Incorporation of information diffusion model for enhancing analyses in HIV molecular surveillance.

Molecular surveillance of infections is essential in monitoring their transmission in the population. In this study, newly diagnosed HIV patients' phylogenetic, clinical and behavioural data were integrated, and an information diffusion model was incorporated in analysing transmission dynamics. A genetic network was constructed from HIV sequences, from which transmission cascades were extracted. From the transmission cascades, CRF01_AE had higher values of information diffusion metrics, including scale, speed and range, than that of B, signifying the distinct transmission patterns of two circulating subtypes in Hong Kong. Patients connected in the network, were more likely male, younger, of main circulating subtypes, to have acquired HIV infection locally, and a higher CD4 level at diagnosis. Genetic connections varied among men who have sex with men (MSM) who used different channels of sex networking and varied in their engagement in risk behaviours. MSM using recreational drugs for sex held positions of greater importance within the network. Significant differences in network metrics were observed among MSM as differentiated by their mobile apps usage patterns, evidencing the impact of social network on transmission networks. The applied model in the presence of consistently collected longitudinal data could enhance HIV molecular epidemiologic surveillance for informing future intervention planning.

Latent Tuberculosis Infection Testing Strategies for HIV-Positive Individuals in Hong Kong.

Importance: With immune recovery following early initiation of antiretroviral therapy (ART), the risk of tuberculosis (TB) reactivation among individuals with HIV could be reduced. The current strategy of annual latent TB infection (LTBI) testing should be revisited to increase cost-effectiveness and reduce the intensity of testing for individuals. Objective: To analyze the cost-effectiveness of LTBI testing strategies for individuals in Hong Kong with HIV who had negative LTBI test results at baseline. Design, Setting, and Participants: This decision analytical model study using a cost-effectiveness analysis included 3130 individuals with HIV in Hong Kong, China, which has an intermediate TB burden and a low incidence of HIV-TB coinfection. A system dynamics model of individuals with HIV attending a major HIV specialist clinic in Hong Kong was developed and parameterized by longitudinal clinical and LTBI testing records of patients during a 15-year period. The study population was stratified by age group, CD4 lymphocyte level, ART status, and right of abode. Alternative strategies for LTBI testing after a baseline test were compared with annual testing under different coverages of ART, LTBI testing, and LTBI treatment scenarios in the model. An annual discounting rate of 3.5% was used in cost-effectiveness analysis. Main Outcomes and Measures: Proportion of new TB cases averted above base case scenario, discounted quality-adjusted life-years gained (QALYG), incremental cost, and incremental cost-effectiveness ratios in 2017 to 2023. Results: A total of 3130 patients with HIV (2740 [87.5%] male and 2800 [89.5%] younger than 50 years at HIV diagnosis) with 16 630 person-years of follow-up data from 2002 to 2017 were analyzed. Of these, 94 patients (0.67 [95% CI, 0.51-0.91] per 100 person-years) developed TB. Model estimates of cumulative number of TB cases would reach 146 by 2023, with the annual number of new TB diagnoses ranging from 6 to 8. For patients who had negative LTBI test results at baseline, subsequent LTBI testing strategies were ranked by ascending effectiveness as follows: (1) no testing, (2) test by risk factors, (3) biennial testing for all, (4) up to 3 tests for all, and (5) annual testing for all. Applying a willingness-to-pay threshold of $50 000 per QALYG, none of the subsequent testing strategies were cost-effective. Test by risk factors and up to 3 tests for all were cost-effective only if the willingness-to-pay threshold was increased to $100 000 per QALYG and $200 000 per QALYG, respectively. More new TB cases would be averted by expanding LTBI testing and/or treatment coverage. Conclusions and Relevance: Changing the current testing strategy to less intense testing strategies is likely to be cost-effective in the presence of an increased coverage of baseline LTBI testing and/or treatment.

A longitudinal study on latent TB infection screening and its association with TB incidence in HIV patients.

Latent TB infection (LTBI) in HIV patients, its treatment, and immunological recovery following highly active antiretroviral therapy (HAART) could interact and impact TB disease progression. We aim to examine the factors associated with LTBI and TB disease development among HIV patients. Longitudinal clinical and laboratory data were accessed from the largest HIV specialist clinic in Hong Kong, where HAART and yearly LTBI screening are routinely provided for HIV patients. Between 2002 and mid-2017, among 2079 HIV patients with 14119 person-years (PY) of follow-up, 32% of LTBI screened patients (n = 1740) were tested positive. The overall TB incidence was 1.26/100 PY from HIV diagnosis to HAART initiation, falling to 0.37/100 PY. A lower risk of TB disease progression was associated with local residence, Chinese ethnicity, negative baseline LTBI result, being on HAART, LTBI treatment, higher baseline CD4 and CD4/CD8 ratio. A positive test at baseline, but not subsequent testing results, was significantly associated with TB disease development. Baseline LTBI screening is an important strategy for identifying HIV patients at risk of TB disease progression. Routine repeat LTBI screening on an annual basis might not give additional benefits to patients on HAART with good immunological responses. Such practice should require re-evaluation.

