used to test for the significance between the two progression distributions. We investigated the rate of change of CD4 counts, comparing those individuals with and without IRIS-associated KS. In this case, using all of the available results since the start of HAART, we used repeated measures of analysis of variance allowing for within and between patient variability.
Total lymphocyte and subset analysis was performed using whole blood stained with murine antihuman monoclonal antibodies to CD4 (T helper cells), CD8 (a cytotoxic T cell marker), CD19 (B cells), and CD16/56 (natural-killer cells; tetraONE, Beckman Coulter, High Wycombe, United Kingdom) and were evaluated on an Epics XL-MCL multiparametric four-color flow cytometer (Beckman Coulter). Appropriate institutional review board approval was obtained.
RESULTS
Between 1996 and 2004, a total of 5,832 HIV-1–positive patients were eligible for analysis, representing 34,133 patient-years of follow-up at our unit. From these 5,832 patients, 300 patients (5%) were diagnosed for the first time with KS, the majority (96%) of whom were men, reflective of the entire cohort. For 237 (79%) of these 300 patients, KS was their first AIDS-defining illness. Of the 300 patients diagnosed for the first time with KS, 242 patients (81%) are alive and on follow-up after a median of 3.1 years from their initial diagnosis of KS. These patients have a median of 6.7 years from diagnosis of HIV-1 infection.
At the time of diagnosis of KS, 61 patients (20%) had been prescribed HAART for at least 3 months, but only 38% of these patients had an undetectable HIV viral load. A total of 239 patients (of whom 229 were men) diagnosed with KS were HAART-naive, although 40 patients had received prior antiretroviral therapy with single or dual nucleoside reverse transcriptase inhibitor therapy, which does not constitute HAART. The median CD4 cell count at the time of KS diagnosis for these 40 patients was 110 cells/mm3 (interquartile range, 214 cells/mm3).
The initial treatment for 150 of 239 patients was HAART alone. The clinicopathologic characteristics of these patients is listed in Table 1; these patients are the denominators of this study. Importantly, ten of the 150 HAART-naive patients who started HAART alone as therapy for HIV infection with KS developed rapid clinical progression of KS within 2 months of starting HAART. All ten patients developed new KS lesions and progression of established lesions during the first 2 months following the start of HAART. It was documented that the rate of progression of KS accelerated during this time period, compared with the weeks and months before starting HAART.
We observed no differences in demographic or virologic parameters in patients who developed IRIS-KS, compared with patients who did not. A significantly higher CD4 count at KS diagnosis was observed in those patients who developed IRIS-KS (P = .028, examining CD4 count alone; P = .045 for KS immunologic stage24). The site of KS was not significant, although KS-associated edema was more likely to be observed in patients with IRIS-KS (P = .013). Specific classes of HAART were not associated with the development of IRIS-KS, although using both major HAART classes together, protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) in a single regimen, was found to be significant (P = .033).
Comparing the time to treatment failure for the IRIS-KS and KS groups, we observed no significant differences (Fig 1; log-rank P = .0735). Importantly, HAART was continued in patients with IRIS-KS, although five of 10 patients required chemotherapy and/or radiotherapy within 1 year.
Following the start of HAART, we followed immunologic parameters in terms of CD4 count (T helper), CD8 count (cytotoxic T cells), CD3 count (total T cells), CD16/56 count (natural-killer cells), CD19 count (B cells), and HIV viral load (data not shown). No significant conclusions could be drawn from these data; the median viral load was suppressed to less than 50 copies/mL in both groups, and the CD8, CD3, CD19, and CD16/56 counts were generally unchanged over a period of 1 year. The rate of increase of CD4 count relative to baseline in patients with IRIS-KS versus patients without IRIS-KS suggested that those patients without IRIS-KS demonstrated an increase in their CD4 counts over time, whereas there was no sustained improvement in CD4 counts in patients with IRIS-KS (Fig 2).
