High yield of new HIV diagnoses during active case-finding for tuberculosis.

OBJECTIVE: To evaluate the utility of a broad and nonspecific symptom screen for identifying people with undiagnosed HIV infection. DESIGN: Secondary analysis of operational data collected during implementation of a cluster-randomized trial for tuberculosis case detection. METHODS: As part of the trial, adults reporting cough, fever, night sweats, weight loss, or difficulty breathing for any duration in the past month were identified in health facilities and community-based mobile screening units in western Kenya. Adults reporting any symptom were offered HIV testing. We analysed the HIV testing data from this study, using modified Poisson regression, to identify predictors of new HIV diagnoses among adults with symptoms and initially unknown HIV status. RESULTS: We identified 3818 symptomatic adults, referred 1424 (37%) for testing, of whom 1065 (75%) accepted, and 107 (10%) were newly diagnosed with HIV. The prevalence of new HIV diagnoses was 21% [95% confidence interval (CI) 17-25%] among those tested in health facilities and 5% (95% CI 4-7%) among those tested in mobile units. More men were diagnosed with HIV than women, despite fewer men being screened. People who reported 4-5 symptoms were over twice as likely to be diagnosed with HIV compared to those reporting 1-3 symptoms (adjusted prevalence ratio in health facilities = 2.58, 95% CI 1.65-4.05; adjusted prevalence ratio in mobile units = 2.63, 95% CI 1.37-5.03). CONCLUSION: We observed a high yield of new HIV diagnoses among adults identified by active application of a broad symptom screen. Use of integrated tuberculosis and HIV screening could help close the detection gap for both conditions.

Geographic differences in time to culture conversion in liquid media: Tuberculosis Trials Consortium study 28. Culture conversion is delayed in Africa.

BACKGROUND: Tuberculosis Trials Consortium Study 28, was a double blind, randomized, placebo-controlled, phase 2 clinical trial examining smear positive pulmonary Mycobacterium tuberculosis. Over the course of intensive phase therapy, patients from African sites had substantially delayed and lower rates of culture conversion to negative in liquid media compared to non-African patients. We explored potential explanations of this finding. METHODS: In TBTC Study 28, protocol-correct patients (n = 328) provided spot sputum specimens for M. tuberculosis culture in liquid media, at baseline and weeks 2, 4, 6 and 8 of study therapy. We compared sputum culture conversion for African and non-African patients stratified by four baseline measures of disease severity: AFB smear quantification, extent of disease on chest radiograph, cavity size and the number of days to detection of M. tuberculosis in liquid media using the Kaplan-Meier product-limit method. We evaluated specimen processing and culture procedures used at 29 study laboratories serving 27 sites. RESULTS: African TB patients had more extensive disease at enrollment than non-African patients. However, African patients with the least disease by the 4 measures of disease severity had conversion rates on liquid media that were substantially lower than conversion rates in non-African patients with the greatest extent of disease. HIV infection, smoking and diabetes did not explain delayed conversion in Africa. Some inter-site variation in laboratory processing and culture procedures within accepted practice for clinical diagnostic laboratories was found. CONCLUSIONS: Compared with patients from non-African sites, African patients being treated for TB had delayed sputum culture conversion and lower sputum conversion rates in liquid media that were not explained by baseline severity of disease, HIV status, age, smoking, diabetes or race. Further investigation is warranted into whether modest variation in laboratory processes substantially influences the efficacy outcomes of phase 2 TB treatment trials or if other factors (e.g., nutrition, host response) are involved. TRIAL REGISTRATION: ClinicalTrials.gov NCT00144417.

Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies.

