Dolutegravir/ Emtricitabine/ Tenofovir Alafenamide

Registered South African indications:

• Human immunodeficiency virus-1 (HIV-1) infection

Lactic acidosis/severe hepatomegaly with steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including emtricitabine, a component of dolutegravir/ emtricitabine/ tenofovir alafenamide tablets, and tenofovir disoproxil fumarate, another prodrug of tenofovir, alone or in combination with other antiretrovirals. WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Tenofovir alafenamide, one component of dolutegravir/ emtricitabine/ tenofovir alafenamide tablets, is approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued medicines containing tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of dolutegravir/ emtricitabine/ tenofovir alafenamide tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue dolutegravir/ emtricitabine/ tenofovir alafenamide tablets. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Coadministration with dofetilide
• Coadministration with pilsicainide
• Patients taking metformin
• Should not be co-administered with other tenofovir-containing medicines or with other emtricitabine-containing medicines
• Should not be administered with lamivudine-containing medicines due to similarities between emtricitabine and lamivudine
• Moderate and severe hepatic impairment
• Severe renal impairment, creatinine clearance <30ml/min
• Antiretroviral-experienced patients with HIV-1 harbouring the K65R mutation
• Pregnancy
• Lactation

South African recommendations

Women of childbearing age

• A reliable method of contraception should be used to avoid pregnancy while taking dolutegravir/ emtricitabine/ tenofovir alafenamide

Renal impairment

• In moderate to severe renal impairment, the elimination half-life of tenofovir disoproxil fumarate is prolonged due to reduced clearance therefore before starting dolutegravir/ emtricitabine/ tenofovir alafenamide, evaluate estimated creatinine clearance, urine glucose, and urine protein
• All patients should be regularly monitored for renal function. Special attention is needed for patients with chronic kidney disease to detect potential Fanconi syndrome (characterised by severe hypophosphatemia and renal tubular injury)
• Renal impairment, including acute renal failure and Fanconi syndrome, has been reported with tenofovir prodrugs
• Discontinue if clinically significant decreases in renal function or Fanconi syndrome are observed
• Increased risk of renal-related adverse reactions when dolutegravir/ emtricitabine/ tenofovir alafenamide is used with or after nephrotoxic drugs, including NSAIDs
• Dolutegravir/ emtricitabine/ tenofovir alafenamide is not recommended for patients with a creatinine clearance below 50ml/min or those on haemodialysis

Elderly

• Dolutegravir
  • Clinical trials did not have enough participants aged 65 and over to determine if their response to dolutegravir differs from younger subjects
  • Caution is advised when administering dolutegravir to elderly patients, considering the increased likelihood of reduced hepatic, renal, or cardiac function, as well as the presence of other diseases or medications
• Emtricitabine and tenofovir alafenamide
  • In clinical trials, 80 out of 97 enrolled subjects aged 65 and over received treatments including FTC + TAF and EVG + COBI. No significant differences in safety or effectiveness were noted between elderly subjects and adults aged 18 to less than 65 years

Hypersensitivity reactions

• Reactions reported with integrase inhibitors such as dolutegravir, including severe rash and organ dysfunction (like liver injury)
• Discontinue dolutegravir/ emtricitabine/ tenofovir alafenamide and other potential causative drugs immediately if hypersensitivity symptoms (severe rash, fever, malaise, fatigue, muscle or joint aches, blisters, oral lesions,
  conjunctivitis, facial oedema, hepatitis, eosinophilia and angioedema) occur. Prompt action is crucial to prevent life-threatening outcomes
• Monitor liver function (liver aminotransferases) and initiate appropriate medical response

Risk of adverse reactions due to drug interactions

• Using dolutegravir/ emtricitabine/ tenofovir alafenamide with other medications can lead to significant interactions. These interactions may cause a loss of dolutegravir/ emtricitabine/ tenofovir alafenamide's effectiveness, drug resistance, and severe side effects due to increased levels of other drugs
• Assess potential interactions before and during treatment, and monitor for adverse reactions from other drugs

