Bone and renal changes in the ADVANCE trial

Polly Clayden, HIV i-Base

Smaller decreases in bone mineral density (BMD) in the TAF-containing versus TDF-containing arms of the ADVANCE trial, according to findings presented at EACS 2019. [1] 

The 96-week ADVANCE trial, conducted in South Africa, randomised 1053 treatment-naive participants to three first-line regimens: tenofovir alafenamide (TAF)/emtricitabine (FTC)/dolutegravir (DTG) vs tenofovir disoproxil fumarate (TDF)/FTC/DTG vs TDF/FTC/efavirenz (EFV).

Week 48 results, showing DTG-based regimens to be non-inferior to EFV-based ones (but associated with substantial weight gain) were presented at IAS 2019 and published in the NEJM in July. [2, 3, 4]

One of the aims of the ADVANCE study was to compare bone and renal changes over 96 weeks in participants receiving TDF-containing regimens versus those receiving TAF-containing regimens. At the time of analysis, all participants had completed 48 weeks and approximately half had reached 96 weeks.

In this sub study, the investigators used DEXA scan to measure BMD for whole body, spine and hip and baseline, week 48 and week 96.

T-scores for BMD results were calculated using WHO categories to diagnose treatment emergent osteopenia and osteoporosis.

The FRAX (Fracture Risk Assessment) tool was used to assess fracture risk in all participants aged 40 and above. This method calculates the overall 10-year probability of fracture with BMD based on: age and sex; height and weight; previous history of fractures; presence of glucocorticoids and/or rheumatoid arthritis; presence of secondary osteoporosis; alcohol and smoking and femoral neck BMD. Of note, FRAX is based on population-based cohorts from Europe and South America and is not validated in African patients.

Renal tests included uric acid, phosphate, B2 microglobulin, urine retinol-binding protein, serum creatinine clearance and urine albumin-to-creatinine ratio. Changes from baseline were measured every study visit.

At baseline, participants were about 33 years old, 99.5% were black and about 60% were women. Mean BMD scores were: 1.20 g/cm2, 1.03 g/cm2 and 1.00 g/cm2 for whole body, hip and spine respectively. These were similar across the three treatment arms and <1% had a history of bone fractures.

Mean renal markers were also balanced across the treatment arms and approximately 8% had a history of renal and urinary disorders.

All participants showed similar decline (approximately -7%) in whole body BMD to week 48, which levelled out to week 96. There were no significant differences in changes in whole body BMD across the three study arms at either time point.

There was a decrease across all three arms in spinal BMD, which at weeks 48 and 96 was greater in the two TDF-containing arms compared to the TAF-containing one (mean per cent change: -6% vs -4%). The difference was statistically significant at week 96 (p<0.001).

There was also a decrease in hip BMD across all three arms at weeks 48 and 96, which was greater in the two TDF-containing arms than the TAF-containing arm (mean per cent change: -4.5% and -6% vs -3%). Notably the greatest decrease was seen in the EFV arm. All comparisons are statistically significant at week 96, including the difference between the TDF/FTC/DTG arm compared to the EFV/FTC/TDF arm (p<0.001).

The percentage of participants developing treatment-emergent whole body osteopenia at weeks 48 and 96 was small across all three arms: 1.8%, 2.3% and 0% for TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/ EFV, at week 96 respectively. (All comparisons NS except TDF/FTC/DTG vs TDF/FTC/ EFV, p=0.05).

The percentage of participants developing treatment-emergent spinal osteopenia at weeks 48 and 96 was higher than seen with whole body across all three arms: 21%, 23% and 30% for TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/ EFV, at week 96, respectively. There were no significant differences between the three arms. And 1% of participants in the TDF/FTC+DTG arm developed osteoporosis at week 96.

A higher percentage of participants had treatment-emergent hip osteopenia in the EFV arm at both weeks 48 and 96 than in the other two study arms: 6.3%, 11.1% and 30% for TAF/FTC/DTG, TDF/FTC/DTG and TDF/FTC/EFV, at week 96, respectively.

At week 48, only the difference between the TAF/FTC/DTG and TDF/FTC/EFV arms is significant (p=0.005). At week 96 the differences between the EFV arm and the other two study arms are both statistically significant (both p<0.001).

As with the whole body data, no participants in this paired analysis developed treatment emergent osteoporosis at week 48 or week 96 in any treatment arm.

Seven fractures were reported during the study and were balanced across the arms and none were related to study drugs.

Using FRAX, the predicted 10-year risk of major fractures was 0.2% lower in the TAF/FTC/DTG arm compared with the TDF/FTC/DTG arm. There was no difference between TAF/FTC/DTG and TDF/FTC/EFV.

There were very few grade 3 or 4 renal adverse events (<1%) seen in the study. Grade 3 or 4 abnormalities in creatinine clearance were infrequent with no statistical differences by treatment arm. No consistent difference between TAF and TDF arms in elevations of renal markers above the normal range.But there was an apparent difference in B2M and RBP with in the EFV arm.

The investigators concluded that longer-term follow-up is needed to continue to balance the risks of clinical obesity observed with DTG and TAF and follow up changes in bone and renal markers for these first-line regimens.

Polly Clayden is on the scientific committee of ADVANCE and a co-author of the NEJM paper.


  1. Qavi A et al. The ADVANCE trial: the impact of DXA-assessed bone mineral density of TDF/FTC/EFV and TDF/FTC+DTG versus TAF/FTC+DTG. 17th European AIDS Conference (EACS). Basel, Switzerland. 6–9 November, 2019.Oral abstract PS4/3. (abstract)
  2. Venter WDF et al. The ADVANCE trial: Phase 3, randomised comparison of TAF/FTC/DTG, TDF/FTC/DTG or TDF/FTC/EFV for first-line treatment of HIV-1 infection.10th IAS Conference on HIV Science. Mexico City, Mexico. 21–24 July 2019. Oral abstract WEAB0405LB. (abstract)
  3. Venter WDF et al. Dolutegravir plus two different prodrugs of tenofovir to treat HIV. New England Journal of Medicine. Online ahead of print. 24 July 2019.
  4. Clayden P. Dolutegravir-based first-line non-inferior to efavirenz-based ART but associated with substantial weight gain: results from the ADVANCE study. HTB. 23 August 2019.

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