Crude odds ratio (OR) and 95% confidence intervals (CI) for residual disease six months after cryotherapy (cryo) for CIN2/3 by persistence of hrHPV infections detected in pre-cryo cells or biopsies.

<p>Crude odds ratio (OR) and 95% confidence intervals (CI) for residual disease six months after cryotherapy (cryo) for CIN2/3 by persistence of hrHPV infections detected in pre-cryo cells or biopsies.</p

Performance of hrHPV testing for the detection of CIN2/3 six months after cryotherapy.

<p>Performance of hrHPV testing for the detection of CIN2/3 six months after cryotherapy.</p

Odds ratio (OR) and 95% confidence intervals (CI) for residual disease six months after cryotherapy (cryo) for CIN2/3 by selected pre-treatment characteristics.¹Kenya, 79 HIV-positive women.

<p>Odds ratio (OR) and 95% confidence intervals (CI) for residual disease six months after cryotherapy (cryo) for CIN2/3 by selected pre-treatment characteristics.^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111037#nt101" target="_blank">1</a>}Kenya, 79 HIV-positive women.</p

Presence of hrHPV after cryotherapy (cryo) by type of pre-cryo sample in women who were hrHPV-positive before cryotherapy.

<p>Presence of hrHPV after cryotherapy (cryo) by type of pre-cryo sample in women who were hrHPV-positive before cryotherapy.</p

Flowchart study population.

<p>HPV, human papillomavirus; CIN, cervical intraepithelial neoplasia; cryo, cryotherapy; ASCUS, atypical squamous cells of undetermined significance; LSIL, low-grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesion.</p

Role of p16 testing in cervical cancer screening among HIV-infected women

<div><p>Background</p><p>p16 immunohistochemistry is used to evaluate for HPV-associated cervical intraepithelial neoplasia. The diagnostic performance of p16 in HIV infection is unclear.</p><p>Methods</p><p>Between June-December 2009, HIV-infected women underwent Papanicolaou (Pap) smear, human papillomavirus (HPV) testing, visual inspection with acetic acid (VIA), and colposcopy-directed biopsy as the disease gold standard at a HIV clinic in Kenya. Pap smears were evaluated for p16 expression. Sensitivity, specificity, positive predictive value (PPV), and area under the receiver operating characteristic curve (AUC) of p16 to detect CIN2/3 on histology and the impact of immunosuppression and ART was assessed.</p><p>Results</p><p>Of 331 cervical samples with p16 expression, p16 sensitivity and specificity to detect CIN2/3 was 54.1% and 72.4% respectively, which was lower than Pap and HPV in sensitivity, but higher in specificity than Pap, HPV, and VIA. Combining tests and p16 reduced sensitivity and increased specificity of Pap from 90.5% to 48.7% and 51.4% to 81.7%; of VIA from 59.5% to 37.8% and 67.6% to 89.9%; and of HPV from 82.4% to 50.0% and 55.3% to 84.8%. Combination p16 increased the PPV of Pap from 34.9% to 43.4%; of HPV from 34.7% to 48.7%; and VIA from 34.9% to 51.9%. Adjunctive p16 did not change AUC (P>0.05). P16 performance was not altered by immunosuppression or ART use. Combining p16 with HPV and VIA reduced the variation in HPV and VIA performance associated with CD4 and ART.</p><p>Conclusion</p><p>As an adjunctive test in HIV-infected women, p16 immunohistochemistry increased specificity and PPV of HPV and VIA for CIN2/3, and was not altered in performance by immunosuppression, ART, or age.</p></div

Receiver operating characteristic curves of screening methods individually and in combination with p16 for detection of CIN2/3 in HIV-infected women.

