Changing HIV Treatment: What to Do if Viral Load Rebounds

This is an adaptation of an educational booklet published by HIV i-Base, a British treatment activist group, in February 2015. The full version of the booklet is available on their website, as well as in PDF format.

Table of Contents

Reasons to Change Treatment

There are two main reasons to change treatment.

  1. If your viral load never became undetectable.
  2. If your viral load was undetectable but started to rise again (viral rebound).

In both cases your treatment could have failed.

This booklet is about these two situations.

A third reason to change is if you have side effects.

It is always important to talk to your doctor about side effects. Changing treatment is usually easy. It can really improve your quality of life.

A separate guide is available if you are changing because of side effects.

Why is viral load important?

A viral load tests checks how well your treatment is working. When you are on treatment this test is often a more useful than your CD4 count.

If you are starting treatment, it can show whether the drugs are working.

If you are on treatment is shows whether treatment is still working.

How accurate are viral load tests?

In the UK, viral load tests have a cut-off of 20, 40 or 50 copies/mL. Below this level, viral load is called undetectable.

The differences between these tests are not significant.

It is common for viral load to be less than 5 copies/mL

However, viral load tests have "a three-fold margin of error."

This means that a result of 50 could really be anywhere between 16 (3-fold lower) and 150 (3-fold higher). A result of 500 could be anywhere between 50 and 1500.

This is why it is essential to confirm an unexpected result.

If Your Viral Load Never Became Undetectable

How quickly should viral load become undetectable?

When you first start treatment, viral load drops quickly.

Many people get undetectable within the first month and most within three months. Some people take longer.

The time it takes to get undetectable depends on several things:

  • Your viral load when you start. The higher it is, the longer it will take.
  • Which HIV drugs you use. Integrase inhibitors reduce viral load faster than other meds.
  • Adherence. Drugs can only work if you take them. If you take your meds on time, viral load comes down more quickly.

Viral load should drop by at least 90% in the first month. This is sometimes referred to as 1 log (see Table 1 below). If not, your doctor will ask you about adherence and may take other tests.

If viral load is still detectable after 3-6 months, it is normal to change treatment.

What is second-line treatment?

Second-line is the name for your second combination.

If this second treatment fails, your next treatment is called third-line.

How long should I wait?

This will depend on your individual situation.

It will depend on why treatment may have failed and on the results of other tests.

Table 1: Log Scales (A Log 10 Scale Is a Multiple of a Factor of 10)
1 log = 101.5 log = 301.7 log = 50
2 log = 1002.5 log = 3002.7 log = 500
3 log = 1,0003.5 log = 3,0003.7 log = 5,000
4 log = 10,0004.5 log = 30,0004.7 log = 50,000

What to Do if Your Viral Load Rebounds

Getting a second test

  • A low-level rebound may not be serious.
  • It may be a lab or test error.
  • It may just be a small blip that goes back down again.

This is why it is important to repeat the test.

The second test should be taken when you get the detectable result.

Don't just wait for weeks or months until your next routine test.

If the second test is still detectable this is a "confirmed viral rebound."

Viral Load Blips

Viral load blips are common.

A blip is when viral load goes above 50 for a short time and then drops back down. See Figure 1.

Most blips are not detected because viral load is only tested twice a year in people on stable treatment.

Blips can be defined as an increase from less than 50 to 200, 500 or even 1000. Most blips are under 200. Blips can be caused by other infections, such as flu or herpes, or a recent vaccination.

Some blips are just lab errors.

Figure 1. Viral Load Blips
Figure 1. Viral Load Blips A single blip above 50 is common. It doesn't mean you need to change treatment. A blip is usually undetectable again on the confirmatory test.

Confirmed Viral Rebound

If the second test shows your viral load is detectable at a similar or higher level -- and you have been taking your meds -- this confirms viral rebound. See Figure 2.

It is likely you have started to develop resistance to some or all of the drugs in your combination.

Most guidelines recommend changing treatment.

This is because HIV can develop resistance even when viral load is relatively low (between 50-500).

Figure 2. Viral Load Rebound
Figure 2. Viral Load Rebound If the second viral load test is still detectable, and the person has been taking their meds, this is more likely to be a real rebound. This can be a reason to change treatment.

How Can Drugs "Fail" When I Feel Fine?

"Viral failure" relates to results from a blood test but not to how well you feel.

If you stay on a failing treatment, your CD4 count will start to drop.

This might not be for several months but it will happen.

