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5

Management of patients on antiretroviral treatment

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Contents

Objectives

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

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 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. Antiretroviral treatment therefore decreases both the morbidity and mortality related to HIV. Antiretroviral treatment is best started at an antiretroviral clinic. Antiretroviral therapy 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 antiretroviral treatment 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 when they have met the criteria for treatment. An antiretroviral clinic is staffed by doctors and nurses who have had special training in the use of antiretroviral drugs and the management of patients on these drugs.

5-3 What is the first antiretroviral treatment visit?

This is the visit when antiretroviral treatment is started (i.e. commencement visit). Patients should already have been prepared for antiretroviral treatment at one or two screening visits. A decision would already have been made that the patient is ‘treatment ready’ and baseline blood tests done. A final check is made that the patient is fully prepared for treatment. At the first antiretroviral treatment visit the following should be done:

  1. A second count of co-trimoxazole tablets is done to assess adherence.
  2. The importance of excellent adherence is again stressed by the counsellor.
  3. The patient sees the doctor or nurse for the final instructions and support. A detailed description of the drugs and their doses is given using a treatment chart. A graphic treatment chart is very useful and should be given to each patient.
  4. The patient should be given a patient-carried treatment card.
  5. The patient’s details are entered into the antiretroviral treatment 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 nurse. The instructions must be clearly written on the pill container with a permanent marker.
  8. The patient is given one month’s supply of drugs by the pharmacist.
  9. 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.

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.

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

Almost all patients are started on the first-line single dose combination tablet of TDF, FTC and efavirenz. Nevirapine may be 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. 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 antiretroviral drugs.

5-6 What other medication will be given?

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 six months of antiretroviral treatment.

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

Usually patients are seen at the antiretroviral clinic at one, two and three or four months after starting treatment.

Patients who are taking nevirapine have an extra visit two 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 one tablet daily to one 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 ART 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 and take the necessary blood samples. The nurse 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 antiretroviral drugs and advise the patient on how to take them every time medicines are dispensed.

Trained lay counsellors and community care workers are very important members of the health team.

Follow-up visits

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

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

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

Monthly to 3-monthly. A missed visit for medication suggests poor adherence. When medicine is collected, the patient should also be seen by a nurse or counsellor who will assess adherence and ask about side effects. Excellent adherence must be promoted at every visit. The antiretroviral treatment register or electronic database must be updated each time medication is provided.

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

  1. Creatinine clearance monitoring is done at three, six and twelve months for patients on TDF.

    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 one and two months after starting ART.
  2. A haemoglobin level and differential count should be done at one, two, three and six months for patients taking AZT.
  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.
Note
The normal range for serum ALT is 5 to 40 u/l. Any patient with an ALT above five 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 three months. Patients should also be into the routine of taking their antiretroviral drugs regularly. Few problems are expected after three months therefore patients, will then only be seen by a doctor six-monthly. They may collect their medicines every one to three months.

Some antiretroviral clinics are able to follow their patients for six months after starting treatment. However, some patients can be referred back to the HIV clinic sooner or may be enrolled in adherence clubs for long term support during treatment.

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 three 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 a value of less than 40 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 antiretroviral treatment. With successful treatment the viral load will steadily drop until it is undetectable. Measuring the viral load is of very little value before antiretroviral treatment 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 antiretroviral treatment.

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.

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 antiretroviral treatment is good the viral load should fall by 1 log within six weeks. (See 5-25.)

5-22 What are viral ‘blips’?

These are transient (short-lived) 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 if less than 200cells/µl should be repeated at 6 monthly intervals until two consecutive CD4 counts are above 200cells/µl .

Note
Should funding permit, more frequent CD4 and viral load monitoring is preferable and should be done every 4 to 6 months for tighter control of treatment.

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 four months after starting treatment. The lower the CD4 count at the start of antiretroviral treatment, the slower will be the return to normal.

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 six months, the patient should be followed at the ART clinic and seen every three months. 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 with excellent adherence).

Antiretroviral treatment can be successful for many years.

5-29 What is treatment failure?

The feature of treatment failure after six months on antiretroviral therapy is a viral load above 1000 copies/ml.

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

Note
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.

5-30 What should be done if the first-line treatment is unsuccessful?

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 50 to 1000 copies/ml, the viral load should be repeated in six months after active intervention to improve adherence; but if the viral load is above 1000 copies/ml it should be repeated sooner (in three 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.
  2. If adherence appears to have been good, drug resistance may still have occurred through one or two 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
Treatment failure is defined as two viral loads above 1000 copies/ml taken at least two months apart.

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 antiretroviral drugs before must be discussed with an antiretroviral expert before starting treatment.

Note
Patients who have previously been exposed to one or more antiretroviral drug(s) are no longer ‘antiretroviral naive’ and may already be resistant to one 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.

