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5 Management of patients on antiretroviral treatment

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Contents

Objectives

When you have completed this chapter you should be able to:

  1. Describe the first treatment visit.
  2. List the schedule of follow-up visits.
  3. Explain what is done at each visit.
  4. List what blood tests are needed.
  5. Define treatment success and failure.
  6. Manage patients on successful treatment.
  7. Manage patients with failed treatment.
  8. Promote excellent adherence.
  9. Explain the dangers of drug resistance.
  10. Describe the immune reconstitution syndrome.

Starting antiretroviral treatment

5-1 What are the goals of antiretroviral treatment?

  1. The patient should feel well and have few illnesses related to HIV infection.
  2. The CD4 count should increase and remain above the baseline count.
  3. The viral load should become undetectable and remain undetectable.

Antiretroviral treatment (ART) reduces the multiplication of HIV and this allows the immune system to recover. As a result the patient loses the symptoms and signs of HIV infection and is able to return to a normal lifestyle. ART therefore decreases both the morbidity and mortality related to HIV. ART is usually started at an antiretroviral clinic. ART may also be started in a TB clinic for TB patients, at a MOU for pregnant women or in a hospital or hospice for very sick patients.

The main goal of antiretroviral treatment is to get the patient well again.

Note
An extended programme of free ART was started in South Africa in 2004.

5-2 What is an antiretroviral clinic?

This is a clinic where antiretroviral treatment is started and managed. Patients are referred to the antiretroviral clinic to start HIV treatment. An antiretroviral clinic is staffed by doctors and nurses who have had special training in the use of antiretroviral drugs (ARVs) and the management of patients on these drugs.

5-3 What is the first antiretroviral treatment visit?

This is the visit when ART should be started (i.e. commencement visit) if there are no contraindications to starting ART. The aim is to initiate treatment within 7 days of diagnosis. At the first ART visit the following should be done:

  1. Counselling on HIV infection, HIV medications, importance of adherence to medications and general healthy living. The patient sees the doctor or nurse where:
    • A history is taken
    • Clinical examination done including weight and vital signs
    • An assessment of HIV infection made
    • Search for co-morbidities is done (TB screening, STI screening, pregnancy screening)
    • Baseline investigations are done, that include CD4 count, syphilis testing (RPR), kidney function(creatinine test) and others if clinically indicated.
  2. The doctor or nurse then discusses treatment options with the patient. Give information on first line regimen, side effects, dosing information and re-inforce the importance of adherence to treatment.
  3. If patient is eligible for preventative medications, such as clotrimoxazole, they should be prescribed if the CD4 count is available and below 200 cells/µl.
  4. The patient can be given a patient-carried treatment card, which may be combined with the appointment card.
  5. The patient’s details are entered into the ART register or electronic database.
  6. An HIV summary record is started which will be kept by the clinic and updated by the doctor or nurse at each visit. Examination notes from the screening visits should be included.
  7. The instructions and dosing are reinforced by the clinician, pharmacist and counsellor. Ideally, the instructions should be clearly written on the pill container with a permanent marker.
  8. The patient is given 1 month’s supply of drugs by the pharmacist. Each person in the team makes sure that the patient understands which medicine to take, how much and when. They also check that the patient knows the side effects of the drugs to be taken and the importance of excellent adherence.

If possible, antiretroviral treatment should be started within 7 days of HIV diagnosis.

5-4 What is a patient-carried HIV treatment card?

This is a treatment card kept by the patient (similar to the antenatal cards and Road-to-Health cards). It includes all the important information about the patient’s management. Patient-carried cards are a very important tool in helping patients become responsible for their care. It also improves communication between health facilities. Managing HIV infection like any other disease helps to reduce stigma. This information is usually incorporated into the appointment card, similar to a TB card.

5-5 What antiretroviral regimen is used for first-line treatment?

The current first line regimen for the treatment of HIV is tenofovir (TDF), emtricitabine (FTC) and dolutegravir (DTG) given as a fixed dose combination (FDC) tablet once a day, as recommended by the WHO and South African National Department of Health October 2019).

Until this recent change, almost all patients were started on the first-line single dose combination tablet of TDF, FTC and efavirenz. Nevirapine or Aluvia was used instead of efavirenz for patients with psychiatric disorders or other contraindications to efavirenz, e.g. shift workers who would not want to take their medication before starting night shift. These remain options for patient who have contraindications to dolutegravir.

All patients who have previously been started on a first-line regimen containing d4T should have the d4T changed to TDF.

Treatment is almost always started with the first-line combination of TDF, FTC and DTG as a daily combination tablet.

5-6 What other medication will be given?

If prescribed, co-trimoxazole prophylaxis will be continued until the CD4 count is above 200 cells/µl. This usually implies that prophylaxis is continued for at least the first 6 months of ART.

5-7 How often are these patients seen at the antiretroviral clinic?

Usually patients are seen at the antiretroviral clinic at 1, 2 and 4 months after starting treatment. Then 2 to 4 monthly if all is well.

Patients who are taking nevirapine have an extra visit 2 weeks after starting treatment as they need to be assessed for possible side effects and the dose of nevirapine needs to be increased from the starting dose of 1 tablet daily to 1 tablet twice daily at this visit.

5-8 How often should education and counselling be offered?

At every clinic visit. The importance of excellent adherence and support must always be stressed. Patients must have an opportunity to ask questions or discuss problems.

The patient should be counselled at every visit.

5-9 Who are the members of the multi­disciplinary team at the antiretroviral clinic?

  1. The doctor or NIMART trained nurse, who should take a history and perform a general examination at the first treatment visit, and again if necessary at follow-up visits.
  2. The nurse, who should see the patient to complete the treatment register, where applicable, and take the necessary blood samples. The nurse or counsellor should also check adherence at every visit.
  3. The counsellor/educator, who should see the patient at every visit.
  4. The pharmacist, who should provide the ARVs and advise the patient on how to take them every time medicines are dispensed.
  5. Trained lay counsellors and community care workers are very important members of the health team.

Therefore all the staff members make up the multidisciplinary team.

Follow-up visits

5-10 What should be done at the follow-up visits?

