Viread

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep the bottle tightly closed. Use the medicine dispensed only in its original container.

Viread is part of the drug class:

• Nucleoside and nucleotide reverse transcriptase inhibitors

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Viread, there are no specific foods that you must exclude from your diet when receiving Viread.

• Store Viread tablets or oral powder at 59 °F to 86 °F (15 °C to 30 °C).
• Keep Viread in the original container.
• Do not use Viread if the seal over the bottle opening is broken or missing.
• Keep the bottle tightly closed.
• Keep Viread and all medicines out of the reach of children.

Avoid drinking alcohol. It may increase your risk of liver damage.

Taking this medicine will not prevent you from passing HIV to other people. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients;1 200 201 202 used in conjunction with other antiretrovirals.1 200 201 202

Single-entity tenofovir DF used with another NRTI (dual NRTIs) in conjunction with an HIV integrase strand transferase inhibitor (INSTI), HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), or HIV protease inhibitor (PI) in INSTI-, NNRTI-, or PI-based regimens.200 201 Also commercially available in various fixed combinations containing tenofovir DF and emtricitabine with or without a third antiretroviral;230 232 233 235 these fixed combinations used in certain patient groups to decrease pill burden and improve compliance.200 201

For initial treatment in HIV-infected adults and adolescents, experts state that tenofovir DF and emtricitabine or tenofovir DF and lamivudine are recommended dual NRTI options for use in most INSTI-, NNRTI-, and PI-based regimens.200

For initial treatment in antiretroviral-naive pediatric patients, experts state that tenofovir DF and emtricitabine or tenofovir DF and lamivudine are alternative dual NRTI options in adolescents ≥12 years of age at sexual maturity rating (SMR) 3, but should be used in children ≥2 years of age or adolescents at SMR 1 or 2 only in special circumstances after weighing potential risks versus benefits.201

Because all 3 drugs have activity against both HIV and HBV, tenofovir DF and emtricitabine or tenofovir DF and lamivudine are preferred dual NRTI options for antiretroviral regimens in HIV-infected patients coinfected with HBV.200

Emtricitabine/tenofovir DF fixed combination (Truvada) can be used in adults, adolescents, and children weighing ≥17 kg;200 230 used in conjunction with other antiretrovirals for treatment of HIV-1.230

Efavirenz/emtricitabine/tenofovir DF fixed combination (Atripla) can be used in adults and adolescents ≥12 years of age weighing ≥40 kg;200 232 used alone as a complete treatment regimen or used in conjunction with other antiretrovirals.232

Emtricitabine/rilpivirine/tenofovir DF fixed combination (Complera) can be used alone as a complete treatment regimen in antiretroviral-naive adults and adolescents ≥12 years of age weighing ≥35 kg with baseline plasma HIV-1 RNA levels ≤100,000 copies/mL;200 233 also can be used to replace a stable antiretroviral regimen in antiretroviral-experience patients who are virologically suppressed (i.e., plasma HIV-1 RNA levels <50 copies/mL) on their current regimen for ≥6 months, are currently receiving only their first or second antiretroviral regimen, have no history of treatment failure, and have no current evidence or history of resistance to the components of the fixed combination.233

Preexposure Prophylaxis for Prevention of HIV-1 Infection (PrEP)

Emtricitabine/tenofovir DF (Truvada) used for preexposure prophylaxis (PrEP) in conjunction with safer sex practices to reduce the risk of sexually acquired HIV-1 in HIV-1-negative adults at high risk.197 230 450 457 463

Adults at high risk include those with partner(s) known to be infected with HIV-1 or those engaging in sexual activity within a high prevalence area or social network and with ≥1 of the following factors: inconsistent or no condom use, diagnosis of sexually transmitted infections, exchange of sex for commodities (e.g., money, food, shelter, drugs), use of illicit drugs, alcohol dependence, incarceration, or partner(s) of unknown HIV-1 status with any of these risk factors.230

PrEP with emtricitabine/tenofovir DF not always effective in preventing acquisition of HIV-1 infection; must be used as part of a comprehensive prevention strategy that includes safer sex practices.230 (See Precautions Related to HIV-1 Preexposure Prophylaxis under Cautions.)

