Lesson 3. HIV PrEP Medications and Dosing Options

There are three medications approved by the United States Food and Drug Administration (FDA) for HIV preexposure prophylaxis (PrEP): oral tenofovir DF-emtricitabine (TDF-FTC), oral tenofovir alafenamide-emtricitabine (TAF-FTC), and long-acting injectable cabotegravir (CAB-LA). These medications have unique characteristics, and clinicians should be familiar with appropriate indications and populations for use of these medications for HIV PrEP. The medications tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and emtricitabine (FTC) are nucleoside reverse transcriptase inhibitors (NRTIs). The NRTIs work by blocking the HIV enzyme reverse transcriptase, which plays a critical role in converting HIV RNA into HIV DNA. Cabotegravir is an integrase strand transfer inhibitor (INSTI); this medication inhibits the function of the HIV integrase enzyme, which normally functions to integrate newly formed HIV DNA into human DNA.

Tenofovir DF-emtricitabine (TDF-FTC)

• Indication: Tenofovir DF-emtricitabine (TDF-FTC) is indicated by the FDA for HIV PrEP to reduce the risk of sexually acquired HIV in adults and adolescents (weighing at least 35 kg) who are at risk of acquiring HIV. Individuals must have a negative HIV test prior to starting TDF-FTC for HIV PrEP. Although TDF-FTC does not have an FDA indication to prevent HIV through injection drug use, it is recommended by the Centers for Disease Control and Prevention (CDC) as HIV PrEP for people who inject drugs (PWID).
• Dosing: When used for HIV PrEP, the indicated dosing for TDF-FTC is one tablet once daily. Alternative dosing, such as on-demand (2-1-1) dosing, is not FDA-approved, but it can be considered among men who have sex with men (MSM) who request on-demand HIV PrEP.
• Formulation: A single oral tablet of TDF-FTC is a two-drug fixed-dose combination that consists of tenofovir DF (TDF) 300 mg and emtricitabine (FTC) 200 mg. In the United States, there are now multiple generic versions of TDF-FTC, and these generic versions are at a dramatically reduced price compared with the brand-name medication.[1,2]
• Food Requirements: Take with or without food.
• Use in Persons with Renal Impairment: For use as HIV PrEP, TDF-FTC is not recommended in persons who have an estimated creatinine clearance less than 60 mL/min.
• Side Effects: Tenofovir DF (TDF) has been associated with nephrotoxicity and decreased bone mineral density when used for HIV treatment, but renal adverse events in large HIV PrEP trials were similar to or only slightly more common with TDF-FTC versus placebo.[3,4,5] In addition, small decreases in bone mineral density among persons taking TDF-based HIV PrEP have been shown to reverse after HIV PrEP discontinuation.[6,7,8] Serum lipid profiles are not adversely impacted by TDF-FTC.

Tenofovir alafenamide-emtricitabine (TAF-FTC)

• Indication: Tenofovir alafenamide-emtricitabine (TAF-FTC) is indicated for HIV PrEP in adults and adolescents (weighing at least 35 kg) who are at risk of sexually acquiring HIV, excluding individuals at risk of acquiring HIV from receptive vaginal sex. Individuals must have a negative HIV test prior to starting TAF-FTC for HIV PrEP. It is important to note that TAF-FTC is not indicated for receptive vaginal sex because effectiveness in this population has not been evaluated. Although the HIV PrEP indication for TAF-FTC does not exclude use for men at risk of sexual acquisition of HIV via insertive vaginal sex, it is important to note that TAF-FTC has not been studied as a prevention measure for insertive vaginal sex.
• Dosing: For HIV PrEP dosing, TAF-FTC should be taken as one tablet once daily. Alternative dosing, such as on-demand use, has not been adequately studied and is not recommended.
• Formulation: A single oral tablet of TAF-FTC is a two-drug fixed-dose combination that contains 25 mg of tenofovir alafenamide (TAF) and 200 mg of emtricitabine (FTC).
• Food Requirements: Take with or without food.
• Use in Persons with Renal Impairment: For HIV PrEP, use of TAF-FTC is not recommended for persons who have an estimated creatinine clearance of less than 30 mL/min, unless they are receiving chronic hemodialysis. For those on hemodialysis, TAF-FTC should be taken as a once daily dose, but should be given after hemodialysis on the days of hemodialysis.
• Side Effects: Daily TAF-FTC has been shown to have more favorable effects on bone mineral density and renal biomarkers when compared to daily TDF-FTC, but TAF-FTC has been associated with greater weight gain and less favorable lipid profiles.[9,10] When used as daily HIV PrEP, TAF-FTC caused a slight decrease in high-density lipoprotein (HDL) levels, a slight increase in triglyceride levels, but no change in total cholesterol or low-density lipoprotein (LDL) levels.[9] 

