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Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3408-3414 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.4072 Differential Impact of Combination Antiretroviral Therapy in Preventing Kaposi's Sarcoma With and Without Visceral Involvement
From the Service de Biostatistique et Informatique Médicale, Hôpital Cochin, Université René Descartes; Institut National de la Santé Et de la Recherche Médical, Unité Mixte de Recherche 720, Université Pierre et Marie Curie, Paris; Service de Médecine interne, Hôpital de Brive-la-Gaillarde, Brive-la-Gaillarde; Service de Médecine interne, Carémeau University Hospital, Nîmes; Service de Dermatologie, Hôpital de Fréjus, Fréjus; and the Service de Médecine Interne-Cancérologie, Hôpital l'Archet, Nice, France Address reprint requests to Sophie Grabar, MD, PhD, Hôpital Cochin, Service de Biostatistique et Informatique Médicale, 27 Rue du Fg St Jacques, 75 679 Paris CEDEX 14, France; e-mail: sophie.grabar{at}univ-paris5.fr
PURPOSE: To study the impact of different potent combined antiretroviral treatment (cART) on the incidence of HIV-associated Kaposi's sarcoma (KS) with and without visceral involvement. PATIENTS AND METHODS: Patients were selected from the French Hospital Database on HIV, a large hospital cohort. The risk of KS was estimated by using Cox proportional hazards models adjusting for age, the CD4 cell nadir, the HIV exposure category, prior AIDS, cART, and the type of cART regimen. cART regimens were distinguished according to whether they contained protease inhibitor (PI), non-nucleoside analog (NNRTI), both, or only nucleoside analog (NRTI). Separate analyzes were conducted according to the initial visceral involvement of KS. RESULTS: Among the 54,999 patients included in this study (182,756 person-years of follow-up), 1,634 patients were diagnosed with KS during follow-up, of whom 421 had visceral involvement at diagnosis. The KS incidence rate fell from 32 per 1,000 person-years in 1993 to 1994 to 3 per 1,000 person-years after 1999. PI-containing and NNRTI-containing cART regimens were associated with similar reductions in the risk of KS (hazard ratio, 0.68; 95%CI, 0.61 to 0.75; HR, 0.62; 95% CI, 0.54 to 0.71, respectively). The risk of visceral KS fell more strongly than the risk of cutaneous KS (> 50% and < 30%, respectively). CONCLUSION: The incidence of KS, and especially visceral KS, has fallen sharply since the advent of cART. This effect is likely due to immune restoration rather than to a specific effect on the tumoral process, as PI-containing and NNRTI-containing regimens had similar preventive efficacy.
Kaposi's sarcoma (KS) is one of the most common opportunistic diseases associated with HIV infection, and remains the most frequent malignancy in this setting.1-3 Human herpes virus 8 (HHV-8) is now recognized as the causative agent.4,5 The main risk factors for KS are profound immunodeficiency and acquisition of HIV infection through male homosexual intercourse.6 The morbidity and mortality associated with HIV infection have fallen markedly in industrialized countries since the advent of potent antiretroviral drug combinations. The incidence of KS started to decline before the introduction of combination antiretroviral therapy (cART)7,8 and thereafter.1,8-11 Among all the AIDS conditions that declined with the introduction of cART, the reduction of KS incidence was found to be more profound.9,12 This decline has been widely attributed to immune reconstitution after cART, but there is some evidence that protease inhibitors (PI) might have specific anti-KS activity on the tumoral process independently to the immune response suggesting that a PI-containing regimen might thus be more effective than other cART regimens in preventing KS.13,14 The preventive efficacy of various cART regimens on KS was the focus of one previous study,15 however, no study has documented the impact of cART according to the initial visceral involvement as it requires large numbers of patients with KS that has now became rare. It is therefore unclear whether the decline of KS incidence equally concerns KS with and without visceral involvement. Here, we analyzed a large hospital cohort of HIV-infected patients in order to assess the impact of the type of cART regimen on the incidence of KS according to the initial visceral involvement. Impacts of regimens based on nucleoside reverse transcriptase inhibitor (NRTI), non-NRTI (NNRTI) and PI on the development of KS were evaluated.
