in Resource-limited Settings

in Resource-limited Settings
Second-line Regimens in Resource-limited Settings Somnuek Sungkanuparph, M.D. Professor of Medicine, Division of Infectious Diseases, Faculty of Medicine Ramathibodi Hospital Mahidol University, Bangkok, Thailand Adjunct Professor, Washington University School of Medicine St Louis, Missouri, United States

Outline Background Objectives Methods Results & Discussion Conclusions
Recommendations

Effect of Antiretroviral Therapy
Immunological response Viral load Clinical response less illnesses improved weight better well being back to work better quality of life CD4 Limit of detection Virological response Time

Immunological failure
Treatment Failure Clinical failure CD4 HIV-RNA Viral load Immunological failure CD4 Virological failure Criteria for failure Time

Misclassification of First-line ART Failure Based on CD4 Monitoring
Adult patients in western Kenya with first-line ART with suspected immunologic failure (CD4 decreased 25% in 6 months) Misclassification of treatment failure = immunologic failure but VL < 400 149 patients, treated for 23 months criteria number of patients misclassified 25% decrease in CD % 50% decrease in CD % Immunological failure criteria would lead to a premature switch to second-line regimens Kantor R, et al. Clin Infect Dis 2009.

Risk of Disease Progression/Death
Years since start of therapy 1 Cumulative probability of death or a new AIDS-defining event 0.05 0.10 0.15 0.20 0.25 2 3 4 5 Non-responders Immunologic-only responders Virologic-only responders Complete responders Viral control is the most important response. There may be a significant immune component of successful therapy Nicastri E, et al. J Med Virol 2005.

Treatment Failure and HIV Drug Resistance in A Chinese Cohort

Impact of HIV Drug Resistance on Mortality in A Chinese Cohort

Insufficient Drug Level Viral Replication in the
Causes of Treatment Failure Social/Personal Issues Regimen Issues Poor Potency Toxicities Wrong Dose Poor Adherence Host Genetics Poor Absorption Insufficient Drug Level Rapid Clearance Poor Activation Viral Replication in the Presence of Drug Drug Interactions Resistant Virus Transmission Treatment Failure

Patients with virological failure (%)
Adherence and HIV Drug Resistance Patients with virological failure (%) Adherence† (%) Degree of non-adherence was significantly associated with risk for virological failure (P<0.001) †Defined as number of pills taken/number of pills prescribed Paterson DL, et al. Ann Intern Med 2000;133:21–30.

Suboptimal Adherence to ART in Asia

Case 1 Resistance-associated RT Mutations: M184V, Y181C
Nucleoside and Nucleotide RT Inhibitors Resistance Interpretation abacavir (ABC) No Evidence of Resistance didanosine (ddI) No Evidence of Resistance lamivudine (3TC)/emtricitabine (FTC) No Evidence of Resistance stavudine (d4T) No Evidence of Resistance tenofovir (TDF) No Evidence of Resistance zidovudine (AZT) No Evidence of Resistance Non-nucleoside RT Inhibitors Resistance Interpretation efavirenz (EFV) No Evidence of Resistance etravirine (ETR) No Evidence of Resistance nevirapine (NVP) No Evidence of Resistance rilpivirine (ETR) No Evidence of Resistance Resistance-associated PR Mutations: - Protease Inhibitors Resistance Interpretation atazanavir (ATV) No Evidence of Resistance ATV + ritonavir (ATV/r) No Evidence of Resistance fosamprenavir + ritonavir (FPV/r) No Evidence of Resistance darunavir + ritonavir (DRV/r) No Evidence of Resistance indinavir + ritonavir ((IDV/r) No Evidence of Resistance lopinavir + ritonavir (LPV/r) No Evidence of Resistance saquinavir + ritonavir (SQV/r) No Evidence of Resistance tipranavir + ritonavir (TPV/r) No Evidence of Resistance

Predicting Factors for Genotypic Resistance Test Results that Associated with Poor Adherence

The 6th National Scientific Conference on HIV/AIDS
Durability of d4T/3TC/NVP regimen A 144-week Prospective Study Thailand: 140 patients Manosuthi W, et al. BMC Infect Dis 2008; 8:136. The 6th National Scientific Conference on HIV/AIDS