  1. A pill count is recommended to be done before the patient sees the doctor.
  2. A history is taken for adherence, side effects and any other problems.
  3. The patient is weighed.
  4. A general examination is completed.
  5. Family planning and the use of condoms are discussed with each patient.
  6. The patient is counselled.
  7. Routine blood samples are taken if indicated.
  8. Condoms are dispensed.

5-11 How often are the medicines given by the clinic?

Every 1 to 2 months. A missed visit for medication suggests poor adherence. When medicine is collected the patient should see a counsellor who will assess adherence and ask about side effects. If there are side effects the patient should be seen by a clinician. Excellent adherence must be promoted at every visit. The ART register or electronic database must be updated each time medication is provided.

If a patient is not well they should be encouraged to attend clinic before their date and not to wait.

5-12 What blood tests are routinely done during the first year of first-line treatment?

  1. Creatinine clearance monitoring is done at baseline, 1, 4 and 12 months for patients on TDF. Then annually.

    Note
    The 2014 SA HIV Clinicians Society Guidelines recommend that high-risk patients (particularly those with coexistent hypertension or diabetes) should also have creatinine checked at 1 and 2 months after starting ART.
  2. A haemoglobin level and differential count should be done at baseline, 1, 2, 3 and 6 months for patients taking AZT. Then annually.
  3. The liver function is not routinely monitored on treatment but an ALT should be checked at any time if the patient develops a rash or has signs or symptoms of hepatitis, especially if on nevirapine.
Note
The normal range for serum ALT is 5 to 40 u/l. Any patient with an ALT above 5 times the upper limit of normal (200 u/l) requires an immediate review. There is an increased risk of drug induced hepatitis in patients with hepatitis B or C co-infection.

5-13 What monitoring for side effects is needed for other antiretroviral drugs?

Clinical monitoring without blood tests is adequate for 3TC, efavirenz and d4T provided the patient is clinically well.

5-14 How should patients be followed up after three months?

Most of the side effects will have cleared by 3 months. Patients should also be into the routine of taking their ARVs regularly. A viral load is usually done at 4 or 6 months so a patient will have to come to have blood taken at that time, and should return within a month for their results. If virally suppressed and clinically well, patients will be seen by a clinician every 6 to 12 months; or if they are not well.

They may collect their medicines every 1 to 3 months.

Some patients may be eligible to be enrolled in adherence clubs for long term support during treatment, and for decentralised care.

Monitoring the response to anti­retroviral treatment

5-15 How is the response to antiretroviral treatment assessed?

  1. By the clinical response
  2. By the viral load
  3. By the CD4 count

5-16 What is the expected clinical response to antiretroviral treatment?

With successful treatment patients should start to feel and look well again. Most patients develop a good appetite and gain weight. Associated infections such as thrush and diarrhoea disappear and skin rashes clear up. The clinical response follows the gradual recovery of the immune system. By 3 months patients should notice a big difference in their general health.

5-17 What is the viral load?

The viral load is a measure of the amount of HIV in the blood. The higher the viral load, the faster HIV is multiplying. Therefore, a high viral load indicates that there is a lot of HIV in the blood (and other body secretions). Viral load is usually expressed as RNA copies/ml (which is the same as copies/ml).

The viral load is a measure of the amount of HIV in the blood.

Note
The viral load is the concentration of free virus in the plasma. In its free form HIV is an RNA virus. Therefore the RNA PCR test is used to measure the viral load.

5-18 What is the range of viral load results?

People with HIV infection can have a viral load ranging from less than 50 copies/ml to several million copies/ml. A viral load of less than 50 copies/ml is regarded as ‘undetectable’.

Note
Some units use values ranging from less than 20 copies/ml to less than 100 copies/ml to define an undetectable viral load.

5-19 What is the value of knowing the viral load?

The viral load is the best indicator of the response of the immune system to ART. With successful treatment the viral load will steadily drop until it is undetectable. Measuring the viral load is of very little value before ART is started.

Viral load is the best indicator of the success of antiretroviral treatment.

Note
The viral load is the best measure of the rate at which the infection will progress. The higher the viral load, the sooner the person will become ill. Patients with symptomatic HIV infection have a higher viral load than people with HIV infection who are still well. A patient with a viral load above 6 log has a poor prognosis without urgent ART.

5-20 How is the viral load expressed?

The viral load is expressed as copies/ml or a log value. The log value is preferred if the change in viral load is determined. If the viral load drops by 1 log the number of copies/ml will fall by a factor of 10. Similarly a 2 or 3 log drop means that the number of viral copies has decreased 100 or 1000 fold respectively. The log value will fall by 0.3 if the number of viral copies is halved.

For example, if a viral load starts at 60 000 copies/ml, a 1 log drop will be 6000 copies/ml, a 2 log drop will be 600 copies/ml and a 3 log drop will be 60 copies/ml.

Log values are used to measure changes in viral load.

Note
Only a change in viral load of greater than 0.5 log is significant.

5-21 What viral load indicates a good response to treatment?

If the response to ART is good the viral load should fall by 1 log within 6 weeks. (See 5-25.)

5-22 What are viral ‘blips’?

These are transient (short-lived) small (usually less than 400 copies/ml) increases in the viral load of patients who are being successfully treated. They may be caused by an acute infection or an immunisation. Therefore, it is important that the viral load is not measured when the patient is ill.

5-23 When should the CD4 count and viral loads be measured?

Viral loads should be measured once at 4 to 6 months and again 12 months after starting treatment and every 12 months thereafter. The CD4 count should be measured at 12 months after starting treatment and then annually if less than 200 cells/µl or if otherwise clinically indicated, otherwise it does not need to be routinely monitored on ART.

Note
Should funding permit, more frequent CD4 and viral load monitoring is preferable and should be done every 6 to 12 months for tighter control of treatment, and for earlier detection of a failing regimen.

5-24 What change should take place in the CD4 count by one year?

The CD4 count should increase. People with CD4 counts below 200 cells/µl may expect an increase of 80% or more.

Note
The CD4 count should be increasing by 4 months after starting treatment. The lower the CD4 count at the start of ART, the slower will be the return to normal.

Some patients with a very low CD4 count at the start of treatment may fail to show a rise in the CD4 count despite good viral suppression and clinical improvement.

5-25 What change should take place in the viral load by four to six months?