If first line treatment consisted of TDF, 3TC or FTC plus efavirenz, change to a second-line regimen of AZT, 3TC and lopinavir/ritonavir. If AZT is contraindicated due to severe anaemia (Hb below 8g/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.

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

Note
3TC is recycled in the second-line regimen. Although the virus will almost certainly be resistant to 3TC this resistance results in a greater susceptibility 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 one, two and three or four months. Patients are then seen again at six months followed by three-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 three and six 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 three months.

Note
Some guidelines recommend a fasting cholesterol and triglycerides for patients on lopinavir/ritonavir at baseline, 4 months, 12 months and then every 12 months.

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

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

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 specialist for resistance testing and consideration for third-line treatment, provided they have been on a protease-inhibitor (PI) containing regimen for at least a year and have not achieved viral suppression.

Note
Should resistance to a boosted PI 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 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 two years of second-line treatment with three 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 antiretroviral drugs 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.

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 antiretroviral drugs 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). This means that not more than three doses can be missed in a month. It is also important that the doses are taken at the same time each day. Taking all the drugs at the correct dose and at the correct time each day is very important if antiretroviral treatment is going to be successful. Antiretroviral treatment can suppress the viral load reliably only if adherence is excellent.

Not more than three doses a month should be missed.

Note
Owing to the short half-life of antiretroviral drugs, blood levels fall rapidly if a single dose is missed. The correct dose must be taken at the correct time in the correct way.

Excellent adherence is the key to treatment success.

5-39 What is poor adherence?

Poor adherence is missing doses or taking doses at the wrong time. Any adherence of less than 95% is not good enough (i.e. poor). Even adherence of 80 to 95% may be inadequate.

5-40 What are the dangers of poor adherence?

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

Every effort must be made to ensure excellent adherence. Without excellent adherence the progression of HIV will not be stopped.

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.

A simple card for recording each dose on a daily basis helps promote and assess excellent adherence.

5-42 What factors are associated with poor adherence?

  1. Poor patient preparation for antiretroviral treatment
  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 antiretroviral treatment
  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?

Excellent adherence must 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 antiretroviral treatment, patients must make a firm decision to take medication at the correct time every day for the rest of their lives. They must have a positive attitude and be ready to take antiretroviral treatment. A clearly understood treatment plan must be negotiated with the patient.
  2. Patients must 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 supportive and non-judgemental approach is needed.
  3. Give and monitor the adherence to treatment with co-trimoxazole for a month before starting antiretroviral treatment.
  4. 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 and re-educate about the importance of adhering to treatment.
  5. 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. A cellphone message or pager call can be arranged. Get the patient to use a pill box where tablets for the day can be counted out beforehand. Counsellors who know the community well can often offer the best adherence advice that will be suitable to the patient’s lifestyle.
  6. Patients need constant monitoring, education, encouragement and support. Good preparation and long-term support is essential for excellent adherence.
  7. If possible, they should disclose their HIV status to a friend or family member who can support them.
  8. Regular support groups with other patients on antiretroviral treatment are very helpful.
  9. Continuing education should be provided at every visit.
  10. Side effects must be promptly and correctly managed.
  11. Provide a more caring service.

Patients must be ready and prepared before starting antiretroviral treatment.

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

Adherence can be improved if the clinic provides a more caring service.

  1. Healthcare providers must make every effort to establish a trusting relationship with each patient. If possible the patient should see the same dedicated carer at each visit.
  2. The clinic should provide a safe environment where the patient can feel protected. Patients should feel they are welcome 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 update 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.

A good, caring service by the clinic 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 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 can 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 immediately. Vomiting more than one hour after the medication is probably not important.

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

Taking ddI with meals results in poor absorption. Therefore ddI is always taken well before or well after a meal.

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 antiretroviral drugs 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 will help in reminding people on antiretroviral treatment 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 antiretroviral treatment in order to reduce the risk of HIV drug resistance and the further spread of HIV.

A national adherence programme is urgently needed.

Drug resistance

5-51 What is drug resistance?

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

5-52 Is drug resistance important?

Yes. The development of resistance to one or more antiretroviral drugs 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 is uncommon.

5-53 How can drug resistance be avoided?

  1. By using a combination of three drugs from two 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 antiretroviral drugs (‘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 used in the prevention of mother-to-child transmission (PMTCT) may cause later 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 the 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 classes is uncommon.

Note
Drug resistance may be primary (when the person is infected by a virus which is already resistant to one 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 in Gauteng. 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 antiretroviral treatment fails to produce and maintain an adequate suppression of the viral load. There are two forms of treatment failure.

  1. Treatment failure right from the start of treatment when the viral load does not fall as expected within six months.
  2. There may initially be a good fall in viral load but the viral load later increases again despite continuing treatment.

