During the study period, 1,599 women with NILM at first Pap test had at least one follow-up Pap cytology screening test. Of the 1,556 women who reported their HIV status, 3.7% (57/1,556) were HIV infected. The median age at first Pap was 39 years (IQR; 33-45), and HIV infected women were significantly younger (36.3 ± 8.1) than those uninfected (39.3 ± 6.6; p=0.005) at age at first Pap test. The mean follow-up time was similar for women who developed an ECA compared to those with NILM at follow up (2.3 ± 1.6 vs 2.4 ± 1.6 years, respectively: p-value=0.383). The mean time between first CCS to last follow up time for HIV infected women was comparable to the HIV uninfected (2.1 ± 1.5 years vs 2.4 ± 1.6 years, respectively: p-value=0.217). The baseline comparability of women with NILM versus women who developed an ECA at follow-up is presented in Table 1.
Table 1: Distribution of baseline socio-demographic characteristics by follow up cervical cytology outcome of women with normal cervical cytology category at first CCS in an opportunistic screening program in Jos, Nigeria (N=1,599)
Variable
|
Normal cytology (NILM)
|
Abnormal cytology (ECA)
|
p-value
|
Patient-reported HIV (N=1,556)
Not infected
Infected
|
1,272 (84.9)
48 (84.2)
|
227 (15.1)
9 (15.8)
|
0.894†
|
Mean follow up time in yrs(Mean ± SD)
Median follow up time in yrs (IQR)
|
2.4 ± 1.6
2.0 (1.2-3.1)
|
2.3 ± 1.6
1.9 (1.1-2.9)
|
0.383‡
|
Mean Age at first CCS (Mean ± SD)
Age at first CCS (N=1,599)
<35 years
≥35 years
|
38.8 ± 7.9
422 (90.6)
934 (82.4)
|
41.9 ± 8.6
44 (9.4)
199 (17.6)
|
0.001‡
0.001†
|
Age at first sex (N=1,565)
<20 years
≥20 years
|
496 (83.8)
829 (85.2)
|
96 (16.2)
144 (14.8)
|
0.451†
|
Parity (N=1,488)
< 3
≥3
|
426 (90.4)
830 (81.6)
|
45 (9.6)
187 (18.4)
|
0.001†
|
Total life-time Sex partners (N=1,575)
<3
≥3
|
928 (84.3)
408 (86.1)
|
173 (15.7)
66 (13.9)
|
0.364†
|
History of Smoking (ever) (N=1,590)
No
Yes
|
1,339 (84.8)
9 (90.0)
|
241 (15.2)
1 (10.0)
|
0.536*
|
History of Alcohol (ever) (N=1,581)
No
Yes
|
1,261 (84.5)
80 (90.9)
|
232 (15.5)
8 (9.1)
|
0.101
|
Reported history vaginal infection (N=1,560)
No
Yes
|
199 (80.6)
1,124 (85.6)
|
48 (19.4)
189 (14.4)
|
0.043†
|
Ever diagnosed with STI (N=1,228)
No
Yes
|
908 (84.9)
136 (85.5)
|
161 (15.1)
23 (14.5)
|
0.844†
|
‡Student’s t-test and †Pearson’s Chi-Square. *Fisher’s Exact. Percent in parenthesis, SD (standard deviation), IQR (interquartile range). Note: Due to incomplete responses, some of the variables may not add to the total sample of N=1,599)
Unadjusted and adjusted Cox-regression for development of ECA by HIV and other sociodemographic variables at follow up after normal cervical cytology at first CCS
After a total accrued follow-up time of 3,809 person-years, 243 women (15%) had an ECA at follow up with an event rate of 6.38 per 100 person-years (PYs). Women ≥ 35 years old at first Pap were significantly more likely to have an ECA at follow-up Pap test compared to women younger than 35 (7.5 per 100 PYs vs 3.8 per 100 PYs, HR=1.96; 95% CI: 1.4, 2.8). HIV infection was not significantly associated with developing an ECA during a follow up Pap test in either unadjusted (7.4 per 100 PYs vs 6.4 per 100 PYs, HR=1.17; 95% CI: 0.53, 2.3) or adjusted analyses (aHR=1.78; 95% CI: 0.87, 3.65). Figure 2 shows the Kaplan-Meier curve of HIV and development of an ECA at follow up with no significant difference between HIV infected and uninfected women. However, Figure 3 shows a significant hazard for an ECA during follow-up in women age ≥ 35 years at first CCS (Log-rank p-value <0.001).
