ART Guidelines

ART Guidelines


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  • ABBREVIATIONS
    /r ritonavir-boosted
    3TC lamivudine
    ABC abacavir
    ADR adverse drug reaction
    AKI acute kidney injury
    ALT alanine transaminase
    ANC antenatal care
    ART antiretroviral therapy
    ARV antiretroviral
    AST aspartate transaminase
    ATV atazanavir
    ATV/r ritonavir-boosted atazanavir
    AZT zidovudine
    bd twice daily
    CD4+ cluster of differentiation 4
    CM cryptococcal meningitis
    CNS central nervous system
    CrAg cryptococcal antigen
    CrCl creatinine clearance rate
    CSF cerebrospinal fluid
    CTX cotrimoxazole
    d4T stavudine
    ddI didanosine
    DILI drug-induced liver injury
    DNA deoxyribonucleic acid
    DRV darunavir
    DRV/r ritonavir-boosted darunavir
    DTG dolutegravir
    eGFR estimated glomerular filtration rate
    ELISA enzyme-linked immunosorbent assay
    ETR etravirine
    FBC full blood count
    FTC emtricitabine
    GI gastrointestinal
    Hb haemoglobin
    HBsAg hepatitis B surface antigen
    HBV hepatitis B virus
    HIV human immunodeficiency virus
    ICU intensive care unit
    INH isoniazid
    INR international normalised ratio
    InSTI integrase strand transfer inhibitor
    IPT isoniazid preventive therapy
    IRIS immune reconstitution inflammatory syndrome
    LAM lipoarabinomannan
    LDL-C low-density lipoprotein cholesterol
    LFT liver function test
    LP lumbar puncture
    LPV lopinavir
    LPV/r ritonavir-boosted lopinavir
    MDRD modification of diet in renal disease
    MTCT mother-to-child transmission of HIV
    MVC maraviroc
    NGT nasogastric tube
    NNRTI non-nucleoside reverse transcriptase inhibitor
    NRTI nucleoside reverse transcriptase inhibitor
    NTDs neural-tube defects
    NtRTI nucleotide reverse transcriptase inhibitor
    NVP nevirapine
    OI opportunistic infection
    PAS p-aminosalicylic acid
    PCR polymerase chain reaction
    PI protease inhibitor
    PI/r ritonavir-boosted protease inhibitor
    PMTCT prevention of mother-to-child transmission of HIV
    PPIs proton pump inhibitors
    PrEP pre-exposure prophylaxis
    QTc corrected QT interval
    RAL raltegravir
    RCTs randomised controlled trials
    RIF rifampicin
    RFB rifabutin
    RNA ribonucleic acid
    RPV rilpivirine
    RTV or /r ritonavir
    sCr serum creatinine
    sCrAg serum cryptococcal antigen
    TAF tenofovir alafenamide
    TAM thymidine analogue mutation
    TB tuberculosis
    TB-IRIS tuberculosis immune reconstitution inflammatory syndrome
    TBM tuberculosis meningitis
    TC total cholesterol
    TDF tenofovir disoproxil fumarate
    TG triglycerides
    TST tuberculin skin test
    UDP uridine 5’-diphospho
    ULN upper limit of normal
    VL viral load
    WHO World Health Organization
    WOCP women of childbearing potential








    NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITOR CLASS OF ANTIRETROVIRAL DRUGS
            Key points
     
    • The recommended nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) drugs for first-line therapy are tenofovir disoproxil fumarate (TDF) and either lamivudine (3TC) or emtricitabine (FTC).
    • Patients with a creatinine clearance rate (CrCl) < 50 mL/min should generally be started on abacavir (ABC) instead of TDF for first-line therapy.
    • Zidovudine (AZT) should only be used in special circumstances as a first-line drug.
    • TDF can cause renal failure or a renal-tubular wasting syndrome. Creatinine monitoring at regular intervals is recommended.
    • ABC can cause a fatal hypersensitivity reaction in patients with HLA-B*5701. If feasible, this allele should be excluded prior to starting ABC, although it is very rare in people of African descent.
    • AZT can cause anaemia and neutropenia, and regular monitoring of haemoglobin (Hb) and neutrophil count is recommended for the first 6 months.

    Available nucleoside/nucleotide reverse transcriptase inhibitors

    Nucleoside reverse transcriptase inhibitors (NRTIs) and nucleotide reverse transcriptase inhibitors (NtRTIs) work by acting as nucleotide base analogues. Following incorporation into the DNA chain by HIV’s reverse transcriptase enzyme, they block further chain elongation. A summary of NRTIs is provided in Table 1, and the appropriate baseline investigations and required monitoring are presented in Table 2. NRTIs may be available as single tablets or in fixed-dose combination (FDC). The latter is recommended where possible to decrease the overall pill burden. Many NRTIs require dose adjustment in renal failure (see Module 21).
     