<p>Receiver operating characteristic curves of screening methods individually and in combination with p16 for detection of CIN2/3 in HIV-infected women.</p

Pre-exposure Prophylaxis Use by Breastfeeding HIV-Uninfected Women: A Prospective Short-Term Study of Antiretroviral Excretion in Breast Milk and Infant Absorption

<div><p>Background</p><p>As pre-exposure prophylaxis (PrEP) becomes more widely used in heterosexual populations, an important consideration is its safety in infants who are breastfed by women taking PrEP. We investigated whether tenofovir and emtricitabine are excreted into breast milk and then absorbed by the breastfeeding infant in clinically significant concentrations when used as PrEP by lactating women.</p><p>Methods and Findings</p><p>We conducted a prospective short-term, open-label study of daily oral emtricitabine–tenofovir disoproxil fumarate PrEP among 50 HIV-uninfected breastfeeding African mother–infant pairs between 1–24 wk postpartum (ClinicalTrials.gov Identifier: NCT02776748). The primary goal was to quantify the steady-state concentrations of tenofovir and emtricitabine in infant plasma ingested via breastfeeding. PrEP was administered to women through daily directly observed therapy (DOT) for ten consecutive days and then discontinued thereafter. Non-fasting peak and trough samples of maternal plasma and breast milk were obtained at drug concentration steady states on days 7 and 10, and a single infant plasma sample was obtained on day 7. Peak blood and breast milk samples were obtained 1–2 h after the maternal DOT PrEP dose, while maternal trough samples were obtained at the end of the PrEP dosing interval (i.e., 23 to 24 h) after maternal DOT PrEP dose. Tenofovir and emtricitabine concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays.</p><p>Of the 50 mother–infant pairs enrolled, 48% were ≤12 wk and 52% were 13–24 wk postpartum, and median maternal age was 25 y (interquartile range [IQR] 22–28). During study follow-up, the median (IQR) daily reported frequency of infant breastfeeding was 15 times (12 to 18) overall, 16 (14 to 19) for the ≤12 weeks, and 14 (12 to 17) for the 13–24 wk infant age groups. Overall, median (IQR) time-averaged peak concentrations in breast milk were 3.2 ng/mL (2.3 to 4.7) for tenofovir and 212.5 ng/mL (140.0 to 405.0) for emtricitabine. Similarly, median (IQR) time-averaged trough concentrations in breast milk were 3.3 ng/mL (2.3 to 4.4) for tenofovir and 183.0 ng/mL (113.0 to 250.0) for emtricitabine, reflecting trough-to-peak breast milk concentration ratios of 1.0 for tenofovir and 0.8 for emtricitabine, respectively. In infant plasma, tenofovir was unquantifiable in 46/49 samples (94%), but emtricitabine was detectable in 47/49 (96%) (median [IQR] concentration: 13.2 ng/mL [9.3 to 16.7]). The estimated equivalent doses an infant would ingest daily from breastfeeding were 0.47 μg/kg (IQR 0.35 to 0.71) for tenofovir and 31.9 μg/kg (IQR 21.0 to 60.8) for emtricitabine, translating into a <0.01% and 0.5% relative dose when compared to the 6 mg/kg dose that is proposed for therapeutic treatment of infant HIV infection and for prevention of infant postnatal HIV infection; a dose that has not shown safety concerns. No serious adverse effects were recorded during study follow-up.</p><p>The key study limitation was that only a single infant sample was collected to minimize venipunctures for the children. However, maternal daily DOT and specimen collection at drug concentration steady state provided an adequate approach to address the key research question. Importantly, there was minimal variation in breast milk concentrations of tenofovir and emtricitabine (respective median trough-to-peak concentration ratio ~1), demonstrating that infants were exposed to consistent drug dosing via breast milk.</p><p>Conclusion</p><p>In this short-term study of daily directly observed oral PrEP in HIV-uninfected breastfeeding women, the estimated infant doses from breast milk and resultant infant plasma concentrations for tenofovir and emtricitabine were 12,500 and >200-fold lower than the respective proposed infant therapeutic doses, and tenofovir was not detected in 94% of infant plasma samples. These data suggest that PrEP can be safely used during breastfeeding with minimal infant drug exposure.</p><p>Trial Registration</p><p>ClinicalTrials.gov, Identifier: <a href="https://clinicaltrials.gov/ct2/show/NCT02776748" target="_blank">NCT02776748</a></p></div

Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC) of screening methods individually and in combination with p16 to detect CIN2/3 (n = 331).

<p>Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC) of screening methods individually and in combination with p16 to detect CIN2/3 (n = 331).</p

Sensitivity and specificity of screening methods to detect CIN2/3 compared by CD4 count (A), ART duration (B), and age at screening (C) (n = 331).

<p>Sensitivity and specificity of screening methods to detect CIN2/3 compared by CD4 count (A), ART duration (B), and age at screening (C) (n = 331).</p