High microbial translocation limits gut immune recovery during short-term HAART in the area with high prevalence of foodborne infection.

BACKGROUND: Individuals residing in areas with high prevalence of foodborne infection could have a higher risk of gut microbial translocation which may affect monocyte activation, gut immune recovery and intestinal epithelial cell damage. We aimed to measure alterations in microbial translocation, monocyte activation, gut immune recovery, and intestinal epithelial cell damage in HAART treated individuals. METHODS: A prospective, single-arm, longitudinal, cohort study was conducted among antiretroviral naïve HIV-1 infected Thai participants. All participants were in chronic stage of HIV-1 infection before starting HAART. Data and samples were collected prior to initiation of HAART and then after 24 and 48 weeks of HAART. Plasma biomarkers for microbial translocation (16S rDNA and LBP), monocyte activation (sCD14) and intestinal epithelial cell damage (I-FABP) were evaluated. We measured circulating gut-homing CD4+ T cells and circulating gut-homing Th17 cells to assess recoveries of gut immunity and gut immunity to microbial pathogens. RESULTS: The kinetic studies showed no reduction in the levels of plasma 16S rDNA, sCD14 or I-FABP, significant decrease of plasma LBP level, and slow but significant increases in the frequencies of circulating gut-homing CD4+ T cells and circulating gut-homing Th17 cells during 48 weeks of HAART. Dividing participants into low and high microbial translocation (low and high MT) groups at baseline, both groups showed persistent plasma levels of 16S rDNA, sCD14 and I-FABP, and significantly decreased plasma level of LBP. The low MT group had significantly increased frequencies of circulating gut-homing CD4+ T cells and circulating gut-homing Th17 cells during 48 weeks of HAART but this was not observed in the high MT group. CONCLUSIONS: We demonstrated persistent high microbial translocation, monocyte activation and intestinal epithelial cell damage with slow gut immune recovery during successful short-term HAART. Additionally, gut immune recovery was apparently limited by high microbial translocation. Our findings emphasize the adverse impact of high microbial translocation on gut immune recovery and the necessity of establishing a novel therapeutic intervention to inhibit microbial translocation.

Broad-Spectrum Antiviral Activity of an Ankyrin Repeat Protein on Viral Assembly against Chimeric NL4-3 Viruses Carrying Gag/PR Derived from Circulating Strains among Northern Thai Patients.

Certain proteins have demonstrated proficient human immunodeficiency virus (HIV-1) life cycle disturbance. Recently, the ankyrin repeat protein targeting the HIV-1 capsid, AnkGAG1D4, showed a negative effect on the viral assembly of the HIV-1NL4-3 laboratory strain. To extend its potential for future clinical application, the activity of AnkGAG1D4 in the inhibition of other HIV-1 circulating strains was evaluated. Chimeric NL4-3 viruses carrying patient-derived Gag/PR-coding regions were generated from 131 antiretroviral drug-naïve HIV-1 infected individuals in northern Thailand during 2001⁻2012. SupT1, a stable T-cell line expressing AnkGAG1D4 and ankyrin non-binding control (AnkA32D3), were challenged with these chimeric viruses. The p24CA sequences were analysed and classified using the K-means clustering method. Among all the classes of virus classified using the p24CA sequences, SupT1/AnkGAG1D4 demonstrated significantly lower levels of p24CA than SupT1/AnkA32D3, which was found to correlate with the syncytia formation. This result suggests that AnkGAG1D4 can significantly interfere with the chimeric viruses derived from patients with different sequences of the p24CA domain. It supports the possibility of ankyrin-based therapy as a broad alternative therapeutic molecule for HIV-1 gene therapy in the future.

The 10-year effectiveness of combination antiretroviral treatment in perinatally HIV-infected children participating in Thailand's National Access Program.

BACKGROUND: The National Access to Antiretroviral Program for People Living with HIV/AIDS was launched in Thailand in 2002. HIV-infected, antiretroviral-naive, severely immunosuppressed children were initiated on highly active combination antiretroviral treatment (cART). This study aimed to determine the long-term effectiveness of cART. METHODS: Data were extracted from medical records. Primary end points were mortality rate, proportion of children who remained on first-line cART regimen and children with plasma HIV RNA level (pVL) <50 copies/ml at week 520. RESULTS: From August 2002 to July 2003, 107 children were enrolled. The baseline median age was 7.6 years (IQR 5.7-10.0), the median CD4(+) T-cell count was 60 cells/mm(3) (IQR 21-272) and the median pVL was 5.37 log10 copies/ml (IQR 5.01-5.76). The mortality rate during and after the first year was 3.7 and 0.006 deaths/100 person-years, respectively. At week 520, 90 (84%) continued to be actively followed. Their median age was 17.8 years (IQR 15.8-19.8). 73 (81% as-treated) remained on the first-line regimen, while 18 (20%) had switched to a second-line cART regimen, at the median time of 272 weeks (IQR 256-363) after the first-line cART initiation. 69 (77%) had pVL<50 copies/ml and the median CD4(+) T-cell count was 636 cells/mm(3) (IQR 466-804). 83 (92%) and 64 (71%) had CD4(+) T-cell counts ≥200 and >500 cells/mm(3), respectively. CONCLUSIONS: Long-term virological control, favourable immunological outcomes and healthy survival was achieved in severely immunosuppressed, perinatally HIV-infected children who started first-line NNRTI-based cART. Continuing surveillance for long-term complications is warranted.

