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ARV therapy Past, present and future What is old, what is new, what is next? • 1980’s – No anti-HIV treatments were promising • 1990’s – – – – • Anti-HIV Rx ~ worked, but made drug resistance Acute and chronic drug toxicities were expected and delivered Drug resistance led to illness and death optimal management of drug toxicity versus HIV disease? 2000’s – Successful anti-HIV Rx is expected, less toxic, taken for granted – MDR HIV is evolving with super-infections – NYC: transmissible and virulent MDR HIV What did we learn in the past? • High doses of inadequate drug combinations do not work – ZDV 300 mg Q4H is intolerable, and ineffective – ZDV 300 mg BID is tolerable and transiently effective • Early treatment (high CD4) is generally better tolerated – anemia, neuropathy on ZDV + ddI with baseline CD4 > 200 • Early treatment is generally less prone to failure – ZDV + 3TC + IDV with baseline high CD4 and low VL have lower virologic failure • Drug interactions are complex, and clinically important – More than two simultaneous non-linear bidirectional drug-drug interactions are more than hard to predict, and may be managed empirically or avoided – PI’s are all CYP450 3A4 substrate, blocker and inducers to different degrees • Ritonavir is the best blocker • Tipranvir is the best inducer (more than rifampin) • Saquinavir is the best substrate (like itraconzole) The Present: 2005 DHHS HIV treatment guidelines Preferred lopinavir + ritonavir + efavirenz + ZDV + (3TC / FTC) (ZDV / TDF) + (3TC / FTC) Alternative PI-Based Atazanavir, fosamprenavir, or fosamprenavir, indinavir, nelfinavir, saquinavir + ritonavir NNRTI-Based Efavirenz + (3TC / FTC) + (ABC / ddI / d4T) Nevirapine + (3TC / FTC) + (ZDV / d4T / ddI/ ddI/ ABC / TDF) All used in conjunction with (3TC / FTC) + (ZDV / d4T / ABC/ TDF / ddI) lopinavir/ritonavir + (3TC / FTC) + (d4T / ABC / TDF / ddI) Triple NRTI abacavir + 3TC + ZDV (definitely the third choice) Efavirenz is not recommended for use in 1st trimester or in women with high pregnancy potential Ritonavir is used in low dose: 100 to 400 mg/day as a pharmacologic booster; 100 mg/day is recommended for tenofovir + atazanavir. Nevirapine has increased risk of rash and hepatitis in adult dult females and males with CD4 cell counts >250 and >400 cells/mm cells/mm3, respectively. Saquinavir is supplied as softsoft- or hardhard-gel capsules or tablets. Available at: http://aidsinfo.nih.gov/Default.aspx. Revision October 6, 2005. When-to’s in ARV treatment • When to start treatment – When the patient is ready – When the treatment will work best – Before the patient gets sick • When to change treatment – When the treatment has stopped working – When the treatment has caused harm – When there is a better treatment to try • When to stop treatment – – – – When the treatment has stopped working When the treatment has caused harm When there is no alternative left to try When the patients says stop What are the requirements for successful ARV therapy? • HIV diagnosis, acceptance and knowledge – Social as well as individual levels • Access to general and specific health care – Socialised versus commoditised medicine – Distributive justice versus the social lottery • Drug reimbursement, access and supply – Only a societal issue More requirements for successful ARV therapy • susceptible HIV infection, adequate ARV prescription – individual safety and tolerance of drug combination treatment – Individual required potency