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)

Postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and others exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.199 Used in conjunction with other antiretrovirals.199

USPHS recommends 3-drug regimen of raltegravir in conjunction with emtricitabine and tenofovir DF as the preferred regimen for PEP following occupational exposures to HIV.199 Several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs) also recommended.199 Preferred dual NRTI option for PEP regimens is emtricitabine and tenofovir DF (may be given as emtricitabine/tenofovir DF; Truvada); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be given as lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.199

Management of occupational exposures to HIV is complex and evolving;199 consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible.199 Do not delay initiation of PEP while waiting for expert consultation.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)

Postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission.198 Used in conjunction with other antiretrovirals.198

When nPEP indicated in adults and adolescents ≥13 years of age with normal renal function, CDC states preferred regimen is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (given as emtricitabine/tenofovir DF; Truvada);198 alternative recommended in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada).198

Consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) if nPEP indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if considering a regimen not included in CDC guidelines, source virus is known or likely to be resistant to antiretrovirals, or healthcare provider is inexperienced in prescribing antiretrovirals.198 Do not delay initiation of nPEP while waiting for expert consultation.198

Chronic HBV Infection

Treatment of chronic HBV infection in adults and adolescents ≥12 years of age.1

Used in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative adults with compensated liver disease who had not previously received a nucleoside antiviral (nucleoside-naive) and in treatment-experienced adults with documented resistance to lamivudine.1 26

Only limited data in patients with decompensated liver disease.1

Insufficient data in patients with adefovir-associated substitutions at baseline.1

Do not use for treatment of chronic HBV infection in HIV-infected individuals who are not currently receiving antiretroviral therapy.1 97 155 156 200

Treatment of chronic HBV infection is complex and evolving;97 consult specialized references.97 155 156 Information from the American Association for the Study of Liver Diseases (AASLD) regarding management of chronic HBV infection is available at .97

Administration

Oral Administration

Tenofovir DF (Viread): Administer orally once daily without regard to meals.1 Use in conjunction with other antiretrovirals for treatment of HIV-1 infection;1 can be used alone for treatment of chronic HBV infection.1

Emtricitabine/tenofovir DF (Truvada): Administer orally once daily without regard to meals.230 Use in conjunction with other antiretrovirals for treatment of HIV-1;230 use alone as a complete regimen for PrEP for prevention of sexually transmitted HIV-1.197 230

Efavirenz/emtricitabine/tenofovir DF (Atripla): Administer orally once daily on an empty stomach, preferably at bedtime.232 Use alone as a complete regimen or in conjunction with other antiretrovirals for treatment of HIV-1.232

Emtricitabine/rilpivirine/tenofovir DF (Complera): Administer orally once daily with a meal.233 Use alone as a complete treatment regimen.233

Because antiretrovirals contained in the fixed combinations also may be available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals.230 232 233 (See Precautions Related to Use of Fixed Combinations under Cautions.)

Oral Powder (Viread)

Measure dosage using only the scoop provided by the manufacturer.1

Mix required number of scoops of oral powder with 2–4 ounces of soft food that can be swallowed without chewing (e.g., applesauce, baby food, yogurt);1 immediately ingest entire mixture to avoid a bitter taste.1

Do not administer the powder in liquid since powder may float to the top, even after stirring.1

Dosage

Available as tenofovir DF;1 dosage expressed in terms of tenofovir DF.1

Dosage of tenofovir DF (Viread) oral powder is expressed as number of scoops of powder.1 The oral powder contains 40 mg of tenofovir DF per g;1 scoop provided by the manufacturer delivers 1 g of powder for each level scoop.1

Pediatric Patients

Treatment of HIV Infection Oral

Tenofovir DF (Viread) in children ≥2 to <12 years of age: 8 mg/kg (up to 300 mg) once daily as a tablet or oral powder.1 In those weighing ≥17 kg who can reliably swallow tablets, use a single tablet containing appropriate dosage (see Table 1).1 When oral powder is used, use required number of scoops of powder (see Table 2).1

Table 1. Tenofovir DF Dosage (Viread Tablets) for Treatment of HIV-1 Infection in Pediatric Patients ≥2 Years of Age Weighing ≥17 kg1

Weight (kg)	Dosage (as Tablets) Once Daily
17 to <22	150 mg
22 to <28	200 mg
28 to <35	250 mg
≥35	300 mg