5-57 How is treatment failure confirmed?

Before diagnosing treatment failure it is important to repeat the viral load measurement after two to three months. The diagnosis of treatment failure is confirmed if the viral load remains high or increases further. Sometimes the viral load will be increased at the time of the first measurement but falls with the second measurement. Transient rises in the viral load 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 two to three months before diagnosing treatment failure.

5-58 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

5-59 What is the commonest cause of treatment failure?

Poor adherence is by far the commonest cause of treatment failure.

Poor adherence is the commonest cause of treatment failure.

5-60 How should 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 measurement of the viral load is usually done two to three months after the first measurement.

The treatment regimen should not be changed in haste.

Drug interactions

5-61 What is a drug interaction?

This is the interference of one drug with another drug. Common examples of drug interaction 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 two drugs have similar side effects, these side effects are more likely to occur and be more severe if the two drugs are used together.

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

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

Note
AZT should not be used together with d4T due to their competing sites of action. ddI and d4T should be avoided in combination due to additive toxicities.

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

Rifampicin, used in the treatment of TB, increases the rate at which some antiretroviral drugs are broken down by the liver. As a result, these drugs may not act adequately because their blood levels are 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 nevirapine is often changed to efavirenz when first-line antiretroviral treatment is being given at the same time as anti-TB treatment.
  3. Rifampicin causes serious problems with ‘PIs’ as it lowers blood levels of most of these drugs by about 80%. Therefore higher doses of ‘PIs’ are needed when they are used with rifampicin. The dose of lopinavir/ritonavir (Aluvia) should be doubled from 2 tablets 12 hourly to 4 tablets 12 hourly when used with rifampicin. This should be done slowly over two weeks with monitoring of the patients liver function as high doses of lopinavir/ritonavir may cause hepatitis.

Higher than normal doses of ‘PIs’ 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 d4T and ddI. Therefore, the risk of peripheral neuropathy is greater if either d4T or ddI are 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 siezures.

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 antiretroviral treatment is stopped for a short period (a temporary interruption).

5-67 What are the reasons for drug interruptions?

Causes of drug interruptions are:

  1. Intolerable side effects. Once the symptoms are under control treatment may be changed to another drug combination, or the same drug combination may be restarted.
  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. This should never happen but unfortunately it does.

5-68 What is the danger of drug interruption?

If only one antiretroviral drug is stopped there is a danger that resistance will develop to the remaining drugs. Therefore, it is best to stop all the antiretroviral drugs if drug interruption cannot be avoided. When stopping a regimen containing a ‘non-nuc’ the ‘nucs’ should be continued for one week after stopping the ‘non-nuc’. This is because the ‘non-nuc’ remains for a longer period in the body than the ‘nucs’ and the continuation of the ‘nucs’ therefore ensures that the patient continues to receive triple therapy until the ‘non-nuc’ has been eliminated. 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 antiretroviral drug combination should be started as soon as possible. Never interrupt treatment if it can be avoided.

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

Note
Planned drug interruptions at regular intervals are not being used in the treatment of HIV.

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 one drug. The whole drug combination must be assessed. Either of the following may be done:

  1. All three drugs can be changed to another combination.
  2. 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 a the same class. For example, do not swap efavirenz for nevirapine. Rather replace nevirapine with lopinavir/ritonavir.
  3. 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 antiretroviral treatment is begun. Functional immune recovery starts within weeks of beginning antiretroviral treatment. An inflammatory response to HIV-associated infections was not possible before antiretroviral treatment was started as the immune system was too suppressed. As the immune system recovers, the body may develop an inflammatory response to any of the following:

  1. Hidden or mild infections which have been missed clinically (i.e. unmask unrecognised infection). An example would be silent TB.
  2. Worsen existing infections. An example would be TB which has only been treated for a few weeks.
  3. 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 How many patients develop the immune reconstitution inflammatory syndrome?

Up to a third of patients starting antiretroviral treatment 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.

5-72 How does the immune reconstitutional inflammatory syndrome present clinically?

It usually presents with fever and a worsening of the patient’s symptoms after starting antiretroviral treatment. All cases of severe immune reconstitution inflammatory syndrome must be urgently referred to an antiretroviral clinic. The immune reconstitution inflammatory syndrome usually presents abruptly within two weeks to a month after antiretroviral treatment is started. Consider immune reconstitution inflammatory syndrome in anyone who is not thriving after six weeks of antiretroviral treatment.

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

5-73 Which patients are most likely to develop the immune reconstitution inflammatory syndrome?

Patients with a CD4 count below 100 cells/µl when 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 antiretroviral treatment. Immune reconstitution inflammatory syndrome is not caused by treatment failure, side effects or drug interactions.

