Non-Hodgkin's lymphoma (NHL) is a type of lymphoma - a tumour that involves the uncontrolled multiplication of a type of white blood cell called lymphocytes. NHL may occur either in the lymph nodes or elsewhere, such as the spinal cord and brain (the central nervous system [CNS]), the gastrointestinal tract, the liver or kidneys. It has also occurred in unusual sites such as the anus, rectum, mouth, muscle and other soft tissue.

NHL, also known as B-cell lymphoma, is the most common lymphoma seen in people with HIV, and is diagnostic of AIDS. There are several types of AIDS-associated lymphomas:

• Small non-cleaved cell or Burkitt's lymphoma.

• Diffuse large cell lymphomas: large non-cleaved cell lymphomas, immunoblastic plasmacytoid lymphomas, and primary central nervous system lymphomas.

• Primary effusion lymphomas.

The other main kind of lymphoma is Hodgkin's disease - see Hodgkin's disease in Symptoms and illnesses: A to Z of illnesses.

When NHL first occurs in the CNS it is known as primary CNS lymphoma. This can occur at a wide range of CD4 counts: 75% of people with primary CNS lymphoma have a count above 50 cells/mm³, although most have a CD4 count below 200 cells/mm³. If the lymphoma occurs outside the CNS it is called systemic lymphoma. Seventy-five percent of cases occur in people who have already experienced multiple opportunistic infections. Longer duration of HIV infection is associated with greater risk of lymphoma, independent of CD4 cell count.

NHL among people with HIV is more aggressive, and responds less well to therapy, than in HIV-negative people. NHL has been associated with a poor prognosis in people with HIV although survival time has been extended since the introduction of highly active antiretroviral therapy (HAART). In the past, people with AIDS-related NHL lived for an average of four to eleven months after their NHL diagnosis, depending on the severity of immune suppression, while those with primary CNS lymphoma lived for an average of two to four months, regardless of CD4 cell count. However, recent research has shown that people with NHL who were treated with HAART had a median survival time of two years.

Cause

The cause of NHL is unknown, but the disease is usually associated with over-active B-lymphocytes and immune deficiency. B-cells are blood cells of the immune system produced in the bone marrow and the spleen, and they are involved in the production of antibodies.

Indicators of B-cell stimulation, high levels of immunoglobulin and p24 antigen in the blood, are apparent for several years before the emergence of NHL.

No-one knows exactly why the B-cells become over-activated. Possible causes include:

• HIV-related damage to the germinal centres in the lymph nodes where, in the healthy immune system, B-cells are normally exposed to foreign organisms.

• HIV-related disruption to normal levels of cytokines (chemical messengers).

• Repeated stimulation by organisms such as viruses.

The most common virus to cause this kind of problem is thought to be Epstein-Barr virus (EBV), which can be isolated from a high proportion of lymphomas. EBV is a common virus which has infected most people by adult life. On infection it may cause glandular fever, but afterwards it stays dormant in cells. EBV is particularly associated with the immunoblastic plasmacytoid subtype and may directly contribute to B-cell proliferation (Cohen 2000). Whether EBV plays a role in the development of Burkitt's lymphoma is more controversial.

NHL is more common among people who had Kaposi's sarcoma at their time of AIDS diagnosis than in people with other AIDS-defining infections such as Pneumocystis pneumonia (PCP). The link between the two conditions is unclear. However, it is clear that people with AIDS-related NHL are at increased risk of KS, and vice versa. Human herpes virus 8 (HHV-8), the virus linked to Kaposi's sarcoma, has been demonstrated to be present in the cells of one rare type of AIDS-related lymphoma, known as body-cavity based lymphoma.

A person's genetic make-up also influences his or her risk of NHL. The genetic variation known as SDF1-3'A is strongly associated with development of NHL in HIV-infected people. This genetic variation is more common among people of white European origin compared to those of black African origin.

Impact of antiretroviral therapy on non-Hodgkin's lymphoma

Antiretroviral therapy can play a crucial part in slowing or resolving AIDS-related NHL. Early research had produced conflicting evidence about the impact of antiretroviral therapy on the incidence of lymphoma. However, a growing body of research has found improved health outcomes among people with AIDS-related NHL.

For example, several studies have shown that antiretroviral therapy extends the survival of people diagnosed with AIDS-related NHL. Retrospective analysis of over 4500 people with HIV in France found that antiretroviral therapy reduced the risk of death due to NHL by 12-fold (Thiessard 2000). An Italian study of 44 people with NHL found that antiretroviral therapy reduced the aggressiveness of NHL. Suppression of viral load while on antiretroviral therapy, regardless of whether treatment was commenced before or after NHL diagnosis, was associated with a better response to antiretroviral therapy and chemotherapy, as well as improved survival (Antinori 2001). A recent Australian study has also shown that the median survival time of patients with AIDS-related NHL has increased from 4.2 months prior to the availability of antiretroviral therapy to 19 months in the HAART era (Robotin 2004).

Another study found that co-administration of chemotherapy and antiretroviral therapy was associated with a greater chance of complete remission of NHL (Navarro 2001). A review of NHL patients attending the Hô°©´al Saint-Louis in Paris found that overall survival at two years had risen to 62% in the era of HAART, with 69% achieving complete remission of NHL (G鲡rd 2002). An Italian study of 30 people with NHL reported 80% survival at two years. Treatment with HAART and chemotherapy (cyclophosphamide [Endoxana], doxorubicin [Caelyx / Myocet] and etoposide [Etopophos / Vepesid] plus rituximab [MabThera) produced a complete remission rate of 86% (Tirelli 2002).

