Next 3 lectures will go backwards
- the therapy
- the targets that therapy might help
- the disease that needs therapy
Currently Available Therapy
- Three drug cocktail
- Three kinds of drugs available that attack two different targets
- Reverse Transcriptase inhibitors
- nucleoside analogs
- non-nucleoside analogs
- Protease inhibitors
Nucleoside analogs
- Look like the building blocks of DNA
- Reverse transcriptase (RT) uses one and then can’t continue the chain
- all are “dideoxy-” compounds
- all are chain terminators because it takes two hooks to make a chain and they only have one
- all are toxic
Problems with nucleoside analogs
- They also affect normal RNA synthesis somewhat (about 1% as much as RT)
- There are lots of mutations in RT that leave the RT fully active but not affected by the analog
- These work because RT recognizes them 100 times better than the human RNA polymerase
- RT mutants don’t see them
What are their names?
- Lots of names (most are funny letter combinations)
- generic names, brand names, slang names
- AZT (azidothymidine) was the first
- aka zidovudine (ZDV), or Retrovir
- ddC, ddI, 3TC, d4T — all 3 have lots of other names
- real danger of confusion in pharmacies!
Do they work?
- They seemed to delay the onset of AIDS but only briefly and not to prolong life
- They seemed to reduce transmission from mother to fetus
- They are now abandoned as monotherapy
Why do they fail
- They don’t stop RT 100%, only slow it down
- Many mutations allow resistance
- many are “cross resistant” to other nucleoside analogs
- Toxic with very unpleasant side effects
Non-nucleoside analogs
- Bind to RT and inhibit its action
- Mutants arise very rapidly
- Monotherapy abandoned almost immediately
- Strange names and no pattern to the names
- e.g. Nevirapine, Loviride, Delaviridine, Efavirenz, etc.
Protease inhibitors
- Block maturation of HIV (internal proteins)
- everything stuck to membrane and can’t coalesce around the RNA or make active RT, integrase, or protease
- Newest of the approved drugs
- Mutation to resistance is common
- Names tend to end in -navir
- e.g. Sequinavir, Ritonavir, Indinavir, etc.
Drug Resistance
Mutation leads to resistance
- HIV mutates very rapidly because it lacks a “proofreading function”
- Thus drug resistant mutants already exist even before the drug is added (Darwinian)
- In the presence of the drug, the resistant mutants have an advantage and soon fill the void created by inhibiting the sensitive HIV
Cross resistance
- Mutation to one member of a class is sometimes specific, sometimes general
- Mutation across classes seems to be rarer
- Points out the need for more classes of drugs
The tricks of 3 drug cocktails
- The statistical trick:
- The probability of three mutations on the same piece of RNA is very much more rare
- unfortunately, not rare enough, given the numbers
- recombination works against us too
- The biological trick:
- By slowing down reproduction, you slow down the number of mutations
Are 3 drug cocktails a cure?
- For established infections? NO!
- The virus comes back as soon as you stop
- For relatively recent infections? NO!
- The virus comes back as soon as you stop
- For VERY recent infections? Unknown but probably not.
Good news from cocktails
- Massive reduction in free virus in bloodstream
- Less damage to infected individual
- Probably makes the person less infectious
- rebound of number of circulating T4 cells
- prevention and even reversal of AIDS — but NOT elemination of HIV disease.
- moves the patient back on the timeline.
Bad News about Cocktails
- Lots of side effects (not pleasant)
- VERY complicated dosage schedule
- some drugs require an empty stomach, others require a stomach full of fatty foods
- even a few missed, late, or taken wrong lead to failure of the therapy
- Failure can lead to completely resistant virus
- Cost is enormous — minimul is $12,000/yr
Should therapy be “rationed”
- Who can (should) bear the costs?
- Non-compliant patients put the world at risk
- Patient’s age and ability to tolerate the regimen?
- The patient’s value to society?
- Lotteries?
