A Breakthrough in Emergency Prevention
Imagine a medical emergency that unfolds silently inside your body within hours of a single exposure. HIV transmission represents precisely this scenario—the virus quickly establishes footholds in susceptible cells, often within 24 to 36 hours after exposure 3 . But what if you could stop this process with a simple pill regimen? This isn't science fiction; it's the reality of modern HIV prevention through Post-Exposure Prophylaxis (PEP).
PEP must be started within 72 hours of exposure, ideally within the first 2 hours for maximum effectiveness 1 .
For years, PEP regimens were burdened by side effects and complex dosing schedules that limited their effectiveness. Now, a revolutionary approach combining once-daily raltegravir with tenofovir/emtricitabine is transforming emergency HIV prevention, offering unprecedented tolerability and protection in the critical window after potential exposure.
Post-Exposure Prophylaxis (PEP) refers to the use of antiretroviral medications to prevent HIV infection after a potential exposure has occurred. Think of it as a "morning-after pill" regimen for HIV, but with an important distinction—it must be taken for 28 days to fully block infection 3 .
PEP comes in two forms: occupational PEP (for healthcare workers exposed to needlesticks or bodily fluids) and non-occupational PEP (for exposures through sex or injection drug use) 2 .
Highest chance of preventing HIV establishment 1
Significant protection still achievable
Effectiveness decreases but still recommended
Virus may have established permanent reservoirs
Traditional HIV drugs target the virus at various stages of its life cycle—most commonly by blocking reverse transcriptase, an enzyme that helps the virus replicate its genetic material. Raltegravir represents a different approach entirely.
As an integrase strand transfer inhibitor, it blocks the HIV enzyme that allows the virus to insert its genetic material into human DNA 6 .
This mechanism is particularly valuable for PEP because integrase inhibitors prevent HIV from becoming established in latent reservoirs of susceptible cells 6 .
By acting at this critical step of the infection process, raltegravir essentially stops the virus from "setting up shop" in the body's cells, making it ideally suited for post-exposure prevention.
Fewer gastrointestinal side effects compared to protease inhibitor-based regimens 6
Once-daily option improves adherence and completion rates
Blocks viral integration into host DNA, preventing reservoir establishment
In 2012, researchers at Boston's Fenway Health conducted a landmark study to evaluate the effectiveness and tolerability of a novel PEP regimen containing raltegravir, tenofovir DF, and emtricitabine 6 .
The study enrolled 100 participants who had experienced high-risk sexual exposures to HIV. These individuals were prescribed the three-drug regimen of raltegravir (400 mg twice daily at that time) plus tenofovir DF/emtricitabine to be taken for 28 days.
100 Participants
High-risk sexual exposures
28-day treatment
HIV Seroconversion
Of 85 participants completing follow-upPerfect Adherence
Completed regimen exactly as prescribedGood Adherence
Took medication daily with occasional missed doses| Side Effect | Percentage of Participants | Severity |
|---|---|---|
| Nausea/Vomiting | 27% | Mild, self-limited |
| Diarrhea | 21% | Mild, self-limited |
| Headache | 15% | Mild |
| Fatigue | 14% | Mild |
| Abdominal Symptoms | 16% | Mild |
| Muscle/Joint Aches | 8% | Mild |
The side effects were "significantly less common than those reported by historical controls, who used a 3-drug PEP regimen including zidovudine, lamivudine, and a ritonavir-boosted protease inhibitor" 6 .
The initial success of raltegravir in PEP regimens faced one significant practical limitation: the need for twice-daily dosing (400 mg twice daily). This changed with the development of a new 600 mg tablet formulation that allowed for once-daily dosing at 1200 mg (2×600 mg tablets) .
The ONCEMRK trial, a phase 3 multicenter study, compared these two dosing strategies in treatment-naive HIV-infected adults.
The long-term results from the ONCEMRK trial demonstrated remarkable durability. At week 96, 81.5% of once-daily recipients and 80.1% of twice-daily recipients maintained viral suppression (HIV-1 RNA <40 copies/mL) .
The similar efficacy rates between groups established the non-inferiority of the once-daily option.
| Parameter | Raltegravir 1200 mg Once Daily | Raltegravir 400 mg Twice Daily |
|---|---|---|
| Participants with HIV-1 RNA <40 copies/mL | 81.5% (433/531) | 80.1% (213/266) |
| Discontinuations due to lack of efficacy | 1.1% | 1.1% |
| Discontinuations due to adverse events | 1.3% | 2.3% |
| CD4+ T-cell count increase from baseline | >260 cells/mm³ | >260 cells/mm³ |
The study concluded that "raltegravir 1200 mg QD demonstrated noninferior efficacy to raltegravir 400 mg BID that was durable to week 96, with a safety profile similar to raltegravir 400 mg BID" .
The latest guidelines from the Centers for Disease Control and Prevention (CDC), updated in 2025, continue to emphasize the importance of rapid initiation of PEP after high-risk exposures 2 .
While the preferred regimens have evolved to include newer options like bictegravir/tenofovir alafenamide/emtricitabine, raltegravir-based regimens remain an important alternative, particularly when newer options aren't available or appropriate 1 2 .
The 2025 guidelines also streamlined follow-up protocols, recognizing that "no routine follow-up laboratory testing for antiretroviral drug toxicity" is needed when baseline testing is normal and no symptoms develop during PEP 9 .
This reduction in medical burden makes PEP more accessible and manageable for patients.
| Timeline | Required Assessments | Purpose |
|---|---|---|
| Baseline | HIV test, kidney function, liver enzymes, hepatitis B/C tests, STI screening | Confirm HIV-negative status, establish baseline safety parameters |
| 24 hours after starting PEP | Follow-up visit (in-person or remote) | Assess tolerance, reinforce adherence, address side effects |
| 2-4 weeks during PEP | Clinical assessment, adherence counseling | Support regimen completion, manage any side effects |
| 4-6 weeks after exposure | Repeat HIV testing | Confirm prevention success, detect early infection |
| 12 weeks after exposure | Final HIV testing | Confirm long-term prevention success |
Seek immediate medical care
Receive rapid assessment
Take first PEP dose immediately
Continue medication for 28 days
Attend all follow-up appointments
Consider transition to PrEP
Healthcare providers should offer information about transitioning to pre-exposure prophylaxis (PrEP) for individuals with ongoing HIV risk, creating a seamless prevention continuum from emergency intervention to long-term protection 2 .
The field of HIV prevention continues to advance rapidly. Researchers are exploring:
As these innovations mature, they may further improve the effectiveness and accessibility of emergency HIV prevention.
The development of once-daily raltegravir with tenofovir/emtricitabine as PEP represents more than just a pharmaceutical advance—it embodies the progress we've made in four decades of HIV science.
From the early days of the epidemic when a diagnosis seemed like a death sentence, we now have multiple prevention tools that, when used effectively, can stop transmission.
While no single intervention will end the HIV epidemic alone, effective PEP regimens form a crucial component of our comprehensive prevention strategy. Together with PrEP, treatment as prevention, condom use, and harm reduction services, these advances bring us closer to the goal of ending HIV transmission entirely.
Emergency prevention after exposure
Ongoing protection before exposure
Undetectable = Untransmittable
Comprehensive prevention approach
The story of raltegravir in PEP demonstrates how scientific innovation, when translated into practical solutions, can transform fear into hope and vulnerability into protection. As research continues, each breakthrough brings us closer to a world where HIV is no longer a public health threat.