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  1. Al-Darraji HA, Kamarulzaman A, Altice FL
    Int J Tuberc Lung Dis, 2012 Jul;16(7):871-9.
    PMID: 22410101 DOI: 10.5588/ijtld.11.0447
    Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide and the main cause of death in correctional facilities in middle- and low-income countries. Due to the closed environment and the concentration of individuals with TB-related risk factors, effective measures are required to control TB in such settings. Isoniazid preventive therapy (IPT) represents an effective and cost-effective measure. Despite international recommendations that IPT be integral to TB control, it is seldom deployed. A systematic review of interventions used to assess IPT initiation and completion in correctional facilities was conducted using published studies from two biomedical databases and relevant keywords. Additional references were reviewed, resulting in 18 eligible studies. Most (72%) studies were conducted in the United States and in jail settings (60%), with the main objective of improving completion rates inside the facility or after release. Studies that provided data about initiation and completion rates showed poor success in correctional facilities. Adverse consequences and treatment interruption ranged from 1% to 55% (median 5%) in reported studies; hepatotoxicity was the most prevalent adverse reaction. Despite its accelerating effect on the development of active TB, information on human immunodeficiency virus (HIV) status was provided in only half of the studies. Among the four studies where IPT effectiveness was assessed, the results mirror those described in community settings. Future studies require thorough assessments of IPT initiation and completion rates and adverse effects, particularly in low- and middle-income countries and where comorbid viral hepatitis may contribute significantly to outcomes, and in settings where TB and HIV are more endemic.
  2. Al-Darraji HA, Kamarulzaman A, Altice FL
    BMC Public Health, 2014 Jan 10;14:22.
    PMID: 24405607 DOI: 10.1186/1471-2458-14-22
    Prisons continue to fuel tuberculosis (TB) epidemics particularly in settings where access to TB screening and prevention services is limited. Malaysia is a middle-income country with a relatively high incarceration rate of 138 per 100,000 population. Despite national TB incidence rate remaining unchanged over the past ten years, data about TB in prisons and its contribution to the overall national rates does not exist. This survey was conducted to address the prevalence of latent TB infection (LTBI) in Malaysia's largest prison.
  3. Margolis B, Al-Darraji HA, Wickersham JA, Kamarulzaman A, Altice FL
    Int J Tuberc Lung Dis, 2013 Dec;17(12):1538-44.
    PMID: 24200265 DOI: 10.5588/ijtld.13.0193
    There are currently no routine screening procedures for active tuberculosis (TB) or latent tuberculous infection (LTBI) in Malaysian prisons.
  4. Al-Darraji HA, Tan C, Kamarulzaman A, Altice FL
    Occup Environ Med, 2015 Jun;72(6):442-7.
    PMID: 25794506 DOI: 10.1136/oemed-2014-102695
    OBJECTIVES: Although prison employees share the same tuberculosis (TB) risk environment with prisoners, the magnitude of TB problems among prison employees is unknown in most resource-limited prisons. This survey was conducted to investigate the prevalence and correlates of tuberculin skin test (TST) positivity among employees in Malaysia's largest prison.

    METHODS: Consented, full-time prison employees were interviewed using a structured questionnaire that included sociodemographic data, history of working in the correctional system and TB-related risk. TST was placed intradermally and read after 48-72 h. Induration size of ≥10 mm was considered positive. Logistic regression analyses were conducted to explore associations with TST positivity.

    RESULTS: Of the 445 recruited prison employees, 420 (94.4%) had complete data. Most were young (median=30.0 years) men (88.8%) who had only worked at this prison (76.4%) for a median total employment period of 60 months (IQR 34.5-132.0). The majority were correctional officers, while civilian employees represented only 7.6% of the sample. Only 26 (6.2%) reported having ever been screened for TB since employment. Prevalence of TST positivity was 81% and was independently associated with longer (≥12 months) prison employment (AOR 4.9; 95% CI 1.5 to 15.9) and current tobacco smoking (AOR=1.9, 95% CI 1.2 to 3.2).