BACKGROUND: The World Health Organization recommends the screening of all people living with HIV for tuberculosis (TB) disease, followed by TB treatment, or isoniazid preventive therapy (IPT) when TB is excluded. However, the difficulty of reliably excluding TB disease has severely limited TB screening and IPT uptake in resource-limited settings. We conducted an individual participant data meta-analysis of primary studies, aiming to identify a sensitive TB screening rule. METHODS AND FINDINGS: We identified 12 studies that had systematically collected sputum specimens regardless of signs or symptoms, at least one mycobacterial culture, clinical symptoms, and HIV and TB disease status. Bivariate random-effects meta-analysis and the hierarchical summary relative operating characteristic curves were used to evaluate the screening performance of all combinations of variables of interest. TB disease was diagnosed in 557 (5.8%) of 9,626 people living with HIV. The primary analysis included 8,148 people living with HIV who could be evaluated on five symptoms from nine of the 12 studies. The median age was 34 years. The best performing rule was the presence of any one of: current cough (any duration), fever, night sweats, or weight loss. The overall sensitivity of this rule was 78.9% (95% confidence interval [CI] 58.3%-90.9%) and specificity was 49.6% (95% CI 29.2%-70.1%). Its sensitivity increased to 90.1% (95% CI 76.3%-96.2%) among participants selected from clinical settings and to 88.0% (95% CI 76.1%-94.4%) among those who were not previously screened for TB. Negative predictive value was 97.7% (95% CI 97.4%-98.0%) and 90.0% (95% CI 88.6%-91.3%) at 5% and 20% prevalence of TB among people living with HIV, respectively. Abnormal chest radiographic findings increased the sensitivity of the rule by 11.7% (90.6% versus 78.9%) with a reduction of specificity by 10.7% (49.6% versus 38.9%). CONCLUSIONS: Absence of all of current cough, fever, night sweats, and weight loss can identify a subset of people living with HIV who have a very low probability of having TB disease. A simplified screening rule using any one of these symptoms can be used in resource-constrained settings to identify people living with HIV in need of further diagnostic assessment for TB. Use of this algorithm should result in earlier TB diagnosis and treatment, and should allow for substantial scale-up of IPT.

The effect of highly active antiretroviral therapy on human papillomavirus clearance and cervical cytology.

OBJECTIVE: To examine the association of highly active antiretroviral therapy (HAART) with human papillomavirus (HPV) clearance and progression or regression of cervical cytological abnormalities in women with human immunodeficiency virus (HIV). METHODS: Five hundred thirty-seven women with HIV participating in the HIV Epidemiology Research Study, an observational, multisite cohort study, were evaluated semiannually from 1996 to 2000. Cervical Pap tests were collected for cervical cytology. Testing for HPV was conducted by polymerase chain reaction. Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals (CIs). Number needed to treat (NNT) at 2 years was calculated for HAART. RESULTS: Among women with cervical squamous intraepithelial lesions, HAART was associated with an increased likelihood of HPV clearance (hazard ratio 4.5, 95% CI 1.2-16.3, NNT 22.4). Use of HAART was not associated with an increased likelihood of HPV clearance among women with normal cervical cytology (hazard ratio 1.7, 95% CI 0.9-3.1, NNT 6.5) or atypical squamous cells of undetermined significance cytology (hazard ratio 1.0, 95% CI 0.4-2.5, NNT 174.0). Use of HAART was not significantly associated with an increased likelihood of cervical cytologic regression (hazard ratio 1.3, 95% CI 1.0-1.7, NNT 10.9) or cervical cytologic progression (hazard ratio 0.7, 95% CI 0.6-1.0, NNT 12.8). CONCLUSION: Among women with preexisting abnormal cervical cytology, HAART was associated with enhanced HPV clearance but not with Pap test regression. Close monitoring of women with HIV for cervical cytologic abnormalities, regardless of HAART treatment status, is warranted. LEVEL OF EVIDENCE: II.

Nutritional biomarkers associated with gynecological conditions among US women with or at risk of HIV infection.