A lower CD4 count increases the risk of new or progressing illness. This is called "clinical failure." See Figure 3.

Figure 3. From Rebound to Symptoms
Figure 3. From Rebound to Symptoms 1. Viral load rebounds. If you stay on the same meds, viral load will continue to rise. 2. Your CD4 count will go down over time. 3. As your CD4 count drops the risk of symptoms increases.

Do Some Drugs Develop Resistance More Easily?

Some drugs only need one mutation for the virus to be complete resistance. This is the case with NNRTIs and some nukes like 3TC and FTC. See Figure 4.

These drugs are more vulnerable if used in a combination that doesn't keep your viral load below 50 c/mL.

They are also often cross-resistant to similar drugs in the same class.

Other drugs, including protease inhibitors, develop resistance more gradually.

The first mutations do not make much impact but as more complex resistance develops the drugs eventually stop working. See Figure 5. These drugs take longer to develop cross-resistance to other drugs in the same family.

Some nukes need only one mutation and some develop more complicated patterns of resistance.

Integrase inhibitors are more similar to NNRTIs in being vulnerable to resistance.

Figure 2. Viral Load Rebound
Figure 4: How One Mutation Can Stop Some Drugs Working

Some drugs stop working after only one mutation.

These include NNRTIs (nevirapine, efavirenz, rilpivirine and etravirine), integrase inhibitors (raltegravir) and some nukes (3TC and FTC).

Figure 2. Viral Load Rebound
Figure 5: Resistance Increases Slowly With Some Drugs

With some other drugs, the first one or two mutations make little difference.

If you continue taking the same drug, more mutations will develop that eventually stop the drugs working. These include most PIs and some nukes.

Reasons a Combination Can Fail

If your viral load rebounds it is important to find out why.

This is to help make sure the next combination will work.

Your doctor will need your help to find out which of the reasons below are most important.

There are more than 25 HIV drugs in six different drug classes. However, there are only a limited number of combinations.

This is because resistance to one drug can limit the use of other drugs that are similar.

Reasons a Combination Can FailWhat to Do About It
1) Information.Maybe you did not have enough information or support to understand how to get the best from your meds.Take control of your own health. Ask questions about treatment until you are happy with the answers.Talk to your doctor, health advisors and friends.

Read leaflets and websites. Ask for help.

2) Adherence. You might have missed doses or been late taking your meds.Your doctor is likely to talk about adherence first.Be as honest as you can when discussing this.If you did not miss doses it is important that your doctor believes you. See these tips.
3) Taking meds with or without food.Some drugs need to be taken with food and others without food to reach the right levels.Check that you had the right information. Not following this advice might mean you were only getting only half the dose.
4) Low drug levels. You were taking your drugs on time but they were not absorbed properly.Some people absorb low drug levels.This is less common with modern meds but may still be worth checking..Drug levels can be checked for some drugs. These include PIs, NNRTIs, integrase inhibitors, maraviroc and T-20.
5) Drug resistance before treatment.Resistance might have been missed before you started. Even taking all your meds on time can't overcome drug resistance.Get a new resistance test and an expert review of previous tests.This will help chose your next drugs.
6) If your combination had side effects.No matter how good your combination is on paper, if you have difficult side effects, or it is too difficult to take, then ask your doctor if there are other options.Use new drugs that are still likely to be active.If side effects were a reason for missing doses, it is important that your doctor knows this.There are likely to be other meds you can use.
7) Drug interactions may have reduced the drug levels of your HIV drugs.Other medications, supplements or herbs can interact with HIV drugs.This includes meds you can buy over the counter without a prescription.It can include vitamins and minerals and some recreational drugs.

Your HIV doctor and pharmacist need to know about all your drugs and supplements. This is to check for potential interactions.

See: www.hiv-druginteractions.org

8) The drugs in your last combinations.Some drugs are not recommended at high viral loads.

Check that the drugs in your last combination were right for your viral load.

Why Adherence Is Linked to Drug Resistance

The doses of HIV drugs are worked out to give you effective drug levels for 24 hours a day.

These levels should be high enough to be active and not get resistance. They should not be so high that they cause side effects. See Figure 6.

Figure 6: Drug Levels With Good Adherence
Figure 6: Drug Levels With Good Adherence Drug doses are worked out to cover the whole dose period. Levels need to be high enough to be active against HIV without risking resistance. Levels need to be low enough to minimise the risk of side effects.

But HIV drugs can only work if you take them.

Missing doses or being late taking your meds increases the chance of drug resistance. See Figure 7.

