Association of low-level viremia with mortality among people living with HIV on antiretroviral therapy in Dehong, Southwest China: A retrospective cohort study.

OBJECTIVES: To investigate the association of low-level viremia (LLV) with mortality among people living with HIV (PLHIV) on antiretroviral therapy (ART) in Dehong, Southwest China. METHODS: We analysed data collected from a cohort of PLHIV on ART in Dehong. PLHIV were enrolled in this cohort after they started ART, with viral load (VL) tested once a year afterwards. Each VL level was then categorized into one of the four groups: <50, 50-199, 200-999 and ≥1000 copies/ml. VL levels of 50-199 and 200-999 copies/ml were defined as LLV. The VL level for each participant was re-categorized and fitted into an extended Cox regression model as a time-varying covariate to examine the associations of VL level with all-cause and AIDS-related deaths. RESULTS: Among the included 7273 of 8762 PLHIV in this study, median age (interquartile range, IQR) was 36 (30-43) years and 59.9% were male. The patients were followed up for a median duration (IQR) of 6.2 (4.3-8.2) years. Compared with VL <50 copies/ml, LLV 200-999 copies/ml (adjusted hazard ratio [aHR] and 95% confidence interval [95% CI]: 1.56 [1.04, 2.32]) were associated with elevated risk of all-cause mortality and LLV50-199 (aHR [95% CI]: 1.00 [0.68, 1.45]) were not. Similarly, only LLV200-999 copies/ml (aHR [95% CI]: 2.37 [1.36, 4.14]) corresponded to higher risk of AIDS-related mortality. CONCLUSIONS: This study suggests that PLHIV on ART may have elevated death risks even though the viremia is suppressed at a low level. Interventions targeting PLHIV with LLV should be developed to reduce their mortality.

Genetic diversity and drug resistance among newly diagnosed and antiretroviral treatment-naive HIV-infected individuals in western Yunnan: a hot area of viral recombination in China.

BACKGROUND: The emergence of an HIV-1 epidemic in China was first recognized in Dehong, western Yunnan. Due to its geographic location, Dehong contributed greatly in bridging HIV-1 epidemics in Southeast Asia and China through drug trafficking and injection drug use; and also extensively to the HIV genetic diversity in Yunnan and China. We attempt to monitor HIV-1 in this area by studying the HIV-1 genetic distribution and transmitted drug resistance (TDR) in various at-risk populations. METHODS: Blood samples from a total of 320 newly HIV-1 diagnosed individuals, who were antiretroviral therapy (ART)-naive, were collected from January 2009 to December 2010 in 2 counties in Dehong. HIV-1 subtypes and pol gene drug resistance (DR) mutations were genotyped. RESULTS: Among 299 pol sequences successfully genotyped (93.4%), subtype C accounted for 43.1% (n=129), unique recombinant forms (URFs) for 18.4% (n=55), CRF01_AE for 17.7% (n=54), B for 10.7% (n=32), CRF08_BC for 8.4% (n=25) and CRF07_BC for 1.7% (n=5). Subtype distribution in patients infected by different transmission routes varied. In contract to the previous finding of CRF01_AE predominance in 2002-2006, subtype C predominated in both injecting drug users (IDUs) and heterosexually transmitted populations in this study. Furthermore, we found a high level of BC, CRF01_AE/C and CRF01_AE/B/C recombinants suggesting the presence of active viral recombination in the area. TDR associated mutations were identified in 4.3% (n=13) individuals. A total of 1.3% of DR were related to protease inhibitors (PIs), including I85IV, M46I and L90M; 0.3% to nucleoside reverse transcriptase inhibitors (NRTIs), including M184I; and 2.7% to non-nucleoside reverse transcriptase inhibitors (NNRTIs), including K103N/S, Y181C, K101E and G190A. CONCLUSION: Our work revealed diverse HIV-1 subtype distributions and intersubtype recombinations. We also identified a low but significant TDR mutation rate among ART-naive patients. These findings enhance our understanding of HIV-1 evolution and are valuable for the development and implementation of a comprehensive public health approach to HIV-1 DR prevention and treatment in the region.

Longitudinal impact of compliance with routine CD4 monitoring on all cause deaths among treated people with HIV in China.

