Xiaojing Song

CRF01_AE subtype is associated with X4 tropism and fast HIV progression in Chinese patients infected through sexual transmission.

Background:The molecular epidemiology of the HIV-1 CRF01_AE subtype as a risk factor for fast HIV-1 progression remains poorly understood. Methods:We analyzed HIV-1 tropism by utilizing samples from 201 treatment-naive patients in our multicenter cohort (12 research centers in different provinces of China). Tropism was determined by V3 loop sequencing. Data from 235 treatment-naive patients infected sexually (including aforementioned 201 patients) in this cohort with date of estimated seroconversion (EDS) were retrospectively evaluated. Median time from EDS to AIDS was analyzed by Kaplan–Meier curves. Hazard ratios were determined by Cox proportional model. Results:CRF01_AE subtype was predominant (46.0%), especially in the MSM group. Further analysis revealed that the proportion of X4 tropism was higher in the CRF01_AE subtype (45.5%) than in others (C/CRF07_BC/CRF08_BC, 4.3%; B, 6.1%; P <0.001). CRF01_AE subtype was associated with faster progression from EDS to AIDS (4.8 vs. 6.4 years, P = 0.018) compared with non-CRF01_AE subtypes. In a multivariate model, the adjusted hazard ratio (aHR) of CRF01_AE was 1.42 (95% confidence interval, CI 0.99–2.03, P = 0.057), independent of HIV-1 viral load; it was also associated with fast progression to advanced immunodeficiency (aHR, 1.81, 95% CI 1.03–3.18, P = 0.038). Conclusion:CRF01_AE, a predominant HIV-1 subtype in Chinese HIV-1 sexually infected patients, tends to be associated with fast progression to AIDS and advanced immunodeficiency, which might be ascribed to high proportion of X4 tropism. Further investigation of these risk factors may have significant implications to clinical practice and policy-making.

Impact of a tenofovir disoproxil fumarate plus ritonavir-boosted protease inhibitor-based regimen on renal function in HIV-infected individuals: a prospective, multicenter study

BackgroundThe aim of this study was to investigate the impact of a tenofovir disoproxil fumarate (TDF) plus ritonavir-boosted protease inhibitor (PI/r) regimen on renal function in Chinese HIV-infected patients.MethodsSeventy-five HIV-1 infected patients failing first-line antiretroviral therapy (ART) comprised the TDF+PI/r group. Seventy-five HIV-1 infected patients matched for gender, age, and renal function made up the control. All subjects completed follow-up visits over 48 weeks. CD4 cell count, plasma HIV-1 viral load, and urine protein level were assessed at the trial start (baseline, week 0) and at week 48. The serum creatinine and estimated glomerular filtration rate (eGFR) were monitored at each follow-up point. Change in eGFR from baseline to week 48 was also compared.ResultsCompared to control, the TDF+PI/r group exhibited higher levels of serum creatinine (79 vs. 69.7 μmol/L, P<0.001) and a lower rate of eGFR (93.0 vs. 101.6 ml/min/1.73m2, P=0.009) at the end of week 48. Patients treated with TDF+PI/r showed greater decline in eGFR than control (−8.8 vs. 6.4ml/min/1.73m2, P<0.001). Compared to baseline renal function of the control group, the TDF+PI/r group exhibited a greater median decline in eGFR at the end of week 48 (P<0.001).ConclusionsWe found that a TDF+PI/r based ART regimen resulted in greater renal function decline over 48 weeks. Therefore, renal function should be monitored especially when TDF is used in combination with PI/r.Trial registrationClinicalTrials.gov identifier: NCT00872417

Prevalence and risk factors for chronic kidney disease among HIV-infected antiretroviral therapy-naïve patients in Mainland China: A multicenter cross-sectional study

The aim of the study was to evaluate the prevalence and risk factors of chronic kidney disease (CKD) among HIV‐infected antiretroviral therapy (ART)‐naïve patients in Mainland China.

