Limited impact of immunosuppression and HAART on the incidence of cervical squamous intraepithelial lesions in HIV positive women
Polly Clayden, HIV i-Base
Before HAART the prevalence of squamous intraepithelial lesions (SILs) – that can lead to invasive cervical cancer – and invasive cervical cancers (ICC) was high in HIV positive women. Additionally, the incidence of SILs appeared higher in HIV positive women than in HIV negative women.
Studies looking at immunosuppression and other risk factors for the increased incidence of SILs in HIV positive women have had conflicting findings. Some have found an association between low CD4 count and high incidence of SILs and others not.
Although HAART has greatly decreased the incidence of many opportunistic infections, its impact on the incidence of SILs caused by human papillomavirus (HPV) remains unclear.
A study published in Antiviral Therapy authored by Isabelle Heard and coworkers from Inserm in Paris compared the incidence of SILs in HIV positive women receiving HAART with those not receiving HAART to evaluate the role of risk factors, including immunosuppression, in the pathogenesis of SIL. This was a prospective study conducted in two HIV outpatient clinics in Paris between June 1993 and December 2005.
1,124 women enrolled in the study. Data collected at enrolment and every 6-months included structured questionnaire, pelvic examination, Papanicolaou (Pap) smear and standardised colposcopic examination of the cervix. Women with major colposcopic abnormalities or high-grade SILs also underwent a biopsy. Most recent CD4 counts and viral load within 6 months preceding the gynaecological examination and antiretroviral treatment were also recorded.
Pap smears were interpreted and classified as negative, atypical squamous cells of uncertain significance (ASCUS), low SIL (LSIL) and high SIL (HSIL).
Women diagnosed with SIL prior to or at the time of enrollment (n=607), those with normal findings but no follow up data (n=173) and those who presented colposcopic abnormalities at initial examination (n=46) were excluded.
Data from 298 women with negative Pap smear, normal colposcopic findings at enrollment, who had at least one follow up visit were included in the analysis. The study end-point was the detection of incident lesions by cytology.
The investigators looked at the following risk factors: age, race, group of transmission, parity, total number of sexual partners, hormonal contraception, condom use, tobacco smoking, time of enrolment (before and after widespread use of HAART in France before1997 versus after1997).
They reported changes in the demographics of the women throughout the study. Women enrolled after 1997 were likely to be slightly older (34.2 vs 32.5 years), of sub Saharan Africa origin (53.6% vs 30.8%), infected by heterosexual contact (87.4% vs 73.4%), non smokers (47.2% vs 21.6% smoked) and to consistently use condoms (82.1% vs 68.4%).
Low CD4 counts (200cells/mm3) were reported in 169/1,223 visits for which results were available (14%). The investigators note that this suggests only few women included in the study were severely immunocompromised.
Among the group of women that were enrolled from 1997 onward the median CD4 count was 400 cells/mm3, the median plasma HIV load was undetectable (<500 copies/mL), and (69%) were receiving HAART at enrollment.
An analysis of the 113 women who had at least two study visits while receiving HAART, the median viral load decreased from 199 copies/mL (range: 50949 copies/mL) at first visit while receiving HAART to 50 copies/mL (range: 5056 copies/mL) at last visit under HAART (p=0.001) and the median CD4 cell count increased significantly from 301 cells/mm3 (217444 cells/mm3) at first visit while receiving HAART to 434 cells/mm3 (300558 cells/mm3) at last visit under HAART (p=0.0006).
The investigators reported a cumulative incidence of SIL at 2 years of 16.9% (95%CI: 12.1%21.5%).
Over a median follow-up of 28 months (range:1652 months) 88 women evaluated developed SIL giving an incidence rate of 8.7 cases/100 person years. The median CD4 cell count at SIL detection was 418 cells/mm3 (range: 269528 cells/mm3), median viral load was 499 copies/mL (5015,500 copies/mL) and 31 women (35%) were receiving HAART.
The majority of the SIL (n=75, 85%) were low grade cases. Thirteen of the cases were high grade and the investigators reported that all 13 women had normal Pap smear test results within 10 months preceding diagnosis. None of the women were diagnosed with invasive cervical cancer.
Within 12 months follow up after SIL detection, Pap smear test results reversed to normal in 23 cases; SIL was confirmed by colposcopy and/or biopsy in 59 cases; and 6 women missed their follow up appointment.
In univariate analysis the incidence of SILs was 6.5 cases/100 person-years of follow-up in the women receiving HAART and 10.7 cases/100 person-years of follow-up in women not receiving HAART (p=0.02). The risk factors associated with SIL were age at inclusion (<40years), smoking, more than 5 lifetime sex partners, contraceptive pill use, inconsistent condom use, enrollment before 1997 and no HAART.
The relative risk of SIL was also calculated separately in women receiving HAART and in women not receiving HAART and the investigators found that it was not significantly associated with CD4 count in either group (p=0.15 and p=0.92, respectively).
Multivariate analysis found that the risk of incident SILs was twice as high in women <40 years at inclusion than in older women >40 years. Women between 30 and 39 years of age had a risk to develop SIL of almost 4 times higher than older women. (30-39 years, RR: 3.5, 95% CI:1.48.9; 19-29 years, RR: 2.4 95% CI: 0.96.6, p=0.02). Smoking, number of sexual partners, contraceptive pill use, condom use and enrollment before or after 1997 were not associated with SIL development.
The risk of incident SIL was slightly lower, though did not reach statistical significance, in women receiving HAART than in women not receiving HAART (RR: 0.7, 95% CI: 0.41.2, p=0.15).
The investigators wrote: This study indicates that HIV-positive women have high risk of developing SILs and suggests little if any benefit of HAART on the occurrence of cervical lesions. Additionally, in this study HIV associated immunodeficiency did not strongly affect the risk of developing SIL. These results suggest that CD4+ T-cell mediated response has limited contribution in the control of SIL development. They explain however, that this study had limitation including only 40% power to detect as significant a moderate effect (0.7) of HAART on incidence of SIL. There was also no record at enrollment of HPV status or evaluation of its impact on SIL development in this study.
The investigators concluded: Our findings have implication for the gynaecological care of HIV positive women. The high incidence of SIL observed among patients with normal Pap smear at inclusion suggests that they should be offered to participate with at least an annual visit whether or not they are on HAART.
Heard I, Potard V and Costagliola D. Limited impact of immunosuppression and HAART on the incidence of cervical squamous intraepithelial lesions in HIV-positive women. Antiviral Therapy 2006; 11: 1091-1096.