Figure 7: A Missed or Late Dose Increases the Risk of Resistance
Figure 7: A Missed or Late Dose Increases the Risk of Resistance Missing doses or being late taking your meds lets the drug levels fall below the minimum level needed. Drug resistance can then develop. The more often you are late or miss a dose, the greater the chance that resistance will occur.

Drug resistance will stop treatment working. Resistance changes your virus forever. It reduces your choice of drugs.

This can affect current meds and new drugs in the future.

What Is HIV Drug Resistance?

Drug resistance can explain why a drug no longer works.

Resistance can develop to drugs used to treat viral, bacterial and fungal infections.

The drugs stop working because the virus (or other organism) has evolved or changed while on treatment.

The risk of drug resistance increases when drug levels are low.

Resistance and adherence are closely related. If you miss doses or are late taking your meds, this increases the chance of resistance.

This is because when you are late, drug levels can fall below the minimum level needed to control the virus.

The mutations that develop when you have only low levels of meds can stop the drugs working. Then, when you restart treatment, they may not work as well.

Adherence is even more critical when you are on your second, third or later combination as you have fewer drugs left to use.

What If I Forget My Meds?

Almost everyone will forget or be late with their meds at some time. If this happens you will still be okay.

But there is a difference between occasionally missing a dose and regularly forgetting on a daily or weekly basis.

  • Each time you miss or are late there is a chance that resistance can develop.
  • Be honest when looking at your adherence.
  • If your adherence is not good, your doctor can help but you need to talk about it. Support is available but you will need to ask.

Adherence Tips

The following tips are from the i-Base Introduction to Combination Therapy.

Some drugs are more flexibility with how exact you have to be with timing.

Remember that recommendations to take with or without food are important.

  • Find out what is involved. How many pills? How often? How exact is timing?
  • Use a daily or weekly pill box. You can see if you miss a dose.
  • Use the timetable on the next page. Mark off each dose and the time that you take it.
  • Talk to your doctor if you have trouble.
  • Set up an alarm using your mobile phone or watch.
  • Take extra meds if you travel in case flights change.
  • Keep an emergency supply.
  • Ask a friend to help you remember.
  • Ask friends if they have ideas that can help.

More tips ...

Important Monitoring Tests

The following tests are used in different circumstances when changing treatment.

Viral Load Tests

Viral load is the most sensitive test to check whether a combination is still working.

Testing 2-4 weeks after any change in treatment will show whether the new drugs are working, repeating monthly until undetectable.

Once undetectable, monitor every 3-6 months, based on the CD4 count.

For more information on viral load see these other sections in this guide:

Resistance Tests

Resistance tests can show whether HIV is resistant to HIV drugs that you are taking. The test doesn't always tell you about other drugs you have taken in the past.

Drug resistance involves changes to the structure of HIV that are called mutations.

For example, the mutation called M184V will stop 3TC and FTC from working. It reduces abacavir from being fully active.

The mutation K103N stops efavirenz and nevirapine from working.

These results need to be interpreted by an expert.

UK guidelines recommend a resistance test before changing treatment. This is because you need to have blood taken while you are still on the failing combination.

There are two main types of drug resistance tests. See Figure 8 below.

Figure 8: Types of Resistance Tests
Figure 8: Types of Resistance Tests

Resistance tests can only detect resistance to drugs that you are currently taking or have recently been taking. A "virtual phenotype" test compares results from your genotype test to a large database of phenotype results to predict your phenotype.

Genotype tests (mutation changes)

Genotype resistance tests are the only type of test that is likely to be used in the UK in 2015.

A genotypic resistance test looks at the structure of your virus and how it has changed from normal "wild-type" virus. Different changes are associated with resistance to different drugs.

Checking the changes in your virus gives a good idea of which drugs are unlikely to work.

Although this test does not register very low levels of resistance, it can still be vital as a guide to choosing drugs for your next combination.

Results should take about a week.

Although genotype tests cannot predict which drugs WILL work, they can predict which drugs WILL NOT. With drug resistance, this information is just as important.

Phenotype tests ("fold" changes)

In 2015, phenotypic test are now rarely used in the UK.

A phenotypic resistance test adds each increasing concentrations of a drug in a test tube that contains your HIV. It shows how sensitive or resistant you are and how active each drug is.

Results are given in terms of how much drug is needed to have the same effect as a regular dose on non-resistant HIV.

For example, 10-fold resistance to a drug means 10 times as much drug is needed to get the same antiviral effect.

