Pilot Study of a Novel Short-Cycle Antiretroviral Treatment Interruption Strategy: 48-Week Results of the Five-Days-On, Two-Days-Off (FOTO) Study

Cohen, Calvin; Colson, Amy E.; Sheble-Hall, Alexander G.; McLaughlin, Karen; Morse, Gene D.

doi:10.1310/hct0801-19

Cited by 72 publications

(49 citation statements)

References 10 publications

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“…On study days 10 to 13, darunavir and ritonavir plasma concentrations were assessed predose and at 1, 2, 3, 4,6,8,10,12,16,20,24,30,36,48,60, and 72 h postdose.…”

Section: Methodsmentioning

confidence: 99%

“…A recent study found that doses might be missed in the case of regimens containing long-half-life drugs, such as the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (8). However, the strategy appeared much riskier for patients on protease inhibitors like lopinavir-ritonavir or saquinavirritonavir that achieved subtherapeutic drug concentrations at the end of the second day off therapy, suggesting that despite the presence of the ritonavir boosting effect, lopinavir and saquinavir plasma concentrations declined rapidly (7).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics of Once-Daily Darunavir-Ritonavir and Atazanavir-Ritonavir over 72 Hours following Drug Cessation

Boffito

Jackson

Amara

et al. 2011

Antimicrob Agents Chemother

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The object of this study was to investigate the pharmacokinetics of darunavir-ritonavir and atazanavirritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavirritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0-to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0-to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC 50 ] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the proteinbinding-corrected IC 50 for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval of 24 h which were above the cutoff used to define therapeutic concentrations.The combination of a ritonavir-boosted protease inhibitor and two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) has shown sustained suppression of plasma HIV replication and continued immunological recovery in naïve and experienced HIV-infected individuals (11).The advantages associated to ritonavir boosting are a consequence of the increased drug exposure and prolonged halflife that allow reducing the pill burden and dosing frequency and lead to the achievement of a high genetic barrier to resistance (11, 16).Drug persistence (the presence of drug at a detectable level high enough to exert an effect) in plasma mainly depends on the half-life (which itself is dependent on clearance and volume of distribution). Long-half-life antiretroviral agents may allow for forgotten doses, especially if they are able to delay the decline in drug concentration to a subtherapeutic level for a period of time that is long enough for the concentrations to be above target until th...

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“…On study days 10 to 13, darunavir and ritonavir plasma concentrations were assessed predose and at 1, 2, 3, 4,6,8,10,12,16,20,24,30,36,48,60, and 72 h postdose.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Pharmacokinetics of Once-Daily Darunavir-Ritonavir and Atazanavir-Ritonavir over 72 Hours following Drug Cessation

Boffito

Jackson

Amara

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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“…Of those on a nonboosted regimen, one was on nonboosted atazanavir while two were on ritonavir and seven were on nelfinavir. The following NRTIs were used: zidovudine (13), lamivudine (16), tenofovir (9), stavudine (7), didanosine (8), and emtricitabine (4). There was one subject also on T-20.…”

Section: Regimens and Resistance Genotypingmentioning

confidence: 99%

“…15 Cohen and colleagues studied a strategy of five days on-two days off (FOTO) strategy with overall good viral control in 89.6% of subjects with 100% virologic control in subjects on an efavirenz-based HAART regimen. 16 As adolescents and young adults face a lifetime of HAART once meeting guidelines, a short-cycle management approach is particularly appealing in this population to limit ART exposure as well as potentially impact on long-term adherence. The Adolescent Trials Network 015 study was a proof of concept study of a 4-day on=3-day off short-cycle therapy in adolescents and young adults, on a protease inhibitor-based HAART regimen, who demonstrated good viral control for at least 6 months and CD4 þ T cells above 350 cells=mm 3 at study entry.…”

Section: Introductionmentioning

confidence: 99%

Short-Cycle Therapy in Adolescents after Continuous Therapy with Established Viral Suppression: The Impact on Viral Load Suppression

Rudy

Sleasman

Kapogiannis

et al. 2009

AIDS Research and Human Retroviruses

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This was a proof-of-principle study to evaluate the impact of short cycle therapy (SCT; 4 days on=3 days off) in adolescents and young adults with good viral suppression on a protease inhibitor-based antiretroviral regimen. Subjects were recruited by the Adolescent Trials Network for HIV=AIDS Interventions and the Pediatric AIDS Clinical Trials Group. Subjects were infected either through perinatal=early childhood transmission or later via risk behaviors. All subjects were required to have at least 6 months of documented viral suppression below 400 copies=ml plus a preentry value below 200 copies=ml and an entry CD4 þ T cell count above 350 cells=mm 3 . Of the 32 subjects enrolled, 12 (37.5%) had confirmed viral load rebound >400 copies, with 18 subjects (56%) coming off for any reason. The majority of subjects resuppressed when placed back onto continuous therapy using the same agents. Although no difference was found in virologic rebound rates between the early and later transmission groups, those infected early in life had higher rates of coming off SCT for any reason. There was no impact of SCT on the CD4 þ T cell counts in those who remained on study or those who came off SCT for any reason. Subjects demonstrated good adherence to the SCT regimen. This study suggests that further evaluation of SCT may be warranted in some groups of adolescents and young adults infected with HIV.

