Study shows importance of resistance testing before start of HIV treatment

European research published in the February 28^th edition of The Lancet shows the importance of considering the results of tests for transmitted resistance when selecting a patient’s first combination of antiretroviral drugs.

Individuals treated with a regimen which was not completely active were three times more likely to experience virologic failure during the first year of treatment than individuals with no resistance or those who had resistance but were treated with therapies to which the strain of HIV they had was fully susceptible.

There was also some evidence that baseline resistance impaired immune recovery.

“Transmitted drug resistance was associated with virological failure in patients who received at least one drug to which the virus had lost susceptibility,” write the investigators, who say their findings underscore “the need for at least three fully-active antiretroviral drugs to optimise virological response to a first-line regimen.”

In Europe, use of antiretroviral therapy has dramatically improved the prognosis of many patients with HIV. However, expanded use of HIV treatment has been accompanied by an increase in the transmission of drug-resistant HIV. Approximately 10% of all new infections in Europe involve a strain of virus that is resistant to at least one antiretroviral drug.

Resistance is the major reason why anti-HIV drugs cannot control viral load. European and British guidelines recommend that all patients should be tested for drug resistance soon after their diagnosis with HIV and again before they start antiretroviral therapy. First-line HIV therapy should take into account the results of this surveillance.

However, there is uncertainty about the impact of transmitted resistance on responses to first-line HIV treatment. This is especially the case if a patient with resistance takes a fully active combination of drugs.

To gain a better understanding of this issue, European investigators examined outcomes in 10,000 patients who started HIV therapy after 1998. The patients were enrolled in 25 different adult and paediatric cohorts.

All the patients had a resistance test before they started therapy. Changes in viral load and CD4 cell count in the first year of treatment were examined.

The risk of virologic failure (two consecutive viral loads above 500 copies/ml after six months of treatment) was compared between patients according to whether they had no transmitted resistance; resistance, but treated with a combination of drugs that were fully active; or transmitted resistance and treated with a sub-optimal combination.

Approximately 10% of patients had transmitted resistance. Half were treated with antiretrovirals to which their HIV was fully susceptible. The others received therapy to which their HIV was at least partially resistant.

After a year of treatment, 4.2% of patients without transmitted resistance had experienced virologic failure. The rate was marginally higher (4.7%) for individuals with transmitted resistance who received therapy with three fully active drugs. However, a far greater proportion (15%) of patients with resistance and reduced susceptibility to a drug they received experienced virologic failure.

The investigators calculated these patients had a threefold increase in their risk of virologic failure (p < 0.001).

Furthermore, patients with high-level resistance to the drug(s) they were taking had a sixfold increase in their risk of viral load remaining detectable or rebounding after six months of treatment (p < 0.001).

There was some evidence that therapy that included a ritonavir-boosted protease inhibitor was a good option for individuals with resistance who received fully active treatment. They were no more likely to experience virologic failure than individuals with no resistance who received this class of drug.

However, there was weak evidence of a higher risk of treatment failure for patients with transmitted resistance who received fully active treatment based on an NNRTI, compared to individuals with no resistance who were also treated with this class of drug (hazard ratio = 2.0; 95% CI, 0.9-4.7, p = 0.093).

After one year of therapy, the median increase in CD4 cell count was 183 cells/mm³. There was modest evidence that patients with resistance who took therapy which was not fully active had smaller increases in their CD4 cell count during the first month of therapy. This was most apparent among patients who received an NNRTI (p = 0.0514).

“This finding is important because it suggests a poor immunological response in patients with transmitted drug resistance who are started on a suboptimum regimen will result in poorer CD4 response and ultimately risk of disease progression,” write the authors.

They conclude, “this European observational multicohort study confirms present treatment guidelines that state that the initial treatment choice should be based on resistance testing in treatment-naïve patients.” In settings where resistance testing is not available, they suggest that a treatment based on a ritonavir-boosted protease inhibitor “should probably be considered.”

Wittkop L et al. Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study. The Lancet Infectious Diseases, early online publication, 28 February 2011.