1. Switching HIV Regimens – When, Why, and to What Pedro Cahn, MD Frank Palella, MD Graeme Moyle, MD Calvin Cohen, MD

2. Reasons to Switch Virologic failure There is a better treatment with: – Fewer current side effects – Less potential for future side effects

3. Is the Regimen Broken? Evaluating problems with cART – Are you re-assessing side effects? – Looking for new side effects? Is a new regimen available? The decision to prescribe should be an active one. Ask yourself “Is this the regimen I would offer to a new patient just walking into my office today?”

4. Switching Strategies STRATEGYRESULT Switching virally suppressed patients from Efavirenz (EFV) to a single-tablet regimen containing Rilpivirine (RIL) Safe Reduces toxicity NEW FROM AIDS 2012 Switching suppressed patients from boosted PI regimen to same single-tablet regimen: Preserves viral suppression Avoids hyperlipidemia Switching to a regimen without a dual nucleoside Less data on safety and efficacy May not be recommended

5. Switching with Confidence When a person has been suppressed < 50 copies/ml – Little replication and mutation – Drugs effective before suppression are still suppressive after – If every drug was active when you started, than every drug remains active BUT – If they were already somewhat resistant, and you switch to a regimen that requires full activity, you won’t have an ongoing suppressive regimen

6. Who to Switch Patient selection is critical Criteria to consider: – Never failed therapy – No exposure to mono-therapy or dual- therapy – No history of transmitted resistance Availability of historical genotypes is important in determining a switching strategy

7. Switching Trade-offs Patients may be doing well on their current regimen Not all switching problems are related to side-effects Regimens need to be simple for patients to follow Inform patients about: – Potential side effects – Changes in dosing schedule – Other requirements for the new regimen Ask the patient – “Does this make sense for you?” And remind them that, without a virologic failure, they can always go back if the switch doesn’t work out

8. Does Switching = Simplification? Simplification is a subset – Fewer pills – Less often – How medication needs to be taken By mouth With food, or certain types of food Ensure patients understand simplification – Need to be clear on pill numbers/dosing time

9. Even a Simplification Constitutes a Change Re-education, re-assessment, and re-evaluation is necessary – Is it making a patient’s life simpler? – Is it reducing toxicity? – Is it resulting in fewer doses or fewer pills? – Is it something the patient will be happier with?

10. The SWATCH Study Randomized, open-label, pilot trial Patients randomized to either alternate triple-drug regimens every three months or stay on one regimen At 48 weeks, the virologic failure rates were: – 4.8/1,000 person weeks in the two standard treatment groups – 1.2/1000 weeks in the switching group Source: Martinez-Picado J et al. Ann Intern Med. 2003;139:81

11. Potential Benefits of Change Encourages patient education Reinforces adherence Facilitates conversations between healthcare providers and patients

12. Error Reduction The more pills, and more detailed the medication schedule, the easier it is to make mistakes It is harder to make dosing errors if patients only need to take a single pill, once or twice a day When patients are taking multiple pills they may – Forget pills – Accidentally double-up the wrong pills – Think that they can fill one prescription and not another, when finances are difficult

13. SWITCH-ER Study Randomized, double-blind, crossover study in patients controlled by EFV – Raltegravir(RAL) twice a day with Efavirenz (EFV) placebo – EFV once a day with RAL placebo – Switch after two weeks to alternate regimen Outcome – Half preferred twice daily RAL, even though it meant switching from a one pill, once a day regimen, they had previously tolerated well – RAL significantly improved lipid levels, stress, & anxiety Source: Nguyen, A. et al. AIDS. 25(12):1481-7

14. It’s Not Always About Less Pills Simplification can be: – Getting rid of a side effect – Getting rid of an anticipated side effect

15. Monitoring a Switch Viral load checks – Standard schedule is fine, if the regimen is just a pill simplification (same drugs, combination pill) – Should be checked at week 4 with a regimen switch Double check adherence Make certain that patients are properly following guidelines for taking the pill

16. Considerations with a Regimen Change Increased monitoring – Biologic factors – Patient compliance Need for patient education – Dosing time – Restrictions among meals Monitoring after a switch is a good way to make certain that patients understand instructions correctly

17. One Month Check Check at week 4 to assess – Virologic failure – Hepatotoxicity – Nephrotoxicity (some cases) – Adherence Then return to a standard follow-up schedule Harm is rare when switching regimens, but it’s better to make certain

18. CD4 Count – A Reason to Switch? Suppressed patients who don’t have CD4 improvements – May not be a problem – May have wide range of “normal” CD4 levels* (350- 1500 cells/ml) CD4 increase does not necessarily predict clinical outcomes Where are patients’ CD4 levels stuck? – A very low count might be a reason to switch – With moderate levels, one can wait and see * Levels are not well assessed in HIV negative populations

19. Historical Note Zidovudine (AZT) and tenofovir/dideoxyinosine (TDF/DDI) regimens did impair immunological reconstitution This is not known to be a concern with “modern” cART regimens With respect to immune reconstitution, current differences between medications are subtle, and probably not clinical important

20. What affects CD4 Rise? Genetic environment Ongoing immune activation Trials have varying results Does it really matter? CD4 count may not actually significantly impact clinical outcomes

21. Switching and Aging Increases in certain health risks are widely associated with age – Cardiovascular disease – Renal disease Should consider these factors when looking at side effect profiles of cART drugs Greater potential for drug-drug interactions – Older people take larger numbers of non-HIV medications

22. When is it Safe to Switch? If the regimen you are switching to would have worked before the patient was suppressed, it should work now Switching interval varies by circumstance: – Early toxicity = early switch – Late toxicity = late switch Switching to modernize therapy – After at least 6 months on previous therapy – With two consecutive undetectable viral loads

23. What about people with long-term success on other regimens? There is some data which suggests switching may add security in maintaining a long-term undetectable viral load – Particularly when switching to a regimen that would not be appropriate for the treatment naïve patient – Such regimens may work very well in those who have already been suppressed in the long term

24. Oh, Brave New World… Treatments are: – Increasingly effective – Increasingly safe – Increasingly convenient Many good options Multiple single-tablet, fixed dose combinations – Potential financial advantage, as well as convenience

25. Use The Guidelines Regimens recommended in IAS/DHHS Guidelines – Are strongly supported by clinical trials – Are considered to be the best in terms of safety, efficacy, and tolerability If patients aren’t on these regimens – ask yourself why not?

26. DON’T JUST MAKE SURE PATIENTS ARE ON THE SAME REGIMEN MAKE CERTAIN THEY ARE ON THE REGIMEN BEST SUITED FOR THEM