of regimens (3 drugs at maximal tolerated doses?) – Uniform or individual dosing and prescribing? • medical follow-up and monitoring – – – – – • Maintain the established relationship Recruit the patient into their own health maintenance Anticipate acute and chronic toxicities, IRIS, drug interactions Monitor clinical, immunologic and virologic outcomes Rotate the poisons for chronic toxicities? care for concurrent health problems – sexual and reproductive health, especially other STD’s – tuberculosis, pneumocystosis, candida, cryptococcosis, toxoplasmosis – Malnutrition and micronutient supplementation? The most important requirement for successful ARV therapy • Adherence & compliance – health locus of control, personal daily organisation – depression and survivor guilt – Empiric 95% rule for virologic success • What to do about it? – – – – Better to start right, than to start now When the patient is ready is right Empiric pragmatic self-evaluation (30 pills/ 10 days) Psychoeducational interventions HOMER Cohort: Is >95% Adherence Needed to Maintain Viral Suppression? • Previously treatment-naïve patients on suppressive HAART (n=1634; 1996-2003) - • Association Between <95% Adherence and Viral Breakthrough HIV RNA <500 copies/mL on 2 consecutive occasions Regimen Primary outcome - Time to viral breakthrough • HIV RNA >1000 copies/mL on 2 consecutive occasions • <95% adherence was most strongly associated with breakthrough with unboosted PI- and NNRTI-regimens - No association for boosted PI regimens Adjusted Hazard Ratio (95% CI) Unboosted PI (n=752) 1.77 (1.41-2.24) NNRTI (n=631) 1.47 (1.01-2.14) Boosted PI (n=251) 1.05 (0.46-2.42) Adjusted for sex, age, IDU, CD4 cell count, AIDS diagnosis, physician experience. Gross R, et al. 13th CROI. Denver, 2006. Abstract 533. HOPS Cohort: Improved Outcomes With Early Initiation of HAART - 8-year follow-up • Mortality (per 1000 person-years) Prospective cohort (n=4421) Higher pre-HAART CD4 cell count and >95% adherence - Lower incidence of: • • 80 Incidence • 40 These data suggest there are immunologic benefits and less toxicity when HAART is initiated earlier and adherence is >95% * 20 <50 5050-199 200200-349 350350-499 >500 Pre-HAART CD4 Category (cells/mm3) OIs (per 1000 person-years) 80 Incidence RNA <50 copies/mL (P<0.01) *P<0.05. * Renal insufficiency, distal symmetrical polyneuropathy, and lipoatrophy - Higher percentage achieving HIV • 60 0 Mortality and OIs Adherence <95% >95% Adherence <95% >95% 60 40 20 0 * * * <50 5050-199 200200-349 * 350350-499 >500 Pre-HAART CD4 Category (cells/mm3) Lichtenstein KA, et al. 13th CROI. Denver, 2006. Abstract 769. Still more requirements for successful ARV therapy • Individual dosing, ADME (PK) – Adequacy of systemic drug exposure – Inter-person & disease-related variation • PK and pharmacodynamic (PD) interaction – oxidative enzymes (CYP450 3A4) – Epithelial, endothelial and cellular MDT (P-gp) – Drug-drug interactions of concurrent treatments • anti-HIV, -TB, -fungal and -coagulant therapies • phytochemical, and micronutrient interactions What is anti-HIV drug potency? • Inhibition of HIV replication (per unit time) per unit drug mass (concentration) in vitro • Clinically, ‘completeness’, speed and duration of plasma viremia suppression, meaning anti-HIV activity in vivo: BUG susceptibility activity potency DRUG Clinical potency of therapy means the net rate and degree of treatment-related suppression of HIV plasma viremia, which is a relationship between drug and bug