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Tenofovir Disoproxil Fumarate

Pronunciation

Pronunciation

(ten OF oh vir dye soe PROX il FUE ma rate)

Index Terms

  • PMPA
  • TDF

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Powder, Oral, as disoproxil fumarate:

Viread: 40 mg/g (60 g)

Tablet, Oral, as disoproxil fumarate:

Viread: 150 mg, 200 mg, 250 mg

Viread: 300 mg [contains fd&c blue #2 aluminum lake]

Brand Names: U.S.

  • Viread

Pharmacologic Category

  • Antihepadnaviral, Reverse Transcriptase Inhibitor, Nucleotide (Anti-HBV)
  • Antiretroviral, Reverse Transcriptase Inhibitor, Nucleotide (Anti-HIV)

Pharmacology

Tenofovir disoproxil fumarate (TDF), a nucleotide reverse transcriptase inhibitor, is an analog of adenosine 5'-monophosphate; it interferes with the HIV viral RNA dependent DNA polymerase resulting in inhibition of viral replication. TDF is first converted intracellularly by hydrolysis to tenofovir and subsequently phosphorylated to the active tenofovir diphosphate. Tenofovir inhibits replication of HBV by inhibiting HBV polymerase.

Distribution

Vd: 1.2 to 1.3 L/kg

Metabolism

Tenofovir disoproxil fumarate (TDF) is converted intracellularly by hydrolysis (by non-CYP enzymes) to tenofovir, then phosphorylated to the active tenofovir diphosphate

Excretion

Urine (70% to 80%) via filtration and active secretion, primarily as unchanged tenofovir within 72 hours; after multiple oral doses (administered with food): 32% ± 10% is excreted in the urine within 24 hours

Clearance: Total body clearance is decreased in patients with renal impairment

Time to Peak

Serum: Fasting: 36 to 84 minutes; With high-fat meal: 96 to 144 minutes

Half-Life Elimination

Serum: 17 hours; intracellular: 10 to 50 hours

Protein Binding

<7% to serum proteins

Special Populations: Renal Function Impairment

In patients with CrCl <50 mL/minute or with ESRD requiring dialysis, Cmax and AUC of tenofovir were increased. Following a single 300 mg dose, a 4-hour hemodialysis session removed ~10% of the administered tenofovir dose.

Use: Labeled Indications

Chronic hepatitis B: Treatment of chronic hepatitis B virus (HBV) in patients ≥12 years of age

HIV-1 infection, treatment: Treatment of HIV-1 infection in patients ≥2 years of age, in combination with other antiretroviral agents.

Off Label Uses

HIV-1 nonoccupational postexposure prophylaxis

Based on the Centers for Disease Control and Prevention, US Department of Health and Human Services updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV, tenofovir is effective and recommended (in conjunction with other antiretrovirals) as postexposure prophylaxis of HIV-1 infection following nonoccupational exposure (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that may contain HIV when that exposure represents a substantial risk for HIV transmission.

HIV-1 occupational postexposure prophylaxis

Based on the US Public Health Service updated guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis, tenofovir (in combination with emtricitabine and raltegravir) is effective and recommended for postexposure prophylaxis of HIV-1 infection in health care personnel following occupational exposure (oPEP) to blood and/or other body fluids that may contain HIV.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to tenofovir or any component of the formulation

Dosing: Adult

Hepatitis B infection: Oral: 300 mg once daily

Note: Concurrent use with adefovir and/or tenofovir combination products should be avoided.

Treatment duration (AASLD practice guidelines): Treatment duration for nucleos(t)ide analog-based therapy (eg,tenofovir) is variable and influenced by HBeAg status, duration of HBV suppression, and presence of cirrhosis/decompensation (AASLD [Terrault 2016]):

Patients without cirrhosis:

Hepatitis B e antigen (HBeAg) positive immune-active chronic hepatitis: Treat until HBeAg seroconversion; after seroconversion, prolonged duration of therapy is often required in patients treated with nucleos(t)ide anaglogues,. Optimal duration is unknown; however, consolidation therapy is generally a minimum of 12 months of persistently normal ALT and undetectable serum HBV DNA levels after HBeAg seroconversion

HBeAg-negative immune-active chronic hepatitis: Indefinite antiviral therapy is suggested unless there is competing rationale for discontinuation (risk/benefit decision); treatment discontinuation may be considered in patients with loss of HBsAg; however, there is insufficient evidence to guide decisions in these patients.

