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Cryptococcosis is a life-threatening fungal infection among human immunodeficiency virus (HIV)-positive patients and also occurs frequently in HIV-negative patients. A retrospective cohort study was conducted among patients with cryptococcosis. Clinical manifestations, laboratory findings, treatment, and outcomes for 149 HIV-positive and 29 HIV-negative patients were compared. Neurological involvement occurred more frequently in HIV-positive patients (91.9 versus 20.7%, P0.001), whereas pulmonary involvement was more frequently observed in HIV-negative patients (34.5 versus 2.7%, P0.001). Ninety percent of HIV-positive patients and 74% of HIV-negative patients had positive serum cryptococcal antigen (P=0.119). HIV-positive patients were more likely to have a cerebrospinal fluid (CSF) preparation that is positive for India ink staining (81 versus 50%, P0.001) and a CSF cryptococcal antigen titer ofor =1:1,024 (61.1 versus 16.7%, P=0.038). Most of the patients in both groups received amphotericin B as the primary therapy. Cryptococcosis-related mortality was high and did not differ between the two groups (22.2 versus 34.5%, P=0.162). Kaplan-Meier analysis revealed that HIV-positive patients had a higher relapse rate (P=0.011), especially among those lacking antiretroviral therapy. In conclusion, clinical presentation of cryptococcosis among HIV-negative patients varies and differs from that of HIV-positive patients. Awareness and prompt management are crucial for establishing a diagnosis and initiating proper treatment.

Nevirapine (NVP) is commonly used as a component of first-line antiretroviral therapy in resource-limited countries. We aimed to determine the risk factors for NVP-associated rash among HIV-infected patients who were initiated NVP at low CD4 cell counts in a resource-limited setting. A case-control study was conducted in HIV-infected patients who developed rash after taking NVP (case) and those who did not have rash (control). A total of 357 patients with a mean (SD) age of 36.4 (7.5) years and 52.1% male were included in the study. Mean body weight (SD) was 55.5 (10.5) kg. Of all, 179 (49.0%) patients had a history of AIDS-defining illness and 57 (16.0%) patients had history of drug allergy. Median (IQR) CD4 cell counts at the time of NVP initiation was 95 (31-226) cells/mm(3). There were 115 patients in case group and 242 patients in control group. In case group, 43.0%, 54.4%, and 2.6% of patients developed grade 2, 3, and 4 of rash, respectively. Median time to develop rash was 12 (95%CI, 10.5-13.5) days. By logistic regression, history of drug allergy (OR, 3.41; 95%CI, 1.79-6.52), body weight (OR, 1.22 per each 5 kg decrement; 95%CI, 1.08-1.38), CD4 cells counts (OR, 1.20 per each 50 cells/mm(3) increment; 95%CI, 1.12-1.30), and AIDS-defining illness (OR, 0.42; 95%CI, 0.25-0.70) were significantly associated with rash. In resource-limited settings where patients were initiated NVP at low CD4 cell counts, history of drug allergy, lower body weight, and higher CD4 cell count are the risk factors for NVP-associated rash. Initiation of NVP in patients with these risks needs closed monitoring.

Objectives Long-term nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral treatment failure in most developing countries has led to broad cross-resistance within NNRTI and nucleoside reverse transcriptase inhibitor (NRTI) classes. In this study, we investigated the efficacy and tolerability of a double boosted protease inhibitor (PI) regimen in this setting. Methods A total of 64 HIV-infected patients who had failed NNRTI-based regimens were randomized to receive either lopinavir/saquinavir/ritonavir [LPV/SQV/r; 400/1000/100 mg twice a day (bid)] alone or indinavir/ritonavir (IDV/r; 800/100 mg bid) plus two NRTIs optimized with genotypic drug resistance guidance. Patients who had no available optimized NRTI backbone were allocated to the LPV/SQV/r arm. Results At 48 weeks, the percentages of patients with plasma viral load

fixed-dose combination of stavudine/lamivudine/nevirapine (d4T/3TC/NVP) is extensively used in developing countries because it is the most accessible antiretroviral therapy (ART). In resource-limited settings the majority of patients for whom this initial ART regimen failed cannot afford resistance testing. Protease inhibitor (PI)-based regimens are commonly used as the second ART regimen in this population. The choice of nucleoside reverse transcriptase inhibitors (NRTIs) as the backbone in the second ART regimen is primarily based on the history of ART experience when resistance testing is not available. However the options for NRTI as the backbone are limited by NRTI cross resistance and the cost of abacavir and didanosine. In a multicenter study of Asian patients nearly 40% who stop d4T/3TC/NVP cannot afford the next regimen. Tenofovir is expected to be available in Thailand and other developing countries in Asia in early 2007 at a low cost. For a large number of patients for whom a fixed-dose combination of d4T/3TC/NVP failed their physicians plan to use tenofovir in the second regimen. Some mutation patterns after failure of d4T/3TC/NVP regimen may limit the use of tenofovir in this setting. (excerpt)

A fixed-dose combination of stavudine lamivudine and nevirapine is extensively used as an antiretroviral regimen in developing countries because of its affordability. Virological failure with this regimen has become more common and a second-line regimen needs to be prepared in the national program. Genotypic resistance testing was conducted among human immunodeficiency virus type 1 (HIV-1)-infected patients who experienced treatment failure with their first antiretroviral regimen (a fixed-dose combination of stavudine lamivudine and nevirapine) during 2003-2005. Patterns of resistance mutations and options for a second-line regimen were studied. We studied 98 patients (mean age 35.2 years) of whom 63% were male. The median duration of antiretroviral therapy was 20 months. The median HIV-1 RNA load at the time of virological failure detection was 4.1 log copies/mL. The prevalences of patients with >/= 1 major mutation conferring drug resistance to nucleoside reverse-transcriptase inhibitorsand nonnucleoside reverse-transcriptase inhibitors were 95% and 92% respectively. M184V was the most common nucleoside reverse-transcriptase inhibitor resistance mutation (observed in 89% of patients). Thymidine analogue mutations K65R and Q151M were observed in 37% 6% and 8% of patients respectively. Patients with an HIV-1 RNA load of >14 log copies/mL at the time of treatment failure had higher prevalence of thymidine analogue mutations (P = .041) K65R (P = .031) and Q151M (P = .008) mutations. The second-line regimen was determined in a resource-limited setting where tenofovir and enfuvirtide are not available; the options were limited for 48% of patients. After experiencing treatment failure with a fixed-dose combination of stavudine lamivudine and nevirapine almost all patients have lamivudine and nonnucleoside reverse-transcriptase inhibitor resistance. The options for a second-line regimen are limited for one-half of these patients. In resource-limited settings where availability of antiretroviral agents is limited strategies for prevention of HIV-1 resistance are crucial. Early detection of virological failure may provide more options and better treatment outcomes. (authors)

Summary Background Thai patients with HIV have higher exposure to HIV protease inhibitors than do white people and dose reduction might be possible. We compared the efficacy of low-dose with standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai patients with HIV. Methods In this randomised, open-label, non-inferiority trial, we recruited patients aged 18 years or older who were receiving ritonavir-boosted protease-inhibitor-based antiretroviral therapy (ART) with HIV plasma viral loads of less than 50 copies per mL, an alanine aminotransferase concentration of less than 200 IU/L, and a creatinine clearance of at least 60 mL/min from 14 hospitals in Thailand. We excluded patients who had active AIDS-defining disease or opportunistic infections, had a history of an HIV viral load of 1000 copies per mL or more after 24 weeks of any ritonavir-boosted protease-inhibitor-based ART, used concomitant medications that could interact with the study drugs, were pregnant or lactating, had illnesses that might change the effect of the study drugs, or had a history of sensitivity to the study drugs. A biostatistician at the study coordinating centre randomly allocated patients (1:1) to switch the protease inhibitor for oral atazanavir 200 mg and ritonavir 100 mg or for atazanavir 300 mg and ritonavir 100 mg once daily, both with two nucleoside or nucleotide reverse transcriptase inhibitors at recommended doses. Randomisation was done with a minimisation schedule, stratified by recruiting centre, use of tenofovir, and use of indinavir as a component of the preswitch regimen. The primary endpoint was the proportion of patients with viral loads of less than 200 copies per mL at week 48, and we followed up patients every 12 weeks. Treatments were open label, the non-inferiority margin was −10%, and all patients who received at least one dose of study medication were analysed. This trial is registered with ClinicalTrials.gov, number NCT01159223. Findings Between July 6, 2011, and Dec 23, 2013, we randomly assigned 559 patients: 279 to receive atazanavir 200 mg and ritonavir 100 mg (low dose) and 280 to atazanavir 300 mg and ritonavir 100 mg (standard dose). At week 48, 265 (97·1%) of 273 in the low-dose group and 267 (96·4%) of 277 in the standard-dose group had viral loads of less than 200 copies per mL (difference 0·68; 95% CI −2·29 to 3·65). Seven (3%) of 273 in the low-dose group and 21 (8%) of 277 in the standard-dose group discontinued their assigned treatment (p=0·01). 46 (17%) of 273 participants in the low-dose group and 97 (35%) of 277 in the standard-dose group had total bilirubin grade 3 or higher toxicity (≥3·12 mg/dL; p Interpretation A switch to low-dose atazanavir should be recommended for Thai patients with well controlled HIV viraemia while on regimens based on boosted protease inhibitors. Funding The National Health Security Office and Kirby Institute for Infection and Immunity in Society.

