The human papilloma virus, or HPV, refers to a group of viruses which cause warts on the skin and the genital region. The types of HPV that cause genital warts (known as condylomata acuminata) are spread by sexual activity. Sexually transmitted HPV is an important causal factor in cervical and anal cancers. People with damaged immune systems are at increased risk of HPV-related cancers.

Human papilloma virus, warts and genital cancers

HPV causes warts on the skin and mucous membranes. Most people remember having had warts at different times in their lives. These often disappear after a few weeks or months, because the immune system can fight them off. Some types of HPV can be spread sexually, causing genital warts in women at the cervix (the 'neck' of the womb at the top of the vagina) and vulva, on the penis in men and around and inside the anus in both sexes. If genital warts are successfully treated the HPV becomes inactive, but remains in the body.

HPV is a very common infection, with prevalence rates of 30 to 40% in young adults: in 2004, there were around 80,000 cases in the United Kingdom, representing an increase of 4% on the previous year. Infection rates are higher in people with HIV.

Infection with some strains of HPV may lead to the development of genital cancers through reactivation of the virus. HPV has also been linked to some mouth and throat cancers (Gillison 2001). In HIV-positive people, HPV is more likely to become reactivated. Skin cells infected with HPV may be slightly changed by the virus, leading to cancer. Strains 16, 18, 31, 33 and 35 are more strongly associated with the development of genital cancers, so it should not be assumed that a history of genital warts inevitably predicts the development of genital cancers in immunosuppressed people.

There are several ways of classifying HPV-associated lesions and cell changes:

• Dysplasia refers to abnormal cells. It is graded on the scale: normal, very mild, mild, moderate, severe, carcinoma (cancer). Dysplasia may sometimes be called 'pre-cancer'.

• Cervical or anal intraepithelial neoplasia (CIN or AIN) refers to an abnormal growth within the cells lining the cervix or the anus. CIN or AIN may be graded as warts (condylomata), grade 1, 2 or 3.

• Squamous intraepithelial lesion (SIL) also refers to an abnormal cell growth within the cell lining of the cervix or the anus, as well as the vagina or vulva (vulvovaginal lesions). Classification is either low-grade or high-grade. Low-grade SIL is equivalent to CIN or AIN grade 1, and high-grade SIL is equivalent to CIN or AIN grades 2 or 3.

If untreated, these growths may lead to invasive cancer which can be a life-threatening condition. In most cases, however, such lesions will remain stable and will not cause life-threatening invasive cancer.

A test called a Papanicolaou ('Pap') smear can be used to identify abnormal or pre-cancerous cells which then can be treated if necessary. Advanced immune deficiency is associated with a greater rate of abnormal Pap smear results.

Many people are infected with the HPV but only a few develop HPV-related cancer. Current research is trying to determine what factors lead to the development of cancer. There is some evidence to suggest that abnormal hormone levels and viral mutations may play a role in the development of cancer. Immune damage caused by HIV may increase the risk of developing cervical or anal cancer.

Despite assumptions to the contrary, two recent Dutch studies have shown that consistent condom use can help the clearance of HPV and the regression of CIN in women, as well as speed the regression of penile warts in men whose female partners have CIN (Bleeker 2003; Hogewoning 2003).

Human papilloma virus in women with HIV

Risk factors for HPV infection in women include:

• A large number of sexual partners.

• Having had sex with men who have high numbers of sexual partners.

• Age below 40 years.

• Smoking (Minkoff 2004).

• Infection with bacterial vaginosis or Trichomonas vaginalis, bacterial infections of the vagina (Watts 2005).

HIV-infected women are more likely to be infected with HPV than are HIV-negative women. Data from the American Women's Interagency HIV Study (WIHS) found that 58% of HIV-infected women had HPV compared with 24% of controls, and that 42% of the HIV-infected women were infected with multiple HPV subtypes compared with 16% of controls (Palefsky 1999c). These data provide some support for the hypothesis that HPV infection increases a woman's risk of contracting HIV.

The WIHS reported that advanced HIV disease was strongly associated with HPV infection. Women with CD4 cell counts below 200 cells/mm³ were at greatest risk of HPV infection, regardless of viral load. A viral load over 100,000 copies/ml was independently associated with HPV infection. The HIV Epidemiology Research Study has similarly reported a connection between high HIV viral load and low CD4 count, and increased likelihood of HPV infection (Shah 1998).

Women with HIV are more likely to have high levels of HPV in cervical cells and they are less likely to clear HPV infection. One study reported clearance rates of 41% among HIV-infected women with CD4 counts above 200 cells/mm³, and 16% among women with CD4 cell counts below 200 cells/mm³. In contrast, among HIV-negative controls the clearance rate was 74% (Andieh 2001). HIV-positive women are also more likely to experience reactivation of HPV, especially when their CD4 cell count is below 200 cells/mm³ or viral load is above 100,000 copies/ml (Strickler 2005).

There is also evidence from a number of studies that HIV-infected women have high rates of infection with HPV-16 and HPV-18 - the subtypes most likely to cause cancer (Hankins 2000; Minkoff 2004; Wright 1998). High levels of HPV-16 have been shown to be linked to the development of high-grade CIN (Fontaine 2005).

Several studies have reported that women with HIV are more likely to have abnormal Pap smear results than HIV-negative women. The WIHS reported abnormal Pap smear results in 38% of HIV-infected women compared with 16% of HIV-negative controls. Amongst the HIV-infected group, 21% had atypical cells, 15% had a low grade SIL, 2% had high grade SIL and less than 1% had cancer. In contrast, 17% of controls had abnormal results and only 3% had SIL (Massad 1999). Follow-up of women in this study suggests that HIV-positive women are not at greater risk of invasive cervical cancer than uninfected women, despite higher rates of cervical cell abnormalities (Hessol 2004; Massad 2004a). This result has been attributed to the thorough screening and follow-up care of women enrolled in this WIHS, and demonstrates the capacity of health care services to prevent cervical cancer in high-risk patients.

Two recent studies of teenage HIV-positive girls in the United States have revealed that most are already infected with HPV and that HPV clearance is slower than in HIV-negative girls. The HIV-positive teenagers also have a high prevalence of high grade SIL in the cervix, which is independent of CD4 cell count: 22% of the HIV-positive girls tested were found to have developed high grade SIL, in contrast to 5% of a comparative group of HIV-negative girls. The researchers also found an association between the use of hormonal contraceptives and high grade SIL (Moscicki 2004a,b).

HIV-positive women with CIN grade 1 are less likely to regress to normal cytology than HIV-negative women. They are also more likely to progress to a higher grade of the disorder, although the frequency of this is low: in one study, progression occurred with an incidence of 1.2 per 100 person-years of follow-up (Massad 2004b). A recent study confirmed this finding, concluding that the risk of recurrence or progression is four to five times greater in HIV-positive than -negative women (Nappi 2005).

Women with CD4 counts below 200 cells/mm³ or high viral load, are most at risk of precancerous and cancerous cervical cells (Palefsky 1999c; Shah 1998; Schatfer 1991). Furthermore, women with HIV-infection are more likely to develop neoplasia that affects the vulva (Spitzer 1999). Conversely, recent results from the WIHS study have suggested that HIV-positive women with CD4 cell counts above 500 cells/mm³ and who do not have cervical HPV infection have a similar risk of going on to develop CIN to HIV-negative women in the next three years (Harris 2005).

There has been some dispute about whether women with HIV are at increased risk of cervical cancer, despite the clear evidence of higher rates of abnormal Pap smears and neoplasia. Cervical cancer or invasive cervical carcinoma became an AIDS-defining illness in 1993, despite few cases of cervical cancer among HIV-infected women being reported in the medical literature. However, several studies have confirmed that women with HIV have higher rates of cervical cancer than HIV-negative women (Chin 1998; Boni-Quattara 2000), and that cervical cancer is more severe, progresses more quickly and remains in remission following treatment for a shorter period in HIV-infected women (Campbell 1999).