Interpreting phenotype tests is complicated. Sometimes it is not clear at what level individual drugs remain active, and each drug can be different.

Phenotype tests are only recommended in the UK guidelines when genotype results alone do not provide a clear result.

Phenotype resistance tests are 3-4 times more expensive than genotype tests. They take longer to get results (usually 2-4 weeks) because the tests cannot be run in your own clinic and it takes time for the virus to grow.

Virtual phenotype tests

The "Virtual Phenotype" test compares results from a genotype test to those in a large database of matched phenotype results.

This test is therefore not really a phenotype test but can still be useful.

Again, this is rarely used in the UK in 2015.

Therapeutic Drug Monitoring (TDM)

TDM measuring the blood levels of a drug. TDM can be used for protease inhibitors, NNRTIs, integrase inhibitors, T-20 and maraviroc.

TDM is only used in certain situations to individualise dosing, including:

  • When using combinations where they may be a drug interaction. This is important with new drugs.
  • With pre-existing liver or kidney damage, or haemophilia, and some other medical conditions. For example, drug levels of both amprenavir and abacavir can be too high if your liver is damaged. TDM can find the safest dose.
  • When using not-recommended doses -- for example to use atazanavir without ritonavir boosting.
  • If you may not be absorbing drugs properly. For example, if you have severe diarrhoea.
  • For children. Differences in growth rates and the way children process drugs at different ages are not always accounted for. Even when doses are calculated by body weight or body surface area they often need altering.

TDM is recommended in UK guidelines in these and other situations. Poor drug absorption or faster clearance can cause a combination to fail.

Using TDM and resistance tests together produces better results than either test alone.

TDM costs around £70 per drug from Lab21:

www.lab21.com

Lab 21 TDM information

IQ and VIQ

At one time research was looking to individualise treatment further by using tests that measure the Inhibitory Quotient (IQ) or Virtual Inhibitory Quotient (VIQ). These blood tests report on how well your virus reproduces (called "viral fitness").

IQ and VIQ tests were being integrated with TDM and resistance tests to further individual results.

These tests are still sometimes used in research but are not generally available.

Viral Tropism Tests

This is a test that is only used if you are going to use maraviroc, which is an HIV drug called a CCR5 inhibitor.

In the UK and Europe, tropism is tested using a genotype resistance test. A special type of resistance test (testing proviral DNA) can be used if your viral load is low or undetectable.

UK (BHIVA) guidelines for tropism testing. (2009)

When Should I Change and Which Drugs Can I Use?

If viral rebound is confirmed, changing treatment will reduce the risk of further resistance.

With some drug classes, switching early may mean you can still use other drugs in the class. This is important for NNRTIs, integrase inhibitors and T-20.

Each situation will be different. When you change will depend on how high viral load has rebounded.

It will also depend on the reasons for the rebound.

Some people change treatment if their viral load stays consistently detectable above 50 copies/mL.

Other people wait until viral load is confirmed above 200 or 500 copies/mL in case this is still a blip.

A resistance test can help decide.

Anyone with drug resistance needs to consider their treatment history before choosing the next meds.

  • Usually you will have to change all your drugs.
  • Sometimes you can just change one or two drugs.
  • Sometimes you can just add one drug to intensify treatment. This is not generally recommended.

How Do I Choose New Drugs?

If you are changing treatment the choice of new drugs depends on:

  • Your previous treatment history. This includes the meds you have already used and whether you developed resistance to them.
  • Your current CD4 count and lowest ever CD4 count (called CD4 nadir).
  • Your general health.

When choosing a new combination, you and your doctor will want to pick drugs that are most likely to work.

This will include looking at study results for new drugs.

It will include avoiding drugs with cross-resistance.

Cross-resistance is when resistance to a drug you have used applies to other drugs that you haven't used.

Cross-resistance is common for all types of HIV drugs. All PIs, NNRTIs, nukes and integrase inhibitors have some cross-resistance to meds in the same class.

Cross-resistance is complicated. This is why your care needs to be managed by a doctor who is an expert in drug resistance.

General Ideas or Principles

Three general ideas increase the chance of your next treatment working.

  1. Using drugs from a new class.
  2. Using drugs from classes you have used before but did not develop resistance to.
  3. Using more, rather than fewer drugs, may have an added benefit.

Treatment guidelines also outline ways to choose new drugs. See: www.bhiva.org.

Your new combination will depend on your HIV history.

It will also depend on the reason that your previous combination failed and on the results of other tests.

