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

    Liver Disease
            Key points
    • There is no single blood test for accurate quantification of liver impairment.
    • Child-Pugh class C liver disease may require dose adjustment for some ART drugs
    • ATV can cause jaundice due to elevation of unconjugated bilirubin (indirect) which is benign.
    • The combination of TDF (or TAF) + 3TC (or FTC) + DTG is regarded as least hepatotoxic.
    Antiretroviral dose adjustments

    Table 22 outlines dose adjustments for the relevant ART drugs in patients with Child-Pugh class C liver impairment 1.

    TABLE 22: Prescribing antiretroviral therapy in liver impairment.
    Class Drug Prescribing notes
    NRTI TDF No dose adjustment necessary.
    3TC No dose adjustment necessary.
    FTC No dose adjustment necessary.
    AZT Decrease dose by 50% or double dosage interval in significant liver disease.
    ABC Reduce adult dose to 200 mg twice daily in significant liver disease.
    Contraindicated in severe liver disease.
    InSTI DTG No data on recommendation for those with severe liver disease (Child-Pugh class C).
    RAL No dose adjustment necessary.
    PI DRV Use with caution or avoid in significant liver disease.
    ATV Avoid in severe liver disease.
    LPV/r LPV is highly metabolised in the liver and concentrations may be increased in patients with hepatic impairment. Therapeutic drug monitoring should be done if available.
    NNRTI EFV Not recommended in severe liver disease.
    ETR Use with caution in severe liver disease.
    RPV Use with caution in severe liver disease (Child-Pugh class C) – dose recommendation not established.
    CCR5 blocker MVC Concentrations likely to be increased with liver impairment.
    3TC, lamivudine; ABC, abacavir; ATV, atazanavir; ARVs, antiretrovirals; AZT, zidovudine; CCR5, C-C chemokine receptor type 5; DTG, dolutegravir; DRV, darunavir; EFV, efavirenz; ETR, etravirine; FTC, emtricitabine; InSTI, integrase strand transfer inhibitor; LPV, lopinavir; LPV/r, lopinavir/ ritonavir; MVC, maraviroc; NNRTI, non-nucleoside reverse transcriptase inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate.

    1 The Child-Pugh score consists of five clinical features and is used to assess the prognosis of chronic liver disease and cirrhosis. Five factors (total bilirubin level, serum albumin, and international normalized ratio, or INR, degree of ascites and hepatic encephalopathy) are graded into a composite score and divided into 3 classes. Class C represents a score of 10-15 and is associated with a 45% one-year survival (

    Concomitant hepatitis B and HIV
            Key points
    • All patients with HIV should be screened for active hepatitis B virus (HBV) – hepatitis B surface antigen (HBsAg) screening is an appropriate test.
    • The HBV VL correlates with disease progression and is used to monitor anti-HBV therapy
    • All children and adults eligible for HBV vaccination should be vaccinated.
    • ART drugs with anti-HBV activity are TDF (or TAF) + 3TC (or FTC).
    • For all HIV-positive HBsAg-positive patients, the ART regimen should include TDF (or TAF) + 3TC (or FTC).
    • Using 3TC without TDF to treat concomitant HBV/HIV leads to HBV resistance in most patients.
    • Interruption of TDF (or TAF) and/or 3TC (or FTC) has been associated with flares of life-threatening hepatitis in patients with hepatitis B.
    • For patients with chronic HBV infection and chronic kidney disease, options include TAF (down to eGFR of 15 ml/min/1.73m2 or for those on intermittent haemodialysis) and/or adjustment of the dosing frequency of TDF. If renal function is severe or deteriorates with TDF (or TAF), then 3TC monotherapy or other drugs with anti-HBV activity should be considered.

    Hepatitis B virus (HBV) is a common concomitant infection with HIV in Southern Africa, with significant implications for progression to cirrhosis, as well as for treatment options. Access to vaccination, laboratory resources and treatment options are to some extent limited in Southern African countries, and each recommendation below should each be considered in the light of its local context.

    Concomitant HBV/HIV is associated with

    • an increased risk of chronic liver disease
    • a higher HBV VL
    • an increased risk of drug-induced hepatotoxicity
    • a flare of hepatitis within 3 months of commencing ART (due to HBV-related IRIS, which is difficult to differentiate from drug hepatotoxicity)

    Drugs directed against HBV that have no or minimal anti-HIV activity (e.g. entecavir and telbivudine) are largely unavailable or extremely expensive in our region. Instead, it is usually necessary to use ART drugs that also have anti-HBV activity: TDF (or TAF) + 3TC (or FTC). As with HIV, these drugs suppress HBV, but do not eradicate it. Effective treatment prevents or slows progression to cirrhosis. For all HIV-positive hepatitis B surface antigen (HBsAg)-positive patients, the ART regimen should include TDF (or TAF) + 3TC (or FTC). Using 3TC without including TDF/TAF leads to the development of HBV resistance in 80–90% of patients within 5 years of treatment. 114 If a patient switches to a second-line ART regimen (to treat HIV), then tenofovir (either TDF or TAF) + 3TC (or FTC) should be continued to suppress HBV infection, as interruption of tenofovir and/or 3TC/FTC has been associated in case reports with flares of life-threatening hepatitis in case reports. 115 The second-line ART regimen should be shaped around these two drugs.

    In patients with HBV and chronic kidney disease, the following options can be considered for hepatitis B treatment:

    • TAF + FTC/3TC (preferred). 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 administered down to an eGFR of 15 mL/min/1.73m2, as well as to patients on chronic haemodialysis. Dose-adjusted 3TC can be given with this (see module 21).
    • TDF may be considered with dosing frequency adjustment based on eGFR (Table 23) and with more frequent monitoring.
    • If renal dysfunction is severe or renal function deteriorates with TDF, then 3TC monotherapy or other drugs with anti-HBV activity should be considered.
    • For information on the management of partners of those with HBV see the National guidelines for the management of viral hepatitis here.

    TABLE 23: Suggested TDF dose adjustment in patients with hepatitis B and renal dysfunction if TAF not available. Use TAF- preferentially if eGFR between 30 and 50 ml/min/1.73 m2
    (mL/min/1.73 m2)
    Suggested dose of TDF
    ≥ 50 Usual dose
    30–49 300 mg every 48 hours
    10–29 300 mg every 72–96 hours
    < 10 Avoid (consider 3TC monotherapy, or other drugs with anti-HBV activity)
    Haemodialysis 300 mg every week (dose after dialysis on dialysis days)

    3TC, lamivudine; eGFR, estimated glomerular filtration rate; HBV, hepatitis B virus; TDF, tenofovir disoproxil fumarate.

    Common pitfall:
    • Not continuing with a combination of TDF (or TAF) + 3TC (or FTC) when switching to secondline ART. The second-line ART regimen should be shaped around these two drugs.
    • Using 3TC without including TDF or TAF in the treatment of HIV/HBV co-infected patients.
    • Not reviewing other causes of liver disease in patients with concomitant hepatitis B and counselling them about risks (e.g. alcoholic liver disease).