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

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.

• Fluoxetine (Drug), also known as Prozac, Fluoxetine hydrochloride, Rapiflux, Sarafem, Selfemra, Fluoxetin, Lilly-110140, N-Methyl-gamma-(4-(trifluoromethyl)phenoxy)benzenepropanamine: 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..
• Cognitive-behavioral therapy (Behavioral), also known as Psychotherapy, Cognitive Behavioral Therapy, Cognitive Behavioural Therapy, Cognitive Psychotherapy, Cognitive Therapy, CBT: 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 outcomes

• Mean change in the Hamilton Depression Rating Scale (HAM-D) scores from baseline to 12 weeks [Baseline to the end of treatment at 12 weeks]: The total HAM-D scores provide an indication of depression and, over time, a guide to evaluate response and recovery. The higher the HAM-D scores, the higher the severity of depression. HAM-D is graded as follows None 0-7 Mild 8-16 Moderate 17-23 Severe ≥ 24
• Mean changes in the AUC of dolutegravir [Week 2 to the end of treatment at 12 weeks]: The effect of chronic administration of fluoxetine on the steady-state pharmacokinetics of dolutegravir and by intrasubject comparison in the participants. This will be assessed with mean changes in the Area under the plasma concentration-time curve (AUC) before and after the administration of fluoxetine.
• Mean changes in the Cmax of doultegravir [Week 2 to the end of treatment at 12 weeks]: The effect of chronic administration of dolutegravir on the steady-state pharmacokinetics of fluoxetine by intrasubject comparison in the participants. This will be assessed with mean changes in the Maximum plasma concentration (Cmax) before and after the administration of fluoxetine.
• Mean changes in the Cmin of dolutegravir [Week 2 to the end of treatment at 12 weeks]: Description: The effect of chronic administration of fluoxetine on the steady-state pharmacokinetics of dolutegravir and by intrasubject comparison in the participants. This will be assessed with mean changes in the Minimum plasma concentration(Cmin) before and after the administration of fluoxetine.
• Mean changes in the AUC of fluoxetine [Week 2 to the end of treatment at 12 weeks]: The effect of chronic administration of dolutegravir on the steady-state pharmacokinetics of fluoxetine by intrasubject comparison in the participants. This will be assessed with mean changes in the Area under the plasma concentration-time curve (AUC) before and after the administration of fluoxetine.
• Mean changes in the Cmax of fluoxetine [Week 2 to the end of treatment at 12 weeks]: The effect of chronic administration of dolutegravir on the steady-state pharmacokinetics of fluoxetine by intrasubject comparison in the participants. This will be assessed with mean changes in the Maximum plasma concentration (Cmax) before and after the administration of fluoxetine
• Mean changes in the Cmin of fluoxetine [Week 2 to the end of treatment at 12 weeks]: The effect of chronic administration of dolutegravir on the steady-state pharmacokinetics of fluoxetine by intrasubject comparison in the participants. This will be assessed with mean changes in the Minimum plasma concentration (Cmin) before and after the administration of fluoxetine.

