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Hidden Drug Resistant HIV to Emerge in the Era of Universal Treatment Access in Southeast Asia
Alexander Hoare,Stephen J. Kerr,Kiat Ruxrungtham,Jintanat Ananworanich,Matthew G. Law,David A. Cooper,Praphan Phanuphak,David P. Wilson
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010981
Abstract: Universal access to first-line antiretroviral therapy (ART) for HIV infection is becoming more of a reality in most low and middle income countries in Asia. However, second-line therapies are relatively scarce.
Use of Human Papillomavirus DNA, E6/E7 mRNA, and p16 Immunocytochemistry to Detect and Predict anal High-Grade Squamous Intraepithelial Lesions in HIV-Positive and HIV-Negative Men Who Have Sex with Men
Nittaya Phanuphak, Nipat Teeratakulpisarn, Somboon Keelawat, Tippawan Pankam, Jiranuwat Barisri, Surang Triratanachat, Amornrat Deesua, Piyanee Rodbamrung, Jiratchaya Wongsabut, Patou Tantbirojn, Saranya Numto, Preecha Ruangvejvorachai, Praphan Phanuphak, Joel M. Palefsky, Jintanat Ananworanich, Stephen J. Kerr
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078291
Abstract: Background Men who have sex with men (MSM) are at high risk of having anal cancer. Anal high-grade squamous intraepithelial lesion (HSIL) is the precursor of anal cancer. We explored the use of different biomarkers associated with human papillomavirus (HPV) infection and HPV-mediated cell transformation to detect and predict HSIL among HIV-positive and HIV-negative MSM. Methodology/Principal Findings A total of 123 HIV-positive and 123 HIV-negative MSM were enrolled and followed for 12 months. High-resolution anoscopy (HRA) with biopsies were performed at every visit along with anal sample collection for cytology, high-risk HPV DNA genotyping, HPV E6/E7 mRNA, and p16 immunocytochemistry. Performance characteristics and area under the receiver operator characteristics curve were calculated for these biomarkers at baseline, and Cox regression compared the usefulness of these biomarkers in predicting incident HSIL. High-risk HPV DNA, E6/E7 mRNA, and p16 immunocytochemistry each identified 43–46% of MSM whose baseline test positivity would trigger HRA referral. E6/E7 mRNA had the highest sensitivity (64.7%) and correctly classified the highest number of prevalent HSIL cases. With the exception of p16 immunochemistry, most tests showed significant increases in sensitivity but decreases specificity versus anal cytology, while the overall number of correctly classified cases was not significantly different. Baseline or persistent type 16 and/or 18 HPV DNA was the only test significantly predicting incident histologic HSIL within 12 months in models adjusted for HIV status and low-grade squamous intraepithelial lesions at baseline. Conclusions/Significance Countries with a high HIV prevalence among MSM and limited HRA resources may consider using biomarkers to identify individuals at high risk of HSIL. E6/E7 mRNA had the highest sensitivity for prevalent HSIL detection regardless of HIV status, whereas type 16 and/or 18 HPV DNA performed best in predicting development of incident HSIL within 12 months.