Long-Acting Injectable Cabotegravir (CAB-LA)

• Indication: Long-acting injectable cabotegravir (CAB-LA) is indicated for HIV PrEP in adults and adolescents (weighing at least 35 kg) to prevent sexual acquisition of HIV.
• Dosing: CAB-LA is given as a single 600 mg (3 mL) injection 1 month apart for 2 consecutive months and then every 2 months thereafter. An optional lead-in with oral cabotegravir 30 mg once daily may be used for approximately 1 month to assess the tolerability of cabotegravir. If the oral cabotegravir lead-in is used, the first injection of cabotegravir should be given on the last day of the oral lead-in (or within 3 days of completing the oral lead-in).
• Formulation: Injectable cabotegravir is available in a 200 mg/mL solution and is administered as a 3 mL intramuscular injection in the gluteal region. Oral cabotegravir is a 30 mg tablet that is taken once daily.
• Food Requirements: There are no food restrictions with CAB-LA. Oral cabotegravir can be taken with or without food.
• Use in Persons with Renal Impairment: For HIV PrEP, cabotegravir has no renal restrictions. For persons who have a creatinine clearance less than 30 mL/min, increased monitoring for cabotegravir toxicity is recommended. Hemodialysis is not expected to impact cabotegravir levels.
• Side Effects: Injection site reactions are the most common adverse events with CAB-LA, with pain and tenderness being the most common symptoms.[11,12]

Cabotegravir Guide

Review the Information Guide on Long-Acting Injectable Cabotegravir for HIV PrEP below (Figure 2) and answer the Check on Learning questions below.

Among the three medications recommended for HIV PrEP, only TDF-FTC is associated with a significant risk of nephrotoxicity. The following table summarizes recommendations for the use of HIV PrEP medications in persons with renal insufficiency (Figure 1). These recommendations are based on the prescribing information for TDF-FTC, TAF-FTC, and CAB-LA.

On-demand HIV PrEP is the concept of taking oral HIV PrEP centered around specific sexual events.[10,13] The term on-demand HIV PrEP is also commonly referred to as 2-1-1 or non-daily PrEP. Since CAB-LA is not administered on a daily basis and is not taken on an on-demand basis, we recommend not using the older term “non-daily” HIV PrEP when describing on-demand or 2-1-1 HIV PrEP. On-demand HIV PrEP with TDF-FTC was shown to be highly effective for MSM in the French IPERGAY study.[13] Oral TDF-FTC is the only medication that has been studied for use as on-demand HIV PrEP. 

• Recommendations for On-Demand HIV PrEP: On-demand HIV PrEP is only recommended with oral TDF-FTC and only when used in MSM. Although TDF-FTC is not FDA-approved specifically for use as on-demand HIV PrEP, several major guidelines recommend on-demand TDF-FTC as an HIV PrEP option for MSM.[10,14] There are no other medications that are FDA-approved or recommended for use as on-demand HIV PrEP.
• Dosing Schedule with On-Demand HIV PrEP: The recommended TDF-FTC dosing schedule for on-demand HIV PrEP (for a single episode of sex) consists of taking two tablets 2-24 hours before sex, one tablet 24 hours after the initial 2-pill dosing, and one tablet 48 hours after the initial 2-pill dosing. If sexual activity continues, one tablet daily of TDF-FTC should continue, ensuring that two doses (taken 24 hours apart) have been taken after the last sexual encounter. 