Patients Patients were selected from the French Hospital Database on HIV (FHDH), a nationwide hospital-based cohort described in detail elsewhere.16 In brief, this epidemiological network was created in 1989, and 68 participating hospitals across France currently provide data on HIV-infected patients. FHDH inclusion criteria are HIV-1 or HIV-2 infection and written informed consent. Trained research assistants prospectively collect clinical, biologic, and therapeutic data from medical records by using specialized software (DMI2 v16.1; Dossier Médical Informatisé; developed and owned by the French Ministry of Health). A follow-up form is completed at least every 6 months or at each visit or hospital admission during which a new clinical manifestation is diagnosed, a new treatment prescribed, or a change in biologic marker is noted. In each center, diagnoses are validated by an HIV-expert physician. For this analysis, we considered all adult patients who were enrolled in the database between January 1, 1993 and March 31, 2003, and selected those who had had at least two follow-up visits and one CD4 cell count, in whom KS had not been diagnosed before enrollment in the database, and who had not participated in a double-blind clinical trial.
Statistical Analysis The incidence of KS per 1,000 person-years was calculated for four calendar periods according to antiretroviral drug availability in France, as follows: 1993 to 1994 (period 1, mainly NRTI monotherapy), 1995 to March 1996 (period 2, mainly dual-NRTI therapy), April 1996 to December 1998 (period 3, mainly PI-containing regimens), and January 1999 to March 2003 (period 4, multiple cART regimens, mostly containing PI and/or NNRTI). Factors associated with occurrence of KS were analyzed by using Cox proportional-hazards models. We used the following right-censoring strategy to take into account the time lag before clinical events were recorded in the database: patients free of events during the 6 months before the last database update (ie, between October and March 2003) were censored on April 1, 2003; and patients who did not attend a follow-up visit during this 6-month period were considered lost to follow-up and were censored at the date of their last visit.
Multivariate models were adjusted for age, the nadir CD4 cell count ( Sensitivity analyses were run by restricting the study population to homosexual men. Separate analyses were conducted according to the initial KS location. KS without visceral involvement (skin, soft tissues, palate, lymph nodes) and KS with visceral involvement (mostly lung, gastrointestinal tract, or multiple organs) were considered as separate end points. The initial KS location was not specified in the database for 112 of 1,634 incidents of KS identified in this study. These incidents of KS were considered as nonvisceral, as the median CD4 cell count at KS diagnosis did not differ from that of patients with documented nonvisceral KS (63 per mm3 v 58 per mm3, respectively; P = .43) and was significantly higher than that of patients with documented visceral KS (37 mm3; P = .003). Control of a random sample in the centers concerned also indicated that most unspecified incidents of KS were cutaneous. Moreover, sensitivity analyses excluding these undocumented incidents of KS did not affect the main results. cART was defined as a regimen comprising at least three antiretroviral drugs for more than 3 months. We distinguished four types of cART: cART with PI, cART with NNRTI, cART with NRTI alone, and cART with both PI and NNRTI. Diagnosis of AIDS before KS and cART during the follow-up period were considered as time-dependent covariates. All analyses are based on an intent-to-continue-treatment approach and thus ignored subsequent treatment changes, including interruptions and terminations. We used the clinical definition of the 1993 Centers for Disease Control and Prevention revised AIDS case definition.17 All tests were two sided, and P values below .05 were considered to denote statistical significance. Statistical analyses were done with SAS software package, version 8.02 (SAS Institute, Cary, NC).
A total of 56,275 HIV-infected patients met the inclusion criteria, of whom 1,276 patients had a prevalent KS at FHDH enrollment (ie, had been diagnosed with KS at inclusion in the database and were therefore excluded from the analysis of incident KS). Among the remaining 54,999 patients (182,756 person-years of follow-up), KS was diagnosed after database enrollment in 1,634 patients, of whom 421 had visceral involvement at diagnosis. Among the 1,213 KS patients with no visceral involvement, 954 patients (79%) had documented cutaneous localizations. Table 1 shows the characteristics of the patients with KS at enrollment (prevalent KS), the patients with incident KS, and the patients without KS. Patients with prevalent KS were more likely than patients with incident KS to be homosexual, were older at recruitment, were enrolled a median of 1 year later, and had a lower median CD4 cell count at recruitment (74 per mm3 v 98 per mm3). In contrast, their median CD4 cell count at KS diagnosis was slightly higher (74 per mm3 v 52 per mm3).
Overall, KS was the first AIDS-defining illness in 856 incident cases (52.4%). The corresponding proportions were approximately 45% during the first two calendar periods (January 1993 to March 1996) and close to 60% thereafter. The proportion of heterosexual men among patients with incident KS tended to increase overtime (18.5% in period 1; 35.5% in period 4), and so did the proportions of women (2.5% v 9.1%) and patients of sub-Saharan origin (1.4% v 10.0%); the proportion of homosexual men fell accordingly (79.0% v 55.4%; Fig 1). These trends were more marked among patients with visceral KS than among patients with nonvisceral KS.
