Patients who start antiretroviral therapy with a combination based on a “boosted” protease inhibitor are less likely to develop drug-resistant HIV than patients who take therapy based on either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a non-boosted protease inhibitor, according to a large Canadian study published in the July 1st edition of the Journal of Infectious Diseases. The study also showed that the risk of resistance amongst patients starting anti-HIV treatment for the first time has fallen significantly in more recent years.
Another interesting finding of the study was that patients taking a combination of drugs based on a boosted protease inhibitor who had suboptimal adherence were less likely to develop resistance than patients who took treatment based on a non-boosted protease inhibitor or an NNRTI.
Although the most recent edition of the British HIV Association (BHIVA) HIV treatment guidelines recommend that patients starting antiretroviral therapy for the first time should take a regimen based on the NNRTI efavirenz (Sustiva), they note that a boosted protease inhibitor is likely to be preferable for patients with a risk of poor adherence given that treatment with this type of drug is less likely to lead to the emergence of resistance.
Treatment with anti-HIV drugs can mean significantly longer and healthier life for HIV-positive patients. But HIV can become resistant to the drugs used to treat it. A number of factors have been associated with an increased risk of resistance including poor treatment adherence, a high viral load when treatment is started, and a low CD4 cell count.
Researchers have also noted that the risk of resistance can differ between the different classes of anti-HIV drugs.
There have been significant improvements to HIV therapy since the first potent combinations of anti-HIV drugs first became available in the mid 1990s. A major innovation was the introduction of “boosted” protease inhibitors. These drugs have their potency increased by the addition of a small dose of ritonavir (Norvir), which is also a protease inhibitor. The use of ritonavir-boosted protease inhibitors has been associated with improved suppression of HIV and better clinical outcomes in both clinical trials and cohort studies.
Until now, there had been no information about the impact of different antiretroviral regimens – boosted protease inhibitor, non-boosted protease inhibitor, or NNRTI – on the development of resistance in a population-based study.
Therefore investigators in British Columbia, Canada, designed a study to determine the probability of developing drug resistance, in patients starting anti-HIV drugs for the first time between 1996 and 2004. They adjusted their results for adherence, baseline viral load and the type of drug on which a patient’s anti-HIV treatment combination was based. Preliminary results from this study, with shorter follow-up and a smaller population, were presented at the Thirteenth Conference on Retroviruses and Opportunistic Infections in 2006.
A total of 2350 patients were included in the study, and the median duration of follow-up was 4.8 years. A total of 42% of patients started treatment with a regimen that included non-boosted protease inhibitor, 20% initiated antiretroviral therapy with a boosted protease inhibitor, and the remaining 38% took a combination based on an NNRTI.
During the study 28% of patients developed resistance to at least one class of anti-HIV drugs.
The investigators’ analysis showed that the following factors were all significantly (p
Further analysis showed that there was no real difference between the probability of resistance developing in patients who took a non-boosted protease inhibitor or an NNRTI (odds ratio [OR] 1.09; 95% CI, 0.84 – 1.42). But the probability of resistance was significantly lower in patients treated with a boosted protease inhibitor (OR = 0.42; 95% CI, 0.28 – 0.62).
The association between adherence and resistance was then studied. Patients with sub-optimal adherence who started therapy between 1996–98 had the highest risk of resistance, and this declined until 2002-04. Furthermore, patients who had suboptimal adherence and baseline viral load above 100,000 copies/ml were particularly likely to develop resistance.
Particular attention was drawn by the investigators to a finding that patients treated with a boosted protease inhibitor with a baseline viral load above 100,000 copies/ml, and the worst level of adherence had a probability of resistance equal or lower to that of patients taking a non-boosted protease inhibitor with any level of adherence, and was similar to that seen amongst the NNRTI-treated patients with adherence around 80%.
Further statistical analysis was conducted focusing on patients with a viral load above 1000 copies/ml. This is because resistance tests are more reliable in patients with a viral load above this threshold. This analysis confirmed the investigators’ initial findings, as did an analysis which excluded patients with evidence of transmitted resistance.
“Our results demonstrate that the probability of emergent drug resistance decreased steadily during 1996 – 2004”, write the investigators. They add “incomplete adherence and nonboosted PI-based or NNRTI-based antiretroviral regimens were associated with a greater probability of the development of drug resistance. In contrast, PI-based regimens were significantly associated with a lower emergence of resistance, even after adjustment for plasma viral load and CD4 cell count.”
The investigators conclude, “our results demonstrate increased resilience to the development of drug resistance with modern boosted-PI based [antiretroviral therapy].”
Lima VD et al. Increased resilience to the development of drug-resistance with modern boosted protease inhibitor-based highly active antiretroviral therapy, J Infect Dis 198: 198:51–58, 2008.