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Cancer and HIV
   Last updated: 25.08.04
Is cancer occurring more or less often in people on HAART? by Michael Carter
It is generally agreed that the incidence of the AIDS-defining cancer Kaposi's sarcoma (KS) in people on HAART has declined dramatically. It is also likely that the incidence of cervical cancer has fallen among women on HAART. And although non-Hodgkin’s lymphoma (NHL) diagnoses have risen sharply since 1996, doing well on HAART appears to be a very important factor when it comes to surviving NHL.1

However, the incidence of non-AIDS-defining cancers – such as Hodgkin's lymphoma, anal, liver, lung, and testicular cancer – has been the subject of some debate since the US National Cancer Institute published a study last year which found that such cancers have not become much more common as HIV-positive people in resource-rich countries live longer, despite other studies suggesting that non-AIDS-defining cancers have become more common. Additionally, they argued that non-AIDS-defining cancers were unrelated to CD4 counts.2



The Chicago-HOPS Study
Adding to the debate was a presentation in February from The Chicago-HOPS Study at the Eleventh Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco, which asserted not only that non-AIDS-defining cancers were more common nowadays in HIV-positive people, but that they were related to lowest-ever, or nadir, CD4 counts.3

The researchers looked at the five most common non-AIDS-defining cancers in two major cohorts - 6700 patients at the two largest Chicago HIV clinics and a further 5400 members of the multi-centre HIV Outpatient Study (HOPS) cohort - and compared them with the general population to determine the incidence and relative risk of these cancers in people with HIV for the years 1992 to 2002.

The five non-AIDS-defining cancers were lung cancer, head/neck cancer, Hodgkin's lymphoma, anorectal cancer, and melanoma (skin cancer). Among the HOPS cohort, in analyses adjusted for age, race, smoking, and gender, incidence of four cancers was significantly greater than expected compared with the general population. These were, in order of risk, anorectal, Hodgkin's disease, melanoma and lung cancer. Among Chicago clinic patients, however, the risk for all five cancers was significantly increased, although the relative risk appeared to be much higher for Hodgkin's lymphoma than it did for head/neck, anorectal, melanoma and lung cancer.

When looking at factors associated with these cancers, the researchers found that those who had developed cancer had a significantly lower mean nadir (lowest ever) CD4 count – strongly suggesting that immune suppression plays an important role in the pathogenesis of these cancers. Additionally, both lung and head/neck cancers were significantly associated with being a current or past smoker, as in the general population. There was also a trend to older age in those with cancer, which is similar to the general population.


Q & A with Dr. Mark Bower
To help explain what this all means, ATU spoke with Dr. Mark Bower, Consultant Medical Oncologist, at the Chelsea and Westminster Hospital, London.

ATU: Let’s start with the AIDS-defining cancers. What can you say about Kaposi’s sarcoma and non-Hodgkin's lymphoma in the HAART era?

Mark Bower (MB): There has been a dramatic decline in the incidence of KS since the introduction of HAART, and we now see about a third of the number of cases we saw in the pre-HAART era.
Of the people we see who develop KS, about three-quarters are not on HAART at the time, either because they are unaware that they have HIV, or because they are from areas where HAART is not available.
However, there is a small minority of patients who present with KS whilst on HAART. Of these, about three-quarters are failing HAART, have a detectable viral load and are probably resistant to some anti-HIV drugs.
Then you get down to a very small number of patients - five to ten patients a year, here at the Chelsea and Westminster - who really shouldn’t be getting KS. Their viral loads are undetectable and they have a good CD4 cell count, about 300 – 400 cells/mm3. The jury is out as to why this might be happening. It could well be that they’ve only experienced partial restoration of their immune systems and still have ‘holes’ in it that allow the virus that causes KS (HHV-8) to cause disease. An interesting factor that might be worth investigating is what these patients’ lowest-ever CD4 count was – I just don’t know.

ATU: How do you treat KS?

MB: If you have the odd KS lesion on your skin that isn’t troublesome, either in terms of symptoms or looks, then in treatment-naïve individuals we’ll use HAART as the first-line treatment. The trouble is that it can take up to six months for the KS to improve. Indeed, for the first couple of months, it can even get worse, and it can take up to two years for the colour to come out of lesions. Nevertheless, for about two-thirds of patients started on HAART alone as KS treatment, that’s enough.
For patients with more extensive KS, or systemic KS, then chemotherapy is needed.
Although treatments for KS have improved dramatically, when KS affects internal organs - particularly the lungs - it causes a significant amount of mortality in patients, even in the era of HAART.