Asalaysa Bushyakanist,1 Apichaya Puangpetch,2,3 Chonlaphat Sukasem,2,3 Sasisopin Kiertiburanakul11Department of Medicine, 2Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 3Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, ThailandObjectives: The objectives of this study were to describe the use of pharmacogenetics in clinical practice for the treatment of individuals with human immunodeficiency virus (HIV) infection and to determine the treatment outcomes of HIV-infected patients in whom pharmacogenetic testing was performed.Methods: This study involves a retrospective collection of medical records of HIV-infected patients who attended Ramathibodi Hospital during January 2011 to November 2014 and in whom pharmacogenetic testing was performed. We reviewed patients' characteristics, reasons for pharmacogenomic testing, results of human leukocyte antigen-B* (HLA-B*) 5701, HLA-B*3505, HLA-B*4001, CYP2B6, and antiretroviral drug (ARV) levels, treatment planning after the physicians were informed the results, and outcome after changing the treatment.Results: A total of 103 HIV-infected patients with a median age of 46 (range, 20–85) years were enrolled, and 68.9% of them were male. The reasons for pharmacogenomic testing were having adverse drug reactions besides rash (37.9%), screening before prescribing ARV (36.9%), choice of next ARV (19.4%), and confirmation of the cause of skin rash (5.8%). After the physicians knew the results, they adjusted the treatment plan including changing the regimens, changing the ARV dose for avoiding toxicity, and stopping ARV. Among 45 patients, side effects, such as dizziness from efavirenz or rash from abacavir, were improved in 96.4%. Among 27 patients, abnormal laboratory results, such as renal insufficiency from tenofovir or anemia from zidovudine, were improved and some returned to normal in 59.3%. HIV RNA was undetectable after treatment adjustment in 94.9%.Conclusion: The benefits of pharmacogenetic testing are either guiding the initial drug regimen or individualizing regimen, increasing efficacy, and simultaneously avoiding adverse drug reactions. Use of pharmacogenetic testing in HIV-infected Thai adults should be considered.Keywords: adverse drug reaction, antiretroviral drugs, clinical practice, HIV, pharmacogenetics, Thailand

Background There is an urgent need for a simple and accurate test for the diagnosis of human Mycobacterium tuberculosis, the infectious agent causing tuberculosis (TB). Here we describe a serological test based on light emitting recombinant proteins for the diagnosis of pulmonary Mycobacterium tuberculosis infection. Methods Luciferase Immunoprecipitation Systems (LIPS), a fluid-phase immunoassay, was used to examine antibody responses against a panel of 24 different M. tuberculosis proteins. Three different strategies were used for generating the constructs expressing the recombinant fusion M. tuberculosis proteins with luciferase: synthetic gene synthesis, Gateway recombination cloning, and custom PCR synthesis. A pilot cohort of African pulmonary TB patients was used for initial antibody screening and confirmatory studies with selected antigens were performed with a cohort from Thailand and healthy US blood donors. In addition to testing M. tuberculosis antigens separately, a mixture that tested seven antigens simultaneously was evaluated for diagnostic performance. Results LIPS testing of a pilot set of serum samples from African pulmonary TB patients identified a potential subset of diagnostically useful M. tuberculosis antigens. Evaluation of a second independent cohort from Thailand validated highly significant antibody responses against seven antigens (PstS1, Rv0831c, FbpA, EspB, bfrB, HspX and ssb), which often showed robust antibody levels up to 50- to 1000-fold higher than local community controls. Marked heterogeneity of antibody responses was observed in the patients and the combined results demonstrated 73.5 % sensitivity and 100 % specificity for detection of pulmonary TB. A LIPS test simultaneously employing the seven M. tuberculosis antigen as a mixture matched the combined diagnostic performance of the separate tests, but showed an even higher diagnostic sensitivity (90 %) when a cut-off based on healthy US blood donors was used. Conclusion A LIPS immunoassay employing multiple M. tuberculosis antigens shows promise for the rapid and quantitative serological detection of pulmonary TB. Electronic supplementary material The online version of this article (doi:10.1186/s12866-015-0545-y) contains supplementary material, which is available to authorized users.

BACKGROUND:HIV drug resistance (HIVDR) is the major cause of treatment failure after scaling up of antiretroviral therapy (ART). HIVDR testing prior to ART initiation is not routinely performed in resource-limited settings. We aimed to assess the prevalence of primary HIVDR by short reverse transcriptase (RT) genotypic resistance assay and evaluate of the impact of the mutations on the treatment outcomes. METHODS:A prospective cohort study was conducted in treatment-naïve HIV-infected patients. Fourteen major mutations of codon 99-191 on the RT gene were selected (K103N, V106A/M, V108I, Q151M, Y181C/I, M184V/I, Y188C/L/H, and G190S/A) at a cost of testing of 35 USD. The association between the presence of primary HIVDR and undetectable HIV RNA (

HIV drug resistance assessments and interpretations can be obtained from genotyping (GT), virtual phenotyping (VP) and laboratory-based phenotyping (PT). We compared resistance calls obtained from GT and VP with those from PT (GT-PT and VP-PT) among CRF01_AE and subtype B HIV-1 infected patients. GT predictions were obtained from the Stanford HIV database. VP and PT were obtained from Janssen Diagnostics BVBA's vircoType(TM) HIV-1 and Antivirogram®, respectively. With PT assumed as the "gold standard," the area under the curve (AUC) and the Bland-Altman plot were used to assess the level of agreement in resistance interpretations. A total of 80 CRF01_AE samples from Asia and 100 subtype B from Janssen Diagnostics BVBA's database were analysed. CRF01_AE showed discordances ranging from 3 to 27 samples for GT-PT and 1 to 20 samples for VP-PT. The GT-PT and VP-PT AUCs were 0.76-0.97 and 0.81-0.99, respectively. Subtype B showed 3-61 discordances for GT-PT and 2-75 discordances for VP-PT. The AUCs ranged from 0.55 to 0.95 for GT-PT and 0.55 to 0.97 for VP-PT. Didanosine had the highest proportion of discordances and/or AUC in all comparisons. The patient with the largest didanosine FC difference in each subtype harboured Q151M mutation. Overall, GT and VP predictions for CRF01_AE performed significantly better than subtype B for three NRTIs. Although discrepancies exist, GT and VP resistance interpretations in HIV-1 CRF01_AE strains were highly robust in comparison with the gold-standard PT.