Lipodystrophy and metabolic abnormalities

• Combination  antiretroviral therapy, including dolutegravir/ emtricitabine/ tenofovir alafenamide, may cause changes in body fat distribution, such as central obesity, dorso-cervical fat enlargement (buffalo hump), peripheral and facial wasting, breast enlargement, and changes in serum lipid and glucose levels
• Regular clinical evaluations for signs of fat redistribution are recommended. Patients showing signs of lipodystrophy should undergo comprehensive cardiovascular risk assessment
• A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors
• Caution is advised in patients with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors
• Suspend treatment 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) (See additional prescribing points)

Mitochondrial dysfunction associated with nucleoside and nucleotide analogues

• Emtricitabine and tenofovir disoproxil fumarate can cause mitochondrial damage and this may be the case for dolutegravir/ emtricitabine/ tenofovir alafenamide
• Reports indicate mitochondrial dysfunction in HIV-negative infants exposed to nucleoside analogues in utero and/or post-natally, especially with regimens including zidovudine
• Symptoms of mitochondrial dysfunction include lactic acidosis/hyperlactataemia, haematological disorders (anaemia, neutropenia), peripheral neuropathy, and neurological disorders (hypertonia, convulsions, abnormal behaviour)
• The permanence of neurological disorders is uncertain
• Infants exposed in utero, even if HIV-negative, should be monitored for signs and symptoms of mitochondrial dysfunction and investigated if relevant symptoms appear

Immune Reconstitution Syndrome

• In HIV patients with severe immune deficiency, starting antiretroviral therapy (ART) can trigger an inflammatory response to asymptomatic or residual opportunistic infections
• Commonly occurs in the initial weeks or months following ART initiation, especially in patients with low CD4 counts
• Examples include reactions to tuberculosis, cytomegalovirus retinitis, atypical mycobacterial infections, and Pneumocystis jiroveci pneumonia
• Immediate evaluation and necessary treatment of any inflammatory symptoms are crucial
• Auto-immune disorders conditions like Graves' disease, polymyositis, and Guillain-Barre syndrome may arise as a part of immune reconstitution. These can occur several months after starting ART and may present atypically
• Liver chemistry elevations may occur in hepatitis B and/or C coinfected patients beginning dolutegravir therapy, consistent with immune reconstitution syndrome
• Recommended to monitor liver chemistries in patients coinfected with hepatitis B and/or C
• Careful initiation and maintenance of effective hepatitis B therapy are essential when starting dolutegravir-based therapy in hepatitis B coinfected patients

Osteonecrosis

• Osteonecrosis, often linked to factors like corticosteroid use, alcohol consumption, severe immunosuppression, and high body mass index, has been reported in patients with advanced HIV or those on long-term combination antiretroviral therapy (cART)
• Patients experiencing joint pain, stiffness, or mobility issues should seek medical consultation promptly

Hepatotoxicity

• Dolutegravir's unbound fraction is doubled in patients with moderate hepatic impairment
• Increased risk of transaminase elevations in patients with underlying hepatitis B or C using dolutegravir, emtricitabine, and tenofovir alafenamide
• Elevations in transaminases may relate to immune reconstitution syndrome or hepatitis B reactivation, especially if anti-hepatitis therapy is withdrawn
• Liver biochemistry elevations, hepatitis, and acute liver failure reported in patients taking dolutegravir without pre-existing hepatic disease or risk factors
• Medicine-induced liver injury leading to transplant has been reported with fixed-dose abacavir, dolutegravir, and lamivudine
• Regular monitoring for hepatotoxicity is advised. In patients with existing liver dysfunction or chronic active hepatitis, closely monitor liver functions
• Consider discontinuing treatment if liver disease worsens
• Emtricitabine and tenofovir disoproxil fumarate usage may lead to hepatomegaly from hepatic steatosis
• Safety and efficacy are not established in patients with significant liver disorders/diseases

Coinfection with hepatitis B or C

• Chronic hepatitis B or C patients on antiretroviral therapy have a higher risk for severe and potentially fatal liver-related adverse reactions
• HIV-1 patients should be tested for chronic HBV before starting antiretroviral therapy
• Phase III studies allowed hepatitis B/C coinfected patients if liver tests were below 5 times the ULN
• Safety profile in coinfected patients was similar to non-coinfected, though higher rates of AST/ALT abnormalities were noted
• Liver chemistry elevations, possibly due to immune reconstitution syndrome, were observed at the start of dolutegravir therapy, especially when anti-hepatitis B therapy was stopped
• Tenofovir alafenamide, part of this combination medicine, is also approved for chronic HBV treatment
• Severe acute exacerbations of hepatitis B have been reported after discontinuing medications containing TDF or emtricitabine
• Close monitoring of liver function is recommended after discontinuation of emtricitabine or tenofovir, components of this combination product
• Consider initiating anti-hepatitis B therapy, particularly for patients with advanced liver disease or cirrhosis, to prevent exacerbations leading to liver failure

