Shujia Liang

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.

Prevalence of transmitted HIV-1 drug resistance remains low in Guangxi, China, eight years after scale-up of highly-active antiretroviral therapy.

Objectives: Highly-active antiretroviral therapy (HAART) was scaled up in Guangxi, China in 2005. The number of individuals receiving free HAART increased dramatically from June 2010 under the Guangxi Governments anti-HIV programme. We aimed to determine the prevalence of HIV-transmitted drug resistance (TDR) of Guangxi. Methods: HIV-positive, antiretroviral-naive individuals were recruited from the east (Hezhou), south (Qinzhou), west (Baise), north (Guilin) and centre (Laibin) of Guangxi. The pol gene of the virus from the individuals was analysed. Results: The overall prevalence of HIV TDR was 3.2% (7/216, 95% CI 0.9-5.5). The prevalence rates in Baise, Guilin, Hezhou, Qinzhou and Laibin are 4.9% (2/41, 95% CI -1.7 to 11.5), 2.3% (1/44, 95% CI -2.1 to 5.7), 4.7% (2/43, 95% CI -1.6 to 11.0), 2.6% (1/38, 95% CI -2.5 to 7.7) and 2.0% (1/50, 95% CI -1.9 to 5.9), respectively. No significant difference in the prevalence was found among them. No factors were found to be associated with TDR, including CD4 cell counts, viral loads and genotypes. The subtypes CRF01_AE, CRF07_BC, CRF08_BC and B were found. Subtype CRF08_BC is the predominant subtype in Baise while CRF01_AE is the predominant subtype elsewhere in Guangxi. Conclusions: The prevalence of TDR in antiretroviral-naive patients in Guangxi remains low 8 years after scale-up of HAART.

Genetic Characteristics of CRF01_AE Among Newly Diagnosed HIV-1-Infected 16- to 25-Year Olds in 3 Geographic Regions of Guangxi, China.

AbstractThe aim of this study was to analyze the distribution of clusters and drug resistance of CRF01_AE among newly diagnosed, treatment-naïve HIV-infected teenagers and young adults in 3 major HIV-affected geographic regions of Guangxi Province, including the cities of Hezhou, Liuzhou, and Nanning.Samples were sequentially collected from newly diagnosed HIV-infected 16- to 25-year olds in these 3 regions from 2009 to 2013. The viral genome was extracted, and the partial pol gene was amplified and sequenced. Phylogenetic analyses were used to determine HIV-1 subtypes and CRF01_AE clusters. Transmitted drug resistance (TDR) mutations were identified using the 2009 WHO list of TDR mutations.A total of 216 sequences were obtained from CRF01_AE strains, which accounted for 83.1% of the 260 genotyped samples, of which 36 were from Hezhou, 147 from Liuzhou, and 33 in Nanning. Most (83.3%, 180/216) were from heterosexuals, followed by injection drug users (5.6%), homosexuals (4.2%), and unknown risk group (6.9%). Based on phylogenetic analyses by the maximum likelihood method, 5 distinct clusters (cluster 1–5) were identified with 213 (98.6%) sequences, whereas 3 (1.4%) sequences were ungrouped. In Hezhou, 88.9% (32/36) of CRF01_AE infections were caused by cluster 2, and 11.1% (4/36) were caused by cluster 1. In Liuzhou, 83.0% (122/147) of the CRF01_AE strains were found in cluster 1, 11.6% (17/147) from cluster 2, 1.4% (2/147) from cluster 3, 2.7% (4/147) from cluster 4, and 0.7% (1/147) from cluster 5. The distribution of CRF01_AE clusters was more even in Nanning than it was in the other 2 regions, with 18.2% (6/33) from cluster 1, 36.3% (12/33) from cluster 2, 9.1% (3/33) from cluster 3, 18.2% (6/33) from cluster 4, and 12.1% (4/33) from cluster 5. The most frequent TDR mutations were M46I (2) in the protease region and Y181C (2) from the reverse transcriptase fragment.Clusters 1 and 2 of CRF01_AE strains were prevalent in Liuzhou and Hezhou, respectively. However, multiple CRF01_AE clusters existed in Nanning. This can be partially explained by the high mobility of laborers in Nanning, the capital city of Guangxi. The prevalence of TDR was low.

Low Virologic Failure and Drug Resistance among HIV-Infected Patients Receiving Hospital-Based ART While Care and Outreach through Community in Guangxi, China.