Overall, the incidence rate of KS fell from 31.9 per 1,000 person-years (95% CI, 28.9 to 34.8) in 1993 to 1994 to 21.9 (95% CI, 19.7 to 24.1) in 1995 to 1996 (period 2), corresponding to a decline of 31%. The decline accelerated strongly thereafter. Between period 2 and period 3 (early in the cART era) the decline was 67%, with an incidence rate of 7.2 per 1,000 person-years (95% CI, 6.5 to 7.8) in period 3. Between period 3 and period 4 the decline was 59%, with an incidence rate in period 4 of 2.9 per 1,000 person-years (95% CI, 2.6 to 3.2). Figure 2 shows the incidence rates of KS in homosexual men versus other HIV transmission groups according to the initial visceral/nonvisceral location of KS. The incidence rate fell far more strongly among homosexuals than in other transmission groups, and the reduction in visceral KS was far more marked than the reduction in nonvisceral KS.
In the most recent period, KS occurred at higher median CD4 cell count (P < .0001), whatever the location (Fig 3). Patients with visceral KS had a significantly lower median CD4 cell count at diagnosis than patients with nonvisceral KS. In the first two calendar periods, visceral KS occurred at a median CD4 cell count of 23 per mm3 (nonvisceral KS, 28 per mm3), while in the last period visceral KS occurred at 83 CD4 cells per mm3 and nonvisceral KS at 150 CD4 cells per mm3.
A PI-containing cART regimen was prescribed for at least 3 months to 19,528 patients (35.5%; median duration, 24.3 months), while 7,950 patients (14.5%; median duration, 18.5 months) received an NNRTI-containing regimen, 1,928 patients (3.5%; median duration, 13.8 months) received an NRTI-only regimen, and 2,965 patients (5.4%; median duration 16.8 months) received a regimen containing both NNRTI and PI (plus an NRTI in more than 90% of cases). In multivariate analysis (Table 2), older age at enrollment in the database, a lower nadir CD4 cell count, pre-existing AIDS, and male homosexuality were associated with an increased risk of KS.
Prescription of PI-containing cART and NNRTI-containing cART was associated with a similar significant decrease in the risk of KS (hazard ratio [HR], 0.68; HR, 0.62, respectively) in the overall population and when the analysis was restricted to homosexual men (17,610 patients; HR, 0.64; HR, 0.58, respectively). NRTI-only regimens were associated with slightly lower risk reduction of KS, both in homosexual men and in the overall population (HR, 0.76; HR, 0.77, respectively; both statistically significant). cART regimens containing both NNRTI and PI was associated with nonstatistically significant reduction (HR, 0.96; HR, 0.97, respectively). Table 3 presents the factors associated with the risk of visceral and nonvisceral KS. PI-containing and NNRTI-containing cART regimens were associated with larger reductions in the risk of visceral KS than in the risk of nonvisceral KS (respective HRs 0.42 and 0.41 for visceral KS; 0.79 and 0.71 for nonvisceral KS). NRTI-only regimens and regimens containing both NNRTI and PI did not have a statistically significant preventive effect on nonvisceral KS but reached statistical significance for visceral KS.
