Publications by authors named "Ray Y Chen"

56 Publications

Fourteen-day PET/CT imaging to monitor drug combination activity in treated individuals with tuberculosis.

Sci Transl Med 2021 Feb;13(579)

Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.

Early bactericidal activity studies monitor daily sputum bacterial counts in individuals with tuberculosis (TB) for 14 days during experimental drug treatment. The rate of change in sputum bacterial load over time provides an informative, but imperfect, estimate of drug activity and is considered a critical step in development of new TB drugs. In this clinical study, 160 participants with TB received isoniazid, pyrazinamide, or rifampicin, components of first-line chemotherapy, and moxifloxacin individually and in combination. In addition to standard bacterial enumeration in sputum, participants underwent 2-deoxy-2-[F]fluoro-d-glucose positron emission tomography and computerized tomography ([F]FDG-PET/CT) at the beginning and end of the 14-day drug treatment. Quantitating radiological responses to drug treatment provided comparative single and combination drug activity measures across lung lesion types that correlated more closely with established clinical outcomes when combined with sputum enumeration compared to sputum enumeration alone. Rifampicin and rifampicin-containing drug combinations were most effective in reducing both lung lesion volume measured by CT imaging and lesion-associated inflammation measured by PET imaging. Moxifloxacin was not superior to rifampicin in any measure by PET/CT imaging, consistent with its performance in recent phase 3 clinical trials. PET/CT imaging revealed synergy between isoniazid and pyrazinamide and demonstrated that the activity of pyrazinamide was limited to lung lesion, showing the highest FDG uptake during the first 2 weeks of drug treatment. [F]FDG-PET/CT imaging may be useful for measuring the activity of single drugs and drug combinations during evaluation of potential new TB drug regimens before phase 3 trials.
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http://dx.doi.org/10.1126/scitranslmed.abd7618DOI Listing
February 2021

Current and future treatments for tuberculosis.

BMJ 2020 03 2;368:m216. Epub 2020 Mar 2.

Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Medicine, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Guidelines on the treatment of tuberculosis (TB) have essentially remained the same for the past 35 years, but are now starting to change. Ongoing clinical trials will hopefully transform the landscape for treatment of drug sensitive TB, drug resistant TB, and latent TB infection. Multiple trials are evaluating novel agents, repurposed agents, adjunctive host directed therapies, and novel treatment strategies that will increase the probability of success of future clinical trials. Guidelines for HIV-TB co-infection treatment continue to be updated and drug resistance testing has been revolutionized in recent years with the shift from phenotypic to genotypic testing and the concomitant increased speed of results. These coming changes are long overdue and are sorely needed to address the vast disparities in global TB incidence rates. TB is currently the leading cause of death globally from a single infectious agent, but the work of many researchers and the contributions of many patients in clinical trials will reduce the substantial global morbidity and mortality of the disease.
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http://dx.doi.org/10.1136/bmj.m216DOI Listing
March 2020

Quantitative 18F-FDG PET-CT scan characteristics correlate with tuberculosis treatment response.

EJNMMI Res 2020 Feb 10;10(1). Epub 2020 Feb 10.

Department of Science and Technology/National Research Foundation, Centre of Excellence for Biomedical Tuberculosis Research and South African Medical Research Council Centre for Tuberculosis Research, Cape Town, South Africa.

Background: There is a growing interest in the use of F-18 FDG PET-CT to monitor tuberculosis (TB) treatment response. Tuberculosis lung lesions are often complex and diffuse, with dynamic changes during treatment and persisting metabolic activity after apparent clinical cure. This poses a challenge in quantifying scan-based markers of burden of disease and disease activity. We used semi-automated, whole lung quantification of lung lesions to analyse serial FDG PET-CT scans from the Catalysis TB Treatment Response Cohort to identify characteristics that best correlated with clinical and microbiological outcomes.

Results: Quantified scan metrics were already associated with clinical outcomes at diagnosis and 1 month after treatment, with further improved accuracy to differentiate clinical outcomes after standard treatment duration (month 6). A high cavity volume showed the strongest association with a risk of treatment failure (AUC 0.81 to predict failure at diagnosis), while a suboptimal reduction of the total glycolytic activity in lung lesions during treatment had the strongest association with recurrent disease (AUC 0.8 to predict pooled unfavourable outcomes). During the first year after TB treatment lesion burden reduced; but for many patients, there were continued dynamic changes of individual lesions.

Conclusions: Quantification of FDG PET-CT images better characterised TB treatment outcomes than qualitative scan patterns and robustly measured the burden of disease. In future, validated metrics may be used to stratify patients and help evaluate the effectiveness of TB treatment modalities.
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http://dx.doi.org/10.1186/s13550-020-0591-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010890PMC
February 2020

Neurotuberculosis: Control of Steroid-Refractory Paradoxical Inflammatory Reaction With Ruxolitinib.

Open Forum Infect Dis 2019 Oct 26;6(10):ofz422. Epub 2019 Oct 26.

Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Paradoxical inflammatory reactions associated with treatment of neurotuberculosis can lead to severe morbidity and mortality and may not be controlled by steroids alone. We report the use of the Janus kinase inhibitor ruxolitinib to treat a steroid-refractory neurotuberculosis paradoxical reaction.
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http://dx.doi.org/10.1093/ofid/ofz422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821379PMC
October 2019

A semi-automatic technique to quantify complex tuberculous lung lesions on F-fluorodeoxyglucose positron emission tomography/computerised tomography images.