Anal intraepithelial neoplasia and anal cancer

Anal cancer appears to have the same pattern of development as cervical cancer in women, and is strongly associated with HPV infection (Fortin 2003). Anal HPV infection is known to be associated with:

• Number of sexual partners.

• High frequency of sexual activity.

• A history of sexual partners with genital warts.

• HIV infection.

• Low CD4 cell count (Duval 2005).

Beginning with a squamous intraepithelial lesion, these precancerous lesions take many years to develop. However, it appears that AIN is associated both with cancer-causing and non-cancer causing HPV types, possibly indicating that AIN is not necessarily a precursor to anal cancer in all patients (Manzione 2004)

Since receptive anal intercourse is a risk factor for HPV infection, gay men as a group have an increased risk of AIN and anal cancer, while HIV-positive gay men have an even greater risk of anal cancer. In one cross-sectional study of mostly young Latino and black men with HIV in New York, 40% were found to have AIN and 9% to have high-grade AIN. Low nadir CD4 cell count was the strongest risk factor for the condition. HAART use and undetectable viral load were strongly protective against abnormal cells and AIN. However, it is noteworthy that 40% of the men in this study reported never having had receptive anal sex, indicating that anal sex may not be a prerequisite for the development of AIN or anal cancer (Wilkin 2004). Similarly, HIV-positive heterosexual men and women who reported never having receptive anal sex have been found to have a 46% prevalance of anal HPV infection (Piketty 2003).

A similar rate of HPV infection of 57% was found in a large study of HIV-negative gay men from four large cities in the United States, with receptive anal intercourse in the past six months as the only identified risk factor (Chin-Hong 2004). In contrast, a more recent study has shown higher levels of HPV infection and AIN in HIV-positive gay men. Of 357 men tested, 81% had AIN, 52% had high-grade AIN and 95% had anal HPV infection. The authors found that having more than six types of HPV was linked to an increased risk of having AIN, but that use of HAART was not linked to a reduced prevalence (Palefsky 2005).

Nevertheless, anal cancer is rare, with one study reporting an incidence of 65 to 70 cases per 100,000 person-years (Goedert 1998). Data from the Chelsea and Westminster HIV cohort, providing over 40,000 patient years of follow-up, shows that 26 cases of invasive anal cancer were diagnosed between 1986 and 2004, with all but one case occurring among gay men. This study found that anal cancer occurs more frequently in HIV-positive men and does not respond to combination antiretroviral therapy. It also found that the five-year overall survival rate is 47%, and that 66% of the surviving patients had no recurrence of anal cancer following treatment (Bower 2004).

Anal cancer is not a listed AIDS opportunistic illness, and the Chelsea and Westminster cohort study found that the development of anal cancer was not linked to severe immune suppression, with individuals presenting with anal cancer having a median CD4 cell count of 206 cells/mm³. Some doctors are now speculating that the improvements in life expectancy seen with HAART may increase the incidence of anal cancer amongst gay men with HIV. This is supported by the repeated observation that the incidence of anal abnormalities does not correlate with CD4 cell count, HAART use or HIV viral load (Bower 2004; Guillemi 2005).

Women who engage in receptive anal sex may also be at risk of anal cancer. Two studies have suggested that like HIV-positive gay men, HIV-infected women are more likely to show anal lesions than HIV-negative women (Palefsky 2001b; Holly 2001). A positive cervical cancer smear has been associated with a positive anal smear in HIV-infected women. However, a recent study examining paired cervical and anal Pap smears revealed that 36% of the 214 HIV-positive women tested who had normal cervical smears were found to have abnormal cells in the anus (Young 2005). This suggests that anal lesions may occur independently of CIN in HIV-positive women, and that this group may also benefit from routine anal screening programmes.

At present, screening for pre-cancerous lesions is not routine in HIV-positive men but Australian and French research suggests that screening may be appropriate. Thirty per cent of HIV-positive gay men at an Australian clinic had abnormal anal cells (Anderson 2003) while 85% of 67 gay men in the French study had HPV infection. Of note, just under half of a group of 50 HIV-positive male injecting drug users with no reported history of anal intercourse were infected anally with HPV. Among the gay men, low-grade SIL was found in 49% and high-grade SIL in 18% (Piketty 2003).

Some experts have claimed that yearly or two-yearly screening of HIV-infected gay and bisexual men for anal SIL is clinically effective and cost-effective (Goldie 1999). The French clinicians who conducted the research described above have recommended screening for anal SIL in all HIV-positive men with CD4 cell counts below 500 cells/mm³.

However, the Chelsea and Westminster team found that screening for precancerous anal cells was of little value. They failed to identify any factors, including HPV subtype or CD4 cell count associated with progression to anal cancer, which means it is difficult to target men at greatest risk of progression to cancer (Bower 2004). Similarly, a recent comparison of cytological findings from Pap smears and anal biopsy has suggested that smears may not accurately detect the presence of high grade AIN, bringing into question the effectiveness of routine Pap smearing in high-risk groups unless anal biopsy is also made available to assess AIN grade (Panther 2004).

Human papilloma virus in the age of highly active antiretroviral therapy

There is conflicting evidence about the impact of HAART on the development or progression of SIL. It seems that even when the immune system is partially restored by HAART, anal and cervical cancer may progress.

Nevertheless, there is some evidence that HAART can play a part in successful regression of SIL. Two small studies reported cases of SIL regression after treatment with HAART (Heard 1998; Robinson 2001). However, due to methodology and size, neither of these two studies provides conclusive evidence that anti-HIV treatment is active against HPV-related anogenital lesions. A more recent two-year study of over 600 women found that women on HAART were less likely to develop new abnormalities but regression rates did not improve due to HAART (Duerr 2000).

Several other studies have found mixed effects of HAART on SIL and HPV activation:

• Italian researchers reviewed the charts of 229 HIV-infected women from 1994 to 1998 and found that HAART does not influence cervical SIL (del Mistro 1999).

• An American study looked at anal SIL in 78 HIV-infected men six months before and six months after initiation of HAART. There was no clear trend in progression or regression attributable to HAART although men with higher CD4 cell counts were more likely to regress. Only twelve out of 28 men with high grade SIL showed any improvement, and five out of 50 with lower grade lesions developed serious lesions during six months of follow-up (Palefsky 2001).

• Antiretroviral therapy failed to prevent a small proportion (4%) of women in one study becoming positive for HPV during the course of the study. Furthermore, only 8% reverted to HPV negativity during treatment with HAART, despite increasing CD4 cell counts and falling viral loads (Hoesly 1999). This suggests that antiretroviral therapy may not have any effect on HPV levels in the cervix.

• A review of 163 women followed for a median of 15 months showed no significant difference between those receiving HAART, those receiving two NRTIs and treatment naﶥ patients in the persistence of high risk HPV infection or the progression of SIL (Uberti-Foppa 2001).

• The Chelsea and Westminster team investigated whether HAART had an impact on anal neoplasia. Twenty-three gay men were assessed six months after starting HIV therapy. The grade of neoplasia fell in 35% of individuals, remained stable in 43%, and became worse in 22%. Changes in CD4 and CD8 cell counts, and viral load after starting HAART were not related to alterations in the grade of anal neoplasia (Bower 2004). This study also reported that two-year survival of men with anal cancer was 47% and that the introduction of HAART did not improve survival.

• Abnormal anal cells were more common in HIV-positive men with lower CD4 cell counts and higher HIV viral loads, but the use of HAART was not associated with a reduction in the prevalence anal dysplasia (Young 2004). This finding is in agreement with results from other studies, which have failed to observe a reduction in the prevalence of AIN in patients after they start taking HAART (Piketty 2004).

