Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Principles and reality of HIV drug resistance in sub-Saharan Africa Doug Richman INTEREST WORKSHOP 8 May 2015 CLINICAL DATA DURING SIXTEEN WEEKS OF INH THERAPY WEEKS OF TREATMENT PRE RX 2 180 4 6 8 10 12 14 16 100 BODY 90 WT. TEMP 98.6 70 ++ + ROENTGEN CHANGES IMPR. NO CHANGE WORSE X 200 SPUTUM WT. 100 (GM) GAFFKY COUNT V 0 0 4+ SPUTUM CULT. 4+ 4+ 4+ 4+ 4+ 3+ ISONIAZID SENSITIVE SL RESISTANT INT HIGH ISONIAZID MG./DAY 150 0 PRE RX 2 4 6 8 10 12 14 16 Coates et al, The Clinical Significance... N Engl J Med 248:1085, 1953 INH SUSCEPTIBILITY OF ISOLATES FROM PATIENTS WITH PULMONARY TB TREATED WITH INH MONOTHERAPY 100 NEGATIVE PERCENTAGE OF CASES 80 SENSITIVE SLIGHT 60 INTERMEDIATE 40 “RESISTANT” 20 HIGH 0 0 2 4 6 8 10 12 14 16 WEEKS OF TREATMENT Coates et al, The Clinical Significance... N Engl J Med 248:1083, 1953 PREEXISTENCE OF DRUG RESISTANT MUTANTS OF TB Number of plates Colonies per plate (actual) Prevalence of resistance mutants 99.101, 106,107 1 in 5 x 104 Inoculum* per plate Drug conc. 4 5 x 106 µg./ml. INH† 1.0 4 5 x 107 SM‡ 2.0 55, 59 64,70 1 in 1 x 106 100 1 x 108 INH 1.0 SM 2.0 No growth <1 in 1 x 1010 * Number of viable, bacterial units from a seven to 10 day old vigorously growing, well dispersed H37Rv culture in liquid medium (ST). † Isoniazid ‡ Streptomycin Cohn et al, J Clin Invest 38:1349, 1959 HIV-1 Drug Resistance is the RESULT and the CAUSE of drug failure Emergence of drug-resistant virus is an inevitable consequence of the failure to fully suppress HIV-1 (HCV, HBV, influenza virus, TB, etc) replication with antiviral therapy. Drug resistance is a major factor contributing to the failure of antiretroviral therapy. Diversity of RNA Virus Populations RNA viruses constitute a quasispecies. Genetically distinct viral variants evolve from an initial monoclonal or oligoclonal virus inoculum. Variants are generated due to errorprone nature of RT. Drug-Resistant Mutants Preexist in Untreated Patients The HIV genome contains 104 nucleotides. The mutation rate of HIV is ~3 x 10-5 nucleotides/ replication cycle. ~1011 virions are generated by 107 - 108 rounds of replication each day. Preexisting Drug Resistance Mutations Single mutants produced daily Isolated from treatment-naive patients or those infected before antiretroviral drug availability Double mutants less common 3 or more specific resistance mutations in the same genome rare Rapid Turnover of Viral Quasispecies Most of the virus population in plasma is cleared and replaced each day. Rapid turnover allows rapid emergence of drugresistant variants under selective pressure. Resistant variants may be replaced by residual wild-type virus if selective pressure is removed. Resting latently infected cells may continue to harbor drug-resistant provirus. HIV-1 infection and a model of the distribution of viral quasispecies in the era of antiretroviral therapy Metzner, Future Virology 1:377, 2006 HIV drug resistance is generated by one of two major mechanisms Acquired resistance following nonsuppressive treatment (secondary resistance) Transmitted resistance (primary resistance) • Both mechanisms are too prevalent. • Prevention strategies for these two mechanisms are completely different. Plaque reduction (%) AZT Susceptibility of Sequential Isolates of HIV-1 From a Patient Administered AZT Larder, Darby and Richman, Science 1989; 243:1731. 0 A036C (11 mos) A036D (20 mos) A036B (2 mos) 50 100 0.001 0.01 0.1 1 AZT (µM) 10 HCSUS: Prevalence of HIV Drug Resistance Representative as possible to all HIV-positive persons receiving medical care in early 1996 1080 samples with HIV RNA >500 copies/mL Resistance more common Lowest CD4 count nadir Higher HIV RNA More access to care Proportion With Phenotypic Resistance HCSUS population 78% 70% 51% 42% 31% 14% Resistance less common Patients cared for by the most experienced providers Any NRTI NNRTI PI Drug >2 3 Drug Classes Richman et al, AIDS 18:1393, 2004 Transmission of Drug-Resistant HIV in Treatment-Naïve Patients IC50 >10-fold increase via PhenoSense HIV (ViroLogic) Phenotypic Resistance (% patients) NNRTI 14 PI NRTI 1995 1996 1997 1998 1999 2000 (n=11) (n=56) (n=101) (n=97) (n=90) (n=23) Little SJ, et al. N Engl J Med. 2002;347:385-394 450 90 80 70 60 50 40 30 R2 = 0.97 20 400 50,000 350 300 40,000 250 30,000 200 150 20,000 100 10,000 10 50 0 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 Year 60,000 Patient-months of ARV Exposure 100 Decreasing resistance despite increased ARV exposure in BC, 1997-2008 Increasing proportion of VL levels <50 c/mL in BC, 2000-2008 Annual Incidence of Resistance (N) Percentage of patients with pVL <50 copies/mL Improved Virologic Outcomes Concomitant with Decreasing Incidence of Drug Resistance 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 