Ray Y. Chen

Linezolid for Treatment of Chronic Extensively Drug-Resistant Tuberculosis

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.).

Five-Year Outcomes of the China National Free Antiretroviral Treatment Program

Context In 2002, China began the National Free Antiretroviral Treatment Program, which included more than 52000 persons by 2008. Contribution Among 48785 program participants over 5 years, mortality was highest in the 3 months after highly active antiretroviral therapy (HAART) initiation, decreased to 4 to 5 deaths per 100 person years by 6 months, and stayed stable through year 5. The cumulative rate of immunologic treatment failure, measured by CD4 cell count, was 50% by year 5. Implication The program to implement HAART for HIV infection in 1 developing country was associated with a reduction in mortality, but immunologic failure was common in the setting of a limited range of HAART regimens. The Editors In China, an estimated 700000 persons are infected with HIV, of whom approximately 85000 have developed AIDS (1). Of these, a cumulative 223501 and 62838 persons, respectively, had been identified as of October 2007 (2). Before 2002, when China initiated its National Free Antiretroviral Treatment Program as a pilot project among former plasma donors (3, 4), antiretroviral therapy (ART) was not readily available. Treatment was rapidly scaled up, and by August 2008, more than 52000 persons had received first-line highly active antiretroviral therapy (HAART). A few nongovernmental organizations also provide treatment in Chinaand some patients self-paybut an estimated 97% of patients in China receive free treatment through the national program. Currently, all HIV-infected individuals who meet the national treatment criteria are eligible for treatment, and patients have been treated in all 31 provinces, autonomous regions, and municipalities in China. Multiple studies (510) have demonstrated the feasibility of implementing HAART in developing countries, with 1-year outcomes often similar to those in developed countries. Longer-term data on the sustainability of such outcomes have also been reported (1122), but these studies have had either relatively small sample sizes or only slightly longer treatment durations. We report the 5-year outcomes on mortality, immunologic treatment failure rates, and risk factors of all previously treatment-naive adult patients enrolled in the China National Free Antiretroviral Treatment Program. Methods Study Design and Setting The National Free Antiretroviral Treatment Program and its observational database have been previously described (3, 4, 23, 24). Briefly, all HIV-positive patients in China who meet the national treatment guidelines of a CD4 cell count less than 0.200109 cells/L, total lymphocyte count less than 1.2109 cells/L, or World Health Organization (WHO) stage 3 or 4 disease are eligible to receive HAART (25). The first-line treatment regimen consists of zidovudine or stavudine with nevirapine, all generically produced in China. Didanosine (generic) was used as the third drug until 2005, when lamivudine (branded) became available. After treatment initiation, visits are scheduled at 2 weeks, 1 month, 2 months, 3 months, and then every 3 months thereafter. Local health care providers from the program complete visit-specific forms at each visit. Patient Selection All patients who were in the database from June 2002 through 30 August 2008 were eligible. We excluded patients if they did not receive treatment through the national program, were not previously naive to ART, were younger than 18 years at treatment initiation, had not initially received appropriate triple therapy, or had missing treatment dates. We considered 35 CD4 cell counts greater than 3.000109 cells/L to be inaccurate and excluded them as well. We considered patients without a treatment termination date to be active if their most recent follow-up visit was within 6 months of 30 August 2008 and late if it was not. Because Henan province did not participate in the national treatment database until July 2006, we instead collected baseline CD4 cell counts for patients from Henan before July 2006 from the national HIV epidemiology database, which is independently maintained at the Chinese Center for Disease Control and Prevention (China CDC). Variables and Data Collection Case report forms from each visit were forwarded to the China CDC through DataFax (Clinical DataFax Systems, Hamilton, Ontario, Canada). Data collected included demographic characteristics, current symptoms, laboratory results, treatment regimen start and stop dates and the reason for change, and reasons for treatment termination (25). Two reviewers manually compared each data field of each form with the faxed digital image to ensure accurate electronic transcription of data. We sent quality control queries to each site to resolve missing or discrepant data. We considered patients with a prefectural or city-level address to be urban and those with a district, county, or lower-level address to be rural. We calculated survival