Note
When starting antiretroviral treatment, TB may present for the first time (previously missed clinically) 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 commonest 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 antiretroviral treatment if at all possible. The patient may need to be referred to an HIV specialist.

Immune reconstitution inflammatory syndrome is not 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 the 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 antiretroviral treatment is started. Patients become more responsible.

Expense

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

Unfortunately some antiretroviral drugs 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 antiretroviral treatment is not made available to all patients who need it. It is hoped that more cheaper generic drugs will be produced for poor countries.

Case study 1

A patient who is ‘treatment ready’ 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 are almost always started on the first-line combination (3TC or FTC, TDF and either nevirapine or efavirenz). Co-trimoxazole prophylaxis will also be continued until the patients CD4 count is above 200cells/µl.

3. What choice would you make for this patient?

3TC, TDF and nevirapine. Most patients would start on a fixed dose combination tablet of TDF, FTC and efavirenz but as this patient does shift work, efavirenz is not the best option as it often causes drowsiness.

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 two 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 two 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 is done, routine blood samples are taken and one month’s supply of medication is given.

Case study 2

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

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

At six months after starting treatment. However, he should immediately return to the antiretroviral treatment clinic if he experiences side effects or has other problems.

2. How often do patients collect their medication?

Every one to three months. These visits should be used to assess and promote excellent adherence.

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

By measuring the CD4 count and viral load as well as finding out whether the clinical signs of HIV have disappeared.

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

The viral load should be measured at four or six 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 one year on treatment if the CD4 count at the start of treatment was greater than 200 cells/µl. If the CD4 count at the start of treatment was less than 200 cells/µl, it should be measured at 6 monthly intervals until it is above 200 cells/µl on two occasions. 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.

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 antiretroviral treatment has been successful the patient may be seen every three months. However, he should continue to collect his medication regularly. His CD4 count and viral load should be measured at one 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 antiretroviral treatment for six months. Her CD4 count remains below 200 cells/µl and her viral load is above 1000 copies/ml.

1. What is your diagnosis?

Possible antiretroviral treatment 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 two to three months. If it remains high the patient has failed antiretroviral treatment and treatment should be stopped until the patient has been fully prepared to start a second-line treatment regimen.

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

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 Aluvia without interrupting treatment. 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 six months and then every three 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), glucose, triglyceride and cholesterol tests are done for baseline values.

After treatment has been started an Hb and differential should be done at months three and six to screen for anaemia, which is a common side effect of AZT. Fasting glucose, cholesterol and triglyceride should be measured at three 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 antiretroviral treatment 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 antiretroviral drugs.

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 one or more drugs. Therefore it is in the interest of the whole community that patients take their antiretroviral treatment correctly.

6. How is the risk of drug resistance reduced?

By excellent adherence and always using combinations of at least three antiretroviral drugs.

Case study 5

Three weeks after starting antiretroviral treatment 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 antiretroviral treatment 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 antiretroviral treatment.

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 antiretroviral treatment is continued provided that the underlying cause is also treated. Immune reconstitution inflammatory syndrome is not an indication to stop antiretroviral treatment.

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 antiretroviral drugs may also be high in the private sector. These difficulties should be discussed with the treatment counsellor.

Dosing for patients on first-line combination

Medicine Timing of doses Possible side-effects
1. TDF (Tenofovir) 300mg daily 24 hours Kidney damage
2. 3TC (lamivudine) 300mg daily or FTC (emtricitabine) 200mg daily 24 hours Diarrhoea, headache
3. Efv (Efavirenz) 600 mg daily 24 hours Skin rash (allergy), vivid dreams, dizziness, sleep changes in first four weeks

Most side effects get better after one to two months of treatment.

Where possible, prescribe as a fixed dose combination tablet of TDF, FTC and Efavirenz as a once daily tablet (e.g. Atripla or Odimune one tablet daily).

Dosing for patients on second-line combination

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

Medicine Timing of doses Possible side-effects
1. AZT (Zidovudine) 300 mg twice daily 12 hours Numbness or pain in the feet, abdominal pain, hepatitis, acidosis
2. 3TC 150mg twice daily 12 hours Diarrhoea, headache
3. LPV/r (Lopinavir + ritonavir) 400/100 twice daily (Aluvia 2 tablets twice daily) 12 hours Skin rash (allergy), hepatitis

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

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

Medicine Timing of doses Possible side-effects
1. TDF 300 mg once daily 24 hours Kidney damage
2. 3TC 150mg twice daily 12 hours Diarrhoea, headache
3. LPV/r (Lopinavir + ritonavir) 400/100mg twice daily (Aluvia 2 tablets twice daily) 12 hours Skin rash (allergy), hepatitis

Most side effects get better after one to two months of treatment.