Pharmacogenetic interactions of efavirenz or rifampin and isoniazid with levonorgestrel emergency contraception during treatment of HIV or tuberculosis.

OBJECTIVE: In AIDS Clinical Trials Group study A5375, a pharmacokinetic trial of levonorgestrel emergency contraception, double-dose levonorgestrel (3 mg, versus standard dose 1.5 mg) offset the induction effects of efavirenz or rifampin on plasma levonorgestrel exposure over 8 h post-dose (AUC 0-8h ). We characterized the pharmacogenetics of these interactions. METHODS: Cisgender women receiving efavirenz- or dolutegravir-based HIV therapy, or on isoniazid-rifampin for tuberculosis, were followed after a single oral dose of levonorgestrel. Linear regression models, adjusted for BMI and age, characterized associations of CYP2B6 and NAT2 genotypes (which affect plasma efavirenz and isoniazid exposure, respectively) with levonorgestrel pharmacokinetic parameters. RESULTS: Of 118 evaluable participants, 17 received efavirenz/levonorgestrel 1.5 mg, 35 efavirenz/levonorgestrel 3 mg, 34 isoniazid-rifampin/levonorgestrel 3 mg, and 32 (control group) dolutegravir/levonorgestrel 1.5 mg. There were 73 Black and 33 Asian participants. Regardless of genotype, women on efavirenz and isoniazid-rifampin had higher levonorgestrel clearance. In the efavirenz/levonorgestrel 3 mg group, CYP2B6 normal/intermediate metabolizers had levonorgestrel AUC 0-8h values similar to controls, while CYP2B6 poor metabolizers had AUC 0-8h values of 40% lower than controls. In the isoniazid-rifampin group, NAT2 rapid/intermediate acetylators had levonorgestrel AUC 0-8h values similar to controls, while NAT2 slow acetylators had AUC 0-8h values 36% higher than controls. CONCLUSION: CYP2B6 poor metabolizer genotypes exacerbate the efavirenz-levonorgestrel interaction, likely by increased CYP3A induction with higher efavirenz exposure, making the interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the rifampin-levonorgestrel interaction, likely by increased CYP3A inhibition with higher isoniazid exposure.

Efficacy and safety of switching to bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed Asian adults living with HIV: A pooled analysis from three international phase III randomized trials.

OBJECTIVES: Data on switching to bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) in virologically suppressed Asian people living with HIV are limited. We performed a pooled analysis of virologically suppressed Asian participants from three international phase III trials to evaluate the efficacy and safety of switching to B/F/TAF. METHODS: Virologically suppressed people living with HIV were randomized to switch to B/F/TAF or to stay on baseline regimens. The primary endpoint was the proportion of participants with plasma HIV-1 RNA ≥50 copies/ml at week 48. We analysed the incidence of adverse events (AEs), laboratory abnormalities, and changes in relevant tolerability parameters through 48 weeks. RESULTS: Overall, 136 Asian participants were included. The proportions of participants with plasma HIV-1 RNA ≥50 copies/ml at week 48 were low in both arms (0% for B/F/TAF vs 1.4% for those who stayed on baseline regimens). Those who switched to B/F/TAF had virological suppression rates similar to those who stayed on baseline regimens (100% vs 95.9%, p = 0.2485), with no treatment-emergent resistance. Drug-related AEs occurred in three participants in each arm; none were serious. No participants discontinued the study drug because of AEs, and no deaths were observed. No significant differences were observed between the arms in the median changes in estimated glomerular filtration rate, body weight, and most lipid parameters. Switching from tenofovir disoproxil fumarate-containing regimens to B/F/TAF resulted in a significant decrease in tubular proteinuria compared with those who stayed on baseline regimens (p < 0.01). CONCLUSIONS: Virologically suppressed Asian people living with HIV who switched to B/F/TAF maintained 100% virological suppression at week 48, with no treatment-emergent drug resistance and safety profiles comparable to those seen in people who stayed on baseline regimens. CLINICAL TRIAL NUMBER: ClinicalTrials.gov (NCT02603120, NCT02652624, and NCT02603107).

Geographical Differences in the Self-Reported Functional Impairment of People With Human Immunodeficiency Virus (HIV) and Associations With Cardiometabolic Risk.