from the date of ART initiation until death or the date of the last follow-up. For the analysis of immunologic treatment failure and CD4 cell count response, we included only patients with 1 or more follow-up CD4 cell count. We defined immunologic treatment failure by using WHO criteria: CD4 cell count less than 0.100109 cells/L after receiving treatment for 6 months, CD4 cell count at or less than pretreatment level after receiving treatment for 6 months, or CD4 cell count less than 50% of peak on-treatment level (26). We considered treatment to have failed for any patients who met any of these criteria. We defined time to failure as treatment initiation date to the first CD4 cell count date when the patient met 1 of the 3 criteria. We censored data for other patients on the date of their last follow-up visit. We also performed a sensitivity analysis, for which we used 1 year as the treatment failure cut-point instead of 6 months. For the analysis of CD4 cell count response, we used a 3-month window around each time point (6 weeks before and after) to define the CD4 cell count for that interval. We included the initial 6 weeks after treatment within the 3-month time point. If more than 1 CD4 cell count was done during any interval, we used the one closest to each 3-month time point. We defined the last pretreatment CD4 cell count as the baseline. Because of the difficulty in definitively diagnosing opportunistic infections in rural settings, we used easily identified signs and symptoms as a proxy. These were collected as part of a general review of systems and a physical examination during the baseline patient visit and were categorized as fever, pulmonary (cough, dyspnea, chest pain, night sweats, or lymphadenopathy), gastrointestinal (nausea, vomiting, or diarrhea), skin or mucosal (rash, thrush, or oral hairy leukoplakia), or central nervous system (headache or visual changes). Statistical Analysis We compared baseline characteristics between cohorts by using the MannWhitney test for continuous variables, because none fulfilled the KolmogorovSmirnov test for normality. We used the Pearson chi-square statistic for dichotomous and categorical variables. We used Cox proportional hazards modeling to assess hazard ratios (HRs) between the outcome (mortality or treatment failure) and potential risk factors. We entered covariates that we predetermined to be clinically significant into full multivariate Cox models. We calculated survival curves by using life tables and assessed statistical significance between groups by using the log-rank test because the assumption of proportionality was fulfilled. We modeled CD4 cell counts over time by using the mixed linear model with maximum likelihood estimation. We used SPSS, version 13.0 (SPSS, Chicago, Illinois), and SAS, version 9.13 (SAS Institute, Cary, North Carolina), for all analyses. All hypothesis testing was 2-sided, with an level of 0.05. The institutional review board of the China CDC approved this analysis. Role of the Funding Source This study was funded by the applied research program on AIDS prevention and treatment of the China Ministry of Health, the U.S. National Institutes of Health, and a cooperative agreement from the U.S. Centers for Disease Control and Prevention Global AIDS Program to the China CDC. The U.S. sponsors were involved in the study design, data analysis and interpretation, writing of the manuscript, and decision to submit the paper for publication. Results Of 52191 patients with AIDS in the National Free Antiretroviral Treatment Program database through 30 August 2008, 3406 were excluded (Figure 1). Of the 48785 patients we included, 70% were active, 10% were late, and 13% died (90% of these deaths were AIDS related). Seven percent terminated treatment because of medication adverse effects (46%), patient request (35%), poor adherence (9%), or other (10%). Forty-seven percent of included patients were from Henan province; 15% from Yunnan; 11% from Guangxi; 5% from Anhui; and 3% each from Xinjiang, Hubei, and Guangdong, with the remaining 13% distributed among the other 24 provinces, autonomous regions, and municipalities. Median follow-up time was 17 months (interquartile range [IQR], 5 to 37), with a median of 7 follow-up visits (IQR, 4 to 9). Median age was 38 years, 58% were men, 75% were married, and 53% were infected through plasma or blood (Table 1). We classified 82% as rural, with 91% of plasma donors and 72% of those infected through other routes as rural (P for difference< 0.001). Baseline median CD4 cell count was 0.118109 cells/L (among those with a baseline CD4 cell count), and 81% of patients had at least 1 baseline symptom category. Treatment regimens consisted of zidovudine or stavudine and nevirapine as 2 of the 3 drugs, with similar rates of zidovudine and stavudine use. Didanosine was the third drug for 46% of patients and lamivudine for 43%. These 4 regimens made up 89% of all initial regimens. Patients who received a diagnosis of HIVtuberculosis co-infection (9%) received efavirenz instead of nevirapine. Figure 1. Study flow d

