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.

A French case control study, which identified cases of NHL and matched them according to sex, CD4 count and length of follow-up with other HIV-positive individuals in the Aquitaine cohort database found that more than six months of HAART significantly reduced the risk of developing NHL.1

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.2 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.3 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.4

An analysis of survival after a diagnosis of NHL in 847 individuals from 33 European HIV cohorts found that overall, five-year survival was 54%; a poorer prognosis was associated with a nadir CD4 count below 25, older age and lymphoma of the brain. 5 The incidence of NHL was significantly lower (RR 0.44) in people taking antiretroviral therapy, and a CD4 count above 350 and a viral load below 500 copies/ml were protective.6 The German Clinical Surveillance of HIV Disease study identified 66 NHL cases diagnosed between 1999 and 2006 among 6000 HIV patients receiving care, and found that the cumulative viral load rather than the most recent viral load, age or CD4 count was the strongest predictor of developing lymphoma.7

Another study found that co-administration of chemotherapy and antiretroviral therapy was associated with a greater chance of complete remission of NHL.8 A review of NHL patients attending the Hospital 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.9 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%.

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.
  • Another retrospective US study found that mortality rates due to NHL among people with HIV remained essentially unchanged between 1996 and 2005.10
  • The incidence of lymphoma has not declined in the HAART era and NHL now constitutes a greater proportion of first AIDS-defining conditions.11
  • 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.12
  • 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.13

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 months.14
  • 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.15
  • A review of cancer registry data from California between 1981 and 2003 showed that the incidence of NHL fell from 29.6 per 1000 person-years pre-HAART to 6.5 per 1000 person-years post-HAART (1996 onwards).16

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.[ref] A US study similarly found more deaths from NHL among patients with a prior AIDS-defining illness or CD4 cell count below 200 cells/mm3; patients with higher CD4 cell counts and no history of AIDS-defining illnesses were no more likely to die of NHL than HIV-negative individuals.10

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.17

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 Burkitt's lymphoma patients with AIDS remains poor, and that poor survival is related to low CD4 cell counts.18 This was in agreement with a sub-study of the PETHEMA-LAL3/97 study, showing significantly better two-year survival in Burkitt's lymphoma patients with a successful virological response to HAART, compared with those who did not reach viral loads below 80 copies/ml.19

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.

References

  1. Bonnet F et al. Factors associated with the occurrence of AIDS-related non-Hodgkin lymphoma in the era of highly active antiretroviral therapy: Aquitaine Cohort, France. Clin Infect Dis 42(3):411-7, 2006
  2. 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), 2000
  3. 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
  4. Robotin MC et al. Clinical features and predictors of survival of AIDS-related non-Hodgkin's lymphoma in a population-based case series in Sydney, Australia. HIV Med 5: 377-384, 2004
  5. COHERE study group Prognosis of HIV-associated non-Hodgkin lymphoma in patients starting combination antiretroviral therapy. AIDS 23(15):2029-37, 2009
  6. COHERE study group Incidence and risk factors of HIV-related non-Hodgkin's lymphoma in the era of combination antiretroviral therapy: a European multicohort study. Antivir Ther 14(8):1065-74, 2009
  7. Zoufaly A et al. Cumulative HIV viremia during highly active antiretroviral therapy is a strong predictor of AIDS-related lymphoma. J Infect Dis 200: 79-87, 2009
  8. 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
  9. Gérard L et al. Systemic non-Hodgkin lymphoma in HIV-infected patients with effective suppression of HIV replication: persistent occurrence but improved survival. J Acquir Immune Defic Syndr 30: 478-484, 2002
  10. Chao C et al. Survival of non-Hodgkin lymphoma patients with and without HIV infection in the era of combined antiretroviral therapy. AIDS 24: online edition DOU:10. 1097/QAD.0b013e32833a0961, 2010
  11. 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
  12. Ledergerber B et al. Risk of HIV related Kaposi's sarcoma and non-Hodgkin's lymphoma with potent antiretroviral therapy: prospective cohort study. British Medical Journal 319(7201): 23-24, 1999
  13. 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
  14. Mocroft A et al. AIDS across Europe, 1994-98: the EuroSIDA study. Lancet 356(9226): 291-296, 2000
  15. Hessol NA et al. Cancer risk among participants in the Women's Interagency HIV Study. J Acquir Immune Defic Syndr 36: 978-985, 2004
  16. Diamond C et al. Changes in acquired immunodeficiency syndrome-related non-Hodgkin lymphoma in the era of highly active antiretroviral therapy: incidence, presentation, treatment, and survival. Cancer 106(1):128-35, 2006
  17. Biggar RJ et al. Survival after cancer diagnosis in persons with AIDS. J Acquir Immune Defic Syndr 39: 293-299, 2005
  18. 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
  19. Oriol A et al. Highly active antiretroviral therapy and outcome of AIDS-related Burkitts lymphoma or leukemia. Results of the PETHEMA-LAL3/97 study, 2005
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