Despite the encouraging news regarding treatment, researchers are still unsure if the incidence of NHL among people with AIDS is declining. Several studies have suggested that immune restoration does not protect against NHL to the same extent as it protects against other AIDS-related diseases and cancers:

• The American MACS study found rates of lymphoma increased by 21% between 1989 and 1994, and 1996 and 1997.

• The incidence of lymphoma has not declined in the HAART era and NHL now constitutes a greater proportion of first AIDS-defining conditions (Matthews 2000).

• The Swiss HIV Cohort Study has found that individuals with a history of immunodeficiency continue to be at risk of NHL despite the advent of antiretroviral therapy (Ledergerber 1999).

• An Australian study found that antiretroviral therapy was associated with a non-significant decline in the incidence of NHL. Long-term immune deficiency and B-cell stimulation were the factors associated with NHL (Grulich 2000).

However, several studies have recently reported significant declines in the incidence of NHL:

• The EuroSIDA group has reported that HAART is reducing the number of new cases of NHL. Of 8507 HIV-infected people followed from 1994 to 1999, 209 cases of NHL were diagnosed. Among people on HAART, the number of new cases of NHL was 0.7 per 100 person-years in comparison to a rate of 1.4 per 100 person-years among those who did not receive HAART - a statistically significant difference. The reduced rate of NHL was most pronounced for people with CD4 cell counts below 50 cells/mm³. In contrast to the above studies which demonstrated extended survival of people with NHL in the age of HAART, median survival was unchanged at three month (Mocroft 2000).

• A New York study reported that NHL declined by 53% from 1995 to 1997.

• The International Collaboration on HIV and Cancer reported that incidence of AIDS-associated NHL fell from 6.2 during 1992 to 1996 to 3.6 during 1997 to 1999, based on a study group of over 47,000 people.

• The Women's Interagency HIV Study has found that HAART has reduced the incidence of NHL in HIV-positive women, but that it remained above that of HIV-negative women (Hessol 2004).

The reasons for this conflicting evidence are unclear. The impact of HAART on the incidence of lymphoma may take years to emerge, because lymphoma is in part the result of the long-term over-stimulation of the immune system. On the other hand, some experts have suggested that the longer survival of people with damaged immune systems and over-stimulated B-cells may explain the increased rate of lymphoma reported in some studies.

Certainly there is evidence that the profile of patients developing NHL has changed since HAART became available. The British prospective cohort study has found that patients with NHL in the HAART era were older, were less likely to have had a previous AIDS-defining condition, and had a higher average CD4 cell count (Matthews 2000). A recent analysis of cancer survival in patients with AIDS in New York City has also shown improvements in survival since 1996, although these did not reach the levels of patients without AIDS between 1996 and 2000. This trend was found for CNS NHL, as well as immunoblastic, Burkitt's and large cell diffuse types of non-CNS NHL (Biggar 2005).

Similarly, a study of 363 patients with AIDS-related lymphoma found that survival of patients with diffuse large cell lymphoma increased in the HAART era. In contrast, however, survival of Burkitts lymphoma patients with AIDS remains poor, and that poor survival is related to low CD4 cell counts (Lim 2005). This was in agreement with a sub-study of the PETHEMA-LAL3/97 study, showing significantly better two-year survival in Burkitts lymphoma patients with a successful virological response to HAART, compared with those who did not reach viral loads below 80 copies/ml (Oriol 2005).

Rapid progression, development and spread of cancerous lesions or tumours have been reported in patients responding to HAART. It is postulated that these growths are an immune reconstitution response to the viruses that trigger these cancers.

Symptoms

Nearly all people with HIV-related NHL are found to have systemic lymphoma. Common symptoms are fevers, enlarged lymph nodes and spleen, unexplained weight loss or drenching night sweats. Neurological problems can include headaches, confusion, memory loss, lethargy, partial paralysis affecting one side of the body (hemiparesis), loss of ability of speak or understand language (aphasia) and seizures.

Diagnosis

NHL can be diagnosed from a sample of bone marrow or lymph node, or from any other part of the body which is affected. Doctors will often also perform a computed tomography (CT) scan of the head, chest, abdomen and pelvis, although a brain scan will not necessarily tell the difference between NHL and other brain problems such as toxoplasmosis. A sample of the cerebrospinal fluid (CSF) may be taken by lumbar puncture to check for malignant lymphoma cells. The presence of EBV in the CSF increases the likelihood that a brain mass is lymphoma. If there are gastro-intestinal symptoms, the gut may be examined used a fibre-optic endoscope. Some blood tests can also be useful. These look for unusually high levels of lactase dehydrogenase (LDH) or uric acid.

If lymphoma is found, it is graded as low, intermediate or high grade, based on how rapidly the cancerous cells are growing. It is also staged (stages I to IV) based on the extent of tissue involvement, as assessed by body scans and CSF tests. A further classification takes account of the shape and size of the B-cells that make up the lymphoma.

Treatment

All treatment for HIV-related lymphoma should be considered experimental, although treatment for NHL among people who do not have HIV is well established.

The usual treatment for NHL which is concentrated in the brain (primary CNS lymphoma) is radiotherapy of the whole brain. This is usually accompanied by a short-term course of steroids such as dexamethasone (Decadron) to shrink oedema (swelling due to the accumulation of fluid) and the tumour. Whole-brain radiotherapy seems to result in improvement in symptoms in about three-quarters of recipients. There is no evidence that more aggressive treatments such as chemotherapy are more effective. NHL in lymph nodes and skin may also respond well to radiotherapy.