EJNMMI Res 2018 Jun 25;8(1):55. Epub 2018 Jun 25.

Division of Nuclear Medicine, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Background: There is a growing interest in the use of F-FDG PET-CT to monitor tuberculosis (TB) treatment response. However, TB causes complex and widespread pathology, which is challenging to segment and quantify in a reproducible manner. To address this, we developed a technique to standardise uptake (Z-score), segment and quantify tuberculous lung lesions on PET and CT concurrently, in order to track changes over time. We used open source tools and created a MATLAB script. The technique was optimised on a training set of five pulmonary tuberculosis (PTB) cases after standard TB therapy and 15 control patients with lesion-free lungs.

Results: We compared the proposed method to a fixed threshold (SUV > 1) and manual segmentation by two readers and piloted the technique successfully on scans of five control patients and five PTB cases (four cured and one failed treatment case), at diagnosis and after 1 and 6 months of treatment. There was a better correlation between the Z-score-based segmentation and manual segmentation than SUV > 1 and manual segmentation in terms of overall spatial overlap (measured in Dice similarity coefficient) and specificity (1 minus false positive volume fraction). However, SUV > 1 segmentation appeared more sensitive. Both the Z-score and SUV > 1 showed very low variability when measuring change over time. In addition, total glycolytic activity, calculated using segmentation by Z-score and lesion-to-background ratio, correlated well with traditional total glycolytic activity calculations. The technique quantified various PET and CT parameters, including the total glycolytic activity index, metabolic lesion volume, lesion volumes at different CT densities and combined PET and CT parameters. The quantified metrics showed a marked decrease in the cured cases, with changes already apparent at month one, but remained largely unchanged in the failed treatment case.

Conclusions: Our technique is promising to segment and quantify the lung scans of pulmonary tuberculosis patients in a semi-automatic manner, appropriate for measuring treatment response. Further validation is required in larger cohorts.
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http://dx.doi.org/10.1186/s13550-018-0411-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020088PMC
June 2018

Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial.

Gates Open Res 2017 Nov 6;1. Epub 2017 Nov 6.

Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.

: By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01).  We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment. : This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C. : Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified.

Trial Registration: NCT02821832.
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http://dx.doi.org/10.12688/gatesopenres.12750.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841574PMC
November 2017

Renal Fanconi syndrome with meropenem/amoxicillin-clavulanate during treatment of extensively drug-resistant tuberculosis.

Eur Respir J 2017 12 28;50(6). Epub 2017 Dec 28.

Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA

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http://dx.doi.org/10.1183/13993003.02023-2017DOI Listing
December 2017

Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis.

N Engl J Med 2017 09;377(11):1043-1054

From the Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda (Y.L.X., L.E.V., R.Y.C., C.E.B.), and Johns Hopkins University School of Medicine, Baltimore (D.T.A., S.E.D.) - both in Maryland; the Center for Emerging and Re-Emerging Pathogens, Rutgers New Jersey Medical School, Newark (S.C., L.E.S., N.D., D.A.); Boston Medical Center and Boston University School of Medicine, Boston (S.L.H., J.J.E.); the International Tuberculosis Research Center, Changwon (T.S., M.L., J.L., S.-N.C.), and the National Medical Center (J.S.J.), Seoul Metropolitan Seobuk Hospital (Y.C.), and the Department of Microbiology, College of Medicine, Yonsei University (S.-N.C.), Seoul - all in South Korea; Henan Provincial Chest Hospital (X.Y., X.M., X.L., X.R., L.L.) and Sino-U.S. Tuberculosis Research Collaboration (H.Z.), Zhengzhou, and Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Science, Fudan University, Shanghai (P.X., Q.G.) - all in China; and the Institute of Infectious Disease and Molecular Medicine and Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa (C.E.B.).

Background: Fluoroquinolones and second-line injectable drugs are the backbone of treatment regimens for multidrug-resistant tuberculosis, and resistance to these drugs defines extensively drug-resistant tuberculosis. We assessed the accuracy of an automated, cartridge-based molecular assay for the detection, directly from sputum specimens, of Mycobacterium tuberculosis with resistance to fluoroquinolones, aminoglycosides, and isoniazid.

Methods: We conducted a prospective diagnostic accuracy study to compare the investigational assay against phenotypic drug-susceptibility testing and DNA sequencing among adults in China and South Korea who had symptoms of tuberculosis. The Xpert MTB/RIF assay and sputum culture were performed. M. tuberculosis isolates underwent phenotypic drug-susceptibility testing and DNA sequencing of the genes katG, gyrA, gyrB, and rrs and of the eis and inhA promoter regions.

Results: Among the 308 participants who were culture-positive for M. tuberculosis, when phenotypic drug-susceptibility testing was used as the reference standard, the sensitivities of the investigational assay for detecting resistance were 83.3% for isoniazid (95% confidence interval [CI], 77.1 to 88.5), 88.4% for ofloxacin (95% CI, 80.2 to 94.1), 87.6% for moxifloxacin at a critical concentration of 0.5 μg per milliliter (95% CI, 79.0 to 93.7), 96.2% for moxifloxacin at a critical concentration of 2.0 μg per milliliter (95% CI, 87.0 to 99.5), 71.4% for kanamycin (95% CI, 56.7 to 83.4), and 70.7% for amikacin (95% CI, 54.5 to 83.9). The specificity of the assay for the detection of phenotypic resistance was 94.3% or greater for all drugs except moxifloxacin at a critical concentration of 2.0 μg per milliliter (specificity, 84.0% [95% CI, 78.9 to 88.3]). When DNA sequencing was used as the reference standard, the sensitivities of the investigational assay for detecting mutations associated with resistance were 98.1% for isoniazid (95% CI, 94.4 to 99.6), 95.8% for fluoroquinolones (95% CI, 89.6 to 98.8), 92.7% for kanamycin (95% CI, 80.1 to 98.5), and 96.8% for amikacin (95% CI, 83.3 to 99.9), and the specificity for all drugs was 99.6% (95% CI, 97.9 to 100) or greater.

