Disposition Kinetics of Dolutegravir Among People Living With HIV With Major Depression in Nigeria

Official title

Influence of Fluoxetine on the Disposition Kinetics of Dolutegravir Among People Living With HIV With Major Depression in Nigeria

Overview

The goal of this clinical trial is to find out the usefulness and well-being of people when drugs for treating depression (fluoxetine) and HIV (dolutegravir) are used together. It will also learn about how safe it is to take fluoxetine and dolutegravir together by the people living with HIV (PLWH). The main questions it aims to answer are: * Does fluoxetine (antidepressant) make participants taking anti-HIV (dolutegravir) feel better? * What medical problems do participants have when taking fluoxetine and dolutegravir together? * Does what people inherit from their parents affect the effectiveness and medical problems that participants have when taking fluoxetine and dolutegravir together? Researchers will compare depression treatments, fluoxetine and psychological treatment \[cognitive behavioural therapy (CBT)\] together to psychological treatment (CBT) alone among adults PLWH on anti-HIV drug (dolutegravir). Participants on anti-HIV dolutegravir having depression will: * Take both fluoxetine (daily) and CBT together or CBT alone for 3 months * Visit the clinic once every week in the first month, then once every 2 weeks for checkups and tests including blood tests * Keep a diary of their symptoms and other complaints

Detailed description

Depression is the most mental health disorder disorder among people living with HIV (PLWH) and is predictive of increased HIV-related morbidity and mortality. Treatment of depression in the setting of HIV is challenging as adding antidepressants in combination with combination antiretroviral therapy (cART) increases the pill burden and the potential for drug interactions. Studies have reported HIV medication complexity in patients comorbid with major depression to affect cART adherence. Optimal depression control among PLWH predicts and improves cART adherence and treatment outcomes.

Expert consensus is that selective serotonin-reuptake inhibitors (SSRIs) should be the first-line treatment for depression among PLWH. However, it is unclear whether SSRI therapy is effective in PLWH in low-middle-income countries (LMICs). There is an underrepresentation of LMICs in clinical studies involving PLWH and major depression despite the higher burden of PLWH and depression in LMICs than the high-income countries (HICs).

Fluoxetine is the preferred SSRI and most used for the treatment of depression in LMICs and is approved by their drug regulatory authorities. Fluoxetine is the most evaluated SSRI among PLWH with major depression but with different response rates among various ethnic groups reported. Furthermore, while fluoxetine was the most common SSRI used among the available clinical studies among PLWH, the studies did not report the clinical outcomes related to HIV care and cART.

Dolutegravir (DTG), an integrase strand transfer inhibitor, is the preferred and recommended first-line antiretroviral agent for adults and adolescents with HIV in LMICs. DTG is highly effective in suppressing HIV in both treatment-naive and experienced PLWHs, in addition to a low adverse effect profile and a high genetic barrier to developing drug resistance.

The cytochrome P450 (CYP) enzyme system metabolises fluoxetine, while the major enzyme that metabolises DTG is UGT1A1, with some contribution from CYP3A4/5. Fluoxetine and its major metabolite, norfluoxetine, may inhibit multiple enzymes involved in DTG metabolism, especially during chronic administration. A minor interaction via a membrane transporter mechanism may also be more pronounced with chronic use through the inhibition of the P-gp-mediated transport of DTG by fluoxetine. Patients on DTG report neuropsychiatric adverse events, and there is a relationship between plasma DTG trough concentration, neuropsychiatric adverse events, and UGT1A1 single nucleotide polymorphisms (SNPs). Thus, increases in DTG trough concentrations resulting from drug interaction are a potentially important concern.

Understanding potential drug interactions when fluoxetine and DGT-based cART are co-administered together will assist in optimising the dosing regimen, reducing adverse effects, and improving treatment outcomes among PLWH with major depression. To be able to recommend DTG and fluoxetine concomitant use, a prospective study involving PLWH with major depression is proposed. This study will address key knowledge gaps in drug interactions between fluoxetine and DTG among PLWH with major depression.