The viral load should be undetectable (less than 50 copies/ml).

5-26 What is the best indicator of treatment success?

An undetectable viral load.

An undetectable viral load is the best indicator of successful treatment.

5-27 What should be done if the treatment is successful?

If the treatment is successful with an undetectable viral load by 6 months, the patient should be followed at the ART clinic and seen every 2 to 3 months until eligible for a treatment club. The CD4 count and viral load should be measured 12-monthly to determine whether the treatment has remained successful or not. Adherence should be supported at every clinic visit.

5-28 For how long can treatment remain successful?

For many years. Provided drug adherence is excellent, viral resistance is unlikely to develop and a long-lasting response to multi-drug treatment can be expected (15 to 20 years or more with excellent adherence).

Antiretroviral treatment can be successful for many years.

5-29 What is treatment failure?

The feature of treatment failure after 4 to 6 months on antiretroviral therapy is a viral load above 1000 copies/ml, on at least 2 occasions, at least 2 months apart in the presence of good adherence.

Progression of the clinical disease with further development of HIV-associated infections or malignancies despite ART should always suggest treatment failure.

Note
Treatment failure is defined as 2 viral loads above 1000 copies/ml taken at least 2 months apart in the presence of good adherence.

5-30 What should be done if the first line viral load is above 1000 copies/ml?

These patients and their management must be carefully reviewed before a change in treatment is made. Treatment failure may be due to poor adherence or may occasionally occur in spite of excellent adherence.

  1. If adherence is poor, every effort must be made to improve adherence. The causes of poor adherence must be found and corrected if possible. If the viral load is 400 to 1000 copies/ml, the viral load should be repeated in 6 months after active intervention to improve adherence; but if the viral load is above 1000 copies/ml it should be repeated sooner (in 2 months), again after an active intervention to improve adherence. If the viral load remains high, even with poor adherence, the patient should start preparation for second-line treatment. Deciding how long to wait before re-testing the viral load also depends on the CD4 count and clinical picture of the patient. A patient with a first high viral load and very low CD4 count may not be able to wait 6 months to re-test the viral load.
  2. If adherence appears to have been good, drug resistance may still have occurred through 1 or 2 missed or delayed doses and a change in drug regimen to the second-line combination should also be made. Good adherence with a viral load above 1000 copies/ml is usually an indication for a change in drug regimen. Always repeat the viral load after an adherence intervention before considering a regimen change.
Note
Patients with a first raised viral load always need an adherence intervention before repeating the viral load, as they may re-suppress their viral load with good adherence. Always repeat the viral load measurement before considering a change in regimen.

5-31 Can previous exposure to antiretrovirals lead to treatment failure?

Yes. If first-line treatment including nevirapine in a woman has failed, despite excellent adherence, make sure that she was not given nevirapine for the prevention of mother-to-child transmission of HIV. Previous exposure to nevirapine is not a contraindication to standardised first-line treatment. However, treatment of patients who have been exposed to any ARVs before must be discussed with an antiretroviral expert before starting treatment.

Note
Patients who have previously been exposed to 1 or more ARV(s) are no longer ‘antiretroviral naive’ and may already be resistant to 1 or more of these drugs.

5-32 What should be done if first-line treatment has failed despite excellent adherence?

Change from first-line to second-line treatment. The choice of the second-line combination depends on the drugs used in first line treatment.

  1. If first line treatment consisted of TDF, 3TC or FTC plus dolutegravir or efavirenz, change to a second-line regimen of AZT, 3TC and lopinavir/ritonavir. If AZT is contraindicated due to severe anaemia (Hb below 8 g/dL), abacavir may be used in its place.

    Note
    Check hepatitis B status before changing from a first line containing TDF as TDF and 3TC/FTC are also used to treat hepatitis B. If patient is Hep B surface antigen positive maintain patients on TDF and 3TC/FTC i.e. the second-line regimen will be TDF + AZT + 3TC or FTC + Aluvia (4 drugs, not 3).

  2. If first line treatment consisted of d4T or AZT plus 3TC and efavirenz, change to a second-line regimen of TDF, 3TC and dolutegravir or lopinavir/ritonavir.

Note
3TC is recycled in the second-line regimen. Although the virus will almost certainly be resistant to 3TC this type of resistance results in a greater susceptibility of the virus to TDF, AZT and d4T and the mutated virus does not replicate as well.

5-33 How is the second-line of treatment managed?

The schedule of visits is the same as that for the first-line combination with a commencement visit followed by visits at 1 and 2 but they should also have a visit at month 3 to check fasting cholesterol and triglycerides if they are on lopinavir/ritonavir. Patients are then seen again at 6 months for a viral load, within a month for the viral load results. They can then be seen every 3 to 6 months followed by 3-monthly visits.

5-34 What routine blood tests are done with second-line treatment?

Patients receiving AZT should have a baseline Hb and differential white count or FBC before the start of treatment followed by a repeat test at 1, 2, 3 and 6 months, as AZT may suppress the bone marrow.

Patients on lopinavir/ritonavir should have a baseline fasting blood glucose, cholesterol and triglyceride measurement. This should be repeated at 3 months, then annually if indicated.

5-35 What should be done if the second-line treatment fails?

Resistance to protease inhibitors and intergrase inhibitors is rare and raised viral loads in these patients on second-line treatment are most often due to poor adherence. Every effort must be made to improve adherence.

Patients with proven good adherence on second-line may be eligible for third-line treatment. These patients should be referred to an infectious-diseases clinic, or referred directly to the third line committee established by the National Department of Health (tlart@health.gov.za), for resistance testing and consideration for third-line treatment, provided they have been on a protease-inhibitor (PI) or intergrase inhibitor (INSTI) containing regimen for at least a year and have not achieved viral suppression.

Note
Should resistance to a boosted PI/INSTI be identified, a full treatment history will then be submitted to a third-line review committee via the National Department of Health for consideration for third-line treatment.

As PI and INSTI resistance is uncommon and resistance testing is expensive, Western Cape ART guidelines recommend resistance testing in public-sector patients on second-line after at least 2 years of second-line treatment with 3 viral loads above 1000 copies/ml taken 8 to 12 weeks apart.
Patients who are not eligible for third-line treatment should remain on the second-line combination even if the viral load is high, as antiretroviral therapy has been shown to be effective at maintaining the patient’s CD4 counts even with viral loads up to 10000 copies/ml.