Patients with cirrhosis:

HBeAg-positive immune-active chronic hepatitis: In patients who seroconvert on therapy, continue antiviral therapy indefinitely due to concerns with decompensation and death, unless there is a strong competing rationale for discontinuation.

HBeAg-negative immune-active chronic hepatitis: Treatment discontinuation is not recommended due to potential for decompensation and death (limited data).

HIV-1 infection, treatment: Oral: 300 mg once daily (in combination with other antiretrovirals). Note: Tenofovir is a component of recommended initial regimens in treatment-naive patients (when coadministered with emtricitabine plus dolutegravir, with emtricitabine plus darunavir/ritonavir, or with emtricitabine plus raltegravir; lamivudine may be substituted for emtricitabine in any of these regimens) and is a component of a recommended initial regimen in treatment-naive patients with pre-ART CrCl >70 mL/minute (when coadministered with emtricitabine plus elvitegravir/cobicistat) (HHS [adult] 2015).

HIV-1 nonoccupational postexposure prophylaxis (nPEP) (off-label use): Oral: 300 mg once daily for 28 days (in combination with other antiretroviral agents). Initiate therapy within 72 hours of exposure. Note: The fixed dose emtricitabine and tenofovir disoproxil fumarate combination product is recommended for these components of the 3-drug regimen (HHS [nPEP] 2016)

HIV-1 occupational postexposure, prophylaxis (oPEP) (off-label use): Oral: 300 mg once daily in combination with emtricitabine and raltegravir; initiate therapy as soon as possible after occupational exposure (and within 72 hours) and continue for 4 weeks. Note: The fixed dose emtricitabine and tenofovir disoproxil fumarate combination product is recommended for these components of the 3-drug regimen (Kuhar 2013)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Hepatitis B infection: Oral: Children ≥12 years (and ≥35 kg) and Adolescents: Refer to adult dosing.

HIV-1 infection, treatment: Oral:

Children 2 to <12 years: 8 mg/kg once daily (maximum: 300 mg once daily) (in combination with other antiretrovirals).

Dosing recommendations based on body weight if using the oral powder: Note: One level scoop of powder = 40 mg tenofovir

10 to <12 kg: 80 mg once daily

12 to <14 kg: 100 mg once daily

14 to <17 kg: 120 mg once daily

17 to <19 kg: 140 mg once daily

19 to <22 kg: 160 mg once daily

22 to <24 kg: 180 mg once daily

24 to <27 kg: 200 mg once daily

27 to <29 kg: 220 mg once daily

29 to <32 kg: 240 mg once daily

32 to <34 kg: 260 mg once daily

34 to <35 kg: 280 mg once daily

≥35 kg: 300 mg once daily

Dosing recommendations based on body weight if using the oral tablets:

17 to <22 kg: 150 mg once daily

22 to <28 kg: 200 mg once daily

28 to <35 kg: 250 mg once daily

≥35 kg: 300 mg once daily

Children ≥12 years (and ≥35 kg) and Adolescents: Refer to adult dosing. Note: Tenofovir is a component of recommended initial regimens in adolescent treatment-naive patients (when coadministered with emtricitabine plus dolutegravir, with emtricitabine plus darunavir/ritonavir, or with emtricitabine plus raltegravir; lamivudine may be substituted for emtricitabine in any of these regimens) and is a component of a recommended initial regimen in adolescent treatment-naive patients with pre-ART CrCl >70 mL/minute (when coadministered with emtricitabine plus elvitegravir/cobicistat) (HHS [adult] 2015).

HIV-1 nonoccupational postexposure prophylaxis (nPEP) (off-label use): Oral:

Children ≥2 years: Age- and weight-appropriate dosing (see HIV-1 infection, treatment above) for 28 days in combination with other antiretroviral agents. Initiate therapy within 72 hours of exposure (HHS [nPEP] 2016)

Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

Adults:

Manufacturer's labeling:

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl 30 to 49 mL/minute: 300 mg every 48 hours

CrCl 10 to 29 mL/minute: 300 mg every 72-96 hours

CrCl <10 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Hemodialysis: 300 mg following dialysis every 7 days or after a total of ~12 hours of dialysis (usually once weekly assuming 3 dialysis sessions lasting about 4 hours each).