Fig. 2. Kaplan-Meier Plot of patient-reported HIV at first cervical cancer screening with normal cytology and development of ECAs at subsequent follow up Pap cytology (log-rank test, p-value=0.534). Proportional hazards assumption test (global test: X2=0.45, df=1, p=0.501)
Fig. 3. Kaplan-Meier Plot of age at first cervical cancer screening with normal cytology and development of ECAs at subsequent follow up Pap cytology (log-rank test, p-value=0.001). Proportional hazards assumption test (global test: X2=8.84, df=1, p=0.0029)
The unadjusted and adjusted HR for development of ECA for parity of 3 or more compared to lower parity was 2.0 (95% CI: 1.45, 2.78) and 1.65 (95% CI: 1.14, 2.37) respectively. Figure 4 also showed the Kaplan Meier curve for developing an ECA with follow up Pap test by parity group (Log-rank p-value <0.001).
Figure 4: Kaplan-Meier Plot of parity at first cervical cancer screening with normal cytology and development of ECAs at subsequent follow up Pap cytology (log-rank test, p-value=0.001). Proportional hazards assumption test (global test: X2=4.25, df=1, p=0.039)
The unadjusted and adjusted hazard ratios for an ECA for other sociodemographic and clinical variables of the sample are summarized in Table 2. History of vaginal infection at first Pap test was associated with a lower HR for an ECA at follow up Pap test (aHR=0.67; 95%CI: 0.58, 0.98).
Table 2. Results of bivariable and multivariable Cox regression model with unadjusted and adjusted hazard ratio for development of ECA by patient-reported HIV and other sociodemographic variables at follow up after normal cervical cytology at first CCS in Jos, Nigeria (N=1,413 for final multivariable model)
Variable
|
HR (95% CI)
|
p-value
|
aHR (95% CI)
|
P-value
|
HIV status
Uninfected
Infected
|
1.0
1.25 (0.65, 2.41)
|
0.535
|
1.78 (0.87, 3.65)
|
0.116
|
Age at first CCS
<35 years
≥35 years
|
1.0
1.98 (1.43, 2.75)
|
0.001
|
1.63 (1.11, 2.41)
|
0.013
|
Parity
< 3
≥3
|
1.0
2.0 (1.45, 2.78)
|
0.001
|
1.65 (1.14, 2.37)
|
0.008
|
Age at first sex
>20 years
≤20 years
|
1.0
0.89 (0.69, 1.16)
|
0.391
|
-
|
-
|
Total lifetime sex partners
<3
≥3
|
1.0
0.89 (0.67, 1.18)
|
0.426
|
-
|
-
|
History of vaginal infection
No
Yes
|
1.0
0.70 (0.51, 0.96)
|
0.025
|
0.67 (0.48, 0.93)
|
0.015
|
Ever diagnosed with STIs
No
Yes
|
1.0
0.97 (0.63, 1.50)
|
0.885
|
-
|
-
|
History of Smoking
No
Yes
|
1.0
0.50 (0.07, 3.60)
|
0.488
|
-
|
-
|
Alcohol consumption
No
Yes
|
1.0
0.51 (0.25, 1.02)
|
0.059
|
0.49 (0.22, 1.05)
|
0.067
|
Note: Final multivariate Cox regression model included HIV status at first screen, age at first screening, parity, history of vaginal infection and alcohol consumption (N=1,413). Proportional-hazards assumption test based on Schoenfeld residual (global test: X2=18.1, df=5, P=0.0029)