Integrated HIV Training for Healthcare Workers

Session 11: Monitoring Clients on ART

Treatment Failure and Second- and Third-Line Therapy

In this section you’ll learn about ART treatment failure including how it is diagnosed and procedures used to switch a client from a first-line therapy to a second- or third-line therapy.

Learning Objectives

By the end of this session you will be able to:

  • Explain how to diagnose ART treatment failure.
  • Describe viral load testing strategies.
  • Explain the recommended second-line therapy used in Zimbabwe.
  • Discuss third-line therapy.
  • Reading: Monitoring for Treatment Failure (10 min)
    Garikai

    Garikai is a 12-year-old boy who started ART (ABC/3TC/EFV) and cotrimoxazole when he was seven. His paternal grandmother was taking care of him and he was doing well on treatment. When his grandmother died two years ago, he went to stay with a paternal aunt. He started missing his monthly appointments and during a home visit, it was obvious that Garikai’s aunt could not cope with taking care of her family and him.

    The social worker spoke with his family and one of his maternal aunts agreed to take care of Garikai. When Garikai came into the clinic, having missed three previous appointments, he seemed a happier child, but was noted to be losing weight. In three months, he had lost 5 kg (27 kg to 24 kg). He also said that he had a low grade fever (37.8 degrees Celsius). In addition, his aunt reported that Garikai had a cough a month ago, but it was not continuous.

    During this visit, blood was taken for VL, CD4, FBC, LFTS and renal function. Garikai was given a prescription for amoxicillin and a CXR was ordered to be done at the district hospital and he and his aunt were instructed how to obtain a sputum specimen since he was not coughing during this visit. They were instructed to return to the clinic if his symptoms worsened.

    When Garikai came back a week later for his follow-up visit, he seemed happier, but still had a fever and was complaining of abdominal pain. His aunt said that he was not eating well and he had lost a further 500 gm. The viral load result was 110,000 cp/mL. His chest x-ray revealed a widened mediastinum and right lower lobe infiltrate. The healthcare worker met with Garikai and his aunt and explained that his blood test results showed that the HIV was not controlled and the chest x-ray showed some changes that might indicate he had TB. He was referred to the district hospital further TB testing and management and possible HIV treatment failure.

    Monitoring for Treatment Failure

    In Session 10 we learned about the goals of ART. If you remember, an ART regimen is used to reduce the amount of virus in the body (viral load) to a level that can no longer be detected with current blood tests and increase the CD4 count as much as possible.

    As explained in previous sections of this session, clinical, immunologic, and virological methods are used to monitor clients on ART. These methods of monitoring can tell us whether or not ART is successful at reaching its goal and they can also be used to detect treatment failure. Treatment failure occurs when the HIV infection is no longer controlled by an ART regimen. Causes for treatment failure include poor treatment adherence, drug resistance, drug-drug interactions and drug toxicity.

    A client must be on ART for at least six months with good adherence before we can consider treatment failure. If a client becomes unwell during these first six months on ART, he or she may be experiencing IRIS or a new opportunistic infection. Tap on each monitoring method to learn more:

    Clinical monitoring

    Successful ART regimen

    When you are unable to test viral load or CD4, clinical monitoring is used to see if the prescribed therapy is reaching its goal. When the ART regimen is successful, the body's defense mechanism will improve. If the body's defense mechanism works better, fewer OIs should occur.

    signs of successful ART regimen

    For this reason, assessing the client’s clinical status at each visit and evaluating for new or worsening infections is a good way to evaluate if therapy is working effectively. If therapy reaches its goal, the client’s overall health should improve and energy and weight should increase without the occurrence of new OIs.

    Clinical failure

    You will diagnose an adult client with clinical failure when he or she has a new or recurrent clinical event indicating severe immunodeficiency (WHO stage 4 clinical condition) after six months of effective treatment. A child should be diagnosed if he or she has a new or recurrent clinical event indicating advanced or severe immunodeficiency (WHO stage 3 and 4 clinical conditions with exception of TB) after six months of effective treatment.

    It’s important not to confuse clinical failure with IRIS or drug toxicity. In most cases, when clients have symptoms that appear shortly after starting ART, it may be due to IRIS or a drug toxicity. When new symptoms appear at least six months after starting ART you can suspect treatment failure. If new symptoms appear or preexisting symptoms do not improve, or if their weight is decreasing, suspect clinical failure. Remember, new symptoms appearing in the first six months of ART are rarely due to failure. Follow-up all clinical changes with a viral load test (if available) or CD4 count to confirm clinical failure before any changes in the ART regimen.