HIV Drug Resistance after Failing d4T/3TC/NVP regimen 9% (13 of 140) had HIV RNA >1,000 copies/mL 10 had M184V/I 1 had TAMs 2 had K65R 8 had Y181C/I 1 had K103N Manosuthi W, et al. BMC Infect Dis 2008; 8:136. The 6th National Scientific Conference on HIV/AIDS

HIV Drug Resistance at First-line ART Failure in Asia
First-line ART failure often results from the development of resistance-associated mutations (RAMs) 3 patterns are associated with resistance to multiple NRTIs and may compromise treatment options for second-line ART: thymidine analogue mutations (TAMs) 69 Insertion (69Ins) Q151M complex To study patterns and factors associated with multi-NRTI RAMs at first-line failure in patients Impact on virological responses at 12 months after switching to second-line ART Multi-NRTI RAMs = presence of either Q151M; 69Ins; ≥ 2 TAMs; or M184V+≥ 1 TAM

Factors associated with multi-NRTI RAMs were CD4 ≤ 200 cells/µL at genotyping (OR=4.43, 95%CI ) After switch to second-line ART, virological suppression was achieved in 85% Patients with ART adherence ≥ 95% were more likely to be virologically suppressed (OR=9.33, 95%CI )

Case 2 Resistance-associated RT Mutations: Y181C, M184V
Nucleoside and Nucleotide RT Inhibitors Resistance Interpretation abacavir (ABC) Possible Resistance didanosine (ddI) Possible Resistance lamivudine (3TC)/emtricitabine (FTC) Resistance stavudine (d4T) Resistance tenofovir (TDF) Possible Resistance zidovudine (AZT) Resistance Non-nucleoside RT Inhibitors Resistance Interpretation efavirenz (EFV) Resistance etravirine (ETR) Possible Resistance nevirapine (NVP) Resistance rilpivirine (ETR) Possible Resistance Resistance-associated PR Mutations: K20I, M36I Protease Inhibitors Resistance Interpretation atazanavir (ATV) No Evidence of Resistance ATV + ritonavir (ATV/r) No Evidence of Resistance darunavir + ritonavir (DRV/r) No Evidence of Resistance fosamprenavir + ritonavir (FPV/r) No Evidence of Resistance indinavir + ritonavir ((IDV/r) No Evidence of Resistance lopinavir + ritonavir (LPV/r) No Evidence of Resistance saquinavir + ritonavir (SQV/r) No Evidence of Resistance tipranavir + ritonavir (TPV/r) No Evidence of Resistance

Case 3 Resistance-associated RT Mutations: D67N, K70R, V108I, Y181C, M184V Nucleoside and Nucleotide RT Inhibitors Resistance Interpretation abacavir (ABC) Possible Resistance didanosine (ddI) Possible Resistance lamivudine (3TC)/emtricitabine (FTC) Resistance stavudine (d4T) Resistance tenofovir (TDF) No Evidence of Resistance zidovudine (AZT) Resistance Non-nucleoside RT Inhibitors Resistance Interpretation efavirenz (EFV) Resistance etravirine (ETR) Possible Resistance nevirapine (NVP) Resistance rilpivirine (ETR) Possible Resistance Resistance-associated PR Mutations: K20I, M36I Protease Inhibitors Resistance Interpretation atazanavir (ATV) No Evidence of Resistance ATV + ritonavir (ATV/r) No Evidence of Resistance darunavir + ritonavir (DRV/r) No Evidence of Resistance fosamprenavir + ritonavir (FPV/r) No Evidence of Resistance indinavir + ritonavir ((IDV/r) No Evidence of Resistance lopinavir + ritonavir (LPV/r) No Evidence of Resistance saquinavir + ritonavir (SQV/r) No Evidence of Resistance tipranavir + ritonavir (TPV/r) No Evidence of Resistance