A Randomized Comparison of Anthropomorphic Changes With Preferred and Alternative Efavirenz-Based Antiretroviral Regimens in Diverse Multinational Settings.

Background. Existing data on anthropomorphic changes in resource-limited settings primarily come from observational or cross-sectional studies. Data from randomized clinical trials are needed to inform treatment decisions in these areas of the world. Methods. The AIDS Clinical Trials Group Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS) study was a prospective, randomized evaluation of the efficacy of emtricitabine/tenofovir + efavirenz (FTC/TDF + EFV) vs lamivudine/zidovudine + efavirenz (3TC/ZDV + EFV) for the initial treatment of human immunodeficiency virus (HIV)-1-infected individuals from resource-diverse settings. Changes in anthropomorphic measures were analyzed using mixed-effect models for repeated measurements, using all available measurements at weeks 48, 96, and 144. Intent-to-treat results are presented; as-treated results were similar. Results. Five hundred twenty-six participants were randomized to FTC/TDF + EFV, and 519 participants were randomized to 3TC/ZDV + EFV. Significantly greater increases from baseline to week 144 were seen among those randomized to FTC/TDF + EFV vs 3TC/ZDV + EFV in all measures except waist-to-hip ratio, with the following mean changes: weight, 4.8 vs 3.0 kg; body mass index, 1.8 vs 1.1 kg/m(2); mid-arm, 1.7 vs 0.7 cm; waist, 5.2 vs 4.3 cm; hip, 3.8 vs 1.4 cm; and mid-thigh circumference, 3.1 vs 0.9 cm. There were 7 clinical diagnoses of lipoatrophy in the 3TC/ZDV + EFV arm compared with none in the FTC/TDF + EFV arm. The proportion of overweight or obese participants increased from 25% (week 0) to 42% (week 144) for FTC/TDF + EFV and from 26% to 38% for 3TC/ZDV + EFV. Conclusions. Our findings support first-line use of FTC/TDF + EFV in resource-limited settings and emphasize the need for interventions to limit weight gain among overweight or obese HIV-infected participants in all settings.

Recovery from lipodystrophy in HIV-infected children after substitution of stavudine with zidovudine in a non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy.

BACKGROUND: Substitution of stavudine with zidovudine may lead to recovery from lipodystrophy (LD) in HIV-infected children. METHODS: We prospectively followed HIV-infected children enrolled in an earlier LD study conducted between 2002 and 2004 at Chiang Mai University Hospital in northern Thailand. In 2006, stavudine was substituted with zidovudine. All children were evaluated by a clinical LD checklist modified from that of the European Pediatric LD study group together with waist/hip measurement at baseline and 24, 48, 72, and 96 weeks after substitution. The waist-to-hip ratios were converted to age- and sex-adjusted z scores based on normal ranges in healthy Thai children. RESULTS: Forty-five lipodystrophic children with 36 episodes of lipohypertrophy and 22 episodes of lipoatrophy were enrolled. By weeks 48 and 96 after substitution, 40% and 47% of lipohypertrophy resolved, whereas 59% and 73% of lipoatrophy resolved, respectively. The rate of resolution of lipoatrophy was higher than that of lipohypertrophy at 48 weeks after substitution and thereafter. Ninety-six weeks after changing to zidovudine therapy, 8 children still had LD (1 with both lipoatrophy and lipohypertrophy, 7 with lipohypertrophy). No clinically significant hematologic adverse event was observed. CONCLUSIONS: Substitution of stavudine with zidovudine resulted in decreased severity or resolution of LD among HIV-infected children and adolescents.

Lymphocyte homeostasis in HIV-infected northern Thais.

Cross-sectional laboratory data were used to model the patterns of total lymphocyte count and lymphocyte subpopulation counts among persons with chronic HIV-1 subtype E (CRF01_AE) infection during the 6.5 years preceding death. The data cover 331 HIV-infected decedents from a heterosexual HIV transmission study of 590 northern Thai couples enrolled in 1992-1998. From blood collected at enrollment, the lymphocyte phenotypes (CD3, CD8, CD4, natural killer, and B cells) were stained using two-color monoclonal antibody combinations and quantified by flow cytometry. Piecewise linear splines modeled the associations between lymphocyte levels and time before death. Mean CD3, CD8, and B cell levels showed no temporal associations from 6.5 to 2 years before death, but each declined significantly during the 2 years before death. CD3 levels declined 31.0% [95% confidence interval (-40.3%, -19.8%)] and CD8 levels declined 24.6% (-35.4%, -13.5%) annually in the 2 years prior to death. In contrast, CD4 and NK cell levels declined little from 6.5 to 4.5 years before death but declined significantly over the 4.5 years prior to death. CD4 levels declined 22.1% (-29.2%, -12.0%) annually from 4.5 to 2 years prior to death and 63.7% (-72.3%, -53.6%) annually over the remaining 2 years. Similar lymphocyte patterns have been reported in U. S. and European populations with HIV-1 subtype B infection.