A feasibility study of immediate versus deferred antiretroviral therapy in children with HIV infection
Jintanat Ananworanich, Pope Kosalaraksa, Umaporn Siangphoe, Chulapan Engchanil, Chitsanu Pancharoen, Pagakrong Lumbiganon, Jintana Intasan, Wichitra Apateerapong, Theshinee Chuenyam, Sasiwimol Ubolyam, Torsak Bunupuradah, Joep Lange, David A Cooper, Praphan Phanuphak, the HIV-NAT 010 Study Team
AIDS Research and Therapy , 2008, DOI: 10.1186/1742-6405-5-24
Abstract: We conducted an open-label pilot randomized clinical trial study in 43 Thai children with CD4 15 to 24% of starting generic AZT/3TC/NVP immediately (Arm 1) or deferring until CD4 < 15% or CDC C (Arm 2). Primary endpoints were recruitment rate, adherence to randomized treatment and retention in trial. Secondary endpoints were % with CDC C or CD4 < 15%. Children were in the trial until the last child reached 108 weeks. Intention to treat and on treatment analyses were performed.Recruitment took 15 months. Twenty-six of 69 (37.7%) were not eligible due mainly to low CD4%. Twenty four and 19 were randomized to arms 1 and 2 respectively. All accepted the randomized arm; however, 3 in arm 1 stopped ART and 1 in arm 2 refused to start ART. Ten/19 (53%) in arm 2 started ART. At baseline, median age was 4.8 yrs, CDC A:B were 36:7, median CD4 was 19% and viral load was 4.8 log. All in arm 1 and 17/19 in arm 2 completed the study (median of 134 weeks). No one had AIDS or death. Four in immediate arm had tuberculosis. Once started on ART, deferred arm children achieved similar CD4 and viral load response as the immediate arm. Adverse events were similar between arms. The deferred arm had a 26% ART saving.Almost 40% of children were not eligible due mainly to low CD4% but adherence to randomized treatment and retention in trial were excellent. A larger study to evaluate when to start ART is feasible.The Children with HIV Early Antiretroviral Therapy (CHER) study recently found that more infants randomized to deferring antiretroviral therapy (ART) until their CD4 fell below 25% died compared to those who started ART before the age of three months [1] but there is currently no randomized trial to guide when to start ART in children older than one year of age. Although, ART has significantly reduced HIV-related morbidity and mortality, it is associated with side effects, interference with daily activities and resistance [2-6]. Deferring the start of ART could possibly reduce these
HIV Lipodystrophy in Participants Randomised to Lopinavir/Ritonavir (LPV/r) +2–3 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (N(t)RTI) or LPV/r + Raltegravir as Second-Line Antiretroviral Therapy
Allison Martin, Cecilia L. Moore, Patrick W. G. Mallon, Jennifer F. Hoy, Sean Emery, Waldo H. Belloso, Praphan Phanuphak, Samuel Ferret, David A. Cooper, Mark A. Boyd, on behalf of the Second-line study team
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077138
Abstract: Objective To compare changes over 48 weeks in body fat, lipids, Metabolic Syndrome and cardiovascular disease risk between patients randomised 1:1 to lopinavir/ritonavir (r/LPV) plus raltegravir (RAL) compared to r/LPV plus 2–3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) as second-line therapy. Methods Participants were HIV-1 positive (>16 years) failing first-line treatment (2 consecutive HIV RNA >500 copies/mL) of NNRTI +2N(t)RTI. Whole body dual energy x-ray absorptiometry was performed at baseline and week 48. Data were obtained to calculate the Metabolic Syndrome and Framingham cardiovascular disease (CVD) risk score. Linear regression was used to compare mean differences between arms. Logistic regression compared incidence of metabolic syndrome. Associations between percent limb fat changes at 48 weeks with baseline variables were assessed by backward stepwise multivariate linear regression. Analyses were adjusted for gender, body mass index and smoking status. Results 210 participants were randomised. The mean (95% CI) increase in limb fat over 48 weeks was 15.7% (5.3, 25.9) or 0.9 kg (0.2, 1.5) in the r/LPV+N(t)RTI arm and 21.1% (11.1, 31,1) or 1.3 kg (0.7, 1.9) in the r/LPV+RAL arm, with no significant difference between treatment arms (?5.4% [?0.4 kg], p>0.1). Increases in total body fat mass (kg) and trunk fat mass (kg) were also similar between groups. Total:HDL cholesterol ratio was significantly higher in the RAL arm (mean difference ?0.4 (1.4); p = 0.03), there were no other differences in lipid parameters between treatment arms. There were no statistically significant differences in CVD risk or incidence of Metabolic Syndrome between the two treatment arms. The baseline predictors of increased limb fat were high viral load, high insulin and participant's not taking lipid lowering treatment. Conclusion In patients switching to second line therapy, r/LPV combined with RAL demonstrated similar improvements in limb fat as an N(t)RTI + r/LPV regimen, but a worse total:HDL cholesterol ratio over 48 weeks. Trial Registration This clinical trial is registered on Clinicaltrials.gov, registry number NCT00931463.