Molecular Characterization of HIV-1 Minority Subtypes in Hong Kong: A Recent Epidemic of CRF07_BC among the Men who have Sex with Men Population.

BACKGROUND: Over the past years, an increasing trend was noticed for non-B and non- CRF01_AE HIV-1 strains prevalence in Hong Kong. OBJECTIVE: In this study, we aimed at using the available HIV-1 pol sequences collected from 1994 to 2013 through our local antiretroviral resistance surveillance program to investigate the molecular epidemiology and evolution of HIV-1 minority subtypes in Hong Kong. We also aimed at investigating their potential association and impact of those transmission risk groups. METHODS: A total of 2,315 HIV-1 partial pol sequences were included. HIV-1 genotypes were determined by REGA Genotyping Tool and phylogenetic analysis with reference sequences. The viral evolutionary rates and time of the most common ancestor (tMRCA) were estimated by Bayesian Markov Chain Monte Carlo (MCMC) interference. RESULTS: Apart from the two prevalent HIV-1 genotypes in Hong Kong (subtype B,41.6%, CRF01_AE,40.5%), phylogenetic analysis revealed a broad viral diversity including CRF07_BC(5.1%), subtype C(4.5%), CRF02_AG(1.1%), CRF08_BC(0.8%), subtype A1(0.8%), subtype G(0.4%), subtype D(0.4%), CRF06_cpx(0.4%), subtype F(0.1%), CRF12_BF(0·04%) and other recombinants(4.5%). The top five minority subtypes were further analyzed which demonstrated distinct epidemiological and phylogenetic patterns. Over 70% of subtypes A1, C and CRF02_AG infections were circulated among non-Chinese Asians or African community in Hong Kong and were mainly transmitted between heterosexual regular partners. Instead, over 90% of CRF07_BC and CRF08_BC patients were Chinese. An epidemic cluster was identified in CRF07_BC and estimated to expand from 2002 onwards based on skyline plot and molecular clock analysis. CONCLUSION: Our results highlighted the emergence of CRF07_BC epidemic in local MSM community, public health interventions targeting the community should be further enhanced to tackle the epidemic.

Changes of sexual risk behaviors and sexual connections among HIV-positive men who have sex with men along their HIV care continuum.

BACKGROUND: While HIV incidence among men who have sex with men (MSM) is increasing in Hong Kong, unprotected sex apparently remains prevalent among those infected but virally non-suppressed. Little is known about how sexual behaviours and sexual connections may change among MSM along their HIV care continuum. METHODS: In this retrospective cross-sectional study, HIV-positive MSM attending the largest HIV specialist clinic in Hong Kong between October and December 2014 were invited to complete a self-administrated structured questionnaire. Their behavioural profile and partner sourcing patterns during the one-year period respectively (a) before HIV diagnosis, (b) after HIV diagnosis, (c) after initiation of antiretroviral treatment and (d) preceding the survey were examined. RESULTS: Of 345 recruited MSM, 304 (88.1%) had treatment initiated and 272 (78.8%) had viral load suppressed. In the first year after HIV diagnosis, the proportion reporting inconsistent condom use dropped from 47.0% to 17.5% (p<0.05) and from 49.6% to 17.8% (p<0.01) for anal sex with main and casual partners respectively. Except for mobile applications, usage of most sex-networking venues decreased significantly after diagnosis. Inconsistent condom usage rate remained at around 20% after treatment initiation and viral load suppression, but the frequency of use of sex-networking venues further varied among virally suppressed MSM. CONCLUSIONS: Most HIV-positive MSM had persistently low level of sexual risk behaviours along their care continuum and achieved viral load suppression, conferring a general reduction of secondary transmission risk in Hong Kong. To increase the effectiveness of Treatment as Prevention strategy, uptake of HIV testing for undiagnosed HIV-positive MSM shall be emphasised.

Combining CD4 recovery and CD4: CD8 ratio restoration as an indicator for evaluating the outcome of continued antiretroviral therapy: an observational cohort study.