BACKGROUND: We sought to explore multinational differences in functional status by global burden of disease (GBD) regions in the REPRIEVE cohort. METHODS: REPRIEVE is a prospective, double-blind, randomized, placebo-controlled, multicenter, phase III primary cardiovascular prevention study of pitavastatin calcium vs placebo among people with human immunodeficiency virus (HIV, PWH) ages 40-75 on antiretroviral therapy (ART). GBD super regions were defined using World Health Organization classifications. Participants were categorized by impairment on the Duke Activity Status Instrument (DASI: none, some, moderate, severe). Logistic regression models examined risk factors and GBD regions associated with functional impairment. The association between functional impairment and cardiometabolic risk was also explored. RESULTS: Of 7736 participants, the majority were from high-income countries (n = 4065), were male (65%), and had received ART for ≥ 10 years. The median DASI score was 58.2 (interquartile range [IQR] 50.2, 58.2); 36% reported at least some impairment. In adjusted analyses, functional impairment was significantly more frequent among participants from Southeast/East Asia. Other factors associated with greater impairment included female sex, Black race, older age, current/former smoking, higher body mass index, use of ART for ≥ 10 years, and select ART regimens; differences were seen in risks across GBD regions. Functional impairment was associated with increased cardiometabolic risk. CONCLUSIONS: Over 1/3 of middle-aged and older PWH in a global cohort across diverse GBD regions demonstrate functional impairments. The associations between DASI and cardiometabolic risk suggest that a measure of functional status may improve risk prediction; these longitudinal associations will be further investigated over REPRIEVE trial follow-up.

Population Pharmacokinetic Modeling and Simulation of Rifapentine Supports Concomitant Antiretroviral Therapy with Efavirenz and Non-Weight Based Dosing.

The Brief Rifapentine-Isoniazid Efficacy for TB Prevention/A5279 trial demonstrated a 1-month daily regimen of rifapentine and isoniazid was noninferior to 9 months of isoniazid alone for preventing TB in persons living with HIV (PLWH). Our objective was to evaluate rifapentine pharmacokinetics in trial participants receiving antiretroviral therapy (ART) and perform simulations to compare weight-based rifapentine dosing with a standard, fixed dose. Nonlinear mixed effect modeling was used to estimate rifapentine and 25-desacetyl rifapentine population pharmacokinetic characteristics. The pharmacokinetic model was validated using a nonparametric bootstrap and visual predictive checks. Monte Carlo simulations were performed to compare weight-based and fixed dose regimens. Rifapentine and 25-desacetyl rifapentine concentrations (347 of each; 185 participants) were each described with a one-compartment model with one-way conversion between rifapentine and 25-desacetyl rifapentine. The absorption rate was nearly doubled in fed versus fasting states. Rifapentine clearance was increased 31% in those receiving efavirenz (EFV)-based versus nevirapine-based ART. Metabolite clearance was allometrically scaled with fat-free mass. Simulations showed lower rifapentine exposures with weight-based compared with fixed dosing. With 10 mg/kg weight-based regimens, 26% and 62% of simulated exposures in <35 kg and 35-45 kg weight classes were above target (AUC0 to 24 h of 257 mg*hr/L); 85% of simulated exposures across all weight classes with fixed dosing were above target. These data support fixed dosing with rifapentine 600 mg daily for TB prevention regardless of weight for PLWH 13 years or older receiving the 4-week regimen and no need for dose adjustment when given with EFV-based ART. Clinical Trials Registration. NCT01404312.

One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis.