Impact of Multi-Targeted Antiretroviral Treatment on Gut T Cell Depletion and HIV Reservoir Seeding during Acute HIV Infection
Jintanat Ananworanich, Alexandra Schuetz, Claire Vandergeeten, Irini Sereti, Mark de Souza, Rungsun Rerknimitr, Robin Dewar, Mary Marovich, Frits van Griensven, Rafick Sekaly, Suteeraporn Pinyakorn, Nittaya Phanuphak, Rapee Trichavaroj, Wiriya Rutvisuttinunt, Nitiya Chomchey, Robert Paris, Sheila Peel, Victor Valcour, Frank Maldarelli, Nicolas Chomont, Nelson Michael, Praphan Phanuphak, Jerome H. Kim, on behalf of the RV254/SEARCH 010 Study Group
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033948
Abstract: Background Limited knowledge exists on early HIV events that may inform preventive and therapeutic strategies. This study aims to characterize the earliest immunologic and virologic HIV events following infection and investigates the usage of a novel therapeutic strategy. Methods and Findings We prospectively screened 24,430 subjects in Bangkok and identified 40 AHI individuals. Thirty Thais were enrolled (8 Fiebig I, 5 Fiebig II, 15 Fiebig III, 2 Fiebig IV) of whom 15 completed 24 weeks of megaHAART (tenofovir/emtricitabine/efavirenz/ralte?gravir/maraviroc).Sigmoid biopsies were completed in 24/30 at baseline and 13/15 at week 24. At baseline, the median age was 29 years and 83% were MSM. Most were symptomatic (87%), and were infected with R5-tropic (77%) CRF01_AE (70%). Median CD4 was 406 cells/mm3. HIV RNA was 5.5 log10 copies/ml. Median total blood HIV DNA was higher in Fiebig III (550 copy/106 PBMC) vs. Fiebig I (8 copy/106 PBMC) (p = 0.01) while the median %CD4+CCR5+ gut T cells was lower in Fiebig III (19%) vs. Fiebig I (59%) (p = 0.0008). After 24 weeks of megaHAART, HIV RNA levels of <50 copies were achieved in 14/15 in blood and 13/13 in gut. Total blood HIV DNA at week 0 predicted reservoir size at week 24 (p<0.001). Total HIV DNA declined significantly and was undetectable in 3 of 15 in blood and 3 of 7 in gut. Frequency of CD4+CCR5+ gut T cells increased from 41% at baseline to 64% at week 24 (p>0.050); subjects with less than 40% at baseline had a significant increase in CD4+CCR5+ T cells from baseline to week 24 (14% vs. 71%, p = 0.02). Conclusions Gut T cell depletion and HIV reservoir seeding increases with progression of AHI. MegaHAART was associated with immune restoration and reduced reservoir size. Our findings could inform research on strategies to achieve HIV drug-free remission.
