Is tenofovir disoproxil fumarate (TDF) every 48 hours (q48hours) a suitable dosing regimen for a patient with Impaired renal function (creatinine clearance of 35ml/min) and HIV, currently on lamivudine (Lamivudine) 300mg plus dolutegravir (Dolutegravir) 50mg and TDF 300mg tablet once daily?

TDF Every 48 Hours is Acceptable but Requires Careful Monitoring and Consideration of Alternative Strategies

For a patient with HIV and creatinine clearance of 35 mL/min on lamivudine 300mg, dolutegravir 50mg, and TDF 300mg daily, TDF dosed at 300mg every 48 hours is an appropriate dose adjustment according to established guidelines, though this regimen carries significant nephrotoxicity risks and warrants close monitoring. 1, 2

Guideline-Based Dosing Recommendations

The Korean Association for the Study of the Liver (KASL) and FDA labeling explicitly recommend TDF 300mg every 48 hours for creatinine clearance 30-49 mL/min. 1, 2 This patient's CrCl of 35 mL/min falls directly within this dosing range, making q48h dosing the standard recommendation.

Specific Dosing Algorithm by Renal Function:

• CrCl ≥50 mL/min: TDF 300mg every 24 hours 1, 2
• CrCl 30-49 mL/min: TDF 300mg every 48 hours 1, 2
• CrCl 10-29 mL/min: TDF 300mg every 72-96 hours 1, 2
• CrCl <10 mL/min: No recommendation (avoid TDF) 1, 2

Critical Adjustments Required for Other Medications

Lamivudine must also be dose-adjusted at this level of renal function. 1, 3 With CrCl 30-49 mL/min, lamivudine should be reduced from 300mg daily to 100mg first dose, then 50mg every 24 hours (or 150mg once daily as an alternative). 1, 3

Dolutegravir requires no dose adjustment and can continue at 50mg daily, though it will cause a 10% artificial increase in serum creatinine by blocking tubular secretion without affecting true GFR. 3 This must be factored into monitoring.

Significant Safety Concerns with Continued TDF Use

The International Antiviral Society-USA Panel and KDIGO explicitly recommend avoiding TDF in patients with CrCl <60 mL/min or at risk of renal dysfunction. 1 The evidence shows:

• TDF causes progressive renal dysfunction with median eGFR decline of -5.0 mL/min over 96 weeks in patients with risk factors 1
• Risk of proximal tubulopathy, Fanconi syndrome, and acute renal failure increases substantially with impaired baseline renal function 1, 2
• Patients with baseline CrCl 30-59 mL/min have 15-fold increased risk of nephrotoxicity compared to those with normal function 4
• Mortality risk is 3.2-fold higher in patients with moderate renal dysfunction (CrCl 30-59 mL/min) on TDF 4

Preferred Alternative Strategy (When TAF Unavailable)

Since TAF is not available, the optimal approach is to switch away from TDF entirely rather than dose-adjust it. 1 The evidence strongly supports this:

Recommended Regimen Modification:

Switch to dolutegravir + lamivudine (dose-adjusted to 150mg daily) without any tenofovir formulation. 3 This two-drug regimen:

• Eliminates nephrotoxicity risk from TDF 1, 5
• Maintains virologic efficacy 3
• Requires only lamivudine dose adjustment for renal function 1, 3

If Hepatitis B Co-infection is Present:

TDF must be continued (as lamivudine alone risks HBV resistance), making dose-adjusted TDF q48h the only option. 1 In this scenario:

• Use TDF 300mg every 48 hours 1, 2
• Adjust lamivudine to 150mg daily 1, 3
• Continue dolutegravir 50mg daily 3

Mandatory Monitoring Protocol

If TDF q48h is continued, intensive renal monitoring is essential: 1, 2, 6

Baseline Assessment (Before Dose Adjustment):

• Serum creatinine and calculate CrCl using ideal body weight 1, 2
• Serum phosphate (check for hypophosphatemia <2.5 mg/dL) 1
• Urinalysis for proteinuria and glucosuria 1, 2
• Urine protein:creatinine ratio (preferred) or dipstick 5, 6

Follow-up Monitoring Schedule:

• Recheck at 4 weeks after dose adjustment 6
• Every 3 months for the first year, then at least every 6 months thereafter 1, 6
• More frequent monitoring (monthly to quarterly) if CrCl continues declining 5, 6

Criteria for TDF Discontinuation:

• CrCl drops >25% from baseline AND falls to <30 mL/min 1, 3
• New or worsening proteinuria/glucosuria 1, 2
• Serum phosphate <2.5 mg/dL (suggests Fanconi syndrome) 1
• Any evidence of proximal tubular dysfunction 1, 2

Critical Drug Interaction Considerations

Avoid all nephrotoxic co-medications, particularly NSAIDs, which have caused acute renal failure requiring hospitalization in HIV patients on TDF with baseline renal dysfunction. 2 The FDA label specifically warns against concurrent or recent use of nephrotoxic agents. 2

Clinical Outcome Data Supporting Dose Adjustment

Limited evidence suggests dose-adjusted TDF may allow continued therapy: 7

• Patients with dose-adjusted TDF continued their regimens 21 months longer than those without adjustment 7
• Dose-adjusted patients had greater CD4 gains over 12 months 7
• However, no prospective studies validate the safety or efficacy of dose-adjusted TDF in renal impairment 2

Common Pitfalls to Avoid

1. Failing to adjust lamivudine dose when adjusting TDF—both require modification at CrCl <50 mL/min 1, 3
2. Using fixed-dose combination tablets (contraindicated when CrCl <50 mL/min; must use individual components) 3
3. Misinterpreting creatinine increases from dolutegravir as worsening renal function 3
4. Continuing TDF without intensive monitoring in patients already at high risk 1, 5
5. Not screening for hepatitis B before considering TDF discontinuation 1

Bottom Line Recommendation

While TDF 300mg every 48 hours is technically acceptable per dosing guidelines for CrCl 35 mL/min, the weight of evidence strongly favors switching to a non-tenofovir regimen (dolutegravir + dose-adjusted lamivudine) unless hepatitis B co-infection mandates TDF continuation. 1, 3 If TDF must be continued, implement dose adjustment to q48h with mandatory intensive renal monitoring and immediate discontinuation if function deteriorates further. 1, 2