Case 4 Resistance-associated RT Mutations: D67N, K70R, V108I, Y181C, M184V, T215F, K219E Nucleoside and Nucleotide RT Inhibitors Resistance Interpretation abacavir (ABC) Possible Resistance didanosine (ddI) Possible Resistance lamivudine (3TC)/emtricitabine (FTC) Resistance stavudine (d4T) Resistance tenofovir (TDF) Possible Resistance zidovudine (AZT) Resistance Non-nucleoside RT Inhibitors Resistance Interpretation efavirenz (EFV) Resistance etravirine (ETR) Possible Resistance nevirapine (NVP) Resistance rilpivirine (ETR) Possible Resistance Resistance-associated PR Mutations: K20I, M36I Protease Inhibitors Resistance Interpretation atazanavir (ATV) No Evidence of Resistance ATV + ritonavir (ATV/r) No Evidence of Resistance darunavir + ritonavir (DRV/r) No Evidence of Resistance fosamprenavir + ritonavir (FPV/r) No Evidence of Resistance indinavir + ritonavir ((IDV/r) No Evidence of Resistance lopinavir + ritonavir (LPV/r) No Evidence of Resistance saquinavir + ritonavir (SQV/r) No Evidence of Resistance tipranavir + ritonavir (TPV/r) No Evidence of Resistance

HIV Drug Resistance Mutations in Patients Failing d4T/3TC/NVP Detected at HIV RNA <4 vs. >4 log < 4 log > 4 log P = 0.105 P = 0.763 P = 0.041 P = 0.008 P = 0.031 P = 1.000 Sungkanuparph S, et al. The 6th National Scientific Conference on HIV/AIDS

HIV Drug Resistance and Time to Detection of Treatment Failure
VIROLOGIC FAILURE IMMUNOLOGIC FAILURE CLINICAL FAILURE CD4 COUNT Note to Speaker: This is a key slide in the presentation and should be strongly emphasized. Key Points: As virologic treatment failure occurs, the CD4 goes down (immunologic failure) and ultimately clinical failure ensues. Virologic and sometimes immunologic failure, go unrecognized if VL and/or CD4 monitoring is not occurring. In this case, the patient stays on a failing regimen for a prolonged period of time, during which time resistance can occur. This will ultimately lead to increased morbidity and mortality, as discussed, and lead to fewer options in the future. The next few slides explain this process by sharing some data. HIV DRUG RESISTANCE VIRAL LOAD Murri R, et al. JAIDS Sungkanuparph S, et al. CID 2007. Pillay D, et al. 14th CROI 2007, # Losina E et al, 15th CROI 2008, #823 25 25

Resistance patterns after failure of common NRTI backbones
Development of NRTI Resistance Mutations Resistance patterns after failure of common NRTI backbones AZT/3TC d4T/3TC Q151M K65R (d4T) M184V TAMs TDF/3TC TDF/FTC M184V K65R Q151M? ABC/3TC ddI/3TC M184V L74V or K65R Q151M? 3TC, lamivudine; ABC, abacavir; d4T, stavudine; FTC, emtricitabine; TAMs, thymidine-associated mutations; TDF, tenofovir; ZDV, zidovudine. This slide demonstrates the resistance pattern after the initial failure of common NRTI backbones. When patients start with zidovudine/lamivudine, stavudine + lamivudine, or the triple-NRTI combination of zidovudine/lamivudine/abacavir, they first develop M184V and subsequently develop thymidine‑associated mutations. When abacavir/lamivudine is chosen as initial therapy, M184V is the first mutation to develop and is usually followed by L74V and sometimes K65R. When tenofovir/emtricitabine is the first choice, M184V emerges first, followed shortly thereafter by K65R. The important take‑home point from this slide is that the M184V resistance mutation emerges first, followed by a gradual accumulation of either thymidine-associated mutations or either L74V or K65R, depending on the initial NRTIs chosen. Early detection of treatment failure allows more options for the next regimen NNRTI resistance Gallant JE. Top HIV Med Sungkanuparph S, et al. CID 2007.

