The “primary” 90M mutation, which causes resistance to all protease inhibitors, is more likely to develop in people infected with HIV that already contains the naturally occurring “minor” mutations 36I or 10I/V, according to a study published in the June 1st edition of The Journal of Infectious Diseases. This supports calls for genotype testing prior to starting antiretroviral therapy in HIV-positive patients.
Genotype testing for mutations is recommended for patients experiencing treatment failure. However, there is little evidence on the need for genotyping HIV in patients who have not started antiretroviral therapy, since very few treatment-naïve patients have strains of the virus that already contain primary, resistance-causing mutations.
This study suggests that pre-HAART screening for the minor mutations that do not themselves cause resistance may assist in the choice of which anti-HIV drugs to prescribe. “Resistance tests performed before the initiation of the first protease inhibitor-containing regimens may help to identify those patients who may be more prone to virological failure because they are carrying a virus already harbouring certain mutations,” state the authors.
The investigators, from institutions in Italy and the United Kingdom, recruited 93 patients from the Italian Cohort Naïve Antiretrovirals study. The patients had started a treatment regimen containing one protease inhibitor and two NRTIs, but had subsequently experienced virological failure, defined as a viral load of over 500 copies/ml after more than 24 weeks of therapy. Plasma samples from before the initiation of therapy and between two weeks before and six weeks after treatment failure were tested for genotypic resistance in the HIV protease and reverse transcriptase genes.
At baseline, 18 (19%) of the patients had “wild-type” virus with no mutations. Sixty-eight (73%) had mutations in the protease gene, 3 (3%) in the reverse transcriptase gene, and 4 (4%) in both genes.
After virological failure, which occurred at a median of 40 weeks after initiation of HAART, 25 (27%) of the patients had no new mutations. Twelve (13%) had new mutations in the protease gene, 31 (33%) in the reverse transcriptase gene, and 25 (27%) in both genes.
The most common new mutation in the protease gene was 90M, which occurred in 13 (14%) of the patients. In the reverse transcriptase gene, the most common new mutation was 184V, which occurred in 42 (45%) of the patients, all of whom were taking lamivudine.
A multivariate logistic regression analysis revealed that there was a significant relationship between the risk of developing 90M and the presence of the mutations 36I (adjusted odds ratio [OR] = 13.5; p = 0.009) or 10I/V (adjusted OR = 9.1; p = 0.04) before initiation of HAART, after adjusting for baseline CD4 T-cell count and viral load, and the number of other mutations found. The other minor protease mutations analysed (63P and 77I) were not found to be associated with risk of developing 90M.
The development of 90M was also more frequent in patients with partial viral suppression of between 1.0 and 1.4 log10 copies/ml than those with more successful viral suppression, or very small decreases in viral load. This is consistent with observations that drug resistance is least likely to develop in patients with very low or high levels of antiretroviral drugs in the blood.
Since this study was carried out in patients who were mostly taking hard gel saquinavir as their protease inhibitor without ritonavir boosting, further work is required to determine how widely these findings apply. “Further clinical studies are warranted, to confirm this hypothesis and to verify whether it holds for some protease inhibitors more than others,” conclude the authors. “If so, the use of resistance testing in chronically infected, drug-naïve patients before initiation of therapy should become the rule.”
Further information on this website
Resistance - patient information booklet
Genotypic resistance tests – overview
Reference
Perno C F et al. Minor mutations in HIV protease at baseline and appearance of primary mutation 90M in patients for whom their first protease-inhibitor antiretroviral regimens failed. J Infect Dis 189: 1983-1987, 2004.