Dual-targeted anti-TB/anti-HIV heterodimers.
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ABSTRACT:
SUBMITTER: Alexandrova L
PROVIDER: S-EPMC5576140 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
Publications
Dual-targeted anti-TB/anti-HIV heterodimers.
Alexandrova Liudmila L Zicari Sonia S Matyugina Elena E Khandazhinskaya Anastasia A Smirnova Tatiana T Andreevskaya Sofya S Chernousova Larisa L Vanpouille Christophe C Kochetkov Sergei S Margolis Leonid L
Antiviral research 20170722
HIV and M. tuberculosis are two intersecting epidemics making the search for new dual action drugs against both pathogens extremely important. Here, we report on the synthesis and suppressive activities of five dual-targeted HIV/TB compounds. These compounds are heterodimers of AZT, as anti-HIV molecules, and 5-substituted uracil derivatives, as anti-TB molecules. We found that these compounds inhibit the growth of M. tuberculosis and suppress the replication of HIV in human cell cultures and hu ...[more]
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Project description:Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4⁺ T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing β-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1β, MIP-1α and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific β-chemokine upregulation required new mRNA synthesis. The upregulation of β-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host pathways (i.e. CCR5 receptor down regulation).
| S-EPMC3723632 | biostudies-literature
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| S-EPMC5703350 | biostudies-literature
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| S-EPMC4102066 | biostudies-literature
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| S-EPMC4173069 | biostudies-literature
Project description:BACKGROUND: Significant adverse events (AE) have been reported in patients receiving medications for multidrug- and extensively-drug-resistant tuberculosis (MDR-TB & XDR-TB). However, there is little prospective data on AE in MDR- or XDR-TB/HIV co-infected patients on antituberculosis and antiretroviral therapy (ART) in programmatic settings. METHODS: Médecins Sans Frontières (MSF) is supporting a community-based treatment program for drug-resistant tuberculosis in HIV-infected patients in a slum setting in Mumbai, India since 2007. Patients are being treated for both diseases and the management of AE is done on an outpatient basis whenever possible. Prospective data were analysed to determine the occurrence and nature of AE. RESULTS: Between May 2007 and September 2011, 67 HIV/MDR-TB co-infected patients were being treated with anti-TB treatment and ART; 43.3% were female, median age was 35.5 years (Interquartile Range: 30.5-42) and the median duration of anti-TB treatment was 10 months (range 0.5-30). Overall, AE were common in this cohort: 71%, 63% and 40% of patients experienced one or more mild, moderate or severe AE, respectively. However, they were rarely life-threatening or debilitating. AE occurring most frequently included gastrointestinal symptoms (45% of patients), peripheral neuropathy (38%), hypothyroidism (32%), psychiatric symptoms (29%) and hypokalaemia (23%). Eleven patients were hospitalized for AE and one or more suspect drugs had to be permanently discontinued in 27 (40%). No AE led to indefinite suspension of an entire MDR-TB or ART regimen. CONCLUSIONS: AE occurred frequently in this Mumbai HIV/MDR-TB cohort but not more frequently than in non-HIV patients on similar anti-TB treatment. Most AE can be successfully managed on an outpatient basis through a community-based treatment program, even in a resource-limited setting. Concerns about severe AE in the management of co-infected patients are justified, however, they should not cause delays in the urgently needed rapid scale-up of antiretroviral therapy and second-line anti-TB treatment.
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Project description:BACKGROUND:The World Health Organization recommends integrating services for patients coinfected with tuberculosis (TB) and HIV. We assessed the effect of TB/HIV integration on antiretroviral therapy (ART) initiation and TB treatment outcomes among TB/HIV-coinfected patients using data collected from 14 rural health facilities during 2 previous TB and HIV quality of care studies. METHODS:A facility was considered to have integrated TB/HIV services if patients with TB/HIV had combined treatment for both illnesses by 1 provider or care team at 1 treatment location. We analyzed the effect of integration by conducting a cross-sectional analysis of integrated and nonintegrated facility periods comparing performance on ART initiation and TB treatment outcomes. We conducted logistic regression, with the patient as the unit of analysis, controlling for other intervention effects, adjusting for age and sex, and clustering by health facility. RESULTS:From January 2012 to June 2014, 996 patients with TB were registered, 97% were tested for HIV, and 404 (42%) were HIV-positive. Excluding transfers, 296 patients were eligible for analysis with 117 and 179 from nonintegrated and integrated periods, respectively. Being treated in a facility with TB/HIV integration was associated with lower mortality [adjusted odds ratio (aOR) = 0.38, 95% confidence interval (CI): 0.18 to 0.77], but there was no difference in the proportion initiating ART (aOR = 1.34, 95% CI: 0.40 to 4.47), with TB treatment success (aOR = 1.43, 95% CI: 0.73 to 2.82), lost to follow-up (aOR = 1.64, 95% CI: 0.53 to 5.04), or failure (aOR = 1.21, 95% CI: 0.34 to 4.32). CONCLUSIONS:TB/HIV service integration was associated with lower mortality during TB treatment even in settings with suboptimal proportions of patients completing TB treatment and starting on ART.
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Project description:BACKGROUND: The impact of the human immunodeficiency virus (HIV) on tuberculosis (TB), and the implications for TB and HIV control, is a public health challenge in Ghana - almost a quarter (23%) of all TB cases were HIV positive in 2010. The integration of TB/HIV services has therefore emerged as an essential component of the national response to TB and HIV. The aim is to reduce fragmentation, improve access, enhance efficiency and improve quality of care. Ghana's TB/HIV policy comprises three linked sets of activities: effective implementation of the Stop TB Strategy for TB control, improved HIV prevention and care, and the implementation of additional TB/HIV activities. Different models of service delivery with increasing integration of TB/HIV activities are expected to provide greater access to more comprehensive care. The objective of this paper is to assess the impact of TB/HIV integration on TB treatment outcomes and to explore the usefulness of TB treatment outcomes as TB/HIV indicators. METHODS: A before-and-after study to observe the introduction of TB/HIV activities into TB programmes in three hospitals with different levels of integration was conducted. Anonymised patient data was collated from TB registers from each facility, and analysed to determine if TB treatment outcomes changed significantly after integration. RESULTS: TB treatment success was 50% (95% CI 49 - 52) prior to, and 69% (95% CI 65 - 73) after, integration (?2 43.96, p < 0.00). Treatment success increased from 43% to 53% at the one-stop shop (OSS), from 69% to 78% at the partially integrated site (PIS) and substantially from 46% to 78% at the referral site (RS) (?2 64.54; p<0.01). Defaults and cases transferred out reduced from 14.3% and 15.3% prior to integration, to 1.4% and 9.0% after integration, respectively, accounting for a significant increase in treatment success. Death rates remained high at 18% in all cases studied and 25% in HIV-associated cases after integration. CONCLUSION: TB/HIV integration may improve TB treatment success, but its exact impact is difficult to ascertain due to non-specificity and design limitations. TB mortality may be more useful as an indicator for monitoring TB/HIV activities in Ghana.
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