Opportunistic infections

• Patients on dolutegravir/ emtricitabine/ tenofovir alafenamide might still develop opportunistic infections or other HIV-related complications
• Continuous clinical monitoring by healthcare professionals experienced in HIV treatment is essential
• Regular assessments of viral load and CD4 counts are necessary

Transmission of infection

• Dolutegravir/ emtricitabine/ tenofovir alafenamide and other antiretroviral therapies haven't been proven to eliminate the risk of transmitting HIV through sexual contact or blood contamination
• Patients should be advised to maintain appropriate safety precautions
• Dolutegravir/ emtricitabine/ tenofovir alafenamide is not recommended for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in high-risk adults

Pancreatitis

• Pancreatitis has been observed in patients taking emtricitabine and tenofovir disoproxil fumarate and may occur with dolutegravir/ emtricitabine/ tenofovir alafenamide
• Consider pancreatitis in patients who develop abdominal pain, nausea, vomiting, or elevated biochemical markers. Discontinue until pancreatitis is ruled out

Bone effects

• Consider monitoring bone mineral density (BMD) for HIV-infected patients with a history of pathological bone fractures or risk factors for osteopenia
• Tenofovir combination therapy, a component of dolutegravir/ emtricitabine/ tenofovir alafenamide, is linked to decreased BMD
• Evaluate BMD in patients with a history of pathological bone fractures or risk factors for osteoporosis or bone loss during therapy with emtricitabine and tenofovir
• Supplementation with calcium and vitamin D, though not studied in this context, may be beneficial
• Persistent or worsening bone pain, extremity pain, fractures, and muscle pain or weakness could indicate proximal renal tubulopathy. Such symptoms warrant renal function evaluation
• Cases of hypophosphatemia and osteomalacia, related to proximal renal tubulopathy, have been reported with the use of tenofovir disoproxil fumarate and may occur with dolutegravir/ emtricitabine/ tenofovir alafenamide

Paediatric population

• The safety and effectiveness of dolutegravir/ emtricitabine/ tenofovir alafenamide in paediatric patients have not been established
• Administration is recommended only for adolescent patients who weigh at least 40 kg. This restriction is due to dolutegravir/ emtricitabine/ tenofovir alafenamide being a fixed-dose combination, which does not allow for dose adjustments
• The safety and efficacy of the individual components of dolutegravir/ emtricitabine/ tenofovir alafenamide have been established in patients within this weight group

Impact on driving and machinery use

• No specific studies have been conducted on the effects of dolutegravir/ emtricitabine/ tenofovir alafenamide on driving and operating machinery
• The patient's clinical status and the side effect profile of dolutegravir/ emtricitabine/ tenofovir alafenamide should be considered
• Dizziness is a reported side effect of tenofovir disoproxil fumarate, emtricitabine, tenofovir alafenamide fumarate, and dolutegravir
• Due to the risk of dizziness, patients are advised not to drive or operate machinery while undergoing treatment

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Should be initiated by a medical practitioner experienced in the management of HIV infection

Human immunodeficiency virus-1 (HIV-1) infection
- For use alone as a complete regimen

Dolutegravir/ Emtricitabine/ Tenofovir Alafenamide
50/200/25 (mg)

• ≥40kg: Oral (fct): 1 tab, once daily with or without food

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Prior to initiation of dolutegravir/emtricitabine/ tenofovir alafenamide, patients should be tested for hepatitis B virus infection

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Estimated creatinine clearance, urine glucose, and urine protein should be assessed before initiating dolutegravir/emtricitabine/ tenofovir alafenamide therapy and should be monitored during therapy in all patients. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in all individuals

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Dolutegravir/emtricitabine/ tenofovir alafenamide film coated tablets is a fixed dose combination that cannot be adjusted

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Should be initiated by a medical practitioner experienced in the management of HIV infection

