Ongoing viral replication during HIV treatment associated with lymphoma risk

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Ongoing HIV replication when a person is receiving antiretroviral treatment increases the risk of AIDS-related lymphomas developing, German investigators report in the July 1st edition of the Journal of Infectious Diseses. The researchers found that the longer a patient had a detectable viral load, the greater the risk of lymphoma.

“To our knowledge”, write the investigators, “this is the first study to show that uncontrolled HIV replication during HAART [highly active antiretroviral therapy], as assessed by cumulative HIV viremia, is predictive of the development of AIDS-related lymphoma”.

An accompanying editorial suggests that the findings of the study raise “many questions about the optimal care of HIV-infected patients.”

Glossary

lymphoma

A type of cancer that starts in the tissues of the lymphatic system, including the lymph nodes, spleen, and bone marrow. In people who have HIV, certain lymphomas, such as Burkitt lymphoma, are AIDS-defining conditions.

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

detectable viral load

When viral load is detectable, this indicates that HIV is replicating in the body. If the person is taking HIV treatment but their viral load is detectable, the treatment is not working properly. There may still be a risk of HIV transmission to sexual partners.

viraemia

The presence of virus in the blood.

 

AIDS defining condition

Any HIV-related illness included in the list of diagnostic criteria for AIDS, which in the presence of HIV infection result in an AIDS diagnosis. They include opportunistic infections and cancers that are life-threatening in a person with HIV.

The incidence of AIDS-defining illnesses fell dramatically after the introduction of effective antiretroviral therapy in the mid 1990s. AIDS-related lymphomas are the most common cancer seen in HIV-positive patients and account for approximately 30% of deaths in this population

Some earlier research has suggested that HIV replication may influence the development of lymphomas. This is possibly because of ongoing immune stimulation and B cell stimulation.

An undetectable viral load is the goal of HIV treatment and has been shown to be protective against the development of lymphomas. However, little is known about the risk of lymphomas for the substantial minority of patients who have ongoing viral replication when taking antiretroviral therapy.

Researchers from the German Clinical Surveillance of HIV Disease study therefore looked at the risk factor for the development of AIDS-related lymphomas amongst a cohort of 6022 patients who were taking HIV treatment. A total of 66 AIDS-defining lymphomas were diagnosed in these patients during a total of 27,812 person-years of follow up. Study data were gathered between 1999 and 2oo6.

The incidence of any lymphoma developing was 2.4 per 1000 person-years of follow up.

Patients who developed a lymphoma had significantly lower CD4 cell counts when HIV therapy was started than patients who remained lymphoma free (90 cells/mm3 vs. 204 cells/mm3, p

The investigators then conducted statistical analysis to identify the factors independently associated with the risk of developing an AIDS-related lymphoma. Multivariate analysis, which controlled for possible confounding factors, showed that increasing age (p = 0.001), a CD4 cell count below 350 cells/mm3 (p

Next the investigators looked at the risk factors associated with individual types of lymphoma.

Risk factors for the development of non-Burkitt high-grade lymphoma were time receiving HIV treatment, a CD4 cell count below 350 cells/mm3 and cumulative viral load during antiretroviral therapy (p = 0.003). Cumulative viral load was the only factor significantly associated with Burkitt-type lymphoma (p

There was no association between viral load and the development of primary lymphomas of the central nervous system, the only significant factors being age (p = 0.04) and a CD4 cell count below 200 cells/mm3 (p = 0.015).

Cumulative viral load was not a risk factor for the development of oesophageal thrush, an AIDS-defining illness. However, duration of HIV treatment, a CD4 cell count below 350 cells/mm3 and a viral load above 500 copies/ml at the time this condition was diagnosed were all identified as risks.

“The present study provides evidence supporting the strong influence of HIV replication on lymphomagenesis”, write the investigators. “Cumulative HIV viremia (rather than the latest viral load) best predicted the development of lymphoma, suggesting an important effect of sustained viremia over time and a distinct pathogenesis of AIDS-related lymphoma, compared with other opportunistic diseases.”

Monitoring viral load is a fundamental part of HIV care, and ongoing HIV replication during antiretroviral therapy usually triggers further investigative tests and a change in treatment. The investigators believe that the findings of their study provide an additional reason for doctors to take a detectable viral load very seriously in patients taking HIV treatment. They conclude: “these results should encourage physicians to optimize HAART for patients with persisting HIV replication, in an attempt to achieve complete viral suppression and to minimize the risk of this life-threatening complication.”

An accompanying editorial notes that the findings of the German research accord with those of the SMART study. This showed that ongoing HIV replication at any CD4 cell count increased the risk of opportunistic diseases.

However, the author notes that the German investigators did not explore the association between viral load and lymphoma risk in patients not taking HIV treatment. She suggests that a fall in CD4 cell count may allows continuing HIV replication to become a significant risk factor for lymphoma.

Noting that many patients only find out that they have HIV when their CD4 cell count is so low that they are at risk of opportunistic infections, the author concludes, “continued attempts to encourage earlier diagnosis of HIV infection may at least permit individuals to start receiving HAART before their CD4 cell count decreases to levels that place them at risk for lymphoma.”

References

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.

Sabin SA. HIV viremia and the development of AIDS-related lymphoma in patients treated with highly active antiretroviral therapy. J Infect Dis 200: 8-10, 2009.