ART Guidelines

ART Guidelines

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    /r ritonavir-boosted
    3TC lamivudine
    ABC abacavir
    ADR adverse drug reaction
    AKI acute kidney injury
    ALT alanine transaminase
    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
    CrAg cryptococcal antigen
    CrCl creatinine clearance rate
    CSF cerebrospinal fluid
    CTX cotrimoxazole
    CVS cardiovascular
    d4T stavudine
    DILI drug-induced liver injury
    DNA deoxyribonucleic acid
    DOR doravirine
    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
    FDC fixed dose combination
    FTC emtricitabine
    GI gastrointestinal
    Hb haemoglobin
    HBsAg hepatitis B surface antigen
    HBV hepatitis B virus
    HIV human immunodeficiency virus
    ICU intensive care unit
    InSTI integrase strand transfer inhibitor
    IPT isoniazid preventive therapy
    LAM lipoarabinomannan
    LDL-C low-density lipoprotein cholesterol
    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
    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
    PWH people with HIV
    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
    ULN upper limit of normal
    VL viral load
    VTP vertical transmission prevention of HIV
    WHO World Health Organization

            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 an estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73m2 or osteoporosis should generally be started on abacavir (ABC) instead of TDF for first-line therapy, provided they do not have chronic hepatitis B infection.
    • Tenofovir alafenamide (TAF) is recommended instead of TDF or ABC for patients with hepatitis B and an eGFR 30-50 mL/min/1.73m2, or osteoporosis. It can be considered as an alternative to ABC for patients without hepatitis B but with an eGFR 30-50 mL/min/1.73m2 or osteoporosis.
    • Zidovudine (AZT) should only be used in special circumstances.
    • Tenofovir can cause renal failure or a renal-tubular wasting syndrome. Serum 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. Routine testing for HLA-B*5701 is not currently part of the standard of care in the public sector.
    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 in Table 2. NRTIs may be available as single tablets or in fixed dose combinations (FDC). The latter is recommended where possible to decrease overall pill burden. Many NRTIs require dose adjustment in renal failure (see module 21).


    Tenofovir is available in two oral prodrug forms: tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Both are converted to the pharmacologically active form, tenofovir diphosphate, intracellularly. Similar to 3TC/FTC, when tenofovir has been part of an initial ART regimen, it may be continued in subsequent regimens even in the face of high-level resistance, as sufficient antiviral activity is maintained if combined with drugs with a high genetic barrier to resistance. 4

    Both forms of tenofovir offer durable therapy against hepatitis B virus (HBV) as HBV resistance against tenofovir is exceedingly rare. In a minority of patients, tenofovir may cause a tubular wasting syndrome (including wasting of phosphate and potassium). 5 If patients receiving tenofovir develop muscle weakness or other muscle symptoms, then potassium and phosphate levels must be assessed. Tenofovir can also cause acute and chronic renal failure, but this is uncommon. 6 Long-term use of TDF together with other nephrotoxic agents (e.g. aminoglycosides or non-steroidal anti-inflammatory agents) should nonetheless be avoided.

    TDF also causes a decrease in bone mineral density, but this is generally mild, and most studies have not found an increase in fracture risk.

    Of the two forms of tenofovir, we recommend TDF as the drug for use with 3TC or FTC in most instances, as it aligns with public sector programmes, is more widely available as a FDC, and is generally well-tolerated. TDF should not be used if the estimated glomerular filtration rate (eGFR) is < 50 mL/min/1.73m2.

