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"Torpēda" aktivē HIV
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23.11.2015


Preparāts „Disulfirams”, ko izmanto alkoholisma ārstēšanai, izrādījies perspektīvs, lai ārstētu HIV. Zinātnieki, kas nodarbojas ar HIV infekcijas ārstēšanas metožu meklēšanu, atklāja, ka preparāts „Disulfirams”, ko izmanto, lai ārstētu alkoholismu, ir spējīgs aktivēt vīrusu „gulošajās” šūnās,  lai to pēc tam iznīcinātu ar ARV preparātiem. Šī darba rezultāti bija publicēti žurnālā "The Lancet". Kā vēstīts izdevumā, preparāta paaugstinātas devas klīniskajā pētījumā piedalījās 30 pacienti, kas saņēma ARV terapiju Melburnas un Sanfrancisko klīnikās. Visiem eksperimenta dalībniekiem HIV RNS bija mazāk kā 50 kopijas/ml, bet CD4 rādītājs pārsniedza 350 šūnas/mcl. Pacienti tika randomizēti trīs grupās un trīs dienās saņēma 500, 1000 un 2000 mg „Disulfirama”. Kā rādīja iegūtie rezultāti, pēc preparāta ievadīšanas pacientiem novēroja vīrusa slodzes lēcienu, kas liecina par vīrusa aktivāciju. Jāpiebilst, ka šodien izmantotie antiretrovīrusu preparāti kavē vīrusa replikāciju imūnsistēmas šūnās, uz kuru virsmas ir CD4 receptori. Tomēr vīrusa genoms paliek imunsistēmas „gulošajās” šūnās, kas veido tā saucamo „vīrusu rezervuāru”. Ja pārtrauc lietot ARV preparātus, HIV replikācija atjaunojas un slimība, kas noved pie AIDS attīstības, sāk progresēt.
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Source: The Lancet, 17 November, 2015 | "Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study" | http://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(15)00226-X/abstract |
Summary
Background
In vitro, disulfiram activated HIV transcription in a primary T-cell model of HIV latency and in a pilot clinical study increased plasma HIV RNA in individuals with adequate drug exposure. We assessed the effect of disulfiram on HIV transcription in a dose-escalation study.
Methods
In this prospective dose-escalation study, to optimise disulfiram exposure we included adults with HIV on suppressive antiretroviral therapy, with plasma HIV RNA of less than 50 copies per mL and a CD4 cell count greater than 350 cells per μL. Participants were allocated sequentially to one of three dosing groups (500 mg, 1000 mg, and 2000 mg) and received disulfiram daily for 3 days. Only the staff who did laboratory assays were masked to group assignment. The primary endpoint was change in cell-associated unspliced HIV RNA in CD4 cells. The primary analysis method was a negative binomial regression, with the number of copies as the outcome variable and the input total RNA or plasma volume as an exposure variable, which is equivalent to modelling copies or input. We used these models to estimate changes from before disulfiram to timepoints during and after disulfiram administration. This study is registered with ClinicalTrials.gov, number NCT01944371.
Findings
Of 34 participants screened for eligibility at The Alfred Hospital (Melbourne, VIC, Australia), and San Francisco General Hospital (San Francisco, CA, USA), 30 people were enrolled between Sept 24, 2013, and March 31, 2014. The estimated fold increases in cell-associated unspliced HIV RNA from baseline were 1=7 (95% CI 1=3–2=2; p<0=0001) to the timepoint during disulfiram treatment and 2=1 (1=5–2=9; p<0=0001) to the timepoint after disulfiram in the 500 mg group; 1=9 (1=6–2=4; p<0=0001) and 2=5 (1=9–3=3; p<0=0001) in the 1000 mg group; and 1=6 (1=2–2=1; p=0=0026) and 2=1 (1=5–3=1; p=0=0001) in the 2000 mg group. No deaths occurred, and no serious adverse events were noted. Disulfiram was well tolerated at all doses.
Interpretation
Short-term administration of disulfiram resulted in increases in cell-associated unspliced HIV RNA at all doses, consistent with activating HIV latency. Disulfiram may be suited for future studies of combination and prolonged therapy to activate latent HIV.

 


 
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