Kaposi sarcoma was described by Dr. Moritz Kaposi in 1872 as an indolent dermatologic disease characterized by the appearance of purplish nodules or plaques, particularly in the lower extremities of older men of Eastern European, Mediterranean, or Jewish descent (classical KS). Canadian investigators were one of the first ones to note in the 1970s that KS occurred in renal transplant patients exposed to immunosuppressant regimens (ie, azathioprine; transplant or iatrogenic KS). Their observations included reports of remissions when immunosuppressant regimens were temporarily discontinued, suggesting a relationship between immunodeficiency and the malignancies. They also noted a high incidence of NHL. In the 1960s, British investigators reported an aggressive lymphadenopathic form of KS confined to equatorial Africa (African KS). This form occurred in younger patients with aggressive involvement of lymph nodes and appearance of nodules and plaques of the lower extremities that rapidly became ulcerated. With the CDC Morbidity and Mortality Weekly Report of 26 gay men with KS, the disease became one of the hallmarks of the AIDS epidemic (epidemic or AIDS-related KS).
In contrast to the classical form, the AIDS-related KS lesions appear with an aggressive pattern of distribution that includes the trunk, arms, and face in addition to the lower extremities (14). Prior to antiretroviral therapies, patients died of a combination of tumor progression and opportunistic infections. Despite HAART, KS continues to be a prevalent cancer among HIV-infected patients, although HAART has significantly changed the incidence of the disease. From 1990 to 1995, the incidence of KS in the United States was 1,838.9 cases per 100,000 person-years in contrast to 334.6 cases per 100,000 person-years from 1996 to 2002. In the United States and Europe, AIDS-related KS has been almost exclusively diagnosed in homosexual men, suggesting that its prevalence may vary among different categories of AIDS patients. In Africa, where the human herpesvirus 8 (HHV-8), or KS herpesvirus (KSHV), is endemic, the male-to-female ratio of AIDS-related KS in some countries is 2:1, almost the same ratio observed in transplant- or iatrogenic-related KS. Thus, in the presence of profound immune suppression, factors that made the disease more prevalent in males than in females prior to the AIDS pandemic appear to be of little relevance. What is clear is that the incidence of AIDS-related KS is related to the degree of the immune suppression of the infected hosts, with most afflicted patients having CD4+ cell counts of 200 CD4+ cells/μL or less.
The Viral Etiology of Kaposi Sarcoma
The etiologic agent of all forms of KS is HHV-8, also called KSHV (15). Early in the pandemic, other viruses or agents were implicated as the cause of AIDS-related KS, including CMV. In 1994, sequences of a new herpes-like virus were isolated from the lesions of an AIDS-related KS patient. Using a subtractive PCR technique called representative differential analysis, investigators found sequences isolated from KS lesions homologous but not identical to other known herpesviruses, and thus it was named HHV-8, because it became the eighth known herpesvirus. Not all patients infected with HHV-8 develop KS; however, viral DNA and seroconversion can be detected in patients prior to the development of KS, confirming the role of HHV-8 as the cause of all forms of KS and the relationship of its pathogenesis to immunosuppression in addition to other cofactors.
Human herpes virus 8 belongs to the γ-herpesvirus subfamily and the subgroup γ-2 or rhadinovirus (from the Latin term rhadino, referring to the tendency of the viral genome to break apart when it is isolated) and is the first human virus of this subfamily identified. The detection of the infection relies on the presence of antibodies against viral antigens using immunofluorescence assays based on the use of B lymphocytes as the antigen source or ELISA with recombinant immunogenic proteins or peptides of HHV-8. The infection seroprevalence mirrors the geographic distribution of AIDS-related KS, with the highest infection rates in central African countries (80%), rates of 25% to 50% among homosexual men in the Western world, and an intermediate level in the Mediterranean regions. The adult general population of blood donors in North America and Europe has an HHV-8 seroprevalence ranging from 0% to 8%. In addition to being the etiologic agent of AIDS-related KS, HHV-8 has been associated with two other lymphoproliferative disorders: primary effusion lymphoma (PEL, a subset of body cavity–based lymphomas [Fig. 44-1], subsequently called PELs) and multicentric Castleman disease (15).
Scan in a patient with primary effusion lymphoma (PEL) showing multiple sites of increased fluorodeoxyglucose activity and a large right pleural effusion.
Pathogenesis of Kaposi Sarcoma
Human herpes virus 8 incorporates a significant number of host genes such as cyclin D and growth factor interleukin (IL)-6 (16). These genes participate in the replication, survival, and transformation of the infected tumor cells. The viral K1 gene kaposin and viral G protein–coupled receptor (vGPCR) have transformation potential. Others deregulate cell growth and lead to transformation including viral IL-6, viral IL-10, viral cc-class chemokines, and viral FLICE-inhibitory protein (vFLIP). The expression of the different key genes is related to the latency and lytic cycles of HHV-8. During the latency phase, genes such as LANA-1 (latency-associated nuclear antigen 1), in addition to the maintenance of latency, inactivate p53, inhibiting apoptosis. In addition, a viral cyclin prevents cell cycle arrest by cyclin-dependent kinases, pRB and vFLIP, avoiding the activation of the Fas death receptor pathway. During the lytic phase, homologues of replication genes including the K1 kaposin gene, a Bcl-2 homologue, a viral G protein–coupled receptor gene (vGPCRP), a viral homologue of IL (IL-6), and viral macrophages and IFN regulatory factors become active. Some of these genes have immunosuppression functions, such as the inhibition by vFLIP including cytotoxicity of T cells against HHV-8–infected cells and the inhibition of HHV-8 class 2 major histocompatibility complex (MHC)-mediated T-cell activation by K1 (17). Finally, other viral proteins such as K3 and K5 downregulate the presentation of MHC class 1 molecules on the cell surface.