This study, based on one of the largest existing cohorts of HIV-infected patients, shows a major fall in the incidence rate of KS in France since the introduction of cART in 1996. The overall incidence is now roughly 2.9 per 1,000 person-years (95%CI, 2.6 to 3.2), a rate about 10 times lower than in the pre-cART period. The decline has been particularly marked in the homosexual population, and has affected KS with initial visceral involvement more strongly than cutaneous KS. Lastly, we found no evidence for a better effect of PI-based regimens over NNRTI-based regimen on preventing KS. Many other studies1,8-11,18 have shown that the incidence of KS in HIV-infected patients has decreased significantly since 1996, in parallel with the introduction of effective antiretroviral drugs. In contrast, ours is the first study to separately examine the incidence of visceral and nonvisceral KS. Indeed, the limited number of cases of KS since the introduction of cART had made such analysis difficult to perform. A large population of patients from a nationwide study, which included prospective individuals from various transmission groups before and after the advent of potent antiretroviral treatment, and the large number of person-years of follow-up, which allowed us to examine the declining incidence according to the initial visceral involvement are important strengths of this study. However, lack of data that would have allowed us to account for HHV-8 infection is a potential limitation of our study. But these data are not available in the database. We therefore performed sensibility analyzes in a high-prevalence population (ie, among homosexual men).5 Although the incidence of KS had already started to decline in the era of dual-antiretroviral therapy (1995 to 1996), the decrease accelerated as cART use became widespread. Approximately 300 cases of KS per year were recorded before 1995 (31.9 per 1,000 person-years of follow-up), compared with no more than 80 cases per year after 1999 (2.9 per 1,000 person-years of follow-up). Similar figures have been obtained elsewhere, particularly in the Eurosida study,8 in which the estimated KS incidence rate was 1.7 per 1,000 person-years of follow-up (95% CI, 0.7 to 3.4) in 2002 and beyond. The possibility that a decline in the prevalence of HHV-8 might explain this trend was ruled out by a recent study19 showing a similar prevalence of HHV-8 among homosexual men in San Francisco in the early years of the HIV epidemic (1983 to 1984) as in 1995 to 1996. As in the Eurosida study, we found a sharper fall in the incidence of KS in homosexual men than in other risk groups. These differences could be related to earlier cART initiation,20 better health care,21 better adherence, and/or the better immune response to treatment observed in homosexual men than in other risk groups. The trends in visceral and nonvisceral KS were different. The relative decline in recent years was larger for visceral KS than for nonvisceral KS. Likewise, PI-containing and NNRTI-containing cART regimens were associated with sharper reductions in the risk of visceral KS (> 50%) than in the risk of nonvisceral KS (< 30%). The findings corroborate the results of the only other study of the impact of cART on the presenting features of KS.22 In this Italian study of 160 cART-naive and 51 cART-treated patients with KS, cutaneous KS was more localized and indolent and visceral KS was less frequent in the cART group. Cutaneous KS has a far better prognosis than visceral KS, in both the pre-cART and cART eras.23,24 Although the amplitude of decrease in incidence of visceral KS with respect to nonvisceral KS might be amplified by a lower propensity of physicians to perform complete staging procedures in an era where KS has a lower incidence and clinical aggressiveness, our findings indicate that cART is effective in preventing aggressive, life-threatening KS and that KS exhibits less aggressive presentation since the advent of cART. Contrary to a previous report,8 we found that the CD4 cell count at KS diagnosis has increased significantly in recent years, and that this trend is more pronounced for nonvisceral KS than for visceral KS. The changes in the CD4 count distribution among patients at risk between the periods (with more patients with higher CD4 count in recent periods) led to a higher median CD4 cell count among patients with KS. Visceral KS appears to occur at deep level of immunosuppression while cutaneous KS may occur at higher levels of CD4. This might thus explain the differential impact of cART on visceral and nonvisceral KS incidence. It has been suggested that PI may specifically prevent KS by blocking phenomena involved in tumor growth, such as angiogenesis.13 However, we found that PI-containing and NNRTI-containing regimens were associated with similar HRs (respectively, 0.68 and 0.62 overall; 0.64 and 0.58 among homosexual men) indicating no differential impact of these regimens. These data confirm previous observational studies showing that the two cART regimens are equally effective in preventing KS.8,15 To our knowledge no randomized data exist and probably no such data will ever exist to formally compare the effect of PI versus NNRTI-based cART on preventing KS, as it will require large sample size and long duration of follow-up. Only observational data could give insights of the effectiveness of such therapies because it will not be addressed by any comparative trial. Our multivariate analysis showed no clear differential impact between the different cART regimen, and overall, our results suggest than cART prevents KS principally through immune restoration rather than through a class-specific effect on the tumoral process. In keeping with previous reports, we found that patients' epidemiologic characteristics at KS diagnosis have changed over time.25 In particular, KS was more frequently the first AIDS-defining illness in recent years. Also, homosexual men were significantly less likely to develop visceral KS after the advent of cART, and an increasing proportion of cases of KS involved patients from sub-Saharan Africa. These data indicate that KS is now associated with delayed access to care and with less effective antiviral treatment and call for specific efforts to favor access to care in order to prevent KS in these patients. The incidence of KS among HIV-infected patients, and especially the incidence of KS with initial visceral involvement, has fallen drastically since the introduction of cART. PIs and NNRTIs appear to be equally effective in preventing KS. Our results suggest that this preventive effect is due more to immune restoration induced by the treatment than to a class-specific effect.
