Long lasting viral suppression and immune reconstitution (CD4) of great magnitude reduce the risk of cervical dysplasia in HIV-positive women
Reported by Jules Levin, NATAP
EACS 2015 Oct 21-24, Barcelona, Spain
The authors concluded the prevalence and incidence of cervical dysplasia in HIV+ women remains high in Western Europe despite large coverage. But in these women long lasting viral suppression an immune reconstitution "of a great magnitude significantly reduces the risk of cervical dysplasia. Whether these findings will translate into a reduction of incidence of cervical cancer will need long-term follow-up in women optimally treated (namely early ART and full suppression). see results below - having CD4 >350 for at least 17 months decreased risk by 15% for having an abnormal cytology, having a CD4 >500 for at least 17 months decreased risk by 15% for having an abnormal cytology, and having an HIV viral load <50 c/ml for at least 37 months decreased risk for abnormal cytology by 19%.
In Belgium 5,700 women are living with HIV (44% of the HIV-positive population).
In 2002, the burden of HPV-related disease in HIV-positive person was well described in the literature but there were very few studies in Europe and none in Belgium. It was considered that cART did not impact favourably on HPV-related disease.
The objective of this study is to describe the prevalence and incidence of abnormal cervical cytology (ACC) in HIV-positive women and to assess the long-term impact of cART on these ACC, by measuring the impact of the time with undetectable HIV viral load and the time spent within different CD4 cell count strata (<200, 200-350, 350-500, or >500 /μL).
This is a prospective longitudinal cohort from 2002 to 2012 to screen and follow up cervical high risk HPV (HRHPV) infection and ACC among all women in care at Saint-Pierre AIDS reference centre, Brussels.
We have previously shown that sustained viral load suppression and higher CD4+ T-cell count reduces the risk of persistent cervical high-risk human papillomavirus infection (HRHPV), JID 2013 [http://www.natap.org/2013/HIV/040313_03.htm].
Included were all women followed for HIV infection in the AIDS Reference Centre were proposed to have a gynaecological examination by a dedicated gynecologist within the AIDS center.
Excluded were women with previous cervical surgery or high grade cervical dysplasia confirmed by biopsy (≥CIN2).
At the baseline - visit liquid based sample with cytologic brush (SurePathTM and ThinPreP); HRHPV screen; cytology: standard diagnostic technique performed routinely; results acceding to the revised Bethesda Classification 2001. Follwoup visit was yearly, more frequent if symptoms, abnormal cytology (ACC), colposcopy and biopsy
High risk HPV types were detected by molecular techniques:
-by Hybrid Capture (hc2 High-Risk HPV DNA Test®, Digene, USA) up to February 2011 -by PCR (Abbott HRHPV®) from march 2011.
Surrogate markers of HIV infection were retrieved from the Saint-Pierre Cohort which collects prospectively at each consultation all HIV-data for all patients followed in our center. At the inclusion in the HPV cohort, women were already followed in the St-Pierre cohort since 5.5 years .
Characteristics of the 766 Women at the time of first cytology
There were 888 women in cohort, 122 were excluded. 766 women with concomitant HRHPV and cytology screening were analysed (83% Sub-Saharian African origin, 88% HIV heterosexual acquisition). At time of first screening, median age was 40 years and more than 80% were on cART for more than 1 year. The median number of cytology was 2 per woman with a median follow up of 40.5 months.
72% had normal cytology (549).
217 women (28%) had ACC (abnormal cervical cytology): 91 (12%) with atypical cells (ASCUS or ASCH), 102 (13%) with low grade dysplasia (LSIL) and 24 (3%) with high grade dysplasia (HSIL).
HRHPV was detected in 167 women with ACC (77%) versus in 137 (25%) of women without ACC (p< 0.0001).
In univariate Analysis, subjects with abnormal cervical cytology:
-Median age 35 years vs. 40 p<.0001
-Presence of HRHPV 77% vs. 25 p<.0001
-HIV follow up duration 44 months vs. 71 p<.0001
-Median CD4 cell count 353/μL vs. 455 p<.0001
-Median duration of cART 12 months vs. 31 p<.0001
-Time with HIV VL <50 cp/ml 4 months vs. 15 p<.0001
Prevalence of abnormal cytology at baseline according to age and CD4
If you look at the prevalence of abnormal cytological results at baseline according to age and CD4 cells count : the prevalence decreases significantly - as age increases (p=0.0007), as CD4 count increases (p=0.017)-
......for women under 30 years of age (n=145) - with <200 CD4 under 30 years of age (YO) there was a 73% prevalence, 200-350 CD4 prevalence was 54%; 350-500 CD4 prevalence was 29%; for >500 prevalence was 30%; suggesting that a minimum of 350 CD4 is an important marker. It would be interesting to look t prevalence in women who achieve 800-1000 or more CD4.
.....for women 30-39 YO (n=256) there is a similar trend where prevalence levels off at 350 CD4: for women with <200 CD4 prevalence of abnormal cytology was 55%; with 200-350 CD4 prevalence was 35%; with 350-500 CD4 prevalence was 26%; and for >500 CD4 prevalence was 25%.
........for women 40-49 YO (n=224), with <200 CD4 prevalence was 39%; with 200-350 CD4 prevalence was 29%; with 350-500 CD4 prevalence was 27%; and with CD4>500 prevalence takes a dip down to 11% suggesting a trend, see women >50 YO.
........for women 50 YO (n=105), with CD4 <200 prevalence was 0; for women with 200-350 CD4 prevalence was 14%; women with 350-500 prevalence was 13%; and with >500 prevalence was 9%, is this a trend for older women with >500 CD4??
Factors affecting risk of having an abnormal cytology on the first smear (MV)
In multivariate analysis at time of the first screen/first smear these factors increased risk:
.....being less than 35 years (OR 1.8, 1.22-2.62, p=.003)
.....smoking (OR 2.5, 1.6-3.9, p<.0001)
....nadir or median CD4 < 350/μL (OR 1.9, 1.12-3.14, p=.017)
......AIDS stage (OR 1.8, 1.14-2.81, p=.012)
......undetectable viral load (<50 c/ml) for 2 years or more decreased this risk by 66% - (OR 0.34, 0.19-0.60, p=0002)
Follow up and incidence of ACC
Among 284 women with normal cytology at baseline and at least one follow up, 53 presented with ACC
Incidence of ACC:
8.5 if HPVHR+
4.7 if HPVHR-
Incidence of HSIL:
1.4 si HPVHR+
0.3 si HPVHR -
Median time 22.5 months (95%IC: 13-30.5)
Factors affecting risk of having abnormal cytology during the study (MV)
Younger than 30 YO (OR 3.17, 2.5-8.3, p=0.009*)
Age between 30 to 40 YO (OR 2.09, 1.2-3.645, p=0.0001*)
* OR= 1 if ≥50 years
CD4 >350 for ≥ 17 months (OR 0.85, 0.72-0.99, p=0.03)
CD4 >500 for ≥ 17 months (OR 0.85, 0.74-0.91, p<0.0001)
HIV viral load <50 c/ml for ≥ 37 months (OR 0.81, 0.75-0.97, p<0.0001)
Reference: Konopnicki D, Manigart Y, Gilles C, Barlow P, Feoli F, Delforge M, Clumeck N and De Wit S; Saint-Pierre University Hospital
Universite Libre de Bruxelles; Long lasting viral suppression and immune reconstitution of great magnitude reduce the risk of cervical dysplasia in HIV-positive women; abstract PS5/4