Conclusions: This investigational assay accurately detected M. tuberculosis mutations associated with resistance to isoniazid, fluoroquinolones, and aminoglycosides and holds promise as a rapid point-of-care test to guide therapeutic decisions for patients with tuberculosis. (Funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Ministry of Science and Technology of China; ClinicalTrials.gov number, NCT02251327 .).
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http://dx.doi.org/10.1056/NEJMoa1614915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727572PMC
September 2017

Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure.

Nat Med 2016 10 5;22(10):1094-1100. Epub 2016 Sep 5.

National Medical Center, Seoul, South Korea.

The absence of a gold standard to determine when antibiotics induce a sterilizing cure has confounded the development of new approaches to treat pulmonary tuberculosis (PTB). We detected positron emission tomography and computerized tomography (PET-CT) imaging response patterns consistent with active disease, along with the presence of Mycobacterium tuberculosis (MTB) mRNA in sputum and bronchoalveolar lavage samples, in a substantial proportion of adult, HIV-negative patients with PTB after a standard 6-month treatment plus 1 year follow-up, including patients with a durable cure and others who later developed recurrent disease. The presence of MTB mRNA in the context of nonresolving and intensifying lesions on PET-CT images might indicate ongoing transcription, suggesting that even apparently curative treatment for PTB may not eradicate all of the MTB bacteria in most patients. This suggests an important complementary role for the immune response in maintaining a disease-free state. Sterilizing drugs or host-directed therapies, and better treatment response markers, are probably needed for the successful development of improved and shortened PTB-treatment strategies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053881PMC
http://dx.doi.org/10.1038/nm.4177DOI Listing
October 2016

Reply to Tham et al.

Clin Infect Dis 2016 08 25;63(4):573-4. Epub 2016 May 25.

Center for Biologics Evaluation and Research, FDA, Silver Spring, Maryland.

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http://dx.doi.org/10.1093/cid/ciw352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006204PMC
August 2016

Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis.

EBioMedicine 2015 Nov 9;2(11):1627-33. Epub 2015 Oct 9.

Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Long-term linezolid use is limited by mitochondrial toxicity-associated adverse events (AEs). Within a prospective, randomized controlled trial of linezolid to treat chronic extensively drug-resistant tuberculosis, we serially monitored the translational competence of mitochondria isolated from peripheral blood of participants by determining the cytochrome c oxidase/citrate synthase activity ratio. We compared this ratio with AEs associated with mitochondrial dysfunction. Linezolid trough concentrations were determined for 38 participants at both 600 mg and 300 mg doses. Those on 600 mg had a significantly higher risk of AE than those on 300 mg (HR 3·10, 95% CI 1·23-7 · 86). Mean mitochondrial function levels were significantly higher in patients before starting linezolid compared to their concentrations on 300 mg (P = 0·004) or 600 mg (P < 0·0001). Increasing mean linezolid trough concentrations were associated with lower mitochondrial function levels (Spearman's ρ = - 0.48; P = 0.005). Mitochondrial toxicity risk increased with increasing linezolid trough concentrations, with all patients with mean linezolid trough > 2 μg/ml developing an AE related to mitochondrial toxicity, whether on 300 mg or 600 mg. Therapeutic drug monitoring may be useful to prevent the development of mitochondrial toxicity associated with long-term linezolid use.
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http://dx.doi.org/10.1016/j.ebiom.2015.09.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740314PMC
November 2015

Severe Paradoxical Reaction During Treatment of Disseminated Tuberculosis in a Patient With Neutralizing Anti-IFNγ Autoantibodies.

Clin Infect Dis 2016 Mar 8;62(6):770-773. Epub 2015 Dec 8.

Laboratory of Clinical Infectious Diseases.

Interferon-gamma (IFNγ) neutralizing autoantibodies are associated with disseminated nontuberculous mycobacterial infections. We report a previously healthy Thai woman with disseminated tuberculosis and high-titer IFNγ-neutralizing autoantibodies, who developed a severe inflammatory reaction during anti-tuberculosis treatment. IFNγ contributes to host control of tuberculosis but appears inessential for tuberculosis paradoxical reactions.
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http://dx.doi.org/10.1093/cid/civ995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772847PMC
March 2016

A sterilizing tuberculosis treatment regimen is associated with faster clearance of bacteria in cavitary lesions in marmosets.

Antimicrob Agents Chemother 2015 Jul 4;59(7):4181-9. Epub 2015 May 4.

Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA Institute of Infectious Disease and Molecular Medicine, Department of Clinical Laboratory Sciences, University of Cape Town, Cape Town, South Africa

Shortening the lengthy treatment duration for tuberculosis patients is a major goal of current drug development efforts. The common marmoset develops human-like disease pathology and offers an attractive model to better understand the basis for relapse and test regimens for effective shorter duration therapy. We treated Mycobacterium tuberculosis-infected marmosets with two drug regimens known to differ in their relapse rates in human clinical trials: the standard four-drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) that has very low relapse rates and the combination of isoniazid and streptomycin that is associated with higher relapse rates. As early as 2 weeks, the more sterilizing regimen significantly reduced the volume of lung disease by computed tomography (P = 0.035) and also significantly reduced uptake of [(18)F]-2-fluoro-2-deoxyglucose by positron emission tomography (P = 0.049). After 6 weeks of therapy, both treatments caused similar reductions in granuloma bacterial load, but the more sterilizing, four-drug regimen caused greater reduction in bacterial load in cavitary lesions (P = 0.009). These findings, combined with the association in humans between cavitary disease and relapse, suggest that the basis for improved sterilizing activity of the four-drug combination is both its faster disease volume resolution and its stronger sterilizing effect on cavitary lesions. Definitive data from relapse experiments are needed to support this observation.
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http://dx.doi.org/10.1128/AAC.00115-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468655PMC
July 2015

Expanding substance use treatment options for HIV prevention with buprenorphine-naloxone: HIV Prevention Trials Network 058.

J Acquir Immune Defic Syndr 2015 Apr;68(5):554-61

*Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; and Treatment Research Institute, Philadelphia, PA; †Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA; ‡Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; §Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD and Department of Pathology, University of Minnesota, Minneapolis, MN; ‖State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, China; ¶Department of Family Medicine, Faculty of Medicine, Chiang Mai University; #Guangxi Centers for Disease Control and Prevention, Guangxi Center for HIV/AIDS Prevention and Control, Nanning, China; **Xinjiang Autonomous Region Center for Disease Control and Prevention, Xinjiang, China; ††Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD; ‡‡Department of Psychiatry, Yale School of Medicine, New Haven, CT; §§Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD; ‖‖Division of AIDS, Pharmaceutical Affairs Branch, National Institute of Allergy and Infectious Diseases; ¶¶Division of Intramural Research, National Institute of Allergy and Infectious Diseases; ##Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD; ***FHI 360; †††Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division; and ‡‡‡Division of AIDS, Prevention Sciences Branch, National Institute of Allergy and Infectious Diseases.

Background: Injection opioid use plays a significant role in the transmission of HIV infection in many communities and several regions of the world. Access to evidence-based treatments for opioid use disorders is extremely limited.

Methods: HIV Prevention Trials Network 058 (HPTN 058) was a randomized controlled trial designed to compare the impact of 2 medication-assisted treatment (MAT) strategies on HIV incidence or death among opioid-dependent people who inject drugs (PWID). HIV-negative opioid-dependent PWID were recruited from 4 communities in Thailand and China with historically high prevalence of HIV among PWID. A total of 1251 participants were randomly assigned to either (1) a 1-year intervention consisting of 2 opportunities for a 15-day detoxification with buprenorphine/naloxone (BUP/NX) combined with up to 21 sessions of behavioral drug and risk counseling [short-term medication-assisted treatment (ST-MAT)] or (2) thrice-weekly dosing for 48 weeks with BUP/NX and up to 21 counseling sessions [long-term medication-assisted treatment (LT-MAT)] followed by dose tapering. All participants were followed for 52 weeks after treatment completion to assess durability of impact.

Results: Although the study was stopped early due to lower than expected occurrence of the primary end points, sufficient data were available to assess the impact of the interventions on drug use and injection-related risk behavior. At week 26, 22% of ST-MAT participants had negative urinalyses for opioids compared with 57% in the LT-MAT (P < 0.001). Differences disappeared in the year after treatment: at week 78, 35% in ST-MAT and 32% in the LT-MAT had negative urinalyses. Injection-related risk behaviors were significantly reduced in both groups after randomization.

Conclusions: Participants receiving BUP/NX 3 times weekly were more likely to reduce opioid injection while on active treatment. Both treatment strategies were considered safe and associated with reductions in injection-related risk behavior. These data support the use of thrice-weekly BUP/NX as a way to reduce exposure to HIV risk. Continued access to BUP/NX may be required to sustain reductions in opioid use.
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http://dx.doi.org/10.1097/QAI.0000000000000510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382671PMC
April 2015

PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis.

Sci Transl Med 2014 Dec;6(265):265ra167

Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.

Oxazolidinone antibiotics such as linezolid have shown significant therapeutic effects in patients with extensively drug-resistant (XDR) tuberculosis (TB) despite modest effects in rodents and no demonstrable early bactericidal activity in human phase 2 trials. We show that monotherapy with either linezolid or AZD5847, a second-generation oxazolidinone, reduced bacterial load at necropsy in Mycobacterium tuberculosis-infected cynomolgus macaques with active TB. This effect coincided with a decline in 2-deoxy-2-[(18)F]-fluoro-d-glucose positron emission tomography (FDG PET) imaging avidity in the lungs of these animals and with reductions in pulmonary pathology measured by serial computed tomography (CT) scans over 2 months of monotherapy. In a parallel phase 2 clinical study of linezolid in patients infected with XDR-TB, we also collected PET/CT imaging data from subjects receiving linezolid that had been added to their failing treatment regimens. Quantitative comparisons of PET/CT imaging changes in these human subjects were similar in magnitude to those observed in macaques, demonstrating that the therapeutic effect of these oxazolidinones can be reproduced in this model of experimental chemotherapy. PET/CT imaging may be useful as an early quantitative measure of drug efficacy against TB in human patients.
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http://dx.doi.org/10.1126/scitranslmed.3009500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413515PMC
December 2014

PET/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis.

