**2. General aspects of HIV lymphoma**

Lymphomas are known to occur with an increased frequency in PWHA (20,21,23). NHL (Non-Hodgkin's Lymphoma) is the commonest malignancy in the post cART (combination antiretroviral therapy) era in PWHA. The incidence of NHL in resource-rich settings has decreased in the post cART era compared to the pre cART era (23-24). However, the contrary is true in resource-poor settings, with a noticeable increase in NHL incidence (24- 26). This is particularly true of sub-Saharan Africa - the epicenter of the HIV pandemic. The increase in NHL incidence is due mainly to the high prevalence and heavy burden of HIV in sub-Saharan Africa, a region in which two thirds of PWHA reside, and additionally, in many countries in sub-Saharan Africa, there has been a lack of availability of, or delay in initiation of cART. In South Africa, which is home to over 5 million PWHA, the rollout of cART occurred in 2004, 8 years later than in the Western world (introduced in developing countries during the end of 1996 and the beginning of 1997) and until recently, cART was generally only available to individuals with CD4 counts of <200/ul. Although this practice has changed in the last two years, with access/availability of cART to individuals with a higher CD4 count of <350/ul, the burden of diseases related to the immunodeficiency state (with notable exceptions such as Kaposi's sarcoma) appear to be on the increase (17,25,26,27).

In Africa, the HIV/AIDS epidemic was first reported in 1984 (28). The major risk of HIV in Africa occurs in/with heterosexual relationships, and accounts for an approximately equal male to female ratio, as compared to the Western world in which the major risk groups involve intravenous drug use and homosexual relationships, thus predominantly affecting males. Furthermore, early in the HIV epidemic, there was no marked increase in the incidence of NHL compared to the USA. This was attributed to PWHA dying earlier in the course of their disease possibly from infectious complications such as pneumonia and tuberculosis. The decreased longevity prevented the subsequent or later development of NHL. In addition, there may be underreporting of lymphoma or the missed diagnosis of lymphoma, with a diagnosis of an infective cause of lymphadenopathy (such as tuberculosis) being favoured over lymphoma, in the absence of performing a fine needle aspirate or lymph node biopsy (28-30).

At Chris Hani Baragwanath Academic Hospital (CHBAH) – a tertiary, public sector, University of the Witwatersrand linked hospital located in Soweto, Johannesburg, studies in the 1990's with respect to HIV-NHL showed only a modest increase of NHL in seropositive individuals, with an odds ratio of 4.8, 5 and 5.9 respectively (31-33). The first patient at this hospital with HIV-NHL was seen in 1993. Since then, there has been a steady increase in HIV-NHL up to 2000. However, since 2001, the percentage seropositivity of NHL has exceeded 50% (approximately between 60 – 80%), and since 2002, there has additionally been a significant increase in the total number of patients diagnosed with NHL at CHBAH (from 20-30 new patients per year to 70-80 patients per year) (see Table 1 and Figure 1) (25). Indeed, NHL is now the commonest haematological malignancy in South Africa, in the current HIV/AIDS era and the number of seropositive patients continues to increase.

296 Immunodeficiency

(17,25,26,27).

aspirate or lymph node biopsy (28-30).

post solid organ and haematopoietic stem cell transplantation) and autoimmune disease

HIV infection is known to be associated with an increased risk of HL, based on linkage and cohort studies. The relative risk is now 10-15 fold higher compared with the general population (13-15,17,18,20-22). This review will focus on HL in southern Africa, and describe the differences compared to HL in developed countries, highlighting the emerging increase in HL in the HIV seropositive population/people living with HIV/AIDS (PWHA).

Lymphomas are known to occur with an increased frequency in PWHA (20,21,23). NHL (Non-Hodgkin's Lymphoma) is the commonest malignancy in the post cART (combination antiretroviral therapy) era in PWHA. The incidence of NHL in resource-rich settings has decreased in the post cART era compared to the pre cART era (23-24). However, the contrary is true in resource-poor settings, with a noticeable increase in NHL incidence (24- 26). This is particularly true of sub-Saharan Africa - the epicenter of the HIV pandemic. The increase in NHL incidence is due mainly to the high prevalence and heavy burden of HIV in sub-Saharan Africa, a region in which two thirds of PWHA reside, and additionally, in many countries in sub-Saharan Africa, there has been a lack of availability of, or delay in initiation of cART. In South Africa, which is home to over 5 million PWHA, the rollout of cART occurred in 2004, 8 years later than in the Western world (introduced in developing countries during the end of 1996 and the beginning of 1997) and until recently, cART was generally only available to individuals with CD4 counts of <200/ul. Although this practice has changed in the last two years, with access/availability of cART to individuals with a higher CD4 count of <350/ul, the burden of diseases related to the immunodeficiency state (with notable exceptions such as Kaposi's sarcoma) appear to be on the increase