Dear Editor: In Asia, an estimated 4.8 million people were living with HIV in 2012. Women accounted for a growing proportion of HIV infections, increasing from 21% in 1990 to 35% in 2009. Gender-based analysis in clinical and operational research is still considered understudied. Better understanding of the differences in clinical management, care delivery, and outcomes between males and females in this region may enhance individualization of treatment and improve efficacy and safety outcomes of highly active antiretroviral therapy (HAART). The study objective was to evaluate the effect of sex on viro-immunological responses to HAART, treatment outcomes, and toxicities in a regional observational cohort in the Asia-Pacific. Established in 2003, the TREAT Asia HIV Observational Database (TAHOD) is a collaborative observational cohort study involving 21 sites in 12 countries in the Asia-Pacific region. Detailed methods have previously been published. Briefly, observational data on a range of demographic variables, clinical outcomes, and laboratory testing results are semi-annually transferred to a common data management center. Ethical approvals are obtained from participating sites, the coordinating center, and the data management and biostatistics center. Endpoints for this analysis included changes in CD4 count, proportions of patients with undetectable HIV viral load at 96 weeks after HAART initiation, rates of new AIDS or death, loss to follow-up (defined as not seen in clinic for > 12 months), treatment change due to toxicity, and frequency of CD4 and HIV viral load monitoring. Stepwise multivariate linear regression and logistic regression models were used to evaluate the independent associations of baseline variables with change in CD4 counts and proportion of patients reaching undetectable HIV viral load ( < 500 copies/mL) at 96 weeks. Multivariate Cox proportional hazards models were used to determine predictors of new AIDS or death, loss

New evidence has emerged regarding when to commence antiretroviral therapy (ART), optimal treatment regimens, management of HIV co-infection with opportunistic infections, and management of ART failure. The 2014 guidelines were developed by the collaborations of the Department of Disease Control, Ministry of Public Health (MOPH) and the Thai AIDS Society (TAS). One of the major changes in the guidelines included recommending to initiating ART irrespective of CD4 cell count. However, it is with an emphasis that commencing HAART at CD4 cell count above 500 cell/mm3 is for public health, in term of preventing HIV transmission and personal benefit. In tuberculosis co-infected patients with CD4 cell counts ≤50 cells/mm3 or with CD4 cell counts >50 cells/mm3 who have severe clinical disease, ART should be initiated within 2 weeks of starting tuberculosis treatment. The preferred initial ART regimen in treatment naïve patients is efavirenz combined with tenofovir and emtricitabine or lamivudine. Plasma HIV viral load assessment should be done twice a year until achieving undetectable results; and will then be monitored once a year. CD4 cell count should be monitored every 6 months until CD4 cell count ≥350 cells/mm3 and with plasma HIV viral load 1,000 copies/mL while on ART. Ritonavir-boosted lopinavir or atazanavir in combination with optimized two nucleoside-analogue reverse transcriptase inhibitors is recommended after initial ART regimen failure. Long-term ART-related safety monitoring has also been included in the guidelines. Electronic supplementary material The online version of this article (doi:10.1186/s12981-015-0053-z) contains supplementary material, which is available to authorized users.

Background.More than 11.7 million people are currently receiving antiretroviral therapy (ART) in low- and middle-income countries (LMICs), and focused efforts are needed to ensure high levels of adherence and to minimize treatment failure. Recently, international targets have emphasized the importance of long-term virological suppression as a key measure of program performance. Methods.We systematically reviewed publications and conference abstracts published between January 2006 and May 2013 that reported virological outcomes among human immunodeficiency virus type 1 (HIV-1)-infected adults receiving first-line ART for up to 5 years in LMICs. Summary estimates of virological suppression after 6, 12, 24, 36, 48, and 60 months of ART were analyzed using random-effects meta-analysis. Intention-to-treat (ITT) analysis assumed all participants who were lost to follow-up, died, or stopped ART as having virological failure. Results.Summary estimates of virological suppression remained >80% for up to 60 months of ART for all 184 included cohorts. ITT analysis yielded 74.7% (95% confidence interval [CI], 72.2-77.2) suppression after 6 months and 61.8% (95% CI, 44.0-79.7) suppression after 48 months on ART. Switches to second-line ART were reported scarcely. Conclusions.Among individuals retained on ART, virological suppression rates during the first 5 years of ART were high (>80%) and stable. Suppression rates in ITT analysis declined during 4 years.

Characteristics of the cohorts used for LIPS testing. (PPT 79Â kb)

Background Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. Methods and Findings We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05–1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06–1.25), North America (OR = 1.19; 95% CI: 1.12–1.26), Europe (OR = 1.07; 95% CI: 1.01–1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12–1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92–1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. Conclusions Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen., In this individual patient and sequence-level meta-analysis, Soo-Yon Rhee and colleagues measure regional trends in HIV-1 transmitted drug resistance prevalence and investigate the specific mutations responsible for TDR in different regions and in different virus subtypes., Editors' Summary Background About 35 million people are currently infected with HIV, the virus that causes AIDS by destroying immune system cells and leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected individuals died within ten years of infection. Then, in 1996, effective antiretroviral (ARV) therapy—drug combinations that suppress HIV replication by inhibiting reverse transcriptase and other essential viral enzymes—became available. For people living in affluent countries, HIV/AIDS became a chronic condition, but because ARV therapy was expensive, HIV/AIDS remained fatal in low- and middle-income countries (LMICs). In 2003, the international community began to work towards achieving universal access to ARV therapy. Now, more than 10 million HIV-positive individuals in LMICs receive ARV therapy, usually as a fixed-dose combination of two nucleoside reverse transcriptase inhibitors (NRTIs), such as tenofovir and lamivudine, plus a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as efavirenz or nevirapine. Why Was This Study Done? The global scale-up of ARV therapy has reduced deaths from HIV/AIDS and the incidence of HIV infection in LMICs, but the development of resistance to ARV therapy is threatening these advances. HIV rapidly accumulates genetic changes (mutations), some of which make HIV resistant to ARV therapy. Up to 30% of patients receiving a fixed-dose NRTI/NNRTI combination develop virological failure, and a high proportion of these patients develop mutations associated with resistance to the ARVs in their regimen. Moreover, the proportion of newly infected, ARV-naïve individuals with transmitted drug resistance (TDR) is also increasing. Organizations involved in HIV/AIDS control need to understand the regional and temporal mutational patterns of TDR to inform the development of guidelines for first-line ARV therapy and of inexpensive resistance mutation assays for use in LMICs. Here, using a statistical approach called meta-analysis to combine information from individual patients about the resistance mutations they carry, the researchers investigate the molecular epidemiology of TDR (the patterns of molecular changes underlying TDR in populations) and identify the HIV drug-resistance mutations most responsible for TDR in different world regions. What Did the Researchers Do and Find? The researchers identified 287 studies published between 2000 and 2013 from 111 countries that included the reverse transcriptase sequences of HIV viruses from 50,870 ARV-naïve, HIV-positive individuals. The researchers analyzed each virus sequence for the presence of 93 surveillance drug-resistance mutations (SDRMs) previously shown to be specific indicators of TDR. Meta-analysis of these data indicated that the average overall prevalence of TDR (the proportion of ARV-naïve, HIV-positive individuals infected with a virus carrying one or more SDRMs) ranged from 2.8% in sub-Saharan Africa to 11.5% in North America. In sub-Saharan Africa, the odds (chance) of TDR increased 1.09-fold per year following national ARV scale-up; this increase was attributable to an increase in NRTI- and NNRTI-associated resistance. By contrast, in LMICs in south/southeast Asia, the odds of TDR remained unchanged following ARV scale-up. In Latin America/Caribbean, North America, Europe, and upper-income Asian countries, the odds of TDR have increased by around 1.10-fold per year since 1995, mainly as a result of increased NNRTI resistance. Four NNRTI-associated and 16 NRTI-associated SDRMs accounted for most NNRTI- and NRTI-associated TDR, respectively, in all regions. Notably, in sub-Saharan Africa and south/southeast Asia, most of the NNRTI-associated SDRMs detected were associated with high-level resistance to nevirapine or efavirenz. Finally, the researchers report that 95% of TDR viruses in sub-Saharan Africa and south/southeast Asia were unrelated and had therefore arisen independently. What Do These Findings Mean? Because many drug-resistance mutations reduce HIV’s fitness and tend to be lost rapidly in individuals not exposed to ARV therapy, differences among the datasets used in this meta-analysis with respect to how long each ARV-naïve patient had been infected with HIV before virus sampling may limit the accuracy of these findings. Nevertheless, the finding that most of the TDR strains detected in sub-Saharan Africa and south/southeast Asia arose independently suggests that improved patient adherence to ARV therapy and the use of ARV regimens that contain drugs to which HIV rarely develops resistance (regimens with a high genetic barrier to resistance) should reduce the generation of new ARV-resistant strains and mitigate TDR increases. In addition, the finding that a few NNRTI-resistance mutations were responsible for most cases of transmitted high-level resistance suggests that an inexpensive assay that detects these specific mutations may be useful for pre-therapy screening in LMICs with high TDR levels. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001810. Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS NAM/aidsmap provides basic information about HIV/AIDS, summaries of recent research findings on HIV care and treatment, and personal stories about living with HIV/AIDS Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on antiretroviral drugs and on universal access to ARV therapy; Avert also provides personal stories about living with HIV/AIDS The World Health Organization provides information on all aspects of HIV/AIDS (in several languages), including its guidelines on the use of antiretroviral therapy for treating and preventing HIV infection The UNAIDS World AIDS Day Report 2014 provides up-to-date information about the AIDS epidemic and efforts to halt it, including progress towards universal access to antiretroviral therapy The Stanford University HIV Drug Resistance Database includes information about surveillance drug-resistant mutations (SDRMs) and an interactive map displaying HIV drug resistance in ARV-naïve populations