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“…Our study of short, intermittent antiviral treatment cycles of 4 days per week [1 step down from the previously administered 5 day per week regimen (29)] struck a bonanza: 94 patients took intermittent therapy for 157 cumulated years, i.e., 87 treatment weeks per patient, 63 patients having passed 2.5 intermittent treatment years. It should be noted that despite archived, resistant viruses from past failures in 25 patients or the administration of half of the daily recommended dose of a drug base in 11 patients, there was not 1 viral escape over 8164 weeks.…”

Section: Iccarre 4 Day Per Week Treatment: Not a Single Hiv Escapementioning

confidence: 99%

Four days a week or less on appropriate anti‐HIV drug combinations provided long‐term optimal maintenance in 94 patients: the ICCARRE project

et al. 2015

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Short, intraweekly cycles of anti‐HIV combinations have provided intermittent, effective therapy (on 48 patients) (1). The concept is now extended to 94 patients on treatment, 4 days per week or less, over a median of 2.7 discontinuous treatment years per patient. On suppressive combinations, 94 patients volunteered to treatment, 5 and 4 days per week, or reduced stepwise to 4,3,2, and 1 days per week in 94, 84, 66, and 12 patients, respectively, on various triple, standard, antiviral combinations, or nonregistered, quadruple, antiviral combinations. Ninety‐four patients on treatment 4 days per week aggregated 165 intermittent treatment years; no viral breakthrough was observed over 87 average treatment weeks per patient, 63 of 94 having passed 2.5 intermittent treatment years on any of the antiviral combinations prescribed. On the hyperintermittent treatment of 3, 2, and 1 days per week, HIV RNA surged >50 copies, 4 weeks apart, in 18 instances (6.8 viral escapes/100 hyperdiscontinuous maintenance years). Viral escapes could have been a result of erratic adherence (EA) to regimen or follow‐up (3 patients)—drug taken at half of the daily recommended dosage (8 patients) and/or overlooked archival‐resistant HIVs from antecedent treatment failures (6 patients). Aside from the above circumstances, HIV unexpectedly rebounded in 3 patients on 2 days per week treatment and 1 patient on 1 day per week treatment, posting 2.2 intrinsic viral escapes/100 highly discontinuous treatment years. All 18 escapes were eventually reversed by 7 days per week salvage combinations, and 11 of 18 patients have been back for a second course of intermittent therapy, 4 days per week or less. Both cell‐activation markers on the surface of T lymphocytes and cell‐bound HIV DNA levels remained stable or declined. CD4/CD8 ratios rose to ≤1 in 35% of patients, whereas CD4 counts went ≤500/μl in 75%. These values were previously 7 and 40%, respectively, on 7 days per week therapy. In our aging, long, HIV‐enduring, multitreated patient cohort, treatment 4 days per week and less over 421 intermittent treatment years reduced prescription medicines by 60%—equivalent to 3 drug‐free/3 virus‐free remission year per patient—actually sparing €3 million on just 94 patients at the cost of 2.2 intrinsic viral failure/100 hyperintermittent treatment years. At no risk of viral escape, maintenance therapy, 4 days per week, would quasiuniversally offer 40% cuts off of current overprescriptions.—Leibowitch, J., Mathez, D., de Truchis, P., Ledu, D., Melchior, J. C., Carcelain, G., Izopet, J., Perronne, C., David, J. R. Four days a week or less on appropriate anti‐HIV drug combinations provided long‐term optimal maintenance in 94 patients: the ICCARRE project. FASEB J. 29, 2223‐2234 (2015). http://www.fasebj.org

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Pilot Study of a Novel Short-Cycle Antiretroviral Treatment Interruption Strategy: 48-Week Results of the Five-Days-On, Two-Days-Off (FOTO) Study

Cited by 72 publications

References 10 publications

Pharmacokinetics of Once-Daily Darunavir-Ritonavir and Atazanavir-Ritonavir over 72 Hours following Drug Cessation

Pharmacokinetics of Once-Daily Darunavir-Ritonavir and Atazanavir-Ritonavir over 72 Hours following Drug Cessation

Short-Cycle Therapy in Adolescents after Continuous Therapy with Established Viral Suppression: The Impact on Viral Load Suppression

Four days a week or less on appropriate anti‐HIV drug combinations provided long‐term optimal maintenance in 94 patients: the ICCARRE project

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