History of rationing therapy
- Kidney dialysis
- Organ transplants
- Rare drugs in early stages
- for multiple sclerosis
- Lou Gherig’s disease
- Moral weapon
Pregnancy
- HIV is passed from mother to fetus about 30% of births
- Treatment with AZT reduces this to about 8%
- Tests underway with triple drug cocktail
Targets for therapy:
Stages of HIV disease
- HIV disease has three stages
- acute (primary) just after infection
- latent (secondary) while viral load is low, T4 cell count is high, and few if any symptoms
- late (end stage) progression to AIDS. Viral load climbs, T4 count falls, opportunistic infections and cancers abound
Targeting End Stage
- The earliest drugs target AIDS, not HIV
- New and imporved treatments for opportunistic infections
- Remember the story of the pentamidine orders for Pneumocycstis carinii pneumonia?
- anti fungal drugs (esp. against candida, the cause of “thrush”)
- lots of them, we won’t list them
Targeting transition from latent to AIDS
- Early therapy with AZT especially
- Tried to keep the viral load low
- Didn’t start until T4 count dropped and viral load rose
- Effects were short-lived
- Based on a theory that HIV replication was slow during latent phase (now know to be untrue)
Targetting latent stage
- Not much happening here
- Probelm is that we can’t kill the infected cells selectively
- We don’t even know all the reservoirs where HIV hides during latency
- We DO know that HIV replication is massive, despite low viral load
- Triple drug therapy sometimes aimed here
Targeting establishment
- Try to prevent the initial massive “bloom” of circulating virus
- Try to block the actual first infection of the first cell
- Try to prevent activation or replication of the first infected cell until it dies a natural death
- Not yet successful, even with the “72 hour window”
- Next generation of drugs (currently in research) aimed at integrase
- prevent the insertion of DNA into the chromosome and you prevent effective infection
Targeting infection
- Current excitement
- CKR-5 requirement for attachment and penetration of the virus into the cell
- people with CKR-5 deletions are alive and “immune” to HIV — sorta
- if we can block CKR-5, we may be able to prevent HIV infection
- But there are other co-receptors on other cells!
- Older excitement
- gp120 necessary for attachment to CD4
- ideal target for vaccines, drugs, etc.
- BUT it chages so fast that it eludes all vaccines and drugs
- Can’t target CD4 (probably essential)
Ethical Problems with Therapy
Urgent need means less testing
- What are the long-term effects of these drugs
- does it matter if there is no long term otherwise?
- Thalidomide
- Who decides what is safe enough?
- patient? doctors? researcher? government?
Cost means other things suffer
- Should the poor get expensive therapy?
- what other medical care will be sacrificed?
- should it cross national boundaries?
- What about other “health crises”
- cancer, heart disease, homicide, influenza
- malaria, TB, and worms in the third world
- Economics of the zero sum world
Results of non-compliance
- With limited supply, non-compliance wastes and thus dooms somebody else
- should non-compliants be banned from therapy?
- Non-compliance increases then number of multiply resistant strains in circulation
- puts others at risk of getting untreatable forms
Lessons from Penicillin and Syphilis
- Successful treatment was followed by a sexual liberation that was followed by huge increases in syphilis
- Triple drug therapy is being followed by an increase in unsafe sexual behaviours — even in gay men — “the second wave”
- should society take away the “threat”
The tribal issue
- Should resources be devoted to marginalized members of a society
- gay men
- IV drug users
- Africans and Asians
- Hemophiliacs
- Role of Nationalism, religion, racism, eugenics, etc.
The resurrection effect
- Return from AIDS = return from death
- mock execution was a form a brainwashing, used to break people’s spirits
- Viatical settlements
- Economics of end stage
- use it up, sell it off, give it away
- keep reading about the black death — tomorrow we may die
- Now suddenly they are going to live
- disability payments
- job skills
- “victim” mindset
- Survivor’s guilt
- at least 30% are non-responsive to triple drug therapy
- economics again: who will die so these may live?