OBJECTIVES: Immune recovery following highly active antiretroviral therapy (HAART) is commonly assessed by the degree of CD4 reconstitution alone. In this study, we aimed to assess immune recovery by incorporating both CD4 count and CD4:CD8 ratio. DESIGN: Observational cohort study SETTING AND PARTICIPANTS: Clinical data from Chinese HIV-positive patients attending the largest HIV service in Hong Kong and who had been on HAART for ≥4 years were accessed. MAIN OUTCOME MEASURES: Optimal immune outcome was defined as a combination of a CD4 count ≥500/µL and a CD4:CD8 ratio ≥0.8. RESULTS: A total of 718 patients were included for analysis (6353 person-years). At the end of year 4, 318 out of 715 patients achieved CD4 ≥500/µL, of which only 33% (105 out of 318) concurrently achieved CD4:CD8 ratio ≥0.8. Patients with a pre-HAART CD8 ≤800/µL (428 out of 704) were more likely to be optimal immune outcome achievers with CD4 ≥500/µL and CD4:CD8 ratio ≥0.8, the association of which was stronger after adjusting for pre-HAART CD4 counts. In a multivariable logistic model, optimal immune outcome was positively associated with male gender, younger pre-HAART age and higher pre-HAART CD4 count, longer duration of HAART and pre-HAART CD8 ≤800/µL. Treatment regimen and cumulative viral loads played no significant role in the pattern of immune recovery. CONCLUSIONS: A combination of CD4 count and CD4:CD8 ratio could be a useful approach for the characterisation of treatment outcome over time, on top of monitoring CD4 count alone.

Immune recovery of middle-aged HIV patients following antiretroviral therapy: An observational cohort study.

In HIV-infected persons, age is negatively associated with optimal CD4 recovery following antiretroviral therapy. Our understanding of the situation in older adults, especially the middle-aged is, however, limited. We undertook to examine the latter's pattern of CD4/CD8 recovery following antiretroviral therapy.Retrospective clinical cohort data of HIV patients diagnosed between 1985 and 2014 in Hong Kong were collected. They were categorized by age at treatment initiation, viz., young adults (age 18-49), middle-aged (age 50-64), and elderly (≥65 years' old). Predictors of immune recovery (CD4 count, CD8 count, CD4/CD8 ratio) over time were examined using multivariable linear generalized estimating equations.A total of 2754 patients (aged ≥18) have been on antiretroviral therapy, with baseline characteristics similar between middle-aged and the elderly. Late diagnosis, defined as progression to AIDS within 3 months of HIV diagnosis, was less common in middle-aged (odds ratio = 0.58, 95% confidence interval = 0.37-0.91). Among Chinese patients who have been on treatment for ≥4 years (n = 913), 80.6%, 14.6%, and 4.8% were young adults, middle-aged, and elderly respectively. Late treatment initiation, defined as AIDS diagnosis or CD4 count ≤100 cells/µL before treatment, was common in middle-aged and elderly, the former however had faster CD4 recovery (3.95 vs. 3.36 cells/µL/month), but slower CD8 decline (-1.76 vs. -4.34 cells/µL/month) and CD4/CD8 normalization (0.009 vs. 0.0101/month).As a transitional age group, the immune recovery of middle-aged patients lagged behind young adults largely because of late treatment initiation. Following adoption of early and non-CD4-guided treatment initiation, their long-term clinical outcome is expected to improve.

Performance comparison of an in-house integrase genotyping assay versus the ViroSeq™ Integra48, and study of HIV-1 integrase polymorphisms in Hong Kong.

BACKGROUND: Integrase inhibitors are recently prescribed to multi-class drug resistant HIV-1 patients in Hong Kong. Unlike pol gene, there are no FDA-approved genotypic resistance tests available for int. Limited studies compared the performance between an in-house and commercial integrase genotyping system. Information on baseline polymorphisms was also insufficient in our region. OBJECTIVES: To compare integrase genotyping data obtained from an in-house and ViroSeq™ Integra48 assay, and to illustrate integrase polymorphisms on HIV-1 B and non-B subtypes in Hong Kong. STUDY DESIGN: A total of 283 HIV-1 patients were recruited during 2006-2012 in Hong Kong. All samples were genotyped by an in-house assay for pol and int separately, and 46 of them were further genotyped by ViroSeq™ Integra48. Polymorphisms and resistance mutations were analyzed by Stanford HIV Drug Resistance Database. RESULTS: The included patients were mainly infected by HIV-1 subtype B (38.9%) and CRF01_AE (43.1%), followed by CRF07_BC (5.3%), C (3.9%), CRF02_AG (2.8%), D (1.4%), CRF08_BC (1.1%) or others (3.5%). Of 46 samples genotyped by ViroSeq™ and the in-house assays, all major and minor resistance mutations were concordant. Integrase major resistance mutations were identified in two CRF01_AE raltegravir-treated patients. Integrase minor resistance mutations were observed in subtypes B and CRF01_AE. CONCLUSIONS: With 25% of the commercial cost, the in-house integrase genotyping assay managed to regenerate over 96% concordant results as good as the RUO ViroSeq™ assay. Further investigations are required to understand the effect on integrase minor mutations, which are present in many subtype B and CRF01_AE samples.