Alternate recommendations (IDSA [Lucas 2014]):

CrCl <50 mL/minute (and not on hemodialysis) or GFR <60 mL/minute/1.73 m2: Avoid use.

Peritoneal dialysis: Use with caution; dose reduction recommended (no specific adjustment provided)

Children ≥2 years and Adolescents: There are no dosage adjustments provided the in manufacturer's labeling (has not been studied). Dosage should be decreased in patients with CrCl <50 mL/minute (HHS [pediatric] 2016).

Dosing: Hepatic Impairment

No dosage adjustment necessary.

Administration

Tablets may be administered without regard to meals. Powder should be mixed with 2 to 4 ounces of soft food (applesauce, baby food, yogurt) and swallowed immediately (avoids bitter taste); do not mix in liquid (powder may float on top of the liquid even after stirring). Measure powder using only the supplied dosing scoop.

Dietary Considerations

Consider calcium and vitamin D supplementation.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Dispense only in original container.

Drug Interactions

Acyclovir-Valacyclovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Acyclovir-Valacyclovir. Monitor therapy

Adefovir: May diminish the therapeutic effect of Tenofovir Products. Adefovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Adefovir. Avoid combination

Aminoglycosides: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Aminoglycosides. Monitor therapy

Atazanavir: Tenofovir Disoproxil Fumarate may decrease the serum concentration of Atazanavir. Atazanavir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Management: Must use ritonavir-boosting in adults; give combo (atazanavir/ritonavir 300mg/100mg and tenofovir 300mg) as a single daily dose with food. Pediatric patients, pregnant patients, and users of H2-blockers require other dose changes. Consider therapy modification

Cabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib. Monitor therapy

Cidofovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Cidofovir. Monitor therapy

Cobicistat: May enhance the adverse/toxic effect of Tenofovir Products. More specifically, cobicistat may impair proper tenofovir monitoring and dosing. Monitor therapy

Darunavir: Tenofovir Disoproxil Fumarate may increase the serum concentration of Darunavir. Darunavir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Diclofenac (Systemic): May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to this combination whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Didanosine: Tenofovir Disoproxil Fumarate may diminish the therapeutic effect of Didanosine. Tenofovir Disoproxil Fumarate may increase the serum concentration of Didanosine. Management: Avoid concomitant treatment with tenofovir disoproxil fumarate and didanosine. Consider altering even existing, stable treatment to avoid this combination. Avoid combination

Ganciclovir-Valganciclovir: Tenofovir Products may increase the serum concentration of Ganciclovir-Valganciclovir. Ganciclovir-Valganciclovir may increase the serum concentration of Tenofovir Products. Monitor therapy

Ledipasvir: May increase the serum concentration of Tenofovir Disoproxil Fumarate. Management: Avoidance of this combination is recommended under some circumstances. Refer to full monograph for details. Consider therapy modification

Lopinavir: May enhance the nephrotoxic effect of Tenofovir Disoproxil Fumarate. Lopinavir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

Simeprevir: Tenofovir Disoproxil Fumarate may decrease the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Telaprevir: May increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Tipranavir: Tenofovir Disoproxil Fumarate may decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Velpatasvir: May increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Adverse Reactions

Includes data from both treatment-naive and treatment-experienced HIV patients and in chronic hepatitis B.

>10%:

Central nervous system: Insomnia (3% to 18%), headache (5% to 14%), pain (12% to 13%), dizziness (8% to 13%), depression (4% to 11%)

Dermatologic: Skin rash (includes maculopapular, pustular, or vesiculobullous rash; pruritus; or urticaria: 5% to 18%), pruritus (16%)

Endocrine & metabolic: Hypercholesterolemia (19% to 22%), increased serum triglycerides (1% to 4%)

Gastrointestinal: Abdominal pain (4% to 22%), nausea (8% to 20%), diarrhea (9% to 16%), vomiting (2% to 13%)

Neuromuscular & skeletal: Decreased bone mineral density (28%; ≥5% at spine or ≥7% at hip), increased creatine phosphokinase (2% to 12%), weakness (6% to 11%)

