1. ANTIRETROVIRAL RESISTANCE Jennifer Fulcher, MD, PhD

2. Outline What is antiretroviral resistance?  Review HIV-1 life cycle and antiretroviral drug targets  Define antiretroviral resistance  Prevalence of antiretroviral resistance How does antiretroviral resistance occur?  Mechanism of antiretroviral resistance How do we address antiretroviral resistance?  Treatment considerations of antiretroviral resistance  Prevention of antiretroviral resistance

3. History of antiretroviral therapy 1 st cases of opportunistic infections described Term AIDS described by CDC (1982) 1 st antiretroviral drug approved by FDA (NRTI class) 1 st protease inhibitor antiretroviral drug approved by FDA (PI class) Next class of antiretroviral drugs approved by FDA (NNRTI class) New class of antiretroviral drugs approved by FDA (INSTI class) Combination ART started “drug cocktails” New class of antiretroviral drugs approved by FDA (fusion & entry inhibitor class) 19811987 19951997 20032007

4. Why do we have to use combination antiretroviral therapy? one drug therapy combination therapy HIV virus (viral load) Time This virus has become resistant to the drug used

5. What is antiretroviral therapy resistance? Resistance means that the virus has mutated so that certain drugs are no longer effective. Resistance is caused by mutations that occur in the HIV virus  these mutations can cause resistance to one antiretroviral drug or to many antiretroviral drugs Anytime HIV is able to multiply mutations can occur antiretroviral drug HIVBLOCKS VIRUS antiretroviral drug HIV RESISTANCE mutation

6. HIV-1 life cycle Modified from Nature Reviews Genetics 5, 52-61 (January 2004) Virus binds to and enters cell Virus genetic material turned into DNA that integrates into host genome Host cell machinery produces viral proteins to make new virus New virus matures and leaves cell

7. Classes of antiretroviral therapy Modified from Nature Reviews Genetics 5, 52-61 (January 2004) Virus genetic material turned into DNA that integrates into host genome Reverse transcriptase inhibitors (NRTIs or NNRTIs)

8. Classes of antiretroviral therapy Modified from Nature Reviews Genetics 5, 52-61 (January 2004) Protease inhibitors (PIs) New virus matures and leaves cell

9. Classes of antiretroviral therapy Modified from Nature Reviews Genetics 5, 52-61 (January 2004) Virus genetic material turned into DNA that integrates into host genome Integrase inhibitors (INSTIs)

10. Classes of antiretroviral therapy Modified from Nature Reviews Genetics 5, 52-61 (January 2004) Fusion and entry inhibitors Virus binds to and enters cell

11. How does resistance happen? HIV reverse transcriptase is very error prone – it makes at least one mistake every time it makes a new HIV virus Some mistakes don’t affect the virus, but some of those mistakes are in a place that blocks antiretroviral drug activity “mistake” = mutation

12. How does resistance happen? Virus without mutations is the most fit and will dominate when no drugs are present However, when ARVs are present, mutations that block antiretroviral drug activity provide an advantage to the virus The virus that doesn’t have mutations will be blocked by antiretroviral drugs and will no longer grow The virus that has mutations that affects antiretroviral drug activity will continue to grow despite presence of the drugs  these viruses are resistant

13. How does resistance happen? http://www.natap.org/2006/HIV/071906_02.htm Selective pressure from the drug allows the mutant (resistant) virus to grow

14. How does resistance happen? HIV antiretroviral drug BLOCKS VIRUS antiretroviral drug

15. How does resistance happen? Antiretroviral drug resistance can also be transmitted from one person to another at the time of HIV infection So, a person who has not yet taken antiretroviral drugs can have resistance Transmitted drug resistance in persons with acute/early HIV-1 in San Francisco, 2002-2009. PLoS One. 2010;5:e15510

16. How common is resistance? On average, it is estimated that 20-38% of people on ARVs will develop resistance during therapy About 5 to 20% of virus that is transmitted has resistance to at least one antiretroviral drug

17. What factors contribute to resistance? Resistance occurs when drug levels in the body are not adequate to stop replication of the virus  Medication adherence  Medication absorption  Drug-drug interactions  Transmitted resistance

