Viral Determinants of Human Papillomavirus Persistence following Loop Electrical Excision Procedure Treatment for Cervical Intraepithelial Neoplasia Grade 2 or 3

Aimée R. Kreimer; Hormuzd A. Katki; Mark Schiffman; Cosette M. Wheeler; Philip E. Castle

doi:10.1158/1055-9965.EPI-06-0710

DOI: 10.1158/1055-9965.EPI-06-0710 Published January 2007

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Figure 1.
Schema of the continuation ratio model used to simultaneously investigate HPV persistence and reappearance after LEEP.
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Figure 2.
Overall HPV persistence at the visit following LEEP, stratified by HPV carcinogenicity and phylogenetic species. Carcinogenic HPV types include HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. All other HPV types were considered to be either possibly or not associated with cancer (noncarcinogenic). HPV types were grouped into the following species: α9/α11(HPV 16, 31, 33, 35, 52, 58, 67, and 73), α7 (HPV18, 39, 45, 59, 68, and 70), α3 (HPV 61, 62, 72, 81, 83, 84, and 89), α5/α6 (HPV51, 53, 56, 66, and 82), and α1/α8/α10/α13 (HPV 6, 11, 40, 42, 54, and 55).

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Table 1.

HPV infections present before LEEP, persistent after LEEP, cleared after LEEP, and reappeared during the follow-up period, by HPV genotype, carcinogenicity, and phylogenetic species

	Present before LEEP, n	Persistent after LEEP, n (%)	Cleared* after LEEP, n	Reappeared during follow-up, n (%)
Overall HPV infection	1,130	231 (20.4)	820	64 (7.8)
Carcinogenic HPV	839	149 (17.8)	630	43 (6.8)
Noncarcinogenic HPV	291	82 (28.2)	190	21 (11.1)
α9/α11^†	567	100 (17.6)	428	32 (7.5)
16	263	58 (22.1)	195	11 (5.6)
31	74	9 (12.2)	56	3 (5.4)
33	45	3 (6.7)	38	2 (5.3)
35	38	3 (7.9)	31	4 (12.9)
52	75	12 (16.0)	57	8 (14.0)
58	44	11 (25.0)	28	3 (10.7)
67	12	1 (8.3)	10	0 (0)
73	16	3 (18.8)	13	1 (7.7)
P		0.052		0.4
α7	195	35 (17.9)	146	10 (6.8)
18	57	7 (12.3)	46	3 (6.5)
39	40	4 (10.0)	33	1 (3.0)
45	30	8 (26.7)	19	2 (10.5)
59	29	7 (24.1)	20	0 (0)
68	24	5 (20.8)	17	3 (17.6)
70	15	4 (26.7)	11	1 (9.1)
P		0.2		0.3
α3	115	47 (40.9)	62	14 (22.6)
61	18	7 (38.9)	10	5 (50.0)
62	21	12 (57.1)	7	1 (14.3)
72	8	3 (37.5)	5	2 (40.0)
81	8	4 (50.0)	4	0 (0)
83	22	9 (40.9)	13	2 (15.4)
84	18	6 (33.3)	11	2 (18.2)
89	20	6 (30.0)	12	2 (16.7)
P		0.7		0.4
α5/α6	169	27 (16.0)	130	4 (3.1)
51	63	11 (17.5)	47	1 (2.1)
53	29	5 (17.2)	22	1 (4.5)
56	33	7 (21.2)	24	0 (0)
66	24	4 (16.7)	19	2 (10.5)
82	20	0 (0)	18	0 (0)
P		0.2		0.4
α1/α8/α10/α13	84	22 (26.2)	54	4 (7.4)
6	12	1 (8.3)	8	0 (0)
11	6	0 (0)	5	0 (0)
40	6	0 (0)	6	0 (0)
42	16	6 (37.5)	8	1 (12.5)
54	30	9 (30.0)	19	3 (15.8)
55	14	6 (42.9)	8	0 (0)
P		0.1		0.8

NOTE: HPV types considered carcinogenic are in bold. P represents P value for the χ² test for heterogeneity.
↵* Restricted to HPV infections in women with at least two study visits following the LEEP to assess reappearance (n = 79 infections excluded).
↵† Only HPV73 is in the α11 species; the majority of this category represents HPV types in the α9 species.

Table 2.

Predictors of post-LEEP HPV persistence

	Persisted after LEEP, n = 231	Cleared after LEEP, n = 899	OR* (95% CI)
HPV species
α9/α11	100 (17.6)	467 (82.4)	1.0
α7	35 (17.9)	160 (82.1)	1.0 (0.7-1.6)
α3	47 (40.9)	68 (59.1)	3.3 (2.1-5.0)
α5/α6	27 (16.0)	142 (84.0)	0.8 (0.5-1.3)
α1/α8/α10/α13	22 (26.2)	62 (73.8)	1.6 (0.9-2.7)
Infection status at LEEP
Single	24 (14.3)	144 (85.7)	1.0
Coinfected with other types	207 (21.5)	755 (78.5)	1.6 (1.0-2.6)
Adjusted for species^†			1.4 (0.9-2.3)
No. CIN2⁺ blocks cut from the LEEP specimen^‡
0-1	89 (16.4)	453 (83.6)	1.0
2 or more	142 (24.2)	446 (75.6)	1.7 (1.2-2.3)
Adjusted for species^†			1.7 (1.2-2.3)
Diagnosis of the LEEP specimen
<CIN2	51 (17.0)	249 (83.0)	1.0
CIN2⁺	180 (21.7)	650 (78.3)	1.4 (1.0-2.0)
Adjusted for species^†			1.5 (1.0-2.3)

↵* The odds of persistence versus clearance are based on generalized estimating equations, as described in Materials and Methods.
↵† ORs were adjusted for species because that was the strongest predictor of HPV persistence after LEEP.
↵‡ Used to approximate extent of disease at LEEP.

Table 3.
Simultaneous evaluation of HPV persistence and reappearance using continuation ratio models
Persistence OR Reappearance OR P*
HPV species
α9/α11 Referent category
α7 1.6 1.0 0.4
α3 3.2 3.5 0.8
α5/α6 1.0 0.4 0.2
α1/α8/α10/α13 1.0 0.9 0.8
↵* P value tests the hypothesis that each of the persistence ORs is not significantly different compared with the reappearance OR. Because all P values are >0.05, it seems that the odds for persistence and reappearance are similar within each of the categories of phylogenetic species.