DISCUSSION
HAART improves immune function by suppressing HIV viral replication and increasing CD4 cell counts.2,25,26 In this article, we describe 10 cases of IRIS-KS. The only variables that were significantly associated with the development of IRIS among patients with KS after starting HAART, compared with a larger cohort of those patients who did not develop IRIS, were a higher CD4 cell count both when expressed as a continuous variable and when included as part of KS immune (I) staging24 and the presence of tumor-associated edema reflective of the inflammatory component of this disease. Commencing HAART with a regimen containing both a PI and NNRTI was also associated with the development of IRIS, perhaps related to the increased potency of the HAART regimen versus other single PI-based or NNRTI-based regimens. HAART was continued in both of the groups that we compared, although a trend toward more rapid treatment failure was observed in the small number of patients with IRIS-KS (Fig 1).
After commencing HAART, the recovery of CD4 counts observed normally in HIV-positive patients, for example in those patients without IRIS-KS (Fig 2), is thought to occur in two phases. The first phase (redistribution) is associated with an increase in circulating memory T-cells redistributing from lymphoid tissue, the gut in particular.27 The second phase (repopulation) occurs some months later and is characterized by the production of naive T-cells, resulting in an improvement of the immune repertoire.28,29 During early immune restoration, the ability to mount an inflammatory response to a variety of previously indolent antigens is restored,25 and it appears that such reactivation of immune response to indolent pathogens can result in clinical signs of active disease, known as IRIS.
The clinical manifestations depend on the particular antigen, however, the disease has an excellent prognosis with antimicrobial treatment.6 More than 100 cases of IRIS have been described in the literature,30-32 involving a wide range of pathogens including M tuberculosis, M avium, Cryptococcus neoformans, CMV, Pneumocystits carinii pneumonia, and viral hepatitis. IRIS has also been described as the reactivation of autoimmune diseases including Graves' disease and sarcoidosis.6,33-35 Treatment for this disorder includes continuation of primary therapy against the offending pathogen (presumably to decrease the antigenic load), continuation of effective HAART, and judicious use of anti-inflammatory agents, usually steroids. Although the clinical manifestations of IRIS are sometimes dramatic, and result in substantial morbidity, the fact that affected patients are capable of generating an inflammatory response allows many of them to ultimately discontinue secondary prophylaxis for the offending pathogen. Interestingly, unlike for the other IRIS-associated conditions, we successfully continued treatment without use of concomitant steroids.
In this article, we describe a series of 10 patients with IRIS-related progression of KS from a cohort of 150 antiretroviral-naive patients with KS who started HAART. Previously,36-38 three patients have been described in separate reports with similar findings suggestive of IRIS-associated KS. The major factors supporting these previous descriptions of IRIS-associated KS are the temporal relationship between rapid clinical progression of KS and the initiation of HAART, as we observed in our cohort. We also observed a temporal relationship and have identified factors that were significantly more likely to be observed associated with IRIS-KS, despite similar clinical outcomes (Fig 1).
This case series of IRIS-KS, the first of its kind, demonstrates that IRIS-KS occurs frequently in HAART-naive individuals with AIDS-related KS. Those with a higher CD4 count appear more susceptible but have a decreased subsequent rate of increase in their CD4 count. This is reflected by KS progression following the start of HAART.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Autran B, Carcelain G, Li TS, et al: Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277:112-116, 1997
Palella FJ Jr, Delaney KM, Moorman AC, et al: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection: HIV Outpatient Study Investigators. N Engl J Med 338:853-860, 1998
Portsmouth S, Stebbing J, Gazzard B: Current treatment of HIV infection. Curr Top Med Chem 3:1458-1466, 2003
Autran B, Carcelain G: AIDS. Boosting immunity to HIV: Can the virus help? Science 290:946-949, 2000
Autran B, Carcelain G, Debre P: Immune reconstitution after highly active anti-retroviral treatment of HIV infection. Adv Exp Med Biol 495:205-212, 2001
Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, et al: Immune reconstitution inflammatory syndrome: Emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore) 81:213-227, 2002
Powles T, Thirlwell C, Nelson M, et al: Immune reconstitution inflammatory syndrome mimicking relapse of AIDS related lymphoma in patients with HIV 1 infection. Leuk Lymphoma 44:1417-1419, 2003
Portsmouth S, Stebbing J, Gill J, et al: A comparison of regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi's sarcoma. AIDS 17:17-22, 2003
Stebbing J, Bower M, Srivastava P: Kaposi's sarcoma as a model for cancer immunotherapy. Trends Mol Med 10:187-193, 2004
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