Abstract I-666. Tenofovir 24 week Interim Analysis Phase III Trial in
Reported by Jules Levin
||Kathleen Squires reported on this data from study 907 in today's oral HIV
session, which has been previously presented. The study investigated the
efficacy and safety of Tenofovir (PMPA), which is taken 300 mg once per day.
Extensively treated patients were maintained on their regimen and added 300
mg once per day PMPA (n=552). These patients were compared to others who
stayed on their regimen and received PMPA placebo. Baseline HIV-RNA was about
4300 copies/ml, mean CD4 was 445, and patients had 5.5 mean years of prior
therapy. Patient discontinuation rate was about the same in both arms (6%).
Prior ART use: 48% NNRTIs, 58% PI, 94% NRTIs. The mean viral load reduction
for the patient group receiving PMPA was 0.6 log at week 24. This compared to
no viral load change for the patients who received PMPA placebo. I'm not sure
I recollect but I think patients were permitted to change their therapy
during the 24 week period. Nonetheless, the 0.6 log reduction achieved by
patients receiving PMPA occurred by week 4 after starting PMPA in this study.
At week 24, 42% receiving PMPA had <400 copies/ml compared to 13% for the
placebo group (ITT). 21% receiving PMPA had <50 copies/ml at week 24 compared
to 1% for the patients receiving PMPA placebo (ITT). CD4 count increase was
13 for PMPA group at week 24 compared to other patients who saw a decline of
11 CD4s. the number of adverse events were the same in both groups (25% for
PMPA patients vs 38% for placebo patients). So far, the side effect and
adverse event profile looks relatively good for PMPA compared to other drugs.
One concern that has been raised is in preclinical animal studies some bone
problems were seen when using doses that were much higher than that used in
humans. So far in 48 weeks or more of followup in human studies they have not
seen clinical evidence of any bone problems. The kidney toxicity seen with
adefovir, the sister drug to PMPA, has not been seen so far with PMPA.
Squires reported 2% of patients receiving PMPA had grade serum creatinine
(>0.5 mg/dL above baseline) compared to 1% for patients receiving PMPA
placebo. Both groups had 0% grades 2-4 (>2.1 mg/dL). Both groups had similar
serum phosphorus. 6% of PMPA patients had grade 1 elevations compared to 5%
for PMPA placebo patients (2.0-2.2 mg/dL). 6% receiving placebo had grade 2
serum phosphorus compared to 2% for placebo group (1.5-1.9 mg/dL). For grade
3 & 4 serum phosphorus both groups were also about the same 0%-<1%.
In abstract 1929, R. Schooley reported data from 100 weeks of PMPA in study
902 in which PMPA was added to stable ART. Patients with extensive prior HIV
treatment received PMPA or placebo for 48 weeks. After week 48 patients could
elect to receive open-label PMPA. Initially patients (n=189) received PMPA
placebo, or 1 of 3 doses of PMPA (75 mg, 150 mg, or 300 mg). At week 24 the
placebo patients received 300 mg PMPA. Patients receiving 75 or 150 mg
continued on those doses until week 48 where they could switch to 300 mg. At
week 24 patients receiving 300 mg since baseline had a -0.68 log reduction in
viral load. At week 48 patients receiving 300 mg since baseline had a -0.62
(n=43) mean decrease in viral load. Although it doesn't mention it in the
abstract I presume that at some point patients could change their treatment
regimen. Schooley reported a 100 week update. The program abstract says no
patients discontinued from study due to elevations in creatinine or
hypophosphatemia. The poster says no patients have developed treatment
emergent grade 3 or 4 hypophosphatemia. The poster reports that at week 24
the rate of grade 1 elevated serum creatinine was 0% in the 300 mg PMPA arm,
0% in the 75 mg arm, 4% in the placebo & 150 mg arms. And there were no grade
2-4 elevations in any arm. At week 100, 11% in the 75/300 mg arm had grade 1
serum creatinine elevations. 8% in the 150/300 mg arm had grade 1 elevations.
And 6% in the 300/300 arm had grade 1 elevations. No patients had grade 2-4
elevations. Schooley summed by saying there were no clinically significant
renal abnormalities observed.
The development of resistance mutations on PMPA therapy were reported in
poster 1929 and in poster 1928. It appears as though a low percent of
patients delevop additional NRTI or PMPA mutations on PMPA therapy. The K65R
is associated with PMPA resistance and reduced PMPA antiviral activity, and
3% were reported to develop this mutation on therapy. In poster 1928, Mike
Miller of Gilead Sciences concludes there was significant activity in study
907 against NRTI-resistant HIV through 24 weeks of therapy. There was reduced
activity in patients with the K65R or 3 or more thymidine analog mutations
inclusive of M41L or L210W. There appeared to be little development of
additional NRTI mutations and most patients appear to maintain PMPA antiviral
activity despite the development of mutations. Schooley reported there was no
evidence of novel resistance mutations associated with PMPA in study 902.
Patients who developed the K65R (2%) continued to have HIV-RNA suppression
(n=4, -0.52 log at week 48; at week 96, n=2, -0.67 log). Although preclinical
animal studies showed evidence of bone abnormalities when using higher PMPA
doses used in humans, so far in human studies problems have not been
observed. A more in-depth exploration of this question is part of an ongoing
study, results from this study are not available yet.