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Featured researches published by Darma Imran.


The New England Journal of Medicine | 2016

Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis

Justin Beardsley; Marcel Wolbers; Freddie Kibengo; A.-B.M. Ggayi; Anatoli Kamali; Ngo Thi Kim Cuc; Tran Quang Binh; Nguyen Van Vinh Chau; Jeremy Farrar; Laura Merson; Le Thi Phuong; Guy Thwaites; N. Van Kinh; Pham Thanh Thuy; Wirongrong Chierakul; S. Siriboon; E. Thiansukhon; S. Onsanit; W. Supphamongkholchaikul; Adrienne K. Chan; Robert S. Heyderman; Edson Mwinjiwa; Jj van Oosterhout; Darma Imran; Hasan Basri; Mayfong Mayxay; David A. B. Dance; P. Phimmasone; Sayaphet Rattanavong; David G. Lalloo

BACKGROUND Cryptococcal meningitis associated with human immunodeficiency virus (HIV) infection causes more than 600,000 deaths each year worldwide. Treatment has changed little in 20 years, and there are no imminent new anticryptococcal agents. The use of adjuvant glucocorticoids reduces mortality among patients with other forms of meningitis in some populations, but their use is untested in patients with cryptococcal meningitis. METHODS In this double-blind, randomized, placebo-controlled trial, we recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole. RESULTS The trial was stopped for safety reasons after the enrollment of 451 patients. Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P=0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P=0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P<0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, P=0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, P=0.003), renal events (22 vs. 7, P=0.004), and cardiac events (8 vs. 0, P=0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites. CONCLUSIONS Dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo. (Funded by the United Kingdom Department for International Development and others through the Joint Global Health Trials program; Current Controlled Trials number, ISRCTN59144167.).


Neurology | 2009

Age and height predict neuropathy risk in patients with HIV prescribed stavudine

Catherine L. Cherry; Jacquita S. Affandi; Darma Imran; Evy Yunihastuti; K. Smyth; Sasheela Vanar; Adeeba Kamarulzaman; Patricia Price

Objective: Sensory neuropathy is a common problem in HIV-infected patients and is the dose-limiting toxicity of stavudine. Affordable methods of predicting neuropathy risk are needed to guide prescribing in countries where some use of stavudine remains an economic necessity. We therefore aimed to identify factors predictive of neuropathy risk before antiretroviral use. Methods: A total of 294 patients attending clinics in Melbourne, Kuala Lumpur, and Jakarta were enrolled in a cross-sectional neuropathy screening program in 2006. Neuropathy was defined by the presence of symptoms and signs on the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen. Demographic, laboratory, and treatment details were considered as possible risk factors for neuropathy. The role of patient demographics in predicting stavudine neuropathy were then assessed in 181 patients who reported that they were free of neuropathy symptoms when first prescribed this drug. Results: The prevalence of neuropathy was 42% in Melbourne (n = 100), 19% in Kuala Lumpur (n = 98), and 34% in Jakarta (n = 96). In addition to treatment exposures, increasing age (p = 0.002) and height (p = 0.001) were independently associated with neuropathy. Age and height cutoffs of ≥170 cm or ≥40 years predicted neuropathy. Among 181 patients who were asymptomatic before stavudine exposure, the risk of neuropathy following stavudine was 20% in younger, shorter patients, compared with 66% in older, taller individuals. Conclusions: Stavudine neuropathy risk increases with patient age and height. Prioritizing older and taller patients for alternative agents would be an inexpensive strategy to reduce neuropathy rates in countries where the burden of HIV disease limits treatment options.


