New HIV Resistance to Antiretrovirals Almost Disappears in Switzerland

New resistance to antiretrovirals nearly disappeared from 1999 to 2013 in a nationwide study in Switzerland.1 Researchers calculated that 401 people taking antiretrovirals in 1999 had a new resistance mutation, compared with only 23 people in 2013.

The goal of antiretroviral therapy is to stop HIV from making new copies of itself in CD4 cells. Resistance happens when the genetic code of the HIV virus changes in a way that allows HIV to keep making new copies of itself when a person is taking a certain antiretroviral or group of antiretrovirals. Such a change in HIV's genetic code is called a resistance mutation. If resistance mutations start piling up in the HIV of a positive person, fewer and fewer available antiretrovirals will be able to stop HIV from making copies of itself in CD4 cells.

Resistance mutations do not develop when a person is taking an antiretroviral combination that completely stops HIV from making copies of itself. But if a person starts skipping antiretroviral doses and lets HIV make new copies, resistance can emerge. If resistance to certain antiretrovirals develops, a person has to switch to different antiretrovirals to control HIV.

In the past 10 years or so, researchers have made many new, strong antiretrovirals and some new groups of antiretrovirals. New groups of antiretrovirals can usually control HIV that is already resistant to older groups of antiretrovirals. Providers can test HIV in blood with a resistance test to see which antiretrovirals will no longer be effective because of resistance and which new antiretrovirals can still control resistant virus. But a person has to take the new antiretrovirals steadily -- without missing many doses -- or HIV will become resistant to the new drugs. Eventually, a person who does not take antiretrovirals steadily will use up all the antiretrovirals that can control that person's resistant HIV.

People who want to learn more about resistance to antiretrovirals can read an easy-to-understand Fact Sheet from the National Institutes of Health linked at reference 2 below.

Researchers in Switzerland conducted this study to see how development of new resistance mutations has changed since 1999.

How the Study Worked

The Swiss HIV Cohort Study (SHCS) in an ongoing analysis that includes 72% of HIV-positive people taking antiretroviral therapy in Switzerland. SHCS participants make study visits twice a year for testing and interviews, so researchers keep up to date on their health. As part of this ongoing study, researchers test blood samples to find out which antiretroviral resistance mutations developed over time. This information gets stored in a resistance database that can be analyzed at any time. The researchers also examined antiretroviral resistance findings in a national database that includes results of all resistance tests done in Switzerland from 2003 through 2013.

This analysis involved all SHCS members who had one or more study visits from January 1999 through December 2013. The researchers divided study participants into three groups, depending on when they started antiretroviral therapy:

  1. Before January 1999, when people often started weak one- or two-drug therapies or poorly designed three-drug therapies that allowed resistance to develop quickly
  2. January 1999 through December 2006, when people began taking stronger three-drug antiretroviral combinations
  3. 2007 through 2013, when even stronger antiretrovirals that could often control resistant HIV became available

From 1999 through 2013, the investigators determined the yearly rate of antiretroviral resistance based on resistance test results and -- when test results weren't available -- based on logical assumptions that classified people as having a high risk of new resistance mutations, a low risk, or an unknown risk. The research team also estimated the rate of resistance to three of the four main antiretroviral groups -- nucleosides, nonnucleosides, protease inhibitors, and integrase inhibitors.

Finally, for people in the SHCS in 2013 with a resistance test after starting ART, the researchers determined how many antiretroviral combinations would still be able to control each person's HIV. To do this, the investigators used an antiretroviral resistance tool developed at Stanford University. This tool gives a resistance score that allows each antiretroviral to be classified as having (1) full activity, (2) intermediate activity, or (3) no activity against HIV with established resistance mutations.

What the Study Found

The study included 11,084 people, 29% of them women, and 19.5% nonwhite. Similar proportions of the study group became infected with HIV during sex between men (39.6%) or during sex between men and women (37.6%), and 18.8% became infected while injecting drugs. Median (midpoint) age of the study group was 47.

About one third of study participants started antiretroviral therapy before 1999, one third started between 1999 and 2006, and one third started between 2007 and 2013. The proportion of these antiretroviral-treated people with a resistance mutation ever detected fell from 56.2% in the group that started therapy before 1999, to 19.7% in the 1999-2006 group, and to 9.7% in the 2007-2013 group (Figure 1). The last group included 2092 people who had a resistance test before starting antiretroviral therapy; only 1.6% of people in this group acquired resistance during treatment.