Note
Additional ARVs can be used in new combinations in an attempt to control viral replication in patients who have failed on both first- and second-line treatment. This is a complex problem that must only be addressed by an ART specialist. Patients failing a second-line regimen should not stop treatment, as partial viral suppression is better than no treatment and may be life-saving. Resistance testing also requires patients to be on their failing regimen with better than 80% adherence.

Problems with anti­retroviral treatment

5-36 What are the main problems with antiretroviral treatment?

  1. Poor adherence
  2. Viral resistance to drugs
  3. Treatment failure
  4. Drug interactions
  5. Drug interruptions
  6. Side effects
  7. Immune reconstitution syndrome
  8. Complete dependence on long-term medication
  9. Expense

Adherence

5-37 What is adherence?

Adherence is the degree to which patients take their ARVs correctly.

5-38 What is excellent adherence?

Excellent adherence is taking all the pills correctly every day. With excellent adherence, 95% of all doses must be taken (i.e. 19 out of 20 doses). All patient should be aiming for excellent adherence, but adherence above 90% is also acceptable (i.e. 18 out of 20 doses). This means that not more than 3 doses are missed in a month. It is also important that the doses are taken at approximately the same time each day. Taking all the drugs at the correct dose and at the correct time each day is very important. ART can suppress the viral load reliably only if adherence is 90% or above.

Not more than 3 doses a month should be missed.

Note
Owing to the short half-life of ARVs, blood levels fall rapidly if a single dose is missed. The correct dose must be taken at approximately the correct time in the correct way. If a dose is missed or forgotten, it is better to take it late than not at all. And if, on occasion a dose cannot be taken on time and this is known in advance, it can be taken early rather than missed.

Excellent adherence is the key to treatment success. It is better to take treatment a few hours early or a few hours late than not take it at all.

5-39 What is poor adherence?

Poor adherence is missing too many doses. Any adherence of less than 90% is not ideal, and can be considered to be poor.

5-40 What are the dangers of poor adherence?

  1. Drug resistance
  2. Treatment failure
  3. Increased morbidity and mortality

Every effort should be made to ensure excellent adherence.

Poor adherence increases the risk of treatment failure and drug resistance.

5-41 How is adherence measured?

The history given by the patient is an unreliable method of assessing adherence. Better methods include:

  1. Counting tablets that have not been taken (pill count). Patients should be asked to bring all their tablets back to the clinic at every visit.
  2. Daily record cards or dosing diaries.
  3. Unannounced home visits with pill counts.
  4. Measurement of drug levels in the body, e.g. dried blood spots and hair samples for TDF levels.

A simple card for recording each dose on a daily basis helps promote and assess excellent adherence, but is not feasible in every situation.

5-42 What factors are associated with poor adherence?

  1. Poor patient preparation for ART
  2. Inadequate home support
  3. Poor relationship with the clinic staff
  4. Alcohol or drug abuse
  5. Depression or other emotional problems
  6. Side effects to ART
  7. Adherence tends to become worse over time
  8. Non-disclosure of HIV status

Note that excellent adherence does not correlate with gender, education level, socio-economic class or cultural background. Adherence can be excellent even in poor, under-developed communities.

5-43 How can adherence be improved?

Ideal or excellent adherence should be promoted before treatment is started and then promoted continually at every clinic visit. Patients must be encouraged to take an active and responsible role in their treatment.

  1. Before starting ART, patients should understand that they will need to take medication at approximately the same time every day for the rest of their lives. The clinician, nurse or counsellor should help the patient to problem-solve possible situations where treatment may be missed.
  2. Patients should understand why adherence is important and know about the dangers of poor adherence. Education and counselling about adherence should be provided at every visit in the patient’s home language. A non-judgemental approach is very important to help patients feel supported and able to ask for help.
  3. Ideally, the clinic staff should check on adherence at every visit. A pill count should be done. If adherence is poor, ask the patient why doses have been missed, re-educate about the importance of adhering to treatment, and trouble-shoot with the patient in order to try avoid missing doses in the future.
  4. Suggest practical reminders such as an alarm clock, or link the time of taking medication to a particular radio or TV programme or cleaning teeth. Advise the patient to use a pill box where tablets for the week can be packed out beforehand. Counsellors who know the community well can often offer the best adherence advice that will be suitable to the patient’s lifestyle.
  5. Patients need constant monitoring, education, encouragement and support. Good preparation and long-term support is essential for excellent adherence.
  6. If possible, they should disclose their HIV status to a friend or family member who can support them.
  7. Regular support groups with other patients on ART are very helpful.
  8. Continuing education should be provided at every visit.
  9. Side effects must be promptly and correctly managed.
  10. Provide a more caring service.

Every reasonable effort should be made to prepare patients and ensure they are ready to start treatment prior to starting antiretroviral treatment.

5-44 How can health workers provide a more caring service?

Clinics should strive to provide a more caring service, as this can improve adherence. The burden of huge patient loads can make this challenging. Adherence can be improved if the clinic provides a more caring service.

  1. Healthcare providers should make every effort to establish a trusting relationship with each patient. If possible, the patient should see the same health care provider at each visit.
  2. The clinic should provide an environment where the patient feels safe. Patients should be encouraged to come to the clinic with a problem on any day, not just on their appointment day.
  3. Remember that acceptance and emotional support by the clinic staff are very important parts of good care. Regular updates, education and an evaluation of the quality of advice being given by health workers is important.
  4. A patient should never be without the required medication. It is unacceptable for the clinic to run out of drugs or to turn a patient away without ensuring they have enough medication.

A good, caring service by the clinic can improves adherence.

5-45 What are the commonest reasons for missing a dose?

  1. Forgot
  2. Too busy, or away from home
  3. Too ill
  4. Side effects
  5. Angry or depressed
  6. Other urgent family matters such as a sick child or death of a relative

It is very important to find out why doses have been missed and to problem solve how adherence can be improved.

It is important to find out why doses are missed.

5-46 Can a dose be taken late?

If a dose is not taken at the correct time, it should still be safely taken when remembered. It is better to take the dose late than not at all.