Miscellaneous: Fever (4% to 11%)

1% to 10%:

Cardiovascular: Chest pain (3%)

Central nervous system: Fatigue (9%), anxiety (6%), peripheral neuropathy (1% to 5%)

Dermatologic: Diaphoresis (3%)

Endocrine & metabolic: Weight loss (2% to 4%), glycosuria (grades 3/4: ≤3%), hyperglycemia (grades 3/4: 2% to 3%), lipodystrophy (1%)

Gastrointestinal: Increased serum amylase (grades 3/4: 4% to 9%), anorexia (3% to 4%), dyspepsia (3% to 4%), flatulence (3% to 4%)

Genitourinary: Hematuria (≤grades 3/4: 3% to 7%)

Hematologic & oncologic: Neutropenia (3%)

Hepatic: Increased serum ALT (2% to 10%), increased serum AST (3% to 5%), increased serum transaminases (2% to 5%), increased serum alkaline phosphatase (1%)

Neuromuscular & skeletal: Back pain (4% to 9%), arthralgia (5%), myalgia (4%)

Renal: Increased serum creatinine (9%), renal failure (7%)

Respiratory: Sinusitis (8%), upper respiratory tract infection (8%), nasopharyngitis (5%), pneumonia (2% to 5%)

Postmarketing and/or case reports: Angioedema, exacerbation of hepatitis B (following discontinuation), Fanconi’s syndrome, hepatitis, hypersensitivity reaction, hypokalemia, hypophosphatemia, immune reconstitution syndrome, increased gamma-glutamyl transferase, interstitial nephritis, lactic acidosis, myopathy, nephrogenic diabetes insipidus, nephrotoxicity, osteomalacia, pancreatitis, polyuria, proteinuria, proximal tubular nephropathy, renal insufficiency, renal tubular necrosis, rhabdomyolysis, severe hepatomegaly with steatosis

ALERT: U.S. Boxed Warning

Post-treatment exacerbation of hepatitis:

Severe acute exacerbations of hepatitis have been reported in hepatitis B virus (HBV)-infected patients who have discontinued anti-hepatitis B therapy. Monitor hepatic function closely with clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Warnings/Precautions

Concerns related to adverse effects:

• Decreased bone mineral density: In clinical trials, use has been associated with decreases in bone mineral density in HIV-1 infected adults and increases in bone metabolism markers. Serum parathyroid hormone and 1,25 vitamin D levels were also higher. Decreases in bone mineral density have also been observed in clinical trials of HIV-1 infected pediatric patients. Observations in chronic hepatitis B infected pediatric patients (aged 12-18 years) were similar. In all pediatric clinical trials, skeletal growth (height) appears unaffected. Consider monitoring of bone density in adult and pediatric patients with a history of pathologic fractures or with other risk factors for bone loss or osteoporosis. Consider calcium and vitamin D supplementation for all patients; effect of supplementation has not been studied but may be beneficial. Long-term bone health and fracture risk unknown. If abnormalities are suspected, expert assessment is recommended.

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Lactic acidosis/hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported with the use of nucleoside analogs, alone or in combination with other antiretrovirals. Suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (marked transaminase elevation may/may not accompany hepatomegaly and steatosis).

• Osteomalacia and renal dysfunction: May cause osteomalacia with proximal renal tubulopathy. Bone pain, extremity pain, fractures, arthralgias, weakness and muscle pain have been reported. In patients at risk for renal dysfunction, persistent or worsening bone or muscle symptoms should be evaluated for hypophosphatemia and osteomalacia.

• Renal toxicity: May cause renal toxicity (acute renal failure and/or Fanconi syndrome); avoid use with concurrent or recent nephrotoxic therapy (including high dose or multiple NSAID use). Acute renal failure has occurred in HIV-infected patients with risk factors for renal impairment who were on a stable tenofovir regimen to which a high dose or multiple NSAID therapy was added. Consider alternatives to NSAIDS in patients taking tenofovir disoproxil fumarate and at risk for renal impairment. Calculate estimated creatinine clearance prior to initiation of therapy and as clinically appropriate during therapy. In patients at risk for renal dysfunction, including patients who have experienced renal events while taking adefovir, also assess serum phosphorus, urine glucose, and urine protein prior to and periodically during treatment. Dosage adjustment required in patients with CrCl <50 mL/minute. IDSA guidelines recommend discontinuing tenofovir (and substituting with alternative antiretroviral therapy) in HIV-infected patients who develop a decline in GFR (a >25% decrease in GFR from baseline and to a level of <60 mL/minute/1.73 m2) during use, particularly in presence of proximal tubular dysfunction (eg, euglycemic glycosuria, increased urinary phosphorus excretion and hypophosphatemia, proteinuria [new onset or worsening]) (IDSA [Lucas 2014]).