Table 2. Tenofovir DF Dosage (Viread Oral Powder) for Treatment of HIV-1 Infection in Pediatric Patients ≥2 Years of Age

Weight (kg)	Dosage (as Oral Powder) Once Daily (40 mg of Tenofovir DF per Scoop)
10 to <12	80 mg (2 scoops)
12 to <14	100 mg (2.5 scoops)
14 to <17	120 mg (3 scoops)
17 to <19	140 mg (3.5 scoops)
19 to <22	160 mg (4 scoops)
22 to <24	180 mg (4.5 scoops)
24 to <27	200 mg (5 scoops)
27 to <29	220 mg (5.5 scoops)
29 to <32	240 mg (6 scoops)
32 to <34	260 mg (6.5 scoops)
34 to <35	280 mg (7 scoops)
≥35	300 mg (7.5 scoops)

Tenofovir DF (Viread) in adolescents ≥12 years of age weighing ≥35 kg: 300 mg (one 300-mg tablet) once daily.1 In those unable to swallow the tablet, use 300 mg once daily as the oral powder (7.5 scoops of powder).1

Emtricitabine/tenofovir DF (Truvada) in children weighing ≥35 kg: 1 tablet (emtricitabine 200 mg and tenofovir DF 300 mg) once daily.230

Emtricitabine/tenofovir DF in children weighing 17 to <35 kg: Base dosage on weight and use a low-strength fixed-combination tablet.230 (See Table 3.)

Table 3. Emtricitabine/Tenofovir DF (Truvada) Dosage for Treatment of HIV-1 Infection in Children Weighing ≥17 kg230

Weight (kg)	Dosage of Emtricitabine/Tenofovir DF Given Once Daily
17 to <22 kg	1 tablet (emtricitabine 100 mg and tenofovir DF 150 mg)
22 to <28 kg	1 tablet (emtricitabine 133 mg and tenofovir DF 200 mg)
28 to <35 kg	1 tablet (emtricitabine 167 mg and tenofovir DF 250 mg)
≥35 kg	1 tablet (emtricitabine 200 mg and tenofovir DF 300 mg)

Efavirenz/emtricitabine/tenofovir DF (Atripla) in adolescents ≥12 years of age weighing ≥40 kg: 1 tablet (efavirenz 600 mg, emtricitabine 200 mg, and tenofovir DF 300 mg) once daily.232

Emtricitabine/rilpivirine/tenofovir DF (Complera) in adolescents ≥12 years of age weighing ≥35 kg: 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily.233

Chronic HBV Infection Oral

Tenofovir DF (Viread) in adolescents ≥12 years of age weighing ≥35 kg: 300 mg once daily.1 Optimal duration of treatment unknown.1

Adults

Treatment of HIV Infection Oral

Tenofovir DF (Viread): 300-mg tablet once daily.1 Alternatively, in those unable to swallow tablets, 7.5 scoops of oral powder (300 mg) once daily.1

Emtricitabine/tenofovir DF (Truvada): 1 tablet (emtricitabine 200 mg and tenofovir DF 300 mg) once daily.230

Efavirenz/emtricitabine/tenofovir DF (Atripla): 1 tablet (efavirenz 600 mg, emtricitabine 200 mg, and tenofovir DF 300 mg) once daily.232

Emtricitabine/rilpivirine/tenofovir DF (Complera): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily.233

Preexposure Prophylaxis for Prevention of HIV-1 Infection (PrEP) HIV-1-negative Adults at High Risk Oral

Emtricitabine/tenofovir DF (Truvada): 1 tablet (emtricitabine 200 mg and tenofovir DF 300 mg) once daily.230

Use PrEP only in high-risk adults confirmed to be HIV-1-negative;230 do not initiate if signs or symptoms of acute HIV-1 infection are present and recent (<1 month) exposure to HIV-1 is suspected.230 (See Precautions Related to HIV-1 Preexposure Prophylaxis [PrEP] under Cautions.)

