Hodgkin's disease is a type of lymphoma - a tumour of lymph nodes - named after Thomas Hodgkin, a pathologist who first described it in the early nineteenth century. It is caused by cells that normally live in lymph nodes, particularly lymphocytes, growing out of control and making the node swell. Depending on the type of lymphoma, these cells can spread to other parts of the body causing more damage. The other main kind of lymphoma is non-Hodgkin's lymphoma.

Recent research has confirmed that people with HIV are at increased risk of Hodgkin's disease, despite some early research to the contrary. A number of studies have found that the incidence of Hodgkin's lymphoma among people with AIDS is around eight times the rate in the general population. It is also more common in people who had low nadir CD4 cell counts (Patel 2004). Despite these associations, Hodgkin's lymphoma is not recognised as an AIDS-defining illness. The majority of people with HIV who have developed Hodgkin's disease have had CD4 cell counts around 200 to 300 cells/mm³.

Hodgkin's disease tends to be a more aggressive cancer in HIV-infected people, with the 'mixed cellularity subtype' predominating. Most cases of Hodgkin's disease which occur among HIV-infected people are linked to infection with Epstein-Barr virus (Dolcetti 2001; Rapezzi 2001; Vaccher 2001).

Symptoms and diagnosis

Along with swollen glands, which can get very large, Hodgkin's disease causes a characteristic rising and falling fever known as Pel-Ebstein fever, anaemia and weakness. In people with HIV the disease is particularly likely to spread beyond the lymph nodes, affecting the bone marrow and other parts of the body. This more severe form is known as stage III or IV Hodgkin's disease.

Diagnosis is made by taking a biopsy of a lymph node and studying it under the microscope. Occasionally samples of bone marrow or other soft tissue may be biopsied. The presence of a characteristic cell called the Reed-Sternberg cell must be confirmed to establish the diagnosis.

Treatment

Early Hodgkin's disease (stages I and II) is usually treated with radiotherapy. More advanced Hodgkin's disease (stages III and IV) is treated with combination chemotherapy, using either MOPP (chlormethine, vincristine [Oncovin], procarbazine and prednisolone) or ABVD (doxorubicin [Caelyx / Myocet], bleomycin, vincristine and dexamethasone [Decadron]).

Given low rates of disease-free survival using these regimens in HIV-infected people, a more potent regimen has been tested. Known as Stanford V, the regimen includes mechlorethamine, doxorubicin, vinblastine (Velbe), vincristine, bleomycin, etoposide (Etopophos / Vepesid) and prednisolone administered over a 12 week period. Radiotherapy and highly active antiretroviral therapy (HAART) may be used in conjunction with Stanford V. One study of Stanford V plus antiretroviral therapy in 20 HIV-infected people with Hodgkin's disease found that dose reductions due to side-effects were common. Nevertheless, disease-free survival rate at 18 months was 61%.

A recent study has demonstrated that autologous haematopoietic stem cell transplantation is safe and effective in HIV-positive patients being treated with HAART and with high-dose chemotherapy for Hodgkin's disease. This technique involves removal of stem cells from the bone marrow or blood of a patient before chemotherapy. Once the chemotherapy is finished, the cells are transplanted back into the patient. The transplanted cells have the ability to produce new blood cells and aid the reconstitution of the immune system by replacing the cells that are killed during the course of drug treatment (Gabarre 2004).

Chemotherapy is difficult for HIV-infected people to tolerate. Treatment may be better tolerated when the growth factors granulocyte macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) are given.

People who have a higher CD4 cell count at diagnosis, whose Hodgkin's disease is restricted to the lymph nodes and who have not had previous opportunistic infections, have the best prognosis.