BACKGROUND: Tuberculosis is the leading killer of patients with human immunodeficiency virus (HIV) infection. Preventive therapy is effective, but current regimens are limited by poor implementation and low completion rates. METHODS: We conducted a randomized, open-label, phase 3 noninferiority trial comparing the efficacy and safety of a 1-month regimen of daily rifapentine plus isoniazid (1-month group) with 9 months of isoniazid alone (9-month group) in HIV-infected patients who were living in areas of high tuberculosis prevalence or who had evidence of latent tuberculosis infection. The primary end point was the first diagnosis of tuberculosis or death from tuberculosis or an unknown cause. Noninferiority would be shown if the upper limit of the 95% confidence interval for the between-group difference in the number of events per 100 person-years was less than 1.25. RESULTS: A total of 3000 patients were enrolled and followed for a median of 3.3 years. Of these patients, 54% were women; the median CD4+ count was 470 cells per cubic millimeter, and half the patients were receiving antiretroviral therapy. The primary end point was reported in 32 of 1488 patients (2%) in the 1-month group and in 33 of 1498 (2%) in the 9-month group, for an incidence rate of 0.65 per 100 person-years and 0.67 per 100 person-years, respectively (rate difference in the 1-month group, -0.02 per 100 person-years; upper limit of the 95% confidence interval, 0.30). Serious adverse events occurred in 6% of the patients in the 1-month group and in 7% of those in the 9-month group (P = 0.07). The percentage of treatment completion was significantly higher in the 1-month group than in the 9-month group (97% vs. 90%, P<0.001). CONCLUSIONS: A 1-month regimen of rifapentine plus isoniazid was noninferior to 9 months of isoniazid alone for preventing tuberculosis in HIV-infected patients. The percentage of patients who completed treatment was significantly higher in the 1-month group. (Funded by the National Institute of Allergy and Infectious Diseases; BRIEF TB/A5279 ClinicalTrials.gov number, NCT01404312.).

Cardio-ankle vascular index of increased arterial wall stiffness is associated with neurocognitive impairment in well-controlled HIV.

OBJECTIVES: HIV-associated neurocognitive disorders (HAND) remain prevalent in people living with HIV (PLWH) despite widespread use of combined antiretroviral therapy (ART). Vascular disease contributes to the pathogenesis of HAND, but traditional vascular risk factors do not fully explain the relation between vascular disease and HAND. A more direct measure of vascular dysfunction is needed. This cross-sectional study tested whether the cardio-ankle vascular index (CAVI), a novel method to assess arterial stiffness, is associated with HAND among PLWH. METHODS: Participants included 75 non-diabetic adults with well-controlled HIV from an outpatient HIV clinic. We assessed the relation between CAVI and neurocognitive impairment (NCI). The latter was primarily characterized by the Frascati criteria and secondarily (post hoc) using the Global Deficit Score (GDS). Logistic regression models tested whether high CAVI (≥ 8) was independently associated with NCI when controlling for potential confounders. RESULTS: Participants (Mage  = 45.6 ± 8.3 years; 30.1% male) had few traditional cardiovascular disease (CVD) risk factors (hypertension, n = 7; dyslipidaemia, n = 34; body mass index ≥ 25 kg/m2 , n = 12; smoking history, n = 13; 2.2% mean 10-year risk of CVD or stroke). Twelve (16%) participants had high CAVI, which was independently associated with meeting Frascati criteria for NCI [n = 39, odds ratio (OR) = 7.6, p = 0.04], accounting for age, education, gender, income, CD4 nadir, recent CD4 and traditional CVD risk factors. High CAVI was also associated with NCI as reflected by higher GDS (OR = 17.4, p = 0.02). CONCLUSIONS: Cardio-ankle vascular index is a promising measure of vascular dysfunction that may be independently associated with NCI in relatively healthy PLWH. Larger studies should test the utility of CAVI in predicting NCI/decline in PLWH.

Human Immunodeficiency Virus Type 1 Vpu Inhibitor, BIT225, in Combination with 3-Drug Antiretroviral Therapy: Inflammation and Immune Cell Modulation.

BIT225 is a first-in-class inhibitor of human immunodeficiency virus (HIV) type 1 Vpu. A phase II trial enrolled 36 HIV-1-infected, treatment-naive participants in Thailand to receive standard-of-care antiretroviral therapy (ART), tenofovir disoproxil fumarate/emtricitabine/efavirenz (Atripla), with 100 or 200 mg of BIT225 or placebo (daily) for 12 weeks. Combined treatment with BIT225 and ART was found to be generally safe and well tolerated, with antiviral efficacy comparable to that of ART alone. The secondary end point-soluble CD163, a marker of monocyte/macrophage inflammation-was noted to be significantly decreased in the BIT225 arm. Plasma-derived activated CD4+ and CD8+ T cells, natural killer cells, and interleukin 21 were increased in those treated with BIT225. These findings are consistent with inhibition of the known effects of HIV Vpu and may reflect clinically important modulation of inflammatory and immune function. Further clinical study is planned to both confirm and extend these important findings in treatment-naive, and treatment-experienced individuals. Clinical Trials Registration. Australian New Zealand Clinical Trials Registry (Universal Trial Number U1111-1191-2194).