Pathology of Kaposi Sarcoma
The histology of KS is characterized by the abundance of spindle cells in a matrix of neovascular formation and a rich background of mononuclear inflammatory cells and collagen. Vascular spaces are dilated and contain extravasated erythrocytes. Involvement of the reticular dermis, reflected by patchy lesions and the involvement of all the layers of the skin, clinically presents as nodular or plaque lesions that can coalesce, interfering with the lymphatic circulation, and are histologically and clinically associated with surrounding hemorrhage and subcutaneous edema. The spindle KS cells are rich in endothelial factor VIII. Recent microarray studies have demonstrated that the origin of the KS cell is from a virally transformed lymphatic endothelial cell. Kaposi sarcoma spindle cells express angiogenic/inflammatory cytokines and growth factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), IL-1, and IL-6, among others. Kaposi sarcoma cells also overexpress receptors for cytokines, suggesting growth through autocrine or paracrine mechanisms. They also proliferate in response to IL-1, IFN-γ, IL-6, and tumor necrosis factor (TNF), which are abundantly present in the serum of patients with poorly controlled HIV infection, and matrix metalloproteinases (MMPs), enzymes involved in the destruction of extracellular matrix proteins required for angiogenesis and metastasis. In AIDS-related KS, Tat (the trans-activator of transcription protein) stimulates KS spindle and endothelial cell replication, promoting an increase in the concentrations of bFGF. This, in turn, upregulates the integrins α5β1 and αvβ3, receptors for fibronectin and vitronectin, which are highly expressed in AIDS-related KS.
Clinical Features of Kaposi Sarcoma
Most patients with AIDS-related KS have CD4+ cell counts of 200 CD4+ cells/μL of blood, with an increased number and aggressiveness of lesions in those who are more severely immunosuppressed. There are periods of exacerbation alternated with quiescence related to oscillations of the patient’s immunity. Kaposi sarcoma rarely invades the central nervous system. This is of biological interest because many other human malignancies are characterized by the invasion of the central nervous system (18).
The distribution of skin lesions in patients with AIDS-related KS often follows the Langer’s folds of the skin. The occurrence of lesions in acral regions of the body such as the tip of the nose is common. The evolution of the skin lesions correlates with the patient’s immune system status. In the pre-HAART era, severe involvement of the skin of the face by raised purplish lesions was frequent. With KS progression, there is frequent involvement of the gastrointestinal tract. Lesions of the palate and gums are often the first ones to be noted, and diarrhea and occasional bleeding can suggest KS involvement of the gastrointestinal tract. In the case of involvement of the lower extremities, progressive edema with nodular and coalescing plaque lesions can cause significant discomfort and pain. Prior to HAART, this was a frequent and serious complication of KS, because “elephantiasis” secondary to the progression of KS was extremely difficult to treat. Advanced cases often involve ulceration of lesions, particularly when located in the lower extremities. Lymph node involvement is frequent, and when there is only generalized lymph node involvement, a biopsy is required for confirmation of diagnosis. In advanced cases, lung involvement is manifested by bilateral basilar infiltrates mixed with a nodular appearance; however, severe hemoptysis or gastrointestinal bleeding is infrequent. During the early years of the epidemic, a significant number of patients experienced involvement by large masses of KS in vital organs such as the liver and heart, and death was due to from progression of their KS tumors and associated opportunistic infections.
Staging and Prognostic Factors for Kaposi Sarcoma
The usual TNM system used in other solid tumors is not easily applicable to AIDS-related KS. A system based on the work of Chachoua and colleagues was proposed in 1989 by the AIDS Clinical Trial Group (ACTG) (Table 44-1). This staging system included the extent of tumor involvement, the immune status measured by the level of CD4+ cell count, and presence or absence of any systemic illness (B symptoms). In addition to a complete physical examination, it included a complete blood count, serum chemistries, HIV viral load, panendoscopy of the gastrointestinal tract, computed tomography (CT) of the abdomen and pelvis, and when indicated, the performance of bronchoscopy when pulmonary involvement by KS was suspected. Biopsies of skin or lymph nodes were also suggested when indicated to rule out entities that could be similar in presentation, such as bacillary angiomatosis or pyoderma gangrenosum. After HAART, the extent of disease and the presence of HIV systemic symptoms became the most important prognostic factors; however, pulmonary involvement by KS still carries a particularly poor prognosis. Correlations with the levels of HIV viral load and the status of HHV-8 infection are under study in relationship to their impact on survival (19).
Table 44-1TIS Staging System for AIDS-Related Kaposi Sarcoma and Risk Status ||Download (.pdf) Table 44-1 TIS Staging System for AIDS-Related Kaposi Sarcoma and Risk Status
|Characteristics ||Good Risk (0) ||Poor Risk (1) |
|All of the Following ||Any of the Following |
|Tumor (T) ||Tumor confined to skin and lymph nodes and/or minimal oral diseasea ||Tumor-associated edema or ulceration; extensive oral KS; gastrointestinal KS; KS in other nonnodal viscera |
|Immune system (I) ||CD4 cells ≥150/mm3 ||CD4 cells <150/mm3 |
|Systemic illness (S) ||No history of opportunistic infection or thrush; no B symptomsb; performance status ≥70 (Karnofsky) ||History of opportunistic infection and/or thrush; B symptoms; performance status <70 (Karnofsky); other HIV-related illness (eg, neurologic disease, lymphoma) |
Therapy of Kaposi Sarcoma
Highly Active Antiretroviral Therapy
Highly active antiretroviral therapy brought a dramatic decrease in the incidence of AIDS-related KS. Highly active antiretroviral therapy consists of the administration of a combination of agents with anti-HIV activity, including inhibitors of HIV reverse transcriptase and protease inhibitors. The consensus of experts in the field about frontline components of HAART is periodically published in Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents by the Department of Human and Health Services (DHHS; available online by visiting the DHHS website). For patients in whom KS is part of the initial diagnosis of AIDS, HAART therapy should be started irrespective of the extent of the disease. For patients with minimal tumor burden, HAART initiation constitutes frontline therapy of their AIDS-related KS. This approach can control these lesions for long periods of time, often more than 1 year, and in many instances results in complete disappearance of KS lesions (20). Patients with extensive disease or visceral involvement can receive systemic chemotherapy in addition to HAART.