Research

Spina conducted a phase II study of the Stanford V chemotherapy regimen given in conjunction with antiretroviral therapy and PCP prophylaxis to 20 HIV-infected people diagnosed with Hodgkin's disease in Europe between May 1997 and June 1999. The following 28 day Stanford V regimen was given three times: mechlorethamine 6mg/m² intravenously (IV) day 1, doxorubicin 25mg/m² IV days 1 and 15, vinblastine 6mg/m² IV days 1 and 15, vincristine 2 mg/m² IV days 8 and 22, bleomycin 5U/m² IV days 8 and 22, etoposide 60mg/m² IVdays 15 and 16, and prednisone 40mg/m² by mouth every other day. 25% had stage II disease, 25% stage III and 50% stage IV. Median CD4 count was 230 and half had undetectable viral load at Hodgkin's disease (HD) diagnosis. Only 3 subjects had had an AIDS diagnosis before their HD diagnosis. 11/20 completed the prescribed treatment and 40% had dose reductions due to side-effects including constipation, paraesthesias, and bone marrow toxicity. One person who developed life-threatening sepsis ceased chemotherapy. Other common side-effects were mucositis central nervous system toxicity. Neither of the 2 patients with large tumours in their lymph nodes who qualified for radiotherapy took up that option. 16 (80%) patients achieved complete remission, 3 (15%) partial remission and one person progressed. 4/16 with complete remission later relapsed and 3 patients died of HD. At 18 months, overall survival and disease-free survival rates were 76% and 61%, respectively.

Levine reported that treatment with standard doses of ABVD in 21 HIV-positive people with Hodgkin's disease was less effective than observed in HIV-negative people. 56% experienced complete responses, and 25% partial remissions. Haematologic toxicity was significant, despite the use of G-CSF, and hepatic toxicity was common, including grade 4 liver toxicity in 19%. Median survival for the group was 78 weeks, with the primary cause of death intercurrent opportunistic infections.

Tirelli treated 29 HIV-positive people with Hodgkin's disease with intravenous epirubicin (70 mg/m²), bleomycin (10 mg/m²) and vinblastine (6 mg/m²) plus oral prednisone (40 mg/m² on days one to five). After a median of six cycles, the overall response rate was 90%, with 69% complete remissions. 34% developed grade 3 or 4 leukopenia, and 10% grade 3 or 4 thrombocytopenia. median survival was 14 months.

Rapezzi conducted a histological analysis of two large American databases of Hodgkin's disease (HD) of 3245 cases from the Surveillance, Epidemiology and End Results (SEER) database and 1140 cases from the Stanford database. There was a significant difference in histological type by HIV status. Both databases showed that mixed cellularity and lymphocyte depletion were more common among HIV-infected patients.

Poluri compared Hodgkin's disease (HD) in five HIV-infected patients and 11 non-infected patients. 100% of the HIV cases involved the head and neck regions compared to 81% of non-HIV patients. B symptoms (fever, night sweats, fatigue, and wasting) occurred in 40% of HIV cases and 27% of non-HIV cases. 80% of the HIV cases had stage III/IV HD compared to 45% of the non-HIV cases. 75% of HIV cases had mixed cellularity subtype compared to 50% of non-HIV cases.

Re compared 18 HIV patients diagnosed with Hodgkin's disease (HD) with 98 HIV patients with non-Hodgkin's lymphoma (NHL) and 165 uninfected patients with HD. HIV-associated HD was more aggressive in HIV patients with 84% showing stage III/IV disease and 83% with B symptoms. Clinical presentation of HD in HIV patients was similar to NHL, except for a lower frequency of extra-lymph node disease in NHL and a higher frequency of bone marrow involvement in HD patients. Remission rates were similar in the HIV HD and HIV NHL patients.

Goedert studied cancer rates among nearly 100,000 people with AIDS and over a million people with cancer, comparing cancer rates pre- and post-AIDS. People with AIDS had a 7.6 fold increase of Hodgkin's lymphoma, confirming other research. EBV was found in the majority of AIDS-Hodgkin's tumours in contrast to about 25% of non-AIDS tumours.

Hessol observed an excess number of cases of Hodgkin's disease in a cohort of HIV-infected gay men and suggested that it may be an HIV-related malignancy. However, other investigators have not confirmed an excess number of cases.

Grulich (1999) reviewed cases of cancer in HIV-infected people in New South Wales, Australia, between 1980-1993. 716 cases of AIDS-defining cancers and 62 cases of non-AIDS-defining cancers were identified. Nine cases of Hodgkin's lymphoma were detected, well above the number of expected cases of Hodgkin's lymphoma if HIV was not a factor in the development of this cancer.

Grulich (2002) identified 196 non-HIV-related cancers among 8351 HIV cases. 15 cases of Hodgkin's disease occurred among this group, at a significantly higher incidence rate than seen in the general community. Risk of HD was associated with immune deficiency (cases occurring when CD4 counts were between 200-300) and longer duration of HIV infection.

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