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What Are the Effects of Drug Resistance Before Antiretroviral Therapy is Even Started?

Drug-resistant mutations in certain HIV strains do not appear to affect disease progression before antiretroviral therapy is initiated, but other variables may play a role.

Antiretroviral therapy for HIV is unquestionably a success story, but some people are infected with mutated strains of the virus that are resistant to antiretroviral therapy. Although some mutated versions swiftly revert to the naturally occurring wild-type HIV after transmission, other mutated strains may linger in people. Depending on the kinds of mutations present, the virus may be weakened and cause the disease to progress more slowly—or it may be strengthened, enabling an accelerated disease process.

A team of investigators from medical institutions across Europe set out to study what happens when HIV mutations lower the fitness level of the virus, or its robustness. They hypothesized that, in these cases, patients would see their CD4 levels go down less precipitously than might be expected and they’d have lower viral set points (the viral load levels at which the body comfortably settles). In other words, they would be able to slow the progression of the disease compared with individuals who harbored viruses with a higher fitness level.

Using available databases, the investigators looked at 6180 patients, three-quarters of whom were male, from a variety of European countries. All were at least 18 years old and had undergone drug-resistance testing before being put on antiretroviral therapy. They also had been given at least 1 viral load test and 1 CD4-level test prior to beginning treatment.

The study team found that 1 out of 10 subjects displayed primary drug resistance, or resistance before ever having taken HIV medication. However, an examination of each subject’s viral load measurements and CD4 levels over a period of time (median 1.4 years) revealed little connection between primary HIV drug resistance and progression of disease. Subjects with nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI) resistance had initial viral load set points and CD4 levels just a notch lower than subjects demonstrating no resistance, leading the scientists to consider whether resistance has any meaningful impact on disease progression in HIV-positive individuals before they begin antiretroviral therapy.

“[I]n terms of the analyses we did, the presence of resistance mutations prior to the start of treatment did not seem to escalate disease progression before individuals start[ed] treatment in a clinically meaningful way,” Anna Schultze, PhD, a former researcher at University College London and an author of the study, told Contagion®. “This doesn’t mean there is no benefit from testing for resistance, though. This still helps clinicians construct effective regimens for when they are starting patients on treatment.”

In general, Dr. Schultze said, drug resistance has not hampered HIV treatment success in the way the medical community feared it might when antiretroviral therapy first became widely used.

“However, it could still become a challenge, particularly in settings where access to different types of treatment is limited and resistance testing is not widely used,” she said. “Lower CD4 levels at the start of antiretroviral do lead to poorer outcomes, which is why it’s important to start treatment as soon as possible after diagnosis.”

Dr. Schultze added that although drug-resistance mutations appear not to impact the rate of disease progression before the start of antiretroviral therapy, there may be variables that do: “[O]ther changes in the viral genome that don’t confer resistance may have a small impact,” she concluded. “Although it’s not yet clear if this would be clinically relevant.”