Determination of the high prevalence of Dual/Mixed- or X4-tropism among HIV type 1 CRF01_AE in Hong Kong by genotyping and phenotyping methods.

In Hong Kong, the CCR5 antagonist has recently been introduced into salvage therapy for multiclass drug-resistant HIV-1-infected patients. Coreceptor usage must be determined prior to the usage of the CCR5 antagonist, which does not inhibit X4-tropic viruses. This study aimed to determine the tropism prevalence for HIV-1 subtypes B and CRF01_AE in Hong Kong. In addition, a modified promoter-PCR phenotypic assay was used to validate the genotypic tropism prediction on CRF01_AE. One hundred and five subtype B and 98 CRF01_AE antiretroviral-naive patients were recruited for this study. The viral env V3 region isolated from the patients was sequenced and analyzed by Geno2pheno (FPR=5.75% or 10%, Clonal or Clinical), position-specific scoring matrix (WebPSSM, x4r5 subtype B matrix), and the combination of 11/25 and net charge rules. Fifteen concordant and 22 discordant tropism genotyped CRF01_AE samples were further phenotyped by either enhanced sensitivity Trofile assay or an optimized promoter-PCR phenotypic assay. The prevalence of Dual/Mixed- or X4-tropic virus in antiretroviral-naive subtype CRF01_AE was 39.1%, which was significantly higher than subtype B (p<0.05), regardless of the choices of genotypic algorithms. Our phenotypic data proposed that a better genotypic tropism prediction for HIV-1 CRF01_AE would be using both Geno2pheno (FPR=10%, Clonal) and WebPSSM (x4r5 subtype B matrix) algorithms in combination. The sensitivity and specificity for this combination were 88.9% and 89.3%, respectively. The comparatively high prevalence of Dual/Mixed- or X4-tropic virus in CRF01_AE demonstrated the need for special attention to future treatment strategies.

Phylodynamics of HIV-1 subtype B among the men-having-sex-with-men (MSM) population in Hong Kong.

The men-having-sex-with-men (MSM) population has become one of the major risk groups for HIV-1 infection in the Asia Pacific countries. Hong Kong is located in the centre of Asia and the transmission history of HIV-1 subtype B transmission among MSM remained unclear. The aim of this study was to investigate the transmission dynamics of HIV-1 subtype B virus in the Hong Kong MSM population. Samples of 125 HIV-1 subtype B infected MSM patients were recruited in this study. Through this study, the subtype B epidemic in the Hong Kong MSM population was identified spreading mainly among local Chinese who caught infection locally. On the other hand, HIV-1 subtype B infected Caucasian MSM caught infection mainly outside Hong Kong. The Bayesian phylogenetic analysis also indicated that 3 separate subtype B epidemics with divergence dates in the 1990s had occurred. The first and latest epidemics were comparatively small-scaled; spreading among the local Chinese MSM while sauna-visiting was found to be the major sex partner sourcing reservoir for the first subtype B epidemic. However, the second epidemic was spread in a large-scale among local Chinese MSM with a number of them having sourced their sex partners through the internet. The epidemic virus was estimated to have a divergence date in 1987 and the infected population in Hong Kong had a logistic growth throughout the past 20 years. Our study elucidated the evolutionary and demographic history of HIV-1 subtype B virus in Hong Kong MSM population. The understanding of transmission and growth model of the subtype B epidemic provides more information on the HIV-1 transmission among MSM population in other Asia Pacific high-income countries.

Epstein-Barr virus-associated smooth muscle tumor in patients with acquired immunodeficiency syndrome.

Epstein-Barr virus (EBV)-associated smooth muscle tumor (SMT) is a recognized but uncommon disease that is found to occur in patients with immunocompromised conditions such as acquired immunodeficiency syndrome (AIDS). These tumors may be multifocal and located at unusual sites, such as the brain and liver. This report describes the case of 2 AIDS patients with EBV-associated SMT and highlights the features and outcome of this rare but potentially important tumor in human immunodeficiency virus management.