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    TABLE 1: Dosage and common adverse drug reactions of nucleoside/nucleotide reverse transcriptase inhibitors available in southern Africa (adult dosing).
    Generic name Drug class Recommended dosage Common or severe ADR
    Tenofovir disoproxil fumarate (TDF) NtRTI 300 mg daily Renal failure, tubular wasting syndrome, reduced bone mineral density, nausea
    Lamivudine (3TC) NRTI 150 mg 12-hourly or 300 mg daily Anaemia (pure red cell aplasia) (rare)
    Emtricitabine (FTC) NRTI 200 mg daily Anaemia (pure red cell aplasia) (rare), palmar hyperpigmentation
    Abacavir (ABC) NRTI 300 mg 12-hourly or 600 mg daily Hypersensitivity reaction
    Zidovudine (AZT) NRTI 300 mg 12-hourly Anaemia, neutropenia, GI upset, headache, myopathy, hyperlactataemia/steatohepatitis (medium potential), lipoatrophy

    ARV, antiretroviral; ADR, adverse drug reaction; GI, gastrointestinal; NtRTI, nucleotide reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor.
    †, FTC is not available as a single drug in South Africa, only co-formulated.
    ‡, Life-threatening reactions are indicated in bold.

     

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    TABLE 2: Baseline investigations and monitoring required for nucleoside/nucleotide reverse transcriptase inhibitors.
    Generic name Monitoring required Comment
    TDF Creatinine before initiation, then at 3 months, 6 months, and then 6-monthly thereafter Avoid if eGFR < 50 mL/min.

    In high-risk patients (particularly those with co-existent hypertension or diabetes), creatinine should also be checked at 1 and 2 months.
    3TC None routinely required -
    FTC None routinely required -
    ABC HLA-B*5701 before initiation, if testing is affordable and available Allele very rare in people of African descent
    AZT Hb and neutrophil count before initiation, then at months 1, 2, 3 and 6 Avoid if Hb < 8 g/dL.

    If neutrophil count is 1–1.5 x 109, then repeat in 4 weeks.

    If neutrophil count is 0.75–0.99 x 109, then repeat in 2 weeks or consider switching from AZT.

    If neutrophil count < 0.75 x 109, then switch from AZT.

    3TC, lamivudine; ABC, abacavir; ADR, adverse drug reaction; AZT, zidovudine; eGFR, estimated glomerular filtration rate; FTC, emtricitabine; Hb, haemoglobin; TDF, tenofovir disoproxil fumarate.


    Lamivudine and emtricitabine

    Lamivudine (3TC) and emtricitabine (FTC) are well-tolerated drugs recommended as part of a first-line regimen. Although there are minor differences between them, 3TC and FTC are considered functionally interchangeable. Their use may be continued in the presence of ‘high-level resistance’ caused by the M184V mutation, since this mutation impairs HIV’s replication ability, causing a ~0.5 log decrease in VL. Therefore, the drugs are often used in second- and third-line therapies (see the management of patients on second-line ART in Module 13). 3TC and FTC are active against hepatitis B virus (HBV), but when used in the absence of a second drug active against HBV, such as TDF, resistance rates of approximately 50% at 1 year, and 90% at 5 years, are seen.3 See Module 20.

    Tenofovir disoproxil fumarate

    Tenofovir disoproxil fumarate (TDF) is the preferred drug in this class for use with 3TC or FTC in first-line therapy because it aligns with public sector programmes, is widely available as an FDC, and is generally well-tolerated. TDF also offers durable therapy against HBV. HBV resistance against TDF is exceedingly rare. In a minority of patients, TDF may cause a tubular wasting syndrome (including wasting of phosphate and potassium).4 If patients receiving TDF develop muscle weakness or other muscle symptoms, then potassium and phosphate levels must be assessed. TDF can also cause acute and chronic renal failure, but this is uncommon.5

    TDF should be switched to ABC or an alternative NRTI immediately in patients with acute renal failure, as it may exacerbate injury even if it is not the primary cause. Consider recommencing TDF with careful monitoring when the creatinine result is normal if an alternative cause of renal failure is established.

    We recommend estimating the creatinine clearance rate (CrCl) before commencing TDF; the drug should not be used if the estimated glomerular filtration rate (eGFR) or CrCl is < 50 mL/min. For monitoring while on TDF see Table 2. Where TDF is avoided because CrCl is < 50 mL/min at baseline, it may be possible to switch to TDF at a later point if renal function improves. This is often the case where patients had diarrhoea or other opportunistic infections (OIs) at the time of ART initiation.

    Common pitfall: Permanently discontinuing TDF in patients with transiently decreased CrCl. Most cases of acute kidney injury (AKI) are not because of TDF, and if another cause of AKI is identified (e.g. severe diarrhoea or pneumonia), then TDF can be re-introduced with monitoring once renal function improves.