18. When do we suspect resistance? 1. If a patient has an increasing viral load while on ART then we suspect there may be resistance - This assumes the patient has been adherent in taking their HIV medications 2. All patients are screened for resistance prior to starting ART for the first time - Transmitted resistance can occur about 5-20% of the time

19. How do we test for resistance? HIV Genotype Test This test determines the genetic sequence of the HIV virus in the patient’s blood which is then compared to a database to identify if mutations are present. Blood sample taken from patient HIV genetic sequence identified Patient’s HIV sequence is compared to HIV database (Stanford, IAS-USA) then report made which tells which resistance mutations are present

21. Not all mutations are created equal Some mutations cause loss of activity for an entire class of drugs; while some mutations only cause loss of activity for a single drug NRTIs Emtriva® (emtricitabine) Epivir® (3TC, lamivudine) Retrovir® (AZT, zidovudine) Videx-EC® (ddI, didanosine) Viread® (tenofovir) Zerit® (d4T, stavudine) Ziagen® (abacavir) NRTIs Emtriva® (emtricitabine) Epivir® (3TC, lamivudine) Retrovir® (AZT, zidovudine) Videx-EC® (ddI, didanosine) Viread® (tenofovir) Zerit® (d4T, stavudine) Ziagen® (abacavir) NNRTIs Edurant® (rilpivirine) Intelence® (etravirine) Rescriptor® (delavirdine) Sustiva® (efavirenz) Viramune® (nevirapine) NNRTIs Edurant® (rilpivirine) Intelence® (etravirine) Rescriptor® (delavirdine) Sustiva® (efavirenz) Viramune® (nevirapine) PIs Aptivus® (tipranavir) Crixivan® (indinavir) Invirase® (saquinavir) Kaletra® (lopinavir + ritonavir) Lexiva® (fosamprenavir) Norvir® (ritonavir) Prezista®(darunavir) Reyataz® (atazanavir) Viracept® (nelfinavir) PIs Aptivus® (tipranavir) Crixivan® (indinavir) Invirase® (saquinavir) Kaletra® (lopinavir + ritonavir) Lexiva® (fosamprenavir) Norvir® (ritonavir) Prezista®(darunavir) Reyataz® (atazanavir) Viracept® (nelfinavir) INSTIs Isentress® (raltegravir) Tivicay® (dolutegravir) (elvitegravir) INSTIs Isentress® (raltegravir) Tivicay® (dolutegravir) (elvitegravir)

22. Not all drugs are created equal Low barrier to resistance Some drugs easily develop resistance; often a single mutation is enough to cause resistance  Reverse transcriptase inhibitors (NRTIs, NNRTIs) High barrier to resistance Some drugs are more “durable” and need multiple mutations to cause resistance  Protease inhibitors

23. What do we do if there is resistance? 1. Discuss with patient why resistance may have developed. 2. Change HIV medications to a regimen that does not include drugs to which HIV is resistant. - often we have to change to an entirely new class of drugs to avoid resistance - the drugs to which the HIV was resistant can not be used in future regimens 3. Continue to monitor the patient’s viral load for response to the new medications and development of any further resistance

24. What can patients do to protect against resistance? 1. Take all HIV medications regularly. 2. If doses are frequently missed, talk to the doctor immediately to discuss strategies to improve adherence. 3. If adherence is a problem, it may be best to not take any HIV medications until reasons for non-adherence have been addressed.

25. Summary & Review HIV reverse transcriptase is error-prone which leads to mutations when the virus replicates Some mutations affect the activity of antiretroviral drugs  resistance Resistance occurs when people have inadequate amounts of antiretroviral drugs because this allows for some replication (leading to mutations) and also selects for the resistant virus Resistance mutations can affect only one drug, or can affect an entire class of drugs Classes of drugs have different “barriers” to resistance

26. Summary & Review Factors that contribute to resistance are: medication adherence medication absorption drug-drug interactions transmitted adherence Treatment and prevention of resistance involves selecting a new regimen that avoids drugs to which the virus is resistant Underlying factors that led to resistance must be addressed in order to both treat resistance and prevent further resistance