Resistance tests will help pick meds that may work, even when you have some resistance.

Cross-Resistance by Drug Class

There are six main types (or classes) of drugs that work at different parts of the HIV life cycle.

NRTIs

Cross-resistance between NRTIs is complex. Some drugs are active even with some resistance.

NNRTIs

There is strong cross-resistance between some NNRTIs. But, etravirine can work against other NNRTI resistance.

Protease inhibitors (PIs)

There is strong cross-resistance between some PIs. Some PIs, including darunavir/r and tipranavir/r, can work against early PI resistance.

Integrase inhibitors

As a new class, integrase inhibitors work if you have resistance to other drug classes. But they can also have cross-resistance within the class.

Resistance to raltegravir or elvitegravir can sometimes be overcome by dolutegravir by using a higher dose.

Information on each HIV drug.

Table of six main types (or classes) of HIV drugs

Diagram of the HIV lifecyle.

When to Use New Drugs And When to Wait?

Any new combination should use at least two, and preferably three, active drugs.

Using new drugs without other meds that are active will only give a short-term benefit. Viral load is likely to rebound again with more resistance. See Figure 9.

Figure 9. Using Only One Active Drug Will Only Work for a Short Time
Figure 9. Using Only One Active Drug Will Only Work for a Short Time Only one active drug is unlikely to get viral load to less than 50 copies/mL. If a new drug is not helped by other active drugs, resistance will develop.

It is only worth using one new drug if your CD4 count is very low (less than 50 cells/mm3) or if you have other serious symptoms.

Waiting until you can use at least 2-3 new drugs together at the same time is usually a better strategy.

It will make the new combination stronger. It will then perhaps be able to reduce viral load to undetectable, when the benefit will be long term. See Figure 10.

Figure 10: Waiting to Use Three New Drugs Is More Likely to Get Viral Load Undetectable
Figure 10: Waiting to Use Three New Drugs Is More Likely to Get Viral Load Undetectable Waiting to use two or three new drugs together will make the new combination stronger. Viral load can now get to less than 50 copies/mL. If viral load gets to below 50 it is likely to stay there without rebounding or developing further resistance.

Pipeline Drugs

New drugs are being developed in existing and new drug classes.

Following reseach can help you plan when to change and when to wait. There may be studies you can join to use new drugs.

The i-Base website includes updates on new drugs and new research.

This includes the following compounds in each class.

NRTIs: TAF (new version of tenofovir), CMX157 (also similar to tenofovir), EFdA, apricitabine (similar to 3TC).

NNRTIs: doravirine.

Integrase inhibitors: cabotegravir (similar to dolutegravir).

CCR5 inhibitors: cenicriviroc

Attachment inhibitors: BMS-663038

Fusion inhibitors: albuvirtide.

Maturation inhibitors: beviramat.

Additional drugs might become available before this booklet is next updated.

www.PipelineReport.org

Expanded Access Drugs

Some new drugs are available before they are approved for use in the UK. This is called an Expanded Access Programme (EAP) or a Named Patient Programme (NPP).

These drugs can be the key to your next combination. You will also be monitored very carefully for side effects and to check they are working.

You may need to register at another clinic to access EAP drugs. Your doctor can help you do this.

Get to know which drugs are in the pipeline and ask your doctor to give you the choice to use them.

Non-ARV Drugs

Some people may benefit from non-HIV drugs that are still active against HIV.

Many of these drugs are approved for other uses and can be prescribed on a named patient basis.

PEG Interferon (Interferon alpha): A once-weekly injectable hepatitis C drug. Anti-HIV activity (and side effects) increase with the dose used (as with regular interferon alpha).

Gm-CSF: A drug used to boost your immune system, reduced the risk of new illnesses in people with a CD4 count less than 50 cells/mm3.

foscarnet: A CMV drug with anti-HIV activity that may resensitise AZT-resistant virus. This has been used annecdotally for short periods (2-4 weeks) to reduce viral load before starting a new regimen. Foscarnet is too toxic for long-term use.

hydroxyurea (HU): A 30-year-old anti-cancer drug that can resensitise HIV to ddI. Now rarely used or only at a reduced dose of 300 mg once-daily.

mycophenolic acid: May boost abacavir levels in a similar way to hydroxyurea and ddI. Limited studies showed a benefit using 500 mg twice-daily.

L-acetyl carnitine: An amino acid that has no anti-HIV effect but may minimise or reverse peripheral neuropathy associated with (nuke) drugs.