Disseminated lymphoma is usually treated with cytotoxic chemotherapy drugs. In uninfected people, NHL responds well to aggressive treatment with cytotoxic chemotherapy, but this tends to be less successful in HIV-positive people. Studies suggest that people who receive intensive chemotherapy survive for longer than untreated people. People with CD4 cell counts above 200 cells/mm³ are best able to tolerate aggressive treatment. Reduced dose regimens may be better for people with CD4 cell counts below 100 cells/mm³. Chemotherapy is usually given periodically, such as once every two weeks for six months, and anti-anxiety and anti-nausea medicines should also be offered.

One widely used drug combination is CHOP (cyclophosphamide, doxorubicin, vincristine [Onconvin] and prednisolone). Overall response in one trial was 67%. These regimens can cause neutropenia (platelet deficiency). The addition of granulocyte colony stimulating factor (G-CSF) reduces the severity and duration of neutropenia and is to be preferred over granulocyte macrophage colony stimulating factor (GM-CSF) which risks increasing HIV replication.

Another option is m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone). One trial of this achieved a 46% response rate. An American study comparing standard dose mBACOD with intermediate doses (half-doses of doxorubicin, cyclophosphamide and dexamethasone) found no difference in response rates or overall survival.

Researchers from the American National Cancer Institute developed the EPOCH regimen (etoposide, vincristine and doxorubicin administered continuously by infusion for 96 hours and cyclophosphamide and prednisone administered orally) with good results in HIV-negative individuals with NHL. In patients with HIV, the first cycle of cyclophosphamide is given at a reduced dosage, based on the CD4 cell count of the individual, and subsequent dosage is determined by the by neutrophil levels.

Other chemotherapy regimes include:

• Cyclophosphamide, doxorubicin and etoposide (CDE).

• COMP.

• PRO-MACE/MOPP.

Dexamethasone, cytosine arabinoside and cisplatin (DHAP) and etoposide, methylprednisolone, cytosine arabinoside, and cisplatin (ESHAP) have been used to treat NHL which has not responded to other chemotherapy regimens. While DHAP produced very poor response rates, about one third of people receiving ESHAP in two small studies achieved complete remission (Yuzon 2000; Bi 2001).

It is important to take PCP prophylaxis while receiving chemotherapy, because the treatment itself causes immunosuppression which increases the risk of opportunistic infections.

People who have disseminated lymphoma, especially when lymphoma cells can be detected in the bone marrow or the CSF, may be offered treatment to try to prevent the lymphoma from spreading further. This consists of injections of cytarabine (DepoCyte) or methotrexate into the spinal column (intrathecally).

Rituximab is a treatment which kills both normal and cancerous B-cells. The body can replace normal B-cells after several months. Rituximab is an approved treatment in the United Kingdom and the United States for NHL which is resistant to other chemotherapies. The addition of rituximab to a CDE regimen in 41 HIV-infected people who were also taking HAART produced an 76% complete remission rate (Tirelli 2003). Rituximab has also been added to CHOP, with 40 of 50 patients having complete remission at the end of six cycles of treatment. However, over 18 months of follow-up, 17 patients died of lymphoma-related causes (Boue 2003).

Treatment of non-Hodgkin's lymphoma in the age of highly active antiretroviral therapy

The best way to manage HIV-infected people with NHL in the age of HAART has not yet been established. Concurrent HAART and chemotherapy or suspension of HAART are the two main options. Both strategies have risks and benefits.

In a review article, Dr Richard Little and colleagues recommended delaying or interrupting HAART during the period of high intensity chemotherapy. Dr Little gave several reasons for this recommendation:

• Drug-drug interactions.

• Additive toxicities.

• Inability to optimally administer medications.

According to Dr Little, the immediate survival of a person with NHL is dependent on the remission of the cancer. Consequently, optimal administration of chemotherapy is the priority. Interruption of HAART may be warranted given that anti-HIV drugs such as indinavir (Crixivan), ddI (didanosine, Videx / VidexEC), efavirenz (Sustiva) and nevirapine (Viramune) may reduce drug levels of some anti-cancer drugs. In addition, the protease inhibitors may slow drug processing and worsen side-effects. Dr Little argued that worsening side effects may lead to poor adherence and drug resistance to HAART, thus undermining the longer term outcomes for the patient.

Interrupting HAART in people with advanced HIV disease who are taking chemotherapy is not without risks. For instance, CD4 cell counts may drop suddenly due to overall suppression of T-cells by the anti-lymphoma drugs as well as increased HIV replication due to the withdrawal of HAART. Nevertheless, Dr Little argued that the benefits outweigh the risks. "Relatively brief uncontrolled HIV viraemia is unlikely to have unfavourable long-term immunologic or clinical consequences if appropriate opportunistic infection prophylaxis is used," he wrote.

In support of this approach to management, Dr Little cited a study of 23 people who suspended antiretroviral therapy for the duration of chemotherapy. Three-quarters were alive 23 months later, 70% had full remission of NHL, and CD4 T-cell recovery occurred within six to twelve months (Little 1999).

There are alternatives to interrupting HAART in HIV-infected people with NHL. These are:

• Continuation of HAART with close monitoring for drug tolerance and adherence.

• Modification of HAART to reduce likelihood of interactions and overlapping toxicities.