• A recent study has shown that a viral load above 200 copies/ml, as well as having other anal infections, including herpes simplex virus, cytomegalovirus, Epstein-Barr virus, gonorrhoea or syphilis, are associated with an increased risk of progression to anal cancer (Sobhani 2004), suggesting that a good virological response to HAART may be protective against progression.

• An analysis of CIN with 867 person-years of follow-up of women revealed that most incident CIN was low-grade, but that there was a higher risk in young women and that being on HAART halved the risk (Heard 2005b).

Further studies are required to resolve this issue. However, given that the increased risk of cervical and anal cancer in HIV-positive people is not simply a function of immune suppression, it may not be surprising that immune restoration has not had a clear effect on rates of cervical and anal cancer.

There have been some data which suggest that rates of invasive cervical cancer among HIV-infected women were on the rise in Europe in the late 1990s. For instance, an Italian study found that women receiving treatment in the period after 1995 were nearly five times more likely than women in earlier periods to develop invasive cervical cancer. However, the small numbers involved and the wide confidence intervals suggest further evidence is needed to confirm this finding. The authors speculated that extended survival among HIV-infected women due to decreased incidence of other AIDS-related conditions may be an explanation for the increasing incidence of cervical cancer demonstrated in this study (Dorrucci 2001).

HAART has been associated with an increased incidence of oral warts in two studies. Clinicians have suggested that the emergence of oral warts may be an immune reconstitution problem caused by the improved ability of the immune system to detect HPV antigen in the tissue of the mouth (Greenspan 2001; King 2002).

Symptoms

Genital warts are flattish, cauliflower-like protuberances which can be small and single or large and in clumps. Other HPV-related abnormalities, such as cancerous changes in the cells of the cervix or rectum, may not cause any symptoms until the condition is advanced.

Diagnosis

Warts are usually diagnosed visually by examination of the skin. Genital warts can be diagnosed by examination of the vagina, vulva, cervix, anal region, anal canal and penis. However, HPV infection can be present even if warts are not.

Pap smears are designed to detect dysplasia early, before cancer develops. They involve taking a small scraping of cells from the cervix or anus. When these cells are examined under a microscope, it is possible to see if there are any changes in the cells which suggest that cancer could develop in the future.

HIV-positive women are recommended to have Pap smears when they are first diagnosed with HIV, six months later, and then at least once a year. There is no equivalent screening service for gay men. It has been recommended that gay men with anal warts attend genitourinary clinics for regular clinical assessment.

Pre-cancerous changes in cervical cells can also be observed using a more precise procedure called colposcopy. This is an examination of the cervix using a magnifying instrument, and is often accompanied by a biopsy, when a small piece of tissue is snipped away from the cervix for examination. The equivalent procedure for testing for anal dysplasia is called anoscopy and anal biomicroscopy. Anoscopy is not yet used routinely in the diagnosis and classification of AIN, although it has been shown to be a simple and effective method in screening patients at high risk of the disease (Fox 2005).

An American study has found that Pap smears are as effective as colposcopy in detecting cervical abnormalities that merit treatment, although colposcopy is more effective at detecting very early cervical disease, and at detecting lesions of the vulva or vagina. However, Pap smears are generally less accurate in determining the grade of cervical or anal disease than analysis of biopsies (Salit 2005).

A test to determine if a person has HPV is now marketed in the United Kingdom. HPV testing is not routinely used in clinical practice because the implications of the results have not yet been established.

Treatment

Warts can be treated by painting chemicals such as trichloroacetic acid, podophyllum resin (Warticon / Condyline) or 5-fluorouracil (5-FU) onto them. They are sometimes treated by injecting them with interferon alfa. Other treatment options include freezing them with liquid nitrogen or burning them off with a laser. These treatments are rarely fully effective, and recurrence rates are high, particularly in HIV-positive patients.

A cream containing the compound imiquimod (Aldara) has also proved successful in treating genital warts. This is recommended in the British Association for Sexual Health and HIV's (BASHH's) 2006 guidelines for the management of sexually transmitted infections in people with HIV. See Imiquimod in Drugs used by people with HIV: Immune-modulating drugs for further details.

Several studies have tested the effectiveness of a gel formulation of the antiviral drug cidofovir for treating warts. Cidofovir gel can reduce or clear warts in about half of treated patients and when combined with surgery is associated with a low recurrence rate (Kriesel 1997; Calista 2000; Matteelli 2001; Orlando 2002).

One randomised study has shown impressive clearance of genital warts in HIV-negative patients after the application of bacille Calmette-Guérin (BCG) weekly to the warts for six to nine weeks. BCG is usually used as a vaccine against tuberculosis. Twenty-three (92%) of the 25 patients showed clearance of warts, with no recurrence after six months, compared with no improvement in the placebo group. However, this treatment requires validation in larger studies and in HIV-positive patients. It is also expensive, potentially limiting its widespread use in the future (Metawea 2005).

There is no drug to prevent warts or HPV-related abnormalities. The best prophylaxis is careful monitoring to ensure that any problems are detected early and treated as soon as possible. However, HPV vaccines are under development, as explained in the section below.

Early in situ cervical cancer can be treated similarly to warts or by removal of the affected part of the cervix or anus. More serious cancer is treated with surgery or with a combination of local radiotherapy, topical treatments such as 5-fluorouracil and cytotoxic chemotherapy such as mitomycin (Mitomycin C Kyowa) or cisplatin.

If the entire region affected by cervical cancer can be seen by colposcopy, the cancer can be treated by laser vaporisation or loop electric excision procedure (LEEP). If this is not the case, then a cone biopsy (conisation) may be performed. This involves cutting out a cone shaped piece of the cervix. Women with HIV may be more prone to excessive bleeding and infection after such a procedure compared with uninfected women (Cuthill 1995). Cryotherapy is not recommended as an effective therapy among women with damaged immune systems (Spitzer 1999).

Among HIV-infected women treated for CIN grades 2 or 3, there is a high recurrence rate, which may be associated with higher HIV viral load, lower CD4 cell counts and incomplete removal of lesions during surgery (Keller 2000; Heard 2005a). One study found 45 to 50% of women had recurrence within a year of treatment (Maiman 1993). However, it seems recurrence is most common with high-grade abnormalities: low-grade lesions which remain untreated do not necessarily progress to cancer. One study found that application of 5-fluorouracil cream to the vagina reduced the recurrence of CIN among HIV-infected women (Maiman 1999). In addition, the use of HAART has been linked to a reduced likelihood of recurrence after surgery (Heard 2005a).

Surgery is occasionally used to remove precancerous anal lesions or warts, and this may be indicated earlier in disease than in HIV-negative patients. However, in the Chelsea and Westminster cohort, surgery left 50% of individuals in severe pain for over three weeks, and 75% experienced a recurrence of AIN within three years (Bower 2004).

Standard treatments for cervical cancer (chemotherapy and radiation therapy) may have success in the treatment of anal cancer in people with HIV-infection. Clinicians at the Chelsea and Westminster used chemoradiotherapy to treat anal cancer in 22 individuals, surgery in two patients with small cancerous lesions, with the remaining two patients, who had advanced HIV disease, receiving palliative care only. A total of eleven patients died, seven of anal cancer and four of an AIDS-defining condition. This provided a two-year survival rate of 47% (Bower 2004). A similar study from France has shown that high-dose chemoradiotherapy results in similar rates of toxicity, side-effects and cancer control in HIV-positive and -negative patients (Blazy 2005).

Vaccine development

Researchers are trying to develop a vaccine that could prevent initial infection with the strains of HPV associated with anogenital cancers. A phase I study found that the HPV 16 virus-like particle (VLP) vaccine stimulates high levels of antibodies and caused only minor side-effects (Schiller 2000). More recent placebo-controlled clinical trials including over 1500 women have shown that this vaccine prevents persistent HPV infection in 94% of women, and is 100% protective against the development of CIN grades 2 and 3 over 36 months.

