Second major study shows rise in drug resistance is not increasing AIDS or death risk

Liz Highleyman
Published: 05 August 2004

The development of resistance to antiretroviral drugs does not increase the risk of HIV disease progression or death, according to an American study published in the July 23rd issue of AIDS. Moreover, continued use of highly active antiretroviral therapy (HAART) appears to provide ongoing benefit despite resistance.

The study is the second to be published this year demonstrating that the accumulation of drug resistance in the treated population of people with HIV has not yet translated into an increase in the rate of new AIDS cases or deaths.

Gregory Lucas and colleagues conducted an observational cohort study to evaluate the relationship between drug resistance and HIV disease progression and death. Examining the Johns Hopkins HIV Clinic medical records database, they identified 572 patients who had been treated with HAART including a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), and who had undergone genotypic resistance testing. Resistance testing is used to identify patients whose HIV is no longer susceptible to certain drugs, in the hope of finding a regimen that will still suppress the virus. Past research has shown that resistance testing confers a short-term virological benefit, but most such studies have followed subjects only for a short time.

In this study, patients who received genotypic resistance testing were more likely to be men who have sex with men and less likely to be injection drug users; use of resistance testing did not differ on the basis of sex or age. Of the patients analysed, 50% had 0-2 resistance mutations, 33% had 3-6 mutations, and 17% had 7 or more mutations.

As expected, the researchers found that prolonged use of HAART that does not completely suppress HIV replication was significantly associated with the development of drug resistance. Patients with more resistance mutations had started HAART earlier, been exposed to more antiretroviral drugs, and were more likely to have used nucleoside reverse transcriptase inhibitors (NRTIs) before combination therapy including PIs or NNRTIs. Patients with greater resistance had lower CD4 cell counts when initiating HAART; viral load levels when starting HAART were similar, but those with more resistance mutations had a higher average viral load in the period between HAART initiation and their first resistance test.

In a multivariate analysis, patients with a higher number of resistance mutations were significantly more likely to be male (p = 0.009) and less likely to be injection drug users (p = 0.018). Those who had previous exposure to all three drug classes available at the time (NRTIs, NNRTIs, and PIs) had significantly more resistance than those who had used one or two classes (p = 0.006). Longer duration of HAART use (more than two years) was significantly associated with greater resistance in patients with an average HIV RNA level above 5,000 copies/ml between HAART initiation and resistance testing (p < 0.001), but not in those with lower viral loads.

After undergoing resistance testing, 463 patients continued to use HAART, and about half of these (49%) were able to start at least one new drug. Patients with fewer resistance mutations were significantly more likely to achieve a viral load below 400 copies/ml: 35% in the 0-2 mutations group, 23% in the 3-6 mutations group, and just 11% of those with 7+ mutations (p < 0.001).

During a median follow-up of 15 months after resistance testing, 24% of patients experienced disease progression or died. At 24 months, 41% had developed new opportunistic infections (OIs) or died (the mortality rate was 9%). Interestingly, though, patients with 3-6 or 7+ resistance mutations were not at higher risk of disease progression or death than those with 0-2 mutations. “We found little evidence that the extent of drug resistance was associated with subsequent clinical outcomes, at least in moderate-term follow-up,” the authors wrote.

Looking at specific drugs, resistance to 3TC (lamivudine), NRTIs, PIs or NNRTIs was not significantly associated with new OIs or death. However, resistance to all three drug classes was linked to an increased risk of disease progression. HAART was strongly associated with reduced disease progression in patients with fewer than 200 CD4 cells, but not in those with less immune suppression.

Noting that their findings were “somewhat counterintuitive,” the researchers suggested two hypotheses to help explain why resistance did not appear to be associated with disease progression. First, when people continue to use HAART in the setting of continued HIV replication, poor adherence may lead to less resistance than excellent adherence. Second, resistant HIV may be less “fit” than wild-type (non-mutated) HIV, and thus less likely to cause disease progression. Another possibility is that longer follow-up may be required to detect differences in disease progression and death in patients with differing resistance profiles.

Reference

Lucas GM et al. Relationship between drug resistance and HIV-1 disease progression or death in patients undergoing resistance testing. AIDS 18: 1539-1548, 2004.

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