HIV infection occurs inactivated and resting PMBC. Does state of cell cycle impact antiviral activity of approved antiretroviral drug?
What is the Impact of Cell Cycle on the Anti-Viral Activity of RT Inhibitors? AZT has potent antiviral Activity in activated HIV infected cells HIV-1 p24 antigen (ng/ml) AZT –Activated Cell Infection 0 0.03 0.1 0.3 1 4 0 1000 2000 3000 4000 5000
Cell Cycle and AZT Antiviral Activity AZT limited antiviral Activity in resting HIV infected cells 0 0.03 0.1 0.3 1 4 0 200 400 600 800 AZT - Resting Cell Infection HIV-1 p24 antigen (ng/ml)
Cell Cycle and DDI antiviral activity DDI has limited antiviral Activity in activated HIV infected cells 0 0.1 0.3 1 3 10 0 1000 2000 3000 DDI - Activated Cell Infection HIV-1 p24 antigen (ng/ml)
Cell Cycle and DDI antiviral activity DDI has antiviral activity in only resting HIV infected cells 0 0.1 0.3 1 3 10 0 200 400 600 800 DDI-Resting Cell Infection HIV-1 p24 antigen (ng/ml)
Patient is a 23 year old white male who was diagnosed with HIV infection after he presented in 2002 to his PMD for a medical evaluation increasing fatigue. He had several different sexual partners in NYC between 1982-1984; however, he has not been involved in sexual activity since his partner got sick with AIDS in 1992.
His CD4 ranged 190-256 cells/mm3 and viral load ranged 368,000-478,000 copies/ml. After extensive discussion with his PMD he began treatment with AZT, 3TC and Sustiva.
After 12 week viral load was 12,000 copies/ml.
Genotype was drawn.
Patient did not return to clinic until 8 weeks later.
At 20 weeks post treatment his viral load was 47,000 copies/ml. Genotype was repeated.
High failure Rates for selected 3NRTI based regimens
D4T, DDI Abacavir- Gerstoff et.al AIDS 2003
Tenofovir, Abacavir, 3TC – Farthing et. Al 2 nd ISA Paris 2003
Tenofovir abacavir, 3TC- Gallant et al ICAAC Chicago 2003
Tenofovir, DDI, 3TC – Jemsek personal communication/Gilead Warning letter 2003
Therapeutic Strategies to Target Cellular Enzymes and Cell Cycle RIBOSE-5P + ATP PRPP GUANINE GUANOSINE MP INOSINE MP ADENOSINE MP DEOXYGUANOSINE DP DEOXYADENOSINE DP DEOXYGUANOSINE TP DEOXYADENOSINE TP DNA DNA IMP dehydrogenase ADA Mycophenolic Acid HGPRTase PRPP Salvage Pathway PRPP Synthetase DeNovo Pathway Ribonucleotide reductase Hydroxyurea Ribonucleotide reductase AS
Early Virologic Response*: COL40263 vs ESS30009 ESS30009 N = 80 N = 22 N = 102 COL40263 N = 36 N = 52 N = 88 (ABC/3TC + TDF QD) (ABC/3TC/ZDV + TDF QD) * Based on early virologic non-response criteria used in ESS30009: 1: <2 log drop from baseline by week 8 and HIV-1 RNA 50 copies/mL by week 8 2: 1 log increase above nadir at or before 8 weeks 56% 83% 32% 71% 51% 76% Elion R, et al . 11 th CROI, San Francisco 2004, #53.
Correlation Between Adherence* and Virologic Suppression † (N = 84) % Patients With HIV-1 RNA <400 copies/mL Level of Adherence, % *Adherence was measured by MEMScaps electronic pill monitoring device. † P = .00001.Data from Paterson et al. Poster presented at: 6th Conference on Retroviruses and Opportunistic Infections; January 31–February 4, 1999; Chicago, Ill. Poster 92. 70 60 50 40 30 20 10 0 80 90 >95 90–95 80–90 70–80 <70
Relationship Between Adherence and HIV Suppression * Series of 886 treatment-naive HIV patients; CD4 cell count <500 x 10 6 cells/L or plasma viral load >5000 copies/mL. † Prospective, observational study of 81 HIV patients. ‡ MEMS, Medication Events Monitoring System. 1. Low-Beer S et al. JAIDS . 2000;23:360-361. Letter. 2. Paterson DL et al. Ann Intern Med . 2000;133:21-30. 2
Consistency in viral rebound dynamics Davey et al. PNAS 1996 Davey et al. demonstrated in 18 patients that mean time to viral load rebound above 50copies/ml and 500copies/ml was 11 and 18 days respectively.
The JACQUES Initiative (J.I.) A new care delivery model Integrating treatment preparation, clinical management and treatment support for long term treatment success Jacques Initiative J.I. Staff serves as an extension to referring provider Clinical Management Treatment Preparation Treatment Support Directly Observed Therapy (DOT) Our staff will assist and observe the medicine being taken on site or in the community. HIV 101 Workshop Life Skills Workshop Care Partner Supported (CP) - This option is for someone who chooses to be supported by a friend or relative, not HIV positive Treatment Partner (TP) - This system is modeled as a buddy system where two HIV positive people plan together to support each other with therapy Treatment Coach Observed/Supported – A coach from our staff will observe and/or support you with therapy Weekly Observed Therapy (WOT) – This option involves a weekly exchange of a pre-filled pill box
Patient presented (in 1997) as a 33 year old Hispanic male with a 12 year history of HIV infection complicated with PML associated with significant neurological impairment. CD 4 <20 cells/mm3; Viral load >750,000.
Patient had a history of antiretroviral in the late 1980’s early 1990’s to include use of AZT, DDI, 3TC; however he has not used AVR sense 1994.
Patient was treated with Nelfinavir, Saquinavir and Sustiva.
Over the next 6 years, the patient experienced progressive CD4 immune reconstitution (CD 4 450-625 range) associated with sustained viral suppression (VL < 50 copies/ml
After over 6 years, in 2002 simplification of patients regimen was considered.
Patient is a 19 year old African female in labor (2003) HIV diagnosis was confirmed three years earlier when she tested HIV positive during delivery of her first child. She and her child were treated with single dose Nevirapine as part of MTCT program in Cameroon.
Her CD4 cell count was 220; viral load 78,000 copies.ml.
Could the current MTCT program negatively impact general ART programs. If so how could this be minimized?
Use alternative MTCT regimen
Single drug with high mutation threshold and or limited pk profile as single dose drug
Use drugs with matched pk profile
Stopping drugs with different half lives 0 24 48 36 12 Time (hours) Drug concentration Zone of potential replication IC 90 IC 50 Last Dose Day 1 Day 2 S. Taylor et al. 11th CROI Abs 131 MONOTHERAPY