Recent news indicates that TDF, also known as bis-POC PMPA, may reduce
levels of HIV RNA circulating in the bloodstream by more than 80%, and
work effectively in persons who have displayed resistance to a wide
variety of other anti-HIV medications--particularly nucleoside analogs.
This highly active compound also appears to cause very few side effects
and can be taken once a day.
Preliminary Studies
Tenofovir DF is an oral prodrug of tenofovir, which first showed promise
in 1995 when it was reported that the drug, then known simply as PMPA,
was able to prevent simian immune deficiency virus (SIV, an animal model
for HIV) infection in macaque monkeys (see also "Research Notes" in
BETA, December 1995). In a subsequent Phase I/II trial using
the TDF formulation as monotherapy, human subjects showed viral load
reductions of up to 1.2 log copies/mL at a dose of 300 mg.
Clinical Trial Data
Further investigations have been designed to assess the nucleotide
analog in combination with other anti-HIV drugs. Extended interim results
of a double-blind, placebo-controlled Phase II clinical trial were presented
at the 7th Conference on Retroviruses and Opportunistic Infections (CROI),
held January 30-February 2, 2000, in San Francisco. (Twenty-four-week
results had been presented at the 39th Interscience Conference on Antimicrobial
Agents and Chemotherapy [ICAAC], held in September 1999 in San Francisco.)
Known as Study 902, this 48-week investigation enrolled 189 HIV positive
volunteers who were randomized to take one of three once-daily oral
doses of TDF (75 mg, 150 mg, or 300 mg) or placebo in addition to their
existing antiretroviral regimen.
To demonstrate TDF's efficacy in persons whose multidrug regimens did
not completely control HIV replication, Robert Schooley, MD, of the
University of Colorado Health Sciences Center and colleagues chose trial
subjects who had been taking highly active antiretroviral therapy (HAART)
for a mean of over four years without optimal viral suppression. These
extensively pretreated volunteers were required to be on a stable (unchanged)
regimen of no less than four anti-HIV medications for at least eight
weeks prior to trial entry while exhibiting detectable plasma HIV RNA
(ranging from 400 to 100,000 copies/mL).
The mean baseline CD4 cell count among participants was 369 cells/mm3
and the mean viral load was 3.7 log copies/mL. Genotypic analyses indicated
that over 90% of subjects had HIV isolates resistant to AZT (Retrovir),
3TC (Epivir), or both; 59% showed decreased susceptibility to at least
one protease inhibitor (PI); and 34% had resistance to at least one
non-nucleoside reverse transcriptase inhibitor (NNRTI).
As reported by Dr. Schooley at the 1999 ICAAC, treatment with TDF was
well tolerated at all three dose levels. Only 4.4% of the subjects taking
the drug discontinued treatment, compared with 7.4% of those taking
placebo. Serious adverse events were infrequent, and reported by only
four people (7%) in the 300 mg dose group compared with three people
(11%) in the placebo group.
The drug's attractiveness was further underscored by its ability to
reduce levels of HIV RNA in the trial subjects, all of whom were experiencing
viral breakthrough (insufficient viral suppression) on their existing
HAART regimens. Statistically significant viral load decreases were
detected in each dose group
At the 24-week interim follow-up, subjects receiving the 300 mg dose
of TDF displayed a median 0.75 log copies/mL decrease; at week 32, that
rate had been maintained. Subjects in the 150 mg and 75 mg dose arms
had viral load reductions of 0.40 log copies/mL and 0.45 log copies/mL,
respectively. Based on these encouraging results, all subjects taking
placebo were switched to the 300 mg TDF treatment arm at week 24. At
week 32, those in the 150 mg, 75 mg, and former placebo arms displayed
similar HIV RNA reductions (approximately 0.5 log copies/mL). Twelve
percent achieved an undetectable viral load based on ultrasensitive
tests (limit of detection 50 copies/mL).
It should be noted that none of the treatment arms showed changes in
CD4 cell counts at the ICAAC interim analysis; CD4 cell count levels
were not reported at the 7th CROI.
