Jenny H. Hsi

Incidence and associated factors of HIV drug resistance in Chinese HIV-infected patients receiving antiretroviral treatment.

Background A critical indicator of the future success of highly active antiretroviral therapy (HAART) is the incidence of HIV drug resistance, which has not been studied in China on the national scale. Methods HIV drug resistance baseline survey was conducted in the eight provinces with the largest numbers of patients on HAART in 2009, and a prospective cohort study with 12-month follow-up was completed in 2010. Patients completed an interviewer-administrated questionnaire and provided blood for CD4+ T-lymphocyte count (CD4 count), HIV viral load (VL), and HIV drug resistance genotyping. Factors associated with incidence of HIVDR were identified by Cox regression analysis. Results The overall prevalence of HIV RNA ≥1000 copies/ml and HIVDR at baseline was 12.4% and 5.6%, respectively. Incidence of HIVDR in the one year follow-up was 3.5 per 100 person years. Independently associated factors were started treatment with a didanosine-based regimen, received care at township hospital or village clinic, low baseline CD4 counts, and high baseline VL. Conclusions The incidence of HIVDR in China was higher than that of some developed countries. China urgently needs to provide comprehensive education and training to doctors at village clinics and township hospitals to improve quality community-based care and treatment.

HIV virological failure and drug resistance among injecting drug users receiving first-line ART in China

Objective To explore HIV virological failure and drug resistance among injecting drug users (IDUs) receiving first-line antiretroviral treatment (ART) in China. Design A series of cross-sectional surveys from 2003 to 2012 from the Chinese National HIV Drug Resistance (HIVDR) Surveillance and Monitoring Network. Setting China. Participants Data were analysed by the Chinese National (HIVDR) Surveillance and Monitoring Network from 2003 to 2012. Demographic, ART and laboratory data (CD4+ cell count, viral load and drug resistance) were included. Factors associated with virological failure were identified by logistic regression analysis. Results 929 of the 8556 individuals in the Chinese HIVDR database were IDUs receiving first-line ART. For these 929 IDUs, the median duration of treatment was 14 months (IQR 6.0–17.8). 193 of the 929 IDUs (20.8%) experienced virological failure (HIV viral load ≥1000 copies/mL). The prevalence of HIVDR among patients with virological failure was 38.9% (68/175). The proportion of patients with drug resistance to non-nucleoside reverse transcriptase inhibitor (NNRTIs), nucleoside reverse transcriptase inhibitor (NRTIs) and protease inhibitors (PIs) was 52.9%, 76.5% and 4.4%, respectively. Factors independently associated with virological failure include: ethnic minorities, junior high school education or less, farmers, self-reported missing doses in the past month, CD4 cell count at survey from 200 to 349 cells/mm3 or from 0 to 199 cells/mm3, and residence of Guangxi and Yunnan provinces. Conclusions The proportion of virological failure was high among IDUs receiving first-line ART in China. However, better treatment outcomes were observed in Guangxi and Yunnan, which indicates the importance of ART education and adherence to intervention, especially for patients who are farmers, minorities or have a poor educational background.

High-Accuracy Identification of Incident HIV-1 Infections Using a Sequence Clustering Based Diversity Measure

Accurate estimates of HIV-1 incidence are essential for monitoring epidemic trends and evaluating intervention efforts. However, the long asymptomatic stage of HIV-1 infection makes it difficult to effectively distinguish incident infections from chronic ones. Current incidence assays based on serology or viral sequence diversity are both still lacking in accuracy. In the present work, a sequence clustering based diversity (SCBD) assay was devised by utilizing the fact that viral sequences derived from each transmitted/founder (T/F) strain tend to cluster together at early stage, and that only the intra-cluster diversity is correlated with the time since HIV-1 infection. The dot-matrix pairwise alignment was used to eliminate the disproportional impact of insertion/deletions (indels) and recombination events, and so was the proportion of clusterable sequences (Pc) as an index to identify late chronic infections with declined viral genetic diversity. Tested on a dataset containing 398 incident and 163 chronic infection cases collected from the Los Alamos HIV database (last modified 2/8/2012), our SCBD method achieved 99.5% sensitivity and 98.8% specificity, with an overall accuracy of 99.3%. Further analysis and evaluation also suggested its performance was not affected by host factors such as the viral subtypes and transmission routes. The SCBD method demonstrated the potential of sequencing based techniques to become useful for identifying incident infections. Its use may be most advantageous for settings with low to moderate incidence relative to available resources. The online service is available at http://www.bioinfo.tsinghua.edu.cn:8080/SCBD/index.jsp.