Sci Transl Med 2014 Dec;6(265):265ra166

Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA. Institute of Infectious Disease and Molecular Medicine, and the Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Rondebosch 7701, South Africa.

Definitive clinical trials of new chemotherapies for treating tuberculosis (TB) require following subjects until at least 6 months after treatment discontinuation to assess for durable cure, making these trials expensive and lengthy. Surrogate endpoints relating to treatment failure and relapse are currently limited to sputum microbiology, which has limited sensitivity and specificity. We prospectively assessed radiographic changes using 2-deoxy-2-[(18)F]-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) at 2 and 6 months (CT only) in a cohort of subjects with multidrug-resistant TB, who were treated with second-line TB therapy for 2 years and then followed for an additional 6 months. CT scans were read semiquantitatively by radiologists and were computationally evaluated using custom software to provide volumetric assessment of TB-associated abnormalities. CT scans at 6 months (but not 2 months) assessed by radiologist readers were predictive of outcomes, and changes in computed abnormal volumes were predictive of drug response at both time points. Quantitative changes in FDG uptake 2 months after starting treatment were associated with long-term outcomes. In this cohort, some radiologic markers were more sensitive than conventional sputum microbiology in distinguishing successful from unsuccessful treatment. These results support the potential of imaging scans as possible surrogate endpoints in clinical trials of new TB drug regimens. Larger cohorts confirming these results are needed.
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http://dx.doi.org/10.1126/scitranslmed.3009501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567784PMC
December 2014

Predictors of pulmonary tuberculosis treatment outcomes in South Korea: a prospective cohort study, 2005-2012.

BMC Infect Dis 2014 Jul 2;14:360. Epub 2014 Jul 2.

International Tuberculosis Research Center, Changwon, Republic of Korea.

Background: Tuberculosis remains an important health concern in many countries. The aim of this study was to identify predictors of unfavorable outcomes at the end of treatment (EOT) and at the end of study (EOS; 40 months after EOT) in South Korea.

Methods: New or previously treated tuberculosis patients were recruited into a prospective observational cohort study at two hospitals in South Korea. To identify predictors of unfavorable outcomes at EOT and EOS, logistic regression analysis was performed.

Results: The proportion of multidrug-resistant tuberculosis (MDR-TB) was 8.2% in new cases and 57.9% in previously treated cases. Of new cases, 68.6% were cured, as were 40.7% of previously treated cases. At EOT, diabetes, ≥3 previous TB episodes, ≥1 significant regimen change, and MDR-TB were significantly associated with treatment failure or death. At EOS, age ≥35, body-mass index (BMI) <18.5, diabetes, and MDR-TB were significantly associated with treatment failure, death, or relapse. Among cases that were cured at EOT, age ≥50 and a BMI <18.5 were associated with subsequent death or relapse during follow-up to EOS. Treatment interruption was associated with service sector employees or laborers, bilateral lesions on chest X-ray, and previous treatment failure or treatment interruption history.

Conclusions: Risk factors for poor treatment outcomes at EOT and EOS include both patient factors (diabetes status, age, BMI) and disease factors (history of multiple previous treatment episodes, MDR-TB). In this longitudinal, observational cohort study, diabetes mellitus and MDR-TB were risk factors for poor treatment outcomes and relapse. Measures to help ensure that the first tuberculosis treatment episode is also the last one may improve treatment outcomes.

Trial Registration: ClinicalTrials.gov ID: NCT00341601.
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http://dx.doi.org/10.1186/1471-2334-14-360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094632PMC
July 2014

Seroprevalence of antibodies to highly pathogenic avian influenza A (H5N1) virus among close contacts exposed to H5N1 cases, China, 2005-2008.

PLoS One 2013 13;8(8):e71765. Epub 2013 Aug 13.

Key Laboratory of Surveillance and Early-warning on Infectious Disease, Division of Infectious Disease, Chinese Center for Disease Control and Prevention (China CDC), Beijing, China.

To assess the extent of highly pathogenic avian influenza (HPAI) A (H5N1) virus transmission, we conducted sero-epidemiologic studies among close contacts exposed to H5N1 cases in mainland China during 2005-2008. Blood specimens were collected from 87 household members and 332 social contacts of 23 H5N1 index cases for HPAI H5N1 serological testing by modified horse red-blood-cell hemagglutinin inhibition and microneutralization assays. All participants were interviewed with a standardized questionnaire to collect information about the use of personal protective equipment, illness symptoms, exposure to an H5N1 case during the infectious period, and poultry exposures. Two (2.3%) household contacts tested positive for HPAI H5N1 virus antibody, and all social contacts tested negative. Both seropositive cases had prolonged, unprotected, close contact with a different H5N1 index case, including days of bed-care or sleeping together during the index case's infectious period, and did not develop any illness. None of the 419 close contacts used appropriate personal protective equipment including 17% who reported providing bedside care or having physical contact with an H5N1 case for at least 12 hours. Our findings suggest that HPAI H5N1 viruses that circulated among poultry in mainland China from 2005-2008 were not easily transmitted to close contacts of H5N1 cases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071765PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742513PMC
May 2014

Effect of Diagnostic and Treatment Delay on the Risk of Tuberculosis Transmission in Shenzhen, China: An Observational Cohort Study, 1993-2010.