Pharmacogenetic interactions of rifapentine plus isoniazid with efavirenz or nevirapine.

OBJECTIVES: The effect of rifapentine plus isoniazid on efavirenz pharmacokinetics was characterized in AIDS Clinical Trials Group protocol A5279 (NCT01404312). The present analyses characterize pharmacogenetic interactions between these drugs, and with nevirapine. METHODS: A subset of HIV-positive individuals receiving efavirenz- or nevirapine-containing antiretroviral therapy in A5279 underwent pharmacokinetic evaluations at baseline, and again weeks 2 and 4 after initiating daily rifapentine plus isoniazid. Associations with polymorphisms relevant to efavirenz, nevirapine, isoniazid, and rifapentine pharmacokinetics were assessed. RESULTS: Of 128 participants, 101 were evaluable for associations with rifapentine and its active 25-desacetyl metabolite, 87 with efavirenz, and 38 with nevirapine. In multivariable analyses, NAT2 slow acetylators had greater week 4 plasma concentrations of rifapentine (P = 2.6 × 10) and 25-desacetyl rifapentine (P = 7.0 × 10) among all participants, and in efavirenz and nevirapine subgroups. NAT2 slow acetylators also had greater plasma efavirenz and nevirapine concentration increases from baseline to week 4, and greater decreases from baseline in clearance. CYP2B6 poor metabolizers had greater efavirenz concentrations at all weeks and greater nevirapine concentrations at baseline. None of 47 additional polymorphisms in 11 genes were significantly associated with pharmacokinetics. CONCLUSIONS: Among HIV-positive individuals receiving efavirenz or nevirapine, and who then initiated rifapentine plus isoniazid in A5279, NAT2 slow acetylators had greater rifapentine and 25-desacetyl rifapentine concentrations, and greater increases from baseline in plasma efavirenz and nevirapine concentrations. These associations are likely mediated by greater isoniazid exposure in NAT2 slow acetylators.

An Evaluation of Baseline Kidney Function in the REPRIEVE Trial of Pitavastatin in Human Immunodeficiency Virus.

BACKGROUND: Chronic kidney disease is a common comorbid condition among persons living with human immunodeficiency virus (PWH). We characterized baseline kidney function in the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) trial cohort. METHODS: REPRIEVE enrolled PWH with low to moderate cardiovascular risk based on traditional risk factors to evaluate the effect of statin therapy on cardiovascular events. We determined baseline estimated glomerular filtration rate (eGFR) with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease, and Cockcroft-Gault equations, and we evaluated baseline factors associated with eGFR <90 mL/min/1.73 m2 by logistic regression. We performed Bland-Altman plots and scatterplots to assess agreement between equations. RESULTS: Among 7770 participants enrolled, the median age was 50 years, 31% were female (natal sex), 43% black or African American and 15% Asian, the median body mass index (calculated as calculated as weight in kilograms divided by height in meters squared) was 25.8, and the median CD4 cell count 620/µL. The median CKD-EPI eGFR was 97 mL/min/1.73 m2, and 38% had an eGFR <90 mL/min/1.73 m2. In the adjusted model, factors associated with eGFR <90 mL/min/1.73 m2 included white race, older age, higher body mass index, high-income region of enrollment, hypertension, and tenofovir disoproxil fumarate. The CKD-EPI and Modification of Diet in Renal Disease equations demonstrated strong agreement, particularly at lower eGFR values. Overall, there was 56% concordance between the 3 equations (categories <60, 60 to <90, ≥90 mL/min), improving to 73% after accounting for individual body surface area. CONCLUSIONS: REPRIEVE enrolled a diverse cohort including a substantial number of PWH with reduced kidney function. Factors associated with reduced eGFR included traditional risk factors and tenofovir disoproxil fumarate exposure. Three commonly used equations have only fair agreement, with potential implications for both clinical care and epidemiologic studies. CLINICAL TRIALS REGISTRATION: NCT02344290.

Distal Sensory Peripheral Neuropathy in Human Immunodeficiency Virus Type 1-Positive Individuals Before and After Antiretroviral Therapy Initiation in Diverse Resource-Limited Settings.

