HIV i-Base

Appendix 1: Q&A on resistance

The questions below were posted by participants on the i-Base course on HIV and drug resistance.

They are all covered in the course. This list will be added to as part of the course outline.

Please email additional questions or subjects related to resistance and it will be included in this list and in the course.

Questions about resistance

1. Which drugs can someone use if they have already developed resistance?

The person will need to look for drugs that are still active. This choice is informed by the results from a resistance test. Sometimes resistance to one drug in a class means you are likely to have resistance to other drugs in the same class. For example, nevirapine is unlikely to work if you developed resistance to efavirenz (and vice versa). These are both NNRTIs. However etravirine (a newer NNRTI) might work but it depends on the resistance mutations that developed to the first NNRTIs.

A resistance test includes a report that recommends which drugs you can choose. This has to be interpreted by an expert who also knows your treatment history.

In countries that do not have access to resistance tests, the choice is based on using drugs that are as different as possible. For example, if the first combination included an NNRTI, the second combination with use a PI.

2. How are treatment choices made for someone with resistance?

These choices are made by looking at results from resistance test together with someone’s treatment history. Each mutation can be looked up to see if it is important. If the results are complicated then a resistance expert should also be involved.

3. Can drug resistance be passed from mother to child?

Yes. Whenever HIV can be transmitted, drug resistance can also be transmitted. The risk from the mother to baby is dramatically reduced by using HIV treatment to reduce viral load before delivery.

4. Can a person’s genetics contribute to them becoming resistant to a drug?

Although genetics is likely to affect many health risks, in general, genetics is not linked to drug resistance.

The main cause of resistance is missing or being late with drug doses.

Some researchers are looking at whether the K65R mutation (associated with resistance to tenofovir) is more likely in people with HIV sub-type C. By implications, this might make this mutation easier to develop in African people who are more likely to become infected with sub-type C. This is more the genetics of the different HIV sub-types though than genetics of different people.

5. Is it possible to develop resistance to a drug even with perfect adherence?

If your viral load gets to undetectable and you still continue to take all your meds, new resistance is very unlikely. So perfect adherence after your viral load gets to undetectable is just as important as when you first start treatment.

However, if some of the drugs in a combination are not active or not being absorbed properly, resistance can develop even if you are taking all your meds. Drug absorption can be testing for PIs and NNRTIs using drug level monitoring.

Resistance can also occur if you start a new medication that interacts with your HIV drugs. This is why your doctor or pharmacist needs to know about any other meds or drugs you take. This includes herbal supplements, over the counter drugs, meds prescribed by your GP and recreational drugs.

6. Are some drugs easier to become resistant  to than others?

Yes. Drugs that only need one simple mutation are more vulnerable to resistance. These include NNRTIs and some nukes (3TC and FTC). Other drugs that can develop resistance quickly if they are used without other active drugs include integrase inhibitors and the entry inhibitor T-20.

Protease inhibitors are more difficult to get resistance to, and usually involves developing many mutations before a drug stops working. So resistance to protease inhibitors is slower to develop than NNRTIs or integrase inhibitors.

7. I want to understand the terms used about resistance.

Great, please read each section carefully and use the glossary at the end for some more complicated words or the main i-Base glossary.

8. If viral load in the blood is less than 50 copies/mL, but is higher in sanctuary or compartment sites (ie the brain or genital compartments), can resistance develop in those sites?

This is an important question. Luckily, most people with undetectable viral load in blood, remain undetectable without drug resistance. The suggests that resistance developing in other sites is not a major problem for most people.

It is difficult to study because it involves getting sample of fluids from these compartments to compare to blood. However, many studies have reported different resistance patterns in different compartments. The risk of resistance developing in different sites is not clearly understood. It involves the properties of each drug in the combination in each compartment.

9. What is “wild-type” virus and what does it do?

Wild-type virus is the name for HIV that has no resistance. This means that it is still sensitive to every HIV drug. See section 3.3.

10. You need virus present for resistance testing – so you can’t test if the viral load is undetectable. How high does the viral load need to be to be able to use resistance testing?

This will depend on the lab. For many years this needed to be higher than 500-1000 copies/mL. In 2012, some UK labs are even able to get results from samples that are above 100 copies/mL. See section 4.8.