Exercise

• Review the On-Demand HIV PrEP Guide below (Figure 3) and use this guide to answer the Check on Learning questions below.
   

Choosing an appropriate HIV PrEP medication should take into account multiple factors, including type of sexual activity the patient engages in, FDA approval for the indication you are considering prescribing, patient preference for oral versus injectable, renal function, hepatitis B status, medication cost, financial and insurance considerations, and clinic infrastructure for providing the HIV PrEP medications. The table below (Figure 5) summarizes major indications for each of the three FDA-approved HIV PrEP medications and how the CDC recommends using these medications for HIV PrEP.
 

Exercise for Choosing HIV PrEP Medications

Review the section and table above related to Choice of HIV PrEP Medications for Selected Groups and then answer each of the 8 case scenarios in this interactive exercise. (Figure 6)
 

The National HIV PrEP Curriculum team has created HIV PrEP Tools for Clinicians based on the 2021 CDC HIV PrEP Guidelines.[10] These tools includes a component on Medications for HIV PrEP that provides a step-by-step determination to guide the appropriate choice of HIV PrEP medications. These tools also provides a guide for the assessment for HIV PrEP indications and a guide to baseline and monitoring laboratory evaluation. It is important to note that these tools are intended to help guide and educate clinicians, but all final decisions regarding indications for HIV PrEP, medication choices, and laboratory monitoring should be based on the clinician’s judgment (Figure 7). Access these tools by clicking TOOLS on the top navigation bar; once on the Tools page you can use any of the tools directly on the website and by installing it on your mobile device.

• The FDA has approved three drugs for HIV PrEP usage: oral TDF-FTC, oral TAF-FTC, and CAB-LA. A negative HIV test is recommended prior to initiation of HIV PrEP.
• Oral TDF-FTC is indicated for HIV PrEP in adults and adolescents who weigh at least 35 kg (77 lb) to prevent sexual acquisition of HIV infection. For persons with an estimated creatinine clearance less than 60 mL/min, TDF-FTC is not recommended.
• Oral TAF-FTC is indicated for HIV PrEP in adults and adolescents who weigh at least 35 kg (77 lb) to prevent sexual acquisition of HIV, excluding individuals at risk of acquiring HIV from receptive vaginal sex. For persons with an estimated creatinine clearance less than 30 mL/min, TAF-FTC is not recommended, unless the person is receiving chronic hemodialysis.
• CAB-LA is indicated for HIV PrEP in adults and adolescents who weigh at least 35 kg (77 lb) to prevent sexual acquisition of HIV. CAB-LA is given as a single 600 mg (3 mL) injection 1 month apart for 2 consecutive months and then every 2 months thereafter. An optional lead-in with oral cabotegravir 30 mg once daily may be used for approximately 1 month to assess the tolerability of cabotegravir. There are no renal restrictions.
• On-demand (2-1-1) HIV PrEP is only recommended with oral TDF-FTC and only when used for MSM. Dosing for a single episode of sex is two tablets 2 to 24 hours before sex, one tablet 24 hours after the first two tablets, and one tablet 48 hours after the initial two tablets. With ongoing sexual activity, TDF-FTC one tablet daily (at 24-hour intervals) should continue until two doses have been given (24 hours apart) after the last sexual encounter.
• Factors to consider when choosing an appropriate HIV PrEP medication include the individual’s type of sexual activity, medication preferences, renal function, hepatitis B status, medication cost, financial and insurance considerations, and clinic infrastructure for providing injectable medications.
• For MSM there are three recommended options for HIV PrEP: TDF-FTC, TAF-FTC, and CAB-LA.
• For women there are two recommended HIV PrEP options for preventing HIV acquisition via vaginal sex: TDF-FTC and CAB-LA. For women who are pregnant, CAB-LA is not recommended.
• For people who inject drugs, TDF-FTC is the only recommended medication to use for HIV PrEP.
• The use of HIV PrEP medications in adolescents requires the adolescent to weigh at least 35 kg (77 lb).