What is Truvada

• Truvada is an anti-HIV medication. It is in a category of HIV medicines called nucleoside reverse transcriptase inhibitors (NRTIs). Truvada prevents HIV from altering the genetic material of healthy T-cells. This prevents the cells from producing new virus and decreases the amount of virus in the body.

• Truvada is marketed by Gilead Sciences. It was approved by the U.S. Food and Drug Administration (FDA) for use by people living with HIV in August 2004.

• Truvada is a combination of two drugs: 300mg of Viread (tenofovir DF) and 200mg of Emtriva (FTC). Truvada should be prescribed by a healthcare provider for patients who need both of these drugs. Both of these drugs can still be purchased individually for use in combination with other anti-HIV drugs.

• Truvada must be combined with at least one other anti-HIV drug, usually a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI).

• Atripla, a combination tablet containing the NNRTI Sustiva (efavirenz) and the tenofovir and emtricitabine in Truvada, was approved for use in the United States in July 2006. Truvada can still be purchased for use in combination with anti-HIV drugs other than Sustiva.

• Both the Viread and the Emtriva in Truvada are active against the hepatitis B virus (HBV), the virus responsible for causing hepatitis B. Although it has not been approved by the FDA for the treatment of hepatitis B, some doctors may prescribe Truvada to treat both hepatitis B and HIV.

What is known about Truvada?

• Truvada is a tablet taken once a day. It can be taken with or without food.

• Truvada should not be any more or less effective than Viread and Emtriva taken as separate pills together. However, it is considered to be a much more convenient way of taking these two anti-HIV drugs.

• For HIV-positive adults beginning anti-HIV drug therapy for the first time, Truvada is listed as a "preferred" NRTI option—used in combination with the NNRTI Sustiva (efavirenz)—and as an "alternative" NRTI option when combined with Viramune (nevirapine) or a protease inhibitor.

Dosing

Dosage Form: Film-coated tablets containing 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil).

The recommended dose of Truvada for adults 18 years or older is one tablet once a day. Patients with lowered creatinine clearance (30 to 49 ml/min) should receive one tablet every 48 hours. Truvada should not be prescribed for patients requiring dosage adjustment, such as those with reduced renal function (creatinine clearance less than 30 ml/min or requiring hemodialysis).

Storage: Store tablets at 25 C (77 F); excursions permitted to 15 C to 30 C (59 F to 86 F). Keep container tightly closed.

Pharmacology

Administration of Truvada following a high fat meal or a light meal delayed the time of tenofovir peak plasma concentrations (Cmax) by approximately 0.75 hour. The mean increases in tenofovir area under the concentration-time curve (AUC) and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state.

In previous safety and efficacy studies, tenofovir disoproxil fumarate was taken under fed conditions. Emtricitabine AUC and Cmax were unaffected when Truvada was administered with either a high fat or a light meal.

Emtricitabine is rapidly and extensively absorbed following oral administration, reaching Cmax at 1 to 2 hours post-dose. In one clinical trial, the mean absolute bioavailability of emtricitabine was 93% following multiple doses of the drug. The mean steady state Cmax was 1.8 mcg/ml and the AUC over a 24-hour dosing interval was 10.0 hr-mcg/ml. The mean steady state plasma trough concentration 24 hours after an oral dose was 0.09 mcg/ml.

Emtricitabine is less than 4% bound to plasma proteins, and protein binding is independent of drug concentration over a range of 0.02 to 200 mcg/ml. In vitro studies indicate that emtricitabine does not inhibit CYP450 enzymes. Following administration of 14C-emtricitabine, the drug was 86% recovered in urine and 14% in feces. Thirteen percent of urine-recovered drug were metabolites.

The plasma half-life of emtricitabine is approximately 10 hours. Renal clearance of the drug exceeds estimated creatinine clearance, indicating elimination by glomerular filtration and tubular secretion. In patients with renal impairment, Cmax and AUC were increased.

Oral bioavailability of tenofovir in fasted patients is approximately 25%. Administration of tenofovir with a high fat meal increases the oral bioavailability, with an increase in tenofovir AUC of approximately 40% and an increase in Cmax of approximately 14%.

Food delays the time to tenofovir Cmax by approximately 1 hour. Following oral administration of a single 300 mg dose of tenofovir to HIV infected patients in the fasted state, Cmax is achieved in approximately 1.0 hour. Cmax and AUC values are approximately 0.296 mcg/ml and approximately 2.287 hr-mcg/ml, respectively.

The pharmacokinetics of tenofovir are dose proportional over a wide dose range and are not affected by repeated dosing.

Emtricitabine and tenofovir disoproxil fumarate each inhibit viral reverse transcriptase (RT), an enzyme HIV requires in order to replicate, by incorporating into viral DNA and terminating the viral DNA chain. (For more information, see the individual drug records for emtricitabine and tenofovir disoproxil fumarate.)

