Will Drug Resistance Jeopardize the National HIV Drug Resistance Programme? Prof. Tulio de Oliveira Africa Centre for Health and Population Studies, University of KwaZulu-Natal, South Africa Research Department of Infection, University College of London (UCL), U.K. Southern African Treatment Resistance Network (SATuRN) AWACC “19 – 20 November 2015”

Question 1: Will drug resistance jeopardize the National HIV treatment? A)Yes B)Maybe C)No D)No idea 2

Develop advanced yet affordable HIV & TB drug resistance diagnostics, implement it at primary health care clinics in resource limited settings and create a collaborative system for surveillance, research and capacity building. SATuRN Vision ADVANACED DIAGNOSTICS COLLABORATION & CAPACITY BUILDING SURVEILLANCE & RESEARCH

a network consisting of biomedical scientists, clinicians, epidemiologists and public health experts What is the SATuRN? SATuRN managed at the Africa Centre/UKZN and and the SA-MRC CURRENT PARTNERS includes 24 partners in southern Africa DIAGNOSTIC, DATABASE AND RESEARCH More info at Collaborators & implementation sites info at De Oliveira et al. Nature 2010 Libin et al. Bioinformatics 2013 Manasa et al. Database 2014

Surveillance of Drug Resistance Mutations (SDRM) in treatment naïve patients? Manasa et al., CROI & HIVDR 2015 Manasa et al. ARHR, in review. No TDR was detected in and 2012 both had 18 participants with any SDRM, 4.7% and 7.1% respectively The majority of the mutations were NNRTI (103, 106), which provide resistance to EFV.

Question 2: Is transmission of drug resistance increasing? A)Yes B)No 6

Question 3: Will individuals with resistance to 1/3 drugs on fixed dose combination suppress on ART? A)Yes B)No C)More research need to see the long term effects D)A & C 7

Transmitted drug resistance and suppression. Germany: Overall prevalence of TDR remained stable at a rather high level (12%). No significant differences in the frequency of virologic failure were identified during first-line cART between patients with TDR and fully-active cART, patients with TDR and non-fully active cART and patients without TDR. Overall, TDR prevalence in Uganda was relatively low (i.e < 10%) and its presence did not always imply treatment failure. 8 Zu Knyphausen et al Lee et al. 2014

High-level of resistance on patients failing 1 st line Long time on failure give rise to potential for transmission. Non-fixed dose combination. ResultsAdult* (n=516) Children* (n=108) Estimates of HIVDR prevalence 87%84.3% Estimates of HIVDR to >= 2 drugs 82%70.5% GSS for the standard 2 nd line regimen <2, suggesting a compromised regimen 17%7% Viral suppression after genotype 69%60% Average time on therapy 47 months39 months Average time on failing regimen 27 months20 months *Approximately 15% of Adults and 35% children failing regimen after 24 months Manasa et al. ARHR 2010 Manasa et al. PLoS One 2013 Pillay et al. AIDS Res Ther 2014 Virological failure and drug resistance?

Question 4: Which of the factors are involved in the development of failure and drug resistance? A)Adherence B)Poor absorption C)Toxicities D)Social issues E)All of the above. 10

Sergio Carmona and Wendy Stevens (NHLS) presented data from the Global Fund survey, including analysis of resistance in pre-treatment populations, patients failing NNRTI-based regimens and patient failing PI-based regimens –Acquired HIVDR 1L: 793 sequences; median time on ART 36 mo; 96% with drug resistance ~ 4% WT. –92% of the patients with drug resistance to 1 st line susceptible to 2 nd line! Carmona, HIV Drug Resistance National Workgroup, NICD, Oct Virological failure and drug resistance?

Gene sequencing in the clinic: HIV resistance testing Many ‘resistance mutations’ have been defined for HIV - these are changes in viral protein sequence that are associated with decreased susceptibility to specific drugs Mutations in the reverse transcriptase gene associated with resistance to nucleoside and nucleotide reverse transcriptase inhibitors IAS-USA 2008

Question 5: Why most of patients with resistance to first line will be susceptible to second line? A)No cross resistance between TDF and AZT B)Potent PI inhibitor (LPV/r) C)A & B D)None of the above 13

EARNEST Trial design HIV positive adolescents / adults (n=1200) 1 st line NNRTI-based regimen >12m; > 90% adherence last 1m Failure by WHO (2010) clinical, CD4 (VL-confirmed) or VL criteria RANDOMIZE PI NRTIs (NRTIs according to local standard of care) PI + RAL (12 wk induction) PI (Monotherapy) FOLLOW-UP FOR 144 WEEKS Primary outcome at week 96: Good HIV disease control – defined as all of:  Alive and no new WHO4 events from 0-96 weeks AND  CD4 cell count > 250 cells/mm 3 at 96 weeks AND  VL 10,000 c/ml without PI res. mutations at 96 weeks Paton N et al. NEJM 2014

Hypothesis 15 The efficacy of NRTIs is likely to be compromised by cross-resistance from multiple mutations arising during first-line therapy, and the drugs carry well-recognized risks of toxic effects. We hypothesized that combining a boosted protease inhibitor with raltegravir, a heat-stable integrase inhibitor, to create a second-line regimen with two completely new drug classes that would not be compromised by resistance selected from first-line therapy would sufficiently increase efficacy and decrease toxicity to justify the increased cost of the regimen.

Primary endpoint at 96 weeks Good disease control: PI/NRTI: 60% PI/RAL: 64% PI mono+: 56% Risk diff (95% CI): PI/RAL – PI/NRTI: +4.2% (-2.4%,+10.8%; P=0.21) Risk diff (95% CI): PImono+ – PI/NRTI:-4.1% (-10.8%, +2.6%; P=0.23) Note: using multiple imputation for missing CD4 (10%), VL (10%) and resistance (11% with VL >1000 c/ml ) at week 96 P=0.08 P< Paton N et al., IAS 2013; WELBB02

Second line failure and resistance? Many publications show that <25% of the patients failing second line therapy develop high-level resistance to PIs. The majority without resistance will suppress if adherence is increased. Patients failing second line with resistance have access to third line regimens in South Africa. 17

Conclusion I believe that the NDoH have done a great job on establishing new treatment guidelines. These involved recently change of the first, second and third line regimens. Furthermore, the use of FDC and TDF in first line and AZT in the second line allowed that cross-resistance not to become a problem. Low levels of PI resistance in second line failure suggest that patients will suppress with better adherence support. 18

Question 1: Will drug resistance jeopardize the National HIV treatment? A)Yes B)Maybe C)No D)No idea E)None of the above. 19

More info: 20