Truvada at a glance
- FDA approval for preexposure prophylaxis (PrEP), i.e., reducing risk of sexually-acquired HIV infection in uninfected individuals
- Previously approved to be used in combination with other antiretroviral agents for the treatment of HIV-infected adults and children age 12 and older
- Must only be used by individuals confirmed HIV-negative prior to prescribing the drug and at least every 3 months during use
- FDA strengthened boxed warning for lactic acidosis, hepatomegaly with steatosis, acute hepatitis B following withdrawal in undocumented viral hepatitis infections
A newly FDA-approved approach to preventing HIV transmission is pre-exposure prophylaxis (PrEP) by prescribing antiretroviral medications in individuals who are not infected with HIV. Two clinical trials were conducted in 2 distinct groups and evaluated the combination drug containing Tenofovir disoproxil fumarate and emtricitabine (Truvada) for prevention of transmission of HIV.
Highest Risk Group
Recently, a novel study focused on preventing the transmission of HIV among men who have sex with men. This group engages in high-risk behavior and is likely to have co-infections with hepatitis C and other STDs. Some participate in transactional sex, i.e., in exchange for gifts, money, necessities for the household and other reasons. PrEP by prescribing antiretroviral medications in individuals not infected with HIV is expected to be beneficial to this high risk population.
The Preexposure Prophylaxis Initiative (iPrEx study) enrolled 2,499 individuals worldwide who were HIV-negative and men or transgendered women who have sex with men. Individuals had a mean of 18 partners in 12 weeks prior to the study, and 41 percent had transactional sex in the past 6 months. Subjects were followed closely every 4 weeks, and 75-94 percent of visits were completed. A modified intention-to-treat analysis was performed excluding any patients with HIV positivity diagnosed during the enrollment period.
A new HIV infection occurred in 36 subjects in the Truvada group (n = 1251) and 64 in the placebo group (n = 1248) in the modified intention-to-treat population representing a 44 percent relative risk reduction (95 percent CI 15-63; p = 0.005). The intention-to-treat analysis also significantly favored Truvada (p = 0.001). Self-reported medication adherence was lower in the Truvada group than in the placebo group at week 8 (89 percent versus 92 percent, p<0.001), and condom use increased.
The investigators performed a robust analysis to determine factors affecting response to the drug with particular attention to the impact of medication non-adherence on treatment effect. The subgroup analysis depicted a significant reduction in HIV acquisition with > 50 percent "Pill use" with the active drug combination versus placebo [Hazard ratio 0.50 (0.30-0.82), p = 0.02] versus those using < 50 percent of Pill use. Drug resistance was not detected, which the authors called promising for prevention.
Partners PrEP trial
The "Antiretroviral pre-exposure prophylaxis for HIV-1 prevention among heterosexual African men and women: The Partners PrEP study" (PrEP study) enrolled heterosexual couples in Africa where only one partner had HIV. The serodiscordant couples (n = 4,758) were enrolled and HIV-1 susceptible partner was randomized to receive either tenofovir, emtricitabine-tenofovir or matching placebo. The route of HIV transmission was vaginal penetration. Protection against HIV transmission was 62 percent with tenofovir and 73 percent with Truvada.
Additional prevention studies used topical antiretroviral gel for prevention. These trials were performed in women using tenofovir 1 percent vaginal gel for heterosexual couples where vaginal penetration is the method of transmission. The results have been favorable and outcomes are dependent on achieving high drug concentrations in vaginal tissue.
On July 16, FDA approved the combination for prevention of uninfected individuals at high risk for contracting the disease. A boxed warning alerts prescribers to confirm HIV-negative status before initiating the drug, and again every 3 months.