In vitro studies indicate that neither tenofovir disoproxil fumarate nor tenofovir are substrates of CYP450 enzymes.

Following IV administration of tenofovir, approximately 70% to 80% of the dose is recovered in the urine as unchanged drug within 72 hours of dosing. After multiple oral doses of tenofovir disoproxil fumarate under fed conditions, approximately 32% of the administered dose is recovered in urine over 24 hours.

Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated. Tenofovir is principally eliminated by the kidney.

Dosing adjustment is recommended in all patients with creatinine clearance less than 50 ml/min. Dosage adjustments for renal impairment are available in the prescribing information. However, no safety data are available in patients with renal dysfunction who received tenofovir using these guidelines.

One emtricitabine/tenofovir disoproxil fumarate tablet is bioequivalent to one emtricitabine tablet (200 mg) plus one tenofovir disoproxil fumarate tablet (300 mg) following single-dose administration to healthy adults.

Adverse Events / Toxicity

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued emtricitabine or tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue Truvada and are coinfected with hepatitis B virus (HBV) and HIV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Emtricitabine and tenofovir disoproxil fumarate are principally eliminated in the kidney; therefore, dosing interval adjustments of Truvada are recommended for patients with decreased creatinine clearance. Truvada should not be administered to patients with low creatinine clearance or those who require hemodialysis.

The manufacturer (Gilead Sciences of Foster City, CA) recommends that Truvada not be used as a component of a triple nucleoside regimen. Use of Truvada should be avoided in patients who are concurrently using or have recently used a nephrotoxic agent. Patients at risk for, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be monitored for changes in serum creatinine and phosphorus.

Truvada is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product, including emtricitabine and tenofovir disoproxil fumarate.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals. Truvada is not indicated for the treatment of chronic HBV infection, and the safety and efficacy of Truvada have not been established in patients coinfected with HBV and HIV.

The Viread in Truvada may cause bone problems. In one clinical trial conducted by the manufacturer involving HIV-positive patients who were new to anti-HIV therapy, Viread [combined with Sustiva® and Epivir®] was more likely to cause decreased bone mineral density (osteopenia) – which can lead to osteoporosis – than Zerit® (d4T) [combined with Sustiva and Epivir]. This can increase the risk of bone breakage, including the hip, spine, and wrist. Researchers are currently looking into the seriousness of this possible side effect.

If you have a history of bone fracture or are at risk for osteopenia, your doctor may want to consider ordering bone scans on a regular basis while you are taking Truvada. While it's not clear if calcium and vitamin D supplementation can help reverse this side effect, it might be a good idea if you have either osteopenia or osteoporosis and are taking Viread.

Anti-HIV drug regimens containing nucleoside reverse transcriptase inhibitors (NRTIs), including Truvada, can cause increased fat levels (cholesterol and triglycerides) in the blood, abnormal body-shape changes (lipodystrophy; including increased fat around the abdomen, breasts, and back of the neck, as well as decreased fat in the face, arms, and legs), and diabetes.

If you have hepatitis B and HIV and plan to stop taking Truvada, your doctor might want to frequently check your liver enzymes after stopping treatment. This is because the Viread and Emtriva in Truvada are also active against the hepatitis B virus (HBV). If Truvada is stopped abruptly, it can cause liver disease to "flare" and damage the liver.

What about drug interactions?

Truvada should not be taken at the same time as Epivir or other combination tablets that contain Epivir (for example, Epzicom, Combivir, or Trizivir). This is because Epivir is very similar to the Emtriva in Truvada, and it is not believed that combining these two anti-HIV drugs will make a regimen any more effective against the virus.

Truvada should not be used in combination with Videx/Videx EC (ddI).

HIV-positive people should also be careful if they use Truvada in combination with Reyataz (atazanavir), a protease inhibitor used to treat HIV. The Viread in Truvada can decrease Reyataz levels in the bloodstream and Reyataz can increase Viread levels in the bloodstream. Thus, if you are using Reyataz in combination with Truvada, your doctor should also prescribe low doses of Norvir (ritonavir), another protease inhibitor that can significantly boost the amount of Reyataz in the bloodstream. The correct dose is 300mg Reyataz plus 100mg Norvir, combined with the standard daily dose of Truvada. To make sure that the increased Viread levels do not cause kidney damage (a possible side effect of Viread), blood tests to monitor kidney function should be performed regularly.

Levels of lopinavir, one of the two protease inhibitors in Kaletra (lopinavir/ritonavir), can decrease when the drug is combined with Truvada. Kaletra can also increase Viread levels—one of the drugs in Truvada—in the bloodstream. If Kaletra and Truvada are used together, it is important to watch out for potential side effects of Viread (e.g., kidney problems).