In support of concurrent HAART and chemotherapy, one small study reported no additional adverse side-effects during co-administration of HAART and chemotherapy. However, CD4 cell counts may decline during chemotherapy despite HAART, so there may be no apparent benefit in continuing HAART while taking chemotherapy. As mentioned in the treatment sections, chemotherapy plus HAART is producing high rates of complete remission and two-year survival in recent studies.

Managing drug interactions

Limited information is available on the HIV Drug Interactions website run by the Liverpool HIV Pharmacology Group. They provide information on potential interactions between protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) and five anti-cancer drugs: cyclophosphamide, doxorubicin (Adriamycin), paclitaxel (Taxol), vinblastine (Velbe), and vincristine (Oncovin). This advises that doxorubicin does not interact with anti-HIV drugs (whereas the other agents do), and that nevirapine presents fewer problems than other antiretrovirals.

Drugs from the nucleoside analogue reverse transcriptase inhibitor (NRTI) class do not present the same type of drug interaction issues associated with PIs and NNRTIs as they use different routes to pass through the body. However, their use in combination with chemotherapy may still be problematic because of overlapping side effect profiles. AZT (zidovudine, Retrovir) plus chemotherapy increases the risk of bone marrow suppression and so is generally not used in this setting. 3TC (lamivudine, Epivir), d4T (stavudine, Zerit) and ddI present fewer problems. There appears to be little information on the use of abacavir (Ziagen) with chemotherapy. It may be a concern that symptoms of the hypersensitivity reaction associated with this drug may be difficult to distinguish from the systemic side effects seen during chemotherapy.

Given that the daily pill burden may be quite high, taking liquid formulations of anti-HIV medications may be preferable for some people. In addition, chemotherapy can cause mucositis, an inflammation of the mucous membranes which may cause difficulty swallowing.

Experimental treatments

A number of other chemotherapies are being tested in HIV-infected and non-HIV-infected people. For example, a small, phase II study has found that cyclophosphamide, doxorubicin and etoposide are comparable to standard chemotherapy (Sparano 2002). Studies of ECV (etoposide, cyclophosphamide and vincristine plus G-CSF) and FM (fludarabine and mitoxantrone) in HIV-negative people with lymphoma have also been promising (Sehn 1999; Velasquez 1999).

A study of BEMOP/CA was conducted at the Chelsea and Westminster Hospital. The regimen involves alternate weekly infusions of bleomycin, etoposide, methotrexate and vincristine with weekly infusions of cyclophosphamide and doxorubicin for 21 weeks. After two years of follow-up, 40% had died of lymphoma and the overall survival rate was 45% (Bower 2000).

There are a number of experimental approaches to treating NHL. It is thought that one possible cause of the over-active B-cells which are associated with NHL could be the cytokine interleukin-6 (IL-6), which stimulates B-cells and suppresses T-cells. If true, treatments that inhibit IL-6, such as antibodies against it or other cytokines such as IL-4 could be helpful for NHL. IL-6 production is also stimulated by the cytokine tumour necrosis factor α (TNF-α), so TNF-inhibitors such as pentoxifylline (Trental) or thalidomide might also be useful for people with NHL.

Anti-B4-blocked ricin is an experimental treatment which is being tested in combination with CHOP to improve response rates. Anti-B4 is an antibody that attaches specifically to malignant B-cells. Ricin is a toxin attached to the B4 antibody. In theory, the antibodies will attach to the lymphoma cells and the ricin will kill the cells. A similar drug being tested is denileukin diftitox, a fusion protein of interleukin-2 and diphtheria toxin that targets the CD25 receptor on B-cells. This has shown a response rate of 25% in a phase II study (Dang 2004). Researchers are also testing newer chemotherapy drugs such as paclitaxel (Taxol), MGBG and camptothecins such as topotecan (Hycamtin).

Researchers are also investigating anti-EBV therapies as treatment options for NHL and other EBV-associated tumours.

Pegylated L-asparaginase is an anti-cancer drug which is being tested as a second-line treatment for lymphoma.

Liposomal daunorubicin (DaunoXome) has been tested as a treatment for NHL which has not responded to standard chemotherapy regimens.

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 non-Hodgkin's lymphoma. 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 reconsitutution of the immune system by replacing the cells that are killed during the course of drug treatment (Gabarre 2004).

Research into incidence and survival

Marasca (2003) studied 112 cases of NHL which occurred between 1986 and 2001. Two thirds of o people diagnosed with HNHL after Jan. 1997 had been on HAART for at least 6 months. Average survival for people diagnosed before 1997was 204 days; for people diagnosed since Jan. 1997average survival was 506 days. The factor associated with risk of death in the pre 1997 period was age > 35 years. In the post 1997 period, previous AIDS diagnosis was associated with risk of death, while commencing HAART after the diagnosis of NHL was associated with survival.

Balestre reported that HAART and anti-herpes treatment were associated with reduced risk of NHL in the HAART era among HIV-infected people.

Eltom (2002) reported that NHL incidence among white men in the US rose from 10.7 in 1973 to 31.4 in 1995 and then fell to 21.6 in 1998. The declining incidence in the mid-1990s was attributed to the falling number of people with AIDS and improved immune function among those who are HIV-infected.

