PrEP (pre-exposure prophylaxis) is a highly effective medication for preventing HIV acquisition when used correctly. The vast majority of people taking PrEP never acquire HIV. For the small number of cases where PrEP has failed, the reasons are well-documented and typically fall into a few key categories, primarily related to consistent use of the medication. Understanding these causes is essential for maximizing PrEP's protective benefits and ensuring it works as intended.
The single biggest cause: Inconsistent medication adherence
The effectiveness of PrEP is directly tied to a user’s ability to take the medication consistently. Inconsistent use is the leading reason why PrEP might fail. The medications used for oral PrEP, such as tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), need to reach and maintain a specific concentration in the bloodstream and tissues to block HIV replication.
- Missing doses: For oral PrEP, efficacy is estimated to be 99% with seven doses per week, but drops to 96% with four doses per week, and to 76% with only two doses per week. Missing multiple doses, especially in a row, can drop drug levels below the protective threshold.
- Drug distribution differences: Studies have shown that women taking oral PrEP may have lower levels of active drug metabolites in vaginal tissues compared to rectal tissues, meaning that even higher adherence is required for maximum protection during vaginal sex.
- Barriers to adherence: Various social and behavioral factors can impact a person's ability to take PrEP consistently. Common reasons for non-adherence reported in studies include:
- Forgetting doses
- Worrying about side effects
- Social stigma associated with taking PrEP
- Logistical challenges of daily life
- Low perception of HIV risk
Starting PrEP with an undetected HIV infection
Another significant risk factor for PrEP failure involves starting the medication while unknowingly having an acute HIV infection. During the initial “window period” after infection, a person may test negative on standard antibody tests while the virus is already replicating in the body. If PrEP is started during this time, the incomplete viral suppression caused by the two PrEP drugs alone (as opposed to the three or more drugs used for treatment) can quickly lead to the development of drug-resistant mutations. This is why rigorous HIV testing is required before beginning PrEP and every three months while on it.
Transmitted HIV drug resistance
In rare cases, a person on PrEP can be exposed to a strain of HIV that is already resistant to one or both of the medications in their PrEP regimen. This form of transmitted drug resistance is extremely rare in most regions, but is a documented cause of PrEP failure, even in people with confirmed high adherence. This happens when the HIV-positive partner has a drug-resistant strain of the virus and is not virally suppressed.
Pharmacological and medical considerations
In addition to adherence and resistance, other factors can influence the effectiveness of PrEP:
- Drug-drug interactions: Certain medications and supplements can affect the levels of PrEP drugs in the body or increase the risk of side effects. For example, regular use of non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or diclofenac, or certain hepatitis C treatments, can impact kidney function and require careful monitoring while on PrEP. It's crucial to discuss all medications with a healthcare provider.
- Injectable PrEP and resistance: For individuals on injectable long-acting PrEP (e.g., cabotegravir), a unique risk exists. If a person stops their injections and later acquires HIV during the period when drug levels are declining (known as the “pharmacokinetic tail”), the low level of medication can select for drug-resistant viral strains. This emphasizes the importance of consistent injections and a plan for transitioning to oral PrEP if injections are stopped.
- Coinfections: While not a direct cause of failure, some sexually transmitted infections (STIs) that cause inflammation, such as rectal chlamydia (LGV), have been an associated factor in some documented PrEP failures. This suggests that local tissue vulnerability might play a role, though direct evidence is limited.
Comparison of Oral vs. Injectable PrEP Effectiveness Factors
| Factor | Oral PrEP (e.g., TDF/FTC) | Injectable PrEP (e.g., cabotegravir) |
|---|---|---|
| Primary Effectiveness Risk | Inconsistent dosing. Efficacy is highly dependent on daily adherence. | Inconsistent injection schedule or acquiring HIV after discontinuing (in the pharmacokinetic "tail"). |
| Drug Resistance | Most common if started during undiagnosed acute infection. Rare with consistent use. | Rare with consistent injections, but can develop if HIV is acquired during the prolonged period of declining drug levels after stopping injections. |
| Monitoring Needs | Regular blood tests for HIV and kidney function (every 3 months typically). | Regular injection appointments (every 2 months) and HIV monitoring. Close monitoring during transition off regimen. |
| Adherence Challenge | Remembering to take a pill daily. | Keeping regular appointments for injections. |
| Potential Drug Interactions | Some NSAIDs, hepatitis C meds. | Less impacted by daily medications; specific interactions should be discussed with a provider. |
Strategies to maximize PrEP effectiveness
To prevent PrEP failure, users should focus on proactive management of their regimen. Simple strategies can make a substantial difference:
- Set reminders: Use alarms, apps, or daily routines to remember doses for oral PrEP. Many find linking their pill-taking to another daily habit, like brushing their teeth, is effective.
- Maintain open communication with your provider: Talk to your doctor about any challenges with adherence, side effects, or changes in your health or sexual behavior. They can provide support and assess if an alternative regimen, like injectable PrEP, might be a better fit.
- Adhere to testing schedules: Follow the required schedule for HIV and STI testing. This ensures you remain HIV-negative while on PrEP and catches any potential infections early, preventing resistance.
- Understand your formulation: Know the specific requirements for your type of PrEP. Oral PrEP offers flexibility, while injectable PrEP requires a strict schedule of clinic visits.
Conclusion
While PrEP is not 100% effective, it remains one of the most powerful tools available for HIV prevention. The reasons that can cause PrEP to fail are well understood and, for the most part, preventable. The most significant risk stems from inconsistent medication adherence, while other, much rarer causes include starting PrEP with an undetected infection or exposure to a highly resistant strain of HIV. By prioritizing consistent medication use, following all testing and monitoring schedules, and maintaining an open dialogue with healthcare providers, individuals can drastically reduce their risk and harness the full, life-changing power of PrEP. More information on HIV prevention can be found on the Aidsmap website.