In Africa, the HIV/AIDS epidemic was first reported in 1984 (28). The major risk of HIV in Africa occurs in/with heterosexual relationships, and accounts for an approximately equal male to female ratio, as compared to the Western world in which the major risk groups involve intravenous drug use and homosexual relationships, thus predominantly affecting males. Furthermore, early in the HIV epidemic, there was no marked increase in the incidence of NHL compared to the USA. This was attributed to PWHA dying earlier in the course of their disease possibly from infectious complications such as pneumonia and tuberculosis. The decreased longevity prevented the subsequent or later development of NHL. In addition, there may be underreporting of lymphoma or the missed diagnosis of lymphoma, with a diagnosis of an infective cause of lymphadenopathy (such as tuberculosis) being favoured over lymphoma, in the absence of performing a fine needle

At Chris Hani Baragwanath Academic Hospital (CHBAH) – a tertiary, public sector, University of the Witwatersrand linked hospital located in Soweto, Johannesburg, studies in

(12-18). There is also an increased risk of familial aggregation of HL (19).

**2. General aspects of HIV lymphoma** 

With respect to Hodgkin's lymphoma (HL), the data is less dramatic, but is becoming more significant. In a study by Stein et al, 2008 (33), the percentage seropositivity of HL in a South African cohort (which included patients from CHBAH) was 19.5% (OR=1.6, 95% CI=1.0-2.7), during the period 1995-2004. The first patient with HIV-HL was seen in 1994 at CHBAH. Since then, there has been a modest increase in HIV-HL up to 2006. However, in the last 5 years (2007 - 2011) at our single institution, the percentage seropositivity is greater than 50% (see Figure 2) and the number of patients over the years are gradually increasing (doubled compared to an earlier series in the late 1980's and early 1990's – (17,34)(see Figure 3). Thus, the focus of this review relates to the emerging problem of Hodgkin's lymphoma in the setting of HIV in southern Africa.


**Table 1.** Patients with non-Hodgkin's Lymphoma seen at Chris Hani Baragwanath Academic Hospital from 1993 to 2008

Hodgkin's Lymphoma and Human Immunodeficiency Virus Infection 299

**Figure 3.** Total number of patients with Hodgkin's Lymphoma seen at Chris Hani Baragwanath

HL occurring in the setting of immunodeficiency (with particular reference to HIV/AIDS) is generally aggressive, presents with advanced stage disease, frequent constitutional ('B') symptoms, less favourable histology, more frequent bone marrow involvement and a poorer

With the advent of HAART (highly active antiretroviral therapy), now referred to as cART (combination antiretroviral therapy), the AIDS related morbidity, particularly with respect to opportunistic infections has decreased and the survival of HIV/AIDS patients has increased (35,36). In the post cART era, ADCs (AIDS-defining cancers) continue to fall, but the rates of NADCs (non-AIDS defining cancers) such as HL, anal carcinoma, lung carcinoma and skin cancers are on the increase (37). With HL, there is a noticeably increasing relative risk of approximately 10 - 15 fold, compared with the general population

Several epidemiological studies conducted in the last two decades, and summarised in the article by Carbone et al, 2009 (22) strongly support the evidence that HIV positive individuals have a higher risk of developing HL compared to their HIV negative counterparts. This is in contrast to HIV-NHL or HIV-Kaposi's sarcoma (where the incidence

Academic Hospital from 1990 - 2011

(13-15,17,18,20-22).

**3. Hodgkin's lymphoma and HIV** 

**3.1. Introduction and epidemiology** 

prognosis compared to immunocompetent individuals (17,18).

**Figure 1.** HIV seropositive and HIV seronegative patients with non-Hodgkin's Lymphoma from 1993 to 2008 seen at Chris Hani Baragwanath Academic Hospital

**Figure 2.** HIV seropositive and HIV seronegative patients with Hodgkin's Lymphoma from 1990 to 2011 seen at Chris Hani Baragwanath Academic Hospital

**Figure 3.** Total number of patients with Hodgkin's Lymphoma seen at Chris Hani Baragwanath Academic Hospital from 1990 - 2011
