Switching HIV Regimens – When, Why, and to What

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

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 Constitutesa 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