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)† Oral

Tenofovir DF (Viread): 300 mg once daily.199 Use in conjunction with other antiretrovirals (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Emtricitabine/tenofovir DF (Truvada): 1 tablet (emtricitabine 200 mg and tenofovir DF 300 mg) once daily.199 Use in conjunction with a recommended INSTI, NNRTI, or PI (see Postexposure Prophylaxis following Occupational Exposure to HIV [PEP] under Uses).199

Emtricitabine/rilpivirine/tenofovir DF (Complera): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily.233 Use as a complete regimen for PEP.233

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)† Oral

Tenofovir DF (Viread): 300 mg once daily.198 Usually used in conjunction with emtricitabine and a preferred or alternative INSTI, NNRTI, or PI (see Postexposure Prophylaxis following Nonoccupational Exposure to HIV [nPEP] under Uses).198

Emtricitabine/tenofovir DF (Truvada): 1 tablet (emtricitabine 200 mg and tenofovir DF 300 mg) once daily.198 Use in conjunction with a preferred or alternative INSTI, NNRTI, or PI.198

Emtricitabine/rilpivirine/tenofovir DF (Complera): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily.198 Use as a complete regimen for nPEP.198

Initiate nPEP as soon as possible (within 72 hours) following nonoccupational exposure that represents a substantial risk for HIV transmission and continue for 28 days.198

nPep not recommended if exposed individual seeks care >72 hours after exposure.198

Chronic HBV Infection Oral

Tenofovir DF (Viread): 300 mg once daily.1

Optimal duration of treatment unknown.1

Special Populations

Hepatic Impairment

Treatment of HIV Infection Oral

Tenofovir DF (Viread): Dosage adjustments not needed.1

Emtricitabine/tenofovir DF (Truvada): Not studied in hepatic impairment.230

Efavirenz/emtricitabine/tenofovir DF (Atripla): Use usual dosage in patients with mild hepatic impairment;232 caution advised.232 Not recommended in those with moderate or severe hepatic impairment.232

Emtricitabine/rilpivirine/tenofovir DF (Complera): Use usual dosage in patients with mild or moderate hepatic impairment (Child-Pugh class A or B);233 not studied in those with severe hepatic impairment (Child-Pugh class C).233

Treatment of Chronic HBV Infection Oral

Tenofovir DF (Viread): Dosage adjustments not needed.1

Renal Impairment

Treatment of HIV Infection Oral

Tenofovir DF (Viread): Reduce dosage in adults with Clcr <50 mL/minute (see Table 4).1 Dosage adjustments not needed in those with Clcr 50–80 mL/minute; however, monitor calculated Clcr, serum phosphorus, urine glucose, and urine protein.1 Dosage recommendations not available for patients with Clcr <10 mL/minute who are not undergoing hemodialysis.1

Table 4. Tenofovir DF (Viread) Dosage for Treatment of HIV-1 Infection in Adults with Renal Impairment1

Clcr (mL/minute)	Dosage
30–49	300 mg once every 48 hours
10–29	300 mg once every 72–96 hours
Hemodialysis patients	300 mg once every 7 days or after a total of approximately 12 hours of hemodialysis (assuming 3 hemodialysis sessions/week each lasting approximately 4 hours); give dose after hemodialysis

Emtricitabine/tenofovir DF (Truvada): Use usual dosage in adults with Clcr 50–80 mL/minute; however, monitor calculated Clcr, serum phosphorus, urine glucose, and urine protein.230 In adults with Clcr 30–49 mL/minute, reduce dosage to 1 tablet (emtricitabine 200 mg and tenofovir DF 300 mg) once every 48 hours; monitor clinical response and renal function since dosage not evaluated clinically.230 Do not use in adults with Clcr <30 mL/minute (including hemodialysis patients).230 Data insufficient to make dosage recommendations for treatment of HIV-1 infection in pediatric patients with renal impairment.230

Efavirenz/emtricitabine/tenofovir DF (Atripla): Use usual dosage in patients with Clcr ≥50 mL/minute;232 do not use in those with estimated Clcr< 50 mL/minute.232

Emtricitabine/rilpivirine/tenofovir DF (Complera): Do not use in moderate, severe, or end-stage renal impairment (estimated Clcr <50 mL/minute) or if dialysis required.233

Preexposure Prophylaxis for Prevention of HIV-1 Infection Oral

Emtricitabine/tenofovir DF (Truvada): Use usual dosage in adults with Clcr ≥60 mL/minute; however, monitor calculated Clcr, serum phosphorus, urine glucose, and urine protein.230 If Clcr decreases, evaluate potential causes and reassess potential risks and benefits of continued use.230 Do not use if Clcr <60 mL/minute.230