Mocroft (2000) studied 8507 patients enrolled in the EuroSIDA cohort between 1994-1999. 209 cases of non-Hodgkin's lymphoma (NHL) were diagnosed. The incidence among those on HAART was 0.7 per 100 person-years (py) in contrast to 1.4 per 100 py among those not on HAART. Among those on HAART, the incidence of NHL fell from 0.9 per 100 py during the first year of treatment to 0.6. HAART made no significant impact on the incidence of NHL for those with CD4 counts above 200 but did have a substantial impact on incidence among those with CD4 counts below 50 (3.6 vs 8.1 per 100 py). The difference was driven by a reduction in primary CNS lymphoma; other forms of NHL did not fall. Median survival after diagnosis was 3 months. In the HAART era, NHL made up a larger proportion of AIDS-defining conditions as the total number of other AIDS illnesses fell.

Matthews (2000) studied AIDS-related lymphoma among a prospective cohort of 7840 HIV-infected gay and bisexual men. Between 1988-1995 there were 95 cases of lymphoma and between 1996-1999 there were 51 cases. The mean annual incidence of lymphoma did not change between the pre and post-HAART era, although the annual incidence of AIDS conditions did fall significantly. In the post-HAART era, there were several significant changes in the profile of individuals with lymphoma: the proportion of patients with a prior AIDS condition fell from 57% to 34%; the median age rose from 38 to 44 years, and the median CD4 count rose from 38 to 107 in people who had not taken HAART, and to 214 in people who had used HAART. Overall survival at 2 years rose from 29% to 41% - a non-significant increase.

Thiessard (2000) retrospectively analysed the Aquitaine cohort of 4697 people with HIV. 101 cases of NHL were identified, of whom 44 had taken NRTIs and 18 had taken PI containing therapy. At the time of analysis, 85 people had died and there was an average survival time of people with NHL was 6 months. HAART reduced the risk of death 12 fold. Other factors associated with increased survival were: NRTI therapy, CD4 count above 50, haemoglobin above 10, and early stage of disease. Median survival of people with NHL on HAART was about 2 years.

The International Collaboration on HIV and Cancer (2000) calculated the incidence of HIV-related cancers including NHL among HIV-infected people drawing on data from 23 prospective studies involving over 47000 people. The incidence of NHL fell from 6.2 during 1992-1996 to 3.6 during 1997-1999.

Tam (2002) studied 100 HIV-infected men from the MACS cohort who developed NHL between 1990-1999. 13 received HAART. Multivariate analysis showed that HAART was associated with 84% reduced risk of death among those with NHL.

Baiocchi (2002) reviewed 20 cases of NHL, including 7 people who received HAART. Average CD4 count of people with NHL before HAART was 36 compared to 137 for those who developed NHL while receiving HAART. Median survival in the pre-HAART era was 5 months compared with 31 months in the HAART era. 4/7 patients who took HAART remain alive in complete remission.

Gerard (2002) compared characteristics of NHL in the pre- and post-HAART eras, drawing on the records of 246 HIV-infected patients with NHL attending a French hospital. In the HAART era, the majority of people with NHL had untreated or uncontrolled HIV infection, and they had more advanced disease than people with NHL in the pre-HAART era. 24% developed NHL despite undetectable virus. Two-year survival was 62% vs 36% in the post- and pre-HAART eras, while the rate of complete remission was 69% vs 55%.

Diamond (2004) examined AIDS-related NHL in San Diego county between 1988 and 2000. Among 537 AIDS-NHL cases, 410 (76%) were diagnosed pre-HAART (to 1995) and 127 (24%) were diagnosed post-HAART (from 1996). The rate of NHL among reported AIDS cases in San Diego decreased from 61.8 per 1000 in 1988 to a nadir of 35.9 per 1000 in 2000 (r = 0.47, p = 0.11). Although the number of AIDS-NHL cases gradually decreased each post-HAART year (32 in 1996, 31 in 1997, 25 in 1998, 23 in 1999 and 16 in 2000), this mirrored the total decline in AIDS cases in San Diego. Median survival time of systemic NHL increased significantly post-HAART; four months pre-HAART vs. nine months post-HAART (p <0.001). However, among CNS NHL cases, the median survival was two months pre-HAART vs. one month post-HAART (p = 0.39).

Ledergerber (1999) analysed data from 6,636 people with HIV over 18,498 person years, comparing new AIDS defining conditions between 1992-1994 and July 1997-June 1998. Overall, new AIDS defining illnesses fell from about 150 per 1,000 person-years to 35 per 1,000 person-years. The number of new cases of NHL did not decline, although the number of new cases of KS did decline.

Cote (1992) reported that in a study of over 51,000 people with AIDS in the USA, NHL occurred in 4.3%. NHL was part of an AIDS-defining condition for 3.2% of all participants. 39% of cases of NHL among people with AIDS were high grade (versus 12% among HIV-negative people with NHL), 60% were nodal (versus 74% among HIV-negative cases) and 15% had brain primaries (versus 1% among HIV-negative cases).

Sparano (1999) reported an annual incidence of HIV-associated NHL fell by 63% in 1997 compared to 1990-1995 at a New York cancer centre.

Peters (1994) found that the proportion of HIV-positive people who develop lymphomas at one London clinic doubled between 1986 and 1992, with a particularly marked increase in the number of lymphomas of the small bowel. A quarter of lymphomas were in the mouth or throat. The survival of people diagnosed with lymphoma also doubled since 1987; current mean survival was 120 days after diagnosis, or 190 days when lymphoma was the first AIDS-related illness.