Emergence of Lamivudine-Resistant HBV during Antiretroviral Therapy Including Lamivudine for Patients Coinfected with HIV and HBV in China

In China, HIV-1-infected patients typically receive antiretroviral therapy (ART) that includes lamivudine (3TC) as a reverse-transcriptase inhibitor (RTI) (ART-3TC). Previous studies from certain developed countries have shown that, in ART-3TC, 3TC-resistant HBV progressively emerges at an annual rate of 15–20% in patients coinfected with HIV-1 and HBV. This scenario in China warrants investigation because >10% of all HIV-infected patients in China are HBV carriers. We measured the occurrence of 3TC-resistant HBV during ART-3TC for HIV-HBV coinfection and also tested the effect of tenofovir disoproxil fumarate (TDF) used as an additional RTI (ART-3TC/TDF) in a cohort study in China. We obtained 200 plasma samples collected from 50 Chinese patients coinfected with HIV-1 and HBV (positive for hepatitis B surface antigen) and examined them for the prevalence of 3TC-resistant HBV by directly sequencing PCR products that covered the HBV reverse-transcriptase gene. We divided the patients into ART-3TC and ART-3TC/TDF groups and compared the efficacy of treatment and incidence of drug-resistance mutation between the groups. HIV RNA and HBV DNA loads drastically decreased in both ART-3TC and ART-3TC/TDF groups. In the ART-3TC group, HBV breakthrough or insufficient suppression of HBV DNA loads was observed in 20% (10/50) of the patients after 96-week treatment, and 8 of these patients harbored 3TC-resistant mutants. By contrast, neither HBV breakthrough nor treatment failure was recorded in the ART-3TC/TDF group. All of the 3TC-resistant HBV mutants emerged from the cases in which HBV DNA loads were high at baseline. Our results clearly demonstrated that ART-3TC is associated with the emergence of 3TC-resistant HBV in patients coinfected with HIV-1 and HBV and that ART-3TC/TDF reduces HBV DNA loads to an undetectable level. These findings support the use of TDF-based treatment regimens for patients coinfected with HIV-1 and HBV.

HIV-1 subtype B/B' and baseline drug resistance mutation are associated with virologic failure: a multicenter cohort study in China.

Background:Distribution of HIV-1 subtypes, transmitted drug resistance (TDR)/drug resistance mutation (DRM), and their impact on response to combination antiretroviral therapy remain poorly understood in China. Methods:We analyzed data from our multicenter cohort study with 444 antiretroviral-naive participants recruited between 2008 and 2010. HIV-1 subtype and tropism were determined by V3 sequencing, and TDR/DRM was determined by Pol sequencing. Virologic and immunologic responses were monitored over 96 weeks of follow-up. The initial combination antiretroviral therapy regimen for all patients was nevirapine + lamivudine + zidovudine or stavudine. Analysis 1 included patients who finished 96 weeks of follow-up (n = 379), and analysis 2 included all 444 patients. Results:Subtype B/B′ was associated with higher prevalence of TDR/DRM to nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors. Median time to HIV-1 suppression was 18 weeks in all 3 subtype groups. In Cox proportional models for viral suppression, neither viral tropism nor HIV-1 subtypes had any impact on viral suppression; however, subtypes CRF01_AE and C/CRF07_BC/CRF08_BC were associated with lower risk of virologic failure compared with subtype B/B′, with adjusted hazard ratio of 0.11 (P = 0.032) and 0.06 (P = 0.036), respectively in analysis 1, 0.42 (P = 0.047) and 0.22 (P = 0.008), respectively in analysis 2. This association was attenuated by adding DRM profiles to multivariate regression models. Neither subtype nor HIV-1 tropism affected immunologic response. Conclusions:HIV-1 subtype tended to be associated with virologic but not immunologic response; this effect could be ascribed to baseline DRM.

Prospective Echocardiographic Assessment of Cardiac Structure and Function in Chinese Persons Living With HIV