Neurology | 2008

Neurologic disorders are prevalent in HIV-positive outpatients in the Asia-Pacific region

Edwina Wright; Bruce J. Brew; Arkhom Arayawichanont; Kevin R. Robertson; K Samintharapanya; Subsai Kongsaengdao; Megan S. C. Lim; Saphonn Vonthanak; Luxshimi Lal; C Sarim; Sarah Huffam; Patrick Ck Li; Darma Imran; Jenny Lewis; W H Lun; Adeeba Kamarulzaman; Goa Tau; S T Ali; K Kishore; Margaret P. Bain; Robyn Dwyer; G McCormack; Margaret Hellard; Catherine L. Cherry; Julie H. McArthur; Steven L. Wesselingh

Background: A total of 8.3 million HIV-positive people live in the Asia-Pacific region. The burden of HIV-associated neurocognitive impairment and symptomatic sensory neuropathy in this region is unknown. Methods: Between July 2005 and March 2006, we undertook a cross-sectional study at 10 sentinel sites within eight Asia-Pacific countries to determine the prevalence of moderate to severe HIV-related neurocognitive impairment and symptomatic sensory neuropathy. We clinically assessed and administered sensitive neuropsychological and peripheral neuropathy screening tools to 658 patients infected with HIV. Univariate and logistic regression analyses were applied to the data. Results: The results showed that 76 patients (11.7%) (95% CI 9.3–14.2) were significantly neurocognitively impaired, 235 patients (36.4%) (95% CI 32.7–40.2) were depressed, and 126 patients (19.7%) (95% CI 16.6–22.8) had either definite or probable symptomatic sensory neuropathy; 63% of this last group had exposure to stavudine, didanosine, or zalcitabine. Several potential confounders including depression (OR 1.49, 95% CI 0.88–2.51, p = 0.11) and prior CNS AIDS illness (OR 1.28, 95% CI 0.50–2.89, p = 0.54) were not significantly associated with neurocognitive impairment. Conclusions: A total of 12% of patients had moderate to severe HIV-related neurocognitive impairment, 20% of patients had symptomatic sensory neuropathy, and 36% of patients had evidence of depression. This study provides a broad regional estimate of the burden of HIV-related neurologic disease and depression in the Asia-Pacific region.


PLOS ONE | 2013

Geographically Structured Populations of Cryptococcus neoformans Variety grubii in Asia Correlate with HIV Status and Show a Clonal Population Structure

Kantarawee Khayhan; Ferry Hagen; Weihua Pan; Sitali P. Simwami; Matthew C. Fisher; Retno Wahyuningsih; Arunaloke Chakrabarti; Anuradha Chowdhary; Reiko Ikeda; Saad J. Taj-Aldeen; Ziauddin Khan; Margaret Ip; Darma Imran; Ridhawati Sjam; Pojana Sriburee; Wanqing Liao; Kunyaluk Chaicumpar; Varaporn Vuddhakul; Wieland Meyer; Luciana Trilles; Leo van Iersel; Jacques F. Meis; Corné H. W. Klaassen; Teun Boekhout

Cryptococcosis is an important fungal disease in Asia with an estimated 140,000 new infections annually the majority of which occurs in patients suffering from HIV/AIDS. Cryptococcus neoformans variety grubii (serotype A) is the major causative agent of this disease. In the present study, multilocus sequence typing (MLST) using the ISHAM MLST consensus scheme for the C. neoformans/C. gattii species complex was used to analyse nucleotide polymorphisms among 476 isolates of this pathogen obtained from 8 Asian countries. Population genetic analysis showed that the Asian C. neoformans var. grubii population shows limited genetic diversity and demonstrates a largely clonal mode of reproduction when compared with the global MLST dataset. HIV-status, sequence types and geography were found to be confounded. However, a correlation between sequence types and isolates from HIV-negative patients was observed among the Asian isolates. Observations of high gene flow between the Middle Eastern and the Southeastern Asian populations suggest that immigrant workers in the Middle East were originally infected in Southeastern Asia.


