National AIDS Treatment Advocacy Project

Transcription

1 National AIDS reatment Advocacy Project MUAIONS IN HIV-1 PROEASE ASSOCIAED WIH DRUG RESISANCE Pleae be advied that our current wledge on viral reitance to proteae inhibitor i baed largely on laboratory experiment uing many different biochemical technique. A with all approved and experimental antiretroviral drug, the demontration of viral reitance to a particular drug and it ubequent cro-reitance to other drug in vitro (in cell culture) may not necearily predict the preence or abence of viral reitance in vivo (human). Some of the mutation lited for each of the drug below contribute more toward actual reitance than other. he clinical impact of viral reitance to proteae inhibitor in individual undergoing proteae inhibitor treatment i yet to be determined. Viral reitance to antiretroviral drug, including proteae inhibitor, i a natural conequence of antiretroviral therapy. he generation of drug reitant HIV train i a function of the viral reproduction rate. herefore, effective and durable inhibition of HIV reproduction with a afe and potent antiretroviral treatment regimen hould delay the emergence of drug-reitant virue in favor of the individual undergoing uch treatment. A illutrated in the table below, many piece of the viral-reitance-to-proteae-inhibitor puzzle have been dicovered. However, more piece are needed before anyone could attempt to put thi complex puzzle together. Much of the information below i reported from the manufacturer' o reearch and i open to interpretation. It i believed that hutting do HIV reproduction for a long a poible with afe and potent treatment regimen i an effective way of delaying viral reitance, thu optimizing the benefit of uch treatment for people living with HIV/AIDS. Compoun d Amino Acid Chang e In Vitro In Vivo Reitance (in vitro or in vivo) Cro-Reitance to Other Proteae Inhibitor (in vitro or in vivo)

2 10I/V/R Saquinavir G48V 63P V82A/ F/ 90M G48V++90M (30-fold increae _ G48V+90M (20-fold increae in viral reitance to aquinavir in vitro). G48V+90M le common in vivo. 90M frequent in vivo. Majority of patient on aquinavir monotherapy or combination therapy have no G48V and/or 90M mutation after 1 year of treatment. Analyi of 4 patient on aquinavir (from tudie ACG229 and NV 14256) have found viru carrying 90M or G48V+90M (<4- to 44-fold increae in viral reitance to aquinavir. Mutation at 10, 36,63,71 correlate with development of 90M mutation Clinical iolate from majority of patient treated with aquinavir alone or in combination with AZ and/or ddc after 1 year retain full enitivity to both aquinavir and indinavir. Clinical iolate from 4 patient treated with aquinavir (from tudie ACG229 and NV 14256) had a 4-fold increae in viral reitance to indinavir. Similarly, 2 of the 4 iolate had a 4-fold increae in viral reitance to And 1 of the 4 iolate had a 9-fold increae in viral reitance to ritonavir % with previou aquinavir experience develop varying degree of croreitance to indinavir ranging from low to high level.

3 Ritonavir K20R 33F M36I 63P V82F V82A V82 90M Mutation aociated with ritonavir reitance in iolate taken from 41 patient appeared to occur in a tepwie and ordered fahion. V82 (2.5-fold increae in viral reitance to ritonavir in vitro). V82+ (9- fold increae in viral reitance to ritonavir in vitro). V82++A71 V+M36I (17-fold increae in viral reitance in vitro). Clinical iolate taken from two patient had an 8- fold increae in viral reitance to indinavir. One iolate had K20R+ M36I++ A71V+ V82 and another had M36I++ V82S/F/A/. Clinical iolate taken from two patient had a 10-fold increae in viral reitance to nelfinavir. One iolate had K20R+M36I+I5 4V +V82A and another had 20R+M36I+ +A71V+V8 2.

4 Indinavir 10I/V/R K20M /R/I/ 24I V32I 63P I64V V82A/ F/ 90M ne of the mutation lead to phenotypic change alone or in pair. M46I+63P+V82 (4-fold increae in viral reitance to indinavir in vitro). M46I+63P+V82 + (8-fold increae in viral reitance to indinavir in vitro). Indinavir reitant viru (M46I+63P +V82+) had reduced enitivity to aquinavir, ritonavir, and wo-third of indinavir reitant clinical iolate are reitant to aquinavir and All indinavir reitant iolate had a 4- to 30- fold increae in viral reitance to ritonavir. Nelfinavir D30N M36I M46I A71V V77I N880 M46I+ (30-fold increae in viral reitance to nelfinavir in vitro). D30N+A71V in vitro wa reitant (8-fold increae) after 22 paage, but not croreitant to RN, SQV or IDV. In vivo, D30N i thought to be predominant caue of reitance. Alo een in vivo: N88D/S,E35N,M3 6I,M46I, Cro-reitance tudie with clinical iolate are ongoing. In vitro, after 28 paage, double mutant wa croreitant to RN, IDV & SQV.

5 A71/V,V77I 141W94 (VX- 478) I47V I50V I50V (3-fold increae in viral reitance to 141W94). I50V++I47 V (20-fold increae in viral reitance to 141W94). Clinical iolate taken from 5 patient remained fully enitive to