Objectives To investigate human immunodeficiency virus (HIV) virologic suppression and drug resistance among HIV-infected patients receiving first-line antiretroviral treatment (ART) in hospitals while community care and outreach through local health workers in Guangxi, China. Design This was a series of cross-sectional surveys from 2004 to 2012 in Guangxi, supported by the Chinese National HIVDR Surveillance and Monitoring Network Working Group. Settings Guangxi, China. Methods Demographic, ART, and laboratory data (CD4+ cell count, viral load, and drug resistance) were analyzed. Factors associated with virologic suppression were identified by logistic regression analysis. Results A total of 780 patients were included in this study. The median treatment duration was 20.6 months (IQR 6.6–35.9). Of 780 study participants, 95.4% of patients (744/780) had HIV virologic suppression. Among these, of the 143 patients who were infected through drug injection, only 10 (7.0%) experienced virologic failure, and the overall prevalence of HIV drug resistance was 2.8% (22/789). Factors associated with virologic suppression in the final multivariate models included self-reported missing doses in the past month (compared to not missing doses in the past month, AOR = 0.2, 95% CI: 0.1–0.6) and initial ART regimen without 3TC (compared to initial ART regimen with 3TC, AOR = 0.2, 95% CI: 0.1–0.4). Moreover, the trend chi-square test showed that the proportion of virologic suppression increased over time from 2004 to 2012 (P = 0.002). Conclusion This study first demonstrated that HIV patients infected through various transmission routes can achieve an excellent treatment outcome in hospitals at or above the county level for free first-line ART in Guangxi. It is an important of ART education and adherence to intervention for achieving better treatment outcomes.

Cross-neutralizing antibody profile of Chinese HIV-1-infected individuals and the viral envelope features from elite neutralizers.

Objective:Knowledge about the profile of neutralization responses and the viral envelope features of HIV-1-infected individuals in China may provide new insights for vaccine design against local viruses. Methods:Eight hundred sixty plasma samples from antiretroviral treatment-naive HIV-1-infected individuals in Xinjiang province (611) and Guangxi province (249), who had acquired infection over 3 years through intravenous drug use or sexual contact, were examined for their ability to neutralize diverse envelope-pseudoviruses of 5 subtypes. The sequence features of the envelopes from elite neutralizers were analyzed. Results:From Xinjiang and Guangxi, 29.1% and 5.2% of plasmas displayed intrasubtype cross neutralization against subtype B and subtype C, respectively. From Xinjiang, 10.6% of the plasmas displayed broad neutralization against the 3 subtypes, B, C, and CRF01_AE; whereas only 2.4% from Guangxi displayed broad neutralization. Envelopes from 6 elite neutralizers were obtained by single-genome amplification. The variations of their envelopes including the lengths, glycans, and net charges in V1, V2, and V4 regions were compared with those from CRF07_BC env sequences from the HIV Sequence Database. The Envs from 3 elite neutralizers displayed the sensitivities to the monoclonal broadly neutralizing antibodies such as PG9, PG16, and 4E10. Some unique characteristics of the envelope glycoproteins from the Chinese elite neutralizers were found. Conclusions:The neutralization profile of HIV-1-infected individuals in the 2 regions of China, where the HIV-1 subtypes are the representative in China, and the unique characteristics of the envelope glycoproteins from the Chinese elite neutralizers provide useful information for viral infection prevention and an insight for vaccine design against locally epidemic viruses.

Near Full-Length Genomic Characterization of a Novel HIV Type 1 CRF01_AE/CRF07_BC Recombinant Form Transmitted Between a Heterosexual Couple in Guangxi, China.

In this research, we reported a new second generation recombinant form (GXDY460B) between circulating recombinant form (CRF)01_AE and CRF07_BC in a seroconversion couple who obtained the virus from her husband by heterosexual behavior. The analysis result of the near full-length genomic characterization showed that the genome comprises at least 12 interlaced segments, including six CRF07_BC and six CRF01_AE segments, with CRF07_BC as the main framework. Cocirculation of multiple virus subtypes and multiple infection routes have existed for a long time in Guangxi, but the recombinant strain was rarely reported among heterosexual transmission population because of its lower crowd confounding degree than men who have sex with men and injecting drug user population. It is the first time that the unique recombinant form (URF) between CRF01_AE and CRF07_BC was identified among heterosexual transmission in Guangxi. The emergence of the novel recombinant helps to understand the pattern of the URF virus.

Early antiretroviral therapy on reducing HIV transmission in China: strengths, weaknesses and next focus of the program

Early antiretroviral therapy (ART) initiation is a recommended public health approach for the prevention of HIV-1 transmission. In this cohort study, we included 13132 serodiscordant couples. ART was initiated for patients with CD4+ T cell counts less than 200 cells/uL, 350 cells/uL, and 500 cells/uL respectively. This divided the ART treated couples into three groups. Univariate and multivariate intention-to-treat analyses were performed to examine the association between the study groups. Early-ART initiation was associated with a 45% lower risk of partner infection than was late-ART initiation (AHR 0.55, 95% CI, 0.37–0.81). Mid-ART initiation was associated with a 39% lower risk of partner infection than was late-ART initiation (AHR 0.61, 95% CI, 0.48–0.78). However, the risk reduction between the early and mid-ART groups was not significant. Drug compliance (AHR 1.55, 95% CI 1.03–2.35) and increased baseline viral load (AHR 1.41, 95% CI 1.33–1.51) were associated with an increased risk of infections among partners in the treatment. Prevention of HIV transmission as a result of early ART initiation was feasible on national and regional scales; however, many factors, such as the motivation to commence ART, adherence, and attrition, may affect the impact of this strategy in programmatic settings.