ATU: Has non-Hodgkin's lymphoma become any less of a problem with HAART?

MB: Primary cerebral (brain) lymphoma is all but disappearing. In the pre-HAART era we used to see ten or 15 patients a year with primary cerebral lymphoma. We now see one or two patients a year, and this diagnosis can often be questionable.
The prognosis is still terrible, however.
That’s only part of the picture. There are also systemic [spread throughout the lymphatic system] lymphomas. There’s evidence from a number of studies that there has been a modest reduction in incidence since the introduction of HAART, and it’s been shown that being on HAART reduces your risk of developing systemic lymphoma.
On the reverse side though, with the increase in the number of patients with HIV, and the reduction in the number of other opportunistic infections since HAART, and greater life-expectancy, the small reduction in risk has translated, if anything, into us seeing an increase in the number of patients with HIV lymphomas.

ATU: How do you treat systemic lymphoma?

MB: Aggressively, with chemotherapy. Survival is much better than it used to be. But to have the best chance of your treatment working, it’s important to receive treatment in a centre, like the Chelsea and Westminster, that has experience of managing and treating lymphoma.
There’s clear evidence that where there is a working relationship between HIV specialists and cancer specialists, the outcome for patients with systemic lymphoma is much better. If you’re diagnosed with a systemic lymphoma, my message to your readers would be to get yourself to a major HIV treatment centre as soon as possible.

ATU: Are there any characteristics which predict an increased risk of developing lymphoma?

MB: The risk factors for developing systemic lymphomas include some complex genetic factors, such as cytokine and chemokine receptor polymorphisms.
But most important are immunological issues. The older you are, the lower your lowest-ever CD4 cell count (and, to a lesser extent, your nadir CD8 cell count), then the greater your risk of developing systemic lymphoma.
HAART, be it NNRTI- or PI- based, is equally effective at protecting against lymphomas, and it’s very uncommon to see lymphomas in patients with a CD4 cell count above about 350.

ATU: What are your chances of survival with lymphoma?

MB: The two-year overall survival for patients with systemic lymphoma at the Chelsea and Westminster is about 55% with chemotherapy. We don’t see relapse and death from lymphoma more than a year after the end of treatment. Basically, if you get to more than a year after the end of your chemotherapy, you’re probably cured of your lymphoma. I’ll stress again the importance of receiving your treatment at a hospital with integrated HIV and cancer specialities.

ATU: During chemotherapy for lymphoma, do patients remain on HAART?

MB: Remaining on HAART during chemotherapy can protect your immune system. We’ve seen that during chemotherapy your CD4 cell count drops by about 50%, but recovers within a couple of months after the end of chemotherapy.
There is a potential, however, for drug interactions between the chemotherapy and HAART - particularly protease inhibitors – that can lead to rather high levels of the chemotherapeutic drugs and, therefore, more side-effects from the chemotherapy.
However, if you stop HAART during chemotherapy, it can take up to twelve months after your anticancer treatment finishes and you restart your HIV medication for your CD4 cell count to recover.

ATU: Since 1993 cervical cancer has been an AIDS-defining condition. Have you noticed any changes in patterns of this disease since HAART?

MB: As you say, cervical cancer is an AIDS-defining condition, but it was always debatable in the pre-HAART era how increased the risk actually was in women with HIV. However, since HAART, very clear evidence has emerged of increased incidence of invasive cervical cancer in HIV-positive women not on HAART.
Although other centres in the UK have seen that HAART has reduced the incidence of cervical cancer, given the patient population at the Chelsea and Westminster (which is still predominantly gay men), we don’t really see much cervical cancer.

ATU: What about cancers that aren’t traditionally associated with HIV? There’s been a lot of interest in these since the introduction of HAART. Which ones are you chiefly concerned about?

MB: The biggest issue at this treatment centre, where most of the patients are gay men, is invasive and pre-invasive anal cancer. In addition, lung cancer and testicular cancer seem to be occurring more often in HIV-positive individuals. We’ll deal with them one by one.

ATU: What causes anal cancer and how many cases are you seeing?