Gill VS, et al. CID (2010) 50:98-105 Year 15 How did this reduction in resistance with more expanded treatment happen? Better drugs More potent and better half-lives (TDF/FTC, better PIs, integrase inhibitors) More tolerable and less toxic (thymidine analogues are history) Fixed dose combinations Better monitoring of failure and then use of drug resistance testing and better drugs for treatment failure GENEVA/DAKAR, 12 DECEMBER 2002 - HIV Treatment Access Coalition (ITAC) Aimed to boost efforts to provide access to antiretroviral drugs that have saved hundreds of thousands of lives in Europe and the US to the growing number of people with HIV/AIDS in low and middle income countries who need them. Joep Lange the then president of the IAS: “if we can get cold Coca Cola to every remote corner of Africa, it should not be impossible to do the same with drugs” 25,0 % of Patients with Acquired HIVDR 20,7 20,0 15,0 15,0 11,1 10,0 7,2 5,0 0,0 6 to 11 12 to 23 24 to 35 ≥36 Months on ART Figure 1. Changes in rates of acquired HIVDR to any drug class according duration of treatment. HIVDR=human immunodeficiency virus drug resistance. ART=antiretroviral therapy. Stadeli and Richman, Antiviral Therapy 18(1):115-23, 2013 25,0 23,5 21,6 % of Patients wth Drug Resistance 21,6 20,0 20,0 17,3 15,9 15,0 10,5 10,0 NRTI 8,2 7,2 6,7 5,0 NNRTI PI 4,2 3,7 Multi-Class 2,0 0,0 0,1 6 to 11 0,1 12 to 23 0,0 24 to 35 ≥36 Months on ART Figure 2. Distribution of acquired HIVDR to individual drug classes according to time on antiretroviral therapy Stadeli and Richman, Antiviral Therapy 18(1):115-23, 2013 % of Patients with Transmitted HIVDR 7,0 6,6 6,0 5,0 4,0 Total HIVDR 4,0 NNRTI PI 2,8 3,0 2,0 NRTI 3,5 Multi-Class 2,0 2,1 1,4 1,0 1,0 1,2 0,6 0,0 <5 years ≥5 years Time Since ART Availability Figure 3. Changes in rates of transmitted HIVDR according to time since ART availability Stadeli and Richman, Antiviral Therapy 18(1):115-23, 2013 Pham et al, AIDS, 2014 Cost of continuing a regimen failing as defined by virologic criteria M184V + other NRTI mutation M184V or wild type Percent of Patients 100 80 60 40 20 0 0–8 9–16 17–24 25–32 33–40 41–48 Weeks n = 39 34 28 24 20 16 ♦ CNA3005: ZDV/3TC/ABC vs. ZDV/3TC/IDV ♦ “First genotype” performed at time of rebound ♦ “Last genotype” performed prior to changing ART ♦ Early breakthrough with wild type or M184V ♦ Increasing NRTI mutations associated with crossresistance to all RTIs Melby T, et al. 8th CROI; 2001; Chicago, Ill. Abstract 448 Rapid accumulation of DRMs when first-line ART is continued despite virological failure Longitudinal genotyping analysis at first detection of VF (t1) and 6-12 months after (t2) Steep increase in TAMs (+250%) and K65R (+100%) NNRTI susceptibility is already lost at first detection of VF Precedes WHO-defined failure criteria Barth et al. Antiviral Therapy 2012 How much will resistance impact the benefits of the antiretroviral rollout in resource-limited countries? Access to antiretroviral therapy has been a remarkable achievement with a dramatic impact on almost 12 million individuals in resource-limited countries; however, We have been using suboptimal regimens for treatment and for MTCT. We are assessing failure by clinical or CD4 endpoints. We are not optimally monitoring virologic failure in individuals or resistance in populations (both acquired and transmitted). Say NO To CRAP Therapy Continued Replication under Antiviral Pressure Continued replication in the presence of drug will likely lead to further evolution of the viral population. In theory, further evolution can result in a more fit, drugresistant viral population that may remain enriched in the patient, even in the absence of drug pressure. This should be prevented by discontinuing the direct acting antiviral if a patient has a confirmed increase in HCV RNA levels while adhering to therapy. FCHR-HCV DRAG Stuart Ray Prevention of acquired drug resistance requires addressing the causes The patient adherence The prescribing care provider selecting an optimal regimen counseling the patient The drugs Potency tolerability pharmacokinetics Additional factors specific to LMIC that contribute to the emergence of HIV drug resistance Suboptimal Regimens Thymidine analogues Insufficient second-line and salvage regimens Failure of methods and resources to monitor viral loads Drug distribution (stock-outs) Perinatal PMTC rather than treating pregnant women with ART (option B+) Summary The principles of HIV drug resistance are well established (Darwinian evolution). The mistakes and lessons learned in the developed world are being recapitulated in low and middle income countries. Prevention of further increases in drug resistance Better regimens Avoid stockouts Monitor viral load Interventions to improve adherence and reduced risk behaviors