Treatment of Chronic HBV Infection Oral

Tenofovir DF (Viread): Adjust dosage if Clcr <50 mL/minute (see Table 4).1 Dosage adjustments not needed in adults with Clcr 50–80 mL/minute; however, monitor calculated Clcr, serum phosphorus, urine glucose, and urine protein.1 Dosage recommendations not available for adults with Clcr <10 mL/minute who are not undergoing hemodialysis.1

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 230 232 233

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Tenofovir Disoproxil Fumarate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Powder	40 mg per g	Viread	Gilead
	Tablets, film-coated	150 mg	Viread	Gilead
		200 mg	Viread	Gilead
		250 mg	Viread	Gilead
		300 mg	Viread	Gilead

Tenofovir Disoproxil Fumarate Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	150 mg with Emtricitabine 100 mg	Truvada	Gilead
		200 mg with Emtricitabine 133 mg	Truvada	Gilead
		250 mg with Emtricitabine 167 mg	Truvada	Gilead
		300 mg with Emtricitabine 200 mg	Truvada	Gilead
		300 mg with Emtricitabine 200 mg and Efavirenz 600 mg	Atripla	Bristol-Myers Squibb and Gilead
		300 mg with Emtricitabine 200 mg and Rilpivirine Hydrochloride 25 mg (of rilpivirine)	Complera	Gilead
		300 mg with Emtricitabine 200 mg, Elvitegravir 150 mg, and Cobicistat 150 mg	Stribild	Gilead

None.

Exacerbation of Hepatitis after Discontinuation of Treatment

Discontinuation of anti-HBV therapy, including Viread, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue Viread should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

New Onset or Worsening Renal Impairment

Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of Viread [See Adverse Reactions (6.2)].

It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with Viread. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA®, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of Viread, and periodically during Viread therapy.

Dosing interval adjustment of Viread and close monitoring of renal function are recommended in all patients with creatinine clearance below 50 mL/min [See Dosage and Administration (2.3)]. No safety or efficacy data are available in patients with renal impairment who received Viread using these dosing guidelines, so the potential benefit of Viread therapy should be assessed against the potential risk of renal toxicity.

Viread should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) [See Drug Interactions (7.4)]. Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF, alone or in combination with other antiretrovirals. Treatment with Viread should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Coadministration with Other Products

Viread should not be used in combination with other drugs containing tenofovir DF or tenofovir alafenamide, including ATRIPLA, COMPLERA, DESCOVY, GENVOYA, ODEFSEY, STRIBILD, TRUVADA, or VEMLIDY. Viread should not be administered in combination with HEPSERA (adefovir dipivoxil) [See Drug Interactions (7.4)].

Patients Coinfected with HIV-1 and HBV

Due to the risk of development of HIV-1 resistance, Viread should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen.

HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with Viread. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with Viread.

Bone Effects

Bone Mineral Density:

In clinical trials in HIV-1 infected adults, Viread was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving Viread [See Adverse Reactions (6.1)].

Clinical trials evaluating Viread in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the Viread-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected [See Adverse Reactions (6.1)].

The effects of Viread-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.

Mineralization Defects:

Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of Viread [See Adverse Reactions (6.2)]. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF [See Warnings and Precautions (5.2)].

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including Viread. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Early Virologic Failure

Clinical trials in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.

Clinical Efficacy in Adults with HIV-1 Infection

Treatment-Naïve Adult Patients

Study 903

Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter trial comparing Viread (300 mg once daily) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and efavirenz in 600 antiretroviral-naïve subjects. Subjects had a mean age of 36 years (range 18−64); 74% were male, 64% were Caucasian, and 20% were Black. The mean baseline CD4+ cell count was 279 cells/mm3 (range 3−956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417−5,130,000). Subjects were stratified by baseline HIV-1 RNA and CD4+ cell count. Forty-three percent of subjects had baseline viral loads >100,000 copies/mL and 39% had CD4+ cell counts <200 cells/mm3. Treatment outcomes through 48 and 144 weeks are presented in Table 17.