Radiation Therapy for Kaposi Sarcoma
Radiotherapy can be useful for treatment of minimal local disease and when the use of systemic treatment other than HAART is not indicated. It can also be used as an adjunct treatment modality for patients in whom the administration of chemotherapy leads to incomplete results, enhancing the beneficial effects of the systemic treatment. Depending on the general condition of the patient and the size of the lesions to be treated, doses range from the administration of a single fraction to fractionated doses over periods of 2 to 4 weeks. For single lesions and frail patients, the administration of a single 800-cGy dose can be used. Radiotherapy can be used for cosmetic reasons, although this should be done carefully to avoid secondary side effects such as postradiation cataracts in the case of periorbital lesions. For larger lesions or when the therapeutic intent is cosmetic, fractionated doses between 200 and 4,000 cGy are effective and carry less risk. For patients receiving systemic therapy, radiotherapy can be an adjuvant for the treatment of complicated single lesions, particularly when they are bleeding, ulcerated, or painful, or when they affect the well-being of the patient. Such is the case of patients with disseminated disease receiving systemic treatment and in whom oral lesions may affect eating due to local pain or size.
Local Therapy Other Than Radiotherapy for Kaposi Sarcoma
In the modern era, the use of local therapies such as cryotherapy and laser therapy may have a role for patients with few and small lesions. The use of surgery may be appropriate in selected cases such as large skin lesions or when there are complications (bleeding of obstruction of a hollow viscus). Other treatments, such as intralesional injection of chemotherapeutic agents, particularly of the oral cavity, and application of alitretinoin gel, have been abandoned and replaced by a more sophisticated use of radiotherapy techniques, HAART, and systemic chemotherapy.
Immunomodulators in Therapy of Kaposi Sarcoma
After the demonstration of the activity of IFN-α in hairy cell leukemia and renal cell cancer in 1984 (21), there was an impetus to use the same doses of IFN in patients with AIDS-related KS. Low doses of IFN-α effective against hairy cell leukemia and renal cell carcinoma were ineffective against AIDS-related KS (Rios A, personal observation). A dose-response study unequivocally demonstrated the therapeutic effect of IFN-α in KS when used at doses of 20 to 30 MU/m2 (22,23). A different situation was observed with IFN-γ. Under the angiogenic stimuli of IFN-γ, KS has the capacity to replicate, resulting in a deleterious impact on patients treated with this agent in pilot studies. As a result of these trials, recombinant IFNs α-2a (Roferon-A) and α-2b (Intron-A) were approved for the systemic treatment of patients with AIDS-related KS. Expanded use of these agents has revealed their true activity to be in the range of 15% to 20%.
Interferon can block the synthesis of viral proteins and the budding of viral particles from infected cells in addition to other complex pleiotropic effects. Interferon actions are accompanied by significant systemic side effects including tiredness, fatigue, anorexia, hepatotoxicity, and severe myelosuppression. With the development of HAART and the use of more effective systemic chemotherapy regimens in the treatment of AIDS-related KS, the interest in the use of IFN-α in the treatment of AIDS-related KS has declined.
Chemotherapy for Kaposi Sarcoma
Indications for the use of systemic chemotherapy in AIDS-related KS includes extensive skin, mucocutaneous, and visceral involvement by tumor. In patients who require systemic chemotherapy, local radiotherapy is used to treat local complications in addition to systemic disease. The introduction of HAART has resulted in better and more durable responses with increased tolerability and durability than those observed prior to HAART.
Before the discovery of antiretrovirals, a variety of chemotherapeutic agents had modest to significant activity as monotherapy for KS. These agents included etoposide, vinblastine, vincristine, bleomycin, doxorubicin, vinorelbine, and epirubicin, which induced responses in 40% to 69% of patients. After HAART, ABV (doxorubicin 20 mg/m2, bleomycin 10 U/m2, and vincristine at maximum doses of 1 to 2 mg) became the first standard treatment of AIDS-related KS. It produced a response rate of 60%, with complications and tolerance depending on the performance status and general condition of the patient (23). Antiretroviral and other supportive therapies with growth factors (granulocyte-macrophage colony-stimulating factor [CSF] and granulocyte CSF [G-CSF]) paired with vigorous prophylaxis of opportunistic infections reduce the risks of treatment. Complications of ABV were the expected ones with systemic chemotherapy including the potential for cardiac toxicity induced by doxorubicin.
The ABV regimen was followed by the introduction of agents considered today the standard of care for AIDS-related KS, including liposomal encapsulated anthracyclines (doxorubicin and daunorubicin) and taxanes (paclitaxel). The last of these promotes apoptosis and downregulates Bcl-2 protein expression in KS cells in vitro and in KS-like lesions in mice. In addition, it has an important antimitotic effect associated with its capacity for the disruption of tubulin activity during mitosis.
The current treatment of AIDS-related KS is based on the combination of an anthracycline (liposomal doxorubicin 20 mg/m2 or liposomal daunorubicin 40 mg/m2 but not both together) with paclitaxel 25 mg/m2 with or without bleomycin or vincristine. Escalation of the dose of liposomal doxorubicin is not recommended due to a syndrome of desquamation of the skin of the palms and soles of the feet, known as palmar-plantar erythrodysesthesia. In contrast, the dose of liposomal-encapsulated daunorubicin can be increased to up to 60 mg/m2 or even higher for patients who tolerate lower doses. This is of particular relevance in patients with advanced disease or significant pulmonary involvement and for whom prompt control and achievement of a quick therapeutic response is of great importance (Fig. 44-2).
Algorithm for the management of acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma. 1Monthly evaluation of Kaposi sarcoma clinical response and estimation of CD4+ cell count and HIV-RNA levels. 2Highly active antiretroviral therapy (HAART) regimen should be changed in the case of immunovirologic failure. (Reproduced, with permission, from Catellan AM, Trevenzoli M, Aversa SM. Recent advances in the treatment of AIDS-related Kaposi sarcoma. Am J Clin Dermatol. 2002;3:451-462.)
Future Therapies for Kaposi Sarcoma
Only patients with early disease and relatively good performance status consistently achieve durable remissions with current therapies for KS. For the rest of the patients, only palliation and stabilization of disease is achieved with current treatments. For these reasons, efforts are under way to develop new therapies based on the knowledge of the pathophysiology of the disease. For example, because angiogenesis is an important component of AIDS-related KS, agents such as thalidomide and anti-VEGF agents such as bevacizumab are of great interest in the therapy of this disease. Metalloprotease inhibitors are also of great interest, and active clinical trials are in progress. Viruses associated with the production of malignancies tend to constitutively activate the nuclear factor-κB (NF-κB) pathway, and agents that can inhibit this pathway such as bortezomib may be of some value. Inhibition of signaling cell receptors implicated in the stimulation of angiogenesis such as platelet-derived growth factor receptor (PDGFR) and C-kit receptor by agents such as imatinib, an orally administered tyrosine kinase inhibitor, approved by the US Food and Drug Administration (FDA) for treatment of chronic myeloid leukemia and gastrointestinal stromal tumor, is being investigated.
