What does the evidence indicate about breakthrough HIV infections in individuals using daily oral pre‑exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine?

PrEP Breakthrough Infections: Evidence Summary

Breakthrough HIV infections during daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) PrEP are extremely rare when adherence is adequate, occurring at a rate of approximately 0.77 per 100 person-years across global studies, with the vast majority of cases (83%) occurring in individuals with poor adherence (<2 doses per week). 1

Incidence and Overall Risk

The largest pooled analysis to date, encompassing 17,274 participants across 72 global studies, documented only 101 breakthrough infections over the study period 1. This translates to:

• Overall incidence: 0.77 per 100 person-years (95% CI: 0.63–0.94) 1
• Protective efficacy with adequate adherence: 88–91% when tenofovir concentrations indicate consistent dosing 2

When stratified by adherence levels measured through dried blood spot (DBS) tenofovir concentrations 1:

• <2 doses/week: 3.9 infections per 100 person-years
• 2–3 doses/week: 0.24 infections per 100 person-years
• 4–6 doses/week: 0.27 infections per 100 person-years
• ≥7 doses/week: 0.054 infections per 100 person-years

Adherence as the Primary Determinant

The overwhelming majority of breakthrough infections occur in the context of inadequate adherence 1, 3. Among 54 breakthrough cases with available DBS data, 83.3% had average adherence of less than 2 doses per week 1. Even among the rare "true" PrEP failures with documented adherence, only 5 of 29 seroconverters appeared to be consistently adherent 2.

Adherence is particularly challenging in specific populations 1:

• Younger participants
• Hispanic/Latinx individuals
• Black participants
• Cisgender women
• Transgender women

Drug Resistance Patterns

Among breakthrough infections, drug resistance emerges in a minority of cases and is most strongly associated with PrEP initiation during undiagnosed acute HIV infection 4, 5. In 78 cases with resistance data 1:

• 23% developed M184I or M184V mutations (emtricitabine resistance)
• 1.3% developed K65R mutation (tenofovir resistance)
• 3.8% developed both mutations

The most common scenario for resistance development is starting PrEP during unrecognized acute HIV infection, not true breakthrough during established prophylaxis 5. This underscores the critical importance of baseline HIV screening.

Clinical Characteristics of Breakthrough Cases

"True" PrEP failures with documented adherence share common features 3:

• Continued condomless anal sex despite adherence
• Recurrent or multiple sexually transmitted infections (STIs)
• Infection with drug-resistant HIV strains
• Atypical or delayed seroconversion due to significantly suppressed viral loads, making diagnosis challenging

Diagnostic Challenges

Breakthrough infections can be difficult to detect because PrEP partially suppresses viral replication, leading to delayed antibody development and inconsistent viremia 4, 3. The 2025 IAS-USA guidelines address this with specific testing recommendations 4:

• At initiation or resumption: HIV RNA testing (lower limit of quantification ≤50 copies/mL) plus fourth- or fifth-generation laboratory-based antigen-antibody assay
• During follow-up: Point-of-care rapid antibody test plus laboratory-based antigen-antibody test every 3 months
• Routine HIV RNA monitoring is NOT recommended during PrEP follow-up due to low positive predictive value and significant negative consequences of false-positive results 4

Real-World Implementation Data

In France's first-year PrEP implementation involving 3,405 subjects (98.1% male, 96.9% MSM), only 4 breakthrough infections occurred 6. Critically, all four cases involved either:

• PrEP interruption, or
• Acute infection present at the time of PrEP initiation

No breakthrough infections occurred in individuals with continuous, adherent PrEP use 6.

Long-Acting Injectable Alternatives

The evidence now supports superior options for individuals who struggle with daily oral adherence 4:

• Injectable cabotegravir every 8 weeks: HIV incidence 0.10 per 100 person-years (96% reduction) in PURPOSE-2 trial 4
• Injectable lenacapavir every 6 months: Zero detected infections in PURPOSE-1 trial among cisgender women in high-incidence settings 4

Critical Clinical Pitfalls

Common errors that increase breakthrough risk 4, 3, 5:

1. Initiating PrEP during undiagnosed acute HIV infection – Always obtain HIV RNA testing when acute infection is suspected, even with negative antibody tests 4
2. Inadequate baseline testing – Fourth- or fifth-generation antigen-antibody assays are mandatory; third-generation antibody-only tests miss acute infections 4
3. Delayed recognition of seroconversion – Breakthrough infections present with atypical serologic patterns due to partial viral suppression 3
4. Overreliance on self-reported adherence – Pill counts overestimate actual adherence; 96% of controls versus 66% of cases reported >80% adherence, but objective drug levels told a different story 2
5. Failure to address ongoing high-risk behavior – PrEP alone is insufficient; comprehensive STI screening and risk-reduction counseling are essential 3

Population-Level Impact

Mathematical models and real-world data consistently demonstrate that the public health benefit of decreased HIV incidence with widespread PrEP use substantially outweighs any theoretical risk of increased drug resistance prevalence 5. The infrequency of resistance emergence, combined with the dramatic reduction in new infections, supports aggressive PrEP scale-up.