Strategy used to develop a LIPS diagnostic test for TB. (PPT 72Â kb)

Biological activity of the eight informative MTB proteins. (PPT 86Â kb)

To determine the frequency, risk factors and mortality rate of immune reconstitution inflammatory syndrome (IRIS) of tuberculosis (TB) in patients co-infected with HIV/TB and receiving antiretroviral therapy (ART).A retrospective study was conducted in Bamrasnaradura Infectious Diseases Institute and Ramathibodi Hospital, Thailand.There were 167 patients with a mean age of 34.5 years. Median (IQR) CD4 cell counts was 36 (15-69) cells/mm(3) and median (IQR) HIV RNA was 427,000 (189,000-750,000) copies/ml. ART was initiated at a median (IQR) duration of 2.2 (1.4-3.7) months after TB treatment. IRIS was identified in 21 (12.6%) patients. Patients with IRIS had a higher proportion of extrapulmonary TB than patients without IRIS (P0.001). By multivariate analysis, extrapulmonary TB was a risk factor for IRIS (odds ratio=8.225, 95% confidence interval=1.785-37.911, P=0.007). Of 21 patients with IRIS, 15 patients developed IRIS within the first two months of ART. The mortality rate in patients with and without IRIS was not different (9.5% versus 2.1%, P=0.119).The rate of TB IRIS is 13% in patients co-infected with HIV and TB. Extrapulmonary TB is a risk factor for IRIS. Closely monitored clinical care in the first few months of ART initiation and further interventional studies to minimize mortality of TB IRIS are needed.

Increasing prevalence of thyroid function abnormality has been reported in HIV-infected patients. We aim to evaluate the prevalence and assess risk factors of thyroid dysfunction in Thai HIV-infected patients. A cross-sectional study was conducted. Serum thyroid hormone concentrations (FT4, FT3, and TSH) and thyroid autoantibodies (TgAb and TPOAb) were measured by electrochemiluminescence immunoassay. A total of 200 HIV-infected outpatients were included. Ninety-seven patients (48.5%) were men (mean age of 36.3 +/- 8.3 years). Duration of HIV infection was 49.6 +/- 35.1 months and 53% had previous opportunistic infections (OI). Mean CD4 cell count was 340.6 +/- 173.1 cells/mm(3). Of these, 167 patients (83.5%) received antiretroviral therapy (ARV). Abnormal thyroid function test was detected in 32 patients (16%). Twenty-seven patients (13.5%) had decreased thyroid function (primary hypothyroidism 3, subclinical hypothyroidism 12, and low FT4 with low or normal TSH 12) whereas 5 patients had increased thyroid function (overt hyperthyroidism 1, subclinical hyperthyroidism 1, and isolated high FT3 3). None had clinical features of thyroid hormone dysfunction. Thirteen patients (6.5%) had thyroid antibody positive. Patients who received ARV had higher mean FT3 levels than those who were naïve to ARV (p = 0.017). History of previous OI was found to be an independently significant risk factor for decreased thyroid function with the odds ratio of 3.28 (95% CI =1.183-9.099; p = 0.022). Hypothyroidism was common among Thai HIV-infected patients, especially in those who had history of previous OI. It is therefore suggested that screening and/or monitoring of thyroid hormone in HIV-infected patients should be considered.

BACKGROUND: Stopping antiretroviral therapy in patients with HIV-1 infection can reduce costs and side-effects, but carries the risk of increased immune suppression and emergence of resistance. METHODS: 430 patients with CD4-positive T-lymphocyte (CD4) counts greater than 350 cells per muL, and viral load less than 50 copies per mL were randomised to continued therapy (n=146) or scheduled treatment interruptions (n=284). Median time on randomised treatment was 21.9 months (range 16.4-25.3). Primary endpoints were proportion of patients with viral load less than 50 copies per mL at the end of the trial, and amount of drugs used. Analysis was intention-to-treat. This study is registered at ClinicalTrials.gov with the identifier NCT00113126. FINDINGS: Drug savings in the scheduled treatment interruption group, compared with continuous treatment, amounted to 61.5%. 257 of 284 (90.5%) patients in the scheduled treatment interruption group reached a viral load less than 50 copies per mL, compared with 134 of 146 (91.8%) in the continued treatment group (difference 1.3%, 95% CI-4.3 to 6.9, p=0.90). No AIDS-defining events occurred. Diarrhoea and neuropathy were more frequent with continuous treatment; candidiasis was more frequent with scheduled treatment interruption. Ten patients (2.3%) had resistance mutations, with no significant differences between groups. INTERPRETATION: Drug savings with scheduled treatment interruption were substantial, and no evidence of increased treatment resistance emerged. Treatment-related adverse events were more frequent with continuous treatment, but low CD4 counts and minor manifestations of HIV infection were more frequent with scheduled treatment interruption.

Summary Objective To describe the clinical characteristics, treatment, and outcomes of cryptococcosis in HIV-negative patients. Methods HIV-negative adult patients with positive culture for Cryptococcus neoformans who attended Ramathibodi Hospital between 1987 and 2003 were retrospectively reviewed. Results During the 17 year review period, 40 HIV-negative patients with cryptococcosis were identified. Of these, 37 patients had medical records available for study. The mean age was 49±18 (range 16–83) years and 73% were female. Twenty-four patients (65%) had associated underlying conditions. The most common associated conditions included immunosuppressive drug treatment (41%), presence of systemic lupus erythematosus (16%), malignancies (16%), and diabetes mellitus (14%). C. neoformans was mainly recovered from cerebrospinal fluid (32%), blood (28%), and sputum/bronchoalveolar lavage/lung tissue (28%). Twenty-three patients (62%) had disseminated cryptococcosis. Six of 14 patients with cryptococcal meningitis were asymptomatic. About half of the patients were treated with amphotericin B and subsequent fluconazole. Five patients (14%) were initially misdiagnosed and treated for tuberculosis or bacterial infection. The overall mortality rate was 27%. Conclusions Cryptococcosis is not rare in HIV-negative patients. The mortality rate is high. Early recognition of cryptococcosis and use of appropriate antifungal therapy in these patients may improve clinical outcomes.

ObjectiveTo assess the efficacy and safety of first-line treatment with once-daily saquinavir/ritonavir with two nucleoside reverse transcriptase inhibitors (NRTIs), as induction therapy before enrollment in a randomized trial of structured treatment interruption strategies.DesignTwo-hundred antiretroviral-naive patients with CD4+cell counts between 200–350 at screening were enrolled in this open-label 24week study.MethodsPatients were followed up every 8 weeks for CD4+cells, HIV RNA, and clinical and laboratory toxicities. Results: Two-hundred patients were enrolled with median baseline CD4+cell count of 267 cells/μl and HIV RNA 50 118 (4.7 log10) copies/ml. After 24 weeks of treatment, 191 of 200 (96%) patients had below 400 copies/ml HIV RNA, with 177/200 (89%) below 50 copies/ml (intent to treat, missing equals failure method), with a median rise in CD4+cell count of 122 cells/μl. There was no significant correlation between the minimum concentration of saquinavir and HIV RNA reductions at week 8 ( P=0.957) or absolute HIV RNA at week 24 ( P=0.77).ConclusionFirst-line highly active antiretroviral therapy (HAART) with once-daily saquinavir/ritonavir plus two NRTIs showed strong antiviral efficacy over 24 weeks, and should be evaluated in larger prospective randomized clinical trials.