Excellent results have also been achieved in phase II and III trials of an HPV vaccine that targets four virus types: the cervical cancer-causing 16 and 18, and types 11 and 13, which are associated with most cases of genital warts. The vaccine, produced by Merck, is called Gardasil. Over three years, the vaccine caused a 90% decrease in the incidence of persistent infection or disease with these types of HPV, and it was 100% effective against precancerous lesions and genital warts. The vaccine will probably be most effective if given before people become sexually active (Villa 2005). This vaccine is currently being tested in men with anal cancer as an endpoint, as well as in heterosexual transmission.

A third vaccine targeting HPV types 16 and 18, called Cervarix, has been shown to reduce cervical and vaginal infection. The vaccine caused a reduction of new infections with these HPV types by 92% after 27 months, as well as 100% protection against persistent infection and cross-protection against several other HPV types (Harper 2004). However, its manufacturer Glaxo SmithKline plans only to market the vaccine to women, and has no plans to investigate the effect of the vaccine in men or in preventing anal disease.

A vaccine which combines preventative and therapeutic effects is also being developed. It aims to stimulate antibodies against the HPV protein L1, and to stimulate CD8 T-cells to target the cancer-associated proteins such as E7. To date, studies in mice have provided encouraging results (Gissman 1999).

Finally, a vaccine called SGN-00101 or HspE7, which is made from the E7 protein of HPV type 16 fused to a protein from a bacterium, has been found to be safe in HIV-positive patients with anal intraepithelial neoplasia (AIN)^[1]. The study found some evidence that the vaccine could be useful in treating the condition, and further studies are underway.

Research on incidence in women

Massad (2004a) found that women with HIV have a low incidence of invasive cervical cancer (ICC) despite a high prevalence of risk factors. The study involved 2131 women participating in the Women's Interagency HIV Study (1661 HIV-positive, 462 HIV-negative, and eight who seroconverted during the observation period). At study entry, 62.7% of the HIV-positive women and 31.7% of the HIV-negative women had evidence of HPV infection; 13.6% and 3.6%, respectively, had oncogenic HPV strains associated with cervical cancer. At baseline, 37.7% of the HIV positive women and 17.3% of the HIV negative women had abnormal cervical cytology. One HIV-positive woman had cervical cancer at study entry. After 2375 person-years of observation, no new cases of ICC were detected in the HIV-negative women. After 8260 person-years, eight potential new cases were identified in the HIV-positive women, but only one was confirmed as ICC. The incidence rate of ICC among the HIV-positive women was thus 1.2 per 10,000 person-years (95% confidence interval, 0.36.7 cases). There was no significant difference in ICC incidence between the HIV-infected and uninfected women (p=1.0).

Massad (2004b) followed 223 women (202 HIV-positive and 21 HIV-negative) with CIN grade 1 for a mean of 3.3 person-years. Progression occurred in 8 HIV-positive women (1.2 per 100 person-years; 95% CI 0.5, 2.4) and 0 HIV-negative women. Regression occurred in 66 HIV-positive women (13 per 100 person-years) and 14 HIV-negative women (32 per 100 person-years; p < 0.001). Regression was associated with HPV detection and Hispanic ethnicity.

Minkoff (2004) conducted a prospective study of the natural history of HPV infection in 1797 HIV-positive and 496 'at-risk' women. HIV-positive women were 3 times more likely to be infected with HPV than HIV-negative women (p < 0.001). Among HIV-positive women, smokers were more likely to be infected with HPV (OR 1.33, p = 0.003), in particular type 18 (OR 2.45, p = 0.001) but not type 16 (OR 1.44, p = 0.47). They were also more likely to contract HPV type 16 during the 3 years of follow-up (p = 0.02). HPV infection was more likely to persist in HIV-positive than -negative women (OR 5.63, p = 0.001) and in smokers than non-smokers (OR 1.39, p = 0.02).

Moscicki (2004a) measured HPV infection in 222 HIV-positive and 112 HIV-negative girls aged 13-18. Rates of new infections were similar between the 2 groups, but the HIV-positive girls were more likely to be infected with high-risk HPV types (41 vs. 22%, p = 0.003), which may be due to their greater experience of high-risk sexual behaviour, younger age at first sexual intercourse and greater number of sexual partners. The HIV-positive girls took longer to clear HPV (mean 689 vs. 403 days), including both low- and high-risk types. For every 100 cells/mm³ rise in CD4 cell count, there was a 6% increase in the likelihood of HPV clearance (p = 0.015).

Moscicki (2004b) carried out cytological examination of the cervix in 172 HIV-positive and 84 HIV-negative girls aged 13-18 every 6 months for a median of 3 years. None of the girls had high grade SIL at baseline, but 22% of the HIV-positive and 5% of the HIV-negative girls developed high grade SIL. High concentrations of interleukin-12 were seen in the cervical mucus of girls progressing to high grade SIL. Low grade SIL and use of hormonal contraceptives were also associated with progression.

Allen reported on a study of over 1000 Rwandan women including 365 HIV-positive women. At one year, the HIV-positive women were more likely to have HPV infection and cervical dysplasia. During follow-up, 29% of the women with HIV progressed to a more advanced dysplasia compared to 12% of the HIV-negative women.

Delmas enrolled 485 HIV-infected women between 1993 and 1998 and followed them for an average of 2 years. Women with CD4 counts below 200 were twice as likely to have squamous intraepithelial lesions (SIL) than women with CD4 counts above 500. The women with impaired immune systems had a lower response rate to treatment of high grade SIL and those not receiving antiretroviral therapy were at significantly greater risk of SIL.

Holly studied the prevalence of Pap smear abnormalities among 251 HIV-infected women and 68 HIV-negative women. 26% of the HIV-infected women had abnormal anal smears compared to 8% of the HIV-negative women. High grade SIL occurred in 6% and 2% of the HIV-infected and uninfected women respectively. Lower CD4 count and higher viral load were associated with abnormal anal smear in HIV-infected women. Multivariate analysis showed that a history of anal intercourse and abnormal cervical smear were significantly associated with risk of an abnormal anal Pap smear.

Palefsky (2001b) studied 251 HIV-positive women and 68 HIV-negative women for the presence of anal HPV. 76% of HIV-positive and 42% of HIV-negative women were found to have anal HPV DNA (relative risk [RR] 1.8). 200 women had concurrent anal and cervical HPV data which showed anal HPV was more common than cervical HPV in both HIV-positive (79% vs 53%) and HIV-negative women (43% vs 24%). Multivariate analysis indicated that a CD4 count below 200 cells/mm³ compared with a count above 500, and cervical HPV infection were associated with anal HPV infection.

De Vuyst screened 480 women for HIV, sexually transmitted diseases and cervical dysplasia. Among the 12% with HIV, low-grade SIL prevalence was 10% and high grade SIL was 17%. In comparison, low and high grade SIL prevalence was 6.4%and 4% among HIV-negative women. These results were statistically significant.

Boni-Ouattara compared 102 women with cervical cancer with 102 cancer-free controls. Among women under 40 years, cervical cancer was more common about women with HIV (30.8%) compared with controls (10.6%). Among the women with cervical cancer, the age of HIV-infected women was lower (37 years) compared with HIV-negative women (48 years).

Ellerbrock conducted a prospective cohort study of 328 HIV-infected women and 325 uninfected women with no evidence of SILs by Pap smear and colposcopy at baseline. Over 30 months of follow-up, 20% of HIV infected women and 5% of the uninfected women developed a SIL (p<0.001). Low grade SILs were detected among 91% of the infected women with SIL and 75% of the uninfected women with SIL.

Campbell (1999) screened 120 patients with cervical cancer in Nigeria for HIV before and after radiotherapy. 4% of patients had HIV. HIV-positive women had more severe disease state and a shorter duration of remission (mean 18.4 vs. 24.2 months).

