Treatment-experienced individuals who have one or two thymidine analogue-associated resistance mutations still experience a significant reduction in HIV viral load if treated with tenofovir disoproxil fumarate (tenofovir DF), according to a paper to be published in the March 1stJournal of Infectious Diseases, which is now available on-line.
Investigators from the manufacturers of tenofovir DF, a prodrug of the nucleotide analogue tenofovir, looked at the results of two placebo-controlled trials involving HIV-positive treatment-experienced individuals treated with tenofovir DF to assess the effects of phenotypic and genotypic resistance at baseline to treatment response.
The studies were the 907 study, a randomised double-blind, 48-week placebo- controlled trial involving individuals with an HIV viral load of between 400 copies/mL and 10,000 copies/mL who had tenofovir DF added to their existing HAART regimen. The other study included in the investigators' analysis was the 902 study, a phase II dose-ranging study of similar design. However, in this study patients were eligible for inclusion if their viral load was as high as 100,000 copies/mL.
Both studies also involved virology substudies involving genotypic and phenotypic resistance testing in selected individuals at baseline and week 48. Data from 332 individuals were available for the Gilead investigators’ analysis.
As expected of studies recruiting individuals with a persistent viral load despite on-going HAART, a high percentage of patients had nucleoside-associated mutations (71%, particularly the M184V mutation) and thymidine analogue-associated mutations (94%, conferring resistance to AZT and d4T).
Despite this high prevalence of baseline resistance, patients who added tenofovir DF to their existing HAART experienced a significant reduction in their HIV viral load compared to patients treated with a placebo (0.58 log10 reduction in the 902 study, p10 in the 907 study, p
In addition, patients with TAMs or the M184V mutation at baseline experienced statistically significant falls in baseline viral load after being treated with tenofovir DF. The mean number of TAMs in such patients was 2.8 and the reduction in viral load was 0.50 log10. However, patients without TAMs had a significantly greater reduction in viral load (0.80 log10). Further, individuals with the M184V mutation but no TAMs had the largest reduction in viral load (0.98 log10).
The investigators also noted that patients who had the K65R mutation at baseline did not have a significant fall in viral load despite the addition of tenofovir DF (fall in viral load 0.01 log10).
When the investigators analysed these data further, they noted that significantly reduced reductions in viral load were seen in patients with three or more TAMs relative to individuals with no TAMs. What’s more, the response to treatment differed according to the pattern of TAMs present. Patients with three or more TAMs including the M41L and L210W mutations had a reduction in viral load of only 0.21 log10, but in individuals with three or more TAMs who did not have these mutations, the reduction in viral load was 0.67 log10.
Multivariate analysis showed that along with the addition of tenofovir DF (p10, p=0.04).
Pheotypic testing showed that patients with a 1.4-fold reduced sensitivity to tenofovir DF had a significantly weaker reduction in viral load(0.47 log10 versus 0.77 log10 reduction for individuals with less than 1.4-fold reduced sensitivity).
The investigators conclude that "a specific genotypic pattern of [three or more] TAMs, including the M41L or L210W mutations, corresponds to a reduced response to tenofovir DF."
Further information on this website
Miller MD et al. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. JID 189 (on-line edition), 2004.