Antiretroviral treatment failure has been defined by immunological failure (IF) in some resource-limited settings whereas defining by virological failure (VF) has been widely used in developed countries. There is limited comparison of the levels of HIV-1 drug resistance between using VF and IF for the diagnosis of treatment failure. A retrospective cohort study was conducted among HIV-1-infected patients failing first-line antiretroviral therapy (ART). Of 95 patients, median CD4 and HIV-1 RNA were 158 cells/mm3 and 10,200 copies/mL, respectively. Patients in the IF group had higher HIV-1 RNA than those in VF group (23,820 versus 9510 copies/mL, P = 0.008). Nucleoside reverse transcriptase inhibitor (NRTI)-, non-NRTI- and protease inhibitor-resistance-associated mutations (RAMs) were observed in 57.9%, 94.7% and 5.3%, respectively. Q151M, a multidrug RAM, was more commonly observed in the IF group (14.8% versus 2.9%, P = 0.032). Using IF to diagnose treatment failure is associated with higher HIV-1 RNA levels and a higher rate of Q151M, which can limit the options for second-line ART.

We determined the prevalence of a positive tuberculin skin test (TST) and the incidence of TST conversion among new healthcare personnel (HCP) in a hospital in Thailand. During 2005-2008, TST was performed on 1438 HCP and the prevalence of positive TST was 66.3%. Age, male gender, and the presence of Bacille Calmette-Guerin (BCG) scar were associated with odds of positive TST (all P < 0.05). The incidence of TST conversion was 4.8 per 100 HCP-years. Nine (0.6%) HCP were diagnosed with active tuberculosis. The annual surveillance programme is important for the early diagnosis and prevention of tuberculosis among HCP in Thailand.

Introduction Although substitutions of antiretroviral regimen are generally safe, most data on substitutions are based on results from clinical trials. The objective of this study was to evaluate the treatment outcomes of substituting antiretroviral regimen in virologically suppressed HIV‐infected patients in non‐clinical trial settings in Asian countries. Methods The study population consisted of HIV‐infected patients enrolled in the TREAT Asia HIV Observational Database (TAHOD). Individuals were included in this analysis if they started combination antiretroviral treatment (cART) after 2002, were being treated at a centre that documented a median rate of viral load monitoring ≥0.8 tests/patient/year among TAHOD enrolees, and experienced a minor or major treatment substitution while on virally suppressive cART. The primary endpoint to evaluate outcomes was clinical or virological failure (VF), followed by an ART class change. Clinical failure was defined as death or an AIDS diagnosis. VF was defined as confirmed viral load measurements ≥400 copies/mL followed by an ART class change within six months. Minor regimen substitutions were defined as within‐class changes and major regimen substitutions were defined as changes to a drug class. The patterns of substitutions and rate of clinical or VF after substitutions were analyzed. Results Of 3994 adults who started ART after 2002, 3119 (78.1%) had at least one period of virological suppression. Among these, 1170 (37.5%) underwent a minor regimen substitution, and 296 (9.5%) underwent a major regimen substitution during suppression. The rates of clinical or VF were 1.48/100 person years (95% CI 1.14 to 1.91) in the minor substitution group, 2.85/100 person years (95% CI 1.88 to 4.33) in the major substitution group and 2.53/100 person years (95% CI 2.20 to 2.92) among patients that did not undergo a treatment substitution. Conclusions The rate of clinical or VF was low in both major and minor substitution groups, showing that regimen substitution is generally effective in non‐clinical trial settings in Asian countries.

Background The use of abacavir (ABC) and rilpivirine (RPV) in the first-line regimen for naïve HIV-infected patients with pretreatment HIV RNA >100,000 copies/mL is not recommended due to a high rate of treatment failure. If a model could accurately predict pretreatment HIV RNA levels, it would be a useful tool for the selection ABC or RPV in the first-line regimen. Methods Thai HIV-infected adults enrolled in the TREAT Asia HIV Observational Database (TAHOD) and additional patients of Ramathibodi Hospital were eligible if they had an HIV RNA result at the time of antiretroviral therapy initiation. Factors associated with pretreatment HIV RNA Results A total of 1,223 patients were included in the analysis. Among those in the derivation data set, median [interquartile range (IQR)] age was 36.3 (30.5–42.9) years, median (IQR) CD4 count was 122 (39–216) cells/mm3, and pretreatment HIV RNA was 100,000 (32,449–229,777) copies/mL. Factors associated with pretreatment HIV RNA 200 cells/mm3 (OR 3.00 vs. CD4 count 200 cells/mm3 (27), duration of HIV infection >1 year (9), and weight >50 years (11) were included in the clinical prediction tool scores. A score ≥45 yielded a sensitivity of 45.3%, specificity of 76.7%, positive predictive value of 68.1%, and negative predictive value of 56.1% among patients in the derivation. The area under the receiver-operator characteristic curve was 0.655 (95% CI 0.614- 0.696) and 0.600 (95% CI 0.533–0.667) in the derivation and validation patients, respectively. Conclusion Our final prediction model had poor sensitivity and specificity for predicting HIV RNA Disclosures All authors: No reported disclosures.

Background Mycobacterium avium–intracelllulare complex (MAC) prophylaxis is recommended for patients with CD4 counts of < 50 cells/mm3. With the significant decrease in incidence of disseminated MAC infection and the effective immune recovery due to the availability of combination antiretroviral therapy (ART), the benefits of giving MAC prophylaxis were investigated. This study examined the impact of macrolide prophylaxis on AIDS-defining conditions and HIV-associated mortality in a cohort of HIV-infected patients on ART. Methods TREAT Asia HIV Observational Database (TAHOD) patients aged ≥18 years with a CD4 count < 50 cells/mm3 at ART initiation were included. The effect of macrolide prohylaxis on HIV-associated mortality or an AIDS event (as a combined outcome) and HIV-associated mortality alone were evaluated using competing risk regression. Sensitivity analysis was conducted to assess whether results were consistent in patients with a CD4 < 100 cells/mm3 at ART initiation. Results Of 1,345 eligible patients (78% male with median age at ART initiation of 34.8 years), 10.6% received macrolide prophylaxis. The rates of the combined outcome and HIV-associated mortality per 100 patient years were 7.35 [95% confidence interval (CI): 6.04–8.95] and 3.14 (95% CI: 2.35–4.19), respectively. After adjusting for possible confounders, macrolide use was associated with a significantly decreased risk of HIV-associated mortality (HR 0.10, 95% CI: 0.01–0.80, P = 0.031) but not the combined outcome (HR 0.86, 95% CI: 0.32–2.229, P = 0.764). Sensitivity analyses showed that, among patients with a CD4 < 100 cells/ mm3 at ART initiation, these results were consistent. Conclusion Macrolide prophylaxis is associated with significantly improved survival among Asian HIV-infected patients with very low CD4 cell counts. The benefits of giving macrolide prophylaxis remain despite the availability of effective ART. Disclosures All authors: No reported disclosures.

Background Although substitutions of antiretroviral regimen are generally safe, most data on substitutions are based on results from clinical trials. The objective of this study was to evaluate the safety of substituting antiretroviral regimen in virologically suppressed HIV-infected patients in non-clinical trial settings in Asian countries. Methods HIV-infected patients enrolled in the TREAT Asia HIV Observational Database (TAHOD) were included in this analysis if they started combination antiretroviral therapy (cART) after 2002, were being treated at a center that documented a median rate of viral load (VL) monitoring ≥ 1 tests/patient/year, and experienced a minor or major treatment substitution while on virally suppressive cART (VL < 200 copies/mL). Minor regimen substitutions were defined as within-class changes and major regimen substitutions were defined as changes to a drug class. Virologic failure was defined as having had two viral load measurements > 400 copies/mL. The patterns of substitutions and rate of virologic failure after substitutions were analyzed. Results Of 3,994 adults who started ART after 2002, 3,119 (78.1%) had at least one period of virological suppression. Among these, 1,170 (37.5%) underwent a minor regimen substitution, and 296 (9.5%) underwent a major regimen substitution during suppression. The rates of virological failure were 1.48/100person years (95% CI 1.14–1.91) in the minor substitution group and 2.85/100person years (95% CI 1.88–4.33) in the major substitution group, and 2.53/100person years (95% CI 2.20–2.92) among patients that did not undergo a treatment substitution. Conclusion The rate of virological failure was relatively low in both major and minor substitution groups, showing that regimen substitution is generally safe in non-clinical trial settings in Asian countries. Disclosures All authors: No reported disclosures.

