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.
To demonstrate TDF's efficacy in persons whose multidrug regimens did not completely control HIV replication, Robert Schooley, M.D., 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 300mg 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 300mg dose of TDF displayed a median 0.75 log copies/mL decrease; at week 32, that rate had been maintained. Subjects in the 150mg and 75mg 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 300mg TDF treatment arm at week 24. At week 32, those in the 150mg, 75mg, 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.
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).
At the 7th CROI, lead author Michael Miller, Ph.D., 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.
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.
Nicholas Cheonis is Associate Editor of BETA.
Miller, M.D. and others. HIV-1 RT mutations in patients after 24 weeks of tenofovir disoproxil fumarate (formerly PMPA prodrug) therapy added to stable background ART. 7th Conference on Retroviruses and Opportunistic Infections. San Francisco. January 30-February 2, 2000. Abstract 740A.
Schooley, R. and others. A double-blind, placebo-controlled study of tenofovir disoproxil fumarate (TDF) for the treatment of HIV infection. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco. September 26-29, 1999. LB19.
Van Rompay, Koen K.A. and others. Early short-term 9-[2-(R)-(phosphonomethoxy)propyl]adenine treatment favorably alters the subsequent disease course in simian immunodeficiency virus-infected newborn rhesus macaques. Journal of Virology 73(4): 2947-2955. April 1999.
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