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

Disclosures

HIV Medicine. 2021;22(2):83-91. 

In This Article

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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