11. Do you need to be currently taking a drug to see if you are resistant to that drug? Is resistance still detected if you have stopped or changed treatment?

In general you need to be taking a drug when you have the resistance test. After you stop taking a drug the resistant virus becomes dominated by wild-type non-resistant HIV. This make it less likely that the resistance test with detect the resistance. Section 3.5 looked at this.

12. If you have developed resistance to a drug, does that mean that you are resistant to all the drugs in that class?

This depends on the detail of the resistance mutations and the individual drugs. The Standford database lists the implications of cross resistance by drug and by mutation. Drugs that have been developed more recently are usually designed to work against resistance to earlier drugs fro that class. New nukes like tenofovir can work for some people who developed resistance to AZT, d4T or ddI. The newest protease inhibitors darunavir/r and tipranavir/r were both developed to be active against earlier protease inhibitor resistance.

Appendix 6 and Appendix 7 show resources that can show which mutations have cross resistance between drugs in the same class.

13. Is poor adherence the only factor that leads to developing drug-resistance? Are there other factors?

Adherence is the most important factor, but others include:

  • Poor drug absorption
  • Low drug levels
  • Pre-existing resistance
  • Interactions with other drugs, supplements or recreational drugs

14. If your viral load is undetectable but your CD4 still low, could that be a sign of drug-resistance? Would the doctors consider doing a drug-resistance test?

No to both questions. If your viral load is undetectable, you do not have resistance to the drugs in your combination – because, by definition, they are working to control your HIV. Resistance tests do not work when viral load is undetectable.

15. What are the main signs of drug-resistance?

Resistance can only be detected by using a resistance test. If someone has a high or rising viral load when on treatment, then resistance to one of more of the drugs in the combination would be suspected.

16. At what level is viral load considered undetectable?

The current routine cut-off for commercially available test is 20, 40 or 50 copies/mL. There is not thought to be a clinical difference between any of these low tests. So any result below the cut-off for the test is undetectable. Several studies using tests that are sensitive down to 1 or 3 or 5 copies/mL have reported that in people on stable treatment, 60% are likely to be less than 5 copies/mL.

17. What is a viral load ‘blip’ and what should you do about it?

A blip is when viral load that was previously undetectable, rises to above 50 copies/mL and then goes back down again without needing to change treatment. If you suspect a blip, the first thing is to have another viral load test to confirm whether the first result is repeated.

Although blips are generally referred to as being form 50 to 400, sometimes viral load can rebound to even higher levels and still return to undetectable without changing treatment. See this section from the Guide to Changing Treatment.

If someone has two low level rebounds above 50 copies/mL which then become undetectable this is called a ‘bump’.

18. When should you have a resistance test?

See Section 5.3, especially Table 3. In summary, this includes:

  • When diagnosed
  • Before starting treatment
  • If viral load doesn’t reduced by 1-2 logs by 4-8 weeks.
  • Before changing treatment.
  • When viral load increases above 50 copies/mL on two consecutive tests. This could indicate treatment failure or reinfection.
  • After stopping treatment (ie for some women after pregnancy).

19. Seeing as HIV “makes mistakes” and  does not have “proof reading” abilities when replicating, is it possible to introduce “defective or modified” genetic material that would render the virus ineffective?

Some researchers are trying to develop drugs that works in this way. One compound called K-1461 worked by making the virus make so many errors that it was unable to continue reproducing in test-tube studies. Unfortunately, the same results were not seen in the first human studies, and this research is now on hold.

20. What is the difference between the types of tests for resistance – phenotype vs genotype? Which is preferred?

This is covered in detail in Section 4. Genotype types are used most widely in most situations. If the results of a genotype test are unclear, a phenotype test might be used.

21. Are resistance tests the same tests that are used to see if the type of HIV in different people is in some way linked – in prosecution cases of transmission, for example?

No, but they are similar. Genotype resistance test only look at a small section of the HIV genome. The tests used in transmission cases are called ‘phylogenetic tests’ and they compare the whole genome. Although phylogenetic tests can show when two viruses are similar, then cannot show which direction an infection was passed or that one person caught HIV from another.

22. If a woman takes ART during pregnancy for prevention of mother to child transmission (PMTCT) and wants more children, is she likely to become resistant to those drugs?