PLOS ONE | 2012

Resistance of Asian Cryptococcus neoformans Serotype A Is Confined to Few Microsatellite Genotypes

Weihua Pan; Kantarawee Khayhan; Ferry Hagen; Retno Wahyuningsih; Arunaloke Chakrabarti; Anuradha Chowdhary; Reiko Ikeda; Saad J. Taj-Aldeen; Ziauddin Khan; Darma Imran; Ridhawati Sjam; Pojana Sriburee; Wanqing Liao; Kunyaluk Chaicumpar; Natnicha Ingviya; Johan W. Mouton; Ilse Curfs-Breuker; Teun Boekhout; Jacques F. Meis; Corné H. W. Klaassen

Background Cryptococcus neoformans is a pathogenic yeast that causes cryptococcosis, a life threatening disease. The prevalence of cryptococcosis in Asia has been rising after the onset of the AIDS epidemic and estimates indicate more than 120 cases per 1,000 HIV-infected individuals per year. Almost all cryptococcal disease cases in both immunocompromised and immunocompetent patients in Asia are caused by C. neoformans var. grubii. Epidemiological studies on C. neoformans in pan-Asia have not been reported. The present work studies the genetic diversity of the fungus by microsatellite typing and susceptibility analysis of approximately 500 isolates from seven Asian countries. Methodology/Principal Findings Genetic diversity of Asian isolates of C. neoformans was determined using microsatellite analysis with nine microsatellite markers. The analysis revealed eight microsatellite complexes (MCs) which showed different distributions among geographically defined populations. A correlation between MCs and HIV-status was observed. Microsatellite complex 2 was mainly associated with isolates from HIV-negative patients, whereas MC8 was associated with those from HIV-positive patients. Most isolates were susceptible to amphotericin B, itraconazole, voriconazole, posaconazole, and isavuconazole, but 17 (3.4%) and 10 (2%) were found to be resistant to 5-flucytosine and fluconazole, respectively. Importantly, five Indonesian isolates (approximately 12.5% from all Indonesian isolates investigated and 1% from the total studied isolates) were resistant to both antifungals. The majority of 5-flucytosine resistant isolates belonged to MC17. Conclusions The findings showed a different distribution of genotypes of C. neoformans var. grubii isolates from various countries in Asia, as well as a correlation of the microsatellite genotypes with the original source of the strains and resistance to 5-flucytosine.


Tissue Antigens | 2011

Tumour necrosis factor haplotypes associated with sensory neuropathy in Asian and Caucasian human immunodeficiency virus patients.

Constance S N Chew; Catherine L. Cherry; Darma Imran; Evy Yunihastuti; Adeeba Kamarulzaman; S Varna; Rusli Ismail; Maude E. Phipps; Zayd K.A. Aghafar; Ivo Gut; Patricia Price

In human immunodeficiency virus (HIV) patients, neuropathy is a common adverse side effect to some antiretroviral treatments, particularly stavudine. As stavudine is cheap, it is widely used in Asia and Africa. We showed that increasing age and height moderately predict the development of neuropathy. This was improved by the inclusion of tumour necrosis factor (TNF)-1031 (rs1799964). To investigate this association, Malay (n = 64), Chinese (n = 74) and Caucasian patients (n = 37) exposed to stavudine were screened for neuropathy. DNA samples were genotyped for polymorphisms in the central major histocompatibility complex (MHC) near TNF, and haplotypes were derived. The haplotype group FVa6,7,8 (incorporating TNF-1031) was found to be associated with neuropathy in Chinese patients in bivariate analyses (P = 0.03), and in Malays and Chinese in a multivariate analysis correcting for age and height (P = 0.02, P = 0.03, respectively). This trend was also confirmed in Caucasians.


Neurology | 2010

Hepatitis C seropositivity is not a risk factor for sensory neuropathy among patients with HIV

Catherine L. Cherry; Jacquita S. Affandi; Bruce J. Brew; Jason Creighton; Samsuridjal Djauzi; David J. Hooker; Darma Imran; Adeeba Kamarulzaman; Peter R. Kamerman; J. C. McArthur; R D Moore; Patricia Price; K. Smyth; I L Tan; Sasheela Vanar; Antonia L. Wadley; Steven L. Wesselingh; Evy Yunihastuti