BACKGROUND Persons living with human immunodeficiency virus (HIV) are at increased risk of developing cardiovascular disease. Few studies have focused on echocardiographic abnormalities in this population. METHODS China AIDS Clinical Trial 0810 is a prospective, multicenter cohort study of persons living with HIV (PLWH). We performed an echocardiography substudy of 325 PLWH. We examined the prevalence of left ventricular systolic dysfunction (LVSD), diastolic dysfunction (DD), pulmonary arterial hypertension (PAH), and increased left ventricular mass (ILVM) in antiretroviral therapy (ART)-naive PLWH at baseline and week 48 after initiation of ART. RESULTS Compared with age- and sex-matched healthy controls, PLWH had a higher prevalence of DD (16.5% vs 7.2%, P < .027) and a marginally significant higher prevalence of LVSD (7.3% vs 2.1%, P = .056). The increase in the prevalence of DD from baseline to week 48 in PLWH was marginally significant (P = .056). No significant difference was observed in the prevalence of LVSD, PAH, or ILVM at baseline and week 48 in PLWH. In logistic regression analysis of all participants, age was significantly associated with LVSD; HIV infection, age, and hypertension were associated with DD whereas HIV infection and hypertension were associated with ILVM at baseline. Logistic regression analysis of PLWH showed that only age was significantly associated with LVSD and DD. CONCLUSIONS The prevalence of echocardiographic abnormalities was significantly higher in ART-naive PLWH than in controls. HIV infection was significantly associated with cardiac abnormalities. No significant change in echocardiographic abnormalities was observed after 48 weeks of ART. Longer-term prospective studies are warranted.

Lamivudine Monotherapy-Based cART Is Efficacious for HBV Treatment in HIV/HBV Coinfection When Baseline HBV DNA <20,000 IU/mL.

Background:Although combination antiretroviral therapy (cART) including tenofovir (TDF)+lamivudine (3TC) or emtricitabine (FTC) is recommended for treatment of HIV/HBV coinfected patients, TDF is unavailable in some resource-limited areas. Some data suggest that 3TC monotherapy-based cART may be effective in patients with low pretreatment HBV DNA. Methods:Prospective study of 151 Chinese HIV/HBV coinfected subjects of whom 60 received 3TC-based cART and 91 received TDF+3TC-based cART. Factors associated with HBV DNA suppression at 24 and 48 weeks, including anti-HBV drugs, baseline HBV DNA, and baseline CD4 cell count, were evaluated overall and stratified by baseline HBV DNA using Poisson regression with a robust error variance. Results:Baseline HBV DNA ≥20,000 IU/mL was present in 48.3% and 44.0% of subjects in the 3TC and TDF groups, respectively (P = 0.60). After 48 weeks of treatment, HBV DNA suppression rates were similar between these 2 groups (96.8% vs. 98.0% for 3TC and TDF+3TC, P > 0.999) in subjects with baseline HBV DNA <20,000 IU/mL; whereas in those with baseline HBV DNA ≥20,000 IU/mL, TDF+3TC was associated with higher suppression rates (34.5% vs. 72.5% in 3TC and TDF+3TC groups, respectively, P = 0.002). In stratified multivariate regression, TDF use (RR 1.98, P = 0.010) and baseline HBV DNA (per 1 log increase in International Units Per Milliliter, RR 0.74, P < 0.001) were associated with HBV DNA suppression only when baseline HBV DNA ≥20,000 IU/mL. Conclusion:This study suggests that 3TC monotherapy-based cART is efficacious for HBV treatment through 48 weeks in HIV/HBV coinfection when baseline HBV DNA <20,000 IU/mL. Studies with long-term follow-up are warranted to determine if this finding persists.

Baseline Naive CD4+ T-cell Level Predicting Immune Reconstitution in Treated HIV-infected Late Presenters

Background:Among HIV-infected patients initiating antiretroviral therapy (ART), early changes in CD4+ T-cell subsets are well described. However, HIV-infected late presenters initiating treatment present with a suboptimal CD4+ T-cell reconstitution and remain at a higher risk for AIDS and non-AIDS events. Therefore, factors associated with CD4+ T-cell reconstitution need to be determined in this population, which will allow designing effective immunotherapeutic strategies. Methods:Thirty-one adult patients with baseline CD4+ T-cell count <350 cells/mm3 exhibiting viral suppression after ART initiation were followed in the HIV/AIDS research center of Peking Union Medical College Hospital in Beijing, China, from October 2002 to September 2013. Changes in T-cell subsets and associated determinants were measured. Results:Median baseline CD4+ T-cell count was 70 cells/mm3. We found a biphasic reconstitution of T-cell subsets and immune activation: a rapid change during the first 6 months followed by a more gradual change over the subsequent 8 years. Baseline CD4+ T-cell count >200 cells/mm3 in comparison to CD4+ T-cell count ⩽200 cells/mm3 was associated with more complete immune Reconstitution (77.8% vs. 27.3% respectively; P = 0.017) and normalized CD4/CD8 ratio. We showed that the baseline percentage of naive CD4+ T-cell was a predictive marker for complete immune reconstitution (area under receiver operating characteristic curve 0.907), and 12.4% as cutoff value had a sensitivity of 84.6% and a specificity of 88.2%. Conclusions:Baseline naive CD4+ T-cell percentage may serve as a predictive marker for optimal immune reconstitution during long-term therapy. Such study findings suggest that increasing thymic output should represent an avenue to improve patients who are diagnosed late in the course of infection.