Ridolfo (1996) reported that among 363 people with AIDS at an Italian clinic, NHL was more common in the 63 who had Kaposi's sarcoma as their AIDS-defining illness. These patients were five times more likely to develop KS than those whose AIDS-defining event was PCP.

Also see 'Research into HAART and chemotherapy' below.

Research into the cause of NHL

Sei (2001) reported that levels of stromal cell-derived factor 1 (SDF-1) were raised in subjects with non-Hodgkin's lymphoma (NHL) and that elevations were present 1-2 years before NHL diagnosis.

Grulich (2000) found that serum globulin, a marker of B-cell activation, was strongly and independently associated with NHL.

MacMahon (1991) reported finding evidence of latent Esptein Barr virus (EBV) infection in 21 cases of AIDS-related primary central nervous system (CNS) lymphoma studied at necropsy. Cinque (1993) detected EBV DNA in stored cerebrospinal fluid (CSF) from 17/17 patients with necropsy-confirmed primary CNS lymphoma, and in the tissue of 16/16 cases. EBV DNA was found in CSF from 1/68 HIV-infected patients without histologically detectable lymphoma at necropsy. It is suggested that EBV might therefore have a role as a marker in the diagnosis of AIDS-related primary CNS lymphoma.

Cohen (2000) reported that EBV genetic material expresses the latent membrane protein-1 which drives B-cell proliferation and programmed cell death, suggesting that EBV may play a direct causal role in some lymphomas.

Cesarman (1995) reported the presence of HHV-8 in AIDS-related body-cavity based lymphomas.

Martinez-Maza (2002) reviewed factors contributing to the development of NHL in HIV infection. Hyperactivation of B-cells and overproduction of B-cells cytokines are thought to contribute to the condition. A virus encoded, cytokine-like molecule HHV8vIL6 may play a role in inducing B-cell hyperactivation. Previously Martinez-Maza reported that serum sCD23 (B-cell growth factor) was elevated greater than 20-fold in sera from participants in the MACS cohort who developed lymphoma during the following 12 to 18 months, as compared with people with AIDS without lymphoma, or HIV-negative people.

So (1986) reported focal neurologic signs such as hemiparesis (partial paralysis affecting one side of the body) or aphasia (loss of ability to speak or understand language) in 35%, seizures in 15%, and cranial nerve palsies in 10% of people with CNS lymphoma. Confusion, memory loss, and lethargy were reported in 60%. Gill (1988) reported changes in personality, apathy and confusion.

NHL and AZT

In August 1990 a study estimated that an unexpectedly high proportion of people with AIDS who were treated with AZT and survived for three years would develop NHL. This suggestion caused much concern that the NHL might be caused by therapy with AZT. However, no causal link between NHL and therapy with AZT has been shown in subsequent studies. Furthermore, NHL has been seen in people with AIDS since the early years of the epidemic, before AZT was ever used.

The increased incidence of NHL was attributed to the longer survival of people in a state of severe immunosuppression given that less-immunosuppressed patients treated with AZT did not show an increased incidence of NHL. Peters (see above) reported a comparison of people who had taken AZT for over 2 years and people who had never taken AZT. There was no significant difference in the occurrence of lymphoma and no evidence that people who have taken high cumulative doses of AZT were at increased risk of lymphoma.

Research into HAART and chemotherapy

Anti-NHL treatment research

References

Antinori A et al. Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy. AIDS 15: 1483-1491, 2001.

Baiocchi OC et al. Impact of highly active antiretroviral therapy in the treatment of HIV-infected patients with systemic non-Hodgkin's lymphoma. Acta Oncologica 41: 192-196, 2002.

Balestre E et al. Risk factors for non-Hodgkin lymphoma in HIV-infected patients in the HAART era: a case control study in the Aquitaine Cohort (1996-2002). Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 75, 2003.

Baumgartner J et al. Primary central nervous system lymphomas: natural history and response to radiation therapy in 55 patients with acquired immunodeficiency syndrome (AIDS). Journal of Neurosurgery 73: 206-211, 1990.

Bermudez M et al. Non-Hodgkin's lymphoma in a population with or at risk for AIDS: Indications of intensive chemotherapy. Amer J Med 86: 71-76, 1989.

Bi J et al. High-dose cytosine-arabinoside and cisplatin regimens as salvage therapy for refractory or relapsed AIDS-related non-Hodgkin's lymphoma. J Acquir Immune Defic Syndr 28: 416-421, 2001.

Biggar RJ et al. Survival after cancer diagnosis in persons with AIDS. J Acquir Immune Defic Syndr 39: 293-299, 2005.

Boue F et al. CHOP chemotherapy plus rituximab in HIV patients with high-grade lymphoma-results of an ANRS trial. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 805P, 2003.

Bower M et al. Weekly alternating combination chemotherapy for good prognosis AIDS-related lymphoma. European Journal of Cancer 36(3): 363-367, 2000.

Cesarman E et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. New England Journal of Medicine 332: 1186-1191, 1995.

Cinque P et al. Epstein-Barr virus DNA in cerebro-spinal fluid from patients with AIDS-related primary lymphoma of the central nervous system. Lancet 342: 398-401, 1993.

Cohen JI. Epstein-Barr virus infection. New England Journal of Medicine 343(7): 481-492, 2002.

Corales R et al. Regression of AIDS related CNS lymphoma with HAART. Thirteenth International AIDS Conference, Durban, abstract B1086, 2000.

Cote TR et al. Non-Hodgkin's lymphoma among people with AIDS: incidence, presentation and public health burden. International Journal of Cancer 73(5): 645-650, 1997.