Benefits of Early Treatment
There is also evidence that short-term treatment with TDF during the
acute (early) stage of HIV infection may significantly delay the onset
of AIDS in a monkey model. A report in the April 1999 issue of the Journal
of Virology indicated that either 14 or 60 days' use of the drug
in ten newborn, SIV-infected macaques was able to impede disease progression
and boost immune responses without inducing drug-resistant viral strains.
All macaques treated with TDF remained healthy for at least six months
following the initiation of treatment at five days of age.
Since early events in both SIV and HIV infection appear to determine
the ultimate course of disease, results from this study suggest that
TDF may be able to suppress viremia during the initial stage of infection
and, if necessary, later on (due to the absence of drug-resistant mutants).
Resistance Profile
Tenofovir DF's powerful anti-HIV activity stems in part from its unique
resistance profile. While partial resistance to this nucleotide analog
(as well as to abacavir [Ziagen] and ddI [Videx]) has been associated
with the K65R mutation, TDF remains active against virus with the pivotal
nucleoside analog Q151M mutation. Moreover, resistance to TDF
appears to be reversed by the M184V mutation selected by 3TC.
At the 7th CROI, lead author Michael Miller, PhD, of Gilead Sciences
reported on the most recent genotypic resistance testing data available
(through week 24) for 121 of 189 participants (64%). Only three cases
of TDF-associated resistance (at codon 65) emerged, despite high-level
baseline resistance to antiretrovirals.
The K65R mutation may have been due, however, to the presence of abacavir
or ddI in these subjects' regimens. It could not be determined in this
blinded analysis whether these three persons were taking TDF; nevertheless,
none of them experienced HIV RNA rebound by week 24. Although 42 subjects
(35%) displayed new NRTI-related mutations, other resistance mutations
developed at low rates: 6% developed PI-related mutations and only 2%
developed an additional NNRTI mutation. Novel (new) reverse transcriptase
mutations were not detected in any of the 121 subjects. This drug is
therefore likely to confer benefits in persons whose virus does not
respond adequately to their current anti-HIV regimens.
Comparison
with Adefovir Dipivoxil
Like nucleoside analogs, nucleotide analog drugs interfere with reverse
transcriptase, the viral enzyme that normally allows HIV to translate
its genetic material (in the form of RNA) into DNA. The presence of
defective, synthetic nucleotides (the basic structural units of nucleic
acids, such as RNA and DNA) causes premature termination of the viral
DNA chain, thus preventing successful replication. Nucleotide analogs
are potentially more effective than their nucleoside cousins in a wider
range of cells because they are partially phosphorylated, or chemically
preactived with an extra phosphate group. As a result, they are incorporated
directly into a DNA chain more readily than nucleoside analogs, which
must undergo triple phosphorylation inside living cells to be rendered
active.
TDF has consistently shown more promise than the more widely known
drug in its class, adefovir dipivoxil, another Gilead drug that was
denied accelerated approval by the Food and Drug Administration (FDA)
on November 1, 1999 (see "News
Briefs," BETA, 1999 Year-End Special Edition). Adefovir had
been stymied in the research pipeline and was subsequently downgraded
by the FDA because of its nephrotoxicity, or damaging effect on kidney
cells. TDF does not appear to be nephrotoxic in studies to date, nor
does it deplete L-carnitine concentrations in the body like adefovir
(L-carnitine is an amino acid that plays a major role in fat metabolism).
Furthermore, adefovir--which is still under investigation to treat hepatitis
B virus (HBV) infection at a much lower dose--displays less potent antiretroviral
activity (e.g., viral load reductions of only 0.3-0.4 log copies/mL)
compared with TDF.
Future Outlook
Gilead Sciences, building on the encouraging data presented at the
39th ICAAC, launched a multinational, Phase III clinical trial in late
1999 to show that TDF's activity against multidrug-resistant HIV can
be sustained. Despite the fact that the drug will not become available
for at least another year, it is well worth watching the clinical progress
of this potential addition to the anti-HIV arsenal. For information
regarding enrollment in Gilead Sciences' Tenofovir Compassionate Access
Study, call 800-276-0231.
Nicholas Cheonis is Associate Editor of BETA.
Selected Sources