Palefsky (1999c) tested 1,778 HIV-infected women and 500 uninfected women for HPV DNA in the cervicovaginal lavage. HIV-infected women with CD4 counts below 200 were at the greatest risk of HPV infection (odds ratio 10.13). HIV-infected women with CD4 counts above 200 were also at increased risk of HPV infection. Other factors associated with HPV infection were African racial background, age under 30 and current smoking.

Massad identified abnormal cervical cytology (an abnormal smear) in 73% of 1639 HIV-positive women enrolled in the US Women's Interagency HIV Study compared with 42.3% of 452 HIV-negative women between 1994 and 1999 (p<0.001). Women had Pap smears every 6 months. 5.9% HIV-infected women developed high-grade squamous intraepithelial lesions and this did not increase over time. Incidence of abnormal Pap smears, progression and regression did not differ between HIV-negative women and positive women with CD4 counts above 200 and viral loads below 40,000. Abnormal cytology was predicted by the presence of HPV, CD4 count, and viral load.

Shah reported on 561 HIV-infected and 321 uninfected women enrolled in the HERS cohort study. Rates of HPV infection were 79% among women with viral loads (VL) over 30,000 HIV RNA copies, 61% VL 10,000-30,000, 67% VL 200-10,000, 50% VL undetectable, and 28% among HIV-negative women. Low grade (LG) SIL was 33% among women with VL above 30,000, 23% of VL 10,000-30,000, and 4% among HIV-negative women, and 81 among women with CD4 counts below 200. HIV-infected women with CD4 counts below 200 had an 81% rate of LG SIL, above 500 had a 5% rate LG SIL, CD4 count 200-500 had a 15% rate of LG SIL and HIV-negative women had a 4% rate of LG SIL. High grade SIL was also more common among immune suppressed women with high viral load but results were not statistically significant.

Phelps studied the incidence of cancer among 1310 HIV-infected and uninfected women enrolled in the HIV Epidemiology Research Study (HERS) between 1993-95 and followed until 2000. The rate of all cancers was 6.22/1000 person-years among the 871 HIV-infected women and 1.72/1000 p/y among the 439 HIV-negative women. There were 5 cases of cervical cancer, 1 Kaposi's sarcoma, and 12 non-AIDS defining cancers including 4 lung cancers among the HIV-infected women.

Hankins presented a Canadian study of HPV persistence among 108 HIV+, HPV+ women and 71 HPV+, HIV- women at 6 and 12 month time points after original HPV detection. General HPV persistence was significantly greater among HIV+ women (87% vs 52%) with women with CD4 counts below 200 at greater risk of HPV persistence. Persistence of cancer-causing HPV was significantly greater among HIV+ women (59% vs 32%, p<0.001). Oral contraceptives appeared to be protective against HPV persistence in both groups.

Ebrahim reported that invasive cervical cancer was the most common cancer among women with AIDS in Europe and the US between 1994-1998.

Womack investigated 466 women in an HIV/sexually transmitted disease prevalence study in Zimbabwe for HIV, HVP and squamous intraepithelial lesions (SIL). 53.5% of the women were HIV-positive. 47.2% of women were infected with HPV: 64.3% of HIV-positive women and 27.6% HIV-negative women. 14% had high-grade lesions and 12% had low-grade lesions.

Piper and Vernon investigated two groups of (258 'maternal' women with few sexual partners vs 278 sex workers with many sexual partners) in the Cote d'Ivoire. While the sex workers were more likely to be infected with HIV, in both groups, HPV infection was associated with HIV infection. In women with few sexual partners, HIV-1 and HPV were both associated with SIL; in the sex worker group, HPV was and HIV was not associated with SIL.

Wright investigated HPV 16 and 18 in 170 HIV-infected and 136 uninfected women. Blood and cervicovaginal lavage (CVL) were sampled prospectively. Stored samples taken within the last 5 years were also tested. Antibodies to HPV 16/18 were similar for the two groups but 24% of the HIV+ group had HPV 16 or 18 detected in CVL compared with 3% of the HIV- women. Poor antibody responses were detected in the HIV- group. No difference in rates of neoplasia was detected.

Luque studied 93 women with HIV and HPV. Viral load over 10,000 was associated with the presence of high-risk HPV genotypes and abnormal Pap smears.

Moscicki compared 133 HIV-infected and 55 HIV-negative women aged between 13 and 19 years. At entry 62 had not commenced HAART. HPV infection was higher in the HIV+ group (77% vs 54%). Among those with HPV, 70% of the HIV+group had abnormal cells compared with 30% of the HIV- group. CD4 count and HIV viral load did not predict cervical dysplasia.

Watts studied 67 women enrolled in ACTG 196 and 185 women enrolled in ACTG 175. The women were similar for age, race, weight and history of injecting drug use, but the women in ACTG 196 had lower CD4 counts (median 35 vs 356). Changes in menstruation did not differ between the groups. Pap smear results for ACTG 196 and ACTG 175 were as follows: normal 38% and 50%; atypical 24% and 39%; low-grade SIL 27% and 10%; high-grade SIL 11% and 0.7%.

Williams reported that among 144 women, the prevalence of HPV infection was 56% of anal swabs and 13% of cervical swabs in HIV-negative high-risk women, and 77% of anal swabs and 57% of cervical swabs in HIV-positive women. 14% of women, most of whom were HIV-positive. had anal cytologic abnormalities and 11% had cervical abnormalities. The grade of anal disease was generally less severe than that of cervical disease, and the proportion of women with anal HPV infection who had anal disease was lower than the proportion with cervical HPV infection who had cervical disease, suggesting that anal HPV infection may be less aggressive in causing disease than cervical infection.

Sun evaluated 220 HIV-positive and 231 HIV-negative women at two or more semiannual gynaecologic examinations that included a Pap test, a test for HPV DNA, and colposcopy. HPV DNA was detected at the initial examination in 56% of HIV-positive and 31% of HIV-negative women. After four examinations, the cumulative prevalence of HPV infection was 83% of HIV-positive and 62% of HIV-negative women. Persistent HPV infections were found in 24% of HIV-positive women but in only 4%of HIV-negative women. 20% of HIV-positive women and 3% of HIV-negative women had persistent infections with HPV-16-associated viral types (16, 31, 33, 35, or 58) or HPV-18-associated types (18 or 45), which are most strongly associated with cervical cancer.

Ahdieh followed cohorts of HIV-infected and HIV-negative with median follow-up times of 2.5 and 2.9 years respectively. Women with HIV were 1.8, 2.1 and 2.7 times morel likely to have high-, intermediate-and low-risk HPV infections compared to HIV-negative women. HPV persistence was twice as likely in HIV-infected women with CD4 counts below 200 compared with those with CD4 counts above 500.

Klein found that HIV-positive women have a higher rate of squamous intraepithelial lesions (SIL) on Pap smear than HIV-negative women. SIL was detected on Pap smear in 28/111 (25%) HIV+ and 11/107 (10%) HIV-negative women.

Six conducted a prospective study of 271 HIV positive women and 171 HIV-negative women who had pap smears at inclusion, 6 months and 12 months. SIL was detected in 4.9% of negative women, and in 27% of positive women with CD4 counts below 500. The study did not determine whether women with HIV infection who do not have significant damage to their immune systems are at greater risk of SIL.

Conley followed 481 HIV-negative women and 437 HIV-negative women for an average of 3.2 years. 6% of the HIV-positive women and 1% of the HIV-negative women had vulvovaginal or perianal warts or abnormal Pap smear at enrolment compared to only 1% of the HIV-negative group. 9% of the 385 HIV-positive women developed warts or lesions compared to 1% of the 341 uninfected women (p<0.0001). Risk factors associated with new lesions were: HIV infection, HPV infection, lower CD4 count and a history of injecting drug use.

