HIV Disease and Therapy

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?