What are the risks of combining GHB (gamma-hydroxybutyrate) and Biktarvy (tenofovir alafenamide) in a patient with a history of methamphetamine use and possible impaired renal function?

GHB and Biktarvy: Critical Safety Concerns

The combination of GHB (gamma-hydroxybutyrate) and Biktarvy (bictegravir/tenofovir alafenamide/emtricitabine) poses significant risks, particularly in patients with methamphetamine use history and renal impairment—the primary concern is additive central nervous system depression from GHB and potential nephrotoxicity from the tenofovir component, especially given pre-existing renal compromise. 1, 2

Understanding GHB Toxicity

Central Nervous System Effects:

• GHB causes profound CNS depression with drowsiness, euphoria, increased libido, and passivity at low doses 1
• Higher doses produce amnesia, intoxication, dizziness, visual hallucinations, severe respiratory depression, bradycardia, hypotension, and coma 1, 3
• Effects begin within 15 minutes of ingestion and last 3-6 hours alone, or 36-72 hours when combined with other substances 1
• GHB is rapidly cleared and undetectable in urine after only 12 hours 1

Physical Dependence Risk:

• Prolonged GHB use can cause physical dependence with a withdrawal syndrome including insomnia, anxiety, tremor, and seizures that resolves in 3-12 days 4
• GHB has a narrow therapeutic index and is particularly dangerous when combined with other drugs of abuse 4

Biktarvy Components and Renal Considerations

Tenofovir Alafenamide (TAF) Nephrotoxicity Profile:

• TAF has significantly better renal safety compared to tenofovir disoproxil fumarate (TDF), but renal monitoring remains essential 5
• Tenofovir is primarily excreted by the kidneys through glomerular filtration and active tubular secretion 6
• Coadministration with drugs that reduce renal function or compete for active tubular secretion may increase tenofovir concentrations and risk of adverse reactions 6

Critical Renal Function Thresholds:

• TAF is contraindicated in patients with creatinine clearance below 30 mL/min 7
• Patients with baseline renal impairment (eGFR <60 mL/min) require close monitoring when on any tenofovir formulation 1, 2
• Discontinue tenofovir immediately if GFR drops by >25% from baseline to a level <60 mL/min/1.73 m², particularly with evidence of proximal tubular dysfunction 1, 2

Methamphetamine Use History: Compounding Risks

Renal Pathology from Methamphetamine:

• Methamphetamine use is associated with acute tubular necrosis (66% of cases), focal segmental glomerulosclerosis (53%), tubulointerstitial nephritis (37%), and thrombotic microangiopathy (24%) 8
• 97% of methamphetamine users show evidence of kidney dysfunction at biopsy 8
• 65% have proteinuria, with 53% in nephrotic range 8
• More than half demonstrate moderate to severe tubulointerstitial scarring and marked hypertensive vascular disease 8

GHB-Methamphetamine Interaction:

• GHB co-use with methamphetamine is common (54.2% in one series) and attenuates neuropsychiatric features but increases severity of toxicity 9
• Combined use is associated with higher Poisoning Severity Scores and increased need for ICU-level care 9

Specific Drug Interaction Concerns

P-glycoprotein (P-gp) Considerations:

• TAF is a substrate of P-gp and BCRP 6
• Drugs that inhibit P-gp may increase TAF absorption and plasma concentrations 6
• While GHB's effect on P-gp is not well-characterized, the combination with other substances of abuse increases unpredictability 6

Nephrotoxic Drug Combinations to Avoid:

• NSAIDs, aminoglycosides, acyclovir, ganciclovir, and other drugs eliminated by active tubular secretion increase tenofovir concentrations 6
• Ritonavir-boosted protease inhibitors significantly increase risk of tenofovir-associated nephrotoxicity 1, 2

Clinical Management Algorithm

Immediate Assessment:

1. Measure creatinine clearance and eGFR immediately 1, 2
2. Screen for proximal tubular dysfunction: check for euglycemic glycosuria, hypophosphatemia, increased urinary phosphorus excretion, and proteinuria 1, 2
3. Obtain urine drug screen within 12 hours if GHB use suspected (rapid clearance) 1
4. Assess for signs of acute GHB intoxication: altered mental status, respiratory depression, bradycardia, hypotension 1, 3

If Creatinine Clearance 30-60 mL/min:

• Consider switching from TAF to alternative antiretroviral regimen 1, 7
• Zidovudine (AZT) does not require renal dose adjustment and is appropriate for patients with significant renal impairment 7
• Abacavir is another option (no renal dose adjustment needed) but requires HLA-B*5701 testing if not previously done 1, 7
• Monitor renal function every 2-4 weeks if continuing TAF 1

If Creatinine Clearance <30 mL/min:

• Discontinue TAF immediately—it is contraindicated below this threshold 7
• Switch to zidovudine-based regimen with appropriately dose-adjusted lamivudine (150 mg once daily for CrCl 30-49 mL/min; further reduction to 100 mg once daily for CrCl 15-29 mL/min) 7
• Dolutegravir can be continued at standard dosing (50 mg daily) without renal adjustment 7

If Evidence of Proximal Tubular Dysfunction:

• Stop tenofovir immediately regardless of GFR 1, 2
• Look for urinary albumin-to-protein ratio <0.4, which suggests tubular rather than glomerular disease 1
• Switch to tenofovir-sparing regimen 1, 7

Critical Pitfalls to Avoid

Do Not:

• Continue any tenofovir formulation in patients with CrCl ≤30 mL/min when alternatives are available 7
• Use standard-dose lamivudine (300 mg daily) at CrCl 30 mL/min—this constitutes overdosing 7
• Combine GHB with alcohol or other CNS depressants—this can be lethal 3, 4
• Ignore signs of GHB withdrawal (insomnia, anxiety, tremor, seizures) in chronic users 4
• Misinterpret creatinine increases from bictegravir as worsening renal function—this is a benign pharmacologic effect on creatinine secretion, not true nephrotoxicity 7
• Underestimate cardiovascular risks in methamphetamine users—avoid beta blockers during acute intoxication due to unopposed alpha-adrenergic stimulation 10

Do:

• Monitor complete blood counts regularly if switching to zidovudine (risk of anemia and neutropenia) 7
• Assess renal function at least every 3-6 months in patients near threshold creatinine clearance values 7
• Screen for concurrent nephrotoxic medications and discontinue when possible 2, 6
• Educate patients about the narrow therapeutic index of GHB and dangers of polydrug use 4