Background: Sensory neuropathy (SN) is common in patients with HIV. Hepatitis C (HCV) coinfection is often cited as an HIV-SN risk factor, but data to support this are lacking. This collaboration aimed to examine the association between HCV serostatus and SN risk among ambulatory HIV-positive patients. Methods: Patients with HIV were assessed in cross-sectional studies in Baltimore, Jakarta, Johannesburg, Kuala Lumpur, Melbourne, and Sydney for SN (defined by both supportive symptoms and signs). HCV seropositivity was assessed as an SN risk using a χ2 test, followed by logistic regression modeling to correct for treatment exposures and demographics. Results: A total of 837 patients of African, Asian, and Caucasian descent were studied. HCV seroprevalence varied by site (Baltimore n = 104, 61% HCV+; Jakarta 96, 51%; Johannesburg 300, 1%; Kuala Lumpur 97, 10%; Melbourne 206, 16%; Sydney 34, 18%). HCV seropositivity was not associated with increased SN risk at any site, but was associated with reduced SN risk in Melbourne (p = 0.003). On multivariate analyses, the independent associations with SN were increasing age, height, and stavudine exposure. HCV seropositivity was not independently associated with an increased SN risk at any site, but associated independently with reduced SN risk in Baltimore (p = 0.04) and Melbourne (p = 0.06). Conclusions: Hepatitis C (HCV) seropositivity was not associated with increased sensory neuropathy risk among HIV-positive patients at any site. While we were unable to assess HCV RNA or liver damage, the data suggest that HCV coinfection is not a major contributor to HIV-SN. HCV = hepatitis C; SN = sensory neuropathy.


Trials | 2014

CryptoDex: A randomised, double-blind, placebo-controlled phase III trial of adjunctive dexamethasone in HIV-infected adults with cryptococcal meningitis: study protocol for a randomised control trial

Jeremy N. Day; Darma Imran; Ahmed Rizal Ganiem; Natriana Tjahjani; Retno Wahyuningsih; Robiatul Adawiyah; David A. B. Dance; Mayfong Mayxay; Paul N. Newton; Rattanaphone Phetsouvanh; Sayaphet Rattanavong; Adrienne K. Chan; Robert S. Heyderman; Joep J. van Oosterhout; Wirongrong Chierakul; Nicholas P. J. Day; Anatoli Kamali; Freddie Kibengo; Eugene Ruzagira; Alastair Gray; David G. Lalloo; Justin Beardsley; Tran Quang Binh; Tran Thi Hong Chau; Nguyen Van Vinh Chau; Ngo Thi Kim Cuc; Jeremy Farrar; Tran Tinh Hien; Nguyen Van Kinh; Laura Merson

BackgroundCryptococcal meningitis (CM) is a severe AIDS-defining illness with 90-day case mortality as high as 70% in sub-Saharan Africa, despite treatment. It is the leading cause of death in HIV patients in Asia and Africa.No major advance has been made in the treatment of CM since the 1970s. The mainstays of induction therapy are amphotericin B and flucytosine, but these are often poorly available where the disease burden is highest. Adjunctive treatments, such as dexamethasone, have had dramatic effects on mortality in other neurologic infections, but are untested in CM. Given the high death rates in patients receiving current optimal treatment, and the lack of new agents on the horizon, adjuvant treatments, which offer the potential to reduce mortality in CM, should be tested.The principal research question posed by this study is as follows: does adding dexamethasone to standard antifungal therapy for CM reduce mortality? Dexamethasone is a cheap, readily available, and practicable intervention.MethodA double-blind placebo-controlled trial with parallel arms in which patients are randomised to receive either dexamethasone or placebo, in addition to local standard of care. The study recruits patients in both Asia and Africa to ensure the relevance of its results to the populations in which the disease burden is highest. The 10-week mortality risk in the control group is expected to be between 30% and 50%, depending on location, and the target hazard ratio of 0.7 corresponds to absolute risk reductions in mortality from 30% to 22%, or from 50% to 38%. Assuming an overall 10-week mortality of at least 30% in our study population, recruitment of 824 patients will be sufficient to observe the expected number of deaths. Allowing for some loss to follow-up, the total sample size for this study is 880 patients. To generate robust evidence across both continents, we aim to recruit roughly similar numbers of patients from each continent. The primary end point is 10-week mortality. Ethical approval has been obtained from Oxford University’s Tropical Research Ethics Committee (OxTREC), and as locally mandated at each site.Trial registrationInternational Standard Randomised Controlled Trial Number: ISRCTN59144167 26-July-2012