Distribution of Health Care Expenditures for HIV-Infected Patients

BACKGROUND Health care expenditures for persons infected with human immunodeficiency virus (HIV) in the United State determined on the basis of actual health care use have not been reported in the era of highly active antiretroviral therapy. METHODS Patients receiving primary care at the University of Alabama at Birmingham HIV clinic were included in the study. All encounters (except emergency room visits) that occurred within the University of Alabama at Birmingham Hospital System from 1 March 2000 to 1 March 2001 were analyzed. Medication expenditures were determined on the basis of 2001 average wholesale price. Hospitalization expenditures were determined on the basis of 2001 Medicare diagnostic related group reimbursement rates. Clinic expenditures were determined on the basis of 2001 Medicare current procedural terminology reimbursement rates. RESULTS Among the 635 patients, total annual expenditures for patients with CD4+ cell counts <50 cells/microL (36,533 dollars per patient) were 2.6-times greater than total annual expenditures for patients with CD4+ cell counts > or =350 cells/microL (13,885 dollars per patient), primarily because of increased expenditures for nonantiretroviral medication and hospitalization. Expenditures for highly active antiretroviral therapy were relatively constant at approximately 10,500 dollars per patient per year across CD4+ cell count strata. Outpatient expenditures were 1558 dollars per patient per year; however, the clinic and physician component of these expenditures represented only 359 dollars per patient per year, or 2% of annual expenses. Health care expenditures for patients with HIV infection increased substantially for those with more-advanced disease and were driven predominantly by medication costs (which accounted for 71%-84% of annual expenses). CONCLUSIONS Physician reimbursements, even with 100% billing and collections, are inadequate to support the activities of most clinics providing HIV care. These findings have important implications for the continued support of HIV treatment programs in the United States.

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

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 Governments 12th Five-Year Plan, the National Natural Science Foundation of China, and the Canadian International Development Research Centre.

Trends in AIDS-Defining and Non—AIDS-Defining Malignancies among HIV-Infected Patients: 1989–2002

In a comparison of rates of acquired immunodeficiency syndrome (AIDS)-defining malignancies (ADMs) for 1989-1996 versus 1997-2002, we found a decrease in ADMs (rate ratio, 0.31; P<.0001) and a significant increase in non-AIDS-defining malignancies (non-ADMs; rate ratio, 10.87; P<.0002). The mean CD4 cell count was lower among patients with ADMs than among those with non-ADMs. A longer duration of survival during highly active antiretroviral therapy might explain the increasing incidence of non-ADMs.

Prevalence and predictors of HIV infection among female sex workers in Kaiyuan City, Yunnan Province, China

BACKGROUND Sexual transmission is the fastest growing route of HIV transmission in China. We undertook this study to describe the risk factors for HIV infection in female sex workers (FSWs), and to determine the commercial sex venues where FSWs are most at risk of being infected with or infecting others with HIV. METHODS This was a cross-sectional study of 737 FSWs in Kaiyuan City, Yunnan Province in southern China, which took place from March to May 2006. RESULTS The overall HIV prevalence was 10.3%, but prevalence varied with sex venue with 25.8% of FSWs working on the streets being HIV-positive and none of the FSWs working in nightclubs. Adjusted odds ratios (OR) of HIV infection were 9.1 (95% confidence interval (CI) 4.67-17.55) for injection drug use, 3.3 (95% CI 1.46-7.37) for non-injection illegal drug use, 2.7 (95% CI 1.25-5.93) for duration of sex work > or = 5 years, 2.2 (95% CI 1.05-4.70) for infection with herpes simplex virus type 2, and 2.0 (95% CI 1.12-3.47) for working at a higher risk entertainment venue. Although condom use was not a significant risk factor in the overall model, FSWs in lower risk venues who reported consistent use with clients had a 70% reduction in HIV infections (OR 0.30, 95% CI 0.12-0.90). CONCLUSIONS Illegal drug use, particularly with injection drugs, is the single greatest risk factor for HIV infection among FSWs in Kaiyuan City, China. FSWs working on the street or in temporary sub-lets, beauty salons, or saunas are at particularly high risk for transmitting and being infected with HIV. HIV prevention efforts among FSWs should target illegal drug users and these other subgroups.