5-47 Does it matter if the medication is vomited?

Yes. If the patient vomits up the pills or tablets, the dose should be taken again as soon as possible. Vomiting more than 1 hour after taking the medication is probably not important, and so the dose does not need to be taken again.

5-48 What factor may cause poor absorption of drugs?

Most antiretrovirals can be taken with or without food as this has minimal effect on absorption.

Vomiting within an hour of taking drugs or very severe diarrhoea can result in poor absorption of drugs.

5-49 Is an HIV adherence programme the same as the ‘DOT’ programme?

No, there are differences. With the DOT programme (Direct Observation of Therapy) the responsibility for taking the anti-TB medication is shared between the patient and a supporter in the community. This has only had limited success due to the difficulty in finding reliable and motivated supporters. In the HIV programme, patients are motivated and helped to take responsibility for their own treatment. Although family and community support is still important, the main responsibility for taking the medication correctly every day is placed on the patients themselves.

However, in patients who are unable to maintain excellent adherence in spite of help and support, a DOT system, where the responsibility for taking ARVs is given to another reliable person (a ‘treatment partner’), may be useful.

5-50 What is a national HIV adherence programme?

It is hoped that the media and the general community can help to reminding people on ART to take their medication. Reminders could be given over the radio or on television. As HIV is a national problem, it is important that the whole nation helps to make sure that there is excellent adherence to ART in order to reduce the risk of HIV drug resistance and the further spread of HIV.

A national adherence programme could be helpful.

Drug resistance

5-51 What is drug resistance?

Drug resistance in HIV occurs when the replication of HIV is not blocked completely by a particular drug combination. Drug resistance leads to treatment failure.

5-52 Is drug resistance important?

Yes. The development of resistance to 1 or more ARVs will reduce the chance of successful treatment to the individual. It will also increase the risk of other people in the community acquiring HIV infection which is resistant to those drugs. This can be disastrous to both the patient and the community.

Drug resistance can be disastrous to both the patient and the community.

Note
Resistance is most common with non-nucs and 3TC as resistance occurs after a single mutation. Resistance to lopinavir/ritonavir/dolutegravir is uncommon.

5-53 How can drug resistance be avoided?

  1. By using a combination of 3 drugs from 2 drug classes. This is the basis of standardised regimens.
  2. By excellent adherence. The more frequently doses are missed, the greater is the risk of resistance to those drugs.

Excellent adherence to antiretroviral treatment is the best way of avoiding drug resistance.

5-54 Can resistance be caused by previous drug exposure?

Yes. Patients who have previously been given ARVs (‘non-naive patients’) must be carefully assessed by an antiretroviral expert before one of the standard drug combinations is started. There is concern that nevirapine that has been used in the prevention of mother-to-child transmission (PMTCT) may result in drug resistance to nevirapine in mother or infant.

5-55 What is cross-resistance?

If HIV becomes resistant to one drug in a class it is often also resistant to some or all of the other drugs in the same class. This is called cross-resistance (i.e. HIV is resistant to drugs across a drug class). This is particularly common for non-nucs. If patients are resistant to nevirapine there is a high chance that they will also be resistant to efavirenz. Drug resistance between different classes is uncommon.

Note
Drug resistance may be primary (when the person is infected by a virus which is already resistant to 1 or more drugs) or secondary (when the virus becomes resistant during the course of treatment). Primary resistance is relatively uncommon in South Africa with levels of less than 5% reported between 2002 and 2010. However, moderate levels (5 to 15%) of primary resistance to non-nucs have been reported in surveillance studies done in KZN in 2009.

Treatment failure

5-56 What are the two types of treatment failure?

Treatment failure is diagnosed when ART fails to produce or maintain an adequate suppression of the viral load. There are 2 forms of treatment failure.

  1. Treatment failure right from the start of treatment when the viral load does not fall as expected within 6 months.
  2. The viral load increases after initially being suppressed, or falling despite continuing treatment.

5-57 What are the causes of treatment failure?

There are a number of causes:

  1. Poor adherence
  2. Poor absorption
  3. Adverse drug interactions
  4. Infection with drug-resistant HIV

5-58 What is the most common cause of treatment failure?

Poor adherence is by far the most common cause of treatment failure.

5-59 How is treatment failure diagnosed?

Before diagnosing treatment failure it is important to repeat an initial high viral load (above 1000 copies/ml) after 2 to 3 months of adherence support and problem solving. The diagnosis of treatment failure is confirmed if the viral load remains high (above 1000 copies/ml) or increases further. Sometimes the viral load will be increased at the time of the first measurement but falls with the second measurement, especially if adherence education and support are provided. Therefore, always repeat the viral load after 2 to 3 months before diagnosing treatment failure. The only exception is if patients have a very low CD4 count, pregnant or breastfeeding and you think they cannot wait 2 to 3 months before changing to second line. In this case, consult a specialist HIV clinician or call the HIV hotline.

Transient rises in the viral load (usually more than 1000 copies/ml) are called ‘blips’. They are not uncommon, especially if there has been a viral or bacterial infection, or the patient has recently been immunised. Therefore, always repeat the viral load after 2 to 3 months before diagnosing treatment failure.

5-60 How should possible treatment failure be managed?

The cause of the high viral load must be determined as far as possible, and actively managed, before the viral load measurement is repeated. It is important that the treatment regime should not be changed until a careful assessment is done and all the options considered. The second (confirmatory) measurement of the viral load is usually done 2 to 3 months after the first measurement.

The treatment regimen should not be changed in haste. If the patient has a very low CD4 count, or is WHO stage 3 or 4, please consult an HIV clinician or call the HIV hotline.

Drug interactions

5-61 What is a drug interaction?

This is the interference of 1 drug with another drug. Common examples of drug interactions are:

  1. Two similar drugs compete with each other at their site of action.
  2. One drug alters the rate at which another drug is broken down in the body. This may result in the blood level of the drug being too high or too low.
  3. If 2 drugs have similar side effects, these side effects are more likely to occur and be more severe if the 2 drugs are used together.

5-62 Which antiretroviral agents should not be used together?

Using either the first- or second-line combinations for ART avoids drug combinations which compete with each other.

Note
AZT should not be used together with d4T due to their competing sites of action.