PLoS One 2013 27;8(6):e67516. Epub 2013 Jun 27.

National Centre for Tuberculosis Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.

Introduction: To understand better the risk of tuberculosis transmission with increasing delay in tuberculosis treatment, we undertook a retrospective cohort study in Shenzhen, China.

Methods: All pulmonary tuberculosis cases in the Shenzhen tuberculosis surveillance database from 1993-2010 were included. Sputum smear positivity and presence of pulmonary cavity were used as proxies for risk of tuberculosis transmission.

Results: Among 48,441pulmonary tuberculosis cases, 70% presented with symptoms of pulmonary TB, 62% were sputum smear positive, and 21% had a pulmonary cavity on chest x-ray. 95.3% of patients self-presented for evaluation of illness after a median 58 days of delay after symptoms began. The proportion presenting sputum smear positive (p<0.001) and with a pulmonary cavity (p<0.001) increased significantly with increasing duration of delay.

Conclusions: Delayed diagnosis and treatment of tuberculosis is associated with a significantly increased risk of pulmonary sputum smear positivity and pulmonary cavity. To decrease risk of transmission, treatment delay needs to be reduced further.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067516PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694886PMC
October 2017

Impact of HIV drug resistance on virologic and immunologic failure and mortality in a cohort of patients on antiretroviral therapy in China.

AIDS 2013 Jul;27(11):1815-24

State Key Laboratory for Infectious Disease Prevention and Control, and National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Hefei, Anhui, China.

Objectives: To study the dynamics of HIV drug resistance (HIVDR) and its association with virologic and immunologic failure as well as mortality among patients on combination antiretroviral therapy (cART) in China.

Design: We recruited 365 patients on cART in two rural Chinese counties in 2003-2004 and followed them every 6 months until May 2010.

Methods: Virologic failure, HIVDR, immunologic failure and death were documented. We used Kaplan-Meier and the proportional hazards models to identify the timing of the events, and risk factors for mortality.

Results: At the end of study, patients had been followed for 1974.3 person-years, a median of 6.1 years. HIVDR mutations were found in 235 (64.4%) patients and 75 died (20.5%, 3.8/100 person-years). Median time from cART to detection of virologic failure was 17.5 months, to HIVDR 36.6 months and to immunologic failure 55.2 months (≈ 18-month median interval between each adverse milestone). Being male, having a baseline CD4 cell count of less than 50 cells/μl and HIVDR were associated with higher mortality. Patients who developed HIVDR in the first year of treatment had higher mortality than those developing HIVDR later (adjusted hazard ratio 1.90, 95% confidence interval 1.01-3.48).

Conclusion: HIVDR was common and was associated with higher mortality among Chinese patients on cART, particular when HIVDR was detected early in therapy. Our study reinforces the importance of improving patient adherence to cART in order to delay the emergence of HIVDR and obviate the need to switch to costly second-line drug regimens too early.
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http://dx.doi.org/10.1097/QAD.0b013e3283611931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694318PMC
July 2013

Efficacy and safety of metronidazole for pulmonary multidrug-resistant tuberculosis.

Antimicrob Agents Chemother 2013 Aug 3;57(8):3903-9. Epub 2013 Jun 3.

Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Pulmonary lesions from active tuberculosis patients are thought to contain persistent, nonreplicating bacilli that arise from hypoxic stress. Metronidazole, approved for anaerobic infections, has antituberculosis activity against anoxic bacilli in vitro and in some animal models and may target persistent, nonreplicating bacilli. In this double-blind, placebo-controlled trial, pulmonary multidrug-resistant tuberculosis subjects were randomly assigned to receive metronidazole (500 mg thrice daily) or placebo for 8 weeks in addition to an individualized background regimen. Outcomes were measured radiologically (change on high-resolution computed tomography [HRCT]), microbiologically (time to sputum smear and culture conversion), and clinically (status 6 months after stopping therapy). Enrollment was stopped early due to excessive peripheral neuropathies in the metronidazole arm. Among 35 randomized subjects, 31 (15 metronidazole, 16 placebo) were included in the modified intent-to-treat analysis. There were no significant differences by arm in improvement of HRCT lesions from baseline to 2 or 6 months. More subjects in the metronidazole arm converted their sputum smear (P = 0.04) and liquid culture (P = 0.04) to negative at 1 month, but these differences were lost by 2 months. Overall, 81% showed clinical success 6 months after stopping therapy, with no differences by arm. However, 8/16 (50%) of subjects in the metronidazole group and 2/17 (12%) of those in the placebo group developed peripheral neuropathy. Subjects who received metronidazole were 4.3-fold (95% confidence interval [CI], 1.1 to 17.1) more likely to develop peripheral neuropathies than subjects who received placebo. Metronidazole may have increased early sputum smear and culture conversion but was too neurotoxic to use over the longer term. Newer nitroimidazoles with both aerobic and anaerobic activity, now in clinical trials, may increase the sterilizing potency of future treatment regimens.
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http://dx.doi.org/10.1128/AAC.00753-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3719751PMC
August 2013

HIV drug resistance and its impact on antiretroviral therapy in Chinese HIV-infected patients.

PLoS One 2013 6;8(2):e54917. Epub 2013 Feb 6.