Relationships in Drug Therapy of Infectious Disease BUG activity susceptibility pathogenicity EFFICACY virulence potency DRUG pharmacodynamics toxicity immunity pharmacokinetics HOST © DWC 1999 How do we measure and compare drug potency (a fragment of treatment efficacy)? High initial VL (ie exclude < 104 copies/mL) maximizes drop from baseline log10 0 drop from baseline virus 1 load 2 Low quantitation limit (ie 5 x 101 copies/mL) maximizes drop from baseline 3 0 1 2 3 weeks or months Integrase Inhibitor (GS-9137): 10-Day Monotherapy Study • Phase IIb, placebo-controlled, monotherapy study Change in HIV RNA at Day 10 - 40 treatment-naïve and treatment-experienced patients - Baseline • • HIV RNA: 4.75 log10 copies/mL • CD4: 442 cells/mm3 At day 10 - >1 log10 reduction in HIV RNA • • GS-9137: 83% Placebo: 0% - No serious adverse events and no study drug discontinuations - Most common adverse events • Fatigue, diarrhea, headache, nausea (log10 copies/mL) Placebo -0.13 GS-9137 800 mg qd -0.89* 200 mg bid -1.44* 400 mg bid -1.98* 800 mg bid -1.78* 50 mg + RTV qd -2.03*† *P<0.01 versus placebo. P<0.05 versus 800 mg qd. † P<0.05 DeJesus E, et al. 13th CROI. Denver, 2006. Abstract 160LB. Maturation Inhibitor (PA-457): Phase II Dosing Study Phase II, placebo-controlled, monotherapy study - Baseline copies/mL • CD4: 441 cells/mm3 Oral doses of PA-457 - • 25, 50, 100, 200 mg qd At day 11 - 0.2 32 treatment-naïve patients • HIV RNA: 4.73 log10 • Change in HIV RNA at Day 11 AUC and trough levels were significantly associated with antiviral response (P<0.01) 0.046 0 Log10 Copies/mL • -0.2 -0.174 -0.4 -0.483 -0.6 -0.8 -1 -1.05 -1.2 25 50 100 PA-457 mg qd 200 Smith P, et al. 13th CROI. Denver, 2006. Abstract 52. How do we measure and compare drug activity (a bigger fragment of efficacy) ? BLQ 100% Serial point prevalence of viremia suppression DRUG EFFECT - causation 50% COHORT EFFECT - bias 0% 6 MONTHS Cohort: N= 100% 85% 70% Integrase Inhibitor (MK-0518): Study 005 - Baseline • • HIV RNA: 4.7 log10 copies/mL • CD4: 243 cells/mm3 • 3-class resistance Regimens - Placebo - MK-0518: 200, 400, or 600 mg bid oral administration - All patients received an optimized background regimen • Most common adverse events among all groups - Diarrhea, nausea, fatigue, injection site reaction, headache, and pruritus Viral Load (<50 copies/mL) 100 Patients (%) Treatment-experienced patients (n=167) 200 mg 400 mg 600 mg 80 60 40 20 0 Change From Baseline • Placebo 0 2 4 8 Weeks 12 16 CD4 Cell Count (cells/mm3) 200 200 mg 400 mg 600 mg 150 100 50 0 Placebo 0 2 4 8 Weeks 12 16 Grinsztejn B, et al. 13th CROI. Denver, 2006. Abstract 159LB. What is the preferred measure of anti-HIV treatment activity? • Degree and time to virologic suppression – Multifactorial, determined by baseline viremia – Close to ‘clinical potency’ • Proportion ‘suppressed’ over a time period – susceptible to inaccurate rates (ITT) or biased comparison (OT) – Intuitively pleasing • Time to virologic failure, or subsequent re-treatment failure – Multifactorial, low outcome rate – pragmatic • Time to drug discontinuation – Multifactorial, related to either drug intolerance and drug resistance – pragmatic Comparison of anti-HIV outcomes by serial point prevalence differences • OT (on treatment), or AT (as treated) analysis results are biased by non-random, or selective loss to follow-up • ITT (intention to treat) protects from bias at the cost of accuracy: – LOCF (last observation carried forward) – M=F (missing = failure) • Both