BACKGROUND: Distal sensory peripheral neuropathy (DSPN) is a complication of human immunodeficiency virus (HIV). We estimate DSPN prevalence in 7 resource-limited settings (RLSs) for combination antiretroviral therapy (cART)-naive people living with HIV (PLWH) compared with matched participants not living with HIV and in PLWH virally suppressed on 1 of 3 cART regimens. METHODS: PLWH with a CD4+ count <300 cells/mm3 underwent standardized neurological examination and functional status assessments before and every 24 weeks after starting cART. Matched individuals not living with HIV underwent the same examinations once.Associations between covariates with DSPN at entry were assessed using the χ2 test, and virally suppressed PLWH were assessed using generalized estimating equations. RESULTS: Before initiating cART, 21.3% of PLWH had DSPN compared with 8.5% of people not living with HIV (n = 2400; χ2(df = 1) = 96.5; P < .00001). PLWH with DSPN were more likely to report inability to work [χ2(df = 1) = 10.6; P = .001] and depression [χ2(df = 1) = 8.9; P = .003] than PLWH without DSPN. Overall prevalence of DSPN among those virally suppressed on cART decreased: 20.3%, week 48; 15.3%, week 144; and 10.3%, week 192. Incident DSPN was seen in 127 PLWH. Longitudinally, DSPN was more likely in older individuals (P < .001) and PLWH with less education (P = .03). There was no significant association between cART regimen and DSPN. CONCLUSIONS: Although the prevalence of DSPN decreased following cART initiation in PLWH, further research could identify strategies to prevent or ameliorate residual DSPN after initiating cART in RLSs.

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.

Long-term Cross-reactivity Against Nonvaccine Human Papillomavirus Types 31 and 45 After 2- or 3-Dose Schedules of the AS04-Adjuvanted Human HPV-16/18 Vaccine.

This analysis focused on long-term cross-reactive immunogenicity against nonvaccine human papillomavirus (HPV) types 31 and 45 following 2 doses of AS04-adjuvanted HPV-16/18 vaccine in girls aged 9-14 years or following 3 doses in women aged 15-25 years, for up to 3 years (HPV-070 study) and up to 5 years (HPV-048 study) after the first vaccination. Both schedules elicited antibodies against HPV-31 and HPV-45 up to 5 years after first dose. The antibody concentration was similar in young girls as compared to women. Specific CD4+ T-cell and B-cell responses to HPV-31 and HPV-45 at month 36 were similar across groups. Clinical trials registration: NCT01381575 and NCT00541970.

Human Immunodeficiency Virus-associated Neurocognitive Impairment in Diverse Resource-limited Settings.

BACKGROUND: Neurocognitive impairment remains a common complication of human immunodeficiency virus (HIV) despite effective antiretroviral therapy (ART). We previously reported improved neurocognitive functioning with ART initiation in 7 resource-limited countries for HIV+ participants from the AIDS Clinical Trials Group (ACTG) 5199 International Neurological Study (INS). Here, we apply normative data from the International Neurocognitive Normative Study (INNS) to INS to provide previously unknown rates of neurocognitive impairment. METHODS: The A5199 INS assessed neurocognitive and neurological performance within a randomized clinical trial with 3 arms containing World Health Organization first-line recommended ART regimens (ACTG 5175; PEARLS). The ACTG 5271 INNS collected normative comparison data on 2400 high-risk HIV-negative participants from 10 voluntary counseling and testing sites aligned with INS. Normative comparison data were used to create impairment ratings for HIV+ participants in INS; associations were estimated using generalized estimating equations. RESULTS: Among 860 HIV+ adults enrolled in ACTG 5199, 55% had no neurocognitive impairment at baseline. Mild neurocognitive impairment was found in 25%, moderate in 17%, and severe in 3% of participants. With the initiation of ART, the estimated odds of impairment were reduced 12% (95% confidence interval, 9%, 14%) for every 24 weeks (P < .0001) on ART. Mild impairment dropped slightly and then remained at about 18% out to week 168. CONCLUSIONS: Almost half of HIV+ participants had neurocognitive impairment at baseline before ART, based on local norms. With ART initiation, there were significant overall reductions in neurocognitive impairment over time, especially in those with moderate and severe impairments. CLINICAL TRIALS REGISTRATION: NCT00096824.