5-63 What is the effect of rifampicin on antiretroviral drugs?

Rifampicin, used in the treatment of TB, increases the rate at which some ARVs are broken down by the liver. As a result, the blood levels of these drugs become too low.

  1. Rifampicin causes no problems with nucs.
  2. Rifampicin causes some problems with non-nucs and lowers blood level of these drugs, especially nevirapine. Efavirenz is less affected than nevirapine, therefore patients on nevirapine are often changed to efavirenz when first-line ART is being given at the same time as anti-TB treatment.
  3. Rifampicin causes serious problems with protease inhibitors and intergrase inhibitors as it lowers blood levels of most of these drugs by about 80%. Therefore higher doses of protease inhibitors and intergrase inhibitors are needed when they are used with rifampicin. The dose of lopinavir/ritonavir (Aluvia) and dolutegravir should be doubled when used with rifampicin. For Aluvia, this should be done slowly over 2 weeks with monitoring of the patients liver function as high doses of lopinavir/ritonavir may cause hepatitis.

Higher than normal doses of protease inhibitors are needed if used together with rifampicin.

Note
Protease inhibitors alter the metabolism of many drugs by inhibiting the p450 enzyme system (especially CYP3A4) which is used to break down these drugs. Atazanavir cannot be used with rifampicin.

5-64 What is the risk of using INH together with antiretroviral therapy?

Peripheral neuropathy is a side effect of INH (isoniazid) as well as some older antiretrovirals such as d4T. Therefore, the risk of peripheral neuropathy is greater if d4T is used together with INH.

5-65 Can antiepileptic medication be used with ART?

Due to drug interactions with both PIs and NNRTIs, many commonly used antiepileptic medications cannot be used with ART. Patients on phenytoin, phenobarbital and carbamazepine should have their medication changed to sodium valproate (epilim) or lamotrogine before starting ART. The changeover of treatment should occur gradually to avoid precipitating seizures.

Sodium valproate or lamotrogine are the antiepileptic medications of choice for patients starting ART.

Drug interruptions

5-66 What is a drug interruption?

This is when ART is stopped for a short period (a temporary interruption). Drug interruptions can be patient-led (e.g. intolerable side effects) or clinician-led (e.g. drug toxicity).

5-67 What are the reasons for drug interruptions?

Causes of drug interruptions are:

  1. Intolerable side effects. Stopping the drugs may be enough to relieve the side effects. Once the symptoms of the side effects are under control, treatment may be changed to another drug combination; or the same drug combination may be restarted and the patient closely monitored. Medication can also be given to counteract the side effects.
  2. Interaction with other drugs, e.g. TB treatment.
  3. Patient unable to swallow due to severe oesophageal thrush.
  4. Lack of drugs at the clinic, or patients being turned away from full clinics without the clinic ensuring they have enough treatment. This should never happen but unfortunately it does.
  5. Pill fatigue. As patients are living longer and longer on antiretroviral treatmnent, with time they may get tired of having to take medicines every day. This is called pill fatigue.

5-68 What is the danger of drug interruption?

If only 1 ARV is stopped there is a danger that resistance will develop to the remain­ing drugs. If a drug interruption cannot be avoided, it is best to stop all the ARVs.

Nucs should be continued for a week after stopping non-nucs if the regimen contains both these classes of drug. This is because the non-nuc stays in the blood for a week longer than the nuc. Continuing the nuc for an extra week effectively means that there are still 3 drugs in the blood until the non-nuc wears off, at which time the nuc is also stopped. This is referred to as ‘covering the tail’ of the non-nuc. This decreases the chance of the patient developing resistance to the non-nuc.

The same or another ARV combination should be started as soon as reasonably possible. Never interrupt treatment if it can be avoided.

It is essential to stop all drugs and not just the 1 drug believed to be causing a problem.

Note
Planned drug interruptions at regular intervals are not used in the treatment of HIV as they can result in the viral load rebounding to a very high level, and patients can get very sick.

Side effects of antiretroviral agents

5-69 What should be done if the patient has a severe reaction to a drug?

All drugs must be stopped immediately. Never stop only 1 drug. The whole drug combination must be assessed. Either of the following may be done:

  1. Be mindful of a ‘tail’ as some drugs may have longer half–lives (remain in the blood) e.g. efivarenz. To avoid resistance to EFV, you may need to continue the nucs for 5 to 7 days.
  2. All 3 drugs can be changed to another combination.
  3. The drug causing the problem can be swapped, usually to a drug from another class as often there are similar side effects to other drugs in the same class. For example, do not swap stop nevirapine and start efavirenz. If stopping nevirapine due to a severe reaction, then replace it with lopinavir/ritonavir.
  4. All drug side effects should be reported.

Immune Reconstitution Inflammatory Syndrome (IRIS)

5-70 What is the immune reconstitution inflammatory syndrome?

This is an unexpected clinical deterioration which occurs soon after starting ART, and is most commonly seen in patients who start ART when they have a low CD4 count. When the CD4 count is low, the immune system is too suppressed (weak) to mount a response to infections in the body. The immune system starts to recover within weeks of beginning ART. As the immune system recovers, the body starts to fight infections in the body, and may develop an inflammatory response to any of the following:

  1. Hidden or mild infections which have been missed clinically because there hadn’t been any symptoms as the body has not been able to mount an immune response (i.e. unmask infection). An example would be previously undiagnosed TB.
  2. Worsen existing infections. An example would be TB which has only been treated for a few weeks.

Infections which have been treated but antigens still remain. An example would be dead TB bacteria still present after a few months of anti-tuberculous treatment.

5-71 Which patients are most likely to develop the immune reconstitution inflammatory syndrome?

Patients with a CD4 count below 100 cells/µl when ART is started.

5-72 How many patients develop the immune reconstitution inflammatory syndrome?

Up to a third of patients starting ART develop a mild immune reconstitution syndrome which does not require treatment. Rarely the immune reconstitution syndrome is serious and very rarely may be life threatening.

5-73 How does the immune reconstitutional inflammatory syndrome present clinically?

It usually presents with fever and a worsening of the patient’s symptoms after starting ART. All cases of severe immune reconstitution inflammatory syndrome must be urgently referred to a specialist clinic or hospital. The immune reconstitution inflammatory syndrome usually presents abruptly within 2 weeks to a month after ART is started. Consider immune reconstitution inflammatory syndrome in anyone who is not thriving after 6 weeks of ART.