There is significant interest in the development of therapies against the latent phase of HHV-8, the most common form of HHV-8 in KS cells, which does not respond to standard antiherpetic drugs such as foscarnet and cidofovir. This area of research has led to potential development of a vaccine against HHV-8. Despite all these new potential therapeutic developments, the impact of HAART in the incidence of AIDS-related KS cannot be overemphasized. The development of more potent and less toxic HAART regimens and the acceptance of earlier therapeutic intervention against HIV seem to be the main paths to control the epidemic of AIDS-related KS.
Acquired Immunodeficiency Syndrome–Related Non-Hodgkin Lymphoma: Systemic Non-Hodgkin Lymphoma
Non-Hodgkin lymphoma is the second most frequent AIDS-associated malignancy. Both KS and NHL were occurring with an incidence almost linear in its relationship to the patient’s immunodeficiency status (24). In 1985, high- or intermediate-grade B-cell NHLs were considered part of the spectrum of AIDS-related malignancies. Eighty percent of AIDS-related NHLs were systemic (peripheral) lymphomas, involving nodal or extranodal sites, with 15% to 20% originating in the primary central nervous system (PCNSL). A small proportion, less than 3%, of systemic AIDS-related NHL patients had PELs, known as body cavity lymphomas. In general, the risk of AIDS-related NHL in patients with HIV appears to be higher in those who have poor immune function with average CD4+ cell counts of 150 CD4+ cells/μL of blood.
A viral relationship is implicated in the development of AIDS-associated lymphomas. Epstein-Barr virus (EBV) contributes to the development of most of these tumors, although HHV-8 is associated with the development of PEL (24). There is no relationship between the risk of development of AIDS-related NHL and modes of HIV transmission. The incidence of pre-HAART AIDS-related NHL was 60 to 200 times higher than in a matched HIV-seronegative population; the relative risk was higher for PCNSL. Age, nadir of CD4+ cell count, and absence of anti-HIV therapy were critical factors that predicted the development of AIDS-related NHL. In the pre-HAART era, 80% of these NHLs, including systemic and PCNSL cases, were immunoblastic variants associated with CD4+ cell count depletion and EBV infection. In the post-HAART era, there has been a 30% reduction of peripheral cases and a 70% reduction in PCNSL, indicating the impact of immune reconstitution in the incidence of immunosuppression-related lymphomas. In contrast, the incidence of Burkitt lymphoma and of centroblastic DLBCL has remained stable without significant change from the pre- to the post-HAART eras (25). When comparing the AIDS-related lymphomas with non–AIDS-related NHL, the former tend to be of higher histologic grade, with increased frequency of B symptoms, extranodal presentations, and an increased incidence of leptomeningeal and primary CNS involvement (26). In the post-HAART era, the World Health Organization (WHO) has expanded the categories of lymphomas that can occur in HIV patients to include extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma), peripheral T-cell lymphoma (PTCL), and classical Hodgkin lymphoma (HL), as well as lymphomas that more specifically occur in AIDS patients, including plasmablastic lymphomas of the oral cavity, polymorphic B-cell lymphomas (posttransplant lymphoproliferative disorder–like), and PEL (27). Finally, the demographics of AIDS-related NHL patients have changed in the last decade, reflecting changes in the demographics of the AIDS epidemic, with increasing incidence in Hispanic and African American patients and patients who have acquired HIV through heterosexual contact (Table 44-2).
Table 44-2Demographic Profile of 369 Patients With AIDS-Related Lymphoma Over Different Time Intervals ||Download (.pdf) Table 44-2 Demographic Profile of 369 Patients With AIDS-Related Lymphoma Over Different Time Intervals
| ||1982-1986 (%) ||1987-1990 (%) ||1991-1994 (%) ||1995-1998 (%) ||Total (%) ||P Value |
|No. of patients ||44 ||88 ||132 ||105 ||369 || |
|Median age (years) ||40 ||36 ||38 ||39 ||38 ||.18 |
|Sex || || || || || ||.25 |
| Female ||0 (0) ||2 (2) ||6 (5) ||7 (7) ||15 (4) || |
| Male ||44 (100) ||86 (98) ||126 (95) ||98 (93) ||354 (96) || |
|Race || || || || || ||.001 |
| Caucasian ||33 (75) ||50 (57) ||64 (48) ||42 (40) ||189 (51) ||a |
| Hispanic ||7 (16) ||26 (33) ||51 (39) ||58 (55) ||145 (39) ||b |
| Black ||4 (9) ||4 (5) ||17 (13) ||5 (5) ||30 (8) || |
| Asian ||0 (0) ||5 (6) ||0 (0) ||0 (0) ||5 (1) || |
|Risk || || || || || ||.039 |
| MSM ||37 (84) ||67 (76) ||105 (80) ||69 (66) ||278 (75) ||c |
| IDU +/- MSM ||3 (7) ||7 (8) ||4 (3) ||3 (3) ||17 (5) || |
| Hetero ||2 (5) ||4 (5) ||13 (10) ||19 (18) ||38 (10) ||d |
| Transfusion ||0 ||3 (3) ||1 (0.5) ||4 (4) ||8 (2) || |
| Unknown ||2 (5) ||7 (8) ||9 (7) ||10 (10) ||28 (8) || |
|KPS || || || || || ||.0008 |
| >80% ||14 (32) ||28 (32) ||75 (57) ||45 (43) ||162 (44) || |
| <80% ||30 (68) ||60 (68) ||57 (43) ||60 (57) ||207 (56) || |
|Prior OIe ||14 (32) ||40 (45) ||58 (44) ||53 (50) ||165 (45) ||.22 |
|Prior KSe ||2 (5) ||13 (15) ||11 (8) ||14 (13) ||40 (11) ||.20 |
|Median CD4f ||177 ||113 ||54 ||53 ||66 ||.0006 |
|Range ||0-1703 ||2-1927 ||0-710 ||0-700 ||0-1927 || |
Pathogenesis of Acquired Immunodeficiency Syndrome–Related Non-Hodgkin Lymphomas
The development of NHLs in HIV patients is similar to that of malignancies associated with other congenital or posttransplant immunodeficiency disorders (28,29). In such conditions, most of the malignancies consist of NHL and KS. In the case of HIV, immunodeficiency and cofactors, including oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction, are responsible for the development of AIDS-related NHL malignancies. In contrast to AIDS-associated KS, no one has yet found HIV sequences in tumor cells of AIDS-related NHLs (30), although PCR analysis has revealed the presence of HIV in infiltrating T cells. For patients with severe HIV immunodeficiency, the oncogenic nature of both EBV and HHV-8 is responsible for the development of the immunoblastic subtype of DLBCL, PCNSL, plasmablastic lymphoma of the oral cavity, and PEL. The last of these often results from coinfection with HHV-8 and EBV. These lymphomas are the result of active oncogenic viruses released from control by an effective immune surveillance.