    TAF has fewer renal and bone side-effects than TDF, although the extent of this has been questioned. 7, 8 When coformulated with 3TC/FTC, TAF can be given down to a minimum eGFR of 30 mL/min/1.73m2. However, if given as a separate tablet, TAF can be given down to an eGFR of 15 mL/min/1.73m2, as well as to patients on chronic haemodialysis. Compared to TDF, TAF is associated with greater weight gain, an adverse lipid profile, and several important drugdrug interactions (see module 17 for more details). 9- 11 The TAF 25mg dose currently available in South Africa should not be used with ritonavir-containing PI regimens. Although rifampicin reduces serum TAF levels, intracellular concentrations of the active tenofovir metabolite are in fact higher than achieved with TDF, and thus rifampicin-based TB treatment is safe to co-administer. 12 TAF/FTC combinations can be considered as an alternative to TDF in patients with eGFR 30-50 mL/min/1.73m2 or with osteoporosis, although abacavir (ABC) is also available in these instances as an alternative. TAF is recommended in patients who have one or more of these conditions and hepatitis B.

    Tenofovir (either TDF or TAF) should be switched to ABC or an alternative NRTI immediately in patients with acute kidney injury, as it may exacerbate injury even if it is not the primary cause. Consider recommencing tenofovir (either TDF or TAF) with careful monitoring when the eGFR returns to baseline and if an alternative cause of renal failure is established. In patients in whom tenofovir is avoided because of a low eGFR at baseline, it may be possible to switch to tenofovir 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.

    For monitoring while on TDF see Table 2.

    Common pitfall: Permanently discontinuing TDF in patients with a transiently decreased eGFR. Most cases of acute kidney injury (AKI) are not due to 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.

    Lamivudine and emtricitabine

    Lamivudine (3TC) and emtricitabine (FTC) are welltolerated drugs recommended as part of a firstline 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 viral load (VL). Therefore, these drugs are often also recycled in second- and third-line therapy (see the management of patients on second-line ART in module 13). 3TC and FTC are active against hepatitis B, but when used in the absence of a second drug active against hepatitis B, such as TDF, then resistance rates of approximately 50% at 1 year, and 90% at 5 years, are seen. 1 See module 20.

    Pure red cell aplasia (PRCA), which presents with severe anaemia and a low reticulocyte production index, has rarely been associated with 3TC and FTC. 2, 3 A bone marrow examination should be performed to confirm the condition. Parvovirus B19 infection should be excluded with a polymerase chain reaction (PCR) test. If 3TC and FTC are contraindicated due to PCRA, then we suggest contacting an expert for advice about alternative regimens (see module 11 for some 3TC/FTC-sparing regimen options).


    Abacavir (ABC) does not require dose adjustment in renal failure and is especially useful in patients with chronic renal failure, in whom tenofovir is nephrotoxic and zidovudine (AZT) could aggravate the anaemia of renal failure. A meta-analysis showed that virological suppression is equivalent with ABCand TDF-containing first-line regimens regardless of baseline VL. 13

    Common pitfall: Avoiding ABC in patients with a high VL. This is a common misconception and 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 other cohort studies, but the association was not confirmed in a meta-analysis of randomised controlled trials (RCTs). 13- 15

    ABC hypersensitivity is a systemic reaction occurring within the first 8 weeks of therapy in ~6% of people of European ancestry. 16 Fatalities may occur on rechallenge. ABC must be discontinued and never reintroduced 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: if symptoms progress, 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.


    We recommend reserving zidovudine (AZT) for use only in special circumstances where both tenofovir and ABC are unavailable or contraindicated. In these instances, AZT can be used, provided that the haemoglobin (Hb) is > 8 g/dL. AZT can cause neutropenia and anaemia; 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 no consequence. Routine measurement of vitamin B12 and folate concentrations is not needed.

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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
    Tenofovir alafenamide (TAF) NtRTI 25 mg daily Less renal failure and bone mineral reduction than TDF, but more weight gain and worse lipid profile
    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, gastrointestinal upset, headache, myopathy, hyperlactataemia/ steatohepatitis (medium potential), lipoatrophy
    ARV, antiretroviral; ADR, adverse drug reaction; 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.


    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/L, then repeat in 4 weeks.

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

    If neutrophil count < 0.75 x 109/L, then switch from AZT.
    eGFR, estimated glomerular filtration rate; Hb, haemoglobin.