The immune reconstitution inflammatory syndrome presents suddenly and unexpectedly with clinical deterioration in the patient’s condition soon after antiretroviral treatment is started.

5-74 What is the commonest cause of the immune reconstitution inflammatory syndrome in South Africa?

Tuberculosis is the commonest cause of the immune reconstitution syndrome in South Africa. The immune reconstitution inflammatory syndrome presenting with TB is less common if TB is treated for at least a month before starting ART. Immune reconstitution inflammatory syndrome is not caused by treatment failure, side effects or drug interactions.

Note
When starting ART, TB may present for the first time (previously missed clinically, ‘unmasking IRIS’) or partially treated TB (no live bacteria but antigen still present) may flare up with an acute inflammatory reaction. Suddenly enlarged paratracheal nodes, pleural effusions or parenchymal lung disease may be seen on chest X-ray. Mycobacteria avium complex infection is the most common cause of the immune reconstitution inflammatory syndrome in developed countries. Severe acne, cryptococcal meningitis, cytomegalovirus retinitis, extensive molluscum, viral hepatitis, shingles, genital herpes and Kaposi’s sarcoma have also been described with the immune reconstitution inflammatory syndrome.

5-75 How is a patient with the immune reconstitution inflammatory syndrome best managed?

The disease causing the inflammation must be diagnosed and treated. Avoid stopping ART if at all possible. The patient may need to be referred to an HIV specialist or hospital.

Immune reconstitution inflammatory syndrome is not necessarily an indication to stop antiretroviral treatment.

Note
A short course of steroids may have a role in managing a severe reaction.

Quality of life

5-76 How may a patient’s quality of life be negatively affected by antiretroviral treatment?

Some patients become anxious and depressed despite a good response to treatment because they face a lifetime of taking drugs for a chronic disease. A similar problem is seen with patients suffering from other chronic medical conditions such as diabetes and epilepsy. These patients need additional counselling and support. This problem can usually be avoided by good preparation before treatment is started.

Note
Unsafe sexual practices have been shown to decrease once ART is started. Patients become more responsible.

Expense

5-77 Does the cost of drugs affect antiretroviral treatment?

Unfortunately some ARVs are expensive. If the state does not provide a free service, patients have to buy their own drugs. Expense is one of the reasons that not all antiretroviral treatment options are available in the public sector, but the treatment options available in the South African public sector are excellent, non-inferior to the options in private sector, and constantly improving as generics become available.

Case study 1

A patient who is ready for treatment attends her first treatment visit. She is clinically well with a CD4 count of 146 cells/µl and has a good understanding of the treatment but is concerned about side effects as she works as a locum nurse and sometimes does night duties.

1. What should be done at the first treatment (commencement) visit?

After a pill count (of co-trimoxazole) and meeting with the counsellor to discuss the importance of excellent adherence, a final assessment is made by a clinician. This is followed by a visit to the pharmacist to collect the first month’s supply of medication.

2. What medication will be given?

Patients should always be started on the first-line fixed dose combination of TDF, FTC and DTG Co-trimoxazole prophylaxis will also be continued until the patients CD4 count is above 200 cells/µl.

3. What choice would you make for this patient?

DTG is the best choice for first line treatment. If DTG is contra-indicated, consider nevirapine instead of efavirenz as this patient does shift work. But since nevirapine is twice a day, this must be weighed against the effect of fatigue on the night shift.

4. How often should patients be seen during the first four months of treatment?

Routine visits should occur at monthly intervals with an extra visit at 2 weeks for patients receiving nevirapine.

5. Why are patients on nevirapine seen at two weeks?

Because the dose of nevirapine should be started at 1 tablet once daily and increased to 1 tablet twice daily at 2 weeks.

6. What should be done at the routine follow up visits?

At the routine visits the patients are weighed and clinically examined. A history is taken for adherence, side effects or other problems and the patient is counselled. A pill count may be done, routine blood samples are taken and 1 month’s supply of medication is given.

Case study 2

A patient attends all his routine visits for the first 4 months. He feels well and all his symptoms and signs of illness gradually disappear. He has no side effects from the ART.

1. When should he attend the next follow up visit?

Usually at 6 months after starting treatment for viral load. However, he should immediately return to the antiretroviral treatment clinic if he experiences side effects or has other problems. In some services viral load is done at 4 months, and so the patient should return at month 5 for the viral load results.

2. How often do patients collect their medication?

Every 1 to 3 months. These visits should be used to assess and promote excellent adherence.

3. How is the success or failure of treatment determined?

By monitoring the clinical conditions to see whether the clinical signs of HIV have disappeared and by monitoring the viral load.

4. When should the CD4 count and viral load be measured after starting antiretroviral treatment?

The viral load should be measured at 4 or 6 months after starting treatment. Completing the first viral load earlier allows time for an adherence intervention if the viral load is raised, potentially reducing the risk of resistance. The viral load should be undetectable if treatment is successful. The CD4 count should be measured after 1 year on treatment. If the CD4 count at the start of treatment was greater than 200 cells/µl then there will be no routine monitoring of CD4 and it will only be repeated if clinically indicated. If the CD4 count at the start of treatment was less than 200 cells/µl, it should be measured annually until it is above 200 cells/µl. This is to guide prophylactic treatment with co-trimoxazole or fluconazole, both of which are stopped when the CD4 count is above 200 cells/µl and there is no concurrent stage 3 or 4 infection present.

5. What is the single best measure of treatment success?

An undetectable viral load.

6. How should this patient be managed after six months?

If the ART has been successful the patient may be seen every 2 to 4 months. However, he should continue to collect his medication regularly. His CD4 count and viral load should be measured at 1 year on treatment and he should continue to have a viral load test every year.

Case study 3

A patient who was started on a first line regimen of TDF, FTC and efavirenz is still ill after ART for 6 months. Her CD4 count remains below 200 cells/µl and her viral load is above 1000 copies/ml.

1. What is your diagnosis?

Possible ART failure.

2. What is the commonest cause of treatment failure?

Poor adherence.