Initiation of ART during Early Acute HIV Infection Preserves Mucosal Th17 Function and Reverses HIV-Related Immune Activation
Alexandra Schuetz ,Claire Deleage,Irini Sereti,Rungsun Rerknimitr,Nittaya Phanuphak,Yuwadee Phuang-Ngern,Jacob D. Estes,Netanya G. Sandler,Suchada Sukhumvittaya,Mary Marovich,Surat Jongrakthaitae,Siriwat Akapirat,James L. K. Fletscher,Eugene Kroon,Robin Dewar,Rapee Trichavaroj,Nitiya Chomchey,Daniel C. Douek,Robert J. O′Connell,Viseth Ngauy,Merlin L. Robb,Praphan Phanuphak,Nelson L. Michael,Jean-Louis Excler,Jerome H. Kim,Mark S. de Souza,Jintanat Ananworanich,on behalf of the RV254/SEARCH 010 and RV304/SEARCH 013 Study Groups
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004543
Abstract: Mucosal Th17 cells play an important role in maintaining gut epithelium integrity and thus prevent microbial translocation. Chronic HIV infection is characterized by mucosal Th17 cell depletion, microbial translocation and subsequent immune-activation, which remain elevated despite antiretroviral therapy (ART) correlating with increased mortality. However, when Th17 depletion occurs following HIV infection is unknown. We analyzed mucosal Th17 cells in 42 acute HIV infection (AHI) subjects (Fiebig (F) stage I-V) with a median duration of infection of 16 days and the short-term impact of early initiation of ART. Th17 cells were defined as IL-17+ CD4+ T cells and their function was assessed by the co-expression of IL-22, IL-2 and IFNγ. While intact during FI/II, depletion of mucosal Th17 cell numbers and function was observed during FIII correlating with local and systemic markers of immune-activation. ART initiated at FI/II prevented loss of Th17 cell numbers and function, while initiation at FIII restored Th17 cell numbers but not their polyfunctionality. Furthermore, early initiation of ART in FI/II fully reversed the initially observed mucosal and systemic immune-activation. In contrast, patients treated later during AHI maintained elevated mucosal and systemic CD8+ T-cell activation post initiation of ART. These data support a loss of Th17 cells at early stages of acute HIV infection, and highlight that studies of ART initiation during early AHI should be further explored to assess the underlying mechanism of mucosal Th17 function preservation.
Loss to Followup in HIV-Infected Patients from Asia-Pacific Region: Results from TAHOD
Jialun Zhou,Junko Tanuma,Romanee Chaiwarith,Christopher K. C. Lee,Matthew G. Law,Nagalingeswaran Kumarasamy,Praphan Phanuphak,Yi-Ming A. Chen,Sasisopin Kiertiburanakul,Fujie Zhang,Saphonn Vonthanak,Rossana Ditangco,Sanjay Pujari,Jun Yong Choi,Tuti Parwati Merati,Evy Yunihastuti,Patrick C. K. Li,Adeeba Kamarulzaman,Van Kinh Nguyen,Thi Thanh Thuy Pham,Poh Lian Lim
AIDS Research and Treatment , 2012, DOI: 10.1155/2012/375217
Abstract: This study examined characteristics of HIV-infected patients in the TREAT Asia HIV Observational Database who were lost to follow-up (LTFU) from treatment and care. Time from last clinic visit to 31 March 2009 was analysed to determine the interval that best classified LTFU. Patients defined as LTFU were then categorised into permanently LTFU (never returned) and temporary LTFU (re-entered later), and these groups compared. A total of 3626 patients were included (71% male). No clinic visits for 180 days was the best-performing LTFU definition (sensitivity 90.6%, specificity 92.3%). During 7697 person-years of follow-up, 1648 episodes of LFTU were recorded (21.4 per 100-person-years). Patients LFTU were younger ( ), had HIV viral load ≥500?copies/mL or missing ( ), had shorter history of HIV infection ( ), and received no, single- or double-antiretroviral therapy, or a triple-drug regimen containing a protease inhibitor ( ). 