Bone Mineral Density, Kidney Function, Weight Gain and Insulin Resistance in Women Who Switch From TDF/FTC/NNRTI to ABC/3TC/DTG

F Ibrahim; A Samarawickrama; L Hamzah; R Vincent; Y Gilleece; L Waters; S Kegg; B Barbini; L Campbell; FA Post

HIV Medicine. 2021;22(2):83-91.

Abstract and Introduction

Abstract

Objectives: Tenofovir disoproxil fumarate (TDF) is associated with reduced bone mineral density (BMD). We evaluated changes in BMD in women who switched from TDF, emtricitabine and a nonnucleoside reverse transcriptase inhibitor (TDF/FTC/NNRTI) to abacavir, lamivudine and dolutegravir (ABC/3TC/DTG).

Methods: We conducted a randomized controlled trial in which women aged ≥40 years were randomized 1:2 to continue TDF/FTC/NNRTI or switch to ABC/3TC/DTG. The primary endpoint was change in total hip BMD measured by dual-energy X-ray absorptiometry at week 48. Secondary endpoints were changes in BMD of the lumbar spine and femoral neck and markers of bone turnover and kidney function up to week 48. We conducted exploratory analyses of weight gain, insulin resistance and metabolic syndrome. Primary and secondary endpoints were analysed by linear regression, with multiple imputation for missing time points.

Results: In all, 91 women [mean age = 50.4 (standard deviation [SD] = 6.6) years, median CD4 cell count = 600 (interquartile range: 479–800) cells/μL] were randomized. Women who switched to ABC/3TC/DTG maintained viral suppression and experienced improvements in total hip BMD (mean adjusted difference = 1%, P = 0.027) and lumbar spine BMD (3%, P = 0.002), with no change in specific markers of bone turnover or renal tubular function. Although participants in the ABC/3TC/DTG arm gained more weight (1.8 kg, P = 0.046), the switch strategy was not associated with reduced insulin sensitivity or new-onset metabolic syndrome.

Conclusions: Switching from TDF/FTC/NNRTI to ABC/3TC/DTG resulted in improved BMD. Although weight gain was common in women who switched from TDF/FTC/NNRTI to ABC/3TC/DTG, we did not detect adverse effects on glucose homeostasis. Larger studies need to confirm these findings.

Introduction

Antiretroviral therapy (ART) has revolutionized the management of HIV infection, normalizing life span in those who initiate fully suppressive lifelong ART prior to the onset of immunodeficiency.^[1] Efficacy, durability and safety of ART has also improved, and most people with HIV can expect to remain on current ART regimens indefinitely. For much of the past 20 years, these ART regimens have included tenofovir disoproxil fumarate (TDF) despite the potential for adverse effects of TDF on bone and kidney. Regimens containing TDF have been consistently associated with greater initial (first 1–2 years of exposure) reductions in bone mineral density (BMD) than regimens not containing TDF,^[2–5] followed by stabilization of BMD with continued exposure thereafter and improvements in BMD following discontinuation of TDF.^[6–9] The clinical significance of these reductions in BMD remains unclear, with TDF exposure associated with small increases in fracture risk in some cohort studies^[10,11] but not in others.^[12] Nonetheless, a 2.7–3.3% reduction in BMD as observed in the Women AntiretroViral Efficacy and Safety (WAVES) study^[13] is particularly undesirable in older women who are already at risk of accelerated bone loss following the menopause.

Tenofovir disoproxil fumarate has also been associated with reductions in estimated glomerular filtration rate (eGFR), chronic kidney disease (CKD) and proteinuria, and, in severe cases, acute tubular injury and proximal tubulopathy/Fanconi syndrome.^[14–17] Older age is a risk factor for CKD in general and TDF-induced renal injury.^[18,19] While some studies indicate that TDF-associated tubule dysfunction and phosphaturia may contribute to bone loss,^[20,21] other studies suggest that effects of BMD may be observed in the absence of changes in renal tubular function,^[8] although this has not been specifically studied in women.

We conducted a randomized controlled trial in virologically suppressed women aged ≥ 40 years to examine the effect of switching from TDF/emtricitabine plus a nonnucleoside reverse-transcriptase inhibitor (TDF/FTC/NNRTI) to abacavir/lamivudine plus dolutegravir (ABC/3TC/DTG) on bone and kidney function. As dolutegravir has recently been implicated in weight gain, we also explored for differences in body weight, insulin resistance and metabolic syndrome.

