Viral load above 200 and anal coinfections increase anal cancer risk for people with HIV

Individuals with anal human papilloma virus (HPV) infection who are HIV-positive are significantly more likely to develop high grade precancerous cells or anal cancer, if they also have other infections in the anal region such as gonorrhoea and herpes, according to a French study published in the July 23^rd edition of AIDS. Individuals with cancer or precancerous cells had fewer Langerhans’ cells in their anal mucosa and the authors suggest that anal infections may impair immune response to pre-cancerous cells by down-regulating the immune response.

Although the use of antiretroviral therapy did not protect HIV-positive individuals from developing high risk cells or cancer, a viral load above 1,000 copies was significantly associated with the progression of anal HPV infection to precancerous cells or cancer.

Data were available for a total of 199 individuals who were recruited to the study between 1993 and 2002. All the patients had presented with anal warts which had resolved with treatment. At baseline and then at three or six monthly intervals individuals were tested for anal infections including herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus, and the bacterial sexually transmitted infections gonorrhoea and syphilis.

Samples of anal mucosa were also obtained to measure the number of Langerhans’ cells, and samples of tissue from the anal canal were obtained to see if anal warts had relapsed or if precancerous cells or anal cancer had developed.

Individuals were excluded from the study if they had anal cancer at baseline, but were eligible for inclusion if they had high-grade dysplasia (pre-cancerous cells, intraepithelial neoplasia grade III). Individuals were tested for HIV on entry to the study.

At baseline, a total of 26 patients had high-grade dysplasia. The frequency of high-grade dysplasia at baseline did not differ significantly between HIV-positive (16.4%) and HIV-negative (7.6%) patients.

The median duration of follow-up was 23 months, during this period 38 (19%) individuals progressed to high-grade dysplasia or anal cancer. In total 32 (84%, p = 0.007) of these patients were HIV-positive. Anal cancer developed in seven patients, six of whom were HIV-positive men aged between 26-52 years, the other case involving a 62 year old HIV-negative woman.

Anal cancer occurred between 13 and 108 months after entry into the study. All but one of these patients at high-grade dysplasia at baseline.

There were no significant differences between patients with pre-cancerous cells or cancer and those without as regards age, sex, body mass index, anal sex, or drug use.

However, patients with high-grade dysplasia or anal cancer were significantly more likely at baseline to be HIV-positive (p = 0.007), have an anal coinfection (p = 0.0002), and have a lower Langerhans’ cell count in their anal mucosa (16 cells/mm³ versus 27.4 cells/mm³, p = 0.01).

Individuals who experienced a relapse of their anal wart infection were also significantly more likely to develop precancerous cells or anal cancer. In total, 45% of patients with high-grade dysplasia or anal cancer had three or more relapses of their anal warts compared to 10% of patients experiencing three or more relapses who did not go on to develop pre-cancerous or cancerous cells (p <0.001).

The effect of other anal infections

Infection in the anus with HSV, CMV, EPV, gonorrhoea or syphilis at baseline were all significantly associated with a recurrence of anal warts (p <0.0001), and the cumulative frequency of high-grade dysplasia or anal cancer was three times higher in patients with these anal coinfections (37.5% versus 11.5%, p = 0.0001). Individuals who acquired anal infections during follow-up were also more likely to progress to high-grade dysplasia or anal cancer (p <0.01).

Infection with HPV types 18, 16, 31, and 33 at baseline were also significantly associated with a significantly increased risk of progressing to high-grade dysplasia or anal cancer (p = 0.009). Infection with these subtypes during follow-up was also significantly associated with progression in anal disease (p <0.001).

Viral load

When the investigators looked at risk factors for HIV-positive patients they found that a viral load above 200 copies/ml was significantly associated with the risk of developing high-grade dysplasia or cancer (p <0.01). Further, all six HIV-positive patients who developed anal cancer had a viral load above 1,000 copies/ml. None of the 119 HIV-positive patients with a viral load below 1,000 copies/ml developed anal cancer.

Density of Langerhans’ cells in anal mucosa during follow-up was also associated with the progression to precancerous cells or anal cancer (p = 0.001).

“HIV infection and anal coinfection are independent risk factors” for high grade dysplasia or anal cancer, comment the investigators.

Viral load could be a useful tool in determining which HIV-positive patients with anal HPV infection might be at high risk of developing precancerous lesions or anal cancer, the investigators suggest. The investigators believe that anal coinfections contribute to lower densities of Langerhans’ cells, impairing immune response and increasing the chance of anal warts relapsing or progressing to high-grade dysplasia or cancer.