Are there independent (non‑manufacturer) studies comparing the impact of tenofovir disoproxil fumarate (TDF) versus tenofovir alafenamide (TAF) on glucose levels and insulin resistance in patients using Delstrigo (doravirine + lamivudine + TDF) versus Pifeltro + Descovy (darunavir/cobicistat + emtricitabine + TAF)?

TAF-Based Regimens (Pifeltro + Descovy) Are Associated with Greater Weight Gain Than TDF-Based Regimens (Delstrigo), But Evidence on Glucose and Insulin Resistance Remains Mixed

For metabolic outcomes including glucose control and insulin resistance, Delstrigo (doravirine/lamivudine/TDF) appears preferable to Pifeltro + Descovy (darunavir/cobicistat + emtricitabine/TAF), primarily due to TAF's association with greater weight gain and lipid elevations, though direct evidence on insulin resistance is limited.

Weight Gain: Clear Difference Between TAF and TDF

The 2025 IAS-USA guidelines explicitly state that greater weight gain with regimens containing tenofovir alafenamide than with those containing tenofovir disoproxil fumarate has been observed 1. This is not manufacturer-driven data—these are independent guideline recommendations based on multiple cohort studies.

Key findings from independent research:

• The ADVANCE trial demonstrated that women (but not men) who switched from TAF/FTC plus dolutegravir to TDF/3TC/DTG had reductions in weight, likely due to the weight suppressive effect of tenofovir disoproxil fumarate 1
• The Swiss HIV Cohort Study (independent, non-manufacturer) showed weight loss when people switched from TAF to TDF 1
• A 2026 real-world study found that switching to DOR/3TC/TDF resulted in 1.8 kg less weight gain compared to BIC/FTC/TAF over 48 weeks (p < 0.001) 2

Glucose and Insulin Resistance: Limited But Concerning Data

While the guidelines acknowledge insulin resistance as a cardiovascular risk factor in people with HIV 1, direct comparative data on glucose metabolism between TAF and TDF regimens is sparse. However, available independent research suggests potential concerns:

Animal Studies Show Metabolic Dysfunction with TAF

A 2024 independent study in Wistar rats found that TAF-treated animals had significantly increased fasting blood glucose, fasting plasma insulin, insulin resistance, impaired glucose tolerance, and dyslipidemia compared to TDF-treated rats 3. While animal data has limitations, this provides mechanistic evidence for metabolic concerns.

Human Studies Show Mixed Results

• A 2025 retrospective study of 153 treatment-naïve patients found weight gain was more pronounced with TAF versus TDF (3.5 kg versus -1 kg at one year, P < 0.001), but no increase in glucose dysregulation was noted for TAF treatment 4
• A 2024 multi-center study in hepatitis B patients found that switching from TDF to TAF significantly increased fasting glucose, glycemic hemoglobin, insulin, and insulin resistance, while switching from entecavir to TAF did not affect these measures 5
• A 2022 retrospective cohort found that only cholesterol changes (not glucose) were significantly associated with TAF after adjusting for time trends 6

Lipid Profile: Clear Advantage for TDF

The evidence consistently shows TDF has favorable effects on lipids compared to TAF:

• The 2026 real-world study demonstrated that at 48 weeks, the DOR/3TC/TDF group showed mean reductions of 0.453 mmol/L in triglycerides, 0.412 mmol/L in total cholesterol, and 0.241 mmol/L in LDL-C, while the BIC/FTC/TAF group showed increases in TC and LDL-C 2
• Multiple studies confirm TDF has a lipid-lowering effect that is lost when switching to TAF 5, 6

Addressing Your Provider's Perspective

Your Finnish infectious disease doctor's observation about local statistics not showing TDF as "worse" than TAF is actually consistent with the nuanced evidence. The issue is not that TDF is universally "worse"—rather, TDF and TAF have different toxicity profiles:

TDF's Known Toxicities (Why TAF Was Developed):

• Renal toxicity (proximal tubulopathy, Fanconi syndrome) 7, 3
• Bone mineral density loss
• These are well-documented and led to TAF development

TAF's Emerging Concerns:

• Greater weight gain 1, 2
• Worse lipid profiles 5, 2, 6
• Potential insulin resistance (emerging evidence) 5, 3

The 2025 IAS-USA guidelines acknowledge this trade-off by stating: "Currently, because of the known toxicities of tenofovir disoproxil fumarate and lack of benefit seen when changing from an InSTI to a boosted protease inhibitor, changing regimens because of weight gain is not recommended" 1. This reflects that both formulations have risks.

Clinical Algorithm for Choosing Between Delstrigo and Pifeltro + Descovy

Choose Delstrigo (DOR/3TC/TDF) if:

• Patient has metabolic syndrome, pre-diabetes, or diabetes
• Patient has dyslipidemia or elevated cardiovascular risk
• Patient is at risk for significant weight gain (women, Black individuals)
• Patient has normal renal function (eGFR >60 mL/min) and normal bone density
• Patient prioritizes metabolic health over renal considerations

Choose Pifeltro + Descovy (DRV/COBI + FTC/TAF) if:

• Patient has chronic kidney disease (eGFR 30-60 mL/min)
• Patient has osteoporosis or high fracture risk
• Patient has history of renal tubulopathy
• Patient is willing to accept weight gain and lipid monitoring
• Resistance patterns favor boosted PI regimen

Monitoring Recommendations

For patients on TAF-based regimens (Pifeltro + Descovy):

• Document weight and BMI every 6 months 1
• Monitor fasting lipids every 3-6 months
• Screen for diabetes with fasting glucose or HbA1c every 6-12 months
• Emphasize lifestyle modifications (diet and exercise) 1
• Consider statin therapy based on cardiovascular risk 1

For patients on TDF-based regimens (Delstrigo):

• Monitor renal function (serum creatinine, eGFR, urinalysis) every 3-6 months
• Screen for proteinuria and glycosuria
• Monitor bone mineral density in high-risk patients
• Assess for proximal tubulopathy symptoms

Common Pitfalls to Avoid

1. Don't assume TAF is universally "safer"—it trades renal/bone toxicity for metabolic toxicity
2. Don't ignore weight gain as merely "return to health"—the guidelines explicitly state this is not the full explanation 1
3. Don't switch from TDF to TAF solely for perceived safety without considering metabolic risk factors
4. Don't use cardiovascular risk calculators without adjustment—they underestimate risk in people with HIV 1

Bottom Line

Independent evidence supports that TAF-containing regimens cause more weight gain and worse lipid profiles than TDF-containing regimens. While direct evidence on insulin resistance in humans is limited, emerging data suggests TAF may worsen glucose metabolism in susceptible individuals 5, 3. Your provider's observation that TDF isn't universally "worse" is correct—the choice depends on whether you prioritize avoiding renal/bone toxicity (choose TAF) or metabolic toxicity (choose TDF). For patients concerned about glucose levels and insulin resistance, Delstrigo (TDF-based) is the more conservative metabolic choice, provided renal function is adequate.