Study Warns of Threat of Multi-Drug-Resistant HIV

Failure to reverse trend could result in 425,000 deaths

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During the course of the past 10 years, global health authorities have made impressive gains in the delivery of life-saving HIV drugs to people living around the world. According to the United Nations Joint Programme on HIV/AIDS (UNAIDS), nearly 17 million people had been placed on antiretroviral therapy by the end of 2015, correlating to an astonishing 43 percent drop in the number of HIV-related deaths since 2003.

But even as UNAIDS and other global health authorities push for the end of the epidemic by 2030, a disturbing trend threatens to undermine those efforts: the rise of multi-drug-resistant HIV previously thought to be rare by scientists.

It is a problem that is not only affecting resource-limited countries (like those in Africa which bear the largest burden of HIV infections) but high-income countries where rates of transmitted resistance are on the rise.

Causes of Multi-Drug-Resistant HIV

Multi-drug resistance is a phenomenon seen in other medical conditions, like tuberculosis (TB) and staphylococcal infections, in which an infected individual fails to respond to a broad range of drug therapies. In some cases, the resistance can be extreme, such as with extensively drug-resistant TB (XDR TB) seen in parts of southern Africa, for which mortality rates are high and drug treatment options few.

As with other forms of resistance, the emergence of multi-drug-resistant HIV is due largely to a person’s inability to take his or her medications consistently or as directed.

When taken correctly, the drugs will suppress viral activity to a point where HIV is considered "undetectable." When taken incorrectly, viral activity can persist to levels where drug-resistant mutations can not only develop but thrive.

Over time, as treatment failure occurs and a person is exposed to more and more medications, additional mutations can develop, building one atop the next.

If that person then infects another, the multi-drug resistance will passed, spreading further into the population through sexual networks or injecting drug use.

Scale of the Crisis

According to the World Health Organization (WHO), which reviewed data from 12,000 clinics in 59 countries, an average of 20 percent of people prescribed antiretroviral therapy dropped out of the treatment without the course of one year. Of those who remained on therapy, as many as 73 percent dosed inconsistently, while nearly one in three failed to achieve an undetectable viral load consistent with treatment success.

This level of viral activity within a population increases the likelihood of multi-drug resistance, particularly in high prevalence countries where as many as one in five people is infected. Exacerbating the situation are frequent drug stock-outs, which leave patients without medications and impacts nearly 36% of clinics in the developing world.

Even in countries like the U.S., high rates of undiagnosed infection (20 percent) and low rates of patient retention (40 percent) have translated to equally low rates of viral suppression (28 percent).

"Impossible" Multi-Drug Resistance Causes Concerns

A 2016 study from the University College of London (UCL) highlighted a growing concern among scientists who fear that the development of multi-drug resistance may reverse many of the gains made in the global fight against HIV.

In their research, the UCL scientists conducted a retrospective investigation of 712 patients who had received antiretroviral therapy between the years 2003 and 2013 and had failed on first-line therapy.

Of these, 115 patients (16%) had an HIV strain with a thymidine analog resistance, a type associated with early generation drugs like AZT and 3TC. Surprisingly, 80% of these patients also had resistance to tenofovir, a newer generation drug prescribed widely across the world.

This was a shock to many in the research community, who had considered this type of multi-drug resistance rare, if not impossible.

While it had been known for some time that the rate of tenofovir resistance had been growing—from 20% in Europe and the U.S. to over 50 percent in parts Africa—many had believed that these two types of resistant mutations could not co-exist.

If the trend continues, as many suspect, the consequences could be enormous. Some studies have suggested that drug-resistant HIV strains could cause many as many as 425,000 deaths and 300,000 additional new infections over the next five years.

Currently, over 10 percent of persons starting HIV therapy in central and southern Africa are resistant to first-line drugs, while 40 percent will have similar resistance to second-line and subsequent drug therapies. The combination of tenofovir and thymidine analog resistance only exacerbates the issue by limiting a person’s sensitivity to not only one or two drugs, but entire classes of drugs.

Reversing the Trend

While the expansion of HIV therapy—in line with the United Nations' 90-90-90 strategy—is essential to ending the epidemic, equally important is our need to invest in technologies and to identify solutions to overcome systematic barriers to individual-based drug adherence. It's a warning echoed by officials at the WHO, who state that without the means to ensure a patient’s retention in care, the rapid expansion of drug programs will never enough to contain the epidemic.

Hopes, meanwhile, are being pinned on an experimental drug called ibalizumab, which had been granted breakthrough status by the U.S. Food and Drug Administration in 2015. The injectable drug prevents HIV from entering a cell and has been shown to overcome many multi-drug-resistant strains in human trials. While it has not yet been officially licensed by the FDA, the breakthrough status traditionally fast tracks approval from anywhere from six months to a year.

Some research has also suggested that a newer form of tenofovir (called tenofovir AF) may be able to overcome resistance associated with the "older" form of the drug (called tenofovir DF).

From an individual perspective, prevention remains key to avoiding the further spread of multi-drug resistance. It demands both high levels of treatment adherence for people living with HIV and holistic harm reduction strategies to prevent both the acquisition and transmission of drug-resistant virus.

Sources:

Gregson, J.; Kaleebu, P.; Marconi, V.; et al. "Occult HIV-1 drug resistance to thymidine analogues following failure of first-line tenofovir combined with a cytosine analogue and nevirapine or efavirenz in sub-Saharan Africa: a retrospective multi-centre cohort study." Lancet Infectious Diseases. November 30, 2016; S1473-3099(16)30469-8.

The TenoRes Study Group. "Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study." Lancet Infectious Diseases. January 28, 2016; published online.

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