    Long-term use of TDF together with other nephrotoxic agents (e.g. aminoglycosides or non-steroidal anti-inflammatory agents) should be avoided. TDF also causes a decrease in bone mineral density, but this is generally mild and non-progressive, and most studies have not found an increase in fracture risk.

    Abacavir

    Abacavir (ABC) can be used in patients with a CrCl < 50 mL/min at baseline, rather than TDF. ABC does not require dose adjustment in patients with renal failure and is especially useful in patients with chronic renal failure, where TDF is nephrotoxic and zidovudine (AZT) could aggravate the anaemia of renal failure. A meta-analysis showed that virological suppression is equivalent with ABC- and TDF-containing first-line regimens regardless of baseline VL.6

    Common pitfall: Avoiding ABC at high HIV VLs. This is unnecessary, as viral suppression rates are equivalent in meta-analyses.

    ABC has been associated with an increased risk of myocardial infarction in some but not all cohort studies; however, the association was not confirmed in a meta-analysis of randomised controlled trials (RCTs).6-8 Nevertheless, caution is recommended when considering ABC for patients who are at significant risk of, or have established ischaemic heart disease. ABC hypersensitivity is a systemic reaction occurring within the first 8 weeks of therapy in ~3% of cases. Fatalities may occur on rechallenge. ABC must be discontinued and never re-introduced if hypersensitivity is suspected. The manifestations of hypersensitivity include fever, rash, fatigue and abdominal or respiratory symptoms. If there is any doubt concerning the diagnosis (e.g. if the patient has a cough with fever), then the patient should be admitted for observation of the next dose; symptoms progress if hypersensitivity is present. The hypersensitivity reaction has been shown to occur on a genetic basis, with a very strong association with the HLA-B*5701 allele. This allele is very uncommon in people of African descent; thus, ABC hypersensitivity is less frequent. If testing is affordable and available, then the presence of HLA-B*5701 should be excluded prior to prescribing ABC, especially in patients who are not of African descent.

    Zidovudine

    We now recommend reserving zidovudine (AZT) for use only in special circumstances in first-line therapy. If both TDF and ABC are unavailable or contraindicated, then AZT should be used, provided that haemoglobin (Hb) is > 8 g/dL.

    Additional syndromes related to nucleoside reverse transcriptase inhibitors
    Haematological toxicity

    Cytopenias occur commonly in HIV infection without exposure to ART. Patients receiving AZT or cotrimoxazole (CTX) may experience full blood count (FBC) abnormalities. AZT can cause anaemia and neutropenia; platelet counts generally rise with the use of the drug. Monitoring is necessary with AZT (see Table 2). It is unusual, however, to see haematological toxicity develop after 6 months. Macrocytosis is usual with AZT therapy and is of little consequence. Routine measurement of vitamin B12 and folate concentrations is not needed.

    Common pitfall: Discontinuing AZT because of macrocytosis. This is of little consequence, and does not necessarily portend subsequent anaemia.

    Pure red cell aplasia, which presents with severe anaemia and a low reticulocyte production index, has rarely been associated with 3TC and FTC.9,10 A bone marrow examination should be performed to confirm the condition. A polymerase chain reaction (PCR) test should be conducted to exclude parvovirus B19 infection. If 3TC and FTC are contraindicated due to pure red cell aplasia, then we suggest contacting an expert for advice about alternative regimens.

    Hyperlactataemia and lactic acidosis

    Lactic acidosis is a rare but serious and potentially fatal side-effect of NRTIs, most commonly associated with stavudine (d4T), particularly when combined with didanosine (ddI). These drugs are no longer used. It can also occur occasionally with AZT. Symptomatic hyperlactataemia without acidosis is more common and is associated with the same drugs. Neither lactic acidosis nor hyperlactataemia without acidosis is seen with the newer, safer NRTIs such as TDF, ABC, 3TC or FTC. Symptoms are non-specific and include nausea and vomiting, abdominal pain, dyspnoea, fatigue and weight loss. A raised lactate (> 5 mmol/L) together with metabolic acidosis confirms a diagnosis of lactic acidosis. Low serum bicarbonate (< 20 mmol/L) is the most sensitive marker of acidosis. Patients receiving AZT who develop hyperlactataemia should be switched to alternative drugs, and lactate monitored serially until resolution. In severe cases, admission may be required.

    Lipoatrophy

    The thymidine analogue NRTIs (AZT and especially d4T) are associated with subcutaneous fat loss (most noticeable in the face, limbs and buttocks). Lipoatrophy improves when d4T/AZT are substituted with TDF or ABC, but resolution is very slow and often incomplete; therefore, it is important to recognise lipoatrophy early or, better still, to use NRTIs that are not associated with the condition. Although d4T is no longer used, patients who received it historically may still have lipoatrophy.