Human immunodeficiency virus-1 (HIV-1) infection
- For use alone as a complete regimen

Dolutegravir/ Emtricitabine/ Tenofovir Alafenamide
50/200/25 (mg)

• Adolescents ≥40kg: Oral (fct): See adult dosage

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Dolutegravir/ emtricitabine/ tenofovir alafenamide should only be administered to adolescent patients with a body weight of at least 40 kg because it is a fixed-dose combination that cannot be adjusted. The safety and efficacy have been established for the individual components in this weight group

Pregnancy

South African recommendations

• Contraindicated
• Dolutegravir/ emtricitabine/ tenofovir alafenamide is contraindicated in pregnancy
• A urine pregnancy test should be carried out within 24 hours before commencing treatment with dolutegravir containing medicines. Once treatment has started, pregnancy testing should be repeated every 4 weeks
• Pregnancy testing and counselling should be performed if a patient misses her periods or if there are any abnormalities in the menstrual bleeding. Nucleotide analogues, as in dolutegravir/ emtricitabine/ tenofovir alafenamide may impact on mitochondrial function to a variable degree. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/ or post-natally to nucleotide analogues
• The main adverse reactions reported are haematological disorders (anaemia, neutropenia) peripheral neuropathy and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events have often been transitory
• Late onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is unknown. These findings should be considered and investigated for any baby/ infant/ child exposed in utero to nucleos(t)ide analogues who present with severe clinical findings of unknown aetiology, particularly neurologic findings
• Women of childbearing potential should use a reliable method of contraception to avoid pregnancy while taking this combination medicine

Breastfeeding

South African recommendations

• Contraindicated
• Breastfeeding while taking dolutegravir/ emtricitabine/ tenofovir alafenamide is contraindicated
• HIV-infected women should not breastfeed their infants in order to avoid transmission of HIV
• It is expected that dolutegravir and emtricitabine, which are components of dolutegravir/ emtricitabine/ tenofovir alafenamide will be secreted into human milk

Fertility

South African recommendations

• No fertility data is available for humans. No adverse effects on fertility and reproductive performance of male and female rats have been observed

South African recommendations

• Mild (CrCl ≥50-80ml/min): No dose adjustment recommended
• Moderate (CrCl >30-50ml/min): Caution; not recommended
  Should not be administered to patients with creatinine clearance below 50ml/min or patients requiring haemodialysis
• Severe (CrCl<30ml/min): Contraindicated
  Dolutegravir/ emtricitabine/ tenofovir alafenamide tablets are not recommended for patients with severe renal impairment (estimated creatinine clearance below 30ml/min) because dolutegravir/ emtricitabine/ tenofovir alafenamide tablets are a fixed-dose combination, and the dosage of the individual components cannot be adjusted

South African recommendations

• Mild (Child-Pugh grade A): No dose adjustment recommended
• Moderate to severe (Child-Pugh grade B & C): Contraindicated

South African recommendations

• Caution; no dose adjustment recommended
  Dolutegravir:
  Population pharmacokinetic analysis shows no significant age-related effect on dolutegravir exposure in HIV-1 infected adults. Limited pharmacokinetic data for dolutegravir in individuals over 65 years
  Caution is advised when administering dolutegravir to elderly patients due to potential decreased hepatic, renal, or cardiac function and the presence of other diseases or medications
  Emtricitabine and Tenofovir:
  Pharmacokinetics in elderly patients (over 65 years) not fully evaluated. Clinical studies did not include enough elderly subjects to determine differential responses compared to younger subjects. Dose selection for elderly should be cautious, considering potential decreased organ function and concomitant conditions or therapies
  In trials, 80 of 97 subjects over 65 years old received emtricitabine, tenofovir alafenamide, elvitegravir, and cobicistat without observed differences in safety or efficacy compared to adults aged 18 to under 65 years

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Dolutegravir/ Emtricitabine/ Tenofovir Alafenamide

Serious Adverse Reactions

• Hepatotoxicity
• Hypersensitivity reactions
• Severe acute exacerbation of Hepatitis B
• Immune Reconstitution Syndrome
• New onset or worsening renal impairment
• Lactic acidosis
• Severe hepatomegaly with steatosis