Human Immunodeficiency Virus Type 1 and Tuberculosis Coinfection in Multinational, Resource-limited Settings: Increased Neurological Dysfunction.

BACKGROUND: AIDS Clinical Trial Group 5199 compared neurological and neuropsychological test performance of human immunodeficiency virus type 1 (HIV-1)-infected participants in resource-limited settings treated with 3 World Health Organization-recommended antiretroviral (ART) regimens. We investigated the impact of tuberculosis (TB) on neurological and neuropsychological outcomes. METHODS: Standardized neurological and neuropsychological examinations were administered every 24 weeks. Generalized estimating equation models assessed the association between TB and neurological/neuropsychological performance. RESULTS: Characteristics of the 860 participants at baseline were as follows: 53% female, 49% African; median age, 34 years; CD4 count, 173 cells/µL; and plasma HIV-1 RNA, 5.0 log copies/mL. At baseline, there were 36 cases of pulmonary, 9 cases of extrapulmonary, and 1 case of central nervous system (CNS) TB. Over the 192 weeks of follow-up, there were 55 observations of pulmonary TB in 52 persons, 26 observations of extrapulmonary TB in 25 persons, and 3 observations of CNS TB in 2 persons. Prevalence of TB decreased with ART initiation and follow-up. Those with TB coinfection had significantly poorer performance on grooved pegboard (P < .001) and fingertapping nondominant hand (P < .01). TB was associated with diffuse CNS disease (P < .05). Furthermore, those with TB had 9.27 times (P < .001) higher odds of reporting decreased quality of life, and had 8.02 times (P = .0005) higher odds of loss of productivity. CONCLUSIONS: TB coinfection was associated with poorer neuropsychological functioning, particularly the fine motor skills, and had a substantial impact on functional ability and quality of life. CLINICAL TRIALS REGISTRATION: NCT00096824.

Immunogenicity and safety of 4 vs. 3 standard doses of HBV vaccination in HIV-infected adults with isolated anti-HBc antibody.

BACKGROUND: Presence of isolated anti-HBc antibody is common in HIV-infected patients in endemic areas and could be caused by prior HBV infection with loss of anti-HBs antibody. The role of vaccination in these patients remains controversial and is based largely on limited and low quality data. We, therefore, conducted this study to determine immunogenicity and safety of 4 vs. 3 standard doses of HBV vaccination in HIV-infected adults with isolated anti-HBc antibody. METHODS: An open-label, randomized controlled trial was conducted among HIV-infected patients visiting HIV clinic of the Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand between July and September 2017. Inclusion criteria included ≥ 18 years of age, currently on a stable antiretroviral regimen, CD4+ cell count ≥ 200 cells/mm3, plasma HIV-1 RNA < 20 copies/mL, and isolated anti-HBc antibody. The participants were randomized to receive either 3 standard doses (20 µg at month 0, 1, 6) or 4 standard-doses (20 µg at month 0, 1, 2, 6) of IM HBV vaccination, and were evaluated for anamnestic response at week 4 and vaccine response at week 28. RESULTS: Of the 97 patients screened, 54 (32 male, mean age of 46 years) were enrolled and 27 were allocated to each of the vaccination groups. Anamnestic response occurred in 25.9% vs. 33.3% in 3-dose group vs. 4-dose group, respectively (p = 0.551). The vaccine response rates at week 28 were 85.2% in 3-dose group vs. 88.9% in 4-dose group (p = 1.000); geometric mean titer of anti-HBs antibody at week 28 was 63.8 and 209.8 mIU/mL in 3-dose group and 4-dose group, respectively (p = 0.030). No adverse events were reported. CONCLUSIONS: An anamnestic response occurred in one-third of Thai HIV-infected patients with isolated anti-HBc antibody who received one dose of HBV vaccination; however, the majority were still unprotected. The use of either 3 or 4 standard-doses of vaccination was highly effective and should be recommended in all HIV-infected individuals with isolated anti-HBc antibody. Trial registration ClinicalTrials.gov; NCT03212911. Registered 11 July 2019, https://clinicaltrials.gov/ct2/show/NCT03212911.

Higher rate of long-term serologic response of four double doses vs. standard doses of hepatitis B vaccination in HIV-infected adults: 4-year follow-up of a randomised controlled trial.