    Immunologic monitoring

    Successful ART regimen

    The problem with using clinical assessment alone for monitoring treatment failure is that it takes a few months after a client’s CD4 has dropped for clinical manifestations indicating treatment failure to appear. Therefore, testing CD4 count is a better way to identify treatment failure sooner.

    A CD4 count is done at baseline to identify clients that may need additional preventative or treatment for cryptococcal disease (CD4 count less than 100 cells/mm3). CD4 count will be repeated every six months. If the client changes his or her therapy, you will also want to conduct a CD4 test before starting the new regimen.

    It’s important to remember that the time it takes to see the number of CD4 cells increase varies from person to person and depends on the CD4 count that the client starts with. In the first year, if a client has never taken ART before and has good adherence, you can expect to see the CD4 count rise by 50 to up to 200 points. If a client starts with a lower CD4 count, it may take longer before the CD4 count increases.

    Immunologic failure

    When the number of CD4 cells starts to decrease in a client who is taking ART, it can indicate immunologic failure. However, a small decrease in CD4 may not indicate failure, which is why it’s best to call for advice when you have a client whose CD4 count drops.

    Adults and adolescents are classified as having immunological failure when their CD4 counts fall to or below the baseline or they have persistent CD4 levels below 100 cells/mm3. Children have immunological failure when their CD4 count decreases to their pre-therapy number. Children younger than five years of age have immunological failure when they have persistent CD4 levels below 200 cells/mm3 or CD4 less than 10%. Children older than five years old have immunological failure when they have persistent CD4 levels below 100 cell/mm3.

    Virological monitoring

    Successful ART regimen

    With optimal adherence (over 95%), the viral load (VL) usually decreases to undetectable levels within six months of starting an ART regimen. The plasma VL should be less than 1000 copies/mL, or 1000 copies/mL if using DBS technology.

    Virological failure

    Virologic failure results when the viral load isn’t completely suppressed, leading to resistance. Virological failure is defined for adults, adolescents, and children as a viral load of 1000 copies/mL and above based on two consecutive viral load measurements after three months of enhanced adherence counselling (EAC) and good adherence.

    Virologic failure is noticeable before immunologic or clinical failure, which makes it the gold standard for monitoring response to ART. Ideally, you should conduct VL testing at 6 and 12 months after initiation of ART and then annually on PLHIV clients as shown in the following algorithm.

    VL testing algorithm
  • Reading: Recommended Second-Line Regimens (10 min)

    Switching to Second-Line

    It’s important to note that a second-line regimen should only be started after consultation with an appropriate specialist in HIV and AIDS care and treatment or a mentor. It’s also prudent to attempt to improve adherence to the old regimen, before switching. Often ART failure is caused by poor adherence and the VL will improve as adherence improves. If there is still virological failure after at least 24 weeks (6 months) on ART and the client is adherent to his or her medication, it’s then recommended to switch to second-line therapy.

    Prior to switching, exclude IRIS, diagnose and treat any intercurrent OIs, if possible conduct a mental health assessment using the Shona Symptom Questionnaire and thoroughly assess for alcohol and/or substance use and if so, refer for mental health and/or substance use counselling. Make sure the client is getting adequate nutrition

    Second-Line Therapy for Children

    For children on ART, the main clinical indications to switch treatment are the:

    • Development of a new or recurrent WHO stage 3 or 4 event at least 24 weeks (6 months) after starting ART with a first-line regimen
    • Lack or decline in growth rate in children who showed an initial response to treatment
    • Loss of neurodevelopmental milestones
    • Development of encephalopathy
    • Occurrence of new OIs or malignancies
    • Recurrence of infections

    Treatment failure must be confirmed by viral load testing before switch to second-line. Second-line regimens for children are limited by the lack of available paediatric formulations. Consequently, start a second-line regimen only after consultation with a specialist in HIV/AIDS care and treatment. Overall, the same principles are used when prescribing second ART for children as for adults—the combination depends on the medications used in the first-line regimen.

