HIV-1 Resistance - Implications For Clinicians

1. HIV-1 Resistance - Implications For Clinicians Joseph J. Eron Jr., MD Professor of Medicine University of North Carolina

2. Disclosures

3. Types of Resistance Tests Genotype and Phenotype

4. Types of Resistance Tests • Genotype • HIV gene sequencing of the patient’s virus to detect mutations known to confer drug resistance • Phenotype • Measures ability of a recombinant virus derived from the patient sample to grow in different concentrations of antiretroviral drugs Hirsch et al. Clin Infect Dis. 2003;37:113-28.

5. Interpretation of Genotypic Assays • Is an indirect measure of resistance • Requires knowledge of which mutation are associated with a change in susceptibility • Expert advice • May not be available • Experts’ views may be inconsistent • Rules-based algorithms • Provided by most labs, third-party sites • Need regular updating • Virtual Phenotype (VircoType) • Phenotypic information using genotype • Database of matched genotypes and phenotypes

6. Question: What is the significance of the RT mutation K103N? Confers resistance to 3TC/FTC Confers resistance to tenofovir Confers resistance to efavirenz All of the above None of the above

7. 0 Provider Knowledge of Specific Resistance Mutations N = 100 % Providers RecognizingSpecific Mutations Mutations Salama et al. Clin Infect Dis. 2003;36:101-4.

8. Phenotypic SusceptibilityRelationship Between Drug Concentration and Viral Inhibition 100 Wild-type Resistant 50 Inhibition of Virus Replication (%) Fold resistance 0 Wild-type IC50 Resistant IC50 Drug Concentration

9. Interpretation of Phenotypic Assays • Results reported as IC50 or fold-change (FC) compared with IC50 of wild-type virus • Individual results provided for each drug • Thresholds to define reduced susceptibility • Biologic cutoff: based on biologic variations in treatment-naïve patients (usually 2 SD > median) • Clinical cutoff: • As good as clinical data used to estimate cut points • Resistance is a continuum – precise breakpoints unlikely • Two relevant breaks? • Decreased response and • Minimal response

10. Question:Resistance testing should be obtained in which treatment naïve patients? Only in HIV infected patients with acute infection Individuals thought to have been infected within the last 2 years All treatment naïve patients

11. Transmitted ARV Resistance Clinically Important in the Developed World Surveillance Essential in the Developing World

12. How Common is Drug Resistance at Diagnosis? • US Variant, Atypical and Resistant HIV Surveillance System (VARHS) • Estimate prevalence of transmitted resistant mutations • Determine distribution of HIV subtypes • March 2003 to October 2006; 11 states, 409 sites, n=3130 10% 6.9% M41L 45.1% of NRTI K103N 70.1% of NNRTI L90M 40.0% of PI 95% Subtype B 5% 3.6% 2.4% 1.9% MDR Any NRTI NNRTI PI Wheeler et al. 14th CROI, 2007. Abs 648

13. FTC-301A: Impact of Baseline Resistance on Treatment Outcome Naïve pts, baseline VL > 5000 copies/mL Incidence (%) of Virologic Failure Mutation type: FTC + ddI + EFV (n=270) d4T + ddI + EFV (n=276) Borroto-Esoda et al. AIDS Res Hum Retroviruses 2007;23:988-95.

14. How Important Are Minority Variants?

15. Standard Genotype 181C 108I 190A 103N

16. 0 0 6 6 12 12 18 18 24 24 30 30 36 36 Antiretroviral Response Following sdNVP Women Starting ART <6 Months Post Partum Women Starting ART ≥6 Months Post Partum 60 60 50 50 Single dose of NVP 40 40 Cumulative Rate of Failure (%) 30 30 Single dose of NVP 20 20 Placebo 10 10 Placebo 0 0 Months Since the Start of ART Months Since the Start of ART Lockman et al. NEJM 2007;356:135-47.

17. Resistance and Virologic Failure Multiple Causes of Virologic Failure Replication in the Presence of Antiretrovirals Results in Resistance

18. 0 0 Treatment-Experienced Patients:ARV Treatment Failure Social/personal issues Regimen issues Poor potency Toxicities Wrong dose Poor adherence Host genetics Poor absorption Insufficient drug level Rapid clearance Viral replication in the presence of drug Pre-existing resistance Poor activation Resistant virus Resistant virus Drug interactions ART resistance testing. National resource center. Available at: http://www.aidsetc.org/aidsetc?page=et-01-00. Accessed November 29, 2006.

