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British study looks at HAART and cancer

For over 25 years, researchers at London’s Chelsea and Westminster Hospital have been collecting health information on HIV positive people who sought care at this institution. They have amassed a huge data set containing information on more than 11,000 HIV positive people. Recently they analysed this data set as part of a study focusing on cancers unrelated to AIDS.

Their findings suggest that HIV positive people face an increased risk for these cancers in the 21st century. Having a CD4+ count that has fallen below the 200-cell mark at some point in the course of HIV disease appeared to be a significant risk factor for such cancers. Troublingly, the study team also found an association between the class of anti-HIV drugs called non-nukes (NNRTIs) and one type of cancer. We discuss the significance of this association later in our report.

Study details

Researchers reviewed health-related information on 11,112 HIV positive people, focusing particularly on cases of cancer unrelated to AIDS. In total, 150 people developed these types of cancer. Their average profile is as follows:

5% female, 95% male
age – 37 years
ethno-racial background: 81% White, 3% Black, and the remainder were not specified
nearly 50% had been previously diagnosed with AIDS
the lowest-ever CD4+ count – 104 cells

Results

About 1% (150 people) developed cancers unrelated to AIDS.

The study team found no increased risk for these cancers before 1996, the year highly active antiretroviral therapy (HAART) became available in the UK. However, after 1996, the risk for cancers unrelated to AIDS doubled.

Risk factors

Taking many issues into account, researchers found that two factors were linked to an increased risk of non-AIDS-related cancer, as follows:

CD4+ cell count – having a CD4+ count that fell below the 200-cell mark at some point in the past was associated with a 67% increased risk of cancer
non-nukes (NNRTIs) – using a non-nuke was linked to a 45% increased risk of cancer

Specific cancers

The study team examined trends in rates of cancers unrelated to AIDS. Here’s what they found about selected cancers:

Anal cancer

Rates of this type of cancer were more than 100 times greater than would be expected in HIV negative people. And the risk for this type of cancer remained elevated throughout the study. Having a CD4+ count that fell below 200 cells was linked to an increased risk for this cancer.

Liver cancer

Rates of liver cancer were about five times higher than seen in HIV negative people. But this cancer only became more common in HIV positive people from 2002 onward. Obviously, co-infection with hepatitis B or C viruses increases the risk of liver cancer. Apart from that, researchers were not able to find other risk factors.

Head and neck cancers

This is the term used for cancers that occur inside the mouth, nose and throat. Researchers noted a trend for increasing rates of this cancer. Many of these cancers would have been caused by human papillomavirus infection, which is sexually transmitted.

Lung cancer

Cancers affecting this organ increased significantly after 1996. In the present era, the risk of lung cancer doubled. Possible risk factors included prolonged HIV infection and a CD4+ count that fell below 200 cells. However, because of the relatively small numbers of people with this type of cancer, these risk factors were not statistically significant.

Hodgkin’s disease

Since the early 1980s researchers have reported this cancer of the immune system affecting people with AIDS. In the present study, the risk for this cancer was about 13 times greater than in HIV negative people. Use of non-nukes doubled the risk for developing this cancer.

Other cancers unrelated to AIDS

In the British study, there was no significant increase seen in cancers affecting the following organs:

brain
kidney
prostate
skin
testicles

Key findings

In this large study there was, according to the research team, a “modest overall increase” in cancers unrelated to AIDS.
This increase occurred a few years after the introduction of HAART but now seems to have stabilized.
Having a CD4+ count that at some point fell below 200 cells increased the risk for developing many cancers unrelated to AIDS.

The question about non-nukes

Because of its study design, the UK team cannot entirely rule out bias when interpreting its findings. Also, the study design restricts the researchers to finding associations; they cannot prove cause (use of non-nukes) and effect (cancer). So their finding of an association between the use of non-nukes and Hodgkin’s disease is, at best, interesting but not definitive. The British team generously acknowledges this limitation in its call for other researchers to try to assess the cancer-causing potential of non-nukes in other study centres.

Had the UK researchers found an association between the use of nucleoside analogues (nukes) and cancer, that finding would seem more plausible. This is because nukes have long been known to damage cells, cause mutations to DNA, and, in some animal experiments, increase the risk of certain cancers.

In general, non-nukes are safe and effective medicines when used as part of combination therapy for HIV/AIDS. No other research team has found any link between the use of non-nukes and the possible development of cancer. And it is entirely possible that the British team’s association, while statistically significant, is wrong. Taking the study design and these other points into consideration, at this time there is no need for alarm.

However, the UK finding of a possible signal of cancer from exposure to non-nukes should lead to at least the following steps:

Lab experiments need to be conducted using cells and commonly used non-nukes, such as nevirapine (Viramune) and efavirenz (Stocrin, Sustiva), to independently assess their cancer-causing potential. The recently approved non-nuke etravirine (Intelence) has not been associated with cancer in cells or animals and is too new to have played a major role in the UK study.
Other large data sets, such as the Veteran’s Administration (VA) in the U.S. and the DAD in the European Union, need to explore their cases of cancer and see if there is any possible link to the use of non-nukes.

—Sean R. Hosein

REFERENCES:

Friedman-Kein A. Disseminated Kaposi’s sarcoma syndrome in young homosexual men. Journal of the American Academy of Dermatology. 1981 Oct;5(4):468-71.
Stern RG, Gamsu G, Golden JA, et al. Intrathoracic adenopathy: differential feature of AIDS and diffuse lymphadenopathy syndrome. American Journal of Roentgenology. 1984 Apr;142(4):689-92.
Bonnet F and Chêne G. Evolving epidemiology of malignancies in HIV. Current Opinion in Oncology. 2008 Sep;20(5):534-40.
Powles T, Robinson D, Stebbing J, et al. Highly Active Antiretroviral Therapy and the Incidence of Non-AIDS-Defining Cancers in People With HIV Infection. Journal of Clinical Oncology. 2009; in press.

Created on: 01/20/2009

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