Disease-related concerns:

• Chronic hepatitis B: [US Boxed Warning]: Severe, acute exacerbation of hepatitis B may occur upon discontinuation. Monitor liver function several months after discontinuing treatment; reinitiation of antihepatitis B therapy may be required. Treatment of HBV in patients with unrecognized/untreated HIV may lead to HIV resistance; patients should be tested for presence of HIV infection prior to initiating therapy

• Hepatic impairment: Use with caution in patients with hepatic impairment. Limited data supporting treatment of chronic hepatitis B in patients with decompensated liver disease; observe for increased adverse reactions, including renal dysfunction.

• Renal impairment: Tenofovir is predominately eliminated renally. Use with caution in patients with renal impairment (CrCl <50 mL/minute); dosage adjustment required. IDSA guidelines recommend avoiding tenofovir in HIV patients with preexisting kidney disease (CrCl <50 mL/minute and not on hemodialysis or GFR <60 mL/minute/1.73 m2) when other effective HIV treatment options exist because data suggest risk of chronic kidney disease (CKD) is increased (IDSA [Lucas 2014]).

Concurrent drug therapy issues:

• Concomitant therapy: Do not use in combination with other tenofovir disoproxil fumarate or tenofovir alafenamide products, or with adefovir.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Hepatitis B coinfection: Treatment of HBV with tenofovir monotherapy in patients with unrecognized/untreated HIV may lead to rapid HIV resistance. Patients should be tested for coinfection prior to initiation of therapy. In patients coinfected with HIV and HBV, an appropriate antiretroviral combination should be selected due to HIV resistance potential; these patients should receive tenofovir dosed for HIV therapy.

• Appropriate use: HIV treatment: Do not use as monotherapy in treatment of HIV. Clinical trials in HIV-infected patients whose regimens contained only three nucleoside reverse transcriptase inhibitors (NRTI) show less efficacy, early virologic failure and high rates of resistance substitutions. Use three NRTI regimens with caution and monitor response carefully. Triple drug regimens with two NRTIs in combination with a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor are usually more effective.

Monitoring Parameters

Manufacturer’s labeling:

Patients with HIV: CBC with differential, reticulocyte count, creatine kinase, CD4 count, HIV RNA plasma levels, serum phosphorus; serum creatinine (prior to initiation and as clinically indicated during therapy), urine glucose and urine protein (in patients at risk for renal impairment or who experienced renal impairment while taking adefovir), hepatic function tests, bone density (patients with a history of bone fracture or have risk factors for bone loss); testing for HBV is recommended prior to the initiation of antiretroviral therapy; weight (children).

Patients with HBV: HIV status (prior to initiation of therapy); serum phosphorus; serum creatinine (prior to initiation and as clinically indicated during therapy), urine glucose and urine protein (in patients at risk for renal impairment or who experienced renal impairment while taking adefovir); bone density (patients with a history of bone fracture or have risk factors for bone loss); LFTs every 3 months during therapy and for several months following discontinuation of tenofovir; signs/symptoms of HBV relapse/exacerbation following discontinuation of therapy.

Patients with HIV and HBV coinfection should be monitored for several months following tenofovir discontinuation.

Alternate recommendations: Patients with chronic hepatitis B: HBV DNA and ALT (HBV DNA usually done every 3 months until undetectable and then every 3 to 6 months thereafter); HBeAg; anti-HBe (in patients who are HBeAg-positive to monitor for seroconversion); HBsAg; creatinine clearance (baseline); if at risk for renal impairment, creatinine clearance, serum phosphate, urine glucose, and urine protein at baseline and at least annually; in patients with a history of fracture or risks for osteopenia, consider a bone density study (baseline and during treatment); consider lactic acid levels if clinical concern for lactic acidosis; following discontinuation, monitor for recurrent viremia, ALT flares, seroreversion, and clinical decompensation every 3 months for at least 1 year (AASLD [Terrault 2016). As antivirals do not eliminate the risk of hepatocellular carcinoma, continued monitoring for this complication is recommended in at-risk patients.

