Do Duy Cuong

Evaluation of sequence ambiguities of the HIV-1 pol gene as a method to identify recent HIV-1 infection in transmitted drug resistance surveys.

Identification of recent HIV infection within populations is a public health priority for accurate estimation of HIV incidence rates and transmitted drug resistance at population level. Determining HIV incidence rates by prospective follow-up of HIV-uninfected individuals is challenging and serological assays have important limitations. HIV diversity within an infected host increases with duration of infection. We explore a simple bioinformatics approach to assess viral diversity by determining the percentage of ambiguous base calls in sequences derived from standard genotyping of HIV-1 protease and reverse transcriptase. Sequences from 691 recently infected (≤1 year) and chronically infected (>1 year) individuals from Sweden, Vietnam and Ethiopia were analyzed for ambiguity. A significant difference (p<0.0001) in the proportion of ambiguous bases was observed between sequences from individuals with recent and chronic infection in both HIV-1 subtype B and non-B infection, consistent with previous studies. In our analysis, a cutoff of <0.47% ambiguous base calls identified recent infection with a sensitivity and specificity of 88.8% and 74.6% respectively. 1,728 protease and reverse transcriptase sequences from 36 surveys of transmitted HIV drug resistance performed following World Health Organization guidance were analyzed for ambiguity. The 0.47% ambiguity cutoff was applied and survey sequences were classified as likely derived from recently or chronically infected individuals. 71% of patients were classified as likely to have been infected within one year of genotyping but results varied considerably amongst surveys. This bioinformatics approach may provide supporting population-level information to identify recent infection but its application is limited by infection with more than one viral variant, decreasing viral diversity in advanced disease and technical aspects of population based sequencing. Standardization of sequencing techniques and base calling and the addition of other parameters such as CD4 cell count may address some of the technical limitations and increase the usefulness of the approach.

Transmitted drug resistance and phylogenetic analysis of HIV CRF01_AE in Northern Vietnam

The HIV epidemic in Vietnam began in injecting drug users (IDUs), but increasingly affects the general population. It is therefore important to monitor the spread of infection and, since antiretroviral therapy (ART) is now used more frequently, the prevalence of transmitted drug resistance. Sixty-three 1000 bp pol-gene sequences were generated from treatment-naive HIV-1 CRF01_AE infected patients from four clinics in Northern Vietnam. Four drug resistance mutations; Y181C, L210W, L74I and V75M, were found in four different patients, giving a prevalence of 6.3% (4/63). Earlier studies have shown a lower prevalence and the transmission rate should be regularly monitored prospectively in Vietnam. Additional CRF01_AE (N=190) and outgroup subtype B sequences (N=4) were retrieved from databases and included for phylogenetic analysis and calculations of the time of the most recent common ancestor (tMRCA). The 63 samples from our study clustered into two distinct groups; one small clade (N=3) that had a tMRCA in year 1997.5 and a larger group with an estimated tMRCA in 1989.8. The Vietnamese samples in the large group were distinct from CRF01_AE sequences from Thailand, but closely related to previously sequenced isolates from Vietnam, southern China and the Czech Republic, while the samples in the smaller clade appeared to represent a more recent introduction from Southern Vietnam. Our results showed that sequences from IDUs were intermingled with sequences from sexually infected patients, indicating frequent exchange of virus between the transmission risk groups in Northern Vietnam.

A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis

BACKGROUND TALAROMYCES MARNEFFEI infection is a major cause of human immunodeficiency virus (HIV)–related death in South and Southeast Asia. Guidelines recommend initial treatment with amphotericin B deoxycholate, but this drug has substantial side effects, a high cost, and limited availability. Itraconazole is available in oral form, is associated with fewer unacceptable side effects than amphotericin, and is widely used in place of amphotericin; however, clinical trials comparing these two treatments are lacking. METHODS In this open‐label, noninferiority trial, we randomly assigned 440 HIV‐infected adults who had talaromycosis, confirmed by either microscopy or culture, to receive either intravenous amphotericin B deoxycholate (amphotericin) (219 patients), at a dose of 0.7 to 1.0 mg per kilogram of body weight per day, or itraconazole capsules (221 patients), at a dose of 600 mg per day for 3 days, followed by 400 mg per day, for 11 days; thereafter, all the patients received maintenance therapy with itraconazole. The primary outcome was all‐cause mortality at week 2. Secondary outcomes included all‐cause mortality at week 24, the time to clinical resolution of talaromycosis, early fungicidal activity, relapse of talaromycosis, development of the immune reconstitution inflammatory syndrome (IRIS), and the side‐effect profile. RESULTS The risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], ‐3.9 to 5.6; P<0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P=0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and IRIS than itraconazole. The patients who received amphotericin had significantly higher rates of infusion‐related reactions, renal failure, hypokalemia, hypomagnesemia, and anemia than patients in the itraconazole group. CONCLUSIONS Amphotericin was superior to itraconazole as initial treatment for talaromycosis with respect to 6‐month mortality, clinical response, and fungicidal activity. (Funded by the Medical Research Council and others; IVAP Current Controlled Trials number, ISRCTN59144167.)