3. How should this patient be managed?

It is important to establish whether adherence has been excellent or poor. If adherence is poor, every effort must be made to improve it. The viral load should then be measured again after 2 to 3 months. During this time the patient should receive adherence support and be prepared for the possibility of second line. If it remains high the patient has failed ART but treatment should continue for the few weeks it takes to prepare the patient for second line.

4. What should be done if adherence has been excellent?

This patient may have primary resistance but she should still have a confirmatory viral load after 2 to 3 months and should still receive adherence support. If the viral load remains high in spite of excellent drug adherence, the patient should be switched to a second-line regimen of AZT, 3TC and dolutegravir or Aluvia without interrupting treatment, but after ensuring the patient has been prepared for second line. The HIV is probably resistant to the first-line drugs.

5. When are the routine visits with second- line treatment?

The same as first-line treatment with visits every month until 4 months followed by a visit at 6 months and then every 3 months thereafter if treatment is successful.

6. What routine blood tests should be taken if patients are on second-line treatment?

Before treatment is started an Hb with differential white count (or a FBC), triglyceride and cholesterol tests are done for baseline values.

After treatment has been started an Hb and differential should be done at months 3 and 6 and then every 12 months to screen for anaemia, which is a common side effect of AZT. Fasting glucose, cholesterol and triglyceride should be measured at 3 months. These tests screen for metabolic abnormalities caused by lopinavir/ritonavir (Aluvia).

Note
Some guidelines also recommend annual fasting glucose, cholesterol and triglycerides for patients on Aluvia.

Case study 4

A patient on ART admits to poor adherence. He is sent to the treatment counsellor to discuss the importance of excellent adherence.

1. What is the definition of poor adherence?

Taking less than 95% of doses. Even moderate adherence, when between 80 and 95% of doses are taken, is not satisfactory. The goal must be to take all doses at the correct time.

2. What is the danger of poor adherence?

Antiretroviral treatment is likely to fail and there is a high chance of HIV resistance to the ARVs.

3. What can be done to help this patient remember to take his medication?

Link the time for the dose with a particular radio or TV programme or an activity, e.g. cleaning his teeth. An alarm clock can be used or a supporter could remind him or send a cellphone message.

4. Why is drug resistance a danger for a patient?

Because it restricts the choice of drugs which are likely to be effective. If both the first- and second-line combinations fail, patients with good adherence and resistance to protease inhibitors may be eligible for third-line treatment.

5. What is the danger of drug resistance to the community?

It makes HIV more difficult to treat. Others may become infected with a strain of HIV resistant to 1 or more drugs. Therefore it is in the interest of the whole community that patients take their ART correctly.

6. How is the risk of drug resistance reduced?

By excellent adherence and always using combinations of at least 3 ARVs.

Case study 5

Three weeks after starting ART a patient becomes unwell with fever and severe cough. The patient had been reasonably well during the weeks before starting treatment despite having a very low CD4 count.

1. What is the likely diagnosis?

Immune reconstitution inflammatory syndrome (IRIS). Patients with a very low CD4 count at the start of ART are at high risk of this condition.

2. What is the commonest cause of this condition in South Africa?

Tuberculosis. With fever and cough this patient probably has the immune reconstitution inflammatory syndrome due to TB. This can sometimes be prevented if the TB treatment is started before starting ART.

3. What is the immune reconstitution inflammatory syndrome?

This is an inflammatory reaction which develops when the patient’s immune system starts to recover. Before treatment is started, the immune system is too suppressed (weakened) to respond to an infection such as TB. The treatment therefore ‘unmasks’ an infection that previously had been ‘hidden’.

4. How should this condition be managed?

It usually gets better if ART is continued provided that the underlying cause is also treated. Immune reconstitution inflammatory syndrome is not an indication to stop ART.

5. How long can HIV patients survive on antiretroviral treatment?

Provided their adherence is excellent, they can remain well with a good quality of life for many years. Many patients on ART will have a normal life expectancy.

6. What may affect the quality of life in these patients on successful treatment?

The fact that they have a chronic illness and must remain on treatment for life. The price of ARVs may also be high in the private sector. These difficulties should be discussed with the treatment counsellor.

Dosing for patients on first-line combination

Drug and dosage Timing of doses Possible side effects
TDF (Tenofovir) 300 mg daily 24 hours Kidney damage
3TC (lamivudine) 300 mg daily or
FTC (emtricitabine) 200 mg daily		 24 hours Diarrhoea, headache
DTG (dolutegravir) 50 mg 24 hours Insomnia, headache
Efv (Efavirenz) 600 mg daily 24 hours Skin rash (allergy), vivid dreams, dizziness, sleep changes in first 4 weeks

Most side effects get better after 1 to 2 months of treatment.

Where possible, prescribe as a fixed dose combination tablet of TDF, FTC and dolutegravir as a once daily tablet.

Dosing for patients on second-line combination

If the first-line treatment was TDF, FTC or 3TC and efavirenz or nevirapine, prescribe:

Drug and dosage Timing of doses Possible side effects
AZT (Zidovudine) 300 mg twice daily 12 hours Numbness or pain in the feet, abdominal pain, hepatitis, acidosis
3TC 150 mg twice daily 12 hours Diarrhoea, headache
LPV/r (Lopinavir + ritonavir) 400/100 twice daily
(Aluvia 2 tablets twice daily)		 12 hours Skin rash (allergy), hepatitis
DTG (dolutegravir) 50 mg 24 hours Insomnia, headache

TDF should be continued in second-line treatment in patients with Hepatitis B (HepB surface antigen positive). Second-line treatment would then consist of 3 nucs, namely TDF, AZT, 3TC DTG or LPV/r.

If first-line treatment was AZT or d4T, 3TC and efavirenz or nevirapine (i.e. old first line), prescribe:

Drug and dosage Timing of dosage Possible side-effects
TDF 300 mg once daily 24 hours Kidney damage
3TC 150 mg twice daily 12 hours Diarrhoea, headache
LPV/r (Lopinavir + ritonavir) 400/100mg twice daily
(Aluvia 2 tablets twice daily)
OR
DTG (dolutegravir) 50 mg		 12 hours


24 hours		 Skin rash (allergy), hepatitis


Insomnia, headache

Most side effects get better after 1 to 2 months of treatment.

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