Table 17 Outcomes of Randomized Treatment at Week 48 and 144 (Study 903)

	At Week 48		At Week 144
Outcomes	Viread+3TC+EFV (N=299)	d4T+3TC+EFV (N=301)	Viread+3TC+EFV (N=299)	d4T+3TC+EFV (N=301)
* Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 and 144. † Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48 and 144. ‡ Includes lost to follow-up, subject's withdrawal, noncompliance, protocol violation and other reasons.
Responder*	79%	82%	68%	62%
Virologic failure†	6%	4%	10%	8%
Rebound	5%	3%	8%	7%
Never suppressed	0%	1%	0%	0%
Added an antiretroviral agent	1%	1%	2%	1%
Death	<1%	1%	<1%	2%
Discontinued due to adverse event	6%	6%	8%	13%
Discontinued for other reasons‡	8%	7%	14%	15%

Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤100,000 copies/mL) and CD4+ cell count (< or ≥200 cells/mm3). Through 144 weeks of therapy, 62% and 58% of subjects in the Viread and stavudine arms, respectively, achieved and maintained confirmed HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4+ cell count was 263 cells/mm3 for the Viread arm and 283 cells/mm3 for the stavudine arm.

Through 144 weeks, 11 subjects in the Viread group and 9 subjects in the stavudine group experienced a new CDC Class C event.

Study 934

Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + Viread administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received a fixed-dose combination of emtricitabine and tenofovir DF with efavirenz in place of emtricitabine + Viread with efavirenz. Subjects had a mean age of 38 years (range 18−80); 86% were male, 59% were Caucasian, and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2−1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56−6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm3); 41% had CD4+ cell counts <200 cells/mm3 and 51% of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline are presented in Table 18.

Table 18 Outcomes of Randomized Treatment at Week 48 and 144 (Study 934)

Outcomes	At Week 48		At Week 144
	FTC+Viread+EFV (N=244)	AZT/3TC+EFV (N=243)	FTC+Viread+EFV (N=227)*	AZT/3TC+EFV (N=229)*
* Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue the trial after Week 48 or Week 96 were excluded from analysis. † Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144. ‡ Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and 144. § Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons.
Responder†	84%	73%	71%	58%
Virologic failure‡	2%	4%	3%	6%
Rebound	1%	3%	2%	5%
Never suppressed	0%	0%	0%	0%
Change in antiretroviral regimen	1%	1%	1%	1%
Death	<1%	1%	1%	1%
Discontinued due to adverse event	4%	9%	5%	12%
Discontinued for other reasons§	10%	14%	20%	22%

Through Week 48, 84% and 73% of subjects in the emtricitabine + Viread group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial. In addition, 80% and 70% of subjects in the emtricitabine + Viread group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the EMTRIVA + Viread group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).

Through 48 weeks, 7 subjects in the emtricitabine + Viread group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

Treatment-Experienced Adult Patients

Study 907

Study 907 was a 24-week, double-blind, placebo-controlled multicenter trial of Viread added to a stable background regimen of antiretroviral agents in 550 treatment-experienced subjects. After 24 weeks of blinded trial treatment, all subjects continuing on trial were offered open-label Viread for an additional 24 weeks. Subjects had a mean baseline CD4+ cell count of 427 cells/mm3 (range 23−1385), median baseline plasma HIV-1 RNA of 2340 (range 50−75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years. Mean age of the subjects was 42 years; 85% were male, 69% Caucasian, 17% Black, and 12% Hispanic.

The percent of subjects with HIV-1 RNA <400 copies/mL and outcomes of subjects through 48 weeks are summarized in Table 19.

Table 19 Outcomes of Randomized Treatment (Study 907)

Outcomes	0–24 weeks		0–48 weeks	24–48 weeks
	Viread (N=368)	Placebo (N=182)	Viread (N=368)	Placebo Crossover to Viread (N=170)
* Subjects with HIV-1 RNA <400 copies/mL and no prior study drug discontinuation at Week 24 and 48, respectively. † Subjects with HIV-1 RNA ≥400 copies/mL efficacy failure or missing HIV-1 RNA at Week 24 and 48, respectively. ‡ Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation, and other reasons.
HIV-1 RNA <400 copies/mL *	40%	11%	28%	30%
Virologic failure†	53%	84%	61%	64%
Discontinued due to adverse event	3%	3%	5%	5%
Discontinued for other reasons‡	3%	3%	5%	1%

At 24 weeks of therapy, there was a higher proportion of subjects in the Viread arm compared to the placebo arm with HIV-1 RNA <50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4+ cell counts by Week 24 was +11 cells/mm3 for the Viread group and −5 cells/mm3 for the placebo group. Mean change in absolute CD4+ cell counts by Week 48 was +4 cells/mm3 for the Viread group.