Immune System Disorders

Less Frequent

• Hypersensitivity
• Immune reconstitution syndrome

Psychiatric Disorders

Frequent

• Insomnia

Less Frequent

• Suicidal ideation attempt, behaviour, or completion (primarily observed in subjects with pre-existing depression or other psychiatric illness)

Nervous System Disorders

Frequent

• Headache

Gastrointestinal Disorders

Less Frequent

• Abdominal pain
• Abdominal discomfort
• Flatulence
• Upper abdominal pain
• Vomiting

Hepatobiliary Disorders

Less Frequent

• Hepatitis

Skin and Subcutaneous Tissue Disorders

Less Frequent

• Pruritus

Musculoskeletal and Connective Tissue Disorders

Less Frequent

• Myositis

Renal and Urinary Disorders

Less Frequent

• Renal impairment

General Disorders and Administration Site Conditions

Frequent

• Fatigue

Dolutegravir

Immune System Disorders

Less Frequent

• Hypersensitivity
• Immune reconstitution syndrome

Psychiatric Disorders

Frequent

• Insomnia

Frequency Unknown

• Anxiety

Nervous System Disorders

Frequent

• Headache
• Dizziness
• Abnormal dreams

Gastrointestinal Disorders

Frequent

• Nausea
• Diarrhoea
• Vomiting
• Flatulence
• Upper abdominal pain

Less Frequent

• Abdominal pain
• Abdominal discomfort

Hepatobiliary Disorders

Less Frequent

• Hepatitis

Frequency Unknown

• Acute liver failure
• Hepatotoxicity

Skin and Subcutaneous Tissue Disorders

Frequent

• Rash
• Pruritus

Musculoskeletal and Connective Tissue Disorders

Frequency Unknown

• Arthralgia
• Myalgia

General disorders and administration site conditions

Frequent

• Fatigue

Post Marketing Experience - Dolutegravir

Hepatobiliary Disorders

Frequency not specified

• Acute liver failure
• Hepatotoxicity

Musculoskeletal

Frequency not specified

• Arthralgia
• Myalgia

Psychiatric

Frequency not specified

• Anxiety

Emtricitabine/ Tenofovir Alafenamide

Blood and Lymphatic System Disorders

Frequent

• Neutropenia

Less Frequent

• Anaemia

Immune System Disorders

Frequent

• Allergic reaction including angioedema

Metabolism and Nutrition Disorders

Frequent

• Hypertriglyceridemia
• Hyperglycaemia

Frequency Unknown

• Hypophosphataemia
• Lactic acidosis
• Hypokalaemia

Psychiatric Disorders

Frequent

• Insomnia
• Abnormal dreams

Nervous System Disorders

Frequent

• Dizziness
• Headache

Respiratory, Thoracic and Mediastinal Disorders

Frequent

• Dyspnoea

Gastrointestinal Disorders

Frequent

• Diarrhoea
• Nausea
• Vomiting
• Flatulence
• Abdominal pain
• Amylase elevation
• Lipase elevation

Less Frequent

• Dyspepsia

Frequency Unknown

• Pancreatitis

Hepatobiliary Disorders

Frequent

• Hyperbilirubinemia
• Increased liver enzymes (including increased AST, increased ALT and/or gamma GT)

Frequency Unknown

• Hepatitis
• Hepatic steatosis

Skin and Subcutaneous Tissue Disorders

Frequent

• Rash event (rash, maculopapular rash, vesiculobullous rash, pustular rash)
• Skin discoloration

Less Frequent

• Angioedema
• Pruritus
• Urticaria

Musculoskeletal and Connective Tissue Disorders

Frequent

• Creatine kinase elevation

Less Frequent

• Arthralgia

Frequency Unknown

• Myopathy
• Osteomalacia (associated with proximal renal tubulopathy)
• Rhabdomyolysis
• Muscular weakness

Renal and Urinary Disorders

Frequency Unknown

• Increased creatinine
• Renal insufficiency
• Renal failure
• Acute renal failure
• Fanconi syndrome
• Proximal tubulopathy
• Nephrogenic diabetes insipidus
• Proteinuria
• Acute tubular necrosis
• Polyuria
• Interstitial nephritis (including acute cases)

General Disorders and Administration Site Conditions

Frequent

• Pain
• Asthenia
• Fatigue

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Dolutegravir/ Emtricitabine/ Tenofovir Alafenamide

