Treatment interruption in patients with multi-drug resistance virus may have the potential to drive out viruses with mutations that confer cross-class nucleoside analogue resistance, according to a report from French doctors, published in AIDS this week.
The group looked at 632 extensively treated patients in the Marseille area, and found that 29 individuals had genotypic evidence of multi-NRTI resistance in the form of five mutations known to confer cross-class resistance, or else amino acid insertions between codons 67 and 70 of the reverse transcriptase enzyme.
These mutations have been reported in around 4-5% of individuals receiving NRTI treatment, but do not always appear to be a consequence of extensive nucleoside analogue experience. Other groups have reported that such mutations may appear within the first two years of treatment.
The French group reported on the evolution of these mutations during treatment interruptions in four patients, three of whom had viral load above 200,000 copies at the time of treatment interruption.
Patient A had previously received AZT/ddC, then d4T/3TC, and then d4T/ddI/indinavir, and had viral load of 20,000 copies at the time of interruption, together with mutations or insertions at five positions associated with cross-class NRTI resistance. After a five month washout period, all reverse transcriptase codons reverted to wild-type, viral load had increased to 442,000 copies/ml and the CD4 count had fallen from 410 to 333 cells/mm3.
In the three patients with very high viral load at the time of treatment interruption, the strategy was less successful. Although insertion mutations disappeared in some cases, these re-appeared in one patient after NRTI treatment was resumed with ddI. Protease gene changes were less apparent during treatment interruption.
All three also experienced dangerous declines in their CD4 cell counts, from between 51-120 to between 7 and 23 cells/mm3. In one case, a treatment interrupter developed cerebral toxoplasmosis despite resuming prophylaxis, and the authors suggested that in patients with very advanced HIV disease, treatment interruptions may not be a suitable option, and continuation of failing treatment may be preferable until new drugs become available.
These findings are supported by the full report on treatment interruptions in the Frankfurt HIV cohort, also published this week in AIDS. The study has now documented treatment interruptions lasting longer than two months in 48 patients (45 had been exposed to all three drug classes and 42 had taken at least four NRTIs). Twenty-three had virus with greater than tenfold loss of susceptibility to each drug class.
Overall, significant reductions in resistance to AZT, 3TC, abacavir and all the protease inhibitors were noted, with a trend towards reduced ddI and ddC resistance (numbers were too small to determine if the trend was statistically significant). Only phenotypic resistance to d4T appeared unaffected.
Factors associated with a shift to wild-type virus were:
- CD4 cell count at time of treatment interruption (a lower CD4 count was associated with a higher risk of ongoing resistance)
- Duration of antiretroviral therapy (each year of antiretroviral therapy reduced the chances of a shift to wild type)
Viral load at the time of treatment interruption was not significantly associated with the chances of a shift to wild type.
Individuals who reverted to wild type also had a better response to subequent therapy (they were five times more likely to achieve viral load below 500 copies).
Reference
Miller V et al. Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure. AIDS 14: 2857-2867, 2000.
Yahi N et al. Evolution of HIV-1 multidrug-resistant genotypes during combination therapy and after the cessation of antiretroviral drugs. AIDS 14: 2943-2945, 2000.