Assessment of Treatment Failure Review antiretroviral history Physical exam for signs of clinical progression Assess adherence, tolerability, pharmacokinetic issues Resistance testing (while patient is on therapy) Clarify goals: undetectable vs. maximal virological suppression Identify treatment options Base treatment choices on expected efficacy - future treatment options tolerability - past medication history adherence - resistance testing results The 6th National Scientific Conference on HIV/AIDS

Second-line ART for Adults: DHHS Panel Recommendations Goal of treatment for ART-experienced patients with drug resistance who are experiencing virologic failure is to establish virologic suppression (AI) A new regimen should include at least 2, and preferably 3, fully active agents (AI) Adding a single ARV agent to a virologically failing regimen is not recommended because this may risk the development of resistance to all drugs in the regimen (BII) DHHS Guidelines, April 2015. The 6th National Scientific Conference on HIV/AIDS

Second-line ART for Adults: WHO Recommendations Second-line ART should consist of 2NRTIs + boosted PI The following sequence of second-line NRTI options is recommended After failure on TDF+3TC (or FTC), use AZT+3TC After failure on AZT/d4T+3TC, use TDF+3TC Use of NRTI backbones as FDC is preferred approach Heat-stable FDCs of ATV/RTV and LPV/RTV are the preferred boosted PI options for second-line FDC, fixed-dose combination WHO. Consolidated guidelines , June 2013; pp 146. The 6th National Scientific Conference on HIV/AIDS

Recommended second regimens
Switching the ART Regimen After Treatment Failure: Treatment Options First regimen Recommended second regimens 2 NRTIs + NNRTI Boosted PI + 2 active NRTIs indicated by genotype testing results 2 NRTIs + boosted PI 1) active boosted PI + 2 active NRTIs indicated by genotype testing 2) active boosted PI + 1 NNRTI ± 1 NRTI indicated by genotype testing 3) NNRTI + 2 active NRTIs indicated by genotype testing* *This option can be used only when there are 2 active NRTIs and the patient has never been exposed to NNRTI, or NRTI monotherapy or duotherapy. Sungkanuparph S, et al. Thai National Guidelines Asian Biomed 2010;4:

Outcomes of the Second-Line Regimens in Thailand An observational cohort of patients with 1st-line ART failure Of 95 patients, mean age 39 years, 65% were male Median CD4 and HIV RNA at 2nd-line ART initiation were cells/mm3 and 4.1 log10 copies/mL, respectively Boosted PI + 2 NRTIs, indicated by genotype results, was used as 2nd- line regimen At 6, 12, 24, and 36 months of 2nd-line ART, 67%, 62%, 84%, and 90% achieved HIV RNA <50 copies/mL Median CD4 were 258, 366, 444, and 522 cells/mm3 Good adherence, high baseline CD4, and early CDC staging were associated with virologic success (P < .05) Win MM, et al. J Int Assoc Physicians AIDS Care 2011; 10:57-63. The 6th National Scientific Conference on HIV/AIDS

Choosing LPV/r vs ATV/r for 2nd Regimens
PI/r Advantages Disadvantages LPV/r Potent activity (more evidence of successful LPV/r monotherapy) Resistance to LPV/r is less often at virologic failure Low risk of additional NRTI resistance with boosted PI failure Currently only co-formulated PI Metabolic complications due to both LPV and RTV esp. hypertriglyceridemia GI intolerance e.g. diarrhea Insulin resistance and lipodystrophy More pills (4/days) ATV/r Least metabolic complications due to ATV and less with RTV OD Once-daily dose Less pills (2/day) Can be given unboosted (if not using TDF in the regimen) Less evidence of ATV/r monotherapy Resistance to ATV is more often at virologic failure, but less with ATV/r Not a co-formulated PI Increased unconjugated bilirubin (4-9%) Absorption impaired with PPI Food requirement for dosing ART, antiretroviral therapy; EFV, efavirenz; GI, gastrointestinal; LPV, lopinavir; RTV, ritonavir. Key considerations in choosing ritonavir-boosted protease inhibitors in first-line therapy include the advantages that the agents have potent activity with low rates of transmitted protease inhibitor resistance, as we saw in the previous slides; the CD4 count increases are generally greater than with efavirenz; resistance to protease inhibitors are rare at virologic failure; and there’s also low risk of nucleoside reverse transcriptase inhibitor resistance with boosted protease inhibitor failure as well. Options, including protease inhibitors, are therefore retained for future use. However, there are disadvantages for protease inhibitors which include metabolic complications due to some protease inhibitors and/or the low-dose ritonavir that’s used for boosting; GI intolerance which can be observed, again, due to either the protease inhibitor or the ritonavir boosting; the drug–drug interactions that we previously discussed; lopinavir/ritonavir is the only coformulated protease inhibitor to date—though as seen in a previous slide others are in the pipeline; currently boosted protease inhibitor regimens are more pills than other options; and today there is no single-tablet regimen using preferred protease inhibitors available, though again coformulations are in development.