Through Week 24, one subject in the Viread group and no subjects in the placebo arm experienced a new CDC Class C event.

Clinical Efficacy in Adults with Chronic Hepatitis B

HBeAg-Negative Chronic Hepatitis B

Study 0102 was a Phase 3, randomized, double-blind, active-controlled trial of Viread 300 mg compared to HEPSERA 10 mg in 375 HBeAg- (anti-HBe+) subjects with compensated liver function, the majority of whom were nucleoside-naïve. The mean age of subjects was 44 years; 77% were male, 25% were Asian, 65% were Caucasian, 17% had previously received alpha-interferon therapy, and 18% were nucleoside-experienced (16% had prior lamivudine experience). At baseline, subjects had a mean Knodell necroinflammatory score of 7.8; mean plasma HBV DNA was 6.9 log10 copies/mL; and mean serum ALT was 140 U/L.

HBeAg-Positive Chronic Hepatitis B

Study 0103 was a Phase 3, randomized, double-blind, active-controlled trial of Viread 300 mg compared to HEPSERA 10 mg in 266 HBeAg+ nucleoside-naïve subjects with compensated liver function. The mean age of subjects was 34 years; 69% were male, 36% were Asian, 52% were Caucasian, 16% had previously received alpha-interferon therapy, and <5% were nucleoside experienced. At baseline, subjects had a mean Knodell necroinflammatory score of 8.4; mean plasma HBV DNA was 8.7 log10 copies /mL; and mean serum ALT was 147 U/L.

The primary data analysis was conducted after all subjects reached 48 weeks of treatment and results are summarized below.

The primary efficacy endpoint in both trials was complete response to treatment defined as HBV DNA <400 copies/mL (69 IU/mL) and Knodell necroinflammatory score improvement of at least 2 points, without worsening in Knodell fibrosis at Week 48 (Table 20).

Table 20 Histological, Virological, Biochemical, and Serological Response at Week 48

	0102 (HBeAg-)		0103 (HBeAg+)
	Viread (N=250)	HEPSERA (N=125)	Viread (N=176)	HEPSERA (N=90)
* Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis. † The population used for analysis of ALT normalization included only subjects with ALT above ULN at baseline. ‡ NA = Not Applicable
Complete Response	71%	49%	67%	12%
Histology Histological Response*	72%	69%	74%	68%
HBV DNA <400 copies/mL (<69 IU/mL)	93%	63%	76%	13%
ALT Normalized ALT†	76%	77%	68%	54%
Serology HBeAg Loss/ Seroconversion	NA‡	NA‡	20%/19%	16%/16%
HBsAg Loss/ Seroconversion	0/0	0/0	3%/1%	0/0

Treatment Beyond 48 Weeks

In Studies 0102 (HBeAg-negative) and 0103 (HBeAg-positive), subjects who completed double-blind treatment (389 and 196 subjects who were originally randomized to Viread and HEPSERA, respectively) were eligible to roll over to open-label Viread with no interruption in treatment.

In Study 0102, 266 of 347 subjects who entered the open-label period (77%) continued in the study through Week 384. Among subjects randomized to Viread followed by open-label treatment with Viread, 73% had HBV DNA <400 copies/ml (69 IU/ml), and 63% had ALT normalization at Week 384. Among subjects randomized to HEPSERA followed by open-label treatment with Viread, 80% had HBV DNA <400 copies/mL (69 IU/mL) and 70% had ALT normalization through Week 384. At Week 384, both HBsAg loss and seroconversion were approximately 1% in both treatment groups.