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Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Baseline characteristics of the study population
		TDF/FTC/NNRTI (n = 32)	ABC/3TC/DTG (n = 59)
Age (years)	Mean (SD)	49.5 (6.0)	50.9 (7.0)
Ethnicity
Black	n (%)	27 (84.4)	51 (86.4)
White/other	n (%)	5 (15.6)	8 (13.6)
Weight (kg)	Mean (SD)	86.3 (16.2)	77.4 (17.0)
Body mass index (kg/m²)	Mean (SD)	32.7 (7.0)	29.0 (5.8)
Post-menopausal	[n (%)]*	14 (50.0)	26 (52.0)
Diabetes mellitus	n (%)	1 (3.1)	3 (5.1)
Hypertension	n (%)	8 (25.0)	13 (22.0)
Current smoker	n (%)	3 (9.4)	4 (9.8)
Time since HIV diagnosis (years)	Mean (SD)	11.7 (5.2)	13.9 (6.6)
Prior AIDS	n (%)	5 (15.6)	10 (17.0)
CD4 current (cells/mm³)	Median (IQR)	579 (510–712)	612 (454–807)
CD4 nadir (cells/mm³)	Median (IQR)	161 (88–290)	195 (129–323)
Viral load (<50 copies/mL)	n (%)	32 (100)	55 (96)**
Hepatitis B surface antigen-negative	n (%)	32 (100)	59 (100)
Hepatitis C antibody-negative	n (%)	32 (100)	59 (100)
Time on TDF, years	Mean (SD)	7.3 (3.1)	8.7 (3.4)
Taking vitamin D-containing supplements	n (%)	7 (21.9)	13 (22.0)
FRAX: major osteoporotic fracture	Median (IQR)	3.1 (2.5–5.1)	3.2 (2.6–5.5)
FRAX: hip fracture	Median (IQR)	0.2 (0.1–0.4)	0.2 (0.1–0.6)

3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; FRAX, risk of fracture (over 10 years); FTC, emtricitabine; IQR, interquartile range; NNRTI, nonnucleoside reverse transcriptase inhibitor; SD, standard deviation; TDF, tenofovir disoproxil fumarate.
*Menopausal status could be determined for 78 participants.
**Viral load missing (N = 2) and < 200 HIV RNA copies/mL (N = 2).

Table 2. Outcome measures by randomization arm
	Baseline		Week 48		Adjusted mean difference between study arms (baseline to week 48)	P-value
	TDF/FTC/NNRTI	ABC/3TC/DTG	TDF/FTC/NNRTI	ABC/3TC/DTG		P-value
Bone mineral density
Total hip (g/cm²)	1.03 (0.98–1.08)	0.96 (0.92–0.99)	1.03 (0.98–1.08)	0.97 (0.94–1.00)	0.01 (0.002–0.03)	0.027
Neck of femur (g/cm²)	0.90 (0.85–0.96)	0.87 (0.83–0.90)	0.90 (0.84–0.95)	0.88 (0.84–0.91)	0.02 (−0.003 to 0.03)	0.093
Lumbar spine (g/cm²)	1.07 (1.02–1.12)	1.03 (0.99–1.07)	1.06 (1.02–1.11)	1.05 (1.01–1.10)	0.03 (0.01–0.05)	0.002
Bone biomarkers
25(OH) vitamin D (nmol/L)	40.8 (33.1–48.4)	49.0 (42.9–55.1)	37.8 (31.4–44.2)	47.2 (41.3–53.1)	3.7 (−2.5 to 9.9)	0.235
Parathyroid hormone (ng/L)	34.7 (29.3–40.2)	32.5 (27.3–37.7)	35.6 (29.9–41.2)	30.5 (26.6–34.4)	−3.8 (−9.9 to 2.4)	0.230
Alkaline phosphatase (IU/L)	89.9 (79.8–100.0)	93.2 (84.7–101.8)	88.1 (77.9–98.3)	73.0 (67.0–78.9)	−17.8 (−25.9 to −9.6)	<0.001
CTX (μg/L)	0.44 (0.36–0.51)	0.53 (0.45–0.62)	0.42 (0.34–0.50)	0.37 (0.32–0.42)	−0.06 (−0.15 to 0.03)	0.217
P1NP (μg/L)	61.6 (54.6–68.7)	68.7 (62.1–75.3)	59.4 (51.6–67.1)	58.4 (52.4–64.5)	−1.8 (−10.9 to 7.2)	0.691
Renal biomarkers
Creatinine (μmol/L)	67.7 (64.0–71.4)	67.8 (65.4–70.3)	71.4 (67.4, 75.3)	78.1 (75.2, 81.0)	6.7 (2.7–10.7)	0.001
eGFR (creatinine) (mL/min/1.73 m²)	103.5 (97.1–109.9)	102.1 (98.1–106.2)	97.7 (91.3–104.0)	87.8 (83.8–91.8)	−8.8 (−14.5 to −3.2)	0.003
Cystatin C (mg/L)	0.81 (0.74–0.88)	0.80 (0.76–0.85)	0.83 (0.77–0.89)	0.82 (0.78–0.86)	−0.01 (−0.04 to 0.03)	0.624
eGFR (cystatin C) (mL/min/1.73 m²)	101.8 (91.2–112.4)	99.8 (93.1–106.4)	98.1 (88.5–107.7)	96.5 (91.1–102.0)	0.4 (−4.4 to 5.1)	0.881
Albumin/creatinine ratio (mg/mmol)	1.78 (0.61, 2.95)	1.94 (0.79, 3.10)	1.32 (0.69, 1.96)	0.91 (0.58, 1.24)	−0.54 (−1.25 to 0.16)	0.131
Protein/creatinine ratio (mg/mmol)	10.74 (7.12, 14.35)	10.22 (8.05, 12.38)	9.42 (6.95, 11.89)	6.69 (5.56, 7.82)	−0.03 (−0.06 to −0.01)	0.003
Retinol-binding protein/creatinine ratio (μg/mmol)	2.76 (0.97, 4.54)	2.31 (1.50, 3.12)	2.28 (0.63, 3.93)	1.29 (0.68, 1.89)	−0.79 (−1.92 to 0.34)	0.168
Fractional excretion of phosphate (%)	0.10 (0.07–0.12)	0.10 (0.08–0.11)	0.09 (0.07–0.11)	0.09 (0.07–0.10)	−0.003 (−0.03 to 0.02)	0.792
Weight and body mass index
Weight (kg)	86.3 (79.7–93.0)	77.4 (72.7–82.1)	86.3 (79.5–93.0)	79.2 (74.7–83.8)	1.81 (0.03, 3.59)	0.046
Body mass index (kg/m²)	32.7 (30.2–35.1)	29.0 (27.5–30.5)	32.8 (30.2–35.4)	31.1 (27.6–34.7)	1.50 (−2.73 to 5.73)	0.481

