SAS 15 Drug treatment of HIV infection 4/23 4/28/10

Transcription

1 DRUG TREATMENT OF HIV INFECTION rationale at the level of the infected person - HIV replicates during the course of untreated infection; - the immune system fights the virus; - with time, CD4+ T cell counts decline in the blood; - with time, the immune system loses function and the person gets opportunistic infections. - anti-retroviral drugs decrease HIV replication: viral load (amount of virus in blood/body fluids) decreases; - CD4+ T cell counts in the blood are maintained; - the adaptive immune system can regain function to fight HIV and opportunistic infections; - the infected person can live longer and not be as ill. DRUG TREATMENT OF HIV INFECTION The strategy at the level of the infected cell for using anti-retroviral drugs to reduce HIV replication: pathm micro.med.sc.edu find steps in virus life cycle that don t depend on cellular machinery (need to hurt virus without hurting cells) develop drugs to inhibit those steps attack several stages in the HIV life cycle simultaneously to increase the chances of suppressing viral replication try to attack the same stage in the life cycle in several different ways 1

2 Classes of drugs being used to inhibit HIV replication: 1) NRTIs = nucleoside reverse transcriptase inhibitors ( nucs ) 2) NNRTIs = non-nucleoside reverse transcriptase inhibitors ( non-nucs ) 3) PIs = protease inhibitors 4) Entry inhibitors (one is injectable; both used for virus resistant to other drugs) 5) Integrase inhibitor (being used for virus resistant to other drugs) How anti-retroviral drugs inhibit HIV replication Protease inhibitors (PIs): stop production of mature, infectious virus particles Entry inhibitors: stop entry of viral genome into cell X = receptor = co-receptor: CCR5 or CXCR4 RNA X DNA NRTIs ( nucs ) and NNRTIs ( non-nucs ) Inhibit reverse transcriptase two ways to stop production of the DNA form of the HIV genome X Integrase inhibitor: stops insertion of HIV DNA into DNA of the host cell X 2

3 Nucleoside reverse transcriptase inhibitors (NRTIs) nucs - drugs chemically similar to the building blocks (bases) of DNA (for example, AZT is similar to T) -when incorporated into DNA by reverse transcriptase, the false base stops elongation of the growing DNA chain by preventing further addition of bases good copies of viral DNA are not made G C T A G AZT C G A U C A U G from Clavel and Hance, NEJM 350 (04) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) non-nucs - bind to reverse transcriptase enzyme and stop its ability to keep synthesizing viral DNA genome) good copies of viral DNA are not made G C T A G T C G A U C A U G G C T A G C G A U C A U G from Clavel and Hance, NEJM 350 (04) 3

4 Protease inhibitors (PIs) bind to HIV protease and prevent its function: cleavage of long strings of viral proteins is necessary for the formation of mature, infectious virus particles. protease From Fan et al, Fig Drug resistance mutations in HIV Mistakes are made as the viral RNA genome is copied by reverse transcriptase to produce DNA (the wrong base [building block] is incorporated) - The mistakes are called mutations. - Mutations can: - be helpful to virus survival - be detrimental to virus survival - make no difference (be neutral) The fittest virus (best suited to replicate) survives. Mutations allow HIV (1) to escape some aspects of protective immunity (2) to become resistant to anti-retroviral drugs (3) in the past, allowed HIV to evolve from SIV 4

5 Reverse transcriptase makes mistakes when copying HIV RNA genomes to produce HIV DNA genomes = receptor = co-receptor: CCR5 or CXCR4 DNA RNA Immune escape by HIV (antigen) Reverse transcriptase makes mistakes when copying the HIV RNA genome. Mistakes = mutations. ti Different amino acids are coded. d A mutation may alter an antigen (epitope) and make HIV unrecognizable to the immune system. Mutant HIV replicates until the immune system gears up to recognize and contain it. Dimitry Schidlovsky This happens repeatedly (fittest virus survives). 5

6 PROBLEM: HIV develops resistance to drugs - drug-resistant HIVs arise as a result of mutations - mutations result from random mistakes made by reverse transcriptase while copying HIV RNA into DNA Population consists Measured by viral load tests of blood (also called nucleic acid testing) HIVs contain a variety of mutations; by chance, some are resistant to drugs Less likely if multiple drugs used that target different stages of HIV replication Modified from G. Stine, AIDS Update 2002, p. 88. Current treatment: HAART = highly active anti-retroviral therapy Using multiple drugs reduces the chances that an appropriate p collection of mutations will occur in one genome to allow resistance to all the drugs. Drugs are now used in combinations of 3 or more in North America, Western Europe, Brazil, Japan, and anywhere people can pay for them or get them because of aid programs. How soon after a person gets infected should treatment start? (Dr. Flynn will discuss this on Monday) 6

7 Development of drug therapy for HIV infection 3/87 - AZT (nuc) used experimentally in adults Monotherapy (1 drug) improves quality of life for a while. (we now know AZT was used at fairly toxic doses) 5/90 - pediatric use of AZT 10/91 - ddi (nuc) 6/92 - ddc (nuc) 4/93 - Concorde trial: AZT alone does NOT delay the onset of AIDS. Monotherapy doesn t prolong life. Standard therapy becomes two NRTIs (nucs) but: 2/94 - AZT alone decreases transmission of HIV from pregnant women to infants by 67%. (a placebo-controlled trial) Became standard of care in developed countries. 6/94 - d4t (nuc) 11/95-3TC (nuc) 12/95-1 st protease inhibitor (PI) saquinivir 3/96 - ritonavir, indinavir (PIs) 6/96-1 st NNRTI (non-nuc) - nevirapine Adding protease inhibitors to other types of drugs decreased development of viral resistance. Immediately, death rate from AIDS fell in developed countries. 12/96 Multiple ( 3) drug therapy including one PI became the standard of care in USA and other developed countries. HAART (highly active anti-retroviral therapy) Costs $10,000 - $15,000 per year in USA (avg $12,000) (Tom Nelson, pharmacist, will discuss this in May) ARVs = term widely used for anti-retroviral drugs >95% of HIV-positive people live in developing countries How can they be treated? Low-cost drugs needed!! What is the safest, least expensive way to prevent mother to child transmission during birth and breastfeeding? 7

8 3/97 nelfinavir (PI) 3/97 pediatric use of PIs ritonavir and nelfinavir 4/97 delaviridine (non-nuc) 9/98 efavirenz (non-nuc) 12/98 abacavir (nuc) 4/99 amprenavir (PI) 9/00 lopinavir (PI) 11/00 Trizivir (AZT/3TC/abacavir) (all nucs) combination pills 10/01 tenofovir (nuc) now being tested for pre-exposure prophylaxis 8/02 Combivir (AZT/3TC) (both nucs) 3/03 Fuzeon (first entry inhibitor) injectable fusion inhibitor 6/03 atazanavir (PI) 7/03 emtricitabine (nuc) 10/03 fosamprenavir (PI).. more combination pills developed 2006: Atripla (2 nuc, 1 non-nuc) drugs from 2 different companies: 1 pill, 1x daily, ~$1200 per month 2007: maraviroc (entry inhibitor) approved for CCR5-using strains resisting other drugs raltegravir (first integrase inhibitor) for strains resisting other drugs 2008-: in clinical trials of various phases: 3 entry inhibitors, 1 integrase inhibitor, 1 maturation inhibitor, 1 non-nuc, 4 nucs 8