Dang NH et al. Phase II study of denileukin diftitox for relapsed/refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol 22: 4095-4102, 2004.

Diamond C et al. Decreased Cases of and Improved Survival from AIDS-associated Non-Hodgkin's Lymphoma in the Era of Highly Active Antiretroviral Therapy. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 786, 2004.

Eltom MA et al. Trends in Kaposi's sarcoma and non-Hodgkin's lymphoma incidence in the United States from 1973 through 1998. Journal of the National Cancer Institute 94(16): 1204-1210, 2002.

Formenti S et al. Primary central nervous system lymphoma in AIDS: results of radiation therapy. Cancer, 63(6): 1101-1107, 1989.

Franssen E et al. The Canadian phase I-II trial of VACOP-B with G-CSF for HIV related non-Hodgkin's lymphoma (NHL): feasibility of concomitant triple antiretroviral therapy. 35th Annual Meeting of the American Society of Clinical Oncology, Atlanta, abstract 99, 1999.

Gabarre J et al. High-dose therapy plus autologous hematopoietic stem cell transplantation for human immunodeficiency virus (HIV)-related lymphoma: results and impact on HIV disease. Haematologica 89: 1100-1108, 2004.

G鲡rd L et al. Systemic non-Hodgkin lymphoma in HIV-infected patients with effective suppression of HIV replication: persistent occurrence but improved survival. Journal of Acquired Immune Deficiency Syndromes 30(5): 478-484, 2002.

Gill PS et al. HIV-related malignant lymphoma: clinical aspects, treatment, and pathogenesis. Cancer Investigation 6: 413-416, 1988.

Gisselbrecht C et al. Treatment of HIV-related non-Hodgkin's lymphoma adapted to prognostic factors. 35^th Annual Meeting of the American Society of Clinical Oncology, Atlanta, abstract 55, 1999.

Grulich AE et al. B-cell stimulation and prolonged immune deficiency are risk factors for non-Hodgkins lymphoma in people with AIDS. AIDS 14(2): 133-140, 2000.

Herndier BG et al. Pathogenesis of AIDS lymphomas. AIDS 8: 1025-1049, 1994.

Hessol NA et al. Cancer risk among participants in the Women's Interagency HIV Study. J Acquir Immune Defic Syndr 36: 978-985, 2004.

Hoffman C et al. The Short and Intensive B-ALL Protocol Is a Highly Effective Regimen in Patients with AIDS-associated Burkitt or Burkitt-like Lymphoma. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 787, 2004.

International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. Journal of the National Cancer Institute 92(22): 1823-1830, 2000.

Jacobson LP et al. Impact of potent antiretroviral therapy on the incidence of Kaposi's sarcoma and non-Hodgkin's lymphomas among HIV-1-infected individuals. Multicenter AIDS Cohort Study. Journal of Acquired Immune Deficiency Syndromes 21(supp 1): S34-S41, 1999.

Jacomet CH et al. Intravenous methotrexate for primary central nervous system non-Hodgkin's lymphoma in AIDS. AIDS 11(14): 1725-1730, 1997.

Kaplan LD et al. Clinical and virological effects of recombinant human granulocyte-macrophage colony stimulating factor in patients receiving chemotherapy for HIV-associated non-Hodgkin's lymphoma: Results of a randomised trial. Journal of Clinical Oncology 9: 929-940, 1991.

Kaplan LD et al. Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection. New England Journal of Medicine 336: 1641-1648, 1997.

Karp JE et al. Perspectives in Cancer Research: AIDS and non-Hodgkin's lymphomas. Cancer Research 51: 4743-4756, 1991.

Knowles et al. Lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS). Annals of Internal Medicine, 108: 744-753, 1988.

Krown S. Treatment of AIDS-associated malignancy. Cancer Detect Prev 14: 405-409, 1990.

Ledergerber B et al. Risk of HIV related Kaposi's sarcoma and non-Hodgkin's lymphoma with potent antiretroviral therapy: prospective cohort study. Br Med J 319: 23, 1999.

Levine AM. Lymphoma in acquired immunodeficiency syndrome. Semin Oncol 17: 104-112, 1990.

Levine AM. Low dose chemotherapy with CNS prophylaxis and zidovudine (AZT) maintenance in AIDS-related lymphoma. JAMA 266: 84-88, 1991.

Lim ST et al. AIDS-related Burkitts lymphoma versus diffuse large-cell lymphoma in the pre-highly active antiretroviral therapy (HAART) and HAART eras: significant differences in survival with standard chemotherapy. J Clin Oncol 23: 4430-4438, 2005.

Little RF et al. HIV-associated non-Hodgkin lymphoma: incidence, presentation, and prognosis. JAMA 285: 1880-1885, 2001.

Little RF et al. Dose-adjusted EPOCH chemotherapy in previously untreated HIV-associated non-Hodgkin's lymphoma (HIV-NHL). 35^th Annual Meeting of the American Society of Clinical Oncology, Atlanta, abstract 33, 1999.

MacMahon EME et al. Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338: 969-973, 1991.

Marasca G et al. Survival and prognostic factors after non Hogdkin lymphoma in patients infected with the human immunodeficiency virus in a single centre cohort, UCSC, Rome, Italy, 1986-2001. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract H-1929, 2003.

Martinez-Maza O et al. B-cell activation and lymphoma in patients with HIV. Current Opinions in Oncology 14(5): 528-532, 2002.