• Dofetilide
• Pilsicainide
• Metformin
• Other tenofovir-containing medicines
• Other emtricitabine-containing medicines
• Lamivudine-containing medicines
• Didanosine
• Atazanavir
• Lopinavir/ritonavir
• Medicines that reduce renal function or compete for active tubular secretion
• Adefovir dipivoxil
• Cidofovir
• Aciclovir
• Valaciclovir
• Ganciclovir
• Valganciclovir
• Aminoglycosides
• Gentamicin
• High-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)

Dolutegravir

• Medicines that may change the exposure of dolutegravir or medications that may have their exposure changed by dolutegravir
• Polyvalent cation-containing antacids
• Cation-containing antacids or laxatives
• Sucralfate
• Buffered medications
• Rifampicin
• Tipranavir/ ritonavir
• Etravirine
• Efavirenz
• Nevirapine
• Fosamprenavir/ritonavir
• Carbamazepine
• Oxcarbazepine
• Phenytoin
• Phenobarbitone
• Oral calcium or iron supplements, including multivitamins containing calcium or iron

Other interactions

• St. John’s wort (Hypericum perforatum)

Emtricitabine 

• Other medicines containing emtricitabine
• Medicines containing lamivudine, including lamivudine and zidovudine co-formulation, lamivudine for HIV, lamivudine for HBV, abacavir sulfate and lamivudine co-formulation or abacavir sulfate, lamivudine and zidovudine co-formulation
• Zidovudine

Tenofovir Alafenamide

• Other medicines containing tenofovir
• Medicines that strongly affect P-gp and BCRP activity
• Atazanavir
• Cobicistat
• Rifabutin
• Rifampin
• Rifapentine
• Carbamazepine
• Oxcarbazepine
• Phenytoin
• Phenobarbitone

Other interactions

• St. John’s wort (Hypericum perforatum)

• Viral load
• CD4 count
• Renal function (creatinine clearance)
• Urine glucose
• Urine protein
• Serum phosphorus
• Clinical status
• Hepatic function
  - Liver aminotransferases
• Lipid profile
• Hepatitis B virus (HBV)

Specific cases may require

• Bone mineral density
• Serum bicarbonate
• Cardiovascular risk assessment
• Blood glucose
• Venous lactate level
  (See additional prescribing points)

Additional observations

• Fat redistribution
• Opportunistic infections

Pre-exposure prophylaxis (PrEP)

• Dolutegravir/ emtricitabine/ tenofovir alafenamide tablets are not indicated for use as pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk

Management of lactic acidosis in patients on dolutegravir/ emtricitabine/ tenofovir alafenamide

• Clinical features include nausea, vomiting, abdominal pain, dyspnoea, fatigue, weight loss
• Response based on lactate levels and symptoms
  • Lactate 2 to 5mmol/L with minimum symptoms
    • Switch to medications less likely to cause lactic acidosis
  • Lactate 5 to 10mmol/L with symptoms and/or reduced standard bicarbonate
    • Stop dolutegravir/ emtricitabine/ tenofovir alafenamide and change the treatment option
    • Resume treatment with medications less prone to causing lactic acidosis once lactate levels stabilise
    • Investigate other potential causes such as sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis, and hyperthyroidism
  • Lactate >10mmol/L
    • Immediately stop all therapy due to a high mortality risk (80%)

Special considerations

• Paediatric patients: The lactate values and responses may not be directly applicable to children
• Patients with liver disease risk factors
  • Exercise caution when administering dolutegravir/ emtricitabine/ tenofovir alafenamide
  • Suspend treatment if there are signs of lactic acidosis or hepatotoxicity

Dolutegravir
Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle.

Emtricitabine
Emtricitabine, a synthetic nucleoside analogue of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'- triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Ɛ, and mitochondrial DNA polymerase γ.

Tenofovir Alafenamide (TAF)
TAF is a phosphonoamidate prodrug of tenofovir (2’-deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination. Tenofovir has activity against HIV-1. Cell culture studies have shown that both tenofovir and emtricitabine can be fully phosphorylated when combined in cells. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.

COMBINATION PREPARATION

Dolutegravir/ Emtricitabine/ Tenofovir Alafenaminde

Film coated tablet 50mg/200mg/25mg

• Komycitaf (Mylan) originator
• Mylataf (Xixia Pharmaceuticals)