Wellcome Open Research | 2018

Adjunctive dexamethasone for the treatment of HIV-infected adults with tuberculous meningitis (ACT HIV): Study protocol for a randomised controlled trial

Joseph Donovan; Nguyen Hoan Phu; Nguyen Thi Hoang Mai; Le Tien Dung; Darma Imran; Erlina Burhan; Lam Hong Bao Ngoc; Nguyen Duc Bang; Do Chau Giang; Dang Thi Minh Ha; Jeremy N. Day; Le Thi Phuong Thao; Nguyen Tt Thuong; Nguyen Nang Vien; Ronald B. Geskus; Marcel Wolbers; Raph L. Hamers; Reinout van Crevel; Mugi Nursaya; Kartika Maharani; Tran Tinh Hien; Kevin Baird; Nguyen Huu Lan; Evelyne Kestelyn; Nguyen Van Vinh Chau; Guy Thwaites

Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Co-infection with HIV increases the risk of developing TBM, complicates treatment, and substantially worsens outcome. Whether corticosteroids confer a survival benefit in HIV-infected patients with TBM remains uncertain. Hepatitis is the most common drug-induced serious adverse event associated with anti-tuberculosis treatment, occurring in 20% of HIV-infected patients. The suggested concentration thresholds for stopping anti-tuberculosis drugs are not evidence-based. This study aims to determine whether dexamethasone is a safe and effective addition to the first 6-8 weeks of anti-tuberculosis treatment of TBM in patients with HIV, and investigate alternative management strategies in a subset of patients who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy. Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled multi-centre Phase III trial, comparing the effect of dexamethasone versus placebo on overall survival in HIV-infected patients with TBM, in addition to standard anti-tuberculosis and antiretroviral treatment. The trial will be set in two hospitals in Ho Chi Minh City, Vietnam, and two hospitals in Jakarta, Indonesia. The trial will enrol 520 HIV-infected adults. An ancillary study will perform a randomised comparison of three DILI management strategies with the aim of demonstrating which strategy results in the least interruption in rifampicin and isoniazid treatment. An identical ancillary study will also be performed in the linked randomised controlled trial of dexamethasone in HIV-uninfected adults with TBM stratified by LTA4H genotype (LAST ACT). Discussion: Whether corticosteroids confer a survival benefit in HIV-infected patients remains uncertain, and the current evidence base for using corticosteroids in this context is limited. Interruptions in anti-tuberculosis chemotherapy is a risk factor for death from TBM. Alternative management strategies in DILI may allow the safe continuation of rifampicin and isoniazid therapy.


Epilepsia | 2008

Response to Birbeck et al.

Edwina Wright; Bruce J. Brew; Luxshimi Lal; Sophaginine Ty Ali; Arkhom Arayawichanont; Darma Imran; Adeeba Kamarulzaman; Subsai Kongsaengdao; Lim Kruy; Tuti Parwati Merati; Kanoksri Samintharapanya; Chel Sarim; Goa Tau; Chinkholal Thangsing; Charlie Vin‐Samnang; Steven L. Wesselingh

The “Gray Matters” section of Epilepsia provides a forum for the Journal’s owner—for almost 100 years— the International League Against Epilepsy (ILAE). As the ILAE’s centenary is approaching, and as we become involved with the project of documenting the organization’s and the Journal’s history, we have come to regret that the modern Epilepsia provides little information about the ILAE’s agenda and development. The Editors-in-Chief believe that reports from the ILAE President in the Gray Matters section would be instrumental in improving this situation in the future. This first report, in what will hopefully be a regular series of messages, is a midterm report about the first 2 years of the present Executive Committee (EC), which was elected in 2004 and 2005 for the period 2005–2009.

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Catherine L. Cherry

University of the Witwatersrand

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Jacquita S. Affandi

University of Western Australia

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