Risk Factors for Human Illness with Avian Influenza A (H5N1) Virus Infection in China

BACKGROUND In China, 30 human cases of avian influenza A (H5N1) virus infection were identified through July 2008. We conducted a retrospective case-control study to identify risk factors for influenza H5N1 disease in China. METHODS A questionnaire about potential influenza H5N1 exposures was administered to 28 patients with influenza H5N1 and to 134 randomly selected control subjects matched by age, sex, and location or to proxies. Conditional logistic regression analyses were performed. RESULTS Before their illness, patients living in urban areas had visited wet poultry markets, and patients living in rural areas had exposure to sick or dead backyard poultry. In multivariable analyses, independent risk factors for influenza H5N1 were direct contact with sick or dead poultry (odds ratio [OR], 506.6 [95% confidence interval {CI}, 15.7-16319.6]; P<.001), indirect exposure to sick or dead poultry (OR, 56.9 [95% CI, 4.3-745.6]; P=.002), and visiting a wet poultry market (OR, 15.4 [95% CI, 3.0-80.2]; P=.001). CONCLUSIONS To prevent human influenza H5N1 in China, the level of education about avoiding direct or close exposures to sick or dead poultry should be increased, and interventions to prevent the spread of influenza H5N1 at live poultry markets should be implemented.

Duration of Highly Active Antiretroviral Therapy Regimens

The median duration of highly active antiretroviral therapy (HAART) regimens was reported to be 11.8 months in one US study, but that study included both treatment-experienced and treatment-naive patients. The duration of initial HAART regimens for treatment-naive patients alone has not been reported. We selected 405 antiretroviral-naive patients who were seen at the University of Alabama at Birmingham HIV Outpatient Clinic from 1 January 1996 through 9 October 2001, and we assessed the duration of initial and successive HAART regimens in this group. Any antiretroviral medication change, excluding dosage changes, that lasted >or=14 days was considered to indicate the start of a new regimen. The median duration of regimens was determined by Kaplan-Meier analysis, and proportional hazards regression was used to identify factors associated with shorter duration of initial regimen. The median duration of initial regimens was 1.6 years, and medication toxicity-associated events were the cause of one-half of discontinuations. Only a history of opportunistic infection and injection drug use were significantly associated with shorter regimen duration.

The Effect of Highly Active Antiretroviral Therapy on Mortality among HIV-Infected Former Plasma Donors in China

BACKGROUND In China, many former plasma donors were infected with the human immunodeficiency virus (HIV) in the early-mid-1990s. Highly active antiretroviral therapy (HAART) was provided for former plasma donors beginning in 2002. The effect of HAART on mortality in this cohort has not been described. METHODS This study is a retrospective analysis of the national HIV epidemiology and treatment databases for the period 1993-2006. All HIV-infected subjects from 10 counties with a high prevalence of HIV infection in 6 provinces were eligible. Inclusion criteria were: (1) history of plasma donation, (2) positive Western blot result, (3) clinical diagnosis of AIDS or CD4(+) cell count <200 cells/microL at any time, and (4) age >or=18 years at AIDS diagnosis. RESULTS Of 9059 eligible subjects, 4093 met the inclusion criteria. Mean age was 41 years, 51% were male, 99% were farmers, and 87% were from Henan Province. Overall mortality decreased from 27.3 deaths per 100 person-years in 2001 to 4.6 deaths per 100 person-years in 2006. Conversely, the percentage of patient-years receiving HAART increased from 0% in 2001 to 70.5% in 2006. In a multivariate Cox proportional hazards analysis, not receiving HAART was the greatest risk factor for mortality (hazard ratio, 2.8; 95% confidence interval, 2.4-3.3). Among treated patients, those who had lower CD4(+) cell counts and higher numbers of opportunistic infections at the initiation of therapy were at greater risk of death. CONCLUSIONS The national treatment program has significantly reduced the mortality rate among HIV-infected former plasma donors through the use of generic drugs in a rural treatment setting with limited laboratory monitoring. Treatment success can be improved through increased coverage and earlier initiation of therapy.

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

PET/CT imaging in humans with TB correlates with drug response and final treatment outcomes. Visualizing Drug Responses in TB A pair of papers by Chen et al. and Coleman et al. investigate how changes in quantitative positron emission tomography/computed tomography (PET/CT) scans in both nonhuman primates and humans can be used as early surrogate markers of treatment efficacy in tuberculosis. The Coleman et al. study shows that treatment of Mtb-infected macaques with linezolid and the second-generation oxazolidinone AZD5847 resulted in a reduced bacterial load at necropsy and reduced FDG PET avidity and CT-quantified lung pathology. Similar PET/CT changes were seen in human patients infected with extensively drug-resistant Mtb and treated with linezolid. The companion study by Chen et al. corroborated this effect in a prospective analysis of patients with multidrug-resistant tuberculosis and demonstrated that early PET/CT changes predicted final treatment outcomes. 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-[18F]-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.