Epstein-Barr virus is central to the pathogenesis of AIDS-related NHLs, including those that are related to immunodeficiency and those that occur with a reconstituted immune system, such as centroblastic DLBCL and Burkitt lymphoma. The EBV genome presence is very high in immunodeficiency-associated AIDS-related NHLs (100%) (31), although it can only be detected in approximately 60% of centroblastic DLBCLs and 30% of Burkitt lymphomas. This suggests that other factors, including other common latent or chronic viral infections, may be involved in the development of these tumors.
In EBV-infected cells, the EBV virus is, for the most part, in a state of latency with brief periods of lytic activity. The malignant transformation of B cells occurs in the latent phase, requiring multiple molecular events (32). Epstein-Barr virus contributes to the cellular transformation process through expression of genes with oncogenic activity such as LMP-1, LMP-2, EBNA-1, and EBNA-2. There is also expression of small EBV-encoded, nonpolyadenylated nuclear RNAs (EBERs), all of which participate in the oncogenic transformation phenomenon. These proteins can rescue cells from apoptosis by mimicking cell receptors such as CD40 and B-cell receptor. For example, LMP-1 (latent membrane protein-1) is capable of replacing the function of CD40 in germinal B cells which otherwise would follow an apoptotic fate.
The Impact of Highly Active Antiretroviral Therapy on Distribution of Acquired Immunodeficiency Syndrome–Related Non-Hodgkin Lymphoma
In the post-HAART era there has been a decline in the incidence of NHLs associated with immunodeficiency due to AIDS. In contrast, the incidence of centroblastic DLBCL and Burkitt lymphoma appears to be similar before and after introduction of HAART. Factors influencing the pathogenesis of these diseases include an increase in regulatory cells of the immune system, associated with recovery of the immune status of the host, and effects of chronic antigenic stimulation by HIV with a resultant overproduction of cytokines. The existence of more than one pathogenic mechanism for the occurrence of AIDS-related NHLs can be inferred from the variety of genetic abnormalities displayed by the malignant cells (33). The number and type of these genetic abnormalities vary according to the anatomic site and tumor histology. They include c-myc rearrangement, bcl-6 gene rearrangement, ras gene mutations, and p53 mutations/deletions (34).
Pathology of Systemic Non-Hodgkin Lymphomas
The hallmark of AIDS-related NHL is a high-grade histology, regardless of the histologic subtype, including diffuse large cell, immunoblastic, and small noncleaved cell lymphomas and Burkitt and Burkitt-like lymphomas. The cells of PEL express CD45, activation-associated antigens such as HLA-DR, CD30, CD38, CD71, epithelial membrane antigen, and CD 138/syndecan-1. Primary effusion lymphoma cells often lack B-cell antigens and c-myc gene rearrangements and mutations and uniformly contain HHV-8 and frequently also contain EBV (33,34). Other hematologic neoplasms, including low-grade B-cell lymphomas and lymphocytic leukemia, multiple myeloma/plasmacytomas, T-cell neoplasms, and various acute myeloid leukemias and myeloproliferative disorders, have been reported in patients with HIV infection. However, there is no evidence that the incidence of these neoplasms has increased in parallel with the AIDS epidemic (35,36,37,38,39).
Clinical Features of Systemic Non-Hodgkin Lymphomas
Patients with AIDS-related NHLs usually present with advanced stages of the disease and B symptoms, including fever, loss of weight, night sweats, and enlarged lymph nodes or masses. Over 60% of the patients will present with stage III or IV disease. Frequent extranodal sites of involvement are bone marrow, CNS parenchyma and meninges, lungs, and spleen. Patients with PEL present with ascites or a pleural effusion and less frequently with a pericardial effusion. Masses are typically absent in the presentation of PEL, although occasionally a mass may accompany the development of the effusion (40) (see Fig. 44-1).
The staging of patients with AIDS-related NHL is similar to non-HIV patients with NHL and should be reported according to the Ann Arbor system (Table 44-3). The International Prognostic Index has been validated in pre-HAART studies, and significant changes in treatment outcomes have occurred since the initiation of HAART (41). Complete blood count, β2-microglobulin, lactic dehydrogenase, and complete blood chemistries should be performed, and a radiologic staging should include magnetic resonance imaging (MRI) of the brain and positron emission tomography (PET)/CT scan. Patients in remission after two courses of treatment will tend to remain in remission for the duration of induction therapy. Patients with Burkitt types of lymphoma should have a bone marrow aspiration and biopsy and a diagnostic lumbar puncture. All patients should be screened for hepatitis B, because the exacerbation of this virus by the use of rituximab or chemotherapy can be prevented by screening patients for hepatitis B surface antigen and hepatitis B core antibody and treating those found to have positive results. Hepatitis B surface antigen–positive patients or patients who have a history of hepatitis B with a positive e antigen should be treated for hepatitis B prior to the administration of rituximab. For those with only positive core antibodies, measurements of HBV DNA and of the presence or absence of anti–hepatitis B surface antibodies are important in guiding the decision to intervene (42).
