Human Papilloma Virusassociated Neoplasms

Genital cancers have been a world-wide public health problem, especially in the context of HIV infection and immunosuppression.They are common malignancies found in AIDS patients. HIV infection has been shown to substantially enhance the development of cervical cancer and cervical cancer precursor lesions.10,78 It is also the most common female malignancy in many developing countries.118

Genital cancers and cervical intraepithelial neoplasia (CIN) have been strongly implicated in association with HPV infection. The first report demonstrating the association of HPV and cervical cancer was published by Zur Hausen et al.,123 showing that cervical cancer in the female genital tract has HPV-associated lesions. HPV infection of genital can either lead to asymptomatic infection or a wide range of genital lesions, ranging from genital warts to mild dysplasion to invasive carcinomas. Genital lesions are often referred to as cervical intraepithelial abnormalities or CIN, which is graded from I to III depending on the degree of epithelium abnormality. CIN I encompasses mild dysplasia or low-grade squamous intraepithelial lesions (SIL). CIN II represents high-grade SIL with moderate dysplasia, while severe dysplasia is referred to as CIN III.79

In 1993, the CDC has included invasive cervical cancer as one of the AIDS-defining illnesses. HIV infection has become an important risk factor for HPV infection and the development of genital cancers. HIV and HPV infections have a number of common features; both are sexually transmitted diseases (STD), and there is a high prevalence of HPV infection among HIV seropositive women, especially those that are immunosuppressed with low CD4+ T cell counts.5,111

Up to 20% of the HIV and HPV coinfected individuals developed HPV-associated premalignant lesions of the uterine cervix within 3 years of HIV infection.31 The progression of an untreated HPV-induced dysplasia could then lead to cervical cancer. A number of studies have shown that HIV positive women have 2—3 times more HPV DNA in cervicovaginal washings and 15 times more in anal swabs as compared to HIV negative individuals.15,54,111 HIV-infected women were also shown to be much more likely to develop cervical intraepithelial abnormalities. The prevalence and severity of genital tract infection in these women are also more pronounced.27,83 The rates of invasive cervical carcinoma are 15—18 times higher in women with AIDS compared to the general population.32,102 Men fare no better — the incidence of anal cancer in men with history of anal intercourse is at 35 per 100,000 individuals, a number equivalent to that of cervical carcinoma before the advent of Pap-smear screening.89,110 The mechanism by which HIV increases the risk of HPV infection and cervical dysplasia is likely due to immunodeficiency, resulting in the inability of the immune response to control HPV infection. Indeed, cervical dysplasia increased progressively as the patients immune function declined, as determined by CD4+ T cell counts.52 A large, long-term prospective cohort studying of over 1,800 HIV positive and over 500 HIV negative women was carried out to determine how HIV RNA levels and CD4+ T cell counts are associated with the natural history of HPV infection.109 The results demonstrated that in HIV-infected women, the HIV plasma viral load in combination with CD4+ T cell counts has a strong correlation with the detection of HPV infection and reactivation. However, there was only a moderate correlation between HIV coinfection and HPV persistent infection. This partially explains why cervical cancer rates are not even higher than what was observed in HIV+ infected women.

The effects of HAART on HIV and the immune status of HIV-infected individuals are well established, but their effects on the course of HPV-related cervical lesions in HIV-infected women are still not well established. HAART has not been shown to affect HPV detection and its effects on the natural history of cervical intraepithelial neoplasia are unclear.87 There were a number of studies examining the effects of HAART on the course of cervical lesions.4'51 A study by the Women's Interagency HIV Study (WIHS) group has reported an association of the regression of cervical lesions with HAART82 whereas others cannot.76 In addition, a multicenter study of HAART on the repression of cervical lesions in over 700 women followed for over 5 years also did not show any correlation.101 However, these studies primarily focused on evaluating the effects of HAART on prevalent cervical lesions and the date of onset of those lesions is not known, thus it is not surprising that the outcome of these studies was controversial. To address these concerns, a study by Ahdieh-Grant et al.4 determined whether HAART alters the natural history of CIN among HIV-infected women that were regularly followed every 6 months for 7 years. This study provided evidence that HAART has a modest benefit for HIV-infected women that were at risk for cervical neoplasia, with women receiving HAART will survive longer and have better control over cervical HPV infection and low-grade squamous intraepithelial lesions. However, HAART does not seem to lead to a complete reconstitution of the immune system for it to control HPV, the rates of regression among HIV-infected women receiving HAART remained lower than HIV-infected women that were never on HAART or among HIV-uninfected women. Thus, there is a need to actively seek and treat CIN in HIV-infected women, including those that are responding to HAART.

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