Interventions

• Drug Fluoxetine
  Participants in the intervention arm will receive oral fluoxetine capsules starting with 20mg daily for 12 weeks. The dose of the fluoxetine may be adjusted during follow-up by titrating the dose against the participants' response..
• Behavioral Cognitive-behavioral therapy
  Participants with HAM-D score of between 8 and 13 (mild depression) will receive sessions of Cognitive Behavioural Therapy (CBT) as per standard routine care. Participants in the intervention arm will also receive sessions of CBT as per standard routine care.

Primary outcome measures

• Mean change in the Hamilton Depression Rating Scale (HAM-D) scores from baseline to 12 weeks [Time frame: Baseline to the end of treatment at 12 weeks]
• Mean changes in the AUC of dolutegravir [Time frame: Week 2 to the end of treatment at 12 weeks]
• Mean changes in the Cmax of doultegravir [Time frame: Week 2 to the end of treatment at 12 weeks]
• Mean changes in the Cmin of dolutegravir [Time frame: Week 2 to the end of treatment at 12 weeks]
• Mean changes in the AUC of fluoxetine [Time frame: Week 2 to the end of treatment at 12 weeks]
• Mean changes in the Cmax of fluoxetine [Time frame: Week 2 to the end of treatment at 12 weeks]
• Mean changes in the Cmin of fluoxetine [Time frame: Week 2 to the end of treatment at 12 weeks]

Secondary outcome measures (12)

• Proportion of participants reporting grade 3 or 4 Adverse Events as Assessed by the DAIDS AE Grading Table Corrected Version 2.1 [Time frame: Baseline to weeks 2, 4, 8, and 12]
• Proportion of participants with depression remission at week 12 [Time frame: Baseline to the end of treatment at 12 weeks]
• Proportion of participants with a change of greater than or equal to (≥) 50% in the depression score from baseline to weeks 6, 8, and 12 [Time frame: Baseline to weeks 6, 8 and 12]
• Proportion of participants that drop out (study dropouts) during the study [Time frame: Baseline to weeks 2, 4, 6, 8, and 12]
• Proportion of participants with viral suppression (≤ 50 copies/mL) [Time frame: Baseline to the end of study at week 12]
• Mean increase in the CD4 count of participants [Time frame: Baseline to the end of study at week 12]
• AUC of fluoxetine and norfluoxetine [Time frame: Weeks 2, 6,10 and 12]
• Cmax of fluoxetine and norfluoxetine [Time frame: Weeks 2, 6,10 and 12]
• Cmin of fluoxetine and norfluoxetine [Time frame: Weeks 2, 6,10 and 12]
• Tmax of fluoxetine and norfluoxetine [Time frame: Weeks 2, 6,10 and 12]
• Half-life (t1/2) of fluoxetine and norfluoxetine [Time frame: Weeks 2, 6,10 and 12]
• Apparent Total Body Clearance (CL/F) of fluoxetine and norfluoxetine [Time frame: Weeks 2, 6,10 and 12]

Eligibility criteria

Inclusion criteria

• Males and females aged 18 years and above
• Willing to provide informed consent.
• Confirmed HIV positive \[HIV-seropositive by Enzyme Linked Immunosorbent Assay (ELISA) and Western Blot assays\]
• Willingness to receive and or continue anti-HIV therapy (DTG-based cART) \& adhere to follow-up schedule
• Willing and able to comply with antidepressant medication(fluoxetine) regimen and scheduled follow-up visits
• Current depressive symptoms \[Subjects with depression (HAM-D-17 score ≥ 8)\]
• Adequate renal function (serum creatinine < 1.5mg/dl)
• Adequate liver function \[aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤1.5 x Upper Limits of Normal)

