Once-weekly rifapentine and isoniazid for tuberculosis prevention in patients with HIV taking dolutegravir-based antiretroviral therapy: a phase 1/2 trial

Dooley, Kelly E.; Savic, Radojkam; Gupte, Akshay; Marzinke, Mark A.; Zhang, Nan; Edward, Vinodh; Wolf, Lisa; Sebe, Modulakgotla; Likoti, Morongwe; Fyvie, Mark J; Shibambo, Innocent; Beattie, Trevor; Chaisson, Richard E.; Churchyard, Gavin

doi:10.1016/s2352-3018(20)30032-1

Cited by 44 publications

(27 citation statements)

References 21 publications

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“…However, non-nucleoside reverse transcriptase inhibitors (such as efavirenz) and the integrase inhibitors-such as raltegravir or dolutegravir (doubling the dose)-can be coadministered with rifamycins [14]. Increase use of shorter rifamycin-based regimens should be considered, as these may improve TPT completion and are safer, cheaper, and at least as effective as isoniazid regimens [93][94][95][96][97][98][99].…”

Section: Discussionmentioning

confidence: 99%

The latent tuberculosis cascade-of-care among people living with HIV: A systematic review and meta-analysis

et al. 2021

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Background Tuberculosis preventive therapy (TPT) reduces TB-related morbidity and mortality in people living with HIV (PLHIV). Cascade-of-care analyses help identify gaps and barriers in care and develop targeted solutions. A previous latent tuberculosis infection (LTBI) cascade-of-care analysis showed only 18% of persons in at-risk populations complete TPT, but a similar analysis for TPT among PLHIV has not been completed. We conducted a meta-analysis to provide this evidence. Methods and findings We first screened potential articles from a LTBI cascade-of-care systematic review published in 2016. From this study, we included cohorts that reported a minimum of 25 PLHIV. To identify new cohorts, we used a similar search strategy restricted to PLHIV. The search was conducted in Medline, Embase, Health Star, and LILACS, from January 2014 to February 2021. Two authors independently screened titles and full text and assessed risk of bias using the Newcastle–Ottawa Scale for cohorts and Cochrane Risk of Bias for cluster randomized trials. We meta-analyzed the proportion of PLHIV completing each step of the LTBI cascade-of-care and estimated the cumulative proportion retained. These results were stratified based on cascades-of-care that used or did not use LTBI testing to determine eligibility for TPT. We also performed a narrative synthesis of enablers and barriers of the cascade-of-care identified at different steps of the cascade. A total of 71 cohorts were included, and 70 were meta-analyzed, comprising 94,011 PLHIV. Among the PLHIV included, 35.3% (33,139/94,011) were from the Americas and 29.2% (27,460/94,011) from Africa. Overall, 49.9% (46,903/94,011) from low- and middle-income countries, median age was 38.0 [interquartile range (IQR) 34.0;43.6], and 65.9% (46,328/70,297) were men, 43.6% (29,629/67,947) were treated with antiretroviral therapy (ART), and the median CD4 count was 390 cell/mm3 (IQR 312;458). Among the cohorts that did not use LTBI tests, the cumulative proportion of PLHIV starting and completing TPT were 40.9% (95% CI: 39.3% to 42.7%) and 33.2% (95% CI: 31.6% to 34.9%). Among cohorts that used LTBI tests, the cumulative proportions of PLHIV starting and completing TPT were 60.4% (95% CI: 58.1% to 62.6%) and 41.9% (95% CI:39.6% to 44.2%), respectively. Completion of TPT was not significantly different in high- compared to low- and middle-income countries. Regardless of LTBI test use, substantial losses in the cascade-of-care occurred before treatment initiation. The integration of HIV and TB care was considered an enabler of the cascade-of-care in multiple cohorts. Key limitations of this systematic review are the observational nature of the included studies, potential selection bias in the population selection, only 14 cohorts reported all steps of the cascade-of-care, and barriers/facilitators were not systematically reported in all cohorts. Conclusions Although substantial losses were seen in multiple stages of the cascade-of-care, the cumulative proportion of PLHIV completing TPT was higher than previously reported among other at-risk populations. The use of LTBI testing in PLHIV in low- and middle-income countries was associated with higher proportion of the cohorts initiating TPT and with similar rates of completion of TPT.

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Section: Discussionmentioning

confidence: 99%

The latent tuberculosis cascade-of-care among people living with HIV: A systematic review and meta-analysis

