Introduction

Emtricitabine plus tenofovir disoproxil fumarate (TDF) is a safe and well-tolerated PrEP option, but its uptake is hindered by potential adverse effects from off-target tenofovir concentrations, especially in specific populations. Tenofovir alafenamide (TAF) reduces plasma tenofovir concentrations by 90% compared to TDF and shows improved bone and renal safety. However, long-term safety and efficacy data for PrEP with emtricitabine plus TAF are still limited.

Aim

To assess HIV incidence and long-term safety in participants receiving emtricitabine plus tenofovir alafenamide over 144 weeks of follow-up.

Patient Profile

Cisgender men and transgender women aged 18 years and older with a high likelihood of acquiring HIV

Methods

• Open-label extension of the DISCOVER trial

Study drugs

• Emtricitabine plus tenofovir disoproxil fumarate (200/25 mg) tablets daily,
• Emtricitabine plus tenofovir alafenamide (200/300 mg) tablets daily,

Study Outcomes

• HIV-1 incidence, adherence, resistance
  • HIV-1 incidence in participants initially randomly assigned to receive emtricitabine plus tenofovir alafenamide was estimated
  • Adherence based on tenofovir diphosphate concentrations in dried blood spots and genotypic resistance were assessed in participants diagnosed with HIV
• Safety was assessed by hip and spine bone mineral density, renal function, and metabolic parameters up to 144 weeks of follow-up.

Results

Efficacy

• After 15 817 person-years of follow-up, 27 participants were diagnosed with HIV-1 over a minimum of 144 weeks of follow-up,
  • 10 (37%) were initially treated with emtricitabine plus tenofovir alafenamide
  • 17 (63%) received emtricitabine plus tenofovir disoproxil fumarate
• In participants who received emtricitabine plus tenofovir alafenamide for at least 144 weeks,
  • 10 out of 2,670 (less than 1%) were diagnosed with HIV, resulting in an incidence rate of 0.13 per 100 person-years
• During the 48-week open-label extension,
  • 2 participants initially assigned to emtricitabine plus TAF were diagnosed with HIV (0.093 per 100 person-years
  • 1 initially assigned to emtricitabine plus tenofovir disoproxil fumarate was diagnosed with HIV (0.046 per 100 person-years )
• HIV-1 infections were largely observed only in those who had either stopped study drug or who had suboptimal adherence, as measured by tenofovir diphosphate concentrations
• Viral resistance was detected at the time of HIV-1 diagnosis in four of the five participants with suspected baseline infection and all had virus bearing Met184Val or Met184Ile mutations.

Safety

• Participants on emtricitabine plus TAF for up to 144 weeks showed:
  • Improvement or stability in markers of glomerular filtration and proximal renal tubule dysfunction compared with baseline.
  • Increased or stable bone mineral density in the hip and lumbar spine from baseline to week 144 (n=191).
  • Stable cholesterol and glucose concentrations.
  • Median body weight increased by less than 1 kg per year.
• In participants who switched from emtricitabine plus TDF during the open-label phase:

• Markers of glomerular filtration & proximal renal tubule dysfunction improved or remained stable.
• Bone mineral density increased.
• Cholesterol concentrations increased.
• Glucose concentrations remained similar.
• Median body weight increased more compared to those who remained on emtricitabine plus tenofovir alafenamide

Table 1: Overall summary of safety in participants who received up to 144 wks of emtricitabine & TAF (n=2694)

Events	No	%
Any treatment-emergent adverse event	2544	(94%)
Any grade 3 or 4 treatment-emergent adverse event	67	(3%)
Discontinuation of study drug due to adverse event	43	(2%)
Serious adverse events*	257	(10%)
Serious adverse events related to study drug†	3	(<1%)
Deaths‡	7	(<1%)
Common treatment-emergent adverse events§
Anal chlamydia infection	1030	(38%)
Oropharyngeal gonococcal infection	997	(37%)
Proctitis gonococcal	921	(34%)
Exposure to communicable disease	647	(24%)
Diarrhoea	522	(19%)
Syphilis	494	(18%)
Nasopharyngitis	468	(17%)
Upper respiratory tract infection	456	(17%)
Urethritis chlamydial	394	(15%)
Urethritis gonococcal	295	(11%)
Grade 3 or 4 laboratory abnormalities¶
Any	385	(14%)
Increased aspartate aminotransferase	83	(3%)
Increased LDL while fasting	70	(3%)
Increased alanine aminotransferase	54	(2%)
Increased amylase	49	(3%)
Urine glucose (glycosuria)	37	(1%)
Increased γ-glutamyl transferase	34	(1%)
Increased lipase	32	(1%)
Decreased neutrophil count	31	(1%)
Total cholesterol while fasting (hypercholesterolaemia)	27 (1%)
Serum glucose non-fasting (hyperglycaemia)	24	(1%)

*The most common (n≥5) serious adverse events included appendicitis (17 [<1%]); suicidal ideation (9 [<1%]); cellulitis and suicide attempt (each 8 [<1%]); acute kidney injury (7 [<1%]); hepatitis A (6 [<1%]); and pneumonia and depression (each 5 [<1%]). ^†Serious adverse events considered related to study drug were nephrotic syndrome (1 [<1%]), chest pain and loss of consciousness (1 [<1%]), and agranulocytosis and pyrexia in the same participant (1 [<1%]). ^‡Reasons for death were cardiac arrest, traffic accident, amphetamine intoxication, suspected suicide, homicide, fatal drug overdose, and progressive vasodilatory shock with metabolic acidosis and multisystem dysfunction after crystal methamphetamine injection (each 1 [<1%]). ^§Occurring in at least 10% of participants. ^¶Occurring in at least 1% of participants.

Conclusion

Long-term use of emtricitabine and tenofovir alafenamide as daily oral PrEP is safe and well tolerated and can be an especially appropriate choice for people with bone or renal morbidities.

Reference

Lancet HIV 2024; 11: 508–21