Saturday, July 12, 2014

Emerging Resistance to HIV Antiviral Drugs (long)

I was involved in two different discussions this last week regarding people who choose to actively live a "Gay" lifestyle and how that might impact their life expectancy.

The answer is not straightforward.

The first level pass is:  In the absence of effective antiviral drug therapy the life expectancy of a 20 year old male actively living the "Gay" lifestyle is between 10 and 15 years less than a 20 year old male not actively living the "Gay" lifestyle.

The second level pass is:  In the presence of effective antiviral drug therapy there is not a statistically significant aggregate difference in life expectancy at this time.  (See Footnote One) this time

The specter of drug resistant HIV looms on the horizon.

The simplest, most cost effective drug therapies involve using the oldest "commodity" drugs.  In the case of HIV antivirals, that includes nucleoside reverse transcriptase inhibitor (NRTI) approved 1987, protease inhibitor (PI) introduced 1995, nonnucleoside reverse-transcriptase inhibitors (NNRTIs) 1996.

The problem with using the commodity drug approach is that the disease fairly rapidly evolves around it.  Recent studies in Southeast Asia suggest that between 10% and 15% of HIV positive patients do not respond to even the first round of "commodity" therapy.  These patients were presumed to be naive...that is, never subjected to therapy.  It can be assumed that the originating source of the 10%-to-15% resistant strains was either subjected to therapy at some time  or was infected by somebody who was.

Another study was done in sub-Saharan Africa. Anecdotal evidences suggests that sub-Saharan Africa is a less common destination for sexual tourism than Southeast Asia, therefore, antiviral resistances is more likely to be "home grown".  Antiviral treatments were started in 2007 and 5.6% of the patients had some form of antiviral resistant HIV by 2011.  One issue that is of most concern is that the resistance spanned all classes of antiviral drugs.  Specific recommendations were to beef-up the supply chain since sporadic therapy is favorable to selecting for resistant mutations.  Source

The current state-of-the-art is to use a cocktail of three different drugs from three different "classes" or families.

The reason for using drugs from different families is because there is evidence of cross-resistance. That is, if a strain of HIV can defeat one NNRTI it might show resistance to all NNRTIs.  An analogy to delaying resistance by administering three different classes of drugs simultaneously is that most people are capable of bunny hopping up one stair-step.  Very few are capable of bunny hopping directly to the third step in one hop.  In a similar way, a virus might mutate by random chance to defeat one antiviral mechanism.  The chances of a virus simultaneously experiencing three mutations that defeat all three antiviral mechanisms is very, very small

These new drugs generated a major change in the treatment strategy against HIV— highly active antiretroviral therapy (HAART)—that coincided with the start of the monitoring periods in several of the studies mentioned above (1995–1996). With HAART, at least 3 drugs are administered at the same time, which substantially reduces viral load and, compared to results of earlier regimens, increases the life expectancy of patients. These advantages follow because the mutations necessary to confer resistance to HAART are generated at a slower rate and are lost more rapidly than those conferring resistance to monotherapy or dual therapy.  Source

Cool, we have a plan!

Plans are good, but what about the budget?  What does it cost to administer a cocktail of three different drugs?  I know that Long Island Ice Teas (a three shot drink) are more expensive than whiskey-and-coke.  Are these cocktails more expensive?

You bet they are.  Especially since they rely on the newest classes of antivirals and constant switching within the class of antivirals to include the most recent releases.

We assessed inpatient days, outpatient visits, and prescribed antiretroviral and opportunistic illness prophylaxis medications for 14,691 adult HIV-infected patients in primary HIV care in 2006. We estimated total care expenditures, stratified by the median CD4 cell count obtained in 2006 (≤50, 51-200, 201-350, 351-500, >500 cells/μl). Per-unit costs of care were based on Healthcare Cost and Utilization Project (HCUP) data for inpatient care, discounted average wholesale prices for medications, and Medicare physician fees for outpatient care.

Averaging over all CD4 strata, the mean annual total expenditures per person for HIV care in 2006 in three sites was US $19,912 (about $1700/mo)...Average annual per-person expenditures for care were greatest for those with CD4 cell counts 50 cell/μl or less (US $40,678) (about $3,500 per month).  Source

Clearly, $1700-to-$3500 per month is beyond the means of most people in a nation where the median household income is about  $4300/month.  Even more clearly it is pure fantasy to think they can be afforded in any sub-Saharan country with per capita income below $65/month.

