Switching from an antiretroviral treatment (ART) regimen containing tenofovir disoproxil fumarate (TDF) to a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide (ECETA) can improve bone density and kidney safety in those aged 60 and above, a study by researchers from ASST Papa Giovanni XXIII, Bergamo, Italy, School of Clinical Medicine, Faculty of Health Science, University of the Witwatersrand, INSERM, University Hospital Nantes, France, University Hospital 12 de Octubre, Imas12, Universidad Complutense de Madrid, Madrid, Hospital de la Santa Creu I Sant Pau, Barcelona, Saint Louis Hospital, University Paris Diderot, and Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Trust, finds.
Due to improvements in antiretroviral treatment (ART), an increasing number of people living with HIV are ageing. In the USA, for example, 47% of people living with HIV are aged 50 or above, while global estimates suggest that over 50s now account for 13% of the total adult population of people living with HIV – equivalent to around 4.2m people.
In previous studies, TDF regimens have been associated with bone and kidney-related side effects that can result in severe illness. Older people on ART tend to experience more side effects than younger people and this, coupled with older people’s general vulnerability to conditions such as osteoporosis, means it is important to examine the effects of specific ART regimens on this age group. Despite this, older people living with HIV are usually underrepresented in clinical trials.
The study, the first Phase III trial of any HIV-combination ART involving people aged 60 and above, ran between 2015 and 2018 in 36 European clinics. Its purpose was to examine whether an ECETA regimen is less damaging to bone and kidney health for this age group than a TDF regimen, while maintaining viral suppression.
A total of 167 people aged 60 and above who were already on TDF and virally suppressed were randomly assigned to either stay on that regimen (56 participants) or switch to the ECETA alternative (111 participants). Most participants were male and white and the mean age was 66.
Significantly improved bone mineral density was observed among those who had switched regimens after six-months (24 weeks), something that continued to improve as the study went on. In contrast, declines in bone mineral density were observed among those on TDF regimen.
After 12 months (48 weeks), the mean percentage change in spine bone density among those in the ECETA group was 2.24% from baseline, compared to −0.10% in the TDF group, equating to a difference of 2.43%. Similarly, the difference at 48 weeks between hipbone density was 1.33% from baseline in the ECETA group and -0.73% in the TDF group, a difference of 2.04%.
Viral suppression was maintained among those that switched regimens and moderate increases in CD4 cell counts were also observed. Improvements in renal biomarkers, which indicate kidney health, were also found among those on ECETA regimen.
Due to the number of drugs used in the ECETA regimen there was a concern that people could be more vulnerable to side effects caused by adverse drug–drug interactions if they were taking medication for other conditions. This issue is particularly relevant for older people who may be more likely to be on treatment for other health issues than younger people. However, the study found switching to ECETA was generally well tolerated in participants, a substantial proportion of whom were taking other medication alongside their HIV treatment.
Although no serious treatment-related side effects were observed in either group, some milder side effects were reported in both. The most common side effects in the ECETA group were sore throats (12 participants or 11%), back pain (nine participants or 8%), and diarrhoea (eight participants or 7%). The most common side effects in the TDF group were bronchitis (six participants or 11%), vitamin D deficiency (four participants or 7%), and joint pain (four participants or 7%).
The findings are generally consistent with other studies of phase 3 trials of ECETA versus elvitegravir, cobicistat, emtricitabine, and TDF. These trials also showed similar efficacy but significantly fewer renal and bone effects with ECETA compared with those TDF-containing regimens.
Background: Tenofovir alafenamide is associated with less renal and bone toxicity than tenofovir disoproxil fumarate and might improve the long-term safety of antiretroviral therapy. We aimed to investigate the effect on bone mineral density of switching from a regimen containing tenofovir disoproxil fumarate to one containing tenofovir alafenamide in participants aged 60 years and older.
Methods: We did a prospective, open-label, multicentre, randomised trial in 36 European centres. Participants were virologically suppressed (HIV-1 RNA <50 copies per mL), aged 60 years or older, on a tenofovir disoproxil fumarate-containing regimen and were randomly assigned (2:1) via an interactive web-response system to open-label elvitegravir (150 mg), cobicistat (150 mg), emtricitabine (200 mg), and tenofovir alafenamide (10 mg) daily or continued therapy containing tenofovir disoproxil fumarate (300 mg). Participants were stratified by spine and hip bone mineral density categories. Primary endpoints were change from baseline to week 48 in spine and hip bone mineral density with a null hypothesis of zero between-group difference tested at a significance level of 0·05. This study was registered with ClinicalTrials.gov, NCT02616783.
Findings: Between Dec 22, 2015, and March 21, 2018, 167 participants were randomly assigned to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (n=111 [66%]) or tenofovir disoproxil fumarate (n=56 [34%]). One participant in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group did not receive treatment and was excluded from all analyses. At week 48, the mean percentage change in spine bone mineral density was 2·24% (SD 3·27) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and −0·10% (3·39) in the tenofovir disoproxil fumarate group (between-group difference 2·43% [95% CI 1·34–3·52]; p<0·0001), and mean percentage change in hip bone mineral density was 1·33% (2·20) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and −0·73% (3·21) in the tenofovir disoproxil fumarate group (difference 2·04% [1·17–2·90]; p<0·0001). The most common adverse events were nasopharyngitis (12 [11%]), back pain (nine [8%]), and diarrhoea (eight [7%]) in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group; and bronchitis (six [11%]), vitamin D deficiency (four [7%]), and arthralgia (four [7%]) in the tenofovir disoproxil fumarate group. 22 (20%) participants in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group and one (2%) participant in the tenofovir disoproxil fumarate group had an adverse event that was considered to be related to treatment. No treatment-related serious adverse events were observed. The proportions of adverse events leading to premature treatment discontinuation were similar between groups (four [4%] in the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide group; and one (2%) in the tenofovir disoproxil fumarate group).
Interpretation: The significantly improved bone mineral density, overall safety, and efficacy data show the feasibility of switching from a regimen containing tenofovir disoproxil fumarate to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed people living with HIV aged 60 years or older.
Funding: Gilead Sciences.
Franco Maggiolo, Giuliano Rizzardini, François Raffi, Federico Pulido, Maria Gracia Mateo-Garcia, Jean-Michel Molina, Edmund Ong, Yongwu Shao, David Piontkowsky, Moupali Das, Ian McNicholl, Richard Haubrich