    CONCLUSIONS: Latent TB prevalence was high in this sample, approximating that of prisoners in this setting, perhaps suggesting within prison TB transmission in this facility. Formal TB control programmes for personnel and prisoners alike are urgently needed within the Malaysian correctional system.

  5. Al-Darraji HA, Altice FL, Kamarulzaman A
    Trop Med Int Health, 2016 Aug;21(8):1049-1058.
    PMID: 27197601 DOI: 10.1111/tmi.12726
    OBJECTIVES: To investigate the prevalence of previously undiagnosed active tuberculosis (TB) cases among prisoners in Malaysia's largest prison using an intensified TB case-finding strategy.

    METHODS: From October 2012 to May 2013, prisoners housed in two distinct units (HIV-negative and HIV-positive) were approached to participate in the TB screening study. Consenting prisoners submitted two sputum samples that were examined using GeneXpert MTB/RIF, smear microscopy and liquid culture. Socio-demographic and clinical information was collected and correlates of active TB, defined as having either a positive GeneXpert MTB/RIF or culture results, were assessed using regression analyses.

    RESULTS: Among the total of 559 prisoners, 442 (79.1%) had complete data; 28.7% were HIV-infected, 80.8% were men and the average age was 36.4 (SD 9.8) years. Overall, 34 (7.7%) had previously undiagnosed active TB, of whom 64.7% were unable to complete their TB treatment in prison due to insufficient time (<6 months) remaining in prison. Previously undiagnosed active TB was independently associated with older age groups (AOR 11.44 and 6.06 for age ≥ 50 and age 40-49 years, respectively) and with higher levels of immunosuppression (CD4 < 200 cells/ml) in HIV-infected prisoners (AOR 3.07, 95% CI 1.03-9.17).

    CONCLUSIONS: The high prevalence of previously undiagnosed active TB in this prison highlights the inadequate performance of internationally recommended case-finding strategies and suggests that passive case-finding policies should be abandoned, especially in prison settings where HIV infection is prevalent. Moreover, partnerships between criminal justice and public health treatment systems are crucial to continue TB treatment after release.

