Current epidemiological studies show the number of new HIV infections in the US since the mid-1990s has remained approximately 50,000 per year¹. As part of the ongoing fight to prevent the spread of HIV, Truvada was approved in 2004 by the U.S. Food and Drug Administration (FDA). It is a combination drug consisting of emtricitabine (FTC) 200mg and tenofovir disoproxil fumarate (TDF) 300mg². As part of a comprehensive treatment approach known as Highly Active Anti-Retroviral Therapy (HAART), Truvada is commonly used in combination with other anti-retrovirals to treat HIV patients.

On July 16, 2012, the FDA approved the use of Truvada as pre-exposure prophylaxis (PrEP) in HIV-negative patients at high risk of becoming infected. High-risk includes: (1) partnerships where one partner is HIV positive (serodiscordant) and condom use is inconsistent, (2) intercourse with more than three partners in the previous six months, (3) exchanging money, gifts, shelter, or drugs for sex with a partner in the previous six months, (4) intercourse with a partner diagnosed with a sexually transmitted infection (STI) in then last six months, or (5) intercourse with a partner of unknown HIV status in the last six months¹. Two pivotal studies support Truvada’s use as PrEP.

iPrEx Study:

The iPrEx study was sponsored by the NIH. It was designed to evaluate the safety and efficacy of once-daily oral FTC/TDF for HIV prevention among men and transgender women who have sex with men³. The study was conducted in 2499 HIV-seronegative subjects. Patients received a combination of two oral antiretroviral drugs, FTC/TDF, or placebo once daily. Subjects were followed for a maximum of 2.8 years. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections including diagnosis and treatment when warranted.

The study showed a 44% risk reduction in the treatment group. However, in patients with an adherence rate of 90% or more, the risk reduction increased to 73% and 92% in patients with detectable blood levels of the study drug³. Detectable drug concentration was considered to be an indicator of drug efficacy. A limitation of the iPrEx study was a clear definition of a minimum protective drug concentration. In the FTC/TDF group, the study drug was detected in 51% of seronegative subjects and 9% of those patients who became infected with HIV.

Nausea (2%), headache (4%), depression (3%), and weight loss (2%) were the most common side effects. One of Truvada’s components, tenofovir disoproxil fumarate, has been known to decrease renal function and elevate serum creatinine, primarily in those with pre-existing renal impairment.

The Partners Study

The Partners Study was sponsored by the University of Washington and compared daily oral TDF to FTC/TDF. Both drugs were considered potential pre-exposure prophylaxis agents among East African heterosexual men and women in HIV-serodiscordant partnerships⁴. In this study, 4747 HIV-serodiscordant heterosexual couples were randomly assigned to one of three study groups: once-daily TDF, FTC/TDF, or matching placebo. They were followed for 36 months. The primary endpoint was seropositivity in partners previously seronegative for HIV (Partner PrEP).

Results showed a relative risk reduction of 67% in the tenofovir group and 75% in the Truvada group⁴. The study drugs were provided in conjunction with other HIV prevention initiatives such as HIV testing, risk reduction counseling, diagnosis and treatment for any STIs and education on proper condom use (as with the iPrEx Study). A side effect profile similar to that seen in the iPrEx study was noted.

Safety:

Truvada has been known to have an adverse effect on bone mineral density (BMD). The iPrEx study showed no difference in BMD between the FTC/TDF group (1%) and the placebo group (<1%) (p =0.41). Effects seen were reversible upon discontinuation of the drug⁵. Patients with a known history of bone pathologies should not start Truvada. Truvada carries a black box warning for lactic acidosis and severe hepatomegaly with steatosis (fatty liver). As a result, caution should be used in patients with a history of liver disease². Baseline creatinine clearance should be assessed in patients at risk for renal failure before starting the drug. Subsequently, serum phosphate levels should also be assessed in patients at risk for Fanconi syndrome due to the risk of hypophosphatemia⁶.

Risk Evaluation and Mitigation Strategies (REMS) are established to guide healthcare professionals to provide the necessary education to uninfected patients. The REMS emphasizes consistent daily dosing, HIV testing every 3 months if possible, and HIV prevention strategies such as proper condom use, counseling and testing. Prescribers will be required to provide a medication guide and safety brochure for prospective Truvada users. In conjunction, pharmacists will be required to provide a medication guide with every filled prescription. The cost of Truvada is currently $1149.01 for a 30-day supply⁷.

Truvada’s approval marks a major stepping stone in the fight to decrease the spread of HIV. The new indication for Truvada as pre-exposure prophylaxis in HIV negative patients gives high-risk patients a chance to avoid infection and is likely to help decrease the rate of new HIV infections.

References

1. Food and Drug Administration. Truvada® (Emtricitabine/Tenofovir disoproxil fumarate) for preexposure prophylaxis of HIV-1: Antiviral Drugs Advisory Committee Meeting Briefing Document. Retrieved from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM303216.pdf.

2. Gilead Sciences Inc. (2012) Truvada® (emtricitabine/tenofovir disoproxil fumarate): Prescribing Information. Retrieved from: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=54e82b13-a037-49ed-b4b3-030b37c0ecdd

3. Grant RM et al. Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sec with Men. N Engl J Med. 2010 Dec 30;363(27): 2587-2599.

4. Baeten JM et al. Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women. N Engl J Med. 2012 Jul 11:1-12

5. Food and Administration. FDA Approves First Medication to Reduce HIV Risk. Retrieved from: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm311821.htm.

6. PubMed Health website. Fanconi Syndrome. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001374/.

7. Lexicomp Online. Emtricitabine and tenofovir pricing. Retrieved from: http://online.lexi.com.lecomlrc.lecom.edu/lco/action/doc/retrieve/docid/patch_f/6814. Accessed: Jul 24 2012.