BACKGROUND: We previously reported that four doses or four double doses of hepatitis B vaccination regimens could not significantly increase a response rate compared with standard doses. However, the antibody levels were higher in the four doses and four double doses groups. This study followed those patients for at least 3 years and aimed to evaluate the immunogenicity of the three vaccination regimens. METHODS: HIV-infected adults who had CD4+ cell counts > 200 cells/mm3, undetectable plasma HIV-1 RNA, and negative for all hepatitis B virus markers were randomly assigned to receive one of three recombinant vaccines (Hepavax-Gene® Berna, Korea) regimens: 20 µg IM at months 0, 1, and 6 (standard doses group, n = 44), 20 µg IM at months 0, 1, 2, 6 (four doses group, n = 44), or 40 µg IM at months 0, 1, 2, and 6 (four double doses group, n = 44) between February 2011 and May 4, 2012. Of 132 participants, 126 were evaluated from August 2015 to January 2016; 42 in the standard doses, 43 in the four doses, and 41 in the four double doses groups. RESULTS: At a median duration of 49.7 months (range 46.7-53.7) after completion of the primary vaccination schedule, the percentages of responders with anti-HBs ≥ 10 mIU/mL were 57.1% (95% CI 41.5-72.8%) in the standard doses group; 76.7% (95% CI 63.6-89.9%) in the four doses group (P = 0.067 vs. the standard doses group); and 80.5% (95% CI 67.8-93.2%) in the four double doses group (P = 0.033 vs. the standard doses group). Factors associated with a responder were the vaccination schedule (either four doses or four double doses groups) and a younger age. CONCLUSIONS: Despite the highly effectiveness of the standard hepatitis B vaccination regimen at 6 months after completion, the long-term immunogenicity was lower than the four double doses regimen among HIV-infected adults with CD4+ cell counts > 200 cells/mm3 and undetectable plasma HIV-1 RNA. The standard vaccination regimen may not be the best strategy to provide long-term immune response against hepatitis B virus among HIV-infected individuals. Trial registration NCT1289106, NCT02713620.

Dot enzyme-linked immunosorbent assay strip as a screening tool for detection of autoantibody to interferon gamma in sera of suspected cases of adult-onset immunodeficiency.

BACKGROUND: Being able to detect the presence of autoantibodies to interferon (IFN)-γ in serum is essential for evaluating patients with suspected adult-onset immunodeficiency (AOID) with unusual intracellular infections. Most reported patients with AOID have been Asian, although the exact prevalence of this illness is unknown. To date, no standard assay exists to detect autoantibodies to IFN-γ. An easy-to-use, low-cost assay that can be performed in any laboratory would be a valuable tool for clinical management of AOID, as well as better reveal its prevalence. METHODS: Our experimental study exploited a dot enzyme-linked immunosorbent assay (Dot-ELISA) strip to detect autoantibodies to IFN-γ. Sera from 66 HIV-negative patients having autoantibodies to IFN-γ as determined by indirect ELISA were tested. RESULTS: Dot enzyme-linked immunosorbent assay was sensitive (100%) and specific (94.5%), with a positive predictive value of 97.6% and a negative predictive value of 100%. CONCLUSION: This simple method provides prompt qualitative results that can be read visually and used in facilities with limited testing capabilities.

Herpes Simplex Virus Type 2 Acquisition Among HIV-1-Infected Adults Treated With Tenofovir Disoproxyl Fumarate as Part of Combination Antiretroviral Therapy: Results From the ACTG A5175 PEARLS Study.

Objective: Tenofovir disoproxyl fumarate (TDF) disoproxyl fumarate (TDF) has in vitro activity against herpes simplex virus type 2 (HSV-2) and reduced HSV-2 acquisition as preexposure prophylaxis. Whether TDF-containing antiretroviral therapy (ART) reduces HSV-2 acquisition is unknown. Design: Secondary analysis of AIDS Clinical Trials Group A5175, a randomized, open-label study of 3 ART regimens among 1571 participants. Methods: HSV-2 serostatus was assessed at baseline, at study exit, and before a change in ART regimen. Results: Of 365 HSV-2-seronegative persons, 68 acquired HSV-2, with 24 receiving TDF-containing ART and 44 receiving ART without TDF (HSV-2 seroconversion incidence, 6.42 and 6.63 cases/100 person-years, respectively; hazard ratio, 0.89; 95% confidence interval, .55-1.44). Conclusions: HSV-2 acquisition was not reduced in HIV-infected, HSV-2-uninfected persons during TDF-containing ART.