  6. Al-Darraji HA, Abd Razak H, Ng KP, Altice FL, Kamarulzaman A
    PLoS One, 2013;8(9):e73717.
    PMID: 24040038 DOI: 10.1371/journal.pone.0073717
    Delays in tuberculosis (TB) diagnosis, particularly in prisons, is associated with detrimental outcomes. The new GeneXpert MTB/RIF assay (Xpert) offers accurate and rapid diagnosis of active TB, but its performance in improving case detection in high-transmission congregate settings has yet to be evaluated. We assessed the diagnostic accuracy of a single Xpert assay in an intensified case finding survey among HIV-infected prisoners in Malaysia.
  7. Bick J, Culbert G, Al-Darraji HA, Koh C, Pillai V, Kamarulzaman A, et al.
    Int J Prison Health, 2016 12 19;12(4):253-269.
    PMID: 27921633 DOI: 10.1108/IJPH-06-2016-0017
    Purpose Criminalization of drug use in Malaysia has concentrated people who inject drugs (PWID) and people living with HIV into prisons where health services are minimal and HIV-related mortality is high. Few studies have comprehensively assessed the complex health needs of this population. The paper aims to discuss these issues. Design/methodology/approach From October 2012 through March 2013, 221 sequentially selected HIV-infected male prisoners underwent a comprehensive health assessment that included a structured history, physical examination, and clinically indicated diagnostic studies. Findings Participants were mostly PWID (83.7 percent) and diagnosed with HIV while incarcerated (66.9 percent). Prevalence of hepatitis C virus (90.4 percent), untreated syphilis (8.1 percent), active (13.1 percent), and latent (81.2 percent) tuberculosis infection was several fold higher than non-prisoner Malaysian adults, as was tobacco use (71.9 percent) and heavy drinking (30.8 percent). Most (89.5 percent) were aware of their HIV status before the current incarceration, yet few had been engaged previously in HIV care, including pre-incarceration CD4 monitoring (24.7 percent) or prescribed antiretroviral therapy (ART) (16.7 percent). Despite most (73.7 percent) meeting Malaysia's criteria for ART (CD4 <350 cells/ μL), less than half (48.4 percent) ultimately received it. Nearly one-quarter (22.8 percent) of those with AIDS (<200 cells/ μL) did not receive ART. Originality/value Drug addiction and communicable disease comorbidity, which interact negatively and synergistically with HIV and pose serious public health threats, are highly prevalent in HIV-infected prisoners. Interventions to address the critical shortage of healthcare providers and large gaps in treatment for HIV and other co-morbid conditions are urgently needed to meet the health needs of HIV-infected Malaysian prisoners, most of whom will soon transition to the community.
  8. Cheong HT, Ng KT, Ong LY, Takebe Y, Chan KG, Koh C, et al.
    Genome Announc, 2015;3(6).
    PMID: 26543107 DOI: 10.1128/genomeA.01220-15
    Three strains of HIV-1 unique recombinant forms (URFs) descended from subtypes B, B', and CRF01_AE were identified among people who inject drugs in Kuala Lumpur, Malaysia. These three URFs shared a common recombination breakpoint in the reverse transcriptase region, indicating frequent linkage within the drug-injecting networks in Malaysia.
  9. Ng KT, Takebe Y, Chook JB, Chow WZ, Chan KG, Abed Al-Darraji HA, et al.
    Sci Rep, 2015;5:15198.
    PMID: 26459957 DOI: 10.1038/srep15198
    Co-infections with human immunodeficiency virus type 1 (HIV-1) and human pegivirus (HPgV) are common in hepatitis C virus (HCV)-infected individuals. However, analysis on the evolutionary dynamics and transmission network profiles of these viruses among individuals with multiple infections remains limited. A total of 228 injecting drug users (IDUs), either HCV- and/or HIV-1-infected, were recruited in Kuala Lumpur, Malaysia. HCV, HIV-1 and HPgV genes were sequenced, with epidemic growth rates assessed by the Bayesian coalescent method. Based on the sequence data, mono-, dual- and triple-infection were detected in 38.8%, 40.6% and 20.6% of the subjects, respectively. Fifteen transmission networks involving HCV (subtype 1a, 1b, 3a and 3b), HIV-1 (CRF33_01B) and HPgV (genotype 2) were identified and characterized. Genealogical estimates indicated that the predominant HCV, HIV-1 and HPgV genotypes were introduced into the IDUs population through multiple sub-epidemics that emerged as early as 1950s (HCV), 1980s (HIV-1) and 1990s (HPgV). By determining the difference in divergence times between viral lineages (ΔtMRCA), we also showed that the frequency of viral co-transmission is low among these IDUs. Despite increased access to therapy and other harm reduction interventions, the continuous emergence and coexistence of new transmission networks suggest persistent multiple viral transmissions among IDUs.
