There were 2,475 women in this operational cohort of whom 2,325 (94%) had at least one analyzable cervical smear between August 2003 and May 2009. The 150 women not screened had a statistically significantly lower prevalence of STI symptoms, and a higher BMI on entry into the cohort than those women who had at least one cervical smear (); other characteristics however, were similar between the two groups. Out of the 4,425 cervical smears included in the study sample, 39 smears were rejected as unsatisfactory (0.9%). For those participants with subsequent satisfactory cervical smears, this smear was used in the analysis. Twenty-two individuals with rejected smears did not have a subsequent satisfactory smear.
Baseline characteristics of 2,475 wellness cohort women recruited between August 2003 and May 2009 and including both women who had at least one cervical smear and those who did not have a smear on record.
In women who had at least one cervical smear, a median of 7 days (IQR 0-188) elapsed between their first study visit and the smear being taken. At baseline cervical smear, 94.3% of the participants were not yet receiving-HAART. One hundred and fifty-two women were on HAART at the time of their first cervical smear and in follow up, another 457 women were initiated on HAART. The median follow-up time while receiving HAART was 24.3 months (IQR 14.3-33.4).
Prevalence of premalignant cervical lesions
Thirty-eight percent (38%) of women had a prevalent premalignant uterine cervical lesion diagnosed cytologically at their first smear (). The median age and CD4 count of women with premalignant lesions was 31.9 (IQR 27.7-36.4) and 254 cells/μL (IQR 136-401) respectively compared to those with a baseline normal smear whose median age was 32.3 (IQR 28.2-37.6) years (p=0.252) and median CD4 count was 351 cells/μL (IQR 192-530) (p=0.000). Ninety-one percent of participants with a baseline cervical smear result were also syndromically screened for symptoms of other sexually transmitted infections within 5.5 months of their baseline smear. Overall, 18.6% of these women had symptoms of an STIs within 5.5 months of their baseline cervical smear. Amongst women with normal, LSIL and HSIL/ASCH diagnoses at baseline smear, STI symptoms were present in 17.2%, 21.0% and 18.2% respectively. Multiple logistic regression with LSIL as the outcome suggested a 13% decrease in odds of prevalent LSIL at baseline for every 100 CD4 cells/μL increase (OR 0.87, 95% CI 0.83-0.92) and a decrease in the odds of prevalent LSIL of 10% for every five additional years of age (OR 0.90, 95% CI 0.84-0.98). Smoking, weight tertile and presence of STI symptoms at baseline were not associated with prevalent LSIL.
Prevalence normal smears and of pre-malignant lesions of the cervix in HIV-infected women in Soweto at their baseline cervical smear (n=2,325)
In a separate multivariate logistic regression model assessing predictors of prevalent HSIL at baseline, higher CD4 count was also associated with decreased adjusted odds of prevalent HSIL (OR 0.82, 95% CI 0.77-0.87 per increment of 100 CD4 cells/μL). However, age was not associated with prevalent HSIL (OR 1.04, 95% CI 0.96-1.13 per 5 year increase); but being in the highest tertile of weight decreased the adjusted odds of prevalent HSIL (OR 0.71; 95% CI 0.51-0.97).
Progression and regression of cervical premalignant lesions
In the prospective analysis, 1,193 (51.3%) women had at least one smear, > 5.5 months after their baseline smear. Women who had only one smear during this time period were more likely to have a baseline intra-epithelial lesion (45% v 33% [p=0.000]) and more likely to be lost to follow up or have died (p=0.000) than women with two or more smears. However, they did not differ by CD4 count (p=0.202), age (p=0.290) or highly active antiretroviral treatment (HAART) status at time of their first smear (p=0.320). One hundred and nineteen women who had more than one smear at least 5.5 months apart but with a baseline ASCH, HSIL or AGUS smear were excluded from the progression/regression analyses. Thus, 1,074 women with baseline normal or LSIL smears and subsequent smears which were either normal, LSIL, ASCH, HSIL or invasive malignancy were included in the prospective analyses. The median follow-up time from first smear to last smear in women with two or more cervical smears, and whose baseline smear was normal or LSIL, was 2.5 years (IQR 1.7-3.4).