State Key Laboratory for Infectious Disease Prevention and Control, and National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.

Background: Highly active antiretroviral therapy (HAART) has significantly decreased mortality among Chinese HIV patients. However, emerging HIV drug resistance (HIVDR) poses a growing threat to the long-term success and durability of HAART.

Methods: Three cross-sectional surveys were conducted across the country from 2004 to 2006, respectively. Patients completed a questionnaire and provided blood for CD4 cell count, HIV viral load (VL), and HIV resistance genotyping. Factors associated with HIVDR were identified by logistic regression.

Results: 3667 unique patients were included across the three surveys. Among 2826 treatment-experienced patients, median duration of treatment was 17.4 (IQR 8.6-28.4) months and HIVDR was identified in 543 (19.2%). Factors significantly associated with HIVDR included ART drug distribution location, CD4 cell count, initial HAART regimen, self-reported medication adherence, and province.

Conclusions: Virologic failure increased over time on therapy but a significant proportion of patients in failure had no resistance mutations identified, suggesting that treatment adherence is suboptimal and must be emphasized. Due to the significantly higher risk of HIVDR in certain provinces, additional steps to reduce HIVDR should be taken.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054917PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566114PMC
December 2013

Antiretroviral therapy to prevent HIV transmission in serodiscordant couples in China (2003-11): a national observational cohort study.

Lancet 2013 Oct 1;382(9899):1195-203. Epub 2012 Dec 1.

National Institute of Drug Dependence, Peking University, Beijing, China.

Background: On the basis of the results of the randomised clinical trial HPTN 052 and observational studies, WHO has recommended that antiretroviral therapy be offered to all HIV-infected individuals with uninfected partners of the opposite sex (serodiscordant couples) to reduce the risk of transmission. Whether or not such a public health approach is feasible and the outcomes are sustainable at a large scale and in a developing country setting has not previously been assessed.

Methods: In this retrospective observational cohort study, we included treated and treatment-naive HIV-positive individuals with HIV-negative partners of the opposite sex who had been added to the national HIV epidemiology and treatment databases between Jan 1, 2003 and Dec 31, 2011. We analysed the annual rate of HIV infection in HIV-negative partners during follow-up, stratified by treatment status of the index partner. Cox proportional hazards analyses were done to examine factors related to HIV transmission.

Findings: Based on data from 38,862 serodiscordant couples, with 101,295·1 person-years of follow-up for the seronegative partners, rates of HIV infection were 2·6 per 100 person-years (95% CI 2·4-2·8) among the 14,805 couples in the treatment-naive cohort (median baseline CD4 count for HIV-positive partners 441 cells per μl [IQR 314-590]) and 1·3 per 100 person-years (1·2-1·3) among the 24,057 couples in the treated cohort (median baseline CD4 count for HIV-positive partners 168 cells per μl [62-269]). We calculated a 26% relative reduction in HIV transmission (adjusted hazard ratio 0·74, 95% CI 0·65-0·84) in the treated cohort. The reduction in transmission was seen across almost all demographic subgroups and was significant in the first year (0·64, 0·54-0·76), and among couples in which the HIV-positive partner had been infected by blood or plasma transfusion (0·76, 0·59-0·99) or heterosexual intercourse (0·69, 0·56-0·84), but not among couples in which the HIV-positive partner was infected by injecting drugs (0·98, 0·71-1·36).

Interpretation: Antiretroviral therapy for HIV-positive individuals in serodiscordant couples reduced HIV transmission across China, which suggests that the treatment-as-prevention approach is a feasible public health prevention strategy on a national scale in a developing country context. The durability and generalisability of such protection, however, needs to be further studied.

Funding: Chinese Government's 12th Five-Year Plan, the National Natural Science Foundation of China, and the Canadian International Development Research Centre.
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http://dx.doi.org/10.1016/S0140-6736(12)61898-4DOI Listing
October 2013

Mortality and treatment outcomes of China's National Pediatric antiretroviral therapy program.

Clin Infect Dis 2013 Mar 21;56(5):735-44. Epub 2012 Nov 21.

National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, PR China.

Background: The aim of this study was to describe 3-year mortality rates, associated risk factors, and long-term clinical outcomes of children enrolled in China's national free pediatric antiretroviral therapy (ART) program.

Methods: Records were abstracted from the national human immunodeficiency virus (HIV)/AIDS case reporting and national pediatric ART databases for all HIV-positive children ≤15 years old who initiated ART prior to December 2010. Mortality risk factors over 3 years of follow-up were examined using Cox proportional hazards regression models. Life tables were used to determine survival rate over time. Longitudinal plots of CD4(+) T-cell percentage (CD4%), hemoglobin level, weight-for-age z (WAZ) score, and height-for-age z (HAZ) score were created using generalized estimating equation models.

Results: Among the 1818 children included in our cohort, 93 deaths were recorded in 4022 child-years (CY) of observed time for an overall mortality rate of 2.31 per 100 CY (95% confidence interval [CI], 1.75-2.78). The strongest factor associated with mortality was baseline WAZ score <-2 (adjusted hazard ratio [HR] = 9.1; 95% CI, 2.5-33.2), followed by World Health Organization stage III or IV disease (adjusted HR = 2.4; 95% CI, 1.1-5.2), and hemoglobin <90 g/L (adjusted HR = 2.2; 95% CI, 1.2-3.9). CD4%, hemoglobin level, WAZ score, and HAZ score increased over time.