Mechanism of Action
In addition to being approved for PrEP, Truvada (emtricitabine and tenofovir disoproxil fumarate) is approved for treatment of HIV-1 infection. It is a combination of tenofovir, a nucleotide reverse transcriptase inhibitor (NRTI) and emtricitabine, a nucleoside reverse transcriptase inhibitor. It is recommended for use with other antiretroviral drugs in adults and children age 12 and older. The combination was approved for use in 2004. Tenofovir is a competitive inhibitor of viral reverse transcriptase enzymes involved in producing viral DNA; tenofovir is phosphorylated to an active form, tenofovir diphosphate, which is incorporated into viral DNA causing chain termination. Emtricitabine, a chemical analog related to lamivudine, undergoes phosphorylation and has a similar mechanism in terminating DNA viral synthesis.
Dosage, Costs, Pharmacokinetics
CDC provided interim guidance on prescribing for PrEP which emphasizes risk-reduction, medication adherence, and use of condoms. It recommends prescribing a 90-day supply to encourage follow-us to confirm negative HIV status. The drug dose should be Truvada one tablet daily taken with or without food. Each tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate. The drug dose is also based on weight and kidney function for treatment. Consideration should be given to adjusting doses in individuals weighing less than 35 kg or with reduced creatinine clearance. The cost for the drug is approximately $1,200 for a 30-day supply, or $14,000 annually.
Tenofovir disoproxil is a prodrug rapidly hydrolyzed producing improved bioavailability of tenofovir. Taken orally, the bioavailability is 25 percent. The drug is not extensively bound to plasma proteins. The half-life is 14-17 hours, but the intracellular half-life in white blood cells concentrations is much longer in resting cells. The drug is eliminated by the kidneys and 70-80 percent as unchanged drug. Emtricitabine has a 93 percent oral bioavailabiity, and has little protein binding. The half-life is 8-10 hours and the intracellular half-life is considerably longer allowing for once-daily dosing. It also undergoes renal elimination and the dose is adjusted for Clcr < 50 ml/min.
Drug Interactions & Side Effects
There are many significant interactions with the potential for serious adverse effects. Tenofovir increases the concentration of other antiretroviral agents such as didanosine by 44-60 percent, plus other antiretrovirals can increase drug concentrations of tenofovir resulting in added toxicity. Closely monitor therapy when used concurrently with other nephrotoxic drugs such as antibiotics, antivirals and other drugs. Emtricitabine should not be used with lamivudine, another NRTI, due to additive toxicity.
Troublesome side effects are due to gastrointestinal discomfort, which appears to cause medication non-adherence. Moderate nausea (grade 2) was reported in the iPrEx study and unintentional weight loss of 5 percent or more. Common side effects are nausea and diarrhea, dizziness, headache and fatigue. Patients reported insomnia and abnormal dreams, and should be screened for depression. Check for development of a skin rash, allergic reactions, or angioedema. Unwanted cosmetic effects develop including redistribution or body fat such as facial wasting causing a gaunt appearance.
The label contains a Boxed Warning regarding lactic acidosis and severe liver injury, which FDA strengthened with approval. Specifically, cases of severe hepatomegaly with steatosis have been reported with use, and have been fatal. Accumulation of fat in the liver predisposes the patients to additional hepatocellular injury. Liver function tests should be monitored routinely. In situations where patients were co-infected with HIV and hepatitis B, acute worsening of hepatitis B occurred when Truvada was stopped. Closely follow patients and screen for hepatitis B; consider initiating targeted therapy when appropriate. In the iPrEx study, serum creatinine levels increased during the study significantly more often in the treatment group, but resolved once the drug was discontinued.
As per the CDC guidelines, patients taking the drug should have an estimated Clcr > 60 ml/min. Elevated carbon dioxide (CO2) content can indicate the presence of lactic acidosis and additional testing should include arterial blood gas monitoring to determine acid/base status. Liver function tests such as ALT, AST, and alkaline phosphatase should be monitored. Fasting lipid panel should be evaluated for elevated cholesterol and triglycerides.
Resources for this article can be accessed here.
Grace Earl is an Ambulatory Care Pharmacist at the University of the Sciences and her practice site is at Hahnemann University Hospital, Philadelphia.