Keeping adherence to the continuous and standardized CD4 follow-up monitoring service is of great significance to the control of disease progression and the reduction of avoidable mortality for HIV-infected patients. As non-communicable diseases (NCDs) have become main causes of deaths for people with HIV (PWH) in the era of combination antiretroviral therapy (cART), how and to what extent does adherence to routine CD4 monitoring differentially impact on AIDS-related versus NCDs-related deaths in low- and middle-income countries (LMIC) remains elucidated. A CD4 test index was developed by dividing the actual number of received CD4 tests by the theoretical number of CD4 tests that should have been performed according to national treatment guidelines during the study period, with an index value of 0.8-1.2 reflecting compliance. From 1989 to 2020, 14,571 adults were diagnosed with HIV infection in Dehong Prefecture of Yunnan province in Southwestern China, 6,683 (45.9%) PWH had died with the all-cause mortality of 550.13 per 10,000 person-years, including 3,250 (48.6%) AIDS-related deaths (267.53 per 10,000 person-years). Among patients on cART, the median CD4 test index was 1.0 (IQR 0.6-1.3), and 35.2% had a CD4 test index less than 0.8. Cox proportional hazards regression analysis indicated that PWH with CD4 test index at 0.8-1.2 were at the lowest risk of both AIDS-related (aHR = 0.06; 95%CI: 0.05-0.07) and NCDs-related (aHR = 0.13; 95%CI: 0.11-0.16)deaths. Adherence to routine CD4 monitoring is critical for reducing both AIDS-related and NCDs-related mortality of PWH. An appropriate (once or twice a year) rather than an unnecessarily higher frequency of routine CD4 testing could be most cost-effective in reducing mortality in LMIC.

Plasma Inflammatory Biomarkers Associated with Advanced Liver Fibrosis in HIV-HCV-Coinfected Individuals.

BACKGROUND: HIV and HCV coinfection leads to accelerated liver fibrosis, in which microbial translocation and systemic inflammation might play important roles. OBJECTIVE: This study aimed to provide an extensive profile of the plasma microbial translocation and inflammation biomarkers associated with advanced liver fibrosis among HIV-HCV-coinfected patients. METHODS: This cross-sectional study recruited 343 HIV-HCV-coinfected patients on combination antiretroviral therapy (cART) from a rural prefecture of Yunnan province in Southwest China. The plasma concentrations of sCD14 and 27 cytokines and chemokines were assayed and compared against advanced or mild levels of liver fibrosis. RESULTS: Of the 343 HIV-HCV-coinfected patients, 188 (54.8%) had severe or advanced liver fibrosis (FIB-4 > 3.25). The patients with advanced liver fibrosis (FIB-4 > 3.25 vs. FIB-4 ≤ 3.25) had higher plasma levels of interleukin (IL)-1ß, IL-6, IL-7, IL-9, IL-12, IL-15, IL-17, granulocyte macrophage colony stimulating factor (GM-CSF), Interferon-γ (IFN-γ), tumor necrosis factor (TNF-α), IL-4, IL-10, IL-13, fibroblast growth factor 2 (FGF-basic), and Monocyte chemoattractant protein-1 (MCP-1). Multivariable logistic regression models showed that advanced liver fibrosis was associated with an increased plasma level of IL-1ß, IL-6, IL-7, IL-12, IL-17, GM-CSF, IFN-γ, IL-4, IL-10, MCP-1, Eotaxin, and FGF-basic, with FGF-basic continuing to be positively and significantly associated with advanced liver fibrosis, after Bonferroni correction for multiple comparisons (adjusted odds ratio (aOR) = 1.92; 95%CI: 1.32-2.81; p = 0.001). Plasma sCD14 was also significantly associated with advanced liver fibrosis (aOR = 1.13; 95%CI: 1.01-1.30; p = 0.049). CONCLUSIONS: HIV-HCV-coinfected patients are living with a high prevalence of advanced liver fibrosis which coexists with a mixture of elevated plasma inflammation and microbial translocation biomarkers. The significant associations of advanced liver fibrosis with FGF-basic and sCD14 may reveal pathogenic mechanisms and potential clinical intervention targets for liver fibrosis in HCV-HIV coinfection.