Resistance Mutation Ever Detected by Year of Starting Antiretrovirals
Resistance Mutation Ever Detected by Year of Starting Antiretrovirals Figure 1. In an 11,084-person study in Switzerland, the proportion of antiretroviral-treated people with one or more resistance mutations ever detected dropped sharply among people who started antiretrovirals in 1999 or later.
Teresa B. Southwell

Among study participants with resistant HIV in 2013, 59.8% had started antiretroviral therapy before 1999, 25.4% had started between 1999 and 2006, and only 14.8% had started between 2007 and 2013. Whereas 401 people acquired a new resistance mutation in 1999, only 23 did in 2013.

The proportion of people with HIV resistant to three antiretroviral groups fell from 10.7% in those who started therapy before 1999, to 1.6% in the 1999-2006 group, and to 0.2% in the 2007-2013 group.

Among people who started antiretroviral therapy before 1999, the researchers determined that 33.8% no longer had a fully active nucleoside available and 14.4% no longer had a fully active nonnucleoside. ("Fully active" means very likely to control that person's HIV regardless of any resistance mutations the virus may carry.) Among people who started therapy between 1999 and 2006, those proportions improved to 6% without a fully active nucleoside and 9.9% without a fully active nonnucleoside. And among people who started antiretroviral therapy between 2007 and 2013, only 0.7% no longer had a fully active nucleoside available and 8.2% no longer had a fully active nonnucleoside. Almost everyone who started therapy after 1999 had a fully active protease inhibitor and a fully active integrase inhibitor available.

What the Results Mean for You

All of the trends summarized in the preceding section reflect the impact of the stronger antiretrovirals that became available after 1999. The strength of these new antiretrovirals against resistant HIV -- and the variety of different antiretrovirals available -- mean chances of controlling HIV infection have improved over the years. As a result, fewer people are getting AIDS illnesses. Controlling HIV also helps prevent or control some major non-AIDS diseases.

In the Swiss study participants, this lower risk of AIDS and non-AIDS diseases has improved survival with HIV over the years. Proportions of people who died from AIDS fell from 4% in people who started antiretrovirals before 1999, to 2.4% in people who started therapy in 1999-2006, and to 0.5% in people who started in 2007-2013 (Figure 2). Proportions of people who died from any cause in those three periods fell from 18.6% to 10.3% to 2.1%.

AIDS and All-Cause Death Rates by Year of Starting Antiretrovirals
AIDS and All-Cause Death Rates by Year of Starting Antiretrovirals Figure 2. Among people who started antiretroviral therapy in Switzerland, those who started in more recent years had much lower rates of death due to AIDS and to all causes.
Teresa B. Southwell

Do resistance findings like these in Switzerland reflect what's happening in other countries, including the United States? Switzerland differs from the United States in one important aspect of HIV care: Everyone in Switzerland receives free HIV care and free antiretroviral therapy. Some HIV-positive people in the United States still have no health insurance or poor insurance, and that impairs their access to antiretrovirals and care. But the antiretrovirals available and HIV treatment guidelines are very similar in the United States and Switzerland. A study in the United States tracked a drop in resistance among antiretroviral-treated people from 1999 through 2008.3 And a 1997-2008 study in 7 countries across Western Europe made similar findings.4

There are two keys to avoiding resistance when taking antiretroviral therapy. First, everyone should have a resistance test before starting therapy to see if they have been infected with virus already resistant to some antiretrovirals. If a person has resistance before starting therapy, the HIV provider can pick an antiretroviral combination that should control that resistant virus. Second, once a person starts a well-selected antiretroviral combination, quickly reaching and maintaining an undetectable viral load will prevent resistant HIV from developing. Reaching and keeping an undetectable viral load depend on taking all your antiretrovirals every day exactly as your provider instructs.

For almost everyone living with HIV today in the United States, Switzerland, and countries with similar HIV epidemics, providers can find an antiretroviral combination that will control HIV -- even if that person's HIV already carries resistance mutations. Taking those antiretrovirals regularly is essential to reaching an undetectable viral load, preventing resistance mutations from developing, and living a long and productive life.

References

  1. Scherrer AU, von Wyl V, Yang WL, et al. Emergence of acquired HIV-1 drug resistance almost stopped in Switzerland: a 15-year prospective cohort analysis. Clin Infect Dis. 2016;62:1310-1317.
  2. AIDSinfo. Fact sheets. HIV treatment. Drug resistance. 2016.
  3. Buchacz K, Baker R, Ward DJ, et al. Trends in decline of antiretroviral resistance among ARV-experienced patients in the HIV Outpatient Study: 1999-2008. AIDS Res Treat. 2012;2012:230290.
  4. De Luca A, Dunn D, Zazzi M, et al. Declining prevalence of HIV-1 drug resistance in antiretroviral treatment-exposed individuals in Western Europe. J Infect Dis. 2013;207:1216-1220.