This week we highlight two recent papers in TB R&D – TB and HIV treatment and PA-824.

• Tuberculosis is the leading cause of the death in HIV positive individuals in the developing world. Major challenges exist in treating both diseases simultaneously as drug-drug interactions are common between the first-line of TB regimen and antiretroviral therapy (ART). Last week, the New England Journal of Medicine published a report “Timing of combination therapy for HIV and TB” by Abdool Karim et al. This paper reported the results of a trial to investigate the timing to begin antiretroviral therapy (ART) for patients that also present with TB. Initially, HIV positive and sputum smear positive TB patients were randomly assigned to one of three separate trial groups: ART initiation four weeks after start of TB treatment [early integrated-therapy], ART initiation within four weeks of end of intensive TB treatment (for this study- 2-3 months depending on previous TB history) [late integrated-therapy], and ART initiation within four weeks after the completion of TB treatment (for this study- 4-5 months depending on previous TB history) [sequential-therapy]. However, after 2 months after enrollment completion, the data and safety monitoring committee recommended that all patients in the sequential-therapy group be started on ART as soon as possible. Data presented are those for the combined integrated-therapy groups compared to the sequential-therapy group to the time of the recommendation. Results suggest that initiation of ART therapy reduces viral loads for both therapy groups; however immune reconstitution inflammatory syndrome events were significantly higher for the integrated therapy groups. The authors reference a recent study that immune reconstitution events are ‘rarely fatal and that severe episodes can be successfully managed with corticosteroids.’ Therefore, the authors support combination therapy for HIV patients co-infected with TB.

What are your thoughts about the results presented in this paper? Is the sample size large enough to support the conclusions? Are smear samples the most efficient ways to assess TB cure in HIV compromised individuals? Why does initiation of ART significantly increase immune reconstitution syndrome for the integrated therapy group vs. the sequential therapy and what does that tell us about the impact to ADME (absorption, distribution, metabolism, excretion) of antiretrovirals and TB drugs?

• Recently, Palmer et al. published a paper in the Journal of Medicinal Chemistry discussing the synthesis and characterization of (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824) analogues. PA-824 is the lead compound of the nitroimidazole class currently in Phase II clinical trials. (View WGND drug pipeline for more specific information). More than 100 analogues of PA-824 were reported. These analogs were tested against Mycobacterium tuberculosis under both aerobic and anaerobic conditions followed by assessment of selected analogues in an acute mouse model of TB infection. Several analogues with >200-fold better efficacy than PA-824 were identified.

Although some analogues displayed improved potency over PA-824, their increased lipophilicity is a liability. How could decreased lipophilicity of these analogues be achieved while maintaining potency? Suggestions or thoughts?