Hazard ratios for HPV infection clearance probability for HIV-1-infected adolescent females from the REACH cohort, univariable and multivariable Cox proportional hazard regression (results are presented with 95% CIs).

<p>Note: ^†p<0.05; ^‡p<0.001; ns - not significant; n/a – not applicable.</p

Reconstruction of information about the missed measurements when one HPV status is unknown (<b>Figure 1A</b>) or several (e.g., three) HPV statuses in a raw are missed (<b>Figure 1B</b>).

<p>Here, denotes the set of predictors of HPV clearance probability, such as CD4 count, HIV-1 VL, HAART, and HPV type. When one HPV measurement is unknown (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030736#pone-0030736-g001" target="_blank">Figure 1A</a>), <i>i</i> and <i>j</i> describe the HPV status at the first and third visits, respectively, and parameters and denote the sets of predictors for transitions between first-to-second and second-to-third visits, respectively. The probability of changing HPV status from the first (i.e., known) state of HPV infection <i>i</i> to the status of HPV infection at the second visit (i.e., unknown) is <i>P_i</i>₀(<i>x_a</i>) when HPV status at the second visit is negative (i.e., “0”) or <i>P_i</i>₁(<i>x_a</i>) when it is positive (i.e., “1”). Respectively, at the third visit (with measured/known HPV status) HPV status <i>j</i> can be defined as <i>P</i>_0<i>j</i>(<i>x_b</i>) when at the second visit it supposed to be HPV-negative, and <i>P</i>_1<i>j</i>(<i>x_b</i>) when at the second visit it supposed to be HPV-positive. The sum over two possible intermediate states contributes to the total transition probability: so, the transition probability between two subsequent visits with measured HPV status could be presented as . When three subsequent HPV status are unknown (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030736#pone-0030736-g001" target="_blank">Figure 1B</a>), there are eight different combinations of HPV statuses in these states, each denoted by , , and as unmeasured HPV statuses which can be 0 or 1). Therefore, the transition probability between states with known HPV statuses is calculated as three-fold sum over all combinations of HPV statuses in these three unmeasured states.</p

The 3-month HPV type-specific probability of clearance depending on CD4 T-lymphocytes in HIV-1-positive adolescent girls from the REACH cohort.

<p>The 3-month HPV type-specific probability of clearance depending on CD4 T-lymphocytes in HIV-1-positive adolescent girls from the REACH cohort.</p

CD4 T-lymphocyte counts (basic model M1), HIV VL (M6 model), and HAART with PI (M7 model) effects on probability of HPV clearance, by phylogenetic HPV group, in HIV-1-infected adolescent females, REACH cohort.

<p>Note:</p><p>*0.05≤p<0.1;</p><p>**p<0.05.<i>u₀₀</i>, <i>β_00, u_11, and β₁₁</i> are related to the parameters in equation (2)</p>a<p>– the units of <i>β₀₀</i> and <i>β₁₁</i> are 1000/[C], where [C] are the units of CD4 cell counts, i.e., cells/mm³.</p><p>SEs were obtained by re-estimating the model in which probability at specific value of CD4 cell count was chosen as a model parameter instead of .</p

CD4 T-lymphocyte counts (basic model M1), HIV VL (M6 model), and HAART (M7 model) effects on HPV clearance probability, HPV type-specific, in HIV-1-positive adolescent females, REACH cohort.

<p>Note: * 0.05≤p<0.1; ** p<0.05. <i>u₀₀</i>, <i>β_00, u_11, and β₁₁</i> are related to the parameters in equation (2).</p>a<p>– the units of <i>β₀₀</i> and <i>β₁₁</i> are 1000/[C], where [C] are the units of CD4 cell counts, i.e., cells/mm³.; b – non-significant.</p><p>SEs were obtained by re-estimating the model in which probability at specific value of CD4 cell count was chosen as a model parameter instead of .</p

Probability of HPV clearance (in %, ±SE) at specific CD4 levels, by phylogenetic HPV group, in HIV-1-positive adolescent females, REACH cohort.

<p>Note: *The difference with HPV16/16-like type is significant (p<0.05).</p

Demographic, behavioral, and clinical characteristics of adolescent female study participants from the REACH cohort.

<p>Notes: ¹ – results are presented as mean (SD); ² – number of cases (percent);</p>†<p>– p<0.05 for the difference between HIV-1-positive and HIV-1-negative: continuous variables were analyzed by general linear model, and categorical were analyzed by chi-square;</p>‡<p>– p<0.05 for the difference with the referent group; continuous variables were analyzed by general linear model, and categorical were analyzed by PROC LOGISTIC.</p

Dense Genotyping of Immune-Related Loci Identifies Variants Associated with Clearance of HPV among HIV-Positive Women in the HIV Epidemiology Research Study (HERS)

<div><p>Persistent high-risk human papillomavirus (HR-HPV) is a necessary and causal factor of cervical cancer. Most women naturally clear HPV infections; however, the biological mechanisms related to HPV pathogenesis have not been clearly elucidated. Host genetic factors that specifically regulate immune response could play an important role. All HIV-positive women in the HIV Epidemiology Research Study (HERS) with a HR-HPV infection and at least one follow-up biannual visit were included in the study. Cervicovaginal lavage samples were tested for HPV using type-specific HPV hybridization assays. Type-specific HPV clearance was defined as two consecutive HPV-negative tests after a positive test. DNA from participants was genotyped for 196,524 variants within 186 known immune related loci using the custom ImmunoChip microarray. To assess the influence of each single-nucleotide polymorphism (SNP) with HR-HPV clearance, the Cox proportional hazards model with the Wei-Lin-Weissfeld approach was used, adjusting for CD4+ count, low risk HPV (LR-HPV) co-infection, and relevant confounders. Three analytical models were performed: race-specific (African Americans (n = 258), European Americans (n = 87), Hispanics (n = 55), race-adjusted combined analysis, and meta-analysis of pooled independent race-specific analyses. Women were followed for a median time of 1,617 days. Overall, three SNPs (rs1112085, rs11102637, and rs12030900) in the <i>MAGI-3</i> gene and one SNP (rs8031627) in the <i>SMAD3</i> gene were associated with HR-HPV clearance (p<10⁻⁶). A variant (rs1633038) in <i>HLA-G</i> were also significantly associated in African American. Results from this study support associations of immune-related genes, having potential biological mechanism, with differential cervical HR-HPV infection outcomes.</p> </div

Manhattan plot showing the association P-values of single nucleotide polymorphisms (SNPs) in the ImmunoChip with the time to clearance of HR-HPV.

<p>The X-axes display the chromosome on which the SNP is located, the Y-axes display −log₁₀ P-value. The dashed black line represents a significance level needed for multiple testing using the K effective method. Panel A.) Race-adjusted analysis B.) African Americans only C.) European Americans only, and D.) Hispanics only.</p

Cox proportional Hazard Ratios (HR) for the SNPS associated with time to clearance of high-risk (HR-HPV) HPV infection in the race-adjusted analysis, individual race-specific analysis, and pooled analysis of the three races separately.

<p>Cox proportional Hazard Ratios (HR) for the SNPS associated with time to clearance of high-risk (HR-HPV) HPV infection in the race-adjusted analysis, individual race-specific analysis, and pooled analysis of the three races separately.</p