Reductions in virological failure and drug resistance in Chinese antiretroviral-treated patients due to lamivudine-based regimens, 2003–12

BACKGROUND Chinas National Free Antiretroviral Treatment Program (NFATP) has significantly scaled up and standardized treatment since 2008. Meanwhile, no study worldwide has examined on a large scale the effects of rapid ART programme scale-up on treatment outcomes in resource-limited settings. METHODS We used Chinas national HIV drug resistance (HIVDR) surveillance database to determine virological failure, acquired drug resistance and poor adherence rates after 12-15 months of first-line ART. A total of 2252 patients were examined, with 1431 patients having initiated ART before 2008 and 821 since 2008. FINDINGS Since 2008, virological failure at 12-15 months of treatment improved from 26.6% to 12.1%, and HIVDR rates also significantly decreased from 15.4% to 5.4%. However, these successes are strongly associated with the standardized use of lamivudine-based regimens in place of didanosine-based regimens. Patients who initiated lamivudine-based regimens before 2008 showed significant improvement in adherence [missed doses adjusted OR (AOR), 0.65; 95% CI, 0.45-0.96], virological failure (AOR, 0.29; 95% CI, 0.22-0.39) and HIVDR outcomes (AOR, 0.29; 95% CI, 0.20-0.42) compared with those who initiated didanosine-based regimens. Meanwhile, among only patients on lamivudine-based regimens, no significant changes were observed between those who initiated before 2008 and those who initiated since 2008. CONCLUSIONS Chinas NFATP has been largely successful throughout the scale-up, with an overall reduction in virological failure and HIVDR. However, excluding the effect of lamivudine-based regimens, it remains crucial for the programme to improve patient adherence and quality of care, particularly in key vulnerable populations such as those infected through injecting drug or blood routes.

Lamivudine Concentration in Hair and Prediction of Virologic Failure and Drug Resistance among HIV Patients Receiving Free ART in China

Background The assessment of adherence to antiretroviral therapy (ART) is important in order to predict treatment outcomes. Lamivudine (3TC) is one of the most widely used NRTIs in China, but its concentrations in hair and association with virologic failure and drug resistance have not been studied. Methods We conducted a cross-sectional survey to investigate 3TC concentrations in hair as a predictor of virologic failure and drug resistance among HIV patients receiving free ART. We also compared the capacity of hair 3TC concentrations with self-reported adherence in predicting virologic responses. Hair 3TC concentrations were detected through the LC-MS/MS system. Results In patients without HIV drug resistance (HIVDR), with a threshold hair 3TC concentration of 260 ng/g, the sensitivity and specificity in predicting virologic suppression were 76.9% and 89.9%, respectively. Some factors, including CD4+ cell counts, initial treatment regimens with 3TC, and current regimens with second-line drugs, influenced the association between hair 3TC concentrations and virologic suppression. In patients who experienced virologic failure with HIVDR, with a threshold of 180 ng/g, the sensitivity and specificity were 70.0% and 74.4%, respectively. Hair 3TC concentrations had higher sensitivity and specificity in predicting virologic failure and drug resistance than self-reported adherence. Conclusions The hair 3TC concentration was a stronger indicator than self-reported adherence in predicting virologic failure and drug resistance in HIV patients receiving free ART.

Cholera toxin B subunit acts as a potent systemic adjuvant for HIV-1 DNA vaccination intramuscularly in mice

Cholera toxin B subunit (CTB) was investigated as a classical mucosal adjuvant that can increase vaccine immunogenicity. In this study, we found out the in vitro efficacy of cholera toxin B subunit (CTB) in activating mice bone marrow-derived dendritic cells (BMDCs) through Toll-like receptor signaling pathways. In vitro RNA and transcriptional level profiling arrays revealed that CTB guides high levels of Th1 and Th2 type cytokines, inflammatory cytokines, and chemokines. Based on the robustness of these profiling results, we examined the induction of HIV Env-specific immunity by CTB co-inoculated with HIV Env DNA vaccine intramuscularly in vivo. CTB enhanced HIV-Env specific cellular immune responses in Env-specific IFN-γ ELISPOT, compared with DNA vaccine alone. Moreover, CTB induced high levels of Env specific humoral response and promoted antibody maturation after the third round of vaccination. This combination immunization strategy induced a Th2-type bias response which is indicative of a high ratio of IgG1/IgG2a. This study reports that CTB as a classical mucosal adjuvant could enhance HIV-1 DNA-based vaccine immunogenicity intramuscularly; therefore, these findings suggest that CTB could serve as an effective candidate adjuvant for DNA vaccination.

Comparison of Three Intervention Models for Promoting Circumcision among Migrant Workers in Western China to Reduce Local Sexual Transmission of HIV