Scientific committee. Dr E Billaud, Prof F Boué, D Costagliola, Dr X Duval, Dr C Duvivier, Dr P Enel, Dr S Fournier, Dr J Gasnault, Dr C Gaud, Dr J Gilquin, Dr S Grabar, Dr MA Khuong, Prof JM Lang, M Mary-Krause, Prof S Matheron, Prof MC Meyohas, Prof G Pialoux, Dr I Poizot-Martin, Dr C Pradier, Prof E Rouveix, Prof D Salmon-Ceron, Prof A Sobel, Dr P Tattevin, Dr H Tissot-Dupont, Dr Y Yasdanpanah. DMI2 coordinating center. French Ministry of Health (Dr E Aronica, Dr V Tirard-Fleury, I Tortay) Statistical analysis center. INSERM U720 (Dr S Abgrall, D Costagliola, Dr S Grabar, M Guiguet, E Lanoy, H Leneman, L Lièvre, M Mary-Krause, V Potard, Dr S Saidi) CISIH: Paris area. CISIH de Bichat-Claude Bernard (Hôpital Bichat-Claude Bernard: Prof S Matheron, Prof C Leport, JL Ecobichon, Prof P Yeni, Prof E Bouvet, C Gaudebout, Prof B Crickx, Dr C Picard-Dahan), CISIH de Paris-Centre Ouest (Hôpital Européen Georges Pompidou: Prof L Weiss, D Tisne-Dessus; GH Tarnier-Cochin: Prof D Sicard, Prof D Salmon; Hôpital Saint-Joseph: Dr J Gilquin, Dr I Auperin; Hôpital Necker adultes: Dr JP Viard, Dr L Roudière), CISIH de Paris-Sud (Hôpital Antoine Béclère: Prof F Boué, Dr R Fior; Hôpital de Bicêtre: Prof JF Delfraissy, Dr C Goujard; Hôpital Henri Mondor: Dr Ph Lesprit, C Jung; Hôpital Paul Brousse), CISIH de Paris-Est (Hôpital Saint-Antoine: Prof MC Meyohas, Dr JL Meynard, Dr O Picard, N Desplanque; Hôpital Tenon: Prof J Cadranel, Prof C Mayaud, Prof G Pialoux, Prof W Rozenbaum), CISIH de Pitié-Salpétrière (GH Pitié-Salpétrière: Prof F Bricaire, Prof C Katlama, Prof S Herson, Dr A Simon), CISIH de Saint-Louis (Hôpital Saint-Louis: Prof JM Decazes, Prof JM Molina, Prof JP Clauvel, Dr L Gerard; GH Lariboisière-Fernand Widal: Dr P Sellier, Dr M Diemer), CISIH 92 (Hôpital Ambroise Paré: Dr C Dupont, H Berthé, Prof P Saïag; Hôpital Louis Mourier : Dr E Mortier, C Chandemerle; Hôpital Raymond Poincaré: Dr P de Truchis), CISIH 93 (Hôpital Avicenne: Dr M Bentata, P Honoré; Hôpital Jean Verdier: S Tassi, Dr V Jeantils; Hôpital Delafontaine: Dr D Mechali, B Taverne). Outside Paris area. CISIH Auvergne-Loire (CHU de Clermont-Ferrand: Dr H Laurichesse, Dr F Gourdon; CHRU de Saint-Etienne: Prof F Lucht, Dr A Fresard); CISIH de Bourgogne-Franche Comté (CHRU de Besançon; CHRU de Dijon; CH de Belfort: Dr JP Faller, P Eglinger; CHRU de Reims); CISIH de Caen (CHRU de Caen: Prof C Bazin, Dr R Verdon), CISIH de Grenoble (CHU de Grenoble), CISIH de Lyon (Hôpital de la Croix-Rousse: Prof D Peyramond, Dr A Boibieux; Hôpital Edouard Herriot: Prof JL Touraine, Dr JM Livrozet; Hôtel-Dieu: Prof C Trepo, Dr L Cotte), CISIH de Marseille (Hôpital de la Conception: Dr I Ravaux, Dr H Tissot-Dupont; Hôpital Houphouët-Boigny: Prof JP Delmont, Dr J Moreau; Institut Paoli Calmettes: Prof JA Gastaut; Hôpital Sainte-Marguerite: Dr I Poizot-Martin, Prof J Soubeyrand, Dr F Retornaz; CHG d'Aix-En-Provence: Dr PA Blanc, Dr T Allegre; Centre pénitentiaire des Baumettes: Dr A Galinier, Dr JM Ruiz; CH d'Arles; CH d'Avignon: Dr G Lepeu; CH de Digne Les Bains: Dr P Granet-Brunello; CH de Gap: Dr L Pelissier, Dr JP Esterni; CH de Martigues: Dr M Nezri, Dr R Cohen-Valensi; CHI de Toulon: Dr A Laffeuillade, Dr S Chadapaud), CISIH de Montpellier (CHU de Montpellier: Prof J Reynes; CHG de Nîmes), CISIH de Nancy (Hôpital de Brabois: Prof T May, Dr C Rabaud), CISIH de Nantes (CHRU de Nantes: Prof F Raffi, Dr E Billaud), CISIH