Introduction : Our understanding of how to achieve optimal long-term adherence to antiretroviral therapy (ART) in settings where the burden of HIV disease is highest remains limited. We compared levels and determinants of adherence over time between HIV-positive persons receiving ART who were enrolled in a bi-regional cohort in sub-Saharan Africa and Asia. Methods : This multicentre prospective study of adults starting first-line ART assessed patient-reported adherence at follow-up clinic visits using a 30-day visual analogue scale. Determinants of suboptimal adherence (

Introduction First-line antiretroviral therapy (ART) failure often results from the development of resistance-associated mutations (RAMs). Three patterns, including thymidine analogue mutations (TAMs), 69 Insertion (69Ins) and the Q151M complex, are associated with resistance to multiple-nucleoside reverse transcriptase inhibitors (NRTIs) and may compromise treatment options for second-line ART. Methods We investigated patterns and factors associated with multi-NRTI RAMs at first-line failure in patients from The TREAT Asia Studies to Evaluate Resistance – Monitoring study (TASER-M), and evaluated their impact on virological responses at 12 months after switching to second-line ART. RAMs were compared with the IAS-USA 2013 mutations list. We defined multi-NRTI RAMs as the presence of either Q151M; 69Ins; ≥2 TAMs; or M184V+≥1 TAM. Virological suppression was defined as viral load (VL) 2 years (OR=6.25, 95% CI [2.39–16.36], p

We report a case of an HIV-seronegative pregnant woman with disseminated cryptococcosis, poorly controlled during gestation. Immunological studies showed T-lymphocytopenia during gestation, but rapid recovery postpartum. T-lymphocytopenia may play a role in increased susceptibility to and severity of cryptococcal infection during pregnancy.

Data regarding syphilis screening in resource-limited settings is limited. We aimed to determine the prevalence and associated factors of positive syphilis serology in HIV-infected adult patients in an outpatient setting in Thailand. A cross sectional study was conducted among 178 HIV-infected patients. Ninety-eight patients (55%) were male; then median (interquartile range; IQR) age was 43 (36-49) years. The majority of the patients (84.3%) had a heterosexual risk. Three patients (1.7%) had a positive rapid plasma reagin (RPR) test (range, 1:2 to 1:16), 9 (5%) patients had a positive Treponema pallidum particle agglutination (TPPA) test, and 3 patients (1.7%) had positive results on both tests. On multivariate logistic regression analysis, a pruritic papular eruption [odds ratio (OR) 5.37; 95% confidence interval (CI): 1.09-26.38; p = 0.038], current CD4 cell count (OR 1.22, per 50 cells/mm3; 95% CI: 1.01-1.46; p = 0.035), and using abacavir in the current regimen (OR 59.19; 95% CI: 2.15-1,628.68; p = 0.016) were associated with positive syphilis serology. In conclusion, the prevalence of positive syphilis serology among Thai HIV-infected patients was low. Routine screening for syphilis in HIV-infected patients who are asymptomatic may need to be re-considered at the national level in this resource-limited setting.

Background Antiretroviral therapy (ART) has evolved rapidly since its beginnings. This analysis describes trends in first-line ART use in Asia and their impact on treatment outcomes. Methods Patients in the TREAT Asia HIV Observational Database receiving first-line ART for ≥6 months were included. Predictors of treatment failure and treatment modification were assessed. Results Data from 4662 eligible patients was analysed. Patients started ART in 2003–2006 (n = 1419), 2007–2010 (n = 2690) and 2011–2013 (n = 553). During the observation period, tenofovir, zidovudine and abacavir use largely replaced stavudine. Stavudine was prescribed to 5.8% of ART starters in 2012/13. Efavirenz use increased at the expense of nevirapine, although both continue to be used extensively (47.5% and 34.5% of patients in 2012/13, respectively). Protease inhibitor use dropped after 2004. The rate of treatment failure or modification declined over time (22.1 [95%CI 20.7–23.5] events per 100 patient/years in 2003–2006, 15.8 [14.9–16.8] in 2007–2010, and 11.6 [9.4–14.2] in 2011–2013). Adjustment for ART regimen had little impact on the temporal decline in treatment failure rates but substantially attenuated the temporal decline in rates of modification due to adverse event. In the final multivariate model, treatment modification due to adverse event was significantly predicted by earlier period of ART initiation (hazard ratio 0.52 [95%CI 0.33–0.81], p = 0.004 for 2011–2013 versus 2003–2006), older age (1.56 [1.19–2.04], p = 0.001 for ≥50 years versus

Many low-middle income countries, including in Asia, are now facing the intersection of two epidemics-of communicable and non-communicable diseases, including diabetes mellitus (DM) and tuberculosis (TB) specifically.1 DM has been recognised as an important risk factor for TB in the general population, especially in the TB endemic settings.1,2 Poorly controlled diabetics (with HbA1C>7%) are the main group at a higher risk of TB.1 Finally, DM is also believed to elevate the risk of serious infections in general.3 Although the mechanisms of these associations are not clear, they are thought to be directly related to hyperglycemia and cellular insulinopenia, as well as indirect effects of hyperglycemia on macrophage and lymphocyte function.1,3 HIV-positive individuals are at high risk of TB.4 Further, diabetes has emerged as one of the important co-morbidities in HIV-positive individuals, especially in the antiretroviral therapy (ART) era.5,6 However, the relationship between blood glucose levels and TB in HIV positive population has been remarkably understudied.7,8 Investigating this relationship in HIV-positive individuals is important not only for better clinical management of HIV but also for TB control in general. In this study, we model the relationship between fasting blood glucose and risk of TB in the TREAT Asia HIV Observational Database (TAHOD), a multi-country Asian cohort of HIV-positive individuals.

Describe the clinical characteristics, treatment, outcomes, complications, and factors associated with mortality of cryptococcosis in HIV-negative patients.A retrospective cohort study was conducted among HIV-negative adult patients with positive culture for Cryptococcus neoformans between 2005 and 2010.Forty-nine HIV-negative patients were identified with median (IQR) age of 62.5 (45.5-71.9) years of which 40.8% were male. The common underlying medical conditions were cardiovascular diseases (36.7%). The common sites of positive culture were cerebrospinal fluid/intracerebral abscess (46.9%), blood (36%), and sputum/bronchoalveolar larvage fluid (28.6%). Twenty-nine (59.2%) patients had co-infections with another organism, such as Gram-negative bacteria (24.4%), M. tuberculosis (17.8%), and Gram-positive bacteria (13.3%). The common clinical presentations were fever (67.3%), alteration of consciousness (34.7%), and headache (26.5%). Complication was detected in 61.2% such as acute kidney injury (47.0%), coma (38.8%), and shock (22.4%). The overall mortality was 51%. By multivariate logistic regression, factors associated with mortality were alteration of consciousness (adjusted OR = 6.85; 95% CI: 1.41-33.28, p = 0.017) and co-infections (adjusted OR = 5.32; 95% CI: 1.25-22.69, p = 0.024).The mortality rate of HIV-negative patients with cryptococcosis is very high. Early recognition and treatment of cryptococcosis in HIV-negative patients are crucial and may improve the outcome.