MB: As I’m sure many of your readers know, human papilloma virus (HPV), the cause of anal and genital warts, is the underlying reason for anal cancer, and HAART doesn’t work against it. If anything, there’s been a modest increase in the number of cases of anal cancer since HAART was introduced. This could be because people are not dying with other infections, and/or because HAART doesn’t allow the pre-cancerous lesions – AIN (anal intraepithelial neoplasia) – to get better.
There’s a slow rate of disease progression from infection with HPV through the three stages of AIN (AIN I, AIN II and AIN III), and the development of cancer, perhaps ten years or more.
There are high-risk genotypes of HPV for anal cancer. Women with cervical cancer tend to have only a few genotypes of HPV in their cervix. However, in gay men we tend to find infection with multiple genotypes of HPV, some of which are high-risk. However, in a study at the Chelsea and Westminster, we were unable to find any association between high-risk HPV genotypes and the stage of disease progression.

ATU: How do you treat anal cancer?

MB: Treatment for invasive anal cancer is aggressive, involving a combination of chemotherapy and radiotherapy. It’s pretty horrible, but the cure rate is about 60%, although some patients may also need surgery.

ATU: Can you screen for anal cancer?

MB: Yes, we’re starting to get the ability to screen for AIN, using a test very similar to the PAP smear for pre-cancerous cervical cells in women. It involves smearing the anal mucosa, and in San Francisco men are being trained to do this for themselves.
We have yet to establish how we can prevent pre-invasive anal cancer progressing to invasive anal cancer, and if we had an effective therapy to stop that - and let’s be clear, it isn’t HAART - we would have made a major breakthrough in preventing this illness. There are a number of studies looking at potential treatments.
Is screening worthwhile? It’s clear that if you catch anal cancer early, there’s a much better chance of curing it. Further, you can determine who’s at risk of anal cancer by looking at their AIN status. If there’s a small area of AIN, even high-grade AIN, then localised treatment seems effective. If you have an extensive area of AIN, then there are roles for frequent monitoring (to see if aggressive treatment should be started) or surgical resection.. A large, carefully designed study is needed to look at the utility of screening.

ATU: What about lung cancer?

MB: If anything, the risk of lung cancer is rising in patients with HIV. It used to be said that this was because people with HIV were more likely to be smokers. The data for this are pretty poor actually, and it does seem that people with HIV have a two- or threefold increased risk of developing lung cancer compared to similar people without HIV.
The prognosis is awful, as it is for all lung cancer, but it’s no worse in people with HIV.
We really don’t know why the incidence of lung cancer should be elevated in people with HIV.

ATU: And testicular cancer?

MB: Again, this seems to occur more often in men with HIV, but it’s uncommon. The treatment and outcomes for men with HIV are similar to those for HIV-negative men. Data from the UK and Denmark suggest that HIV-positive men with testicular cancer are at no greater risk of dying of the condition than are HIV-negative men.
If you notice a lump in your testicle, get it looked at. If the tumour is localised to the testicle, then treatment will consist of its removal. If the disease has spread elsewhere, chemotherapy will also be used.

ATU: What about liver cancer?

MB: There are very few data on liver cancer in people with HIV. But there does seem to be an increased incidence of liver cancer in people with HIV, particularly in association with hepatitis C and hepatitis B. I think this is going to be a developing issue, though, given the rates of HIV and hepatitis C and hepatitis B co-infection.

ATU: Any good news?

MB: Yes there is! A number of studies have shown that HIV reduces the risk of breast cancer. One possible theory for this is because a functioning immune system contributes to this malignancy, which is more common in well-fed, affluent, immuno-competent women – like Samantha Jones in Sex and the City.

ATU: What about HAART – is there any evidence that the increased incidence of non-AIDS defining cancers could be side-effect of HAART?

MB: Another optimistic point is that there’s no evidence that HAART causes tumours. If there is an increased risk of some malignancies since HAART, it’s because people just aren’t dying of other things.


References

1. Hoffmann C et al. Response to highly active antiretroviral therapy strongly predicts outcome in patients with AIDS-related lymphoma. AIDS 17(10):1521-1529, 2003.

2. Mbulaiteye SM et al. Immune deficiency and risk of malignancy among people with AIDS. JAIDS 32: 527 - 533, 2003.

3. Patel P. et al. Incidence of Non-AIDS-defining Malignancies in the HIV Outpatient Study. Eleventh CROI, San Francisco, abstract 81, 2004.