Conclusions: Our finding that 94% of children engaged in this program are still alive and of improved health after 3 years of treatment demonstrates that China's national pediatric ART program is effective. This program needs to be expanded to better meet treatment demands, and efforts to identify HIV-positive children earlier must be prioritized.
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http://dx.doi.org/10.1093/cid/cis941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657487PMC
March 2013

Linezolid for treatment of chronic extensively drug-resistant tuberculosis.

N Engl J Med 2012 Oct;367(16):1508-18

International Tuberculosis Research Center, Changwon, South Korea.

Background: Linezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis.

Methods: We enrolled 41 patients who had sputum-culture-positive extensively drug-resistant (XDR) tuberculosis and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring.

Results: By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P=0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed.

Conclusions: Linezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.).
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http://dx.doi.org/10.1056/NEJMoa1201964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814175PMC
October 2012

Association between missed early visits and mortality among patients of china national free antiretroviral treatment cohort.

J Acquir Immune Defic Syndr 2012 May;60(1):59-67

Division of Treatment and Care, National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, PR China.

Background: China's National Free Antiretroviral Treatment program has scaled-up rapidly since 2002, leading to a significant reduction of mortality among its participants. However, few studies have evaluated indicators for patient access to medical care and their association with mortality.

Methods: Patients enrolled into this national program between June 2002 and June 2009 for at least 7.5 months were retrospectively analyzed.

Results: Twenty-seven thousand five hundred four patients were included into the analysis, among whom 10,034 (37%) had at least 1 missed visit during the first 6 months of treatment. In Cox proportional hazard regression analysis, controlled for baseline demographic and clinical factors, patients with more missed visits had a higher risk of mortality, with an adjusted hazard ratio of 1.3 (95% confidence interval: 1.1 to 1.5) for 1-2 missed visits and 1.7 (95% confidence interval 1.4 to 2.2) for ≥3 missed visits compared with patients with no missed visits. In multivariate logistic regression models, factors independently associated with a higher likelihood of early missed visits included female gender, age >60, HIV transmission via injection drug use or via plasma donation compared with sexual transmission, baseline alanine aminotransferase >100 IU/L, having more symptoms at antiretroviral therapy initiation and receiving a didanosine-based regimen compared with lamivudine-based regimen. Lower baseline CD4 count was protective against missed visits.

Conclusions: Missing early visits occurred in a sizable number of patients in this cohort and was associated with a higher mortality rate. Early missed visits may serve as an early warning indicator to trigger additional outreach effort.
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http://dx.doi.org/10.1097/QAI.0b013e31824c3d9fDOI Listing
May 2012

Pregnancy outcomes and risk factors for low birth weight and preterm delivery among HIV-infected pregnant women in Guangxi, China.

Chin Med J (Engl) 2012 Feb;125(3):403-9

National Center for AIDS/STD Control and Prevention, Chinese Centers for Disease Control and Prevention, Beijing 100050, China.

Background: Six provinces in China accounted for 70% - 80% of all reported HIV/AIDS cases in the country in 2009 and five provinces accounted for 78% of all reported mother-to-child transmission (MTCT) of HIV cases. Because Guangxi belonged to both groups, the Prevention of Mother-to-Child Transmission (PMTCT) Plus program was established there to understand better low birth weight (LBW) and preterm delivery (PD) birth outcomes and their associated risk factors better.

Methods: Pregnancy outcomes were examined among HIV-infected pregnant women who enrolled in the PMTCT Plus program from June 2006 to February 2009 in Guangxi, China. Multivariate Logistic regression analysis was used to explore the risk factors associated with LBW (< 2500 g) and PD (gestational age < 37 weeks).

Results: The prevalence of LBW and PD among 194 HIV-positive mothers was 19.6% (38/194) and 9.8% (19/194), respectively. Multivariate Logistic regression analysis showed that CD4 cell count < 100 cell/µl (multivariate-adjusted odds ratio (AOR) 5.52; 95%CI 1.11 - 25.55) and CD4 cell count 100 - 199 cells/µl (AOR 3.40; 95%CI 1.03 - 11.25, compared to CD4 cell count ≥ 350 cells/µl), gestational age < 37 weeks (AOR 4.38; 95%CI 1.29 - 14.82, compared to ≥ 37 weeks), maternal weight < 45 kg (AOR 5.64; 95%CI 1.09 - 29.07) and maternal weight 45 - 54 kg (AOR 3.55; 95%CI 1.31 - 9.60, compared to ≥ 55 kg) at enrollment, and HIV RNA ≥ 100 000 copies/ml at enrollment (AOR 4.22; 95%CI 1.24 - 14.32) and 20 000 - 99 999 (AOR 2.77; 95%CI 1.01 - 7.77, compared to < 20 000 copies/ml) were associated with a higher risk of LBW. For PD, only maternal injection drug use as the route of HIV transmission (AOR 5.30; 95%CI 1.33 - 21.14, compared to those infected with HIV through sexual transmission) was significantly associated with a higher risk of PD.

Conclusions: Lower CD4 cell count and higher HIV RNA viral load at enrollment were associated with LBW. Optimal antenatal care, including earlier antenatal screening and HIV diagnosis, is critical to earlier PMTCT prophylaxis and/or HIV treatment to prevent transmission of HIV to the infant and also to prevent LBW pregnancy outcomes.
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February 2012