BACKGROUND: Women infected with HIV face a combination of health threats that include compromised nutrition and adverse gynecological conditions. This relation among HIV, nutrition, and gynecological conditions is complex and has rarely been investigated. OBJECTIVE: Our objective was to investigate nutritional biomarkers associated with several gynecological conditions among US women with or at risk of HIV infection. DESIGN: Data on 369 HIV-infected and 184 HIV-uninfected women with both nutritional and gynecological outcomes were analyzed from a cross-sectional nutritional substudy of the HIV Epidemiology Research Study (HERS). We examined micronutrient distributions comparing HIV-infected with HIV-uninfected participants and both subgroups with the US population. We then modeled the relation of 16 micronutrient serum concentrations to various gynecological conditions, producing partially adjusted odds ratios, adjusted for study site, risk cohort, and HIV status. RESULTS: HIV-infected women's median antioxidant concentrations were lower than the medians of the US population. HERS women had lower median concentrations for vitamin A, selenium, and zinc irrespective of HIV status. Trichomoniasis prevalence was inversely related to serum alpha-carotene. Lower concentrations of vitamins A, C, and E and beta-carotene were associated with an increased risk of bacterial vaginosis. Higher concentrations of serum zinc were associated with lower risk of human papillomavirus. Candida colonization was higher among women with higher concentrations of total-iron-binding capacity. CONCLUSION: We identified several significant associations of micronutrient concentrations with the prevalence of gynecological conditions. These findings warrant further investigation into possible causal relations.

Smoking and time to clearance of human papillomavirus infection in HIV-seropositive and HIV-seronegative women.

Persistent human papillomavirus (HPV) infection seems central to cervical carcinogenesis. Smoking is associated with cervical cancer in HPV DNA-positive women, but its association with HPV persistence is unclear, particularly with respect to human immunodeficiency virus (HIV) serostatus. The authors evaluated smoking and HPV clearance by HIV serostatus among 801 women from the HIV Epidemiology Research Study (United States, 1993-2000). Type-specific HPV duration was defined as the interval between initial MY09/11 polymerase chain reaction positivity and the first of two consecutive HPV-negative study visits. Hazard ratios adjusted for study site and risk behaviors (sexual activity or injection drug use) were estimated using Cox regression. This analysis included 522 HIV-seropositive and 279 HIV-seronegative women (median follow-up, 4.4 years). Ever smoking was associated with reduced clearance of high-risk HPV in HIV-seronegative women (hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.30, 0.88) but not in HIV-seropositive women (HR = 0.96, 95% CI: 0.65, 1.42); similar results were found for current smoking. Current smoking was not associated with clearance of any type-specific HPV in HIV-seropositive (HR = 0.99, 95% CI: 0.82, 1.20) or HIV-seronegative (HR = 0.93, 95% CI: 0.68, 1.26) women. HPV clearance did not appear to vary by amount or duration of smoking. Smoking did not modify overall clearance but was associated with lower high-risk HPV clearance in HIV-seronegative women.

Time to clearance of human papillomavirus infection by type and human immunodeficiency virus serostatus.

Persistent infection with high-risk human papillomavirus (HPV) is central to cervical carcinogenesis. Certain high-risk types, such as HPV16, may be more persistent than other HPV types, and type-specific HPV persistence may differ by HIV serostatus. This study evaluated the association between HPV type and clearance of HPV infections in 522 HIV-seropositive and 279 HIV-seronegative participants in the HIV Epidemiology Research Study (HERS, United States, 1993-2000). Type-specific HPV infections were detected using MY09/MY11/HMB01-based PCR and 26 HPV type-specific probes. The estimated duration of type-specific infections was measured from the first HPV-positive visit to the first of two consecutive negative visits. Hazard ratios (HRs) and 95% confidence intervals (CIs) for HPV clearance were calculated using Cox models adjusted for study site and risk behavior (sexual or injection drugs). A total of 1,800 HPV infections were detected in 801 women with 4.4 years median follow-up. HRs for clearance of HPV16 and related types versus low-risk HPV types were 0.79 (95% CI: 0.64-0.97) in HIV-positive women and 0.86 (95% CI: 0.59-1.27) in HIV-negative women. HRs for HPV18 versus low-risk types were 0.80 (95% CI: 0.56-1.16) and 0.57 (95% CI: 0.22-1.45) for HIV-positive and -negative women, respectively. HPV types within the high-risk category had low estimated clearance rates relative to low-risk types, but HRs were not substantially modified by HIV serostatus.

