Human papillomavirus is a common sexually transmitted infection that can cause abnormal cell changes. Several types cause warts, and "high-risk" types including HPV-16 and HPV-18 can cause malignant cell growth, or cancer. While invasive cervical cancer is considered an AIDS-defining illness, anal cancer is not, even though they have the same cause.

Anal Cancer in Men

In the first study presented at AIDS 2010, Christopher Piketty and colleagues from the French Valparaiso Study Group aimed to assess the impact of combination ART and immune restoration on HPV-related anal cell abnormalities among men with HIV.

This longitudinal analysis included 94 HIV positive men who have sex with men (MSM) seen at 7 academic hospitals in France who started combination ART for the first time. The median age was about 40 years. Only 4% had ever had an AIDS diagnosis, but about 20% had a history of other sexually transmitted infections.

The researchers tested participants for HPV DNA (genetic material), examined anal cells using ThinPrep Pap smears, and looked for tissue abnormalities including squamous intraepithelial lesions (SIL), a precursor of anal cancer. In addition, CD4 and CD8 T-cell responses to the E6 and E7 proteins of HPV-16 were measured in a subgroup of participants who had anal HPV-16 infection at study entry.

Samples were obtained at baseline and at months 12 and 24 after starting ART; 12-month data were reported.

Results

• CD4 cell count rose from about 300 cells/mm3 at study entry to 500 cells/mm3 at month 12.
• Median viral load fell from 4.8 to 1.6 log and more than 90% achieved undetectable HIV RNA < 50 copies/mL.
• Overall, anal SIL did not regress despite CD4 cell gains after starting ART.
• Prevalence of SIL was similar at baseline and at month 12:
  • Anal SIL overall: 54% at baseline vs 58% at month 12;
  • Low-grade SIL: 32% vs 34%, respectively;
  • High-grade SIL: 8% vs 14%, respectively.
• Participants continued to show evidence of overall and high-risk HPV infection after ART initiation:
  • Any HPV type: 97% at baseline vs 94% at month 12;
  • Any high-risk HPV type: 92% at baseline vs 89% at month 12;
  • HPV-16: 40% vs 34%, respectively;
  • HPV-18: 18% vs 16%, respectively.
• Both at baseline and at month 12, participants had a median 5 types of HPV overall and a median 3 high-risk types.
• Among 29 participants who started out with normal cytology and histology findings at baseline, 44% progressed to anal SIL at month 12.
• Conversely, among 41 men with anal SIL at baseline, 49% experienced some degree of SIL regression and 32% achieved normal histology by month 12.
• Participants also did not clear infection with high-risk HPV-16 despite immune restoration on ART.
• No significant changes in CD4 or CD8 T-cell responses to HPV were observed.
• Specific anti-HPV CD4 T-cell responses were mostly undetectable both at baseline and at month 12.

Taken together, the investigators concluded, "the data suggest that combination ART exhibits no effect on the incidence of anal HPV infection, no effect on the incidence of anal SIL, [and] no restoration of anti-HPV T-cell responses."

These data suggest that HIV-positive MSM remain at risk of anal SIL despite immune restoration, they added, a finding in accordance with several epidemiological studies showing no significant decreases -- or even increases -- in the occurrence of anal cancer among HIV positive men in the ART era.

The researchers recommended that HIV positive men -- whether on or off ART -- should be screened for anal cancer, much as women receive regular Pap smears or HPV tests to detect early signs of cervical cancer.

Cervical Cancer in Women

In the second study, Alison Abraham and fellow investigators with the NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) study looked at development of invasive cervical cancer -- the most severe stage -- among women with HIV after ART initiation.

Some prior studies have found that while HIV positive women are more likely to have high-risk HPV infection and precancerous cell changes, frank invasive cervical cancer and related death are not significantly more common compared with the general population in high-income countries like the U.S. Researchers have suggested this is likely due to the fact that HIV positive women typically receive regular screening that catches cervical cell changes at an early more treatable stage.

This nested case-control analysis included some 110,000 HIV positive women enrolled in the NA-ACCORD IeDEA database from 13 cohorts in North America who started ART during follow-up. The median age was 40 years, more than half were African-American, and about one-third had a history on injection drug use.

Women who developed invasive cervical cancer (cases) were matched to women without invasive cancer (controls) according to age, time of ART initiation, CD4 count, calendar period, cohort, and length of follow-up. The investigators compared trends in average CD4 count at various time points prior to invasive cancer diagnosis, starting 4 years before ART initiation.

Results

• The researchers identified 56 cases of invasive cervical cancer following ART initiation, and matched them with 503 controls.
• Women with lower CD4 counts were more likely to develop invasive cervical cancer during follow-up.
• At the time of ART initiation, the mean CD4 count was about 240 cells/mm3 in both case and control groups.
• 4 years prior to starting ART, however, the mean CD4 cell count among women who developed invasive cervical cancer was about 160 cells/mm3 lower than that of control women, a significant difference.
• At 1 year after ART initiation, average CD4 count was about 40 cells/mm3 lower in case women compared with control women, but this difference was not statistically significant.
• At 2 years and 4 years after starting ART, women who developed cervical cancer had CD4 counts about 100 cells/mm3 and 160 cells/mm3 lower than control women, respectively, both of which were significant.
• Mean CD4 counts of control women increased by an average of 8 cells/mm3 more per month than those of women who developed cervical cancer during the year following ART initiation (P < 0.01)
• HIV viral load was not a significant predictor of cervical cancer.

Based on these findings, the investigators concluded that in this large North American cohort, "average CD4 counts were consistently lower over time for women who developed invasive cervical cancerthan for similar women who remained free of invasive cervical cancerover follow-up."

"These differences in CD4 trajectory between cases and controls suggest a role of long-term immunosuppression," they continued. Less robust CD4 cell recovery following ART was not explained by differences in viral load (suggesting poorer adherence) or prior suboptimal use of NRTIs (suggesting drug resistance).

Investigator affiliations:

Piketty study: Hopital Européen Georges Pompidou, Paris, France; INSERM U943 - UPMC UMR S943, Paris, France; Hopital Lariboisiere, Paris, France; Hopital Saint Antoine, Paris, France; Hopital de La Pitie-Salpetriere, Paris, France; Hopital Bichat-Claude Bernard, Paris, France.

Abraham study: Johns Hopkins Bloomberg School of Public Health, Epidemiology, Baltimore, MD; Harvard University, Boston, MA; Centers for Disease Control and Prevention, Atlanta, GA; Yale University, New Haven, CT; University of North Carolina, Chapel Hill, NC; Johns Hopkins School of Medicine, Baltimore, MD; University of Calgary, Calgary, Canada; University of California at San Francisco, San Francisco, CA; BC Centre for Excellence in HIV/AIDS, Vancouver, Canada; University of Washington, Seattle, WA; McGill University, Montreal, Canada; University of Toronto, Toronto, Canada; Kaiser Permanente Northern California, Oakland, CA.

8/24/10

References

C Piketty, A Si-Mohamed, E Lanoy, and others (Valparaiso Study Group). Lack of regression of anal squamous intraepithelial lesions and anal HPV infections despite immune restoration under cART. XVIII International AIDS Conference (AIDS 2010). Vienna, February 18-23, 2010. Abstract WEAB0103.

AG Abraham, S Gange, Y Jing, and others (North American AIDS Cohort Collaboration on Research and Design). CD4 count trajectories of HIV infected women in North America with cervical cancer after initiating ART. XVIII International AIDS Conference (AIDS 2010). Vienna, February 18-23, 2010. Abstract WEAB0104.