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Tenofovir has a high level of transfer across the human placenta. No increased risk of overall birth defects has been observed following first trimester exposure according to data collected by the antiretroviral pregnancy registry. Maternal antiretroviral therapy may increase the risk of preterm delivery, although available information is conflicting possibly due to variability of maternal factors (disease severity; initiation of therapy); however, maternal antiretroviral medication should not be withheld due to concerns of preterm birth. Intrauterine growth has not been affected following use of tenofovir disoproxil fumarate, but data are conflicting about potential growth effects later in infancy. Clinical studies in children have shown bone demineralization with chronic use. Bone mineral content was also decreased in infants following in utero exposure. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities of unknown etiology (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction. Cases of lactic acidosis and hepatic steatosis related to mitochondrial toxicity have been reported with use of nucleoside reverse transcriptase inhibitors (NRTIs). These adverse events are similar to other rare but life-threatening syndromes that occur during pregnancy (eg, HELLP syndrome). In general NRTIs are well tolerated and the benefits of use generally outweigh potential risk.

Combination antiretroviral therapy (cART) therapy is recommended for all HIV-infected pregnant women to keep the viral load below the limit of detection and reduce the risk of perinatal transmission. When HIV is diagnosed during pregnancy in a woman who has never received antiretroviral therapy, cART should begin as soon as possible after diagnosis. The Health and Human Services (HHS) Perinatal HIV Guidelines consider tenofovir disoproxil fumarate a component in preferred regimens for initial therapy in antiretroviral-naïve pregnant women. The guidelines also consider emtricitabine plus tenofovir disoproxil fumarate, or lamivudine plus tenofovir disoproxil fumarate as recommended dual NRTI backbone for HIV/HBV coinfected pregnant women. Hepatitis B flare may occur if tenofovir disoproxil fumarate is discontinued. Limited data indicate decreased maternal exposure during the third trimester; dose adjustments are not needed. In general, women who become pregnant on a stable cART regimen may continue that regimen if viral suppression is effective, appropriate drug exposure can be achieved, contraindications for use in pregnancy are not present, and the regimen is well tolerated. Monitoring during pregnancy is more frequent than in non-pregnant adults; cART should be continued postpartum.

For HIV-infected couples planning a pregnancy, maximum viral suppression with cART is recommended prior to conception for the HIV-infected partner(s) and expert consultation is recommended; modification of therapy (if needed) and optimization of the woman's health should be done prior to conception. HIV-infected women not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. In addition, consistent use of condoms is also recommended (even during pregnancy) to prevent transmission of HIV or other sexually transmitted diseases.

In hepatitis B-infected women (not coinfected with HIV), the AASLD chronic hepatitis B treatment guidelines suggest antiviral therapy to reduce the risk of perinatal transmission of hepatitis B in HBsAg-positive pregnant women with an HBV DNA >200,000 units/mL. There are limited data on the level of HBV DNA for when antiviral therapy is routinely recommended (>200,000 units/mL is a conservative recommendation); however, the AASLD recommends against antiviral therapy to reduce the risk of perinatal transmission in HBsAg-positive pregnant women with an HBV DNA ≤200,000 units/mL. Tenofovir is one of the antivirals that has been studied in pregnant women (and may be the preferred agent); with most studies initiating antiviral therapy at 28 to 32 weeks gestation and discontinuing antiviral therapy between birth to 3 months postpartum (monitor for ALT flares every 3 months for 6 months following discontinuation). There is insufficient long-term safety data in infants born to mothers who took antiviral agents during pregnancy (AASLD [Terrault 2016]),

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2016).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, dizziness, nausea, vomiting, diarrhea, pain, insomnia, or loss of strength and energy. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of lactic acidosis (fast breathing, tachycardia, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), depression, bone pain, muscle pain, muscle weakness, painful extremities, or signs of infection (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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