de Nice (Hôpital Archet 1: Dr C Pradier, Dr P Pugliese; CHG Antibes Juan les Pins), CISIH de Rennes (CHU de Rennes: Prof C Michelet, Dr C Arvieux), CISIH de Rouen (CHRU de Rouen: Prof F Caron, Dr F Borsa-Lebas), CISIH de Strasbourg (CHRU de Strasbourg: Prof JM Lang, Dr D Rey, Dr P Fraisse; CH de Mulhouse), CISIH de Toulouse (CHU Purpan: Prof P Massip, Dr L Cuzin, Prof E Arlet-Suau, Dr MF Thiercelin Legrand; Hôpital la Grave; CHU Rangueil), CISIH de Tourcoing-Lille (CH Gustave Dron; CH de Tourcoing: Dr Y Yasdanpanah), CISIH de Tours (CHRU de Tours; CHU Trousseau). Overseas. CISIH de Guadeloupe (CHRU de Pointe-à-Pitre), CISIH de Guyane (CHG de Cayenne: Dr M Sobesky, Dr R Pradinaud), CISIH de Martinique (CHRU de Fort-de-France), CISIH de La Réunion (CHD Félix Guyon: Dr C Gaud, Dr M Contant).
The authors indicated no potential conflicts of interest.
The authors are grateful to all French Hospital Database on HIV participants and research assistants, without whom this work would not have been possible.
Supported by Agence Nationale de Recherches sur le SIDA (French Hospital Database on HIV), Fondation pour la Recherche Médicale, Institut National de la Santé et de la Recherche Médicale, and the French Ministry of Health. Presented in part at the 12th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 22-25, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Grabar S, Pradier C, Le Corfec E, et al: Factors associated with clinical and virological failure in patients receiving a triple therapy including a protease inhibitor. AIDS 14:141-149, 2000[CrossRef][Medline] 17. Centers for Disease Control and Prevention: 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morb Mortal Wkly Rep 41:1-19, 1992[Medline] 18. Carrieri MP, Pradier C, Piselli P, et al: Reduced incidence of Kaposi's sarcoma and of systemic non-hodgkin's lymphoma in HIV-infected individuals treated with highly active antiretroviral therapy. Int J Cancer 103:142-144, 2003[CrossRef][Medline] 19. Osmond DH, Buchbinder S, Cheng A, et al: Prevalence of Kaposi sarcoma-associated herpesvirus infection in homosexual men at beginning of and during the HIV epidemic. JAMA 287:221-225, 2002 20. Fardet L, Mary-Krause M, Heard I, et al: Influence of gender and HIV transmission group on initial HAART prescription and treatment response. HIV Med (in press) 21. Shapiro MF, Morton SC, McCaffrey DF, et al: Variations in the care of HIV-infected adults in the United States: Results from the HIV Cost and Services Utilization Study. JAMA 281:2305-2315, 1999 22. Nasti G, Martellotta F, Berretta M, et al: Impact of highly active antiretroviral therapy on the presenting features and outcome of patients with acquired immunodeficiency syndrome-related Kaposi sarcoma. Cancer 98:2440-2446, 2003[CrossRef][Medline] 23. Mocroft AJ, Lundgren JD, d'Armino Monforte A, et al: Survival of AIDS patients according to type of AIDS-defining event: The AIDS in Europe Study Group. Int J Epidemiol 26:400-407, 1997 24. 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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50 per mm3, 51 per mm3 to 100 per mm3, 101 per mm3 to 200 per mm3, > 200 mm3), sex, the HIV exposure category (homosexual men v women v nonhomosexual men), diagnosis of AIDS before KS, cART, and sub-Saharan Africa origin. The notion of long stays in sub-Saharan Africa was used as a proxy for sub-Saharan origin. 