et al. 2021

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“…The mechanism of cytokine‐mediated systemic adverse reactions observed in the DTG and 3HP study of four healthy subjects was unclear [ 14 ]. It could be related to robust immune reactions seen in HIV‐negative healthy volunteers, which may be less likely to occur in PLWH [ 12 ], or probably a chance finding.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the pharmacokinetic studies derived from the BRIEF‐TB trial, daily rifapentine can be administered with efavirenz without clinically relevant reductions in the efavirenz plasma concentration or virologic suppression, but not with nevirapine because of a significant decrease of nevirapine trough concentrations [ 10 , 11 ]. Recent studies suggested that both raltegravir and dolutegravir (DTG) can be used at a standard dose with rifapentine once weekly as a part of 3‐month course of isoniazid plus rifapentine regimen (3HP) [ 12 , 13 ]. Rifapentine taken once weekly significantly increased DTG clearance by 36%, resulting in a 26% decrease in DTG area‐under‐the‐curve (AUC) concentration, but the geometric mean trough concentration was well above the protein‐adjusted 90% maximal inhibitory concentration (paIC 90 ), and viral suppression could be maintained [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies suggested that both raltegravir and dolutegravir (DTG) can be used at a standard dose with rifapentine once weekly as a part of 3‐month course of isoniazid plus rifapentine regimen (3HP) [ 12 , 13 ]. Rifapentine taken once weekly significantly increased DTG clearance by 36%, resulting in a 26% decrease in DTG area‐under‐the‐curve (AUC) concentration, but the geometric mean trough concentration was well above the protein‐adjusted 90% maximal inhibitory concentration (paIC 90 ), and viral suppression could be maintained [ 12 ]. Nevertheless, the study of DTG in combination with 3HP in healthy subjects was terminated early because of the development of flu‐like syndrome and elevated aminotransferase and inflammatory cytokine levels in two of four participants after the third weekly dose [ 14 ]; however, this observation was not confirmed by another study of 60 PLWH concurrently received DTG‐based ART and 3HP [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Short‐course daily isoniazid and rifapentine for latent tuberculosis infection in people living with HIV who received coformulated bictegravir/emtricitabine/tenofovir alafenamide

et al. 2021

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IntroductionShort‐course preventive therapy with 1‐month course of daily administration of isoniazid (300‐mg) plus rifapentine (600‐mg) (1HP) and 3‐month course of weekly administration of isoniazid (900‐mg) plus rifapentine (900‐mg) (3HP) has higher completion rates than 9‐month course of daily isoniazid (9H) for individuals with latent tuberculosis infection (LTBI). We aimed to evaluate the effect, safety and tolerability of 1HP in people living with HIV (PLWH) and LTBI who received coformulated bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF).MethodsPLWH testing positive by interferon‐gamma release assay and having received BIC/FTC/TAF for >2 weeks with plasma HIV RNA load (PVL) <200 copies/ml were enrolled. BIC trough plasma concentrations and cytokine profiles were determined before the first dose (day 1/baseline), 24 h after the 14th (day 15) and 28th (day 29) doses of 1HP. PVL were determined on days 15 and 29 of 1HP and every 3 months subsequently after discontinuation of 1HP.ResultsFrom November 2019 to December 2020, 48 PLWH with LTBI were enrolled. One participant (2.1%) discontinued 1HP on day 15 due to fever and generalized rashes with PVL of 72 copies/ml, which was <50 copies/ml in three subsequent determinations while on BIC/FTC/TAF over the 12 months of follow‐up. The percentages of BIC trough plasma concentrations above the protein‐adjusted 95% effective concentration (paEC95 = 162 ng/ml) were 56.3% and 37.0% on days 15 and 29, respectively. The percentage of PVL <200 copies/ml was 91.7% on day 15, 97.8% on day 29 and 100% at both months 3 and 6. After a median observation of 52 weeks (interquartile range, 51–55), all participants continued BIC/FTC/TAF with a median PVL of 20 copies/ml (range 20–331). Except for the participant who discontinued 1HP because of allergic reactions, none of the participants had relevant symptoms or increases of the cytokine levels assessed between baseline and days 15 and 29 of 1HP.ConclusionsBIC/FTC/TAF in combination with 1HP was well tolerated with a high completion rate. BIC trough plasma concentrations were significantly decreased with concurrent use of 1HP among PLWH with LTBI. While transient viral blips were observed during 1HP without causing subsequent treatment failure, such combination should be applied with caution.

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“… 30 Studies have suggested that rifapentine can be coadministered with efavirenz and dolutegravir without jeopardizing antiretroviral activity. 42 , 43 …”

Section: Tb Preventionmentioning

confidence: 99%

HIV-associated tuberculosis

Hamada

Getahun²,

Tadesse

et al. 2021

Int J STD AIDS

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Tuberculosis (TB) remains a leading cause of morbidity and mortality among people living with HIV. HIV-associated TB disproportionally affects African countries, particularly vulnerable groups at risk for both TB and HIV. Currently available TB diagnostics perform poorly in people living with HIV; however, new diagnostics such as Xpert Ultra and lateral flow urine lipoarabinomannan assays can greatly facilitate diagnosis of TB in people living with HIV. TB preventive treatment has been underutilized despite its proven benefits independent of antiretroviral therapy (ART). Shorter regimens using rifapentine can support increased availability and scale-up. Mortality is high in people with HIV-associated TB, and timely initiation of ART is critical. Programs should provide decentralized and integrated TB and HIV care in settings with high burden of both diseases to improve access to services that diagnose TB and HIV as early as possible. The new prevention and diagnosis tools recently recommended by WHO offer an immense opportunity to advance our fight against HIV-associated TB. They should be made widely available and scaled up rapidly supported by adequate funding with robust monitoring of the uptake to advance global TB elimination.

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Once-weekly rifapentine and isoniazid for tuberculosis prevention in patients with HIV taking dolutegravir-based antiretroviral therapy: a phase 1/2 trial

Cited by 44 publications

References 21 publications

The latent tuberculosis cascade-of-care among people living with HIV: A systematic review and meta-analysis

The latent tuberculosis cascade-of-care among people living with HIV: A systematic review and meta-analysis

Short‐course daily isoniazid and rifapentine for latent tuberculosis infection in people living with HIV who received coformulated bictegravir/emtricitabine/tenofovir alafenamide

HIV-associated tuberculosis

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