  10. Cheong HT, Chow WZ, Takebe Y, Chook JB, Chan KG, Al-Darraji HA, et al.
    PLoS One, 2015;10(7):e0133883.
    PMID: 26196131 DOI: 10.1371/journal.pone.0133883
    In many parts of Southeast Asia, the HIV-1 epidemic has been driven by the sharing of needles and equipment among intravenous drug users (IDUs). Over the last few decades, many studies have proven time and again that the diversity of HIV-1 epidemics can often be linked to the route of infection transmission. That said, the diversity and complexity of HIV-1 molecular epidemics in the region have been increasing at an alarming rate, due in part to the high tendency of the viral RNA to recombine. This scenario was exemplified by the discovery of numerous circulating recombinant forms (CRFs), especially in Thailand and Malaysia. In this study, we characterized a novel CRF designated CRF74_01B, which was identified in six epidemiologically unlinked IDUs in Kuala Lumpur, Malaysia. The near-full length genomes were composed of CRF01_AE and subtype B', with eight breakpoints dispersed in the gag-pol and nef regions. Remarkably, this CRF shared four and two recombination hotspots with the previously described CRF33_01B and the less prevalent CRF53_01B, respectively. Genealogy-based Bayesian phylogenetic analysis of CRF74_01B genomic regions showed that it is closely related to both CRF33_01B and CRF53_01B. This observation suggests that CRF74_01B was probably a direct descendent from specific lineages of CRF33_01B, CRF53_01B and subtype B' that could have emerged in the mid-1990s. Additionally, it illustrated the active recombination processes between prevalent HIV-1 subtypes and recombinants in Malaysia. In summary, we report a novel HIV-1 genotype designated CRF74_01B among IDUs in Kuala Lumpur, Malaysia. The characterization of the novel CRF74_01B is of considerable significance towards the understanding of the genetic diversity and population dynamics of HIV-1 circulating in the region.
  11. Al-Darraji HA, Wong KC, Yeow DG, Fu JJ, Loeliger K, Paiji C, et al.
    J Subst Abuse Treat, 2014 Feb;46(2):144-9.
    PMID: 24074846 DOI: 10.1016/j.jsat.2013.08.023
    People who use drugs (PWUD) represent a key high risk group for tuberculosis (TB). The prevalence of both latent TB infection (LTBI) and active disease in drug treatment centers in Malaysia is unknown. A cross-sectional convenience survey was conducted to assess the prevalence and correlates of LTBI among attendees at a recently created voluntary drug treatment center using a standardized questionnaire and tuberculin skin testing (TST). Participants (N=196) were mostly men (95%), under 40 (median age=36 years) and reported heroin use immediately before treatment entry (75%). Positive TST prevalence was 86.7%. Nine (4.6%) participants were HIV-infected. Previous arrest/incarcerations (AOR=1.1 for every entry, p<0.05) and not being HIV-infected (AOR=6.04, p=0.03) were significantly associated with TST positivity. There is an urgent need to establish TB screening and treatment programs in substance abuse treatment centers and to tailor service delivery to the complex treatment needs of patients with multiple medical and psychiatric co-morbidities.
  12. Chow WZ, Takebe Y, Syafina NE, Prakasa MS, Chan KG, Al-Darraji HA, et al.
    PLoS One, 2014;9(1):e85250.
    PMID: 24465513 DOI: 10.1371/journal.pone.0085250
    The HIV epidemic is primarily characterised by the circulation of HIV-1 group M (main) comprising of 11 subtypes and sub-subtypes (A1, A2, B-D, F1, F2, G, H, J, and K) and to date 55 circulating recombinant forms (CRFs). In Southeast Asia, active inter-subtype recombination involving three main circulating genotypes--subtype B (including subtype B', the Thai variant of subtype B), CRF01_AE, and CRF33_01B--have contributed to the emergence of novel unique recombinant forms. In the present study, we conducted the molecular epidemiological surveillance of HIV-1 gag-RT genes among 258 people who inject drugs (PWIDs) in Kuala Lumpur, Malaysia, between 2009 and 2011 whereby a novel CRF candidate was recently identified. The near full-length genome sequences obtained from six epidemiologically unlinked individuals showed identical mosaic structures consisting of subtype B' and CRF01_AE, with six unique recombination breakpoints in the gag-RT, pol, and env regions. Among the high-risk population of PWIDs in Malaysia, which was predominantly infected by CRF33_01B (>70%), CRF58_01B circulated at a low but significant prevalence (2.3%, 6/258). Interestingly, the CRF58_01B shared two unique recombination breakpoints with other established CRFs in the region: CRF33_01B, CRF48_01B, and CRF53_01B in the gag gene, and CRF15_01B (from Thailand) in the env gene. Extended Bayesian Markov chain Monte Carlo sampling analysis showed that CRF58_01B and other recently discovered CRFs were most likely to have originated in Malaysia, and that the recent spread of recombinant lineages in the country had little influence from neighbouring countries. The isolation, genetic characterization, and evolutionary features of CRF58_01B among PWIDs in Malaysia signify the increasingly complex HIV-1 diversity in Southeast Asia that may hold an implication on disease treatment, control, and prevention.