Table 44-3Ann Arbor Staging Classification for Hodgkin Lymphoma ||Download (.pdf) Table 44-3 Ann Arbor Staging Classification for Hodgkin Lymphoma
|Stage ||Characteristics |
|I ||Involvement of a single lymph node region (I) or a single extralymphatic organ or site (IE). |
|II ||Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site (IIE). |
|III ||Involvement of lymph node regions on both sides of diaphragm (III) or localized involvement of an extralymphatic organ or site (IIIE) or spleen (IIIS) or both (IIISE). |
|IV ||Diffuse or disseminated involvement of one or more extralymphatic organs with or without associated lymph node involvement. The organ(s) involved should be identified by a symbol: A, asymptomatic; B, fever, sweats, weight loss >10% of body weight. |
Before HAART, the presence of an opportunistic infection, less than 100 CD4+ cells/μL of blood, bone marrow involvement, and increased age predicted for a poor survival, with patients often suboptimally treated due to poor tolerance to standard doses of chemotherapy. After HAART, two factors have become predictors of poor survival: a CD4+ cell count of less than 100 cells/μL and high-intermediate International Prognostic Index scores (43).
Therapy for Acquired Immunodeficiency Syndrome–Related Systemic Non-Hodgkin Lymphoma
Prior to HAART, all regimens had in common reduced doses of chemotherapy. After 1996, it became clear that patients on HAART can receive standard doses of chemotherapy. The outcomes of treatment in the presence of HAART are related to the subtype of lymphoma and the specific treatment rather than the immunodeficiency status of the patient (Table 44-4). Vigorous prevention of infections with prophylactic antibiotics, aggressive use of growth factors (G-CSF and pegylated G-CSF), and rituximab where indicated have improved the outcomes for these patients (Table 44-5). Although investigators were originally concerned that rituximab might compromise the immune status of patients with CD20+ B-cell lymphomas, studies have demonstrated that rituximab can safely be used for patients with ≥50 CD4+ cells/μL of blood.
Table 44-4Summary of Selected HIV-Related Lymphoma Trials ||Download (.pdf) Table 44-4 Summary of Selected HIV-Related Lymphoma Trials
|Chemotherapy Regimen ||No. of Patients ||Median CD4 Cell Count at Enrollment (/μL) ||CR (%) ||ORR (%) ||HAART ||OI (%) ||OS ||Year (ref.) |
|MTX/LV ||29 ||132 ||46 ||77 ||AZT ||NR ||12 months ||1997 (82) |
62% at 8.5 months
|Infusional CDE ||62 ||NR ||48 ||74 ||NR ||NR ||2.7 years ||2002 (46) |
|G-CSF+CDE-R ||30 ||132 ||86 ||90 ||Yes ||7 ||80% at 2 years ||2002 (47) |
|EPOCH ||39 ||198 ||74 ||87 ||Held during chemotherapy ||a ||60% at 53 months ||2003 (48) |
Table 44-5Suggested Supportive Care for the Patient With HIV Infection and Lymphoma or Other Malignancies ||Download (.pdf) Table 44-5 Suggested Supportive Care for the Patient With HIV Infection and Lymphoma or Other Malignancies
|Indication ||Drug(s) |
|Primary infection prophylaxis || |
| Pneumocystis carinii, Toxoplasma ||Trimethoprim-sulfamethoxazole 1 DS daily. Alternatives for patients with allergy to Bactrim-DS are dapsone 100mg PO once a day or atovaquone 1500mg once a day with food. |
| Oral and/or esophageal candidiasis ||Fluconazole 100 mg daily |
| MAI complex (CD4 <50 cells/μL) ||Azithromycin 1,200 mg weekly |
|Secondary infection prophylaxis || |
| Herpes simplex infections ||Acyclovir 400 mg bid or 200 mg tid |
| Cytomegalovirus infection ||Ganciclovir 1 g tid |
| Mycobacterium avium complex ||Clarithromycin 500 mg bid plus ethambutol |
| ||15 mg/kg daily, with or without rifabutin 300 mg daily |
| Toxoplasma gondii ||Sulfadiazine 1-1.5 g q6h, pyrimethamine 25-75 mg daily |
| ||Leucovorin 10-25 mg daily-qid |
| Cryptococcus neoformans ||Fluconazole 200 mg daily |
| Salmonella bacteremia ||Ciprofloxacin 500 mg bid |
|Hematopoietic growth factors || |
| For selected patients in whom the risk of febrile neutropenia ≥40% ||G-CSF 5 μg/kg or GM-CSF 250 μg/m2 SC daily beginning after completion of chemotherapy and continuing until neutrophil recovery |
|Antiretroviral agents || |
| Selecting patients for therapy ||aFollow NIH guidelines |
| Role of therapy in controlling malignancy || |
| Kaposi sarcoma ||Essential |
| Lymphoma ||Unknown |
| Other tumors ||Unknown |
|May be used with myelosuppressive drugs || |
General principles of HIV treatment:
An INSTI, NNRTI, or PI combined with 2 NRTIs.
NRTIs: emtricitabine/tenofovir (Truvada) or abacavir/lamivudine (Epzicom); with an INSTIs: dolutegravir or raltegravir.
NNRTIs: rilpivirine (weak CYP3A4 inducer); efavirenz. Efavirenz can be combined with emtricitabine/tenofovir in a single capsule (Atripla). Strong inducer of CYP34A.