Overall, 10.5% (95% CI: 8.7-12.4) of women with multiple smears and a baseline of normal or LSIL smear progressed to HSIL during follow-up, and in person years of follow up, progression to LSIL and HSIL amongst those with baseline normal smears was 9.6/100 person years (py) (95% CI 8.3-11.1) and 3.3/100 py (95% CI 2.6-4.2), respectively (). Of 832 women with a baseline normal smear, 69.6% (95%CI 66.5 – 72.7) had a subsequent normal smear, 21.8% (95% CI 18.9-24.6) progressed to LSIL, 7.3% (95% CI 5.6%-9.1%) progressed to HSIL, and 1.3% (95% CI 0.5-2.1) to ASCH. In 242 women with baseline LSIL, the proportion whose subsequent smear at least 5.5. months later was LSIL, ASC-H or HSIL was 45.5% [95%CI 39.1 – 51.8], 0.8% [0.0 – 2.0], and 21.5% [95%CI 16.3 – 26.7], respectively and incidence in these women of HSIL was 9.8/100 py (95% CI 7.5-12.7). Overall, the combined progression to ASCH or HSIL from a baseline normal or LSIL smear was 4.6/100 py (95% CI 3.9-5.5).
Progression in events per 100 person years in women from Soweto who had at least 2 interpretable cervical smears August 2003 – May 2009.
In those women with smears at least 11.5 months apart and whose initial smear was LSIL (n=225), incidence of regression to a subsequent normal smear was 21.2/100 py [95%CI 17.5 – 25.7]. Seventeen of the participants with a baseline LSIL diagnosis had only one subsequent smear which was taken before the full 11.5 months had elapsed. These smears ranged in time from 144-349 days after the baseline LSIL smear. In a sensitivity analysis using all 242 participants with a baseline LSIL smear and at least one subsequent smear, regardless of elapsed time between the first and last smear, the incidence of regression was 20.7/100 py [95%CI 17.1-25.1].
Associations with progression and regression
Women with baseline normal or LSIL smears contributed 2,353 person-years in the analysis of time-to-progression. In the univariate models assessing risk factors for any progression from baseline normal or baseline LSIL, only lower CD4 count was statistically significantly (p<0.05) associated with progression (). Multivariate model results, which assess the effect of CD4 count at time of baseline smear on the risk of progression, controlling for category of age, baseline smear result (normal vs. LSIL), smoking history (ever vs. never) and time-varying HAART status showed that baseline CD4 strata remained strongly associated with progression and followed a dose-response relationship across CD4 categories. The risk of progression was increased two-fold in those with CD4 counts <200 cells/μL vs. >500 cells/μL (aHR 1.96; 95% CI 1.33-2.88); likewise, adjusted hazard ratios for CD4 strata 200-350 and 351-500 as compared to >500 were 1.90 (95% CI 1.32-2.73) and aHR 1.65 (95% CI 1.14-2.39) respectively. This relationship was maintained in a sensitivity analysis using time-varying CD4 count in a subset of the cohort who had CD4 counts within 6 months of every cervical smear (n=632) (results not shown). HAART was also independently and statistically significantly associated with a decrease of 28% in risk of progression (aHR 0.72; 95% CI 0.52-0.99) in adjusted analysis. No other measured variables were associated with progression in the adjusted model. Kaplan-Meier curves suggest a threshold effect of baseline CD4 count <500 cells/μL on time to progression ().
Progression rates and Univariate and Multivariate Hazard Ratios for Progression (n=950)
Kaplan-Meier Survival Curves for Time-to-diagnosis of low grade intraepithelial lesion (LSIL) or worse in women with baseline normal smears stratified by CD4 count at time of baseline cervical smear.
Amongst women with multiple smears separated by at least 11.5 months whose baseline smear was LSIL and who had a CD4 count within six months of the first smear (n=198), the incidence of regression to a normal smear was 20.5/100 py (95% CI 16.7-25.3). In the univariate and final adjusted Cox proportional hazards models, none of the CD4 count strata were strongly or statistically significantly associated with regression to normal. After adjusting for CD4 count at time of baseline smear, time-varying HAART status, smoking history, and age strata, only being in the highest age category (>45) as compared to the reference group of women of 18-25 years was associated with regression to normal (aHR 6.71; 95% CI 2.08-21.67). There was, however, a general trend across the age strata suggesting that older age is associated with higher rates of regression. This trend held across sensitivity analyses, including time-varying CD4 count and age as a continuous variable.