19. Management of Virologic Failure in Treatment Experienced Patients • Definition: detectable plasma HIV RNA on therapy • ‘Is it time to switch therapy?’ • Obtain resistance testing • Assess clinical situation • Adherence • Previous treatment history – ARV tolerability and toxicity • Balance clinical urgency with availability of active agents including new drugs and expanded access • New agents – especially those in a new class are likely to have the most activity

20. New Agents in Existing Classes (PI and NNRTI) Resistance Patterns Are More Complex Darunavir 10 codons; 11 substitutions Tipranavir 16 codons; 21 substitutions Etravirine 8 codons; 13 substitutions

21. New Agents in Existing Classes • Mutations to older agents are likely to be present • Majority variants • Minority variants • Some degree of cross resistance can be anticipated • Cross resistance increases with the number and type of mutations • The activity of a new agent from a new class is likely to be more predictable even with state of the art resistance testing

22. New Agents in New Classes CCR5 Inhibitors Integrase Inhibitor

23. CCR5 Inhibitors • HIV-1 entry into CD4 cells is dependent on a second receptor: CCR5 (R5 viruses) or CXCR4 (X4 viruses) • Early in HIV disease course most individuals have only R5 virus detectable • In more advanced disease and highly treatment experienced patients dual tropic virus or mixtures of R5 and X4 viruses are more common • CCR5 Inhibitors bind to CCR5 blocking entry • Activity only in patients with R5 virus • Maraviroc and vicriviroc

24. CD4+ cell count decline accelerates following detection of SI in patients in whom NSI-only virus was previously detected Will emergence of X4 variants on R5 inhibitor therapy lead to CD4 cell decline? Association Between Emergence of SI Virus and CD4+ Cell Count 800 600 Mean (SE) CD4+ Cell Count (cells/mm3) 400 NSI 200 NSI → SI SI 0 -48 -36 -24 -12 0 12 24 36 Time (Months) Koot et al. Ann Intern Med. 1993;118:681-688.

25. Prevalence of Coreceptor Tropism Demarest et al. ICAAC 2004. Abstract H-1136. 2. Brumme et al. J Infect Dis. 2005;192:466-474. 3. Moyle et al. J Infect Dis.2005;191:866-872. 4. Melby et al. J Infect Dis. 2006;194:238-246.5. Wilkin et al. Clin Infect Dis. 2007;44:591-595. 6. Nelson et al. CROI 2007. Abstract 104aLB. 7. Lalezari et al. CROI 2007. Abstract 104bLB.

26. HIV-1 Resistance to CCR5 Antagonists • Two mechanisms • Selection for (emergence of) viral variants that use CXCR4 (dual tropic viruses or mixed populations) • Occurs about 2/3 of the time • As yet NOT associated with rapid fall in CD4 cell count • Alterations (mutations) in HIV gp 120 • No Change in viral tropism • Allows virus to use CCR5 with inhibitor bound • Plateau in antiviral effect as opposed to change in IC50 • The drug is unable to fully inhibit virus regardless of concentrations achieved

27. Integrase Inhibitors • Integrase mechanism has 3 steps • Association with dsHIV DNA – pre-integration complex • 3’ processing by integrase enzyme • Strand transfer of HIV DNA into host chromosome • Potent inhibitors of stand transfer now in development • Raltegravir – Phase III studies recently presented • Elvitegravir – Phase II studies

28. Integrase Inhibitor Resistance • Primary mutations surround the catalytic site • Raltegravir • Resistance emerged in 3/4 patients with virologic failure who had genotype results • Two major pathways with apparent primary mutations but one or more additional mutations • Likely compensatory for fitness • Cross resistance between integrase inhibitors currently in development appears likely

29. Question: In those patients who have experienced virologic failure on multiple regimens including NNRTI, NRTI and PI, which agent is most likely to be fully active? Darunavir Etravirine Tipranavir Integrase Inhibitors CCR5 inhibitors 4 and 5