Establishing CD4 thresholds for highly active antiretroviral therapy initiation in a cohort of HIV-infected adult Chinese in Hong Kong.

Studies on the use and outcome of highly active antiretroviral therapy (HAART) in HIV-infected Chinese have been scarce. We evaluated risk of progression to (1) nonaccidental death and (2) new AIDS-defining illness (ADI) or death in 223, 89.9% of 248 HIV-1-infected adult Chinese patients who were first initiated on HAART between 1997 and 2002, and followed through 2003. The study subjects were mostly male (88.3%), aged between 30-49 years (43.9%), and acquired HIV via sexual contact (95.7%). After a median follow-up of 38.6 months, 13 nonaccidental deaths were observed. Overall, 25 patients developed new ADI or died. Using Kaplan-Meier analyses, there was no survival difference of starting HAART at various CD4 strata but a higher risk of progression to new ADI/death in patients with pretreatment CD4 count less than 100 cells per microliter (p = 0.01). On Cox proportional hazards multivariate regression analyses, pretreatment CD4 counts of less than 100 cells per microliter and less than 150 cells per microliter but not higher levels were the cutoffs for increased progression to death (adjusted hazard ratio [HR] = 4.90, 95% confidence interval [CI]: 1.08-22.22) and new ADI/death (adjusted HR = 14.44, 95% CI: 1.95-106.89), respectively. Age 50 years or greater was the only other independent predictor of mortality and new ADI/death after HAART. Further studies are indicated to validate and discern implications of these preliminary findings of a lower CD4 threshold for antiretroviral therapy in a small Chinese HIV cohort.

Delayed progression to death and to AIDS in a Hong Kong cohort of patients with advanced HIV type 1 disease during the era of highly active antiretroviral therapy.

BACKGROUND: The magnitude of the impact of highly active antiretroviral therapy (HAART) since its introduction in non-Western countries is not entirely clear. We studied disease progression among adult patients with advanced human immunodeficiency virus type 1 (HIV-1) infection in the pre-HAART (i.e., 1996 and earlier) and HAART eras in Hong Kong. METHODS: The cohort of patients seen at the Integrated Treatment Center (Hong Kong) from 1984 through mid-2003 was retrospectively examined with respect to 3 clinical end points: death after the diagnosis of acquired immunodeficiency syndrome (AIDS), progression to AIDS after achieving a CD4 cell count of <200 cells/microL, and death after achieving a CD4 cell count of <200 cells/microL. RESULTS: A total of 581 patients with advanced HIV-1 disease had AIDS and/or a CD4 cell count of <200 cells/microL. The incidences of death after AIDS (52.3% vs. 13.6%), AIDS progression after a CD4 cell count of <200 cells/microL (47.7% vs. 20.9%), and death after a CD4 cell count of <200 cells/microL (38.8% vs. 7.0%) were significantly higher among patients in the pre-HAART era than among those in the HAART era (P<.001 for all). On the basis of life-table analysis, the probabilities of death after AIDS (P<.0001), AIDS after a CD4 cell count of <200 cells/microL (P=.0063), and death after a CD4 cell count of <200 cells/microL (P<.0001) diminished in the HAART era, compared with the pre-HAART era. Median survival after AIDS increased from 29.8 months during the pre-HAART era to >70 months during the HAART era (P<.001). Compared with patients in the pre-HAART era, adjusted hazard ratios of clinical events were 0.15 (95% confidence interval [CI], 0.08-0.26) for death after AIDS, 0.38 (95% CI, 0.24-0.60) for AIDS after a CD4 cell count of <200 cells/microL, and 0.25 (95% CI, 0.15-0.40) for death after a CD4 cell count of <200 cells/microL for patients in the HAART era. CONCLUSIONS. The clinical outcome of patients with advanced HIV-1 disease in Hong Kong significantly improved during the HAART era. Our findings of extended durations of survival and AIDS-free status may be relevant to the expected health impacts associated with increased access to HAART in non-Western countries.

A novel CCR5 mutation selectively affects immunoreactivity and fusogenic property of the HIV co-receptor.

A Nepalese heterozygous carrier of a CCR5 mutant, designated 118delF, was characterized. There was a 3 basepair deletion at 352-354 in the CCR5 open reading frame, resulting in the deletion of the phe-118 residue located in the third transmembrane domain. The mutant protein has retained antigen specificity near the third extra-cellular loop (ECL3), but that of ECL2 is markedly reduced. The mutation has also abrogated HIV co-receptor activity. Clinically, the HIV disease had progressed slowly.