Resistance develops in 17% of patients starting HIV treatment in UK after eight years

Just over one-quarter of patients taking modern antiretroviral therapy experienced virological failure during a follow-up period of eight years, UK investigators report in the May 1^st edition of Clinical Infectious Diseases. Resistance to at least one class of anti-HIV drugs was detected in 17% of patients.

“When considered against the background of a likely lifelong need for antiretroviral therapy, these levels of resistance emergence are of some concern,” comment the investigators.

Taking antiretroviral treatment can significantly improve the health and life expectancy of patients with HIV. Such treatment is lifelong, and to obtain the most benefit from anti-HIV drugs it is necessary to maintain suppression of the virus. Increases in viral load can lead to the emergence of drug-resistant strains of HIV.

The long-term rate of resistance, and the extent to which this differs according to treatment combination, are crucial factors for understanding the long-term efficacy of HIV treatment.

As both are uncertain, UK investigators followed 7891 patients taking antiretroviral therapy, monitoring their viral load and testing those with viral breakthrough for resistance.

All the patients took antiretroviral therapy that consisted of two nucleoside reverse transcriptase inhibitors (NRTIs), plus either a ritonavir-boosted protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI).

Virological failure was defined as two consecutive viral load measurements above 400 copies/ml six months after starting treatment. Tests were performed for four types of resistance: TAMs, 1841V NRTI resistance, and resistance to protease inhibitors or NNRTIs.

The study included patients who had started antiretroviral therapy after 1997, and individuals were followed for eight years.

Most (82%) of patients started therapy with a regimen that included an NNRTI. Tests performed before the initiation of treatment showed that 4% of individuals had transmitted resistance to protease inhibitors or NNRTIs.

After eight years, 28% of patients had experienced virological failure, and 17% of patients had some form of drug-resistant virus.

However, the risk of resistance differed between classes of antiretrovirals. Treatment failure was significantly more likely to lead to resistance for patients taking an NNRTI than a boosted-protease inhibitor (p < 0.001). This finding remained unaltered when the investigators restricted their analysis to patients who were taking recommended NRTIs.

Older age (p < 0.001) and female sex (p = 0.004) were both associated with a lower risk of resistance.

By contrast, patients who started HIV treatment when their CD4 cell count was below 200 cells/mm³ had an increased risk of resistance compared to individuals who started treatment when their CD4 cell count was above the now-recommended treatment initiation threshold of 350 cells/mm³ (p < 0.001).

In addition, a higher viral load at the time HIV treatment was started was also associated with an increased risk of resistance. Individuals with a viral load above 100,000 copies/ml were significantly more likely to develop resistance than those with a viral load of 10,000 copies/ml or below (p = 0.03).

Patients who took efavirenz (Sustiva) were less likely to develop resistance (p < 0.001) than those taking nevirapine (Viramune).

The investigators then restricted their analysis to the 33% of patients who had had a genotypic resistance test before starting HIV treatment.

Resistance was detected in 11% of these patients. Virological failure occured in 22% of patients, and 14% developed resistance. Once again, the risk of resistance differed between drug classes, and was detected in 15% of those taking an NNRTI compared to 6% of individuals who received a boosted protease inhibitor (p = 0.009). Other significant risk factors were the same as those identified in the main analysis.

“In patients starting currently recommended first-line regimens in routine clinical practice, the rates of virological failure and of resistance detection are appreciable”, conclude the investigators, “the rates are lower for those who started combination antiretroviral therapy with a ritonavir-boosted protease inhibitor.”

An accompanying editorial praises the quality of the study, noting that it “provides an important description of ‘where we are now’”. However, the author suggests that the results should be interpreted with caveats, especially as many of the NRTI pairs taken by patients in the study are no longer used in routine HIV care.