|Avoid with myelosuppressive drugs/regimens ||Zidovudine |
|Avoid with neurotoxic drugs/regimens ||Didanosine, zalcitabine, stavudine |
|May alter the metabolism of cytotoxic drugs metabolized by cytochrome P-450 enzymes ||All PIs and NNRTIs |
Regimens commonly used to treat patients with AIDS-related DLBCL include CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab plus CHOP (R-CHOP), R-CDE (rituximab, cyclophosphamide, doxorubicin, and etoposide), and dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) or dose-adjusted EPOCH plus rituximab (EPOCH-R). Progression-free survival rates at 2 years for these different treatment regimens are 70% for R-CHOP and R-CDE and approximately 90% for dose-adjusted EPOCH-R (44,45,46,47,48,49,50). In the case of Burkitt lymphoma, CHOP and similar regimens are not recommended because the response is poor. Burkitt lymphoma should be treated with R-HyperCVAD (rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone) (51,52) or R-CODOX-M/IVAC (rituximab plus cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high-dose cytarabine) (53). Either protocol can achieve remissions of more than 92% and a 2-year overall survival rate of 49% (Figs. 44-3 and 44-4). Recent data suggest that dose-adjusted EPOCH-R also has excellent activity against Burkitt lymphoma, establishing this regimen as a potential new standard of care. This regimen known as SC(for short)-RR (Rituximab days 1 and 5)-DA-EPOCH for HIV-related Burkitt lymphoma consists of a 4-day infusion of etoposide (50 mg/m2/d), vincristine (0.4 mg/d), and doxorubicin (10 mg/m2/d) admixed in the same solution, along with prednisone, at a dose of 60 mg/m2/d orally on days 1 to 5. Cyclophosphamide is given at a dose of 750mg/m2 as 2-hour infusion on day 5. Rituximab is given at a standard dose of 375 mg/m2 on days 1 and 5. Filgrastim is given subcutaneously starting on day 6 until the absolute neutrophil count is 5,000/μL (post nadir). Cyclophosphamide is increased or decreased from the previous course dose if the absolute neutrophil count nadir is over 500/μL or less than 500/μL ANC, respectively. Importantly, only cyclophosphamide is dose-adjusted for hematologic toxicity. Patients receive one cycle after complete remission is established for a minimum of three cycles and a maximum of six cycles (Table 44-6). All patients receive intrathecal chemotherapy (54). For patients with relapsed or refractory lymphoma, R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) or R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, and cisplatin) can be of value. Patients with disease responsive to salvage therapy can be considered for high-dose chemotherapy and autologous stem-cell transplantation or experimental therapies (55).
Computed tomography positron emission tomography scan in a 51-year-old HIV-positive patient demonstrating extensive involvement by Burkitt lymphoma of the chest, abdomen, and pelvis.
Same patient as in Fig. 44-3. The computed tomography positron emission tomography scan after four courses of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyperCVAD) alternated with high-dose methotrexate-ara-C an leucovorin rescue, reveals a dramatic improvement with no residual hypermetabolic activity. The patient went on to complete eight courses of treatment with hyperCVAD-HD methotrexate-Ara-C-leucovorin rescue. He remains in complete remission of the Burkitt lymphoma 4 years after treatment and on highly active antiretroviral therapy.
Table 44-6Short-Course Dose-Adjusted EPOCHa ||Download (.pdf) Table 44-6 Short-Course Dose-Adjusted EPOCHa
|Drug ||Dose ||Route ||Treatment Days |
|Infused agentsb || || || |
| Etoposide ||50 mg/m2/d ||CIV ||1, 2, 3, 4 (96 h) |
| Doxorubicin ||10 mg/m2/d ||CIV ||1, 2, 3, 4 (96 h) |
| Vincristinec ||0.4 mg/m2/d ||CIV ||1, 2, 3, 4 (96 h) |
|Bolus agents || || || |
| Cyclophosphamide (cycle 1) ||750 mg/m2/d ||IV ||5 |
| Cyclophosphamide dose adjustment (after cycle 1)d nadir ANC <500/μL or platelets <25,000/μL for 2 to 4 days. ||↓ 187 mg/m2. Route and treatment days remains unchanged. below previous cycle ||NA ||NA |
If the nadir ANC <500/μL or platelets <25,000/μL for more than 5 days, reduce cyclophosphamide by 50% of the initial full dose.
|375 mg/m2 below previous cycle. Under route and Treatment Days put NA. || || |
|60mg/m2/d ||PO ||1,2,3,4,5. |
|375 mg/m2 ||IVPB ||1 and 5. |
|Filgrastim ||5 μg/kg/d ||SC ||6→ANC >5000/μL past nadir) |
|Next cyclee || || ||Day 21 |
Acquired Immunodeficiency Syndrome–Related Non-Hodgkin Lymphoma: Primary Central Nervous System Lymphoma
Epidemiology and Pathogenesis
Primary CNS lymphoma became an AIDS-defining malignancy in 1983. Primary CNS lymphoma accounted for up to 15% of NHLs in HIV-infected patients compared to only 1% of NHLs in the general population. In the pre-HAART era, typical patients were men who were younger (median age, 40 years) than their immunocompetent counterparts, with CD4+ cell counts of less than 50 cells/μL of blood. The impact of HAART was evidenced by a significant decrease in the disease incidence after 1996 (from 313.2 per 100,000 person-years to 77.4 per 100,000 person-years) (3). The development of PCNSL is related to the effect of HIV immunodeficiency on the activity of EBV. The virus does not replicate in CNS tissue. Thus, infected B cells most likely reach the CNS in increased numbers as a result of the progression of the HIV infection. There is loss of capacity by specific T cells for the production of IFN-γ in response to EBV peptides with increased expression of EBNA-2, LMPs, and EBERs (EBV latency type III). This pattern is seen when EBV transforms primary B cells in vitro. The expression of type III latency upregulates genes involved in transformation, including Bcl-2 and IRF-7, and inactivation of p53 and Rb tumor suppressor gene products (56).
Clinical Presentation and Diagnosis
Patients with AIDS and PCNSL present with acute organic brain syndrome, in contrast to immunocompetent patients, in whom neurologic deterioration can be slow and progressive. Headaches, seizures, and focal neurologic signs and symptoms are common. Personality changes are frequent, and nausea and vomiting indicate an increased intracranial pressure. When the rare comatose state occurs, it indicates an acute intracranial catastrophe, such as intratumoral hemorrhage.
Patients with a primary lesion in the brain and no history of systemic lymphoma usually have a brain lesion as the sole manifestation of the disease (Fig. 44-5). Radiologic diagnostic methods paired with analysis of the cerebrospinal fluid are the cornerstones of the diagnosis of PCNSL. Diagnostic MRI of the brain is preferred to CT scan because of the capacity of the former to detect small lesions. Whenever MRI is not available, CT scan is acceptable because it allows detection of larger lesions (≥1 cm) and provides information about safety of performing a lumbar puncture. Prior to and after HAART, the most important differential diagnosis of PCNSL has been cerebral toxoplasmosis, the most frequent cause of cerebral infection and masses in severely HIV-immunosuppressed patients (57). In both PCNSL and cerebral toxoplasmosis, multiple lesions can occur, and both can also have enhancing ring lesions, so distinction between the two can be difficult. A positive serology for toxoplasmosis can be helpful if titers are >1:256. If the toxoplasmosis serology is negative, the presence of EBV DNA by PCR in the cerebral spinal fluid and a positive single-photon emission CT–thallium scan of the brain have high specificity for diagnosis of the PCNSL (58,59). More recently, flow cytometry examination of the cerebrospinal fluid has been used to detect occult disease (60).