Pattern of microbial translocation in patients living with HIV-1 from Vietnam, Ethiopia and Sweden

The role of microbial translocation (MT) in HIV patients living with HIV from low‐ and middle‐income countries (LMICs) is not fully known. The aim of this study is to investigate and compare the patterns of MT in patients from Vietnam, Ethiopia and Sweden.

Elevated CD8 T-cell counts and virological failure in HIV-infected patients after combination antiretroviral therapy.

AbstractElevated CD8 counts with combination antiretroviral therapy (cART) initiation may be an early warning indicator for future treatment failure. Thus, we investigated whether elevated CD8 counts were associated with virological failure (VF) in the first 4 years of cART in Asian HIV-infected patients in a multicenter regional cohort.We included patients from the TREAT Asia HIV Observational Database (TAHOD). Patients were included in the analysis if they started cART between 1996 and 2013 with at least one CD8 measurement within 6 months prior to cART initiation and at least one CD8 and viral load (VL) measurement beyond 6 months after starting cART. We defined VF as VL ≥400 copies/mL after 6 months on cART. Elevated CD8 was defined as CD8 ≥1200 cells/&mgr;L. Time to VF was modeled using Cox regression analysis, stratified by site.In total, 2475 patients from 19 sites were included in this analysis, of whom 665 (27%) experienced VF in the first 4 years of cART. The overall rate of VF was 12.95 per 100 person-years. In the multivariate model, the most recent elevated CD8 was significantly associated with a greater hazard of VF (HR = 1.35, 95% CI 1.14–1.61; P = 0.001). However, the sensitivity analysis showed that time-lagged CD8 measured at least 6 months prior to our virological endpoint was not statistically significant (P = 0.420).This study indicates that the relationship between the most recent CD8 count and VF was possibly due to the CD8 cells reacting to the increase in VL rather than causing the VL increase itself. However, CD8 levels may be a useful indicator for VF in HIV-infected patients after starting cART.

HIV sero-discordance among married HIV patients initiating anti-retroviral therapy in northern Vietnam

AbstractBackgroundIn many countries in Asia, the HIV epidemic is in a concentrated phase, with high prevalence in certain risk groups, such as men who inject drugs. There is also a rapid increase of HIV among women. The latter might be due to high levels of sero-discordant couples and increasing transmission from male to female partners over time.MethodsAll adult married patients initiating antiretroviral treatment at four out-patient clinics in Quang Ninh province in north-eastern Vietnam between 2007 and 2009 were asked to participate in the study. Clinical information was extracted from patients’ records, and a structured questionnaire was used to collect social, demographic and economic data.ResultsTwo hundred eighty-eight married patients for whom information on the HIV status of their spouse was available were included in the study. Overall, the sero-discordance rate was 58%. The sero-discordance rate was significantly higher among married males, 71% had spouses not infected, than married females, of whom 18% had spouses not infected. Other factors associated with a high rate of sero-discordance were injection drug use (IDU) history, tuberculosis (TB) history and the availability of voluntary counselling and testing (VCT) in residential locations. High sero-concordance was associated with college/university education.ConclusionThe sero-discordance was significantly higher among married males than married females. Other factors also related to high sero-discordance were history of IDU, history of TB and the availability of VCT in residential locations. In contrast, college/university education and female sex were significantly related to low sero-discordance. To contain the increasing HIV prevalence among women, measures should be taken to prevent transmission among sero-discordant couples. Trial registration NCT01433601

Socio-economic status and risk of tuberculosis: a case-control study of HIV-infected patients in Asia

