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MUTATIONS IN HIV-1 PROTEASE ASSOCIATED WITH DRUG RESISTANCE

Please be advised that our current knowledge on viral resistance to protease inhibitors is based largely on laboratory experiments using many different biochemical techniques. As with all approved and experimental antiretroviral drugs, the demonstration of viral resistance to a particular drug and its subsequent cross-resistance to other drugs in vitro (in cell culture) may not necessarily predict the presence or absence of viral resistance in vivo (humans). Some of the mutations listed for each of the drugs below contribute more towards actual resistance than others.

The clinical impact of viral resistance to protease inhibitors in individuals undergoing protease inhibitor treatment is yet to be determined. Viral resistance to antiretroviral drugs, including protease inhibitors, is a natural consequence of antiretroviral therapy. The generation of drug resistant HIV strains is a function of the viral reproduction rate. Therefore, effective and durable inhibition of HIV reproduction with a safe and potent antiretroviral treatment regimen should delay the emergence of drug-resistant viruses in favor of the individual undergoing such treatment.

As illustrated in the table below, many pieces of the viral-resistance-to-protease-inhibitor puzzle have been discovered. However, more pieces are needed before anyone could attempt to put this complex puzzle together. Much of the information below is reported from the manufacturer's own research and is open to interpretation. It is believed that shutting down HIV reproduction for as long as possible with safe and potent treatment regimen is an effective way of delaying viral resistance, thus optimizing the benefits of such treatment for people living with HIV/AIDS.

Compound

Amino Acid

Change

In Vitro

In Vivo

Resistance

(in vitro or in vivo)

Cross-Resistance to Other Protease Inhibitors

(in vitro or in vivo)

Saquinavir














L10I/V/R

M46I/L

G48V

I54V

L63P

A71V/T

V82A/F/T

I84V

L90M

No

No

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

G48V+I84V+L90M (30-fold increase _

G48V+L90M (20-fold increase in viral resistance to saquinavir in vitro).

G48V+L90M less common in vivo.

L90M frequent in vivo.

Majority of patients on saquinavir monotherapy or combination therapy have no G48V and/or L90M mutations after 1 year of treatment.

Analysis of 4 patients on saquinavir (from studies ACTG229 and NV 14256) have found virus carrying L90M or G48V+L90M (<4- to 44-fold increase in viral resistance to saquinavir.

Mutations at 10, 36,63,71 correlate with development of L90M mutation

Clinical isolates from majority of patients treated with saquinavir alone or in combination with AZT and/or ddC after 1 year retain full sensitivity to both saquinavir and indinavir.

Clinical isolates from 4 patients treated with saquinavir (from studies ACTG229 and NV 14256) had a 4-fold increase in viral resistance to indinavir. Similarly, 2 of the 4 isolates had a 4-fold increase in viral resistance to 141W94. And 1 of the 4 isolates had a 9-fold increase in viral resistance to ritonavir.

13-22% with previous saquinavir experience develop varying degrees of cross-resistance to indinavir ranging from low to high level.

Ritonavir K20R

L33F

M36I

M46I/L

I54V

L63P

A71V/T

V82F

V82A

V82T

I84V

L90M

No

No

No

Yes

No

Yes

Yes

Yes

No

No

Yes

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Mutations associated with ritonavir resistance in isolates taken from 41 ritonavir-treated patients appeared to occur in a stepwise and ordered fashion.

V82T (2.5-fold increase in viral resistance to ritonavir in vitro).

V82T+I54V (9-fold increase in viral resistance to ritonavir in vitro).

V82T+I54V+A71V+M36I (17-fold increase in viral resistance in vitro).

Clinical isolates taken from two ritonavir-treated patients had an 8-fold increase in viral resistance to indinavir. One isolate had K20R+ M36I+I54V+ A71V+ V82T and another had M36I+I54V+ V82S/F/A/T.

Clinical isolates taken from two ritonavir-treated patients had a 10-fold increase in viral resistance to nelfinavir. One isolate had K20R+M36I+I54V +V82A and another had 20R+M36I+ I54V+A71V+V82T.

Indinavir










L10I/V/R

K20M/R/I/L

L24I

V32I

M46I/L

I54V

L63P

I64V

A71V/T

V82A/F/T

I84V

L90M

No

No

No

Yes

Yes

No

No

No

Yes

Yes

No

No

Yes

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

Yes

Yes

None of the mutations leads to phenotypic changes alone or in pairs.

M46I+L63P+V82T (4-fold increase in viral resistance to indinavir in vitro).

M46I+L63P+V82T+I84V (8-fold increase in viral resistance to indinavir in vitro).

Indinavir resistant virus (M46I+L63P +V82T+I84V) had reduced sensitivity to saquinavir, ritonavir, and 141W94.

Two-thirds of indinavir resistant clinical isolates are resistant to saquinavir and 141W94.

All indinavir resistant isolates had a 4- to 30-fold increase in viral resistance to ritonavir.

Nelfinavir D30N

M36I

M46I

A71V

V77I

I84V

N880

Yes

No

Yes

Yes

No

Yes

No

Yes

Yes

Yes

Yes

Yes

Unknown

Yes

M46I+I84V (30-fold increase in viral resistance to nelfinavir in vitro).

D30N+A71V in vitro was resistant (8-fold increase) after 22 passages, but not cross-resistant to RTN, SQV or IDV.

In vivo, D30N is thought to be pre- dominant cause of resistance.

Also seen in vivo: N88D/S,E35N,M36I,M46I, A71T/V,V77I

Cross-resistance studies with clinical isolates are ongoing.

In vitro, after 28 passages, M46I/I84V double mutant was cross-resistant to RTN, IDV & SQV.

141W94

(VX-478)

M46I/L

I47V

I50V

Yes

Yes

Yes

Unknown

Unknown

Unknown

I50V (3-fold increase in viral resistance to 141W94).

I50V+M46I/L+I47V (20-fold increase in viral resistance to 141W94).

Clinical isolates taken from 5 ritonavir-treated patients remained fully sensitive to 141W94.

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Last modified 8/20/96
copyright 1996 natap