Switch Strategies

Switch strategies for virologically suppressed persons

Definition of Virologically Suppressed

Clinical trials exploring switching strategies have generally defined suppression as an HIV-VL < 50 copies/mL for at least 6 months

Indications

  1. Documented toxicity caused by one or more of the antiretrovirals included in the regimen. Examples of these reactive switches: lipoatrophy (d4T, AZT), central nervous system adverse events (EFV, DTG), diarrhoea (PI/r) and jaundice (ATV), proximal renal tubulopathy and low bone mineral density (TDF), see Adverse Effects of ARVs and Drug Classes
  2. Prevention of long-term toxicity. Example of this proactive switch: prevention of lipoatrophy in persons receiving d4T or AZT and prevention of proximal renal tubulopathy with TDF, see Adverse Effects of ARVs and Drug Classes. This may include person's concerns about safety
  3. Avoidance of drug-drug interactions. This includes ART switch when starting HCV treatment to avoid DDIs, see Drug-drug Interactions between DAAs and ARVs
  4. Planned pregnancy or women wishing to conceive, see Antiretroviral Drugs Not Recommended in Women who Wish to Conceive or Become Pregnant while on ART
  5. Ageing and/or co-morbidity with a possible negative impact of drug(s) in current regimen, e.g. on CVD risk, metabolic parameters
  6. Simplification: to reduce pill burden, adjust food restrictions, improve adherence and reduce monitoring needs
  7. Protection from HBV infection or reactivation by including tenofovir in the regimen
  8. Regimen fortification: Increasing the genetic barrier of a regimen in order to prevent resistance (e.g. in persons with reduced adherence)
  9. Cost reduction: switching to the generic form of their current regimen, if available

Principles

Clinicians should always review possible adverse events or tolerability issues with current antiretroviral regimens. Just because the viremia is suppressed it should not be assumed that the PLWH is well adapted and tolerating the current regimen

  1. The objectives of treatment modification should be to eliminate or improve adverse events, facilitate adequate treatment of comorbid conditions, and improve quality of life. The primary concern when switching should be to sustain and not to jeopardize virological suppression. In persons without prior virological failures and no archived resistance, switching regimens entail a low risk of subsequent failure if clinicians select one of the recommended combinations for first-line therapy. The majority of clinical trials showing non-inferiority of the new regimen after the switch have actively excluded persons with prior virological failures and historical resistance
  2. The complete ARV history with HIV-VL, tolerability issue, cumulative genotypic resistance history and/or phases of viremia on previous regimens with the potential of resistance development should be evaluated prior to any drug switch
  3. Switches within the same drug class (e.g. TDF/FTC -> TAF/FTC, EFV -> RPV) are usually virologically safe if  equal potency and in the absence of resistance
  4. Cross-class switches of single drugs with the same genetic resistance barrier (for example EFV to RAL) are usually virologically safe in the absence of resistance to the new compound
  5. In case of prior virologic failures, with or without evidence of resistance, switches have to be planned especially carefully when they result in a lower genetic resistance barrier of the regimen. A PI/b may only be switched to unboosted ATV, an NNRTI, INSTIs RAL and EVG if full activity of the 2 NRTIs in the new regimen can be assumed based on resistance data, ARV history and HIV-VL results before switching (see 2.)
    Due to the higher genetic barrier of DTG and BIC, it is currently unclear if a switch to DTG- or BIC-based regimens also requires full activity of 2 NRTIs in the combination
  6. Before switching, remaining treatment options in case of potential virological failure of the new regimen should be taken into consideration. This requires knowledge about the resistance selection profile of the switch regimen. For example, some mutations (e.g. K65R or M184I/V) might affect the activity of most currently available STRs and preclude their future use. Especially, when reducing the number of drugs in a regimen or its genetic barrier to resistance, the chances of composing a fully suppressive regimen after potential failure following switch should be considered
  7. Proviral DNA genotyping may be useful in persons with multiple virological failures, unavailable resistance history or low-level viremia at the time of switch. Results ought to be taken cautiously as proviral DNA genotype may not detect previous resistance mutations and can also detect clinically irrelevant mutations.  Therefore, routine proviral DNA genotyping is currently not recommended
  8. When selecting a new regimen, clinicians should carefully review the possibility of new drug-drug interactions with antiretroviral and concomitant medication leading to suboptimal drug exposure or toxicity, as well as the lag time for hepatic enzyme induction or blockade following discontinuation of the offending drug. Examples are: increased TDF toxicity with a PI/b or an increase in metformin exposure with DTG
  9. If the switch implies discontinuing TDF and not starting TAF, clinicians should check the HBV and HBV vaccination status. TDF or TAF should not be discontinued in persons with chronic HBV
  10. PLWH should be seen soon (e.g. 4 weeks) after treatment switches to check for maintenance of suppression and possible toxicity or tolerability issues of the new regimen
  11. If a PLWH receives and tolerates a regimen that is no longer a preferred option, and none of the other reasons for change applies, there is no need to change. Example: persons tolerating EFV-containing regimens
  12. See online video lecture How to Change ART from the EACS online course Clinical Management of HIV

Dual therapies

Dual therapies supported by large randomized clinical trials or meta-analyses:

  • DTG + RPV
  • 3TC + DTG
  • 3TC + DRV/b
  • 3TC + ATV/b

In clinical trials, these strategies have not been associated with more virological rebounds than triple therapy. There were a few cases of resistance development on DTG + RPV

 Dual therapy options supported only by small trials:

  • DRV/b + RPV   

In persons with suppression of HIV-VL < 50 copies/mL for the past 6 months these dual therapy strategies should only be given if there is:

  1. no historical resistance and
  2. absence of chronic HBV co-infection

Strategies not recommended

  1. Monotherapy with a PI/b
  2. Monotherapy with DTG
  3. Dual or triple NRTIs combinations
  4. Specific two-drug combination, i.e. 1 NRTI + 1 NNRTI or 1 NRTI + 1 unboosted PI, 1 NRTI + RAL, MVC + RAL, PI/b + MVC, ATV/b + RAL
  5. Intermittent therapy, sequential or prolonged treatment interruptions