In 2008, Antiviral Therapy published the World Health Organization (WHO) recommendations for surveillance of transmitted resistance in countries scaling up antiretroviral treatment.[1] This work described a pragmatic approach to identifying recently infected patients which was subsequently applied in the TREAT Asia Study to Evaluate Resistance – Surveillance (TASER-S) study.[2] Briefly, patients were considered recently infected in TASER-S if they were 1) Less than 25 years of age and newly diagnosed with a confirmed HIV+ test; or 2) Had a confirmed HIV+ test with evidence of recent infection (ie. Positive BED assay or previous negative HIV test in the past year); or 3) Had an indeterminate or negative HIV test with detectable HIV RNA or positive p24 antigen. The mean duration of HIV infection at the time of resistance testing in the TASER-S cohort remains uncertain. As many drug resistance mutations impair HIV fitness [3–6], reversion of transmitted mutations back to wild-type may confer a survival benefit for the virus in the absence of treatment. The rate of reversion may vary depending on the number of back mutations required, the relative fitness of the mutant and back-mutated viruses, the rate of viral turnover, and the presence of compensatory mutations.[7] The interpretation of population-based surveys of transmitted drug resistance, such as TASER-S, depends on understanding how long mutations are detectable after they are transmitted. Surveys provide an underestimation of the prevalence of mutations that are quickly replaced and this may be exaggerated by a long duration between HIV infection and resistance testing. The TASER-S cohort includes 458 recently infected, antiretroviral-naive patients who underwent HIV population sequencing between 2007–2010. Clinical research sites from Thailand (n=2), Hong Kong (n=1) and Philippines (n=1) participated in recruitment. Recently, we reported the overall prevalence of transmitted resistance in TASER-S was 6.1%; mutations associated with nucleoside reverse transcriptase inhibitor (NRTI), non-NRTI (NNRTI) and protease inhibitor (PI) resistance were present in 5.2%, 2.8% and 3.9% of the cohort, respectively. [8] Jain et al [9] utilized data on 75 patients from two prospective cohort studies (one recruited from San Francisco, USA [10], the other from Sao Paulo, Brazil [11]) to estimate the rate at which HIV drug resistance mutations are replaced after seroconversion in the absence of antiretroviral therapy. The cohorts enrolled between 1996–2009 (San Francisco) and 2002–2009 (Sao Paulo). Participants experienced seroconversion within the 12 months leading up to their baseline resistance test as determined by serial antibody testing [10] or the Serologic Testing Algorithm for Recent HIV Seroconversion (STARHS) assay.[11] Mutations were followed longitudinally and replacement rates compared between NNRTI mutations, M184V/I, thymidine analogue mutations (TAMs), T215 revertants, other NRTI mutations and PI mutations. M184V/I became undetectable very rapidly compared to other evaluated mutations with 100% of transmitted M184V/I undetectable within two years of seroconversion. The projected rates of replacement for other drug resistance mutation categories were not dissimilar to one another. For example, at one year after seroconversion the predicted replacement rates were: NNRTI – 4% (95%CI 1–15%), TAMS – 11% (4–26%), T215 revertants – 17% (5–50%), other NRTI – 2% (0–24%), and PI – 5% (2–13%). Using the rates of mutation replacement reported by Jain et al [9] we evaluated how sensitive our reported prevalences of transmitted resistance in TASER-S were to time from seroconversion. We assumed mean duration of HIV infection prior to testing was six months, one, two, three or four years. Mutation frequencies were then projected based on the model’s predicted rate of mutation decay. The prevalence for each mutation category was calculated as the number of mutations over the number of study participants although, for mutation categories other than M184V/I, participants may have contributed more than one mutation each. Results are shown in Table 1. The reported prevalence for M184V/I may differ substantially from the predicted true prevalence depending on mean time from seroconversion. Assuming a mean duration of six months between seroconversion and resistance testing, the true prevalence would be 3-fold greater than the reported prevalence (3.4% vs. 1.1%). With a mean duration of 12 months between seroconversion and testing the true prevalence would be over 30-fold greater than the estimated value (36.4% vs. 1.1%). As other mutation categories do not decay as rapidly, the projected rates of transmitted resistance are not greatly affected by time. At worst, if the mean duration between seroconversion and resistance testing was four years in TASER-S the reported rates of NNRTI, TAM, T215 revertant, other NRTI, and PI resistance would have dropped from 3.5%, 3.8%, 2.2%, 1.2%, 4.5% at seroconversion to 2.8%, 2.2%, 0.9%, 1.1% and 3.5%, respectively, at the time of testing. A rapid rate of M184V/I decay has also been reported by Castro et al [7] in their analysis of transmitted drug resistance reversion in a cohort of patients with mostly chronic (infected for ≥18 months) or unknown duration of infection. If the mean period of HIV infection was greater than two years in TASER-S we may not have found any M184V/I virus. Such results have been reported following work on resistance in chronically infected, treatment-naive patients.[12] Other resistance mutations are relatively insensitive to variation in the time from seroconversion to resistance testing although Castro et al [7] noted that there was considerable heterogeneity in the rate of reversion within the TAMs group, with T215F/Y and K70R being lost more rapidly than other TAMs. As TAMs were grouped together by Jain et al [9], it is uncertain whether this is also true for patients recently infected with HIV. Nevertheless, it is reassuring that, with the exception of M184V/I, and possibly T215F/Y and K70R, the reported mutation prevalences in TASER-S are not likely to differ significantly from the true values. Several limitations may distort the above extrapolation of Jain et al [9] to TASER-S. Population sequencing was used in the San Francisco, Sao Paulo and TASER-S cohorts. Replication of this work using more sensitive methods of genotypic resistance testing would reveal higher baseline resistance levels and possibly different rates of mutation replacement. Jain et al [9] used the WHO 2007 list for surveillance of transmitted resistance [13] to define and categorize mutations. We have used the WHO 2009 list [14]. Adjusting the model and categorization using the latest WHO list is unlikely to significantly alter the results reported above given that the differences between the 2007 and 2009 lists are not substantial. Both the model and TASER-S cohorts were mostly comprised of men who have sex with men and contained few participants exposed to HIV via intravenous drug use. However, differences in viral subtype distribution may be important given the frequency of typical and atypical drug resistance mutations varies among HIV subtypes.[15] Most (68.8%) TASER-S participants were infected with subtype CRF01_AE but unfortunately the dominant subtypes in the model cohorts were not reported. The model also assumed a steady state viral load of 40,000copies/ml and showed that the rate of mutation replacement was increased with increasing viral load. Longitudinal viral load data was not recorded in TASER-S however the median baseline viral load was >50,000copies/ml. This is higher than the median baseline viral loads for the San Francisco and Sao Paulo cohorts (12,710 and 34,050copies/mL, respectively) suggesting mutation replacement may have occurred more rapidly in TASER-S patients. Further, the model showed significant within person variation implying there are patient-level factors aside from viral load and mutation category that drive mutation loss. Jain et al (2011) did not investigate these further and it is therefore unknown if germane patient characteristics in the model cohort differed from those of TASER-S participants. Despite the abovementioned limitations, we believe this extrapolation provides good evidence that the transmitted resistance prevalences reported for TASER-S are reasonably robust. Whilst our estimate of M184I/V prevalence is probably understated, estimates for NNRTI, TAMs, T215 revertant, other NRTI, and PI mutations are likely a good indication of the true extent of resistance at the time of seroconversion as measured by population sequencing. These findings should be taken into consideration when interpreting future transmitted resistance surveillance data.

Etravirine demonstrates activity against NNRTI-resistant HIV-1 but its efficacy depends on the number of etravirine resistance-associated mutations (RAMs). This study aimed to evaluate the role of etravirine in the second regimen in a resource-limited setting. Genotype resistance assay was conducted in a cohort of HIV-infected patients who experienced virological failure from an initial NNRTI-based regimen. We focused on etravirine-RAMs previously described: V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S. Frequency and predicting factors for 2 etravirine- RAMs were evaluated. There were 158 patients with a median duration of ART prior to failure of 22 months. The median CD4 cell count and HIV-1 RNA at the time of virological failure were 173 cells/mm3 and 4.1 log copies/mL, respectively. Of all, 75.3% of patients were predicted to have 2 etravirine-RAMs. From logistic regression, there was no clinical factor to predict etravirine susceptibility. Patients with 2 etravirine-RAMs had lower rates of K65R (3.4% vs 17.9%, p=0.005), Q151M (5.9% vs 20.5%, p=0.012), and multi-NRTI resistance mutations (16.8% vs 48.7%, p 2 etravirine-RAMs. Etravirine may have activity for using in the second regimen in most patients in resource-limited setting who fail an initial NNRTI-based regimen. Genotype testing is needed to identify this group. Some of these patients, indicated by genotype results, may be able to use etravirine plus 2 active NRTIs for second ART regimen. This strategy may be an option for patients who cannot afford or tolerate protease inhibitor. Prospective study to evaluate this strategy should be conducted in resource-limited setting.