Effect of HIV infection on atypical squamous cells of undetermined significance.

BACKGROUND: Detection of atypical squamous cells of undetermined significance (ASCUS) is a cervical cytologic finding that is suggestive but not definitive of squamous intraepithelial lesions (SILs). METHODS: We examined the risk, characteristics, and progression of ASCUS in women with and without human immunodeficiency virus (HIV) infection. Cervical Papanicolou (Pap) test and colposcopy data were obtained at the first 10 semiannual visits for the HIV Epidemiology Research study of 774 HIV-infected and 480 demographically similar, HIV-uninfected women in the United States. Multiple logistic regression models and Cox proportional hazards models were utilized. RESULTS: ASCUS was more common among HIV-infected women (odds ratio [OR], 1.6 [95% confidence interval {CI}, 1.3-2.0] to 2.6 [95% CI, 1.9-3.6]) after adjustment for human papillomavirus (HPV) infection and other risk factors (e.g., race, condyloma, and prior Pap test result). Among women with normal Pap test results at enrollment, the cumulative incidence of ASCUS was 78% among HIV-infected women and 38% among HIV-uninfected women. HIV-infected and HIV-uninfected women with ASCUS did not differ by prevalence of indices of inflammation (inflammation on Pap test and leukocytes on cervical gram stain). HPV infection, including high risk types, was more common among HIV-infected women with ASCUS. Among women with ASCUS, 60% of HIV-infected and 25% of HIV-uninfected women developed SILs (P < .01). Compared with HIV-infected women with higher CD4+ lymphocyte counts, HIV-infected women with CD4+ lymphocyte counts < 200 cells/microL were more likely to present subsequently with a SIL detected by Pap test (OR, 1.7; 95% CI, 0.8-3.6). CONCLUSIONS: Higher risk of SIL following the appearance of ASCUS among HIV-infected women, especially women with low CD4+ lymphocyte counts, supports the need for follow up with colposcopy and histologic examination, as indicated, to allow early detection and treatment of SIL.

Abnormal vaginal cytology in HIV-infected and at-risk women after hysterectomy.

OBJECTIVE: To determine the frequency of and risk factors for abnormal vaginal Papanicolaou smears in HIV-infected women after hysterectomy. METHODS: Data were from the HIV Epidemiology Research (HER) study, a prospective multisite study of HIV-infected and uninfected women. Semiannual vaginal Papanicolaou smears and colposcopy data were obtained from 102 HIV-infected and 46 at-risk women who had hysterectomy either before or during the study. Analytic models used include Cox proportional hazards (women with hysterectomy during the study) and multiple logistic regressions, which corrected for repeated measures (all women). RESULTS: Among the HIV-infected women, evidence of cervical intraepithelial neoplasia before or at hysterectomy was associated with abnormal cytology during follow-up; 63% had squamous intraepithelial lesions (SIL) on vaginal Papanicolaou smears following hysterectomy. CD4 counts of <200 cells/microL at hysterectomy and HIV viral load of >10,000 copies/mL at hysterectomy were predictive of SIL vaginal cytology. Prevalent SIL vaginal cytology was associated with low CD4 count and human papillomavirus risk type. Of the 102 HIV-infected women, 16 (16%) had vaginal intraepithelial neoplasia on biopsy. CONCLUSIONS: The high rate of SIL on vaginal Papanicolaou smears and the presence of high-grade vaginal intraepithelial neoplasia among HIV-infected women after hysterectomy demonstrate the need for continued follow-up for lower genital tract lesions.