HIV-1 Transmissions Among Recently Infected Individuals in Southwest China are Predominantly Derived from Circulating Local Strains

Although the Guangxi region accounts for 10% of all HIV-1 cases new reported in 2011 in China, the sources of the transmitted HIV-1 strains are virtually unknown. To determine the extent to which recent HIV infections were derived from already circulating local strains as opposed to recently introduced strains, we performed a cross-sectional molecular epidemiological investigation of recent infections across Guangxi during 2012–2013. HIV-1 nucleotide sequences were amplified and sequenced. Phylogenetic analyses of pol gene regions were used to determine HIV-1 transmission source strains. Based on 229 sequences generated, the subtype/CRF distribution was as follows: CRF01_AE (61.1%), CRF07_BC (18.8%), CRF08_BC (16.6%), CRF55_01B (3.1%), and subtype B′ (0.4%). In total, 213 of 229 (93.0%) sequenced transmission strains were derived from already-circulating local strains. Multivariate logistic regression analysis showed that only an age of 18–25 years was significantly associated with transmission from outside Guangxi (compared to >25 years, AOR: 5.15, 95% CI: 1.18–22.48, p < 0.01). This is the first study to use a Bayesian discrete phylogeographic approach to analyze transmission source strains in China. Our results provide useful data for designing evidence-based prevention strategies and methods for combating the rapid spread of sexually transmitted HIV in Guangxi.

High Prevalence of HBV Lamivudine-Resistant Mutations in HBV/HIV Co-Infected Patients on Antiretroviral Therapy in the Area with the Highest Prevalence of HIV/HBV Co-Infection in China

Objectives: We aimed to determine the prevalence of hepatitis B virus (HBV) drug-resistant mutations in patients co- infected with HBV/human immunodeficiency virus (HIV), including both drug-naïve subjects and those who received antiretroviral therapy (ART) in Guangxi, where the prevalence of HIV/HBV co-infection is highest in China. Methods: Two hundred and three subjects co-infected with HBV/HIV were recruited, including 123 drug-naïve patients (group 1) and 80 who received ART (group 2). The polymerase gene of HBV in the serum of all study subjects was analysed. Results: The results showed that the prevalence of HBV drug-resistant mutations in group 2 (76.5%, 95% CI 56.3–96.7) was significantly higher than that in group 1 (1.4%, 95% CI –1.4 to 4.2; χ2 = 50.955, p < 0.05). The major pattern of lamivudine (3TC)-resistant mutations is L180M+M204I+L80I (35.7%). In total, 95% of subjects with resistant mutations had cross-resistance to telbivudine and entecavir. No putative tenofovir disoproxil fumarate (TDF) resistance change was found. Five subjects (6.5%) in group 2 had HBV viral loads over 10 × 106 copies/mL. Four of them had 3TC-resistant mutations. Multivariate analysis showed that ART was the only factor associated with the development of drug-resistant mutations. Conclusion: Treating HIV in HIV/HBV co-infection with antiretroviral agents may result in a very high prevalence of HBV 3TC-resistant mutations. TDF could not completely suppress HBV replication.

Phylodynamics of major CRF01_AE epidemic clusters circulating in mainland of China

As the most dominant HIV-1 strain in China, CRF01_AE needs to have its evolutionary and demographic history documented. In this study, we provide phylogenetic analysis of all CRF01_AE pol sequences identified in mainland China. CRF01_AE sequences were collected from the Los Alamos HIV Sequence Database and the local Chinese provincial centers of disease control and prevention. Phylogenetic trees were constructed to identify major epidemic clusters. Bayesian coalescent-based method was used to reconstruct the time scale and demographic history. There were 2965 CRF01_AE sequences from 24 Chinese provinces that were collected, and 5 major epidemic clusters containing 85% of the total CRF01_AE sequences were identified. Every cluster contains sequences from more than 10 provinces with 1 or 2 dominant transmission routes. One cluster arose in the 1990s and 4 clusters arose in the 2000s. Cluster I is in the decline stage, while the other clusters are in the stable stage. Obvious lineage can be observed among sequences from the same transmission route but not the same area. Two large clusters in high-level prevalence were found in MSM (Men who have sex with men), which highlighted that more emphasis should be placed on MSM for HIV control in mainland China.