Week 120 Efficacy of Tenofovir, Lamivudine and Lopinavir/r-Based Second-Line Antiretroviral Therapy in Treatment- Experienced HIV Patients

Background Tenofovir (TDF) and ritonavir-boosted lopinavir (LPV/r) were not introduced to China as second-line medications until 2009. The efficacy and safety of TDF/3TC/LPV/r based second-line regimen have not been evaluated in Chinese HIV patients who failed first-line regimens. Methods This was a multicenter cohort study recruiting patients from Beijing, Shanghai, Guangdong, and Henan provinces between November 2008 and January 2010. Eighty HIV infected patients failing first-line regimens with serum creatinine lower than 1.5 times the upper limit of normal received TDF+ lamivudine (3TC)+ LPV/r were followed up for 120 weeks. CD4 cell count, viral load, and estimated glomerular filtration rate (eGFR) were monitored at each visit. Results At baseline, 31.2% and 48.8% of patients had moderate/high-level resistance to TDF and 3TC, respectively; while 2.5% of patients had only low-level resistance to LPV/r. During 120 weeks of follow-up, virological suppression rate reached over 70% (<40 copies/ml) and 90% (<400 copies/ml), and median CD4 cell count increased from 157 cells/μL at baseline to 307 cells/μL at week 120. Baseline drug-resistance mutations had no impact on the efficacy of second-line antiretroviral therapy. Median eGFR dropped from 104.7 ml/min/1.73m2 at baseline to 95.6 ml/min/1.73m2 at week 24 and then recovered after week 96. Conclusion This study for the first time demonstrated that TDF+ 3TC+ LPV/r was efficacious as second-line regimen with acceptable nephrotoxicity profiles in patients who failed zidovudine or stavudine based first-line regimens in China. Trial Registration ClinicalTrials.gov NCT00872417

CD16-expressing monocytes correlate with arterial stiffness in HIV-infected ART-naïve men

Objectives To determine the association of the markers of monocyte activation and arterial stiffness among HIV-infected antiretroviral therapy (ART)-naïve men. Methods Sixty HIV-infected ART-naïve men and 20 HIV-uninfected male controls without symptoms or history of cardiovascular disease were recruited. Pulse wave velocity (PWV) were used as the marker of arterial stiffness and determined using a pulse pressure analyzer. The percentage of CD16-expressing monocytes was used as a marker of monocyte activation. Plasma neopterin concentration, one of the monocyte/macrophage activation markers and plasma tissue factor (TF), the coagulation marker in response to inflammatory stimuli, were also analyzed. Multivariate analyses were used to explore the association of the percentage of CD16-expressing monocytes with arterial stiffness in HIV-infected men. Results HIV-infected ART-naïve men demonstrated significantly higher PWV (1252.8 ± 161.6 vs.1159.2 ± 108.3 cm/s, p = 0.018). The percentage of CD16-expressing monocytes was significantly higher in HIV-infected men comparing male controls (23.4 ± 6.0% vs. 19.6 ± 4.6%, p = 0.012). Plasma concentrations of neopterin (0.91 vs. 0.64 ng/ml), p < 0.001) and TF (5.29 vs. 4.43 pg/ml, p = 0.04) were higher in HIV-infected men comparing controls. In the multivariate model for PWV among HIV-infected men, the percentage of CD16-expressing monocytes (p = 0.023) and age (p = 0.017) were significantly associated with PWV. HIV viral load, CD4 count, percentage of CD8+CD38+T cells and percentage of CD8+HLA-DR+ T cells were not associated with PWV. Discussion Higher level of monocyte activation marker is associated with higher level of arterial stiffness in ART naïve HIV-infected men. HIV viral load, CD4 count, and the markers of CD8 T cell activation were unrelated to PWV.