analyses have many imputed results • ITT analyses have meaning where one has intention-to-follow the patients Statistics are useful in clinical trials Ritonavir boosted v unboosted atazanavir • Treatment-naïve patients (n=200) 100 • • Patients (%) Open-label, non inferiority trial Baseline CD4: 235 cells/mm3 HIV RNA: 5.0 log10 copies/mL • Regimens - Atazanavir 400 mg qd Atazanavir + ritonavir (300/100 mg qd) All patients received 3TC + d4T qd • At 48 weeks (ATV vs ATV+RTV) - Virologic failures: 10 vs 3 patients PI resistance: 3 vs 0 patients Jaundice: 7% vs 22% • Increased lipids in ATV + RTV arm - T-C +15%, LDL-C +23%, TG +26% ITT 80 75% 60 70% 40 Atazanavir qd (n=105) Atazanavir + RTV qd (n=95) 20 0 Change From Baseline - Viral Load (<50 copies/mL) 0 8 16 24 32 Weeks 40 48 CD4 Cell Count (cells/mm3) 250 224 200 189 150 100 Atazanavir qd Atazanavir + RTV qd 50 0 0 8 16 24 32 40 48 Weeks Malan N, et al. 13th CROI. Denver, 2006. Abstract 107LB. What limits anti-HIV treatment today? • Adherence to treatment - pill burden and dosing schedule • Individual host and disease-related variation - Acute and chronic drug toxicity Drug absorption and anti-HIV activity Primary HIV-1 Infection is Associated with Preferential Depletion of CD4+T Lymphocytes from Effector Sites in the Gastrointestinal Tract Copyright: Rockefeller University Press Saurabh Mehandru, et al. J. Exp. Med. 2004. 200(6):761-770. Model for the Depletion of Gut CD4Expressing T Lymphocytes by SIV/HIV Why is MDR TB associated with HIV everywhere? • Monotherapy of active TB infection? • Intermittent or partial non-adherence? • Under-dosing of anti-TB treatment? Participants 48 persons without TB Group I: 12 healthy volunteers Group II: 12 HIV positive, asymptomatic, CD4+ T-cell counts > 300 cells/mm3 Group III: 12 HIV positive, symptomatic, CD4+ T-cell counts < 200 cells/mm3 Group IV: 12 HIV positive, symptomatic, CD4+ T-cell counts < 200 cells/mm3 persistent diarrhea Isoniazid Mean AUC 0-24h and Cmax P = .192 I - IV P = .713 I - III 15 AUC 10 µg•h/mL 5 0 I P = .046 I - IV P = .802 I - III µg/mL II III 7 6 5 4 3 2 1 0 IV Cmax I II III Group IV Rifampin Mean AUC 0-24h and Cmax P = .065 I - IV P = .085 I - III µg•h/mL 50 AUC 40 30 20 10 0 I P = .006 I - IV P = .006 I - III µg/mL II III 10 IV Cmax 8 6 4 2 0 I II III Group IV Pyrazinamide Mean AUC 0-24h and Cmax 400 AUC 300 µg•h/mL 200 P = .0001 I - IV P = .0147 I - III P = .056 I - IV P = .193 I - III µg/mL 100 0 I II III 30 25 20 15 10 5 0 IV Cmax I II III Group IV Number of Participants with Suboptimal Drug Concentrations G ro u p N = 1 2 /g ro u p B e lo w n o rm a l C m a o f a t le a s t o n e d ru g P = .0 1 x R IF : < P Z A : < II III IV 0 4 6 7 0 0 0 4 0 0 3 3 0 3 3 1 0 0 0 2 0 4 6 6 0 0 3 4 F is h e r’s e x a c t te s t 1 d ru g 2 d ru g s 3 d ru g s IN H : < I 2 .1 µ g /m L 5 .1 µ g /m L 1 9 .5 µ g /m L Conclusions… • Isoniazid was generally well absorbed but diarrhea reduced the rate of absorption • Most frequent and largest decreases in AUC and Cmax (> 30%) were observed for rifampin – 16 of 36 HIV infected patients had suboptimal peak drug exposure • Trend of decreased pyrazinamide exposure in later-stage HIV disease • Below normal Cmax levels of two or more drugs occurred in only symptomatic patients …Conclusions • Malabsorption is likely the cause of low drug levels • Patients with no visible signs of GI dysfunction have low drug levels – therapeutic drug monitoring? – D-xylose screen? • Long-term clinical consequences of reduced drug exposure