The HIV Second-line Therapy AntiRetroviral Study in Patients Who Failed NNRTI-based Regimens
Variable Total (N =195) Age, years 37.5 (6.9) Male, % 58 Weight, kg 58.3 (10.7) CDC clinical classification A:B:C, % 23:22:55 Baseline CD4 count, cells/mm3 204 (135) Baseline HIV-RNA, log10 copies/mL 4.1 (0.6) Genotypic resistance for NRTI, % M184V/I 82 K65R 7 Multi NRTI resistance* 18 98 and 97 2 and 3 pts did not receive allocated intervention Duration of NNRTI-based HAART before enrollment was 2.2 ( ) years * Multi-NRTI mutations were defined as having ≥4thymidine analog mutations (TAMs) or Q151M complex or 69insertion Bunupuradah T et al. Antiviral Ther 2012;17:

The HIV Second-line Therapy AntiRetroviral Study in Patients Who Failed NNRTI-based Regimens
10 20 30 40 50 60 70 80 90 100 Mono-LPV/r-arm TDF/3TC/LPV/r-arm HIV-RNA ≥400 copies/mL HIV-RNA <400 copies/mL HIV-RNA <200 copies/mL HIV-RNA <50 copies/mL % Virological suppression HIV-RNA <400copies/mL 75% vs. 86% p=0.053 HIV-RNA<200copies/mL 69% vs. 86% p=0.01 HIV-RNA<50copies/mL 61% vs. 83% p<0.01 Percentage of patients with virological suppression at week 48 Note: intention to treat analysis HIV-RNA (copies/mL) Mono-LPV/r (%) TDF/3TC/LPV/r (%) P-value <400 75 86 0.053 <200 69 0.01 <50 61 83 <0.01 Bunupuradah T et al. Antiviral Ther 2012;17:

Genetic Barrier to Resistance and Potency of Antiretroviral Agents

Lamivudine, M184V/I , and Viral Fitness
Viral load M184V Time HIV with M184V/I mutations does not replicate as fast as wild-type virus = less fit Schuurman R, et al. J Infect Dis 1995; 171:

Lamivudine Monotherapy in HIV-1-Infected Patients Harboring A Lamivudine-Resistant Virus
In HIV-1-infected patients harbouring a lamivudine-resistant virus, lamivudine monotherapy may lead to a better immunological and clinical outcome than complete therapy interruption. AIDS. 2006;20(6):

EARNEST Study: Design HIV positive adolescents/adults (n=1277)
First-line NNRTI-based regimen >12 months; > 90% adherence last 1 month failure by WHO (2010) clinical, CD4 count (VL-confirmed) or VL criteria Randomised PI NRTIs (NRTIs according to local standard of care) PI + RAL (12 week induction) PI + RAL PI (monotherapy) Follow-up for 144 weeks Primary outcome at Week 96: good HIV disease control defined as all of Alive and no new WHO 4 events from 0–96 weeks and CD4 cell count >250 cells/μL at 96 weeks and VL<10,000 or >10,000 copies/mL without PI mutations at 96 weeks Paton NI, et al. N Engl J Med 2014;371:234–47. RAL, raltegravir The 6th National Scientific Conference on HIV/AIDS

EARNEST Study: VL Suppression* PI/RAL vs PI/NRTI P=0.36 P=0.87 P=0.97 P=0.88 Mono+ vs PI/NRTI P=0.002 P<0.001 *at week 96 Paton NI, et al. N Engl J Med 2014;371:234–47. RAL, Raltegravir The 6th National Scientific Conference on HIV/AIDS

EARNEST Study: Drug Resistance *at week 96 Paton NI, et al. N Engl J Med 2014;371:234–47. The 6th National Scientific Conference on HIV/AIDS

Choices of NRTIs for 2nd-line ART
When genotypic resistance testing is not available

Choices of Main ARV for 2nd-line ART
When genotypic resistance testing is not available

Rilpivirine Resistance
Presence of 1 of the 16 well established mutations: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C, M230I/L, Y188L Presence of 2 or more of L100I, V106I, M230I L100I alone not reduced susceptibility of RPV. It has to combine with K103N/S or combine with K103R+V179D to reduce susceptibility of RPV.