48% of patients LTFU never returned. These patients were more likely to have low or missing haemoglobin ( ), missing recent HIV viral load ( ), negative hepatitis C test ( ), and previous temporary LTFU episodes ( ). Our analyses suggest that patients not seen at a clinic for 180 days are at high risk of permanent LTFU, and should be aggressively traced. 1. Introduction Loss to followup (LTFU) in patients receiving antiretroviral therapy can cause serious consequences such as discontinuation of treatment and increased risk of death [1–3]. At a program level, LTFU can make it difficult to evaluate outcomes of treatment and care [4, 5]. In resource-limited settings, where treatment has become rapidly available following the rollout of antiretroviral therapy, LTFU presents even more challenging obstacles that require special consideration and approaches [6, 7]. One of the key questions in patient followup is how to define a patient as LTFU. This has varied in studies conducted in different settings [8–10]. Defining LTFU using a very early threshold, for example, a patient with no clinic visit in the last three months, may result in many patients being considered as LTFU who would return to clinic naturally at a later date. Defining LTFU with a long threshold, for example, one year, may mean delaying too long before any effort is made to track patients potentially at risk of LTFU. The majority of research into LTFU in HIV-infected patients receiving antiretroviral treatment in resource-limited settings has been conducted in the sub-Saharan Africa region [3, 10–13]. A few studies have been conducted among Asian, mostly female, patients
A Novel Immunodominant CD8+ T Cell Response Restricted by a Common HLA-C Allele Targets a Conserved Region of Gag HIV-1 Clade CRF01_AE Infected Thais
Supranee Buranapraditkun, Ursula Hempel, Patrawadee Pitakpolrat, Rachel L. Allgaier, Pattarawat Thantivorasit, Sven-Iver Lorenzen, Sunee Sirivichayakul, William H. Hildebrand, Marcus Altfeld, Christian Brander, Bruce D. Walker, Praphan Phanuphak, Pokrath Hansasuta, Sarah L. Rowland-Jones, Todd M. Allen, Kiat Ruxrungtham
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023603
Abstract: Background CD8+ T cell responses play an important role in the control of HIV-1. The extensive sequence diversity of HIV-1 represents a critical hurdle to developing an effective HIV-1 vaccine, and it is likely that regional-specific vaccine strains will be required to overcome the diversity of the different HIV-1 clades distributed world-wide. Unfortunately, little is known about the CD8+ T cell responses against CRF01_AE, which is responsible for the majority of infections in Southeast Asia. Methodology/Principal Findings To identify dominant CD8+ T cell responses recognized in HIV-1 clade CRF01_AE infected subjects we drew upon data from an immunological screen of 100 HIV-1 clade CRF01_AE infected subjects using IFN-gamma ELISpot to characterize a novel immunodominant CD8+ T cell response in HIV-1 Gag restricted by HLA-Cw*0102 (p24, 277YSPVSILDI285, YI9). Over 75% of Cw*0102+ve subjects targeted this epitope, representing the strongest response in more than a third of these individuals. This novel CD8 epitope was located in a highly conserved region of HIV-1 Gag known to contain immunodominant CD8 epitopes, which are restricted by HLA-B*57 and -B*27 in clade B infection. Nonetheless, viral escape in this epitope was frequently observed in Cw*0102+ve subjects, suggestive of strong selection pressure being exerted by this common CD8+ T cell response. Conclusions/Significance As HLA-Cw*0102 is frequently expressed in the Thai population (allelic frequency of 16.8%), this immunodominant Cw*0102-restricted Gag epitope may represent an attractive candidate for vaccines specific to CRF01_AE and may help facilitate further studies of immunopathogenesis in this understudied HIV-1 clade.