Fibrosis-4 index predicts mortality in HIV/HCV co-infected patients receiving combination antiretroviral therapy in rural China.

End-stage liver disease (ESLD) is among leading causes of death for people living with HIV and HCV. Little is known how liver fibrosis score predicts mortality in HIV/HCV co-infected population under combination antiretroviral therapy (cART). A retrospective cohort study of 691 HIV/HCV co-infected patients receiving cART in Yunnan, China from 2005 to 2016 was carried out to explore the association between Fibrosis-4 index (FIB-4) and all-cause mortality. Cox proportional hazard models were used to estimate the hazard ratios (HRs) for FIB-4 and covariates. After a median follow-up of 4.8 years with a total follow-up time of 3,696 person-years (PY), 131 deaths occurred and the all-cause mortality was 3.5 per 100 PY. The mortality was 2.9 (95% CI: 2.3-3.5)/100 PY for the FIB-4 ≤ 3.25 group and 5.8 (4.2-7.4)/100 PY for the FIB-4 > 3.25 group at baseline. People with FIB-4 changed from mild to advanced group showed HR of 1.81 (95% CI: 1.01-3.25) for death, and with FIB-4 sustaining advanced showed HR of 3.11 (1.75-5.54), both compared to those with FIB-4 remained mild, while lower risk of death was observed among married people (HR = 0.63, 95% CI: 0.41-0.99) compared to unmarried, among those with most recent CD4+ T cell counts between 200 and 350 cells/µL (0.50, 0.30-0.86) and > 350 cells/µL (0.25, 0.15-0.41) compared to CD4 under 200 cells/µL. Advanced and progressive liver fibrosis is a strong predictor of all-cause mortality in HIV/HCV co-infected patients under cART in China.

[Analysis on HIV-1 genetics and threshold of drug resistance in Dehong prefecture of Yunnan province in 2013].

OBJECTIVE: To study the HIV-1 genotypes and transmitted drug resistance (TDR) in Dehong prefecture of Yunnan province in 2013. METHODS: Referring to the guidelines for HIV drug resistance threshold survey (HIVDR-TS), 54 plasma samples of recently reported HIV-infected individuals, aged between 16 and 25 years, were collected in Dehong prefecture from January to August 2013. Genotyping of partial pol gene was performed by using reverse transcriptional PCR. HIV-1 genotype. Prevalent levels of HIV-1 drug resistance transmission were analyzed. RESULTS: Forty-eight plasma samples were successfully sequenced and analyzed. Among them, 45.8% were Chinese and the rest 54.2% were all Burmese. Based on pol sequences, identified HIV genotypes included subtype C (41.7%), URF (31.3%), CRF01_AE (12.5%), CRF07_BC (10.4%), CRF08_BC (2.1%) and subtype B (2.1%), C subtype appeared dominated in Chinese while URF was dominated in Burmese. One drug resistant mutation to non-nucleoside reverse transcriptase inhibitors (NNRTIs) was detected in one sequence from Burmese. Based on the statistical method of HIVDR-TS, the prevalence of transmitted HIV-1 drug resistance was adjusted as < 5%. CONCLUSION: Diverse HIV-1 genotypes were found in this study, and the current HIV-1 drug resistant strains transmission was catalogued as at low prevalence level, in Dehong. To prevent the increase of the prevalence of transmitted HIV-1 drug resistance, standard treatment and scientific management for people living with HIV/AIDS should be strictly followed. Meanwhile, relevant surveillance, including drug resistance surveillance should also be performed among cross-border migrant population.

[Study on drop-out from antiretroviral therapy among adult HIV-infected individuals in Dehong prefecture, Yunnan province].