Evaluation of brain lesions in patients with human immunodeficiency virus (HIV) disease. CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; NHL, non-Hodgkin lymphoma. (Adapted with permission, from Sparano JA. Clinical aspects and management of AIDS-related lymphoma. Eur J Cancer. 2001;37:1296-1305.)
During the early years of the AIDS pandemic, it was difficult to perform invasive procedures in patients afflicted by an infectious process of which little was known and much was feared. These difficulties resulted in a series of practices borne out of necessity rather than rational approaches to the management and treatment of these patients such as the routine empirical treatment of brain lesions with anti-toxoplasmosis therapy and gauging the diagnosis of the patient based on the clinical response to the anti-toxoplasmosis treatment. Today, there is little room for continuation of such practices, and they should be avoided. They cause unnecessary delays in diagnosis and complicate the patient’s management because there are potential side effects associated with treatment for an illness the patient may not have. Therefore, unless there is an absolute contraindication, the standard of care for a patient with a brain lesion and AIDS is the performance of a stereotactic biopsy of the brain, particularly in patients with a negative serology for toxoplasmosis.
Treatment of Primary Central Nervous System Lymphoma
Highly active antiretroviral therapy is the first step in the treatment of these patients. There is a clear correlation between the immune status of the patient and prognosis. The use of steroids and anticonvulsants is debated among some investigators concerned with the potential of steroids to confound the histologic diagnosis. However, a few days of steroids (4-5 days) can be of clinical benefit, particularly when there is an obvious mass effect. Anticonvulsive therapy administered for a few days can allow the stabilization of the neurologic condition of the patient controlling the risk of focal or grand mal seizures. Even solitary lesions of PCNSL tend to infiltrate surrounding tissues. Thus, there is no role for surgical resection in the treatment of this disease.
Before HAART, whole-brain radiotherapy was standard of care for PCNSL, until replaced by best comfort measures, as the brains of severely immunocompromised patients tolerated poorly the administration of radiotherapy. Similarly to immunocompetent patients with PCNSL, high-dose methotrexate and rituximab have replaced the administration of radiotherapy in patients with HIV and PCNSL. Investigators have suggested a modification of a standard regimen used for the treatment of patients without HIV, which includes rituximab 500 mg/m2 on day 1 and methotrexate 3.5 g/m2 and vincristine 1.4 mg/m2 given only on day 2. Leucovorin rescue is given in standard fashion, and HAART treatment is initiated or continued. This modified regimen is administered for five to six cycles depending on the tolerance of the patient followed by four courses of monthly maintenance with radiotherapy administered in a stereotactic manner at the discretion of the treating physician (61).
Hodgkin Lymphoma: An Aids-Defining Illness?
Epidemiology, Clinical Features, and Therapy
People infected with HIV have a 10-fold higher risk of developing HL than do HIV-seronegative persons. However, in contrast to KS and NHL, the risk is more pronounced in patients with HIV who only have moderate immunosuppression. In general, patients with HIV have a higher incidence of an unfavorable histology, including mixed cellularity and lymphocyte depletion subtypes of HL, when compared with that seen in patients without HIV infection. Instead of observing a decrease in HL in patients in the post-HAART era, as with certain NHL subtypes, investigators have noted an increase in the incidence of HL in HIV patients (62). This observation has made the relationship between immunodeficiency and HL uncertain. Despite the WHO inclusion as an AIDS-defining malignancy, HL is not considered by most experts as a true AIDS-associated disease. From the pathogenesis point of view, EBV is often associated with HIV-related HL, in the range of 80% to 100%. The Reed-Sternberg cells of HIV-related HL express the EBV-encoded LMP-1, known to have oncogenic properties (63). In the post-HAART era, it has been postulated that an increase in CD4+ cells as a result of antiretroviral therapy fosters the development of the appropriate cellular milieu seen in HL in patients without HIV infection. These CD4+ cells, generated as a result of immune reconstitution by HAART, produce ligands for membrane receptors in the Reed-Sternberg cells that activate the classical NF-κB pathway (63).
Clinically, patients with HIV and HL are young and have stage III or IV disease with B symptoms (fever, night sweats, and loss of >10% of body weight). Bone marrow involvement is frequent at the time of diagnosis (64). In the pre-HAART era, the immunodeficiency of the patients limited the use of standard chemotherapeutic regimens in patients with HL. In the post-HAART era, the standards of care applicable to patients without HIV disease and HL have been applied successfully to patients with AIDS and HL once the HIV disease is controlled. Prior to HAART, Levine and colleagues in the ACTG evaluated the efficacy of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with G-CSF in 21 HIV-seropositive patients. There was an overall response rate of 62%, with 43% complete response and 19% partial response. The median survival in this cohort was 1.5 years. Almost half the patients experienced grade 4 neutropenia, and 29% of patients developed opportunistic infections (65). In this study, patients did not receive antiretroviral therapy while on treatment. Following the introduction of HAART during treatment, investigators reported that ABVD induced a 91% complete remission rate and a median time to relapse of over 36 months (66). Other investigators used the Stanford V regimen, administering only short-term chemotherapy (12 weeks) with adjuvant radiotherapy. Of 59 patients who received this therapy, 69% completed the treatment without dose reduction or delays in the administration of the chemotherapy. Eighty-one percent of the patients achieved a complete remission, and with a median follow-up of 17 months, 33 (56%) of 59 patients were alive and free of disease (67). After the introduction of HAART, the response rates for patients treated with ABVD or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) became essentially similar, irrespective of the patient’s stage of the disease. However, more treatment-related mortality occurred in patients who received BEACOPP (68). The available data suggest that ABVD with HAART should be the initial treatment of choice for HIV-related HL. High-dose chemotherapy and autologous stem cell transplantation are being explored for patients who have disease progression while on treatment or relapse after remission induction. Thus, because of HAART, patients with HL and HIV disease can be treated with standard-of-care options that are similar to those used for HL patients who do not have HIV.