The CDC estimates that 1.1% of the US population is HIV positive.  These people create universal precaution hazards.  Some of these people sell their plasma for cash.  Many of these people live bi-sexual lives and expose naive partners to HIV risk.

Even more problematic are the 15% of the HIV positive population who are unaware of their status.  They do not know they are spreading death. 

There are people who are optimistic

Picture from HERE

The percentage of cases in the US that are antiviral resistant has gone down since the year 2000. There are only two ways this can happen.  Either the denominator (the number of people with HIV) is growing very rapidly or the carriers of the resistant HIV strains are dying off without infecting other people.

Literature attributes the "extinction" of strains of resistant HIV to more effective drugs within each class of drugs, to the use of cocktails, and to aggressive efforts to educate the carriers of resistant HIV strain to use "safe" practices in the hope that the resistant strain will die when the carrier does.  The first two reasons reduce the viral loading in the body thereby reducing its transmissibility.  The third reason relies on changes in behavior to reduce exposure of infective materials to new, potential carriers

There are people who are pessimistic

The entire strategy to delay the development of resistance is a delaying tactic.  It really does not stop or reverse emerging resistance.  Delaying works numerically as long as scientists continue to find new families of antiviral drugs and new members within that family. 

Many drugs enter the approval process.  Few get final approval.  Picture from HERE

At some point the universe of chemicals and isomers that are small enough to permeate cell walls will be exhausted and/or that can be synthesized with any economy will be exhausted.  After that, there will be no more newer, better, shinier, silver bullets.

Other reasons for pessimism are that Third World countries are using the same single-drug strategies that incubated the resistant strains in the 1990s.  Kenya, Uganda, Upper Volta and Congo cannot afford, nor can their war-torn infrastructure reliably deliver pricy drug cocktails.  Less than 24 hours separate Chicago O'Hare from prostitutes in Kampala or Bangkok.

A final reason for pessimism is that antivirals have side effects.  Patients go meds non-compliant when they cannot stand the side effects.  Taking a regime of three powerful drugs has more side effects than taking a single drug, thus patients are more likely to go meds non-compliant.

Fearless prognostication

HIV strains that show resistance to all three major classes of antiretrovirals will emerge with increasing frequency.

Reactive medicine will fight a losing, rearguard action against trend.  They will appear to be successful at first but then effective therapies will collapse at a breathtaking rate.

The "Gay" community will become self-policing.  One of the quirks of the active "Gay" lifestyle is the distribution of the number of "partners" various people have.  It is by no means a homogenized (no pun intended), monolithic community.

  • The bottom 10% of men who self-identify as gay claim to have zero new intimate partners per month.
  • The middle (or median) 30% of men who self-identify as gay claim to have three new intimate partners per month
  • The top 10% of men who self-identify as gay claim to have twenty-eight new intimate partners per month.  Source

From an epidemiological standpoint the behaviors of the top 10% creates more hazard than the behaviors of the bottom 90%.  Like many out-of-the-mainstream communities, there seems to be a high degree of internal knowledge that is not accessible to outsiders.  My fearless prediction is that the "sluts and ho's" will be branded with the equivalent of The Red Letter of untouchableness as resistant strains of HIV become the norm.

The "Gay" community will identify the 20% that is out-of-control as a menace and as mentally ill.  They will be the ones who enforce isolation because they have the most at risk and they have the inside information identifying the 20% menace.

Footnote One:

"...there is not a statistically significant aggregate difference in life expectancy at this time."
 The male Gay community is diagnosed with a higher rate of depression and anxiety than the general population.  They also experience a higher rate of death-by-suicide drug-overdose than the general population.  It is likely that these causes of death are linked to the rate of depression.  Gay advocates claim that depression and anxiety are linked to the homophobic general population.  Naysayers counter that there is little difference in rates of depression between "Gay friendly" cities and "Traditional" cities.

In spite of higher death rates due to certain, specific general the life expectancy of the male "Gay" population is not significantly lower than the US male population.  That may be due to the more urban nature of the "Gay" population and the improved access to general medical care offsetting any up-tick due to suicide.

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