New Findings on Drug Resistance

Testing for drug resistance increases treatment costs photo by Richard Feldman
Testing for drug resistance increases treatment costs photo by Richard Feldman

The “Big Three” diseases of Africa are HIV/AIDS, malaria, and TB. To date, we haven’t developed a successful vaccine for any of them, which means that drugs are of enormous importance in controlling the epidemics. For malaria and TB, the spread of drug resistant strains has wreaked public health havoc, restricting our ability to control and eliminate the diseases.

As more and more HIV-positive people are treated with antiretroviral (ARV) drugs in Africa, the question of drug resistance has become increasingly important. In the U.S., if a patient becomes resistant to first-line ARV therapy, he or she will be switched to a second- or third-line drug regimen. In southern Africa and other resource-scarce settings these options are often unavailable. Costly tests are needed to determine which drug a patient has developed resistance to, plus second- and third-line drug regimens are often prohibitively expensive.

While research on drug resistance in HIV-1B, the subtype that most affects the U.S. and Western Europe, has been studied extensively, very little research has been done on HIV-1C, the subtype that affects southern Africa, the heart of the epidemic. Kim Armstrong, a graduate student in the Essex Lab at the Harvard AIDS Initiative, is working to correct this. In a paper published this May in The Journal of Virology, Kim looks at how resistance develops to AZT in HIV-1C. AZT, also called zidovudine, is used in first-line ARV therapy across the developing world.

HIV mutates quickly. A given mutation occurs randomly, but whether a mutated virus survives in a human host depends on how well that virus competes against every other nearby virus. Most mutations end up as a dead virus or have no affect at all, but when a person is taking AZT, mutations that enable the virus to survive in the presence of AZT will out-compete everything else. In other words, AZT keeps the virus from replicating, but drug resistance mutations allow HIV to replicate in the presence of AZT.

Kim ArmstrongIn her research Kim found that some drug resistance mutations behave differently in HIV-1 subtype B than they do in C. Some mutations are more viable in C than in B. The increased capacities of certain mutations may indicate that there will be greater transmitted resistance and persistence in a subtype C setting than what is known for subtype B. For example, someone in Botswana who has developed drug resistance to AZT could infect someone else with a drug-resistant form of HIV. If that newly infected person were put on a drug regimen containing AZT, the AZT would be ineffective.

Mutations have the potential to persist at a population level. In her research, Kim found that some drug resistance mutations in HIV-1C may not compromise the virus’s ability to spread, making it as viable as wild type HIV that has not been altered by selection pressures from ARVs. Kim’s results are based on competitive growth by the virus in laboratory cultures (in vitro), not on epidemic-type transmissions in Africa (in vivo), but they are cause for alarm, warning us about the need to study drug-resistance mutations in southern Africa.