Ceftriaxone is one of the most common empirical antibiotics prescribed at emergency rooms in Thailand. Inappropriate prescriptions of antibiotics have been frequently reported. The authors aimed to study factors that determine the appropriateness ofceftriaxone usage at an emergency room ofa university hospital in Thailand.A cross-sectional study was conducted among patients with age of15 years old who received ceftriaxone as empirical treatment at the emergency room between April 1 and May 31, 2010. Appropriateness ofceftriaxone usage was considered according to local recommendations and current published guidelines.During the 2-months period, 278 patients for whom ceftriaxone was prescribed were included in the analysis. Of these, 109 (39.2%) were men and a median (interquartile range; IQR) age of 62.2 (45.2-75.7) years. Ceftriaxone usage was considered appropriate in 162 (58.3%) cases. By multiple logistic regression, female gender [odds ratio (OR) 1.96, 95% confidence interval (CI) 1.03-3. 70], fever (OR 3.12, 95% CI 1.3-6.11), had signs and symptoms of infections (OR 2.92, 95% CI 1.37-6.28), and suspicion of sepsis (OR 7.90, 95% CI 3.67-17.07), were associated with appropriateness of ceftriaxone usage, while diagnosis of gastrointestinal tract infection was associated with inappropriate ceftriaxone usage (OR 0.20, 95% CI 0.05-0.77).Proportion of appropriate use of ceftriaxone is fair. As assessed by established criteria, clinical suspicion of infection was associated with appropriateness of ceftriaxone usage for empirical treatment in an emergency room setting. Interventions to improve appropriateness of ceftriaxone prescription should focus on these factors.

Introduction : Although antiretroviral therapy (ART) has been rapidly scaled up in Asia, most HIV-positive patients in the region still present with late-stage HIV disease. We aimed to determine trends of pre-ART CD4 levels over time in Asian HIV-positive patients and to determine factors associated with late ART initiation. Methods : Data from two regional cohort observational databases were analyzed for trends in median CD4 cell counts at ART initiation and the proportion of late ART initiation (CD4 cell counts

A retrospective study was conducted by reviewing 459 medical records of adult treatment naive HIV patients who received a fixed dose combination of GPO-VIR-S (stavudine, lamivudine and nevirapine) or GPO-VIR-Z (zidovudine, lamivudine and nevirapine) at Ramathibodi Hospital in Bangkok, Thailand during 2002-2009 following Thai National Treatment Guideline for adults with HIV. The aim of this study was to assess the association between the baseline CD4 cell count and outcome. The median CD4 cell count at baseline, 6, 12 and 102 months were 102 cells/microl, 213 cells/microl, 274 cells/microl and 423 cells/microl. The virologic response (p=0.327), virologic rebound (p=0.626), adverse effects of anti-retroviral therapy (ART) (p=0.976), switching to other ART (p=0.245), occurrence of immune reconstitution inflammatory syndrome (IRIS) (p0.05) and occurrence of drug resistance (p=0.952) were not significantly associated with baseline CD4 count. The Kaplan-Meier estimate showed the median time (95% CI) to achieve virologic response was 10.4 (9.8-11.0) months and the median time to achieve virologic rebound was 30.0 (21.6-38.4) months after initiation of ART. Analysis showed the median time to achieved virologic response (p=0.401) and virologic rebound (p=0.562) were not significantly associated with the baseline CD4 count. This study shows the outcome after onset of ART did not vary by baseline CD4 cell count.

OBJECTIVES In resource-constrained settings, tuberculosis (TB) is a common opportunistic infection and cause of death in HIV-infected persons. TB may be present at the start of antiretroviral therapy (ART), but it is often under-diagnosed. We describe approaches to TB diagnosis and screening of TB in ART programs in low- and middle-income countries. METHODS AND FINDINGS We surveyed ART programs treating HIV-infected adults in sub-Saharan Africa, Asia and Latin America in 2012 using online questionnaires to collect program-level and patient-level data. Forty-seven sites from 26 countries participated. Patient-level data were collected on 987 adult TB patients from 40 sites (median age 34.7 years; 54% female). Sputum smear microscopy and chest radiograph were available in 47 (100%) sites, TB culture in 44 (94%), and Xpert MTB/RIF in 23 (49%). Xpert MTB/RIF was rarely available in Central Africa and South America. In sites with access to these diagnostics, microscopy was used in 745 (76%) patients diagnosed with TB, culture in 220 (24%), and chest X-ray in 688 (70%) patients. When free of charge culture was done in 27% of patients, compared to 21% when there was a fee (p = 0.033). Corresponding percentages for Xpert MTB/RIF were 26% and 15% of patients (p = 0.001). Screening practices for active disease before starting ART included symptom screening (46 sites, 98%), chest X-ray (38, 81%), sputum microscopy (37, 79%), culture (16, 34%), and Xpert MTB/RIF (5, 11%). CONCLUSIONS Mycobacterial culture was infrequently used despite its availability at most sites, while Xpert MTB/RIF was not generally available. Use of available diagnostics was higher when offered free of charge.

Background Dyslipidemia as a risk factor of cardiovascular disease is common especially in HIV-infected patients who are using protease inhibitors (PIs) including atazanavir. Pitavastatin has less drug-drug interactions and demonstrable efficacy in decreasing lipid levels in non HIV-infected individuals. Materials and Methods This study was a randomized, double-blind, crossover study comparing the safety and efficacy of pitavastatin vs placebo in HIV-infected patients with dyslipidemia and receiving atazanavir/ritonavir (ATV/r). Patients were randomized to receive either placebo or pitavastatin for 12 weeks. The follow-up visits were every 4 weeks until the end of the study. Results A total of 12 HIV-infected patients were enrolled to each study group. Of all, 14 (58%) patients were men and mean (standard deviation, SD) age was 48.1 (1.8) years. At 12 weeks of treatment with pitavastatin compared to placebo; mean [95% confidence interval (CI)] total cholesterol (TC) was 207 (187.3, 226.8) mg/dL vs 246.3 (226.5, 266) mg/dL (p

Background/introduction Tenofovir alafenamide (TAF) is a tenofovir prodrug that contains elvitegravir 150mg/cobicistat 150mg/FTC 200mg/TAF 10mg (E/C/F/TAF). Aim(s)/objectives This study assessed efficacy and possible bone and renal safety advantages in patients who switched from a TDF-based regimen to E/C/F/TAF. Methods Virologically suppressed (HIV-1 RNA Results At Week 48, 390/402 (97.0%) of those who switched to E/C/F/TAF and 183/199 (92.0%) of those continuing boosted ATV plus FTC/TDF had HIV-1 RNA Discussion/conclusion At Week 48, patients who switched from a boosted ATV+FTC/TDF regimen to E/C/F/TAF had a significantly higher rate of virologic control, had significant improvements in hip BMD, spine BMD and in serum creatinine, and also had significantly less proteinuria than those continuing on their TDF-based regimen.

A retrospective cohort study was conducted and 129 patients with a diagnosis of HIV infection for more than 10 years were identified. Half the patients were men and mean (standard deviation, SD) age at HIV diagnosis was 33.2 (9.2) years. One third had a diagnosis of AIDS at cohort entry with median (interquartile range, IQR) CD4 counts of 259 (112-430) cells/mm3. All received antiretroviral therapy with median (IQR) current CD4 counts of 502 (363-607) cells/mm3 and 95% had HIV RNA 1.0 mg/dL, and 5% had glucose >126 mg/dL. In conclusion, immunological and virological responses can be achieved among patients with a diagnosis of HIV infection for more than 10 years even in a resource-limited setting. Adverse events are common. Preparation for monitoring and management of these adverse events is a crucial part of successful long-term HIV care.

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 (P=0.002), had HIV viral load ≥500 copies/mL or missing (P=0.021), had shorter history of HIV infection (P=0.048), and received no, single- or double-antiretroviral therapy, or a triple-drug regimen containing a protease inhibitor (P<0.001). 48% of patients LTFU never returned. These patients were more likely to have low or missing haemoglobin (P<0.001), missing recent HIV viral load (P<0.001), negative hepatitis C test (P=0.025), and previous temporary LTFU episodes (P<0.001). 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.