Adherence: study shows protease inhibitors more forgiving of missed doses, even when treatment out of date

Less than perfect adherence to HIV treatment regimens significantly increases the risk of resistance developing to drugs in the NNRTI and NRTI classes, investigators report in the January 28^th edition of AIDS.

Poor adherence to boosted protease inhibitors did not, however, involve a significant risk of resistance.

Adherence is the single most important factor under a patient’s control affecting the success of their antiretroviral therapy. Poor adherence to treatment has been linked to increases in viral load and the development of drug-resistant virus.

However, the relationship between adherence and resistance differs between classes of antiretroviral drugs. A better understanding of the relationship between drug classes, adherence, and the risk of resistance can assist in the design of treatment strategies.

But most studies looking at the connection between adherence and the risk of resistance for specific classes of drugs have either been small or had a short period of follow-up.

Therefore investigators from the US CPCRA FIRST 058 study conducted a prospective analysis involving over 900 patients starting antiretroviral therapy for the first time. The patients had several years of follow-up data available for analysis.

A total of 457 individuals who started a regimen including a protease inhibitor, and 446 patients who started treatment that included a non-nucleoside reverse transcriptase inhibitor (NNRTI), were included in the study. Both groups of patients also took two nucleoside reverse transcriptase inhibitors (NRTIs).

Recruitment to the study was conducted between 1999 and 2002. This meant that many patients took drugs that are no longer recommended for first-line use. In particular, almost two-thirds of patients taking a protease inhibitor were taking nelfinavir (Viracept), and although 21% took a ritonavir-boosted protease inhibitor, most (13%) were treated with ritonavir-boosted indinavir (Crixivan). The most commonly used NNRTI was efavirenz (Sustiva), a drug which remains the cornerstone of initial antiretroviral regimens.

Of the patients taking a protease inhibitor, 71% experienced a rebound (above 1000 copies/ml) in their viral load a median of 1.2 years after starting treatment.

At the time of virological failure, 8% of these patients had resistance to a protease inhibitor and 26% had resistance to an NRTI. Two-class resistance was present in 9% of individuals.

Viral load rebounded in 59% of those taking an NNRTI, and this occurred within a median of three years of starting treatment. A quarter of these patients had resistance to NNRTIs and 14% had NRTI resistance. Resistance to both NNRTIs and NRTIs was found in 11% of patients.

No association was found between adherence and the development of resistance to protease inhibitors.

However, for patients taking an NNRTI, each 10% reduction in adherence levels was association with a 20% increase in the risk of resistance (HR = 1.2; 95% CI, 1.1 – 1.3).

Further statistical analysis that controlled for potentially confounding factors confirmed that adherence levels were not associated with the development of resistance to protease inhibitors.

For patients taking an NNRTI, however, good, but imperfect adherence between 80-99% was associated with a 130% increase in the risk of resistance (HR = 2.3; 95% CI, 1.4-3.7). The risk of resistance was even higher at adherence of 79% and below (HR = 6.5; 95% CI, 3.9-10.7).

Regardless of whether treatment was based on a protease inhibitor or an NNRTI, lower levels of adherence were associated with resistance to NRTIs. The risk of resistance to this class of drugs was especially associated with adherence between 80-99%.

“The data presented here represent one of the largest studies with the longest duration of follow-up to assess class-specific adherence-resistance relationships”, write the investigators.

They note, “no association between cumulative adherence and protease inhibitor resistance was found.” However, “for NNRTIs and NRTIs, we found a significant association between lower levels of cumulative adherence and resistance at initial virological failure.”

The researchers conclude, “in a population initiating antiretroviral therapy, the higher the level of cumulative adherence, the better the outcomes. Excellent adherence and full virological suppression remain the goal of antiretroviral therapy.”

“The message to HIV-infected individuals should be clear”, write the investigators, “complete virological suppression remains the goal of antiretroviral therapy. The best way to achieve complete virological suppression is to optimize adherence to all components of multidrug antiretroviral therapy.”

However, the investigators believe that their findings could “help provide the foundation for rational design of medication combinations and regimen sequencing to improve the longevity of currently available therapies in the era of HIV as a chronic illness.”