    Second-Line Treatment Regimens

    The recommended second-line treatment regimen varies depending on the population being treated. Below you will find second-line treatment recommendations based on the 2016 Guidelines for Antiretroviral Therapy for the Prevention and Treatment of HIV in Zimbabwe, which are also available in the resources section of this training. Tap on the following age groups to read more:

    Adolescents (10 years or older), adults, and pregnant/breastfeeding women

    For adolescents 10 years or older, adults, and pregnant or breastfeeding women where TDF was used in the first-line ART, it’s recommended to use AZT + 3TC + ATV/r or LPV/r as a second-line treatment regimen.

    If AZT was used in the first-line ART instead of TDF, use TDF + 3TC + ATV/r or LPV/r as a second line-treatment regime.

    HIV and TB coinfection

    If clients are receiving rifampicin, the preferred second-line regimen is to use the same NRTI backbone as recommended for adults and adolescents plus doubling the dose LPV/r (800 mg/200 mg BD).

    HIV and HBV coinfection

    For clients with HIV and hepatitis B (HBV) coinfections, it's recommended to use AZT + TDF +3TC (or FTC) + ATV/r or LPV/r*

    ** ATV/r is the preferred PI in all cases

    Children

    The chart below goes over second-line therapy recommendations for children depending on their age range:

    Age First line Second line Third line
    0-2 weeks AZT + 3TC + NVP RAL + 2 NRTIs
    DRV/r + 2 NR-TIs
    DRV/r + RAL
    plus or minus 1 to 2
    2 weeks to less than 3 years

    Preferred: ABC + 3TC + LPV/r

    Alternative: AZT + 3TC +LPV/r
    ABC + 3TC + NVP

    Preferred: AZT + 3TC + RAL

    Alternative: ABC + 3TC + RAL
    3 years to less than 10 years

    Preferred: ABC + 3TC + EFV

    Alternative: AZT + 3TC + EFV
    AZT + 3TC + NVP
    TDF + 3TC + EFV (or NVP)

    Preferred: AZT + 3TC + LPV/r or RAL

    Alternative: ABC + 3TC + LPV/r
    ABC + 3TC + ATV/r
  • Reading: Recommended Third-Line Regimens (10 min)

    Prior to recommending third-line medicines, refer clients who are failing second-line therapy to a specialist for assessment which may include viral load and genotype testing. Below you will find third-line treatment recommendations based on the 2016 Guidelines for Antiretroviral Therapy for the Prevention and Treatment of HIV in Zimbabwe, which are also available in the resources section of this training. Tap on the following age groups to read more:

    Adults

    Adults should take dolutegravir (50 mg) and darunavir (600 mg)/ritonavir (100 mg) twice daily (for PI-experienced clients). Raltegravir (400 mg) twice a day can be used when dolutegravir is not available. In addition, adults should continue to take any other medicines as determined by the laboratory tests. If a genotype was done, there may be an indication to include a fourth ARV that is sensitive.

    Children

    When considering switching a child to a third-line treatment regimen, consult a paediatrician regarding their doses. Darunavir and an intergrase inhibitor (dolutegravir/raltegravir) are the backbone for third-line ART in both children and adults.

  • Quiz: Knowledge Check (10 min)

    1Which of the following are causes for treatment failure? (Select all that apply)

    2Which of the following patients is exhibiting signs of ART treatment failure?

    3Match the definition with the type of failure:

    4Why is viral load monitoring considered the gold standard for monitoring for treatment failure? If viral load is not available, what is the second best option and why? Write down your answer and then tap the compare answer button to compare your answer to an expert's.

    5In the beginning of this section we read about Garikai. He’s taking ABC/3TC/EFV as his first-line ART. When switching him to a second-line regimen, what medications could be used? (Select all that apply.)

    6If after 3 years, Garikai is not responding to the second-line therapy, what should you do?

  • Reading: Key Points (5 min)
    • A diagnosis of treatment failure should only be considered in a client who has been taking ART for at least 6 months.
    • There are clinical and immunological criteria for diagnosing treatment failure, but the gold standard is the VL.
    • Poor adherence must be excluded before a diagnosis of treatment failure is made.
    • Switching to second-line therapy is recommended if there is confirmed virological failure after at least 24 weeks on ART.
    • Rifampicin based TB treatment interacts with ARVs, hence, care must be taken when treating TB-HIV co-infected clients.