  13. Ng KT, Lee YM, Al-Darraji HA, Xia X, Takebe Y, Chan KG, et al.
    Genome Announc, 2013 Jan;1(1).
    PMID: 23409272 DOI: 10.1128/genomeA.00168-12
    We report the full genome sequence of hepatitis C virus (HCV) subtype 6n from Kuala Lumpur, Malaysia. Phylogenetic analysis of the isolate 10MYKJ032 suggests that Southeast Asia might be the origin for the HCV subtype 6n and highlights the possible spread of this lineage from Southeast Asia to other regions.
  14. Culbert GJ, Pillai V, Bick J, Al-Darraji HA, Wickersham JA, Wegman MP, et al.
    J Neuroimmune Pharmacol, 2016 09;11(3):446-55.
    PMID: 27216260 DOI: 10.1007/s11481-016-9676-7
    Throughout Southeast Asia, repressive drug laws have resulted in high rates of imprisonment in people who inject drugs (PWID) and people living with HIV (PLH), greatly magnifying the harm associated with HIV, tuberculosis, and addiction. We review findings from Malaysia's largest prison to describe the negative synergistic effects of HIV, tuberculosis, addiction, and incarceration that contribute to a 'perfect storm' of events challenging public and personal health and offer insights into innovative strategies to control these converging epidemics. The majority of PLH who are imprisoned in Malaysia are opioid dependent PWID. Although promoted by official policy, evidence-based addiction treatment is largely unavailable, contributing to rapid relapse and/or overdose after release. Similarly, HIV treatment in prisons and compulsory drug treatment centers is sometimes inadequate or absent. The prevalence of active tuberculosis is high, particularly in PLH, and over 80 % of prisoners and prison personnel are latently infected. Mandatory HIV testing and subsequent segregation of HIV-infected prisoners increases the likelihood of tuberculosis acquisition and progression to active disease, amplifying the reservoir of infection for other prisoners. We discuss strategies to control these intersecting epidemics including screening linked to standardized treatment protocols for all three conditions, and effective transitional programs for released prisoners. For example, recently introduced evidence-based interventions in prisons like antiretroviral therapy (ART) to treat HIV, isoniazid preventive therapy to treat latent tuberculosis infection, and methadone maintenance to treat opioid dependence, have markedly improved clinical care and reduced morbidity and mortality. Since introduction of these interventions in September 2012, all-cause and HIV-related mortality have decreased by 50.0 % and 75.7 %, respectively. We discuss the further deployment of these interventions in Malaysian prisons.
  15. Dara M, Acosta CD, Melchers NV, Al-Darraji HA, Chorgoliani D, Reyes H, et al.
    Int J Infect Dis, 2015 Mar;32:111-7.
    PMID: 25809766 DOI: 10.1016/j.ijid.2014.12.029
    Tuberculosis (TB) in penitentiary services (prisons) is a major challenge to TB control. This review article describes the challenges that prison systems encounter in TB control and provides solutions for the more efficient use of limited resources based on the three pillars of the post-2015 End TB Strategy. This paper also proposes research priorities for TB control in prisons based on current challenges.
  16. Chow WZ, Ong LY, Razak SH, Lee YM, Ng KT, Yong YK, et al.
    PLoS One, 2013;8(5):e62560.
    PMID: 23667490 DOI: 10.1371/journal.pone.0062560
    Since the discovery of HIV-1 circulating recombinant form (CRF) 33_01B in Malaysia in the early 2000 s, continuous genetic diversification and active recombination involving CRF33_01B and other circulating genotypes in the region including CRF01_AE and subtype B' of Thai origin, have led to the emergence of novel CRFs and unique recombinant forms. The history and magnitude of CRF33_01B transmission among various risk groups including people who inject drugs (PWID) however have not been investigated despite the high epidemiological impact of CRF33_01B in the region. We update the most recent molecular epidemiology of HIV-1 among PWIDs recruited in Malaysia between 2010 and 2011 by population sequencing and phylogenetic analysis of 128 gag-pol sequences. HIV-1 