Regevik found that HIV-infected women with CD4 counts below 500 and with evidence of HPV infection may be at higher risk for developing neoplastic changes in the cervix.

Brosgart reported that Pap smears were highly sensitive in detecting SIL in a cohort of HIV+ women. When compared to colposcopy, confirmed by biopsy, Pap smears were 100% sensitive. Colposcopy was more effective at detecting very early cervical disease.

Research on incidence of anal neoplasia and anal cancer

Bower (2004) reported that anal cancer occurs more frequently in HIV-positive gay men, doesnt respond to HAART, is difficult to treat, has a poor outcome, but is, thankfully, rare, according to data from the largest UK HIV cohort Since 1986, 8,640 individuals have been enrolled into the Chelsea and Westminster HIV cohort, providing over 40,000 patient years of follow-up. A total of 26 cases of invasive anal cancer have been diagnosed during this period, 25 of them in gay men (the remaining case being in a heterosexual woman). The development of anal cancer was not linked to severe immune suppression, the median CD4 cell count of individuals presenting with anal cancer being 206 cells/mm³. The incidence of anal cancer did not fall with the introduction of HAART (p>0.05). Since 1996, 67% of individuals diagnosed with malignancy have been taking HIV therapy, and 28% (18 individuals) have had a viral load below 50 copies/mL.

Manzione (2004) identified HPV type in 39 HIV-positive men with anal warts using the polymerase chain reaction (PCR). High grade AIN was seen in 23% and low grade in 77% of patients. The most frequent HPV types were 6 and 11 (64% of patients) with cancer-causing tyupes 16, 18 and 31 appearing in 21%. Comparing AIN grade with HPV type revealed that cancer-causing and non-cancer causing types were associated with high grade AIN.

Piketty (2004) carried out a cross-sectional study of 45 HIV-positive men who had taken >6 months HAART. Anal swabs were taken: 32 (71%) were abnormal, with 22 being low grade AIN and 6 high grade AIN. 36 men (80%) were infected with HPV, with 22 being infected aith a cancer-causing type. 20 men (56%) were infected with >1 type of HPV. The presence of abnormal cells was not associated with CD4 cell count at enrolment (>/<250 cells/mm³, p = 0.7), lowest-ever CD4 cell count (>/<150 cells/mm³, p = 0.3) or size of CD4 T-cell increase after starting HAART (>/<150 cells/mm³, p = 0.3).

Sobhani (2004) tested 199 individuals who had been treated for anal warts for anal infections (herpes simplex virus, cytomegalovirus, Epstein-Barr virus, gonorrhoea and syphilis) and HIV. The anal mucosa was also biopsied, and 26 were found to have high-grade dysplasia (16% HIV-positive; 8% HIV-negative; not significant). Over a median follow-up of 23 months, 38 individuals (19%) progressed to high grade dysplasia or anal cancer: 32 (84%) of these were HIV-positive (p = 0.007). Anal cancer developed in 7 patients 13-108 months after entry into the study. All but 1 had high grade dysplasia at baseline. There were no significant differences between patients with and without dysplasia or cancer in age, sex, body mass index, anal sex or drug use. Patients with high grade dysplasia or cancer were more likely to be HIV-positive (p = 0.007), to have an anal co-infection (p < 0.001), to have lower Langerhans' cell count in the anal mucosa (16 vs. 27 cells/mm³, p = 0.01), to have experienced a relapse of anal warts (45 vs. 10%, p < 0.001). HPV types 18, 16, 31 and 33 were associated with an increased risk of progression (p = 0.009). HIV VL >200 copies/ml was associated with progression (p < 0.01).

Wilkin (2004) recruited 92 HIV-positive men for a cross-sectional study of AIN. 53% were Latino, 36% black and 8% white. 50% self-reported as gay and 11% as bisexual, and 60% reported ever having had receptive anal intercourse. 82% were on HAART with 67% having VLs <400 copies/ml. 40% had AIN and 9% had high-grade AIN following anal biopsy. 61% were infected with a cancer-causing type of HPV and this was associated with a history of receptive anal intercourse (odds ratio [OR] 7.1, p = 0.001). The strongest risk factor for AIN was low nadir CD4 cell count (OR 5.7, p = 0.03). Current use of HAART protected against abnormal cells (OR 0.06, p < 0.01) and AIN (OR 0.09, p = 0.03).

Young (2004) carried out anal Pap smears on 371 gay men and Pap smears and anal biopsy on 121 gay men. The mean CD4 cell count in men with normal Pap smear results was higher than those with abnormal results (460 vs. 388 cells/mm³, p = 0.02). It was also higher in men with normal anal biospy results (483 vs. 357 cells/mm³, p = 0.02). There was a trend for VL to be lower in men with normal biopsy results (3180 vs. 24,200 copies/ml, p = 0.06). There was no difference in use of HAART (p = 0.26).

Fortin studied 113 HIV-infected men who were recruited consecutively when starting combination antiretroviral therapy. 135 of 138 anal samples were positive for HPV - most commonly genotypes 16, 6, 52, 45 and 18. Of 90 men with anoscopy results, 36 were normal, 36 had anal intraepithelial neoplasia I (AIN - early stage of cell abnormalities) and 18 had more advanced AIN II-III. HPV 16 was more common in men with AIN II-III versus men with normal anal cells (33% vs 61%). A greater number of cancer-causing HPV were found in men with high grade abnormalities compared with men with no abnormalities (average 4 vs 2).

Palefsky (1994) reviewed the literature on anal HPV and anal cancer in HIV infection. Studies in HIV-positive gay men suggest that anal HPV infection is extremely common, and that as the CD4 count declines the prevalence of high level infection increases. The prevalence of anal intraepithelial neoplasia also increases as the CD4 cell count declines, suggesting either a direct effect of immune suppression or an association with active viral replication. Almost nothing is known about anal cancer precursors and anal HPV infection in women. Screening for AIN is recommended for HIV-negative men with a history of receptive anal intercourse, HIV-positive men with a CD4 cell count below 500, HIV-positive or HIV-negative women with a high-grade CIN, and HIV-positive women with a CD4 count below 500. Treatment for high-grade AIN usually consists of electrocautery or excisional biopsy.

Palefsky (1998a and 1998b) enrolled 346 HIV-positive and 262 HIV-negative gay men in a prospective study consisting of an anal examination including HPV testing, anal cytology, anoscopy and biopsy of visible lesions. HIV-positive men were more likely to develop high grade squamous intraepithelial lesions (HSIL) than HIV-negative men (relative risk [RR] 3.7, 95% confidence interval [CI] 2.6-5.7). Estimates of the 4-year incidence of SIL was 49% among HIV-positive men and 17% among HIV-negative men. Lower baseline CD4 counts and persistent HPV infection were associated with greater risk of HSIL. 36% of HIV-positive men developed anal SIL compared to 7% of HIV-negative men (RR 5.7). Risk of anal SIL rose as CD4 levels fell but was elevated even in men with CD4 levels above 500/mm³ (RR 3.8) when compared with HIV-negative men. Also see Palefsky (2001) below.

Voltz investigated 121 HIV-infected men for signs of anal HPV. 19 (15.7%) had HPV infection. 7/19 had genital lesions, 7/19 had anal lesions, 9/19 had neoplasia. 3-6 months after treatment, lesions were recovering in 9 cases, stabilised in 3, recurred in 3 and worsened in 2 cases.

Lacey enrolled 57 HIV-infected gay men in a prospective study to determine the prevalence of high-grade anal intraepithelial neoplasia (AIN) and the value of screening for AIN in this group. Average CD4 count at baseline was 273. Full data was collected on 38 men with an average follow-up time of 17 months. 84% of the men were infected with cancer-causing HPV types. At baseline, high-grade cell abnormality was detected in 6 men (10%). During the follow-up period, 70% of participants developed high-grade cell abnormality. All 23 cases were predicted by tests such as anoscopy and cytology.