Antifungal susceptibility of invasive Candida bloodstream isolates from the Asia-Pacific region.

Bloodstream infections caused by Candida species are of increasing importance and associated with significant mortality. We performed a multi-centre prospective observational study to identify the species and antifungal susceptibilities of invasive bloodstream isolates of Candida species in the Asia-Pacific region. The study was carried out over a two year period, involving 13 centers from Brunei, Philippines, Singapore, South Korea, Taiwan, Thailand, and Vietnam. Identification of Candida species was performed at each study center, and reconfirmed at a central laboratory. Susceptibility testing was performed using a commercial broth dilution panel (Sensititre YeastOne YST-010, Thermofisher, United Kingdom) with susceptibility categorisation (S = susceptible, S-DD = susceptible dose-dependent) applied using breakpoints from the Clinical Laboratory Standards Institute. Eight hundred and sixty-one Candida isolates were included in the study. The most common species were C. albicans (35.9%), C. tropicalis (30.7%), C. parapsilosis (15.7%), and C. glabrata (13.6%). Non-albicans species exceeded C. albicans species in centers from all countries except Taiwan. Fluconazole susceptibility was almost universal for C. albicans (S = 99.7%) but lower for C. tropicalis (S = 75.8%, S-DD = 6.1%), C. glabrata (S-DD = 94.9%), and C. parapsilosis (S = 94.8%). Echinocandins demonstrated high rates of in vitro susceptibility (S>99%) against C. albicans, C. tropicalis, and C. parapsilosis This study demonstrates that non-albicans species are the most common isolates from bloodstream infections in most countries in the Asia-Pacific region, with C. tropicalis as the predominant species. Because of the prevalence of reduced susceptibility to fluconazole in non-albicans species, the study indicates that echinocandins should be the antifungal of choice in clinically unstable or high-risk patients with documented candidemia.

Seroprevalence of antibodies to measles, mumps, and rubella, and serologic responses after vaccination among human immunodeficiency virus (HIV)-1 infected adults in Northern Thailand.

BACKGROUND: After the global implementation of national immunization programs for prevention of measles, mumps, and rubella (MMR), the prevalences of protective antibodies to these viruses are high in general population. However, there are limited data among human immunodeficiency virus (HIV)-1 infected individuals. This study aimed to determine the seroprevalence of antibodies to these viruses, and the serologic responses after vaccination among HIV-infected adults in Northern Thailand. METHODS: A cross-sectional study was conducted in 500 HIV-infected adults, aged 20-59 years, receiving combination antiretroviral therapy, CD4 cell count ≥200 cells/mm(3), and plasma HIV-1 RNA <50 copies/mL, and 132 HIV-uninfected controls, aged 20-59 years, at Chiang Mai University Hospital during July and August 2011. Prevalences of protective antibodies to these viruses as well as serologic responses after MMR vaccination in those without protective antibody to at least one of the three viruses were compared between groups. RESULTS: The prevalences of protective antibodies to measles, mumps, and rubella were 94.2, 55.0, and 84.6 % among HIV-infected adults, and 97.7, 67.5, and 89.4 % among HIV-uninfected controls, respectively. The prevalence of protective antibody to mumps was significantly lower in HIV-infected adults (p-value = 0.010). MMR vaccination was done in 249 HIV-infected and 46 HIV-uninfected controls; at week 8 to 12 after vaccination, the seroprotective rates against measles, mumps, and rubella in HIV-infected adults were 96.4, 70.7, and 98.0 %, respectively, whereas those in HIV-uninfected controls were 100, 87, and 100 %, respectively. No serious adverse effects were observed. CONCLUSIONS: In contrast to measles and rubella, the prevalence of protective antibody to mumps was low in both HIV-infected adults and HIV-uninfected controls in northern Thailand. The seroprotective rates after MMR vaccination in both groups were considerably high, except only for mumps. Therefore, MMR vaccination should be considered in all HIV-infected adults receiving antiretroviral therapy with undetectable plasma HIV-1 RNA and CD4 cell count ≥200 cells/mm(3). TRIAL REGISTRATION: ClinicalTrials.gov: NCT02724852 , registered on March 31, 2016.