Question

What are the current opinions and evidence about drug sequencing?

22 June 2011. Related: All topics, Changing treatment, Living with HIV long-term, Resistance, Starting treatment.

Hello.

I would like to know what are the current opinions and evidence around drug sequencing.

Assuming no resistance or contraindications to therapy, is it better to start treatment for the first time with a boosted protease inhibitor or an NNRTI (both in conjuction with NRTIs)?

Does starting with one particular class limit future treatment options should a person experience treatment failure on the first choice?

I have heard that some doctors prefer to save the protease inhibitors for later? I have also heard that NNRTIs are better in salvage therapy?

Thank you.

Answer

Answer: Simon Collins

Thanks for this question – it is a good one!

This used to be asked a lot when there was more competition between different drug manufacturers.

Now that there is a similar high level of effectiveness of most first line options this has become a less asked question. Tolerability and side effects tend to be more important.

It also used to be asked in terms of drug resistance and sequencing individual drugs in the same class. This is also less important now because the recent availability of new classes has reduced the need to recycle within a drug class.

In general, there is little evidence to suggest any significant difference between whether you start with a PI or an NNTRI-based combination.

Having said this, there are very few randomised studies that run for long enough to study both the first and the second combination results. When they have been run (such as ACTG 364), they often included drugs that are no longer widely used.

UK treatment guidelines have for a long time recommended starting with an NNRTI. This was based on the need for fewer daily doses and fewer daily pills rather than any medical benefit from sequencing. These factors are less important now there are several once-daily protease inhibitors and the latest NNRTI (etravirine) is a twice-daily drug.

HIV treatment should be highly individualised. So for some people, even excluding side effects and pill counts, there are advantages to starting with PIs. One example would be if adherence is chaotic but treatment is still needed. Where someone may sometimes miss meds for days at a time, the risk of developing resistance would be much less on a PI combination.

From this perspective, it is probably better to work out the best combination for your circumstance first, in order to give the first combination the best chance of working. Then, look at second-line options only when you need them.

In theory, the sequencing question might become more important if newer classes of drug become approved for and/or more widely used in first-line therapy. Ongoing research is looking at using integrase inhibitor-based combinations first of CCR5-inhibitors. Some studies at whether combination without nucleosides will show any advantages.