2 Strategies to manage dyslipidemia
HIV-infected Patients and Dyslipidemia 2 Strategies to manage dyslipidemia Switching strategy LPV/rtv  ATV/rtv Adding strategy LPV/rtv + lipid-lowering agent The switching strategy is currently used in Thai National AIDS Program LPV/rtv = Lopinavir/ritonavir ATV/rtv = Atazanavir/ritonavir

ATAZIP Study: Switch LPV/r to ATV/r
Fasting plasma lipids changes from baseline to week 48 Triglycerides Total cholesterol LDL cholesterol HDL cholesterol 200 100 -100 -200 -300 p < 0.001 Median change from baseline (mg/dL) p = 0.149 p = 0.185 - A previous study, the ATAZIP study, has shown that switching from LPV/rtv to ATV/rtv has a beneficial effect on lipids by lowering TC and TG levels while maintaining virological suppression. Switch to ATV/r 300/100 qd (N = 121) Continue on LPV/r 400/100 bid (N = 127) Mallolas J, et al. J Acquir Immune Defic Syndr. 2009; 51:

DHHS Guidelines: ARV Switching
Adverse event Switch from Switch to Dyslipidemia Hypertriglyceridemia (with or without high low-density LDL level) RTV- or cobi-boosted regimens or EFV RAL, DTG, RPV, NVP, or unboosted ATV* *Elevated TG and LDL levels are more common with LPV/r and FPV/r than with other RTV-boosted PIs. Improved TG and LDL levels have been seen following a switch from LPV/r to RTV-boosted and -unboosted ATV K17 DHHS Guidelines, May 2014.

Mean Plasma Cholesterol
Lipid-Lowering Therapy vs PI Switching 3 6 9 12 Months 350 300 250 200 150 100 50 Mean Plasma Triglycerides mg/dL Mean Plasma Cholesterol 12-month, open-label study 130 patients 60% male; mean age 39 years Stable on first ART regimen randomized to: PI  EFV (n = 34) PI  NVP (n = 29) Add bezafibrate (n = 31) Add pravastatin (n = 36) Pravastatin or bezafibrate significantly more effective than switching ART to NNRTI Significantly greater reduction in cholesterol, LDL-C, and TG in combined pravastatin/bezafibrate arms compared with combined NNRTI arms (P <0.01 For more information about this study, see the capsule summary at: Calza L et al. AIDS 2005;19:

Switching LPV/r to ATV/r vs Adding Atorvastatin
Switching Group ATV/r LPV/r Randomized Adding group LPV/r + Atorvastatin 20 mg/day* > 18 years old On LPV/rtv > 1 year HIV RNA < 50 copies/mL TC > 200 mg/dL Follow-up time (weeks) 12 24 Clinical condition Adverse events Lipid profiles (TC, LDL, HDL, TG) CD4 cell count HIV RNA Wangpatharawanit P, et al. IAS Abstract WEPEB349.

Mean change lipid profile levels at week 24
Switching LPV/r to ATV/r vs Adding Atorvastatin ** - This slide more clearly shows the comparison of mean reduction lipid levels - In our adding group we observed a 55.4mg/dl reduction of cholesterol, as well as a 34.6mg/dl reduction of LDL - These two reductions proved statistically significant compared to switching LPV to ATV * * p = 0.004 ** p < 0.001 Mean change lipid profile levels at week 24 Wangpatharawanit P, et al. IAS Abstract WEPEB349.

SUMMARY Causes of treatment failure must be determined: patient-related factors vs ARV drug-related factors Treatment failure and HIV drug resistance are correlated with increased mortality Virologic failure is the most accurate method to define treatment failure Late detection of treatment failure can limit options for second-line regimens The patterns of drug-resistance mutations and cross-resistance are often predictable Second-line ART should consist of 2 active NRTIs + boosted PI An optimal second-line regimen can lead to complete virologic suppression

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