A substantial proportion of HIV-positive patients on antiretroviral therapy fail to achieve or maintain viral levels below the limit of detection, typically 50 copies/mL. Although it is generally recommended that these patients switch to a new antiretroviral regimen containing at least two drugs to which they are likely to respond, this runs the risk of the patient developing side effects associated with the new drugs. It may also exhaust the drug options available for future treatment combinations, or it may be impossible to find two new drugs for patients with substantial treatment experience.
"Our findings demonstrate a relatively slow rate of resistance evolution in patients with HIV-1 subtype B, especially among individuals with multiple mutations, who have stable HIV RNA levels below 1,000 copies/mL," the investigators conclude. "Delaying switching of suboptimal regimens may be indicated in some patients. However, patients with HIV-1, with limited resistance, especially those with plasma HIV RNA above 1,000 copies/mL, are at risk for emergence of increasingly resistant virus."
To gain a better understanding of the risk of developing antiretroviral drug resistance, investigators from the University of North Carolina enrolled 98 adult patients from their HIV clinic who had been on a stable antiretroviral regimen for at least six months but had detectable viral loads. All of the patients had two genotypic resistance tests, taken at least 30 days apart.
Most of the patients had substantial treatment experience, with a median of three prior regimens and six antiretroviral drugs. At the start of the study, the median CD4 count was 246 cells/mm3 and the viral load was 7,940 copies/mL, with 55% of the patients on a protease inhibitor (PI)-based drug regimen.
At the first genotypic test, 88% of the patients had at least one resistance mutation, with a median of three per patient. Resistance mutations were defined according to International AIDS Society-USA recommendations.2 After a median follow-up of 9.3 months, 60% of the patients had acquired at least one new mutation. CD4 counts had remained stable at a median of 242 cells/mm3 but viral loads had risen to 20,000 copies/mL (P = 0.02). The investigators calculated that the development of new mutations was equivalent to an average rate of 1.61 new mutations in every patient every year (95% confidence interval (CI) 1.36 - 1.90).
Despite the overall increase in the number of patients with at least one mutation, the proportion did not increase significantly for patients with PI or nucleoside reverse transcriptase inhibitor (NRTI) mutations. However, there was a significant increase in the proportion of patients with nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, from 57% to 86% (P < 0.001).
This was paralleled by the patients' predicted drug sensitivity over the course of the study. While the investigators found no significant differences in the predicted number of active PIs or NRTIs, among the patients receiving NNRTIs, the number of NNRTIs to which they remained susceptible decreased significantly (P = 0.046). According to the investigators, "because a single mutation may cause resistance to the NNRTIs, which also have a substantial degree of cross-resistance, patients were susceptible to fewer NNRTIs at follow-up, in contrast to baseline."
Using a multivariable analysis, the investigators calculated that the risk of a new mutation was associated with the average viral load across the study (P = 0.001), the rate of change of viral load (P < 0.001), and the number of mutations detected at the first resistance test (P < 0.001). However, they found no link between the risk of new mutations and CD4 count, viral load, sex, race, age, or the number of antiretroviral drugs or regimens previously received.
Specifically, they saw that patients with average viral loads between 1,000 copies/mL and 10,000 copies/mL were twice as likely to develop new mutations than those with higher or lower average viral loads. "Occurrence of new mutations is a function of replication rate, and at HIV RNA levels less than 1,000 copies/mL, ongoing continuous rounds of replication are likely to be low," the investigators explain. "Conversely, at higher replication rates new mutations are more likely to occur."
Patients with viral loads rising at a rate of 0.2 log10 per month were also at a 2-fold greater risk of new mutations than those with stable or falling viral loads. This, the investigators argue, is due to high replication rates allowing any drug-resistant virus particles to increase in number more rapidly.
Finally, having no mutations at the start of the study was also an independent risk factor for the risk of mutations developing, with these patients being at more than three times the risk of developing mutations than those with one to three mutations, and around twice as likely as those with more than three mutations. This could be due to the decreased fitness of HIV with multiple mutations, leading to lower replication rates.
Limitations of this study include the inability of the genotype tests used to detect mutations present in small numbers. The tests were also unable to detect resistance mutations for the fusion inhibitor enfuvirtide (ENF), which was being taken by two (2%) of the 98 patients.
"Further studies monitoring resistance evolution over time are needed, and combined analyses across observational cohorts would strengthen our initial observations," the investigators conclude.
Editor's Note: Reprinted with permission from www.aidsmap.com (first e-published September 5, 2005).