OBJECTIVE: To examine the proportion and reasons of drop-out from antiretroviral therapy (ART) among 8 367 adult HIV-infected individuals in Dehong prefecture, Yunnan province. METHODS: All adult HIV-infected patients receiving ART before September 30 of 2014 were examined for the situation of drop-out from ART. RESULTS: The proportion of drop-out from ART among adult HIV-infected patients in Dehong prefecture was 14.4% (1 202/8 367). Results from the univariate logistic regression analyses indicated that drop-out from ART was significantly correlated with factors as: living area, gender, age, marital status, HIV transmission route, baseline CD4⁺ T cell counts and initial treatment regimen of the patients. After adjusted for potential confounding variables by multiple logistic regression model, drop-out from ART was significantly correlated with residential area, marital status, HIV transmission route, baseline CD4⁺ T cell count and initial treatment regimen of the patients. HIV-infected patients who were living in Mangshi city, Lianghe county or Yingjiang County, being married or living with partner, HIV infection through sexual contact, with baseline CD4⁺ T cell counts ≤ 200 cells/mm³, and ART included in the initial treatment regimen etc., were less likely to drop out from ART. The proportion of drop out from ART was significantly decreasing along with the increasing time of ART. Data from specific investigation revealed that among the 1 202 patients who dropped out from ART, 704 (58.6%) were lost to follow-up, 303 (25.2%) did not adhere to treatment, 74 (6.2%) moved out the region, 64 (5.3%) were Burmese that had returned to Burma, 29 (2.4%) stopped the treatment according to doctors' advice, 18 (1.5%) were incarcerated and 10 (0.8%) were under other reasons. Reasons for the drop-out varied, according to the situation of patients. CONCLUSION: The proportion of drop-out from ART varied significantly according to the characteristics of HIV-infected patients in Dehong prefecture that underscoring the needs for tailored responses to reduce drop-out of ART. Focus should be targeted on reducing the loss to follow-up and improving the treatment adherence.

The sexually driven epidemic in youths in China's southwestern border region was caused by dynamic emerging multiple recombinant HIV-1 strains.

Dehong prefecture, Yunnan province on China's southwestern border was the gateway of the country's AIDS epidemic. Studies on HIV-1 molecular epidemiology will provide key information on virus transmission dynamics and help to inform HIV prevention strategies. HIV-1 infected youths (age 16-25 years) diagnosed in the continuous 3 months in 2009 to 2012 were enrolled. By means of phylogenetic and statistical analyses, It was showed that two thirds (133/205) of youths in Dehong, of which 74.1% were infected sexually, were infected by uncharacterized recombinant HIV-1 strains. Among them about 59.4% (79/131) were unique recombinant forms (URFs) and 40.6% (54/131) formed 11 transmission clusters, termed potential circulating recombinant forms (pCRFs). The emergence of recombinants was statistically significant related with people of low education, residents outside the capital city of Dehong and being Myanmar residents. It was the first report with ongoing HIV-1 recombinant strains in a sexually driven epidemic area in China. Great efforts should be put on reducing multiple risk exposures behavior in local young people, containing the spread of pCRFs to other regions, and preventing the URFs from evolving into future CRFs. Collaborative prevention across border is needed to better control the local AIDS epidemic.

[Study on HIV-1 related genetics and threshold on drug resistance in Dehong prefecture of Yunnan province in 2012].

OBJECTIVE: To study the HIV-1 genotypes and transmitted drug resistance (TDR) in Dehong prefecture of Yunnan province in 2012. METHODS: Referring to the guidelines for HIV drug resistance threshold survey (HIVDR-TS), 60 plasma samples of recently reported HIV-infected individuals between 16 and 25 years old were collected in Dehong prefecture from January to August 2012. Genotyping of partial pol gene was performed by using reverse transcriptional PCR. HIV-1 genotype and the prevalent levels of HIV-1 drug resistance transmission were analyzed. RESULTS: 52 plasma samples were successfully sequenced and analyzed. Among them, 59.6% were Chinese, and the rest (40.4%) were Burmese. Based on pol sequences, identified HIV genotypes would include unique recombinant forms (URFs, 38.5%), subtype C (34.6%), CRF01_AE (21.2%), CRF08_BC (3.8%), and subtype B (1.9%). One drug resistant mutation to non-nucleoside reverse transcriptase inhibitors (NNRTIs) was detected in respective two sequences. Based on the statistical method of HIVDR-TS, the prevalence of transmitted HIV-1 drug resistance was adjusted as a moderate level (5%-15%). CONCLUSION: Diverse HIV-1 genotypes were found in this study, and the current HIV-1 drug resistant strains transmission was catalogued as moderate prevalence level in Dehong.

[Proportion and related influencing factors of HIV-infected individuals that rejecting the antiretroviral therapy among all the HIV infections, Dehong prefecture, Yunnan province].