Place conducted a retrospective review of the tumour registry of patients attending the University of Texas Southwestern Medical Clinic 1980-1999 to determine the outcome of anal squamous cell carcinoma in HIV-positive patients. 73 cases were identified including 23 HIV-infected cases. Low CD4 count at time of diagnosis with anal cancer, in the absence of antiretroviral therapy, was associated with poor prognosis. Patients with anal cancer who died had a lower average CD4 count than those who survived (133 vs 261, p=0.03). People treated with radiotherapy and chemotherapy before the availability of antiretroviral combinations gained little benefit and significant toxicity from treatments.

Melbye reported that the risk of anal cancer was greatly increased among gay and heterosexual people with HIV compared with the general population, especially for young gay men.

Research into HPV in the age of HAART

Dorrucci investigated the incidence of invasive cervical cancer (ICC) among 483 women enrolled in the Italian Seroconversion Study. This cohort was begun in 1987 and the date of seroconversion of participants has been estimated with relative accuracy. The researchers analyzed data using three time periods: 1981-1991, 1992-1995 and 1996-1998. Over time, the proportion of women taking monotherapy fell from 36.2% to 22.3% and the proportion of women taking dual and triple regimens increased to 45% and 27%, respectively, during 1996-1998. A total of 133 women developed AIDS with six women having ICC as their first AIDS-defining illness (4.5%). Receipt of anti-HIV drugs varied for the six women; two had taken monotherapy, two had take dual therapy, one had taken HAART and one had never taken treatment for HIV. The median age of women developing ICC was 38 years compared with an average of 31 years for other AIDS-defining illnesses. The incidence of ICC and other AIDS-defining illnesses rose until 1995. Since that date, the incidence of ICC has continued to rise while the incidence of other AIDS-related illnesses has fallen. The relative hazard of ICC for 1996-1998 compared with 1981-1995 was 7.41 (CI:1.21-45.44). Even after controlling for age at seroconversion, women in the latter period were nearly five times more likely to develop ICC than in the earlier period (RH 4.74, CI:0.80-28.24).

Duerr investigated the rate of abnormal Pap smear results among 602 women with HIV, of whom 159 had begun HAART and 176 had begun antiretroviral therapy (not deemed highly active) within a six month period. Among women on HAART, rates of SIL and atypical cells (ASCUS) at baseline were 26%. After 1 year follow up, these rates were 33% (SIL) and 17% ASCUS, and 33% (SIL) and 19% (ASCUS) after 2 years. There was an absence of regression or loss of HPV among the HAART group suggesting the need for regular smears among women on HAART. However, those on HAART had a reduced risk of new abnormalities.

Minkoff assessed progression or regression of cervical abnormalities among 741 HIV infected women in the WIHS over 3 annual visits. After controlling for CD4 count and Pap smear status, women on HAART were 1.4 times more likely to have regression of abnormal cells than untreated women. However, women with HPV 16/18 were more likely to experience progression over the 3 visits.

Orlando (1999) reported on 15 women with low-grade SIL among women who had been taking HAART for 3 months. Six months later, 47% of lesions had progressed to high grade while only 20% had regressed.

Heard reported that 13 HIV-infected women with high-grade SIL found that two regressed to low-grade SIL and one had full regression after five months of HAART. Furthermore, nine of 21 women with low-grade SIL showed normal results. Overall prevalence of SIL fell from 69% to 53% (p=0.038) among 49 women taking HAART for 5 months.

Del Mistro reviewed the charts of 229 HIV-infected women between August 1994-December 1998. At baseline, 31% of women had low-grade SIL and 14% had high-grade and 2.6% had cancer. Follow-up data on 119 women found that 11 of 83 women with low-grade SIL or normal baseline results progressed. Most women with high-grade SIL showed persistence even after conization. To date, HAART has had not impact on genital lesions.

Palefsky (2001) studied 98 HIV-infected men in an anal SIL study for 12 months. Anal cytology, anal biopsy and CD4 levels were all taken at baseline, at 6 months when HAART was started, and after 6 months of HAART. Anal lesion progression in the six months follow-up period prior to commencing HAART was 27% in those with atypical squamous cells (ASCUS) or low grade intraepithelial lesions (LSIL), while 17% experienced regression of these lesions at six months. 38% of those with a normal anal diagnosis progressed during the six month pre-HAART period, while 50% of those with high grade lesions (HSILs) experienced regression. In the six months after starting HAART, 18% with ASCUS or LSIL progressed, while 21% experienced regression. 17% of those with a normal anal diagnosis experienced progression, while 43% with HSIL experienced regression. There was also little difference between the pre- and post-HAART periods in terms of HPV detection.For each category of lesion a trend towards increased rates of disease regression was observed in the six month period after commencing HAART, but this difference was non-significant.

Giovanna presented data on 40 HIV-infected individuals diagnosed with genital warts. 13 were on HAART, 21 on dual NRTI therapy and 6 on no treatment. Six months after surgical removal of warts, relapse occurred in 0% of the HAART group, 10% of the 2 NRTI group and 75% of the no treatment group. Relapse was associated with high viral load rather than low CD4 count.

Robinson reviewed the charts of 56 HIV-infected women and 62 HIV-negative women with cervical intraepithelial neoplasia (CIN) treated with excisional therapy with or without HAART. 57% of the HIV-infected women had persistent or recurrent CIN compared with 17% of the HIV-negative group - a highly significant result. HIV positive women were also more likely to progress than negative women ( 17% vs 5%). Lower CD4 count was associated with greater recurrence or persistence among the HIV-infected women. HAART was associated with lower recurrence/persistence (70% vs 17%) and lower rates of progression (31% vs 0%).

Uberti-Foppa reported an observational study of 163 women followed for a median of 15 months. 45.6% received HAART, 37.5% received two NRTIs and 17% received no treatment. The relative risk for progression of SIL was 3.5 in the HAART group compared to others (p=0.04), but the risk was not adjusted for CD4 cell count at initiation of therapy or at baseline.

King identified 56 HIV-infected patients with HPV-associated oral warts among 2194 HIV-infected patients attending an urban oral health centre 1997-1999 (prevalence 2.6%). New case of oral warts were significantly more likely in 1999 than in 1997-98 (p=0.001). Multivariate analysis showed that risk of oral warts was associated with a 1 log or greater decrease in HIV viral load in the 6 months before diagnosis and evidence of hepatitis B infection. Oral warts were seen in five patients out of 2194 receiving care in Atlantas Oral Health Center in 1997, compared with 21 in 1999, whilst Greenspan reported that patients receiving HAART were six times more likely to have oral warts compared to those who did not receive HAART. The prevalence of warts in patients with HAART was just over 23% in the period 1996-1999 in the San Francisco clinic.

Although a temporal association with HAART was seen, the Atlanta group did not find clear evidence that wart emergence is associated with immune reconstitution. Similarly, they found that whilst risk of warts was associated with a viral load reduction of more than 1 log within the previous six months, there was no difference between patients with warts and those without in CD4 cell count changes prior to diagnosis with oral warts.

Research on prevention and screening

Bower (2004 above) reported a pilot programme to detect cancers and precancerous cells in the anus (AIN anal intraepithelial neoplasma). A total of 156 screens were conducted on 100 patients. All individuals with AIN were infected with the HPV virus but there was no particular strain of HPV that was associated with the presence of AIN. No correlation was found between the presence of AIN and either CD4 and CD8 cell count, or HIV viral load. To see if HAART had an impact on the AIN, 23 gay men were assessed six months after starting HIV therapy. The grade of AIN went down in 35% of individuals, remained stable in 43%, and become worse in 22%. Changes in CD4, CD8, or viral load after starting HAART were not related to alterations in the grade of AIN. Difficulties in the management of AIN were also encountered by the Chelsea and Westminster clinicians. The use of surgery to remove the precancerous lesions left 50% of individuals in uncontrollable pain for over three weeks, and 75% experienced a recurrence of AIN within three years.