have been studied, and link HIV with MDR-TB through anti-TB drug malabsorption in independent trials in India, South Africa, and in ecologic studies. An RCT of carotene in AIDS • low carotene is a risk factor for death in AIDS – Vitamin A deficiency? – Oxidative stress? – Malnutrition due to malabsorbtion? • 22 centres of the Canadian HIV Trials Network • Community based controlled clinical trial of multi-vitamin, trace element and antioxidant with or without high dose natural carotenoids micronutrient Amount per Caplet Carotenea Natural, mixed carotenoids comprised 95% beta-carotene, 3% alpha carotene, 0·6% zeaxanthin, 0·7% cryptoxanthin, 0·5% lutein) 30,000 IU (18 mg) Vitamin A 1,500 IU Vitamin D 56 IU Vitamin C 63 mg Vitamin E 56 IU Vitamin B1 9·38 mg Vitamin B2 (riboflavin) 4·68 mg Vitamin B2 (riboflavin-5' phosphate Na ) 2·25 mg Vitamin B3 (niacin) 3·75 mg Vitamin B3 (niacinamide) 9·38 mg Vitamin B5 (d-calcium pantothenate) 18·75 mg Vitamin B6 (pyridoxine hydrochloride) 9·38 mg Vitamin B6 (pyridoxine-5'-phosphate) 3 mg Folic acid (folacin) 0·08 mg Biotin 0·06 mg mineral / element Amount per Caplet Magnesium 37·5 mg Zinc 7·5 mg Iron 1·5 mg Copper 0·38 mg Manganese 1·5 mg Potassium 9·38 mg Chromium 0·018 mg Selenium 0·018 mg Molybdenum 0·00938 mg Vanadium 0·00938 mg Choline bitartrate 9·38 mg Iodine 0·00938 mg anti-oxidant Amount per Caplet N-acetyl-Lcysteine 150 mg Glutathione (reduced) 37·5 mg Carotene RCT flow chart Carotene treatment increased serum levels over 18 months Treatment increased CD4 count …and not plasma HIV load (not shown) Treatment increased survival 13 (7·8%) deaths in treatment vs 23 (13·9%) deaths in controls HR 1·76 (0·89, 3·47), p = 0·11 Effect of treatment stratified by baseline characteristics Death by: Treatment Control n=165 n=166 15·6 % 0·0 % HR P 19·4 % 9·5 % 1·25 NC 0·56 0·004 4·5 % 11·5 % 12·3 % 17·9 % 2·70 1·67 0·14 0·23 5·4 % 4·7 % 16·0 % 7·5 % 3·42 1·36 0·03 0·68 CD4 count <50 cells/μL ≥50 cells/μL HIV load < median ≥ median Serum carotene < median ≥ median Multivariate intention-to-treat analysis of time to death for baseline predictors and treatment Variable Adjusted HR 95% CI P CD4 T lymphocyte count 0.63 0.46, 0.87 0.005 0.59 0.35, 0.99 0.04 3.15 1.10, 8.98 0.03 per 25 cell/mcL increase Serum carotene per 1 μmol/L increase Controls v carotenoids Conclusions • High dose natural mixed carotenoids in AIDS – – – – – increases serum carotene levels appeared to increase CD4 did not change plasma viremia had no effect on the incidence of AIDS may improve survival in advanced AIDS • Subsequent study shows – OTC carotene is unstable and unreliable – No PK interaction of carotene and CYP450 drugs What will we learn in the future? • Anti-HIV activity studies are not the same as clinical efficacy (again). • All-cause mortality, or health-related quality of life are better outcome measures in trials of clinical effectiveness, than the familiar epidemiologic case definition of an AIDS-defining or related illness • Therapeutic individualization: Host predictors of drug activity & toxicities – – – – CD4 350, VL 5000 versus CD4 10, VL > 500,000 Phenotypic tests for PK and PD genotypes BMI & disease stage adjusted dosing versus fixed-dose co-formulations Detection of HIV-related anti-HIV drug malabsorption • Which micronutrient deficiencies are present, clinically important, and whether supplementation or replacement works or not in AIDS Rx • What manner of immune modulation enhances ARV efficacy, and immune control of HIV infection