Exclusion criteria

• Current substance use disorder
• Imminent risk of suicide- Acute suicidal ideation, gestures, or attempts
• Presence of psychotic symptoms or known diagnosis of a primary psychotic disorder
• Presence of symptoms of bipolar disorder
• Currently taking antipsychotic medication
• Pregnant or willing to get pregnant or lactation
• Current or chronic medical condition that would likely preclude adherence to protocol or completion of the trial (per investigator judgment)
• Antidepressants, mood stabilisers or other neuroleptics intake within three months
• Use of drugs other than cART, especially known enzyme inducers or inhibitors
• Abnormal ECG (e.g., prolonged QT interval)
• History of intolerance to study drug (fluoxetine)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Nigeria · 1 center

• University College Hospital — Ibadan

Publications

• Adedeji WA, Ma Q, Raji AM, Cha R, Rasaki OM, Hutson A, Taiwo BO, Charurat ME, Yusuf OB, Fehintola FA, Gureje O, Morse GD. Prevalence of depression among people living with HIV in rural hospitals in South-Western Nigeria-Association with clinico-demographic factors. AIDS Res Ther. 2023 Dec 16;20(1):89. doi: 10.1186/s12981-023-00586-0. PMID 38104102
• Borghetti A, Calcagno A, Lombardi F, Cusato J, Belmonti S, D'Avolio A, Ciccarelli N, La Monica S, Colafigli M, Delle Donne V, De Marco R, Tamburrini E, Visconti E, Di Perri G, De Luca A, Bonora S, Di Giambenedetto S. SLC22A2 variants and dolutegravir levels correlate with psychiatric symptoms in persons with HIV. J Antimicrob Chemother. 2019 Apr 1;74(4):1035-1043. doi: 10.1093/jac/dky508. PMID 30561642
• Charlier C, Broly F, Lhermitte M, Pinto E, Ansseau M, Plomteux G. Polymorphisms in the CYP 2D6 gene: association with plasma concentrations of fluoxetine and paroxetine. Ther Drug Monit. 2003 Dec;25(6):738-42. doi: 10.1097/00007691-200312000-00014. PMID 14639062
• Reese MJ, Savina PM, Generaux GT, Tracey H, Humphreys JE, Kanaoka E, Webster LO, Harmon KA, Clarke JD, Polli JW. In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. Drug Metab Dispos. 2013 Feb;41(2):353-61. doi: 10.1124/dmd.112.048918. Epub 2012 Nov 6. PMID 23132334
• Wagner GJ, Maguen S, Rabkin JG. Ethnic differences in response to fluoxetine in a controlled trial with depressed HIV-positive patients. Psychiatr Serv. 1998 Feb;49(2):239-40. doi: 10.1176/ps.49.2.239. PMID 9575014
• Yagura H, Watanabe D, Kushida H, Tomishima K, Togami H, Hirano A, Takahashi M, Hirota K, Ikuma M, Kasai D, Nishida Y, Yoshino M, Yamazaki K, Uehira T, Shirasaka T. Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1. BMC Infect Dis. 2017 Sep 16;17(1):622. doi: 10.1186/s12879-017-2717-x. PMID 28915895
• Fettiplace A, Stainsby C, Winston A, Givens N, Puccini S, Vannappagari V, Hsu R, Fusco J, Quercia R, Aboud M, Curtis L. Psychiatric Symptoms in Patients Receiving Dolutegravir. J Acquir Immune Defic Syndr. 2017 Apr 1;74(4):423-431. doi: 10.1097/QAI.0000000000001269. PMID 27984559
• Eshun-Wilson I, Siegfried N, Akena DH, Stein DJ, Obuku EA, Joska JA. Antidepressants for depression in adults with HIV infection. Cochrane Database Syst Rev. 2018 Jan 22;1(1):CD008525. doi: 10.1002/14651858.CD008525.pub3. PMID 29355886

Identifiers

NCT: NCT07110831 · UI/EC/22/0242 · K43TW011995

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