Secondary outcomes

• Proportion of participants reporting grade 3 or 4 Adverse Events as Assessed by the DAIDS AE Grading Table Corrected Version 2.1 [Baseline to weeks 2, 4, 8, and 12]: The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected version 2.1 consists of parameters, or Adverse Events (AEs), with severity grading guidance that is used in DAIDS clinical trials for safety data reporting to maintain accuracy and consistency in the evaluation of AEs. The DAIDS AEs is graded as follows: Grade 1 mild event, Grade 2 moderate event, Grade 3 severe event, Grade 4 potentially life-threatening event and Grade 5 death
• Proportion of participants with depression remission at week 12 [Baseline to the end of treatment at 12 weeks]: To determine the proportion of participants with depression remission at week 12 This will be measured as the proportion of subjects with HAM-D score of less than 8 (HAM-D<8)
• 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 [Baseline to weeks 6, 8 and 12]: To determine the proportion of participants with a change of greater than or equal to (≥) 50% in the HAM-D scores from baseline to weeks 6, 8 and 12
• Proportion of participants that drop out (study dropouts) during the study [Baseline to weeks 2, 4, 6, 8, and 12]: To determine that proportion of participants that drop out (study dropouts) from baseline till the end of study at week 12.
• Proportion of participants with viral suppression (≤ 50 copies/mL) [Baseline to the end of study at week 12]: To determine the proportion of participants with HIV viral suppression ( viral load ≤ 50 copies/mL) at the end of study at week 12
• Mean increase in the CD4 count of participants [Baseline to the end of study at week 12]: To determine the mean changes in the CD4 counts of participants from baseline to the end of study at week 12
• AUC of fluoxetine and norfluoxetine [Weeks 2, 6,10 and 12]: To determine the Area under the plasma concentration-time curve (AUC) of fluoxetine and norfluoxetine using intensive and sparse pharmacokinetic sampling at steady state.
• Cmax of fluoxetine and norfluoxetine [Weeks 2, 6,10 and 12]: To determine the Maximum plasma concentration (Cmax) of fluoxetine and norfluoxetine using intensive and sparse pharmacokinetic sampling at steady state.
• Cmin of fluoxetine and norfluoxetine [Weeks 2, 6,10 and 12]: To determine the Area Minimum plasma concentration (Cmin) of fluoxetine and norfluoxetine using intensive and sparse pharmacokinetic sampling at steady state.
• Tmax of fluoxetine and norfluoxetine [Weeks 2, 6,10 and 12]: To determine the time to maximum observed plasma concentration (Tmax) of fluoxetine and norfluoxetine using intensive and sparse pharmacokinetic sampling at steady state.
• Half-life (t1/2) of fluoxetine and norfluoxetine [Weeks 2, 6,10 and 12]: To determine the elimination half-life (t1/2) of fluoxetine and norfluoxetine using intensive and sparse pharmacokinetic sampling at steady state.
• Apparent Total Body Clearance (CL/F) of fluoxetine and norfluoxetine [Weeks 2, 6,10 and 12]: To determine the Apparent Total Body Clearance (CL/F) of fluoxetine and norfluoxetine using intensive and sparse pharmacokinetic sampling at steady state.
• Apparent Volume of Distribution (Vd/F) of of fluoxetine and norfluoxetine [Weeks 2, 6,10 and 12]: To determine the Apparent Volume of Distribution (Vd/F) of fluoxetine and norfluoxetine using intensive and sparse pharmacokinetic sampling at steady state.
• AUC of dolutegravir [Weeks 2, 6,10 and 12]: To determine the Area under the plasma concentration-time curve (AUC) of dolutegravir using intensive and sparse pharmacokinetic sampling at steady state.
• Cmax of dolutegravir [Weeks 2, 6,10 and 12]: To determine the Maximum plasma concentration (Cmax) of dolutegravir using intensive and sparse pharmacokinetic sampling at steady state.
• Cmin of dolutegravir [Weeks 2, 6,10 and 12]: To determine the Minimum plasma concentration (Cmin) of dolutegravir using intensive and sparse pharmacokinetic sampling at steady state.
• Tmax of dolutegravir [Weeks 2, 6,10 and 12]: To determine the Time to maximum observed plasma concentration (Tmax) of dolutegravir using intensive and sparse pharmacokinetic sampling at steady state.
• Half-Life (t1/2) of dolutegravir [Weeks 2, 6,10 and 12]: To determine the elimination Half-Life (t1/2) of dolutegravir using intensive and sparse pharmacokinetic sampling at steady state.
• Apparent Total Body Clearance (CL/F) of dolutegravir [Weeks 2, 6,10 and 12]: To determine the Apparent Total Body Clearance (CL/F) of dolutegravir using intensive and sparse pharmacokinetic sampling at steady state.
• Apparent Volume of Distribution (Vd/F) of dolutegravir [Weeks 2, 6,10 and 12]: To determine the Apparent Volume of Distribution (Vd/F) of dolutegravir using intensive and sparse pharmacokinetic sampling at steady state.

Sex: All, ages: 18 Years to any

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)

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• Waheed A Adedeji, Principal investigator, College of Medicine, University of Ibadan, Nigeria

NIH grants: K43TW011995