**2. Human papillomavirus infection and cervical cancer**

The causal relationship between some microbial pathogens, primarily viral, and human carcinogenesis have been suspected but it has only been in the last 20 years that knowledge

Cervical Cancer Screening and Prevention for HIV-Infected Women in the Developing World 233

99% of invasive cervical cancers have been found to be HPV-positive (Sankaranarayanan 2008). Current evidence suggests that over 50% of sexually active adults have been infected with one or more genital HPV types (Ho 1998; Evander 1995); however, most HPV infections resolve or become latent and undetectable (Ho 1998; Moscicki 1998; Evander 1995). Furthermore, although there are well over a 100 distinct molecular subtypes of HPV, only a small subset have been associated with development of cancer and are considered "high risk" or oncogenic (Cogliano 2005). For cervical cancer to develop, persistent infection with an oncogenic HPV subtype is necessary. The oncogenic or high-risk HPV includes HPV subtypes -16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, -68 which are strongly

Cervical cancer is relatively unique in that there is a recognizable preinvasive phase in which progression from initial HPV infection to invasive disease evolves over several years, passing through cytologically and histologically distinct precancerous phases, known as cervical dysplasia (mild, moderate, severe, carcinoma-in-situ) or cervical intraepithelial neoplasia (CIN 1,2,3). The peak prevalence of infection with carcinogenic HPV subtypes is in the teens and twenties, following closely after the initiation of sexual activity; the majority of these infections are transient and are cleared by the body's immune system. When viral persistence and progression do occur, the median time from HPV detection to development of CIN 3 is approximately 7–8 years, with 20% progressing from CIN 1 to CIN 3 within 2 years. Progression from CIN 3 to invasive cancer occurs over an additional 5–7 years. The peak prevalence of invasive cancer occurs in the 40-50 year age range (McIndoe 1984; Kolstad 1976; Melnikow 1998; Josefsson 2000; Schiffman 2005). This prolonged natural history offers numerous opportunities to detect the presence of precancerous lesions and to

Studies have shown that HIV-infected women have higher prevalence of HPV, higher incidence of HPV (Branca 2003; Ahdieh 2001), higher HPV viral load (Jamieson 2002), longer persistence of HPV (Ahdieh 2000; Sun 1997), higher likelihood of multiple HPV subtypes (Jamieson 2002; Firnhaber et al. 2009; Clifford et al. 2007), and greater prevalence of oncogenic subtypes (Minkoff 1998; Uberti-Foppa 1998; Acta Cytol 2009; 53: 10–17) than HIVuninfected women. HPV viral load is independently associated with HPV persistence (Ahdieh 2001). A recent meta-analysis found that the rate of cervical HPV infection in HIVinfected women with normal cervical cytology varied from more than 55% in South and Central America and Africa to over 30% in Asia, North America, and Europe (Clifford 2006). Furthermore, in HIV-positive women the prevalence and persistence of HPV infection increases with decreasing CD4 count and increasing HIV RNA levels (Palefsky 1999; Denny 2008) and some studies show that oncogenic HPV types may be more common with lower CD4 counts and/or higher viral loads. (Luque 1999; Minkoff 1998; Clifford et al. 2007). A recent cross-sectional study of 109 HIV+ women initiating ART in South Africa (median CD4 count 125/mm3) found a high-risk HPV (HR-HPV) prevalence of 78.9% (Moodley et al. 2009). In another South African cohort of over 123 women with HIV seroconversion HR-HPV infection doubled within 36 months of seroconversion (Wang et al. 2011). Higher HPV

associated to cervical precancer (Schiffman 2003).

prevent progression to invasive cancer.

**3. HPV, cervical dysplasia and HIV** 

**3.1 Interrelationship of HIV and Human Papillomavirus** 

viral loads are also associated with lower CD4 counts (Heard 2000).

has accumulated to more clearly define the mechanisms and processes that chronic, persistent infections induce cancer development, see Figure 1. Replication of DNA and RNA tumor viruses involve incorporation of the viral genome into the host cell chromosomes inducing several mutations that disrupt the homeostatic balance between proliferation and cell death; in the case of oncogenic HPV, the expression of viral E2, E6, and E7 genes lead to the production of proteins that initiate cell cycle and disable control of growth, allowing the proliferation of genetic damage to accumulate in HPV infected cells. (Georgakilas et al. 2010). Oxidative stress negatively impacting genetic and cellular processes can be brought about by reactive oxygen species (ROS) or free radicals induced by chronic infection (Kryston et al. 2011; Georgakilas et al. 2010). Although additional researches are needed to accurately define the relationship, oxidative stress is linked in several studies with some tumor virus but not HPV (Kryston, et al. 2011)

Fig. 1. Role of Viral Infection in Carcinogenesis.

Schematic pathway of viral infection leading to cancer adapted from Figure1 Viral pathogens role(s) in human carcinogenesis based on current status of knowledge and clinical evidence.

Alexandros Georgakilas, William Mosley, Stavroula Georgakila, Dominick Ziech, and Mihalis Panayiotidis. Viral-induced human carcinogenesis: an oxidative stress perspective. Molecular BioSystems Vol 6, pp 1162 – 1172, (2010).

In the 1990s a combination of large-scale epidemiologic studies and the application of new molecular techniques clearly established human papillomavirus (HPV) as the etiologic cause of cervical cancer (Clifford 2003; Walboomers 1999). Using the most sensitive assays, over 99% of invasive cervical cancers have been found to be HPV-positive (Sankaranarayanan 2008). Current evidence suggests that over 50% of sexually active adults have been infected with one or more genital HPV types (Ho 1998; Evander 1995); however, most HPV infections resolve or become latent and undetectable (Ho 1998; Moscicki 1998; Evander 1995). Furthermore, although there are well over a 100 distinct molecular subtypes of HPV, only a small subset have been associated with development of cancer and are considered "high risk" or oncogenic (Cogliano 2005). For cervical cancer to develop, persistent infection with an oncogenic HPV subtype is necessary. The oncogenic or high-risk HPV includes HPV subtypes -16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, -68 which are strongly associated to cervical precancer (Schiffman 2003).

Cervical cancer is relatively unique in that there is a recognizable preinvasive phase in which progression from initial HPV infection to invasive disease evolves over several years, passing through cytologically and histologically distinct precancerous phases, known as cervical dysplasia (mild, moderate, severe, carcinoma-in-situ) or cervical intraepithelial neoplasia (CIN 1,2,3). The peak prevalence of infection with carcinogenic HPV subtypes is in the teens and twenties, following closely after the initiation of sexual activity; the majority of these infections are transient and are cleared by the body's immune system. When viral persistence and progression do occur, the median time from HPV detection to development of CIN 3 is approximately 7–8 years, with 20% progressing from CIN 1 to CIN 3 within 2 years. Progression from CIN 3 to invasive cancer occurs over an additional 5–7 years. The peak prevalence of invasive cancer occurs in the 40-50 year age range (McIndoe 1984; Kolstad 1976; Melnikow 1998; Josefsson 2000; Schiffman 2005). This prolonged natural history offers numerous opportunities to detect the presence of precancerous lesions and to prevent progression to invasive cancer.