In Study 0103, 146 of 238 subjects who entered the open-label period (61%) continued in the study through Week 384. Among subjects randomized to Viread, 49% had HBV DNA <400 copies/mL (69 IU/mL), 42% had ALT normalization, and 20% had HBeAg loss (13% seroconversion to anti-HBe antibody) through Week 384. Among subjects randomized to HEPSERA followed by open-label treatment with Viread, 56% had HBV DNA <400 copies/mL (69 IU/mL), 50% had ALT normalization, and 28% had HBeAg loss (19% seroconversion to anti-HBe antibody) through Week 384. At Week 384, HBsAg loss and seroconversion were 11% and 8%, respectively, in subjects initially randomized to Viread and 12% and 10%, respectively, in subjects initially randomized to HEPSERA.

Of the originally randomized and treated 641 subjects in the two studies, liver biopsy data from 328 subjects who received continuing open-label treatment with Viread monotherapy were available for analysis at baseline, Week 48, and Week 240. There were no apparent differences between the subset of subjects who had liver biopsy data at Week 240 and those subjects remaining on open-label Viread without biopsy data that would be expected to affect histological outcomes at Week 240. Among the 328 subjects evaluated, the observed histological response rates were 80% and 88% at Week 48 and Week 240, respectively. In the subjects without cirrhosis at baseline (Ishak fibrosis score 0−4), 92% (216/235) and 95% (223/235) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. In subjects with cirrhosis at baseline (Ishak fibrosis score 5−6), 97% (90/93) and 99% (92/93) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. Twenty-nine percent (27/93) and 72% (67/93) of subjects with cirrhosis at baseline experienced regression of cirrhosis by Week 48 and Week 240, respectively, with a reduction in Ishak fibrosis score of at least 2 points. No definitive conclusions can be established about the remaining study population who were not part of this subset analysis.

Patients with Lamivudine-Resistant Chronic Hepatitis B

Study 121 was a randomized, double-blind, active-controlled trial evaluating the safety and efficacy of Viread compared to an unapproved antiviral regimen in subjects with chronic hepatitis B, persistent viremia (HBV DNA ≥1,000 IU/mL), and genotypic evidence of lamivudine resistance (rtM204I/V +/- rtL180M). One hundred forty-one adult subjects were randomized to the Viread treatment arm. The mean age of subjects randomized to Viread was 47 years (range 18−73); 74% were male, 59% were Caucasian, and 37% were Asian. At baseline, 54% of subjects were HBeAg-negative, 46% were HBeAg-positive, and 56% had abnormal ALT. Subjects had a mean HBV DNA of 6.4 log10 copies/mL and mean serum ALT of 71 U/L at baseline.

After 96 weeks of treatment, 126 of 141 subjects (89%) randomized to Viread had HBV DNA <400 copies/mL (69 IU/mL), and 49 of 79 subjects (62%) with abnormal ALT at baseline had ALT normalization. Among the HBeAg-positive subjects randomized to Viread, 10 of 65 subjects (15%) experienced HBeAg loss and 7 of 65 subjects (11%) experienced anti-HBe seroconversion through Week 96. The proportion of subjects with HBV DNA concentrations below 400 copies/mL (69 IU/mL) at Week 96 was similar between the Viread monotherapy and the comparator arms.

Across the combined chronic hepatitis B treatment trials, the number of subjects with adefovir-resistance associated substitutions at baseline was too small to establish efficacy in this subgroup.

Patients with Chronic Hepatitis B and Decompensated Liver Disease

Viread was studied in a small randomized, double-blind, active-controlled trial evaluating the safety of Viread compared to other antiviral drugs in subjects with chronic hepatitis B and decompensated liver disease through 48 weeks (Study 0108).

Forty-five adult subjects (37 males and 8 females) were randomized to the Viread treatment arm. At baseline, 69% subjects were HBeAg-negative and 31% were HBeAg-positive. Subjects had a mean Child-Pugh score of 7, a mean MELD score of 12, mean HBV DNA of 5.8 log10 copies/mL, and mean serum ALT of 61 U/L at baseline. Trial endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥0.5 mg/dL or confirmed serum phosphorus of <2 mg/dL [See Adverse Reactions (6.1)].

At 48 weeks, 31/44 (70%) and 12/26 (46%) Viread-treated subjects achieved an HBV DNA <400 copies/mL (69 IU/mL), and normalized ALT, respectively. The trial was not designed to evaluate treatment impact on clinical endpoints such as progression of liver disease, need for liver transplantation, or death.