The Importance of Pre-Exposure Prophylaxis for HIV

Approximately 37,000 people in the US are infected with HIV each year.¹ Despite the Ending the HIV Epidemic, A Plan for America, challenges still exist as it relates to the use of HIV pre-exposure prophylaxis (PrEP) to prevent new infections.

In particular, current data suggest that of the more than 1 million people who need PrEP, less than 25% are actually receiving it.² Therefore, additional strategies are needed if we are to meet the 2030 EHE Goals of reducing new infections to fewer than 3000 per year.³ 

PrEP is a medication taken in order to prevent acquiring HIV. Those who are high risk for HIV and who should consider PrEP therapy, in particular, are men who have sex with men (MSM) and transgender (TG) individuals. PrEP should also be considered for individuals with multiple sexual partners, those trading sex for money, goods, or services, and people who inject drugs.⁴

The FDA approved tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg (TDF/FTC) in 2012 based upon data from the IPrEX trial. TDF/FTC was compared to placebo for HIV prevention in high risk, adult males who were HIV-seronegative.

Daily dosed TDF/FTC demonstrated a 44% reduction in the incidence of HIV compared to placebo.⁵ In addition to data with daily dosing, TDF/FTC may also be used as event-driven or on demand. While not endorsed by current USPHS guidelines, it is recommended on the current IAS-USA Guidelines.⁴

Dosing on demand consists of taking 2 tablets 2 to 24 hours before sexual activity, followed by 1 tablet every 24 hours for 2 days. Data supporting this strategy comes from the IPERGAY trial, which compared TDF/FTC to placebo in MSM and TG women who have sex with men.

On demand dosing of TDF/FTC had a relative risk reduction of HIV acquisition of 86% when compared to placebo.⁶ Adverse events (AEs) in trials of daily TDF/FTC are similar to rates in the demand studies, though cross study comparisons should be viewed with caution.

The only notable differences were higher nausea (2% vs <1%) and unintentional weight loss (2% vs 1%) in the TDF/FTC group compared to the placebo group in the iPrEx trial and higher gastrointestinal AEs (14% vs 5%) and elevated plasma creatinine (18% vs 10%) in the FTC-TDF group compared to placebo in the IPERGAY trial.^5,6

The second medication used for PrEP is tenofovir alafenamide (TAF) 25 mg and emtricitabine 200 mg (TAF/FTC). TAF is a prodrug of TDF, which achieves higher intracellular concentration than TDF, resulting in lower serum concentration. This causes TAF to be less likely to affect renal function and bone metabolism in treatment studies.^7,8

TAF/FTC was compared with TDF/FTC for PrEP in the DISCOVER trial, a randomized, double-blind trial in cisgender MSM and TG women.⁹ Patients were randomized 1:1 to receive either TAF/FTC plus placebo (2670 patients) or TDF/FTC plus placebo (2665 patients).

At 96 weeks, TAF/FTC was shown to be noninferior to TDF/FTC for the prevention of HIV with an absolute difference of 0.18 per 100 person-years (IRR 0.47; 95% CI 0.19 to 1.15).

After the exclusion of 5 patients with suspected HIV at baseline, 6 patients in the TAF/FTC group and 11 patients in the TDF/FTC group had contracted HIV, with 88% having subtherapeutic or undetectable concentrations of TDF. TAF/FTC was shown to be superior to TDF/FTC in multiple prespecified safety endpoints.

A significant difference in hip bone mineral density, spine bone mineral density, change in baseline in serum creatinine, and a change in baseline in creatine clearance were all seen by week 48 (all had p<0.0001). All other AEs were similar between both study groups.⁹

Cabotegravir was also recently approved by the FDA for PrEP. Cabotegravir is a long-acting injectable regimen with an optional oral lead-in. The injection is 3 mL that needs to be injected into the deep ventrogluteal or dorsogluteal muscle.¹⁰

If opting for the oral lead in, the tablet is dosed 30 mg once daily for at least 28 days. On the last day of oral therapy, the first 600 mg intramuscular injection should be administered.

The second injection should be administered 1 month after the first with following injections every 2 months.¹⁰ Long-acting cabotegravir was shown to be superior to TDF/FTC for the prevention of HIV infection in the HPTN 083 trial, in which patients were randomized 1:1 to either cabotegravir or TDF/FTC.¹¹

The trial consisted of 5466 cisgender MSM and TG women with negative HIV serologic test, an undetectable HIV RNA viral load within 14 days of study entry, and with creatinine clearance of at least 60 mL/min. The primary endpoint was the incidence of HIV infection.

Over 3 years, 42 incident HIV infections occurred, with 3 patients (0.41 per 100 person-years) in the cabotegravir group and 39 patients (1.22 per 100 person-years) in the TDF-FTC group (HR 0.34; 95% CI 0.18 to 0.62; P<0.001). Using a stratified log-rank test, a significant difference was shown, and the trail was ended early by the DSMB data safety monitoring board.

Moderate AEs or higher occurred in 92.5% of patients and severe but non life-threatening AEs occurred in 32.7% of patients. Both groups reported similar rates of AEs, which included a decrease in creatinine clearance, increased creatinine kinase, nasopharyngitis, and increased serum creatinine.¹¹

Although the HIV epidemic started more than 40 years ago, it is still an ongoing problem worldwide. PrEP therapy has revolutionized HIV treatment by protecting patients who are high risk for acquiring the virus.

With new medications, formulations, and novel dosing strategies, PrEP can significantly reduce the number of new infections each year and get us closer to attaining the 2030 goals in the EHE Plan.

References

1. HIV. Centers for Disease Control and Prevention. Updated February 28, 2022. Accessed June 7, 2022. https://www.cdc.gov/hiv/statistics/overview/index.html.
2. Ending the HIV Epidemic in the US. Center for Disease Control and Prevention. Updated July 27, 2021. Accessed June 7, 2022. https://www.cdc.gov/endhiv/prevent.html.
3. Ending the HIV Epidemic in the US. Health Resources & Services Administration. Updated March 2022. Accessed June 7, 2022. https://www.hrsa.gov/ending-hiv-epidemic.
4. Saag MS, Gandhi RT, Hoy JF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults 2020 recommendations of the International Antiviral Society-USA panel. JAMA. 2020;324(16):1652-1669.
5. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2020;363:2787-2599.
6. Molina JM, Capitant C, Spire B, et al. On-demand preexposure prophylaxis in men a thigh risk for HIV-1 infection. N Engl J Med. 2015;373:2237-2246.
7. Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection. Lancet. 2017;390(10107):2063-2072.
8. Sax PE, Pozniak A, Montes ML, et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection. Lancet. 2017;390(10107):2073-2082.
9. Mayer KH, Molina JM, Thompson MA, et al. Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis; primary results from a randomized, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet. 2020;396:239-254.
10. Cabenuva [package insert]. Research Triangle, NC: ViiV Healthcare Limited; 2021.
11. Landovitz LJ, Donnell D, Clement ME, et al. Cabotegravir for HIV prevention in cisgender men and transgender women. N Engl J Med. 2021;385:595-608.