Patients whose non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral regimen virologically fails are significantly more likely to develop drug resistant HIV than patients who experience virological failure after taking a regimen that contains a ritonavir-boosted protease inhibitor, according to study published in the September 10th edition of the Archives of Internal Medicine.
The investigators, from the Swiss HIV Cohort Study, also found that patients failing NNRTI-based regimens were significantly more likely than those who failed a boosted protease inhibitor to develop resistance to multiple anti-HIV drugs, including 3TC (lamivudine, Epivir), or FTC (emtricitabine, Emtriva).
Current anti-HIV treatment guidelines, such as those of the British HIV Association, recommend that first-line antiretroviral therapy should include two nucleoside reverse transcriptase inhibitors (NRTIs), plus an NNRTI, or a ritonavir-boosted protease inhibitor.
There is considerable variation between the drug classes in the number of mutations required for resistance to individual drugs or for cross-resistance to develop. However, the emergence of a single mutation is usually enough for cross-resistance to the existing NNRTIs, and this resistance usually emerges quickly one virological failure is experienced. By contrast, virological failure with a boosted protease inhibitor is associated with a lower risk of drug resistance emerging.
Few observational studies have assessed how these different genetic barriers to resistance drive the emergence of drug resistance and affect the success of first-line and subsequent antiretroviral regimens.
Therefore Swiss investigators examined the frequency and patterns of drug resistance in patients starting anti-HIV therapy which contained an NNRTI, a boosted protease inhibitor, or an unboosted protease inhibitor. Treatment with an unboosted protease inhibitor is no longer recommended because of the risk of resistance.
The study involved 1812 patients who started HIV treatment for the first time between 1999 and 2005.
A total of 177 patients experienced virological failure. This included 108 individuals taking an unboosted protease inhibitor, 24 taking a boosted protease inhibitor and 45 patients who started therapy with an NNRTI.
Resistance tests were performed on 142 patients. At least one resistance mutation was found in 84% of patients who took an unboosted protease inhibitor, in 30% of those who had virological failure on a boosted protease inhibitor, and in 66% of those experiencing viral breakthrough whilst taking an NNRTI. These differences were statistically significant (p
Patients taking an unboosted protease inhibitor or an NNRTI acquired a median of two resistance mutations compared to a median of zero mutations amongst patients taking a boosted protease inhibitor (p
Furthermore, patients taking either an unboosted protease inhibitor or an NNRTI were much more likely to develop multi-class resistance than patients taking a boosted protease inhibitor. When viral breakthrough occurred, patients taking an unboosted protease inhibitor or an NNRTI acquired resistance to a median of two classes of antiretroviral drugs compared to a median of zero classes for patients taking a boosted protease inhibitor (p
High-level resistance to 3TC or FTC was observed in 73% of patients experiencing failure with a protease inhibitor, 58% of those experiencing failure with an NNRTI, and 25% of those experiencing viral rebound on a boosted protease inhibitor. Once again, these differences were statistically significant (p
Further analysis showed, however, that patients taking an NNRTI were significantly less likely to experience side-effects (8 events per 100 person years, vs. 9 per 100 person years for patients taking an unboosted protease inhibitor and 11 per 100 person years for patients taking a boosted protease inhibitor, p = 0.03).
The rate of virological failure was highest for patients taking an unboosted protease inhibitor (10 per 100 person years), and broadly comparable for boosted protease inhibitors and NNRTIs (2.7 and 2.4 per 100 person years respectively).
When the investigators considered both virological failure and side-effects together, they found that the highest risk was in patients taking an unboosted protease inhibitor (19 events per 100 person years), followed by boosted protease inhibitors (14 per 100 person years), and NNRTIs (10 per 100 person years, p
The investigators then looked at subsequent virological failure in patients who stopped first-line therapy. Patients whose first regimen failed virologically were significantly more likely to experience virological failure with their second regimen (10 failures per 100 person years, vs. 2 per 100 person years, p
“We observed clinically relevant differences in the emergence of drug resistance for the three types of initial regimens”, write the investigators, “although combination antiretroviral therapy containing boosted PIs and NNRTIs appeared to be equivalent with regard to virological failure rate, significantly more resistance emerged in the NNRTI group at virological failure.”
They add, “thus our analysis demonstrates that PI-based regimens are superior to more tolerable NNRTI regimens when comparing the emergence of drug resistance in patients in whom therapy is failing.”
The investigators believe that their findings have importance clinical implications, and write, “given the risk of severely compromising future therapy options in case of virological failure while taking NNRTIs and the equivalent potency of boosted PI regimens, physicians should critically assess a patient’s ability to adhere to NNRTI-based regimens and to cope with the potential toxic effects, such as adverse effects on the central nervous system. If problems are expected, starting or changing to a protease inhibitor boosted by ritonavir represents a safer choice, since a protease inhibitor boosted by ritonavir tends to accumulate less resistance in case of virological failure.”
Von Wyl V et al. Emergence of HIV-1 drug resistance in previously untreated patients initiating combination antiretroviral treatment: a comparison of different regimen types. Arch Intern Med 167: 1782 – 1790, 2007.