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Anti-Cancer Agents: C. KS in HIV-Negative Men

August/September 2008

Studies in Western Europe and the United States suggest that about 25% of gay men are infected with HHV-8. In contrast, in women and in men who are not MSM, rates of infection are less than 5%.

Researchers at two hospitals in Paris have been studying MSM whose KS was detected between 1995 and 2007. All 28 cases of KS were in HIV negative men. The research team reported details on these men as follows:

  • average age -- 53 years
  • 22 of the men identified as gay
  • six of the men described themselves as bisexual
  • 89% of the men had KS in the form of small nodules that appeared on the feet or lower legs
  • other sites included the face, trunk and penis
  • three men had blocked lymph vessels; however, ultrasound and CAT scans did not detect any KS lesions near major organs
  • CD4+ and CD8+ cell counts were within the normal range in all the men as were another type of immune cell called NK (natural killer cells). These cells are important in controlling viral infections and tumours. Note that counting cells and assessing their function are two different issues (more about this point later in our story).

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Risk Factors for KS

About half of the men had the following risk factors for KS:

  • having visited or lived in places where HHV-8 or KS were common
  • a history of sexually transmitted infections

Immune deficiency is also a risk factor for KS. But CD4+ cell counts performed from the men's blood samples found an average reading of 920 cells -- well within the range that is considered normal. However, more subtle conditions that may have suppressed the functioning of the immune system, such as the presence of type 2 diabetes or use of corticosteroids, was noted in only three men. None of the men were taking transplant medications.

Twenty-two patients tested positive for HHV-8, while three tested negative. The test was not performed on blood samples from three patients.


Other Problems

Seven patients developed cancers of the lymphatic system (lymphomas) between two and seven years after doctors diagnosed KS. When these cancers were diagnosed HHV-8 was detectable in their blood samples. This is not surprising, as researchers suspect that HHV-8 can trigger the development of lymphoma in lymph nodes and tissues.


Treatment of KS

The course of treatment given to these 28 patients varied considerably. Some received interferon alpha injected into their blood, sometimes along with chemotherapy. Other patients received treatment directed at lesions, such as the following:

  • radiation treatment
  • surgery
  • liquid nitrogen
  • laser beams
  • the immune-boosting cream imiquimod (Aldara)

The response to therapy was often successful, as there was not any major underlying immune dysfunction.


The Question

The French study has underscored the issue of KS in HIV negative men. Based on this study an important question that needs to be asked is:

Why did these relatively young and mostly healthy gay/bisexual men develop KS?

In attempting to answer this question we may find clues about KS risk factors.


Sex and Drugs

The previous French study and others suggest that in high-income regions KS is much more common among men than women. Until the late 1970s, doctors did not routinely ask questions about the sexuality of their patients. However, it is now clear that MSM are at increased risk for KS.

Precisely which aspect of sexual behaviour places men at risk for KS is not clear. However, the KS-associated virus, HHV-8, can be found in saliva. So one theory is that exposure to HHV-8 in saliva through kissing and perhaps oral sex could help spread this virus. However, this idea awaits further study and KS has not been definitely linked to a particular sexual practice.

Recently there have been reports of sero-sorting among HIV positive MSM who have practiced unprotected anal intercourse. This has inadvertently led to outbreaks of hepatitis C virus (HCV), LGV, rectal gonorrhea and possibly syphilis in some MSM. It is possible that this behaviour could also help transmit HHV-8 or other germs or substances that could act as co-factors for the formation of KS tumours.

Also recently, reports from San Francisco and London, UK, have found that KS tumours have occurred among HIV positive MSM who are taking HAART and who have low levels of HIV replication and moderate levels of CD4+ cells. Unfortunately, details of the sexual behaviours of these men were absent. Also missing were any reports of their substance-using behaviour.


Ethnicity and Geography

Only some of the men in the French study had visited or lived in regions where KS is relatively common. These include Mediterranean countries (particularly southern Italy, Greece, Turkey, Israel and northern Egypt) and parts of Central, Eastern and Southern Africa, North and South America and China. The reasons for this may be related to genetic environmental factors.


Shining a Light on Immunity

Although the French team conducted limited immunologic assessments, these were restricted to CD4+, CD8+ and natural killer cell counts. They did not investigate the functioning of these cells.

A different team of researchers has investigated the functioning of T-cells in people who are infected with HHV-8, some of whom also have KS. Researchers found that, overall, CD4+ counts were similar in people with and without KS. However, T-cells from people who had KS tumours responded poorly when exposed to proteins from HHV-8. By contrast, in people co-infected with HHV-8 and HIV who did not have KS, the immune responses to HHV-8 proteins were much better.

This experiment has uncovered that people who have KS tumours, regardless of HIV co-infection, have some subtle defect in their T cells. This defect is not revealed when CD4+ cell counts are done. Thus, the immune systems of people with KS tumours are somewhat dysfunctional.

Why this dysfunction occurred is not clear. But the French team was able to rule out HHV-8 viral load as a possible factor.

Clearly, more research needs to be done to better understand how and why KS tumours occur and to uncover subtle defects in immunity of people with this problem.

Also, more research is needed to find out how HHV-8 is spread and if there are any other risk factors for KS tumour formation so that people can take steps to protect themselves.


References

  1. Hiatt KM, Nelson AM, Lichy JH, et al. Classic Kaposi Sarcoma in the United States over the last two decades: a clinicopathologic and molecular study of 438 non-HIV-related Kaposi Sarcoma patients with comparison to HIV-related Kaposi Sarcoma. Modern pathology. 2008 May;21(5):572-82.
  2. Lambert M, Gannagé M, Karras A, et al. Differences in the frequency and function of HHV8-specific CD8 T cells between asymptomatic HHV8 infection and Kaposi sarcoma. Blood. 2006 Dec 1;108(12):3871-80.
  3. Woodberry T, Suscovich TJ, Henry LM, et al. Impact of Kaposi sarcoma-associated herpesvirus (KSHV) burden and HIV coinfection on the detection of T cell responses to KSHV ORF73 and ORF65 proteins. Journal of Infectious Diseases. 2005 Aug 15;192(4):622-9.
  4. Lanternier F, Lebbé C, Schartz N, et al. Kaposi's sarcoma in HIV-negative men having sex with men. AIDS. 2008 Jun 19;22(10):1163-8.
  5. El Amari EB, Toutous-Trellu L, Gayet-Ageron A, et al. Predicting the evolution of Kaposi sarcoma, in the highly active antiretroviral therapy era. AIDS. 2008 May 31;22(9):1019-28.
  6. Stebbing J, Powles T, Bower M. AIDS-associated Kaposi's sarcoma associated with a low viral load and a high CD4 cell count. AIDS. 2008 Feb 19;22(4):551-2.


  
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This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication TreatmentUpdate. Visit CATIE's Web site to find out more about their activities, publications and services.
 
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