CRF33_01B was circulating among 71% of PWIDs whilst a lower prevalence of other previously dominant HIV-1 genotypes [subtype B' (11%) and CRF01_AE (5%)] and CRF01_AE/B' unique recombinants (13%) were detected, indicating a significant shift in genotype replacement in this population. Three clusters of CRF01_AE/B' recombinants displaying divergent yet phylogenetically-related mosaic genomes to CRF33_01B were identified and characterized, suggestive of an abrupt emergence of multiple novel CRF clades. Using rigorous maximum likelihood approach and the Bayesian Markov chain Monte Carlo (MCMC) sampling of CRF33_01Bpol sequences to elucidate the past population dynamics, we found that the founder lineages of CRF33_01B were likely to have first emerged among PWIDs in the early 1990 s before spreading exponentially to various high and low-risk populations (including children who acquired infections from their mothers) and later on became endemic around the early 2000 s. Taken together, our findings provide notable genetic evidence indicating the widespread expansion of CRF33_01B among PWIDs and into the general population. The emergence of numerous previously unknown recombinant clades highlights the escalating genetic complexity of HIV-1 in the Southeast Asian region.
  17. Saeidi A, Tien Tien VL, Al-Batran R, Al-Darraji HA, Tan HY, Yong YK, et al.
    PLoS One, 2015;10(4):e0124659.
    PMID: 25894562 DOI: 10.1371/journal.pone.0124659
    Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved antimicrobial MR1-restricted CD8(+) T cells co-expressing the semi-invariant TCR Vα7.2, and are numerous in the blood and mucosal tissues of humans. MAIT cells appear to undergo exhaustion in chronic viral infections. However, their role in human immunodeficiency virus type 1 (HIV-1) mono-infection and HIV/tuberculosis (TB) co-infection have seldom been elaborately investigated. We conducted a cross-sectional study to investigate the frequencies and phenotypes of CD161(++)CD8(+) T cells among anti-retroviral therapy (ART)/anti-TB therapy (ATT) treatment-naïve HIV/TB co-infected, ART/TB treated HIV/TB co-infected, ART naïve HIV-infected, ART-treated HIV-infected patients, and HIV negative healthy controls (HCs) by flow cytometry. Our data revealed that the frequency of MAIT cells was severely depleted in HIV mono- and HIV/TB co-infections. Further, PD-1 expression on MAIT cells was significantly increased in HIV mono- and HIV-TB co-infected patients. The frequency of MAIT cells did not show any significant increase despite the initiation of ART and/or ATT. Majority of the MAIT cells in HCs showed a significant increase in CCR6 expression as compared to HIV/TB co-infections. No marked difference was seen with expressions of chemokine co-receptor CCR5 and CD103 among the study groups. Decrease of CCR6 expression appears to explain why HIV-infected patients display weakened mucosal immune responses.
  18. Lange B, Khan P, Kalmambetova G, Al-Darraji HA, Alland D, Antonenka U, et al.
    Int J Tuberc Lung Dis, 2017 05 01;21(5):493-502.
    PMID: 28399963 DOI: 10.5588/ijtld.16.0702
    SETTING: Xpert® MTB/RIF is the most widely used molecular assay for rapid diagnosis of tuberculosis (TB). The number of polymerase chain reaction cycles after which detectable product is generated (cycle threshold value, CT) correlates with the bacillary burden.OBJECTIVE To investigate the association between Xpert CT values and smear status through a systematic review and individual-level data meta-analysis.

    DESIGN: Studies on the association between CT values and smear status were included in a descriptive systematic review. Authors of studies including smear, culture and Xpert results were asked for individual-level data, and receiver operating characteristic curves were calculated.

    RESULTS: Of 918 citations, 10 were included in the descriptive systematic review. Fifteen data sets from studies potentially relevant for individual-level data meta-analysis provided individual-level data (7511 samples from 4447 patients); 1212 patients had positive Xpert results for at least one respiratory sample (1859 samples overall). ROC analysis revealed an area under the curve (AUC) of 0.85 (95%CI 0.82-0.87). Cut-off CT values of 27.7 and 31.8 yielded sensitivities of 85% (95%CI 83-87) and 95% (95%CI 94-96) and specificities of 67% (95%CI 66-77) and 35% (95%CI 30-41) for smear-positive samples.

    CONCLUSION: Xpert CT values and smear status were strongly associated. However, diagnostic accuracy at set cut-off CT values of 27.7 or 31.8 would not replace smear microscopy. How CT values compare with smear microscopy in predicting infectiousness remains to be seen.

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