Risk and prognostic significance of tuberculosis in patients from The TREAT Asia HIV Observational Database
Jialun Zhou, Julian Elliott, Patrick CK Li, Poh Lim, Sasisopin Kiertiburanakul, Nagalingeswaran Kumarasamy, Tuti Merati, Sanjay Pujari, Yi-Ming A Chen, Praphan Phanuphak, Saphonn Vonthanak, Thira Sirisanthana, Somnuek Sungkanuparph, Christopher KC Lee, Adeeba Kamarulzaman, Shinichi Oka, Fujie Zhang, Goa Tau, Rossana Ditangco
BMC Infectious Diseases , 2009, DOI: 10.1186/1471-2334-9-46
Abstract: The risk of TB diagnosis after recruitment was assessed in patients with prospective follow-up. TB diagnosis was fitted as a time-dependent variable in assessing overall survival.At baseline, 22% of patients were diagnosed with TB. TB incidence was 1.98 per 100 person-years during follow up, with predictors including younger age, lower recent CD4 count, duration of antiretroviral treatment, and living in high TB burden countries. Among 3279 patients during 6968 person-years, 142 died (2.04 per 100 person-years). Compared to patients with CDC category A or B illness only, mortality was marginally higher in patients with single Non-TB AIDS defining illness (ADI), or TB only (adjusted HR 1.35, p = 0.173) and highest in patients with multiple non-TB AIDS or both TB and other ADI (adjusted HR 2.21, p < 0.001).The risk of TB diagnosis was associated with increasing immunodeficiency and partly reduced by antiretroviral treatment. The prognosis of developing TB appeared to be similar to that following a diagnosis of other non-TB ADI.The use of highly active antiretroviral therapy (HAART) has led to dramatic reductions in morbidity and mortality in HIV patients [1,2]. However, tuberculosis (TB) remains a common opportunistic infections and a major cause of death among patients with HIV, especially in sub-Saharan African and Asian countries [3-5], where there is a high background prevalence of TB [5-7].The risk of TB in HIV-infected patients and the impact of TB diagnosis on disease progression in HIV infected patients have been well described in Africa [3,8-10]. The Asia-Pacific region has a large burden of both tuberculosis [7], with nearly 5 million prevalent cases and over 3 million new cases in 2006, and HIV, with an estimated 5 million people living with HIV and 380,000 new infections occurring in 2007 [11]. It is estimated that 2.5 million people are living with both infections in the region [5]. Despite the importance of these inter-related epidemics in the region, fe
Trends in CD4 counts in HIV-infected patients with HIV viral load monitoring while on combination antiretroviral treatment: results from The TREAT Asia HIV Observational Database
Jialun Zhou, Thira Sirisanthana, Sasisopin Kiertiburanakul, Yi-Ming A Chen, Ning Han, Poh_Lian Lim, Nagalingeswaran Kumarasamy, Jun Choi, Tuti Merati, Evy Yunihastuti, Shinichi Oka, Adeeba Kamarulzaman, Praphan Phanuphak, Christopher KC Lee, Patrick CK Li, Sanjay Pujari, Vanthanak Saphonn, Matthew G Law
BMC Infectious Diseases , 2010, DOI: 10.1186/1471-2334-10-361
Abstract: Treatment-naive HIV-infected patients who started cART with three or more and had three or more CD4 count and HIV VL tests were included. CD4 count slopes were expressed as changes of cells per microliter per year. Predictors of CD4 count slopes from 6 months after initiation were assessed by random-effects linear regression models.A total of 1676 patients (74% male) were included. The median time on cART was 4.2 years (IQR 2.5-5.8 years). In the final model, CD4 count slope was associated with age, concurrent HIV VL and CD4 count, disease stage, hepatitis B or C co-infection, and time since cART initiation. CD4 count continues to increase with HIV VL up to 20 000 copies/mL during 6-12 months after cART initiation. However, the HIV VL has to be controlled below 5 000, 4 000 and 500 copies/mL for the CD4 count slope to remain above 20 cells/microliter per year during 12-18, 18-24, and beyond 24 months after cART initiation.After cART initiation, CD4 counts continued to increase even when the concurrent HIV VL was detectable. However, HIV VL needed to be controlled at a lower level to maintain a positive CD4 count slope when cART continues. The effect on long-term outcomes through the possible development of HIV drug resistance remains uncertain.Studies show that latent infection of CD4 cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective anti-retroviral therapy [1]. To suppress viral replication so that the VL is below the level of detection with standard assays is thus one of the aims at the start of antiretroviral treatment. Maximal and durable suppression of HIV VL prevents or delays development of drug resistant mutations, preserves CD4 cells, and eventually results in better clinical outcomes. According to the US guidelines, if HIV VL suppression is not achieved, it is necessary to change to a new regimen, a second or third line regimen, with at least two active drugs [2].HIV-infected patients in most developing countries h
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