Panther (2004) paired the Pap smear cytology results from 153 gay men attending an anal dysplasia clinic with histology results from anal biopsy. 100 men (65%) were HIV-positive. A third of the Pap smears categorised as AIN grade 1 were AIN grade 3 by biopsy.

Bleeker (2003) randomised 100 men with penile warts whose female sexual partners had CIN to use condoms consistently for 3 months or not to use condoms. Condom use shortened the time to regression of flat penile lesions (7.4 vs. 13.9 months).

Hogewoning (2003) randomised 123 women with CIN to use condoms consistently with their regular male sexual partner or not to use condoms. The condom group showed a higher 2-year regression rate (53 vs. 35%, p = 0.03) and a higher degree of HPV clearance (23 vs. 4%, p = 0.02).

Goldie examined the clinical and cost effectiveness of screening HIV-infected gay and bisexual men for anal squamous intraepithelial lesions (ASIL) and anal cancer. Comparing quality of life and life expectancy among screened and unscreened men, there was clear clinical and cost benefit to yearly screening.

Anderson compared two anal smear collection techniques in 200 gay men using a Dacron swab: one blind and the other proctoscope-aided. There was no difference between the methods in terms of cytological classification of the specimen, presence of rectal columnar, abnormal cells, contamination, adequacy rate, the volume of fluid remaining after the ThinPrep procedure, and patient comfort and acceptability. Results on 90 men showed 31% of the HIV+ men and 20% of the HIV-negative men had AIN. The blind smears were more likely to be referred for cytological assessment, and the positive predictive value for high-grade AIN was 78% for the blind smears and 83% for the protoscope-aided smears.

Research on treatment

Bower (2004 above) reported on the use of chemoradiotherapy to treat anal cancer in 22 individuals, surgery in two patients with small cancerous lesions, with the remaining two patients, who had advanced HIV disease, receiving palliative care only. A total of eleven patients died, seven of anal cancer and four of an AIDS-defining condition. This provided a two-year survival rate of 47%. Prognosis did not improve after the introduction of HAART. Neither CD4 cell count, use of HAART, history of a prior AIDS-defining illness, nor length of HIV diagnosis of prognostic value.

Maiman (1999) randomised 101 HIV-infected women to vaginal 5-fluorouracil (5-FU) cream applied twice weakly for 6 months or observation following excisional or ablative cervical treatment for cervical intraepithelial neoplasia (CIN). Overall, 38% of women had recurrence of CIN. 14/50 (28%) of the 5-FU women compared to 24/51 (47%) of the observation group, with the observation group more likely to have recurrence of grade II or III CIN (p=0.014). Lower baseline CD4 count was associated with greater risk of recurrence. 5-FU and HAART were associated with longer time to relapse.

Orlando conducted a open, randomised, prospective study comparing surgery excision, cidofovir gel and combined surgery/cidofovir gel for genital warts in 74 HIV-infected people. Responses rates were: 93% in the surgery group; 76% in the cidofovir group and 100% in the combined treatment arm (p=0.0033). Relapse rates in 49 people with follow-up data were: 74% surgery; 35% cidofovir, and 27% combined (p=0.018).

Adachi conducted a prospective study of women with abnormal Pap smears from a longitudinal cohort of studying HIV, HPV and genital cancer. 48 women were diagnosed with squamous intraepithelial lesions (SIL) and referred for colposcopy and standard gynecological care. Upon colposcopy, 17/25 (68%) HIV-infected women had cervical or vaginal warts or neoplasia (abnormal cells) compared with 3/13 (23%) HIV-negative women. 7 HIV-positive women had SIL grade II or III. After follow-up of between 3-37 months, 3/3 treated HIV-negative and 5/10 treated HIV-positive women had normal examinations. 3 positive women had persistent SIL without progression and 2 progressed to warts.

Calista treated 10 HIV-infected people with HPV-associated warts and 4 with molluscum contagiosum (MC) with 1% cidofovir cream following the failure of standard therapies. All had been taking highly active antiretroviral therapy (HAART) for at least a year. Warts and MC were resolved in 13 people who completed therapy, usually within 2 weeks of first application. At 2 years of follow-up, 4 patients had isolated relapses which were successfully treated with curettage.

Matteelli randomised 12 HIV-infected people with external anogenital warts to 1% cidofovir cream or placebo in a crossover pilot study. Cream was applied once daily for 5 days/week for 2 weeks. Total wart area was reduced by half in 58% of cases compared to no change in the placebo arm (p=0.02). 10/12 people had a reaction to the cidofovir cream.

Keller conducted a retrospective review of 39 women treated for cervical dysplasia (cervical conization or loop excision). After 13.2-16.7 months follow-up, biopsy or pap smear found only 46.2% with a normal result; 23.1% had atypical cells, 20.4% had low grade SIL and 10.3% had high grade SIL. Detectable viral load but not low CD4 count was associated with increased risk of abnormal result on follow-up.

Hoffman reported on 17 HIV positive people with anal cancer treated with either chemotherapy plus radiation or radiation alone. Nine people with CD4 counts over 200 had the cancer controlled with chemo-radiation, and none required hospitalisation. Of 8 with CD4 counts below 200, 4 had falling CD4 counts and symptoms requiring hospitalisation. 4 also required colostomy for side-effects or treatment salvage. Ultimately, anal cancer was controlled in 7/8 people with low CD4 counts.

Kriesel conducted a phase I/II dose escalation study of cidofovir gel (0.3%, 1% and 3%) for the treatment of anogenital warts among HIV-positive people with CD4 counts above 100. 52 participants received either 5 or 10 days treatment, followed by 2 weeks of observation. Complete clearance of warts was seen in 15% of participants, a partial response in 50%, a minor response in 17% and no response in 17%, with a median duration of treatment of 10 days. No recurrence was seen at 3 or 6 months post-treatment in 82% of responders. No systemic toxicities were observed.

Mackerras conducted a double-blind, placebo-controlled randomised study of 30 mg betacarotene and/or 500mg vitamin C in 141 women whose previous pap smears had shown abnormal cells or CIN I. Over 2 years, 43 lesions regressed to normal and 13 progressed to CIN II. Those on beta carotene had a slightly higher regression rate (not statistically significant). Of the 13 who progressed, 7 were taking both compounds. This trend was not statistically significant (p=0.052) but provides some evidence that the 2 compounds together may increased CIN progression rates.

References

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Allen S et al. Longterm follow-up of cervical intraepithelial neoplasia in HIV infected and uninfected urban Rwandan women. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 942, 2003.

Anderson J et al. The optimal anal cell collection technique for screening anal intraepithelial neoplasia in homosexual men. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 1004, 2003.

Andieh L et al. Prevalence, incidence, and type-specific persistence of human papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women. J Infect Dis 184: 682-690, 2001.

Blazy A et al. Anal carcinomas in HIV-positive patients: high-dose chemoradiotherapy is feasible in the era of highly active antiretroviral therapy. Dis Colon Rectum 48: 1176-1181, 2005.

Bleeker MCG et al. Condom use promotes regression of human papilloma virus-associated penile lesions in male sexual partners of women with cervical intraepithelial neoplasia. Int J Cancer 107: 804-810, 2003.

Boni-Quattara E et al. Case-control study of cervical cancer and HIV infection in Abidjan, Cote d'Ivoire. Thirteenth International AIDS Conference, Durban, abstract B233, 2000.

Bower M et al. HIV-associated anal cancer: has highly active antiretroviral therapy reduced the incidence or improved the outcome? J Acquir Immune Defic Syndr 37: 1563-1565, 2004.

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