Handful of Mutations Behind Most Drug-Resistant HIV Strains Globally

A new study published in PLOS Medicine suggests that only a handful of mutations are responsible for the majority of drug-resistant HIV strains. The study’s researchers at Stanford University School of Medicine focused specifically on medications used to treat infections in resource-limited settings — particularly non-nucleoside reverse transcriptase inhibitors — and discovered that a limited number of mutations are behind most cases of transmitted drug-resistant HIV around the world. 

Like other viruses, HIV has the ability to mutate in response to environmental factors, including the presence of antiviral drugs; and those mutations can then be transmitted from one person to the next. Although it's debated, scientists say it is also possible for someone who is HIV-positive to become infected with another strain of the virus in what is known as superinfection. 

According to Infection Control Today, the Stanford study is the largest of its kind. Examining 50,000 patients in 111 countries, researchers found a small group of mutations accounted for a majority of the cases of transmission-related resistance to HIV drugs. The results are a positive sign as they suggest the levels of transmission of drug-resistant strains has not increased dramatically in recent years, as was feared.

"What we are showing is that the rates of transmitted drug-resistant HIV in the low- and middle-income countries most affected by HIV have increased modestly,” said Dr. Robert Shafer, professor of medicine at Stanford and principal investigator for the study, in a written statement. “The rate of increase in sub-Saharan Africa has been low, and an increase has not been detected in South Asia and Southeast Asia. That's good news."

However, the study also found there continues to be an increase in drug resistance among people with HIV in poorer countries because the treatment regimens used there are less vigorous than those available in more affluent countries, including the United States. Maintaining the necessary adherence to a daily, lifetime regimen of multiple medications is also particularly challenging for people in the poorest parts of the world, Shafer added.

"It is inevitable that transmitted drug resistance will increase further,” Shafer said. “So we need to continue ongoing monitoring to ensure successful, long-term treatment outcomes for the millions of people on therapy worldwide."

Still, Shafer noted that the findings have positive implications for treatment of HIV-positive people in hard-hit regions like sub-Sahara Africa. It may now be possible to develop an inexpensive test for key mutations, which would help doctors better target HIV treatments. Such a test might tell doctors which drugs should be given to previously untreated patients.

According to the Joint United Nations Programme on HIV/AIDS, nearly 12 million people in low- and middle-income countries now have access to antiretroviral treatments. But there has continued to be concern that wider availability of HIV meds could result in an increase in drug resistance and ultimately reverse the gains made so far.

To determine how widespread the problem of drug resistance was, Shafer and his colleagues reviewed HIV sequencing data on 50,870 individuals around the world. The data was contributed by nearly 60 medical institutions on five continents and drawn from 287 studies published between 2000 and 2013.

Each virus sequence was examined for the presence of 93 mutations known to indicate HIV drug resistance. The study found the overall prevalence of transmitted drug resistance ranged from 2.8 percent in sub-Saharan Africa to 11.5 percent in North America. In south Asia and Southeast Asia, the numbers actually remained unchanged during the decade of expansion in drug treatment. However, Shafer said more recent studies show rates of drug resistance have risen to more than 5 percent in sub-Saharan Africa.

The increase in transmitted drug resistance is inevitable, Shafer added, but it could weaken the ability to treat HIV in low-income regions and discourage new patients from connecting with care.

To avoid that outcome, the study’s authors urge the creation of a simple, inexpensive test for the key drug resistance-related mutations. Such a test could help doctors pinpoint the medications most likely to be effective for individual patients. In Africa and Asia, the researchers identified four resistance-related mutations associated with the drugs nevirapine and efavirenz. These two medications are in a class of older, less-expensive medications known as non-nucleoside reverse transcriptase inhibitors, which are still used in the developing world as part of standard, daily regimens, but are generally not widely used in the U.S.

“The idea of an inexpensive test for key mutations is attractive,” Shafer explained. “If it were used in conjunction with a viral load test, it would allow physicians to know if therapy should be changed and where adherence counseling should be given.”

Patients who tested positive for those mutations could be switched to newer (and more expensive) protease inhibitors, which are less susceptible to resistance mutation.

“You could therefore shut off the flow of drug resistance by using regimens that are less vulnerable to the development of drug resistance in the first place,” says Shafer.

The study also discovered that the drug-resistant strains of HIV didn’t originate from one specific line of medication resistant viruses, but were each different, indicating they were not part of a single transmission chain. That sets HIV apart from patterns of drug resistance in diseases like malaria and tuberculosis, where drug resistant strains tend to spread rapidly. It’s also at odds with the patterns of HIV drug resistance in many wealthier countries where decades of treatment have given rise to the spread of many highly drug-resistant strains.

“We are finding that the strains being detected in low-income countries are pretty much unrelated to one another,” Shafer said. “So that suggests these have not yet gained a foothold in the population, and are less often being transmitted among people who have never received the drugs before.”

The study was published online in the peer-reviewed medical journal PLOS Medicine. The research was funded by the National Institutes of Health, the Bill & Melinda Gates Foundation and the Center for AIDS Research.

Learn more about drug-resistant HIV and the dearth of treatments available here.