OBJECTIVE: To examine the proportion and influencing factors on HIV-infected individuals who rejecting the antiretroviral therapy among all the HIV positives, in Dehong prefecture, Yunnan province. METHODS: A cross-sectional analysis was conducted on all the local HIV-infected survivals aged over 16 year old who refused to receive antiretroviral therapy (ART) by the end of 2013 in Dehong prefecture. RESULTS: The proportion of those rejecting the ART among HIV-infected survivals and aged over 16 years old in Dehong prefecture, was 7.4% (605/8 136). Factors related to the 'rejection' among the 605 refusals would include: being male (72.9%), aged 31-45 years (57.2%), peasants (75.4%), married (52.2%), with minor ethnicity (41.3%), illiterate or only having primary school education (58.7%), infected through sexual contacts (61.2%), and with CD4(+)T cell counts >350 cells/mm(3) (66.6%). Data from the multiple logistic regression analysis indicated that rejecting the ART was significantly associated with areas, gender, age, ethnicity and CD4(+)T cell counts of the HIV patients. Those who were from Yingjiang county, female, aged 31-45 years old had lower proportions of ART refusals than those who were from Ruili city, male, aged ≤30 year old. Those who were of Dai minority and had no records on CD4(+)T cell counts, had higher proportions of ART refusals than those who were of Han ethnicity and had CD4(+)T cell counts ≤350 cells/mm(3). Reasons for the 605 HIV-infected patients with rejection to the ART would include fear of disclosure of HIV infection status (84, 13.9%), misunderstandings of the effectiveness and side effects of ART (111, 18.3%), self-realized wellness(340, 56.2%) and others (70, 11.6%). Of them, reasons for the 181 patients with CD4(+)T cell counts ≤350 cells/mm(3) that rejecting ART would include fearfulness on the disclosure of HIV infection status(40, 22.1%), misunderstandings of the effectiveness and side effects of ART (36, 19.9%), self-realized wellness (84, 46.4%) and others (21, 11.6%). Among those who rejected ART, reasons for that would vary by areas, gender, age, marital status and routes of HIV transmission, according to the results from Chi-squared tests. CONCLUSION: A substantial proportion of HIV-infected individuals rejected ART in Dehong prefecture of Yunnan province. It was urgently needed to enhance health education programs of ART tailored for those HIV-infected patients, according to different characteristics and reasons for rejection, so as to promote the ART in this prefecture.

[Study on HIV viral load in plasma and drug resistance among AIDS patients receiving antiretroviral treatment in Dehong prefecture,Yunnan province].

OBJECTIVE: To understand HIV rival suppression and drug resistance (HIVDR) among AIDS patients who were receiving antiretroviral treatment (ART) in Dehong prefecture, Yunnan province. METHODS: All AIDS patients who were aged over 15 years and with experience more than six months on ART by the end of 2012 in Dehong prefecture, were enrolled to receive testing for HIV viral load in plasma and genetic mutations associated with HIVDR. RESULTS: A total of 4 390 AIDS patients were qualified for the study according to the selection criteria, of whom 3 964 (90.3%) finally participated in the study. Among them, 2 307(58.2%) had CD4(+) cell counts more than 350 cells/mm³. 3 169 (79.9%) patients showed undetectable plasma HIV viral load which was lower than the detection threshold. Those who had the following factors as:resided in Ruili city, being female, older than 45 years of age, married, heterosexually infected with HIV, having received ART more than 5 years, and CD4(+) cell counts >500 cells/mm³, were more likely to have undetectable plasma virus load, with the differences statistically significant. 402 (10.1%) patients had plasma viral load ≥ 1 000 copies/ml, of whom 353 (87.8%) were successfully amplified and examined for HIVDR. Among them, 198 (56.1% ) were identified to bear genetic mutations associated with HIVDR. Most mutations were related to the resistance to nucleotide reverse transcriptase inhibitors (NNRTIs) or non-nucleotide reverse transcriptase inhibitors (NNRTIs), with M184V and K103N most frequently seen. 12 patients (3.4%) were found to have mutations resistant to protease inhibitors (PI). Data from multiple logistic regression analysis indicated that the period of receiving ART and the initial ART regimen could both significantly predict the occurrence of HIV resistance. CONCLUSION: Viral suppression was highly achieved among ART-prescribed AIDS patients in Dehong prefecture,Yunnan province. However, among those who did not show effective viral suppression, the proportion of HIVDR was high, underscoring the needs for health education so as to improve the adherence to drugs as well as for improving testing for viral load and HIVDR among AIDS patients.