3TC, lamivudine; ABC, abacavir; CTX, type I collagen cross-linked C-telopeptide; DTG, dolutegravir; eGFR, estimated glomerular filtration rate; FTC, emtricitabine; NNRTI, nonnucleoside reverse transcriptase inhibitor; P1NP, procollagen type 1 N-terminal propeptide; TDF, tenofovir disoproxil fumarate.
Data are expressed as means (95% CI) except for weight and body mass index [which are expressed as median (interquartile range)]; BMD was adjusted for age, BMI at baseline, ethnicity, time on TDF, NNRTI (efavirenz vs. other) and BMD at baseline; all other secondary outcomes were adjusted for age, ethnicity, BMI at baseline, time on TDF and baseline measurements except BMI (where weight at baseline was used instead of BMI baseline). Bold values indicate P < 0.05.

Table 3. Outcome measures by randomization arm
Outcome measure	Unit		Baseline		Week 48		Mean difference [95% CI] between arms from baseline to week 48	P-value
Outcome measure	Unit		TDF/FTC/NNRTI	ABC/3TC/DTG	TDF/FTC/NNRTI	ABC/3TC/DTG		P-value
Weight	kg	Mean (SD)	85.0 (17.9)	76.8 (17.1)	85.4 (18.1)	79.7 (16.9)	1.38 [−0.87, 3.63]	0.22
Waist circumference	cm	Mean (SD)	99.6 (10.4)	92.8 (15.1)	100.1 (11.0)	93.2 (20.5)	0.27 [−5.35, 5.88]	0.93
Systolic blood pressure	mmHg	Mean (SD)	123.3 (14.9)	122.9 (20.3)	122.2 (28.3)	125.7 (16.9)	7.87 [−6.97, 22.7]	0.29
Diastolic blood pressure	mmHg	Mean (SD)	78.4 (8.2)	78.5 (13.4)	80.7 (9.8)	78.9 (10.8)	−3.00 [−7.62, 1.61]	0.18
HDL-cholesterol	mmol/L	Mean (SD)	1.6 (0.4)	1.7 (0.4)	1.7 (0.4)	1.8 (0.5)	0.03 [−0.21, 0.27]	0.27
Triglycerides	mmol/L	Median (IQR)	0.9 (0.8–1.4)	0.8 (0.7–1.2)	1.0 (0.8–1.3)	0.8 (0.7–1.2)	0.03 [−0.11, 0.18]	0.66
Glucose	mg/dL	Mean (SD)	89.1 (7.5)	85.1 (8.9)	87.0 (9.5)	88.2 (10.7)	3.56 [−1.94, 9.07]	0.20
Insulin	μU/mL	Median (IQR)	6.6 (4.2–9.1)	5.7 (3.0–9.6)	10.4 (4.9–16.1)	6.4 (4.0–9.3)	−3.23 [−6.20, −0.27]	0.033
HOMA-IR		Median (IQR)	1.6 (0.9–2.2)	1.2 (0.6–2.1)	2.3 (1.1–3.5)	1.9 (0.8–2.2)	-0.29 [−0.90, 0.32]	0.35
QUICKI index		Mean (SD)	0.2 (0.0)	0.2 (0.0)	0.2 (0.0)	0.2 (0.0)	0.002 [−0.005, 0.01]	0.46
Insulin resistance index		Median (IQR)	7.9 (7.4–9.0)	8.4 (7.0–11.0)	7.0 (6.0–9.1)	8.7 (6.7–10.2)	0.56 [−0.24, 1.36]	0.16

3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; FTC, emtricitabine; HDL, high-density lipoprotein; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance [23]; NNRTI, nonnucleoside reverse transcriptase inhibitor; QUICKI, Quantitative Insulin Sensitivity Check Index [24]; Insulin Resistance index [25]; TDF, tenofovir disoproxil fumarate.
Data are for non-diabetic participants with fasting samples: N = 19 in the TDF/FTC/NNRTI arm and N = 34 in the ABC/3TC/DTG arm. Bold values indicate P < 0.05.