SETTING Tuberculosis (TB) is the most common human immunodeficiency virus (HIV) related opportunistic infection and cause of acquired immune-deficiency syndrome related death. TB often affects those from a low socio-economic background. OBJECTIVE To assess the socio-economic determinants of TB in HIV-infected patients in Asia. DESIGN This was a matched case-control study. HIV-positive, TB-positive cases were matched to HIV-positive, TB-negative controls according to age, sex and CD4 cell count. A socio-economic questionnaire comprising 23 questions, including education level, employment, housing and substance use, was distributed. Socio-economic risk factors for TB were analysed using conditional logistic regression analysis. RESULTS A total of 340 patients (170 matched pairs) were recruited, with 262 (77.1%) matched for all three criteria. Pulmonary TB was the predominant type (n = 115, 67.6%). The main risk factor for TB was not having a university level education (OR 4.45, 95%CI 1.50-13.17, P = 0.007). Burning wood or coal regularly inside the house and living in the same place of origin were weakly associated with TB diagnosis. CONCLUSIONS These data suggest that lower socio-economic status is associated with an increased risk of TB in Asia. Integrating clinical and socio-economic factors into HIV treatment may help in the prevention of opportunistic infections and disease progression.

Long-term viral suppression and immune recovery during first-line antiretroviral therapy: a study of an HIV-infected adult cohort in Hanoi, Vietnam

Achieving viral suppression is key in the global strategy to end the HIV epidemic. However, the levels of viral suppression have yet to be described in many resource‐limited settings.

Changes in renal function with long-term exposure to antiretroviral therapy in HIV-infected adults in Asia

Renal disease is common among people living with human immunodeficiency virus (HIV). However, there is limited information on the incidence and risk factors associated with renal dysfunction among this population in Asia.

Factors associated with pre-treatment HIV RNA: application for the use of abacavir and rilpivirine as the first-line regimen for HIV-infected patients in resource-limited settings

Background Abacavir and rilpivirine are alternative antiretroviral drugs for treatment-naïve HIV-infected patients. However, both drugs are only recommended for the patients who have pre-treatment HIV RNA <100,000 copies/mL. In resource-limited settings, pre-treatment HIV RNA is not routinely performed and not widely available. The aims of this study are to determine factors associated with pre-treatment HIV RNA <100,000 copies/mL and to construct a model to predict this outcome. Methods HIV-infected adults enrolled in the TREAT Asia HIV Observational Database were eligible if they had an HIV RNA measurement documented at the time of ART initiation. The dataset was randomly split into a derivation data set (75% of patients) and a validation data set (25%). Factors associated with pre-treatment HIV RNA <100,000 copies/mL were evaluated by logistic regression adjusted for study site. A prediction model and prediction scores were created. Results A total of 2592 patients were enrolled for the analysis. Median [interquartile range (IQR)] age was 35.8 (29.9–42.5) years; CD4 count was 147 (50–248) cells/mm3; and pre-treatment HIV RNA was 100,000 (34,045–301,075) copies/mL. Factors associated with pre-treatment HIV RNA <100,000 copies/mL were age <30 years [OR 1.40 vs. 41–50 years; 95% confidence interval (CI) 1.10–1.80, p = 0.01], body mass index >30 kg/m2 (OR 2.4 vs. <18.5 kg/m2; 95% CI 1.1–5.1, p = 0.02), anemia (OR 1.70; 95% CI 1.40–2.10, p < 0.01), CD4 count >350 cells/mm3 (OR 3.9 vs. <100 cells/mm3; 95% CI 2.0–4.1, p < 0.01), total lymphocyte count >2000 cells/mm3 (OR 1.7 vs. <1000 cells/mm3; 95% CI 1.3–2.3, p < 0.01), and no prior AIDS-defining illness (OR 1.8; 95% CI 1.5–2.3, p < 0.01). Receiver-operator characteristic (ROC) analysis yielded area under the curve of 0.70 (95% CI 0.67–0.72) among derivation patients and 0.69 (95% CI 0.65–0.74) among validation patients. A cut off score >25 yielded the sensitivity of 46.7%, specificity of 79.1%, positive predictive value of 67.7%, and negative predictive value of 61.2% for prediction of pre-treatment HIV RNA <100,000 copies/mL among derivation patients. Conclusion A model prediction for pre-treatment HIV RNA <100,000 copies/mL produced an area under the ROC curve of 0.70. A larger sample size for prediction model development as well as for model validation is warranted.