[Distribution of HIV-1 subtypes among different populations in Dehong prefecture, Yunnan province, in 2011].

OBJECTIVE: To investigate the distribution of HIV-1 subtypes in Dehong prefecture, Yunnan province, in 2011. METHODS: 300 HIV-1 positive plasma samples were collected from Jan. 2011 to May 2011 in Dehong prefecture. HIV-1 gag genes and env genes were amplified by nested-polymerase chain reaction (PCR) from viral RNA. After sequencing, the HIV-1 subtypes were determined by phylogenetic analysis. RESULTS: Based on the phylogenetic trees of gag gene and env gene fragments, a total of 222 samples were genotyped. Subtype C was the predominant strain in Dehong (43.2%, 96/222), followed by unique recombinant forms (URFs, 27.0%, 60/222), CRF01_AE (21.2%, 47/222), CRF08_BC (5.0%, 11/222), B' (2.3%, 5/222) and CRF07_BC (1.4%, 3/222). Subtype C strains were predominant in both heterosexually transmitted population and intravenous drug users (IDUs), but different subtype distribution patterns were found in these two populations. All 6 genotypes including subtype C (40.7%, 70/172), CRF01_AE (25.0%, 43/172), and URFs (25.0%, 43/172) found in this area among heterosexually transmitted population, which showed the diversity of genotypes in this population. Except subtype B' and CRF07_BC, the other 3 subtypes and URFs were detected among IDUs, mainly including subtype C (54.8%, 23/42) and URFs (38.1%, 16/42), which showed the concentration trend of genotypes distribution among IDUs. The proportion of URFs increased significantly in this area, including the new BC recombinants (41.7%, 25/60) and CRF01_AE relative URFs (58.3%, 35/60). However, the distributions of these two URFs among heterosexually transmitted population and IDUs showed no statistical significance. CONCLUSION: The distribution of HIV-1 strains prevailing in Dehong prefecture was diversity, including 5 subtypes and a variety of URFs, of which subtype C was the predominant strain. The distribution patterns of subtype were different among different populations.

[Survival analysis on 3103 HIV/AIDS patients receiving antiretroviral treatment in Dehong prefecture, Yunnan province].

OBJECTIVE: To determine the survival rate of HIV/AIDS patients after receiving free antiretroviral treatment in Dehong prefecture, Yunnan province. METHODS: A retrospective cohort analysis was conducted on all the HIV/AIDS patients aged over 16 years who had started antiretroviral treatment during January 2007 throughout December 2009 in Dehong prefecture. RESULTS: A total of 3103 HIV/AIDS patients had received antiretroviral treatment during the study period. Among them, the mean age was (36.0 ± 9.9) years and 62.4% were males. 66.2% of them were infected with HIV through heterosexual transmission, and the mean treatment follow-up time was 21.7 months. Most patients well complied with the treatment, i.e., the average times of not taking the medicine were less than 5 per month. The cumulative survival rate of antiretroviral treatment after 1, 2, 3, 4, and 5 years were 0.95, 0.94, 0.93, 0.92, and 0.92, respectively. Data from the Cox proportional hazard regression model analysis indicated that, after adjustment for age, gender, and marital status, the baseline CD4(+)T cell counts and transmission route could significantly predicate the rates of survival. Those who were with baseline CD4(+)T cell counts as 200 - 350/mm(3)were less likely to die of AIDS than those with CD4(+) T cell counts < 200/mm(3) (Hazard Ratio or HR = 0.16, 95%CI: 0.09 - 0.28), and HIV-infected through mother-to-child transmission or routes other than heterosexual transmission were less likely to die of AIDS than through injecting drug use (HR = 0.35, 95%CI: 0.13 - 1.00). CONCLUSION: Free antiretroviral treatment had significantly improved the survival of HIV/AIDS patients. Earlier initiation of antiretroviral treatment was likely to have achieved better survival effects.