Matthews GV et al. Changes in acquired immunodeficiency syndrome-related lymphoma since the introduction of highly active antiretroviral therapy. Blood 96(8): 2730-2734, 2000.

Mocroft A et al. AIDS across Europe, 1994-98: the EuroSIDA study. Lancet 356(9226): 291-296, 2000.

Moore A. Changes in CD4 count and viral load during chemotherapy for AIDS-related lymphomas. Fifth Annual Meeting of the British HIV Association, abstract P47, 1999.

Navarro JT et al. Influence of highly active anti-retroviral therapy on response to treatment and survival in patients with acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma treated with cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone. Br J Haematol 112: 909-915, 2001.

Oriol A et al. Highly active antiretroviral therapy and outcome of AIDS-related Burkitts lymphoma or leukemia. Results of the PETHEMA-LAL3/97 study. Haematologica 90: 990-992, 2005.

Oksenhendler E et al. Intensive chemotherapy (LNHIV-91 regimen) and G-CSF for HIV associated non-Hodgkin's lymphoma. Leuk Lymphoma 39: 87-95, 2000.

Peters B et al. Incidence and disease trends for AIDS-associated lymphomas. Fourth European Conference on Clinical Aspects and Treatment of HIV Infection, Milan, abstract O11, 1994.

Pluda J et al. Development of non-Hodgkin's lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Ann Intern Med 113: 276-282, 1990.

Ratner L et al. Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy. Journal of Clinical Oncology 19(8): 2171-2178, 2001.

Remick SC et al. Primary central nervous system lymphoma in patients with and without the acquired immune deficiency syndrome: a retrospective analysis and review of the literature. Medicine 69: 345-360, 1990.

Ridolfo AL et al. High frequency of non-Hodgkin's lymphoma in patients with HIV-associated Kaposi's sarcoma. AIDS 10: 181-185, 1996.

Robotin MC et al. Clinical features and predictors of survival of AIDS-related non-Hodgkin's lymphoma in a population-based case series

Sehn LH et al. High dose ECV consolidation chemotherapy for poor prognosis lymphoma. 35^th Annual Meeting of the American Society of Clinical Oncology, Atlanta, abstract 47, 1999.

Sei S et al. Increased level of stromal cell-derived factor-1 mRNA in peripheral blood mononuclear cells from children with AIDS-related lymphoma. Cancer Research 61(13):5028-37, 2001.

So Y et al. Primary central nervous system lymphoma in AIDS: a clinical and pathological study. Annals of Neurology 20: 566-572, 1986.

Sparano JA et al. Effect of highly active antiretroviral therapy on the incidence of HIV-associated malignancies at an urban medical center. Journal of Acquired Immune Deficiency Syndromes 21 Suppl 1: S18-22, 1999.

Sparano JA et al. Infusional cyclophosphamide, doxorubicin and etoposide in HIV associated non-Hodgkins lymphoma: a review of the Einstein, Aviano and ECOG experience in 182 patients. Fourth International AIDS Malignancy Conference, Bethesda, abstract S15, 2000.

Sparano JA et al. Phase 2 trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with poor-prognosis, intermediate-grade non-Hodgkin lymphoma: an Eastern Cooperative Oncology Group trial (E3493). Blood 100(5): 1634-1640, 2002.

Tam HK et al. Effect of highly active antiretroviral therapy on survival among HIV-infected men with Kaposi sarcoma or non-Hodgkin lymphoma. International Journal of Cancer 98(6): 916-922, 2002.

Thiessard F et al. Prognostic factors after non-Hodgkin lymphoma in patients infected with the human immunodeficiency virus: Aquitaine Cohort, France, 1986-1997. Groupe d'Epidemiologie Clinique du SIDA en Aquitaine (GECSA). Cancer 88(7): 1696-1702, 2000.

Tirelli U et al. Clinical evaluation of 451 patients with HIV related non-Hodgkin's lymphoma: experience on the Italian cooperative group on AIDS and tumors (GICAT). Leukemia and Lymphoma 20(1-2): 91-96, 1995.

Tirelli U et al. Second line chemotherapy in HIV related non-Hodgkins lymphoma. Cancer 77: 2127-2131, 1996.

Tirelli U et al. Rituximab and infusional cyclophosphamide, doxorubicin, and etoposide: A safe and highly active regimen in HIV-related non-Hodgkin's lymphomas. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 804, 2003.

Tulpule A et al. Peg-L-asparagase (Oncospar) in the treatment of relapsed/refractory AIDS-related lymphomas. 35th Annual Meeting of the American Society of Clinical Oncology, Atlanta, abstract 146, 1999.

Tulpule A et al. Liposomal daunorubicin in the treatment of relapsed or refractory non-Hodgkin's lymphoma. Annals of Oncology 12(4): 457-462, 2001.

Velasquez W et al. SWOG 95-01: a phase II trial of a combination of fludarabine and mitoxantrone (FN) in untreated advanced low grade lymphoma. An effective, well tolerated therapy. 35th Annual Meeting of the American Society of Clinical Oncology, Atlanta, abstract 27, 1999.

Walsh D et al. Phase I study of m-BACOD with GM-CSF in AIDS-associated non-Hodgkin's lymphoma (NHL): Preliminary results. Blood 74(suppl 1):126a, 1989.

Yuzon R et al. Treatment of relapsed/refractory AIDS-related lymphoma with high dose cytarabine/cisplatin combination regimens. Thirteenth International AIDS Conference, Durban, abstract B1085, 2000.