If the woman continues on treatment after the pregnancy, then as long as viral load stays undetectable, she will not develop resistance. If she stops treatment after the birth, perhaps because she has a high CD4 count, then if she stops treatment carefully and under supervision, this should also prevent resistance. A resistance test is recommended six weeks after stopping treatment. See Section 5.3.

23. What options does a woman have for future pregnancies?

Treatment during future pregnancies will be based on guidelines and available treatments. If the woman developed resistance then she would not normally use those drugs again in the future. If she did not develop resistance then she can use the same treatment.

24. Some people have never had resistance tests and would not know how to bring this up in a discussion with a doctor. How can this best be addressed?

If someone is not yet on treatment, then it is best to just ask.

Many people have been tested without realising this, as they may not have been given the results.

If they haven’t been tested, ask whether a sample was stored, and if not, then asked for this to be done. UK guidelines state that there is no financial benefit from delaying this test.

If you are already on treatment that is working, there is no need for a resistance test now, unless that treatment fails in the future. If you’d like 1-2-1 information on this question please contact i-Base for advice.

25. With all clinics trying to cut back because of funding cuts, how do we make sure that important tests like the resistance tests are offered to patients when they need them?

This is difficult.

The general answer is good information should help people understand the tests they need, and ensure that they ask for them.

i-Base has received many calls when newly diagnosed people are not given a resistance test until they ask for one. Because resistance tests are so clearly included in guidelines, this should make it more difficult for services to cut. Budget cuts on all services mean this is likely to continue to be a concern though.

26. How expensive (or cheap) are resistance tests?

Costs vary depending on the laboratory, type of test and the turnaround time. Genotype tests are about £150–£200 and phenotype tests are £600–£700.

27. Are resistance tests available in developing countries?

Sometimes yes, but generally not in public health programmes. Sometimes they may be available as part of research or with private health care. When resistance testing is not available, resistance would be estimated based on viral load and treatment history.

28. What happens to a pregnant woman with resistance to the drugs used for PMTCT?

As with other resistance, the choice of drugs will depend on resistance tests. If resistance developed to an NNRTI like nevirapine, the the next combination should include a protease inhibitor.

29. Are the tests always 100% accurate?

No. The results provide information to add to a wider picture about what treatment is likely to work. Some results are very accurate and consistent, but not finding resistance does not guarantee it is not there. If the resistant virus is less than 20% of the total HIV population, is is likely to be missed.

30. Are all possible mutations known?

No. This is a growing and evolving field of research. Every year resistance database describe new mutations and the relevance of different patterns of mutations.

Resistance is understood for most older drugs, but every new drug is likely to bring new relevance to new mutations.

31. Why can boosted protease inhibitors be used as monotherapy without developing resistance?

This is an important example of the different properties of each drug class. PI resistance usually takes an accumulation of at least 3, 4 or more primary mutations before the drug stops working. Some PIs are still active after complicated patterns of over a dozen mutations.

These patterns of resistance do not occur by chance – unlike the single mutations that occur before treatment that might stop an NNRTI from working. Some boosted-PIs are strong enough to reduce viral load and also avoid resistance over the time that it takes to get viral load to undetectable levels. For some people a boosted-PI is not enough and they need to add other drugs – usually two nukes – to make a standard combination.

32. Is resistance inevitable?

No, most people on treatment probably never develop drug resistance. If your combination includes active drugs, your viral load gets to undetectable, and you are very adherent, then resistance is unlikely to develop.

33. How does wild type virus prevent resistant virus from reproducing?

Wild-type virus doesn’t directly attack resistant virus. It is however stronger and fitter when there are no drugs. So resistant virus is weaker and by comparison reproduces less well. Resistant virus only becomes more fit compared to the wild-type virus in the presence of the drug to which it is resistant. So the fitness of each type of virus depends on which drugs are being taken.

34. As a patient, what should I expect to hear back from my resistance test? What should the doctor tell me?

If a resistance test shows you have drug resistance, your doctor should explain these results.

For each drug the report from the test should say whether the drug is still sensitive, partly sensitive, or resistant. You can ask for a copy of the printed report from these tests. If you want to go into more detail, use an online resource, such as the Stanford database. There you can look up each mutation in the report to learn about the consistency of the research on that mutation and the impact on choice of drugs. See Appendix 6.

>> Appendix 2: Supplementary information about genetics

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