Objective Three models for promoting male circumcision (MC) as a preventative intervention against HIV infection were compared among migrant worker populations in western China. Methods A cohort study was performed after an initial cross-sectional survey among migrant workers in three provincial level districts with high HIV prevalence in western China. A total of 1,670 HIV seronegative male migrants were cluster-randomized into three intervention models, in which the dissemination of promotional materials and expert- and volunteer-led discussions are conducted in one, two, and three stage interventions. Changes in knowledge of MC, acceptability of MC, MC surgery uptake, and the costs of implementation were analyzed at 6-month and 9-month follow-up visits. Results All three models significantly increased the participants’ knowledge about MC. The three-stage model significantly increased the acceptability of MC among participants and led to greatest increase in MC uptake. At the end of follow-up, 9.2% (153/1,670) of participants underwent MC surgery; uptake among the one-, two-, and three-stage models were 4.9%, 9.3%, and 14.6%, respectively. Multivariable Cox regression analysis showed that three-stage model was the most effective method to scale up MC, with RR = 2.0 (95% CI, 1.3-3.1, P=0.002) compared to the on-site session model. The two-stage intervention model showed no significant difference with either the on-site session model (RR=1.5, 95% CI, 0.92-2.4, P=0.12) or three-stage model (P=0.10). Conclusions A three-stage intervention with gradual introduction of knowledge led to the significantly increase in MC uptake among migrant workers in western China, and was also the most cost-effective method among the three models.

HIV-infected Female Sex Workers High Risk Behavior and Attitude Changes in Kaiyuan City, Yunnan Province, China

OBJECTIVE To investigate the attitude and sexual behavior status and change among HIV positive female workers in entertainment sites in Kaiyuan city, Yunnan province, China. The key information should be applied in the integrated intervention program in future. METHODS A cohort survey among HIV positive female workers was conducted during 12 months, between 2010 and 2012. All the risk sexual behavior and attitude were collected for assessment for the potential secondary transmission to sexual partners. RESULTS Of 99 HIV positive women who sell sex in Kaiyuan city, 99 participated in the survey at baseline, 80, 80, 75, and 75 at 3-, 6-, 9-, and 12-month follow-ups. The percentage of participants who reported consistently used condoms in the last one month ranged between 94.5% and 95.5%. The client volume in the last one month, income per sex and age group were significant related with non-insistent condom use with their clients. CONCLUSION It was suggested that integrated intervention program package should include 100 percent condom use promotion for the HIV positive FSW with all sexual partners, and also, include socially support involved.

Reductions in virological failure and drug resistance to antiretroviral therapy in Chinese patients associated with lamivudine-based regimens, 2003–12: a cross-sectional study

Abstract Background Chinas National Free Antiretroviral Treatment Program has substantially scaled up and standardised antiretroviral treatment (ART) since 2008. Meanwhile, no study worldwide has examined the effects of rapid ART programme scale-up on treatment outcomes in resource-limited settings on a large scale. Methods The national HIV drug resistance surveillance database included annual cross-sectional surveys HIV drug resistance from 2003–12. We used Chinas national HIV drug resistance surveillance database to determine virological failure, acquired drug resistance, and poor adherence after 12–15 months of first-line ART. The probability proportional to proxy size (PPPS) sampling recommended by WHO was used in this study. χ tests and logistic regression were used for categorical variables. The institutional review board of the National Center on HIV/STD Control and Prevention (NCAIDS), China CDC, approved this study. Findings Of the 2252 patients included in this study, 1180 (52%) were aged less than 40 years; 2100 (93%) belonged to the Han ethnic group; 1331 (59%) were male; 963 (43%) had primary school (1–6 years of education) or less; 1665 (74%) were married; 968 (43%) were farmers; 929 (41%), 947 (42%), and 322 (14%) were infected through blood or plasma transmission, sexual intercourse, and intravenous drug use, respectively. 1431 (64%) patients had initiated ART before 2008, and 821 (36%) initiated ART after 2008. The incidence of virological failure after 12–15 months of treatment was lower in the group of patients who had initiated ART after 2008 than in the group of patients who initiated ART before 2008 (12·1% vs 26·6%). The incidence of HIV drug resistance to ART was also significantly reduced in patients who initiated ART after 2008 compared to patients who intiated treatment before 2008 (5·4% vs 15·4%). However, these improvements are strongly associated with the standardised use of lamivudine-based regimens instead of didanosine-based regimens. Patients who initiated lamivudine-based regimens before 2008 had significant improvement in adherence (missed doses adjusted odds ratio [AOR] 0·65, 95% CI 0·45–0·96), virological failure (AOR 0·29 95% CI 0·22–0·39), and drug resistance outcomes (AOR 0·29 95% CI 0·20–0·42) compared with those who initiated didanosine-based regimens. We found no significant changes in these outcomes between patients who initiated lamivudine-based regimens before 2008 and those who initiated this treatment after 2008. Interpretation Chinas National Free Antiretroviral Treatment Program has been largely successful throughout the scale-up, with an overall reduction in virological failure and HIV drug resistance. However, excluding the effect of lamivudine-based regimens, the programme must improve patient adherence and quality of care, particularly in key vulnerable populations such as those infected through injecting drug use or blood routes. Further monitoring of treatment outcomes is needed to elucidate the determinants of long-term programmatic success. This is the first large scale study in the world evaluating the outcomes of ART treatment during a rapid programmatic scale-up. Funding Ministry of Science and Technology of China (grants 2012ZX10001-002 and 2009DFB30420), Chinese State Key Laboratory for Infectious Disease (development grant 2012SKLID103), and International Development Research Center of Canada (grant 104519-010). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.