Lost Miracles

Editors note on our Health & Development series:

The correlation between access to first-rate healthcare and least developed countries is striking.  That correlation is more than superficial.  Causality runs in both directions: poor health leads to poverty by constraining the ability to work while simultaneously requiring expensive treatment.  But poverty limits access to expensive care and therefore leads to poor health.  All of this is exacerbated in countries without strong healthcare institutions.  As a result, fighting poverty is as much about providing healthcare opportunities as it is about providing economic opportunities.  Our ongoing series on Health & Development this year will focus on how the world is dealing with these interactions.

Part one of a series on HIV/AIDS in South Africa:

Out of the 35 million people worldwide currently living with HIV/AIDS, 24.7 million of them reside in Africa. That’s more than 70% of the people living with HIV worldwide. Of this giant fraction, 6.3 million call South Africa home. An economic, social, and scientific leader of its region, South Africa serves as a model for other sub-Saharan countries grappling with HIV/AIDS. How the global community stems the tide of the AIDS epidemic may indeed depend heavily on how South Africa handles its share.  

“The world is on the brink of losing its miracle cures… At a time of multiple calamities in the world, we cannot allow the loss of essential medicines, essential cures for many millions of people, to become the next global crisis” – Margaret Chan, Director-General of the World Health Organization (2011)

In 2009, 400,000 South Africans died from AIDS. Only three years later, the number of AIDS-related deaths in South Africa stood at 200,000, remarkably reduced by half. That sounds pretty miraculous to me.

Indeed, it has been the work of a “miracle cure” – antiretroviral therapy (ART) – that has brought about the drastic decline in AIDS morbidity and mortality in recent years. Some South Africans actually refer to ART as the “Lazarus drug”, because a steady regimen seems to resurrect patients from near death.

ART works by suppressing viral replication in the host; this means that it reduces the number of times the human immunodeficiency virus replicates over a span of time, thereby reducing the amount of virus in the body overall (referred to as viral load). HIV naturally has a very high replication rate— around 10 billion virions(transport vesicles that carry the virus) are produced and removed every day in an untreated patient.  Properly administered ART reduces the viral load of a patient, which in turn reduces his/her infectiousness and ultimately prevents sexual and vertical (mother-to-child) transmission of HIV by 96%.

But therein lies the catch – only properly administered ART can stop the spread of HIV infection. Patients on ART must be adherent: they must meticulously follow the prescribed interval and dose of their medication regimen.  What does this mean in a working context? It means that a patient on a twice-daily regimen cannot miss or substantially delay more than three doses of antiretroviral medications per month, for every month of the rest of his/her life, while following all the associated dietary and fluid restrictions. For most patients, near-perfect (>95%) adherence is necessary to achieve full and durable viral suppression. This degree of adherence is far higher than that of most other chronic diseases, it is not maintained in first-world countries like America, and, in a resource-poor setting such as sub-Saharan Africa, it’s almost inconceivable.

Numerous studies have shown that non-adherence (missing, delaying, or improperly handling medication intake) is linked to increased morbidity and mortality from HIV/AIDS, including more recurrent, opportunistic infections and more frequent hospitalization. Non-adherence also raises transmission rates by increasing viral load – a multivariate analysis conducted by a group at U.C. San Francisco showed that each 10% decrease in adherence results in a doubling of the viral load. Adherence alone accounted for 40-60% of the variation in viral load.

From a public health perspective, arguably the most dangerous consequence of non-adherence is drug resistance. Not all antiretroviral medications are susceptible to the development of drug resistance. Unsurprisingly, the most resistance-prone treatments are the cheapest, and in South Africa, where ART is almost entirely financed by the government and other public sector organizations, the cheapest drugs (NNRTIs) comprise the first-line treatment regimen. With this low price comes a crucial trade-off – treatment delays as brief as 48 hours may result in drug resistance.

How drug resistance arises in this situation is rather ingenious. Among the billions of virions produced daily in an untreated person living with HIV, most will be of the wild-type strain, while a small minority will be of mutated strains. These mutations arise just by chance during viral replication, as the machinery for HIV replication is not very accurate or precise. ART drugs are tailored to act upon specific sites of the virus; if a mutation, for example, changes the shape of a protein at one of those sites, a once-effective drug may no longer bind and thus may cease working. In this way, the virus that carries that mutation gains drug resistance.

When an untreated person commences ART promptly and properly, his/her viral load will be completely suppressed, leaving very little room for mutations to arise. When that same person continues ART but does not properly adhere, his/her viral load will only be partially suppressed. If enough of the wild-type virion is reduced, the mutated virions that carry drug resistance will then have increased fitness, or a comparative advantage in survival. They can replicate and become the dominant populationin the person’s body, rendering the ART useless. That person can then transfer the drug-resistant virus to others, and anyone infected with this new strain will have to switch to a different (second-line) ART regime, which is typically much more expensive and much less tolerated by the body. One more additional switch in treatment will be the last one—there are no treatment options beyond the [extremely expensive and rather limited] third-line of ART. And just like that, we will have lost our miracle cure.

Grave as this concern may be, history shows that the issue of drug resistance has always been overshadowed by the priority of actually getting this miracle cure to the people who need it. As of 2013, ART covers only 11.7 million of the 35 million people living with HIV (PLHIV) worldwide, a dismal rate of 36%. Nonetheless, even as we rush to distribute ART, we must be very wary, especially since countries with high AIDS burden tend to have extremely weak surveillance systems, making it difficult to catch, trace, and contain any mutant HIV strains that arise.

There are a substantial number of scientists and public health officials who actually advocate against expanding ART coverage in low- to middle-income countries due to the possibility of pervasive drug resistance. While denying this miracle cure to thousands of people who would die without it may seem like a flagrant violation of human rights, the ethical issue of distributing ART without strong adherence programs in place is clearly much more complex than simply choosing or not choosing to save more lives. Mathematical models show that ART can stop the spread of HIV infection and end this epidemic, but ART also has the potential, when misused, to spread a human immunodeficiency virus that is essentially untreatable and impossible to beat.

That said, there is currently not enough evidence of extensive adherence-resistance issues in low- to middle-income countries to flat-out deny ART coverage. Indeed, ART programs are relatively young, even among first-world nations. Not enough time has passed to judge the negative effects of non-adherence on public health, especially since, like most chronic diseases, adherence declines with increasing length of time on treatment. Only time will tell if more severe consequences arise as more people are living longer on ART.

Accordingly, close attention should be paid to South Africa, whose national ART program is the largest of its kind. While it covers over 2.6 million patients, it has only reached 42% of PLHIV. As it continues to expand its ART program, non-adherence must simultaneously be addressed, and with vigor and vigilance. Part of the program already includes at least three intensive counseling sessions on HIV and ART prior to starting treatment; despite this, adherence levels throughout South Africa remain within the range of 50-77%, substantially below the target 95%.

Unfortunately, the issue of adherence is a complex, multifactorial one – the determinants of which will be explained in Part 2 of this series. The only simple conclusion that can be drawn regarding adherence is that it is unequivocally crucial to the success and maintenance of ART. And, as the science continues to show, the benefits of ART are unparalleled. We simply cannot afford to lose this miracle cure.

Image Credit: Ragesoss via Wikimedia Commons.


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