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Tenofovir Resistance and its Role in Therapy
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Tenofovir (TDF) is also known as PMPA or its brand name Viread. It is different than NRTIs; it is a reverse transcriptase nucleoTide inhibitor. It is a new drug for HIV taken as one pill once daily, recently made available in the pharmacy (October 2001). It should be taken with food to maximize its potency. It has a long halflife (presence in the body before elimination), which is why it is taken once daily rather than twice daily. Before the Retrovirus Conference there was data from larger studies on TDF resistance and its use in patients with extensive NRTI resistance. New data was presented at the Conference on TDF resistance in NRTI-experienced patients, its potency in a brief 21-day study comparing it to a protease inhibitor & a 5 drug regimen, and a pilot study on its use for hepatitis B. TDF studies show it to be a potent and important treatment for at least 90% of patients with prior NRTI experience and resistance.
The study results discussed in detail below reported that only 11% of extensively pretreated patients had TDF resistance before starting the drug. This study found that when there were 1 to 4 NRTI-related mutations the response to TDF was equal; the response was reduced when the 210 or 41 NRTI mutation was also present. Resistance testing may be helpful in predicting response to TDF. Knowledge of the patients background therapy and treatment history can also be key in predicting response. Full resistance to TDF was defined as 3.8 fold phenotypic resistance. And these patients all had on average 3.6 TAMS mutations (NRTI-related, see below) with the M41L or the L210W. This data showed that the other 89% of patients had at least a 0.47 log reduction in viral load. 39% had a 0.47 log reduction and 50% of patients had a 0.77 viral load reduction.
Therefore, based on this data most patients with extensive NRTI resistance can expect at least a 0.5 log reduction in viral load, and 50% may achieve a viral load reduction of 0.80 log. Patients with the T69S insertion mutation, which is a mutation associated with resistance to multiple nucleosides, can occur infrequently and has been seen to be associated with TDF resistance. Infrequently the Q151M, another mutation associated with multiple nucleoside resistance, has been seen to be associated with TDF resistance.
Tenofivir Potency and Its Role in HIV Therapy
Researchers at the Aaron Diamond AIDS Research Center and Gilead Sciences reported on a study of 10 patients given the standard dose of TDF (300mg once daily) and confined to the inpatient unit at Rockefeller University for intensive bloodwork. Bloodwork was done at baseline, every 6 hours for the first 72 hours, once daily for days 4-10, and then on days 12, 14, and 21. They compared the slope of decline in HIV RNA to that of both ritonavir monotherapy (n=20) and a 5-drug regimen (Kaletra/TDF, EFV, 3TC; n=9) previously conducted in separate studies.
The average age of the patients was 34; 9 men, 6 African-Americans. Average viral load was 20,000 copies/ml (5,000-125,000), and Cd4 was 645 (340-1260). After 21 days the mean viral load reduction was 1.5 log (0.7-2.7 log range). The first phase decay is a measurement of the viral load decline during the first 7 days. Viral load slope of decline was measured on both days 0 and 7 and these declines were about the same as the mean 7-day decline. Results from previous studies suggest that the initial viral load reduction predicts the potency and antiviral effectiveness over the long-term. This has not been proven at least in part due to such vagaries as the changes in patient adherence and perhaps other vagaries or unidentified factors.
The mean first phase decline for TDF was 0.39 log per day (range 0.24-0.59), which compared to 0.34 for ritonavir and 0.99 for the 5-drug regimen from the prior studies. The study authors concluded that this data suggests that the antiviral effectiveness of TDF is equal to ritonavir, a potent PI.
TDF is a RT nucleotide inhibitor and its antiviral effectiveness appears to act differently than other NRTIs. Why is this? It has been suggested that the chemical distinction (and, perhaps, a clinical one as well) between tenofovir and NRTIs is in the phosphorylation process of tenofovir, . Compared with the other NRTIs which are really pro-drugs and require activation by intracellular phosphorylation, tenofovir is already activated
and thus may be effective in a wider range of body cells and tissues than the activated CD4 cells, where the nukes presumably act. This suggests that tenofovir may have the capacity to act potently against HIV in resting cells, but this benefit remains to be proven. TMC125 is a new NNRTI for NNRTI resistant patients which also appears to be potent, as reported from brief pilot studies presented at Retrovirus. It is speculated that this could be due to the ability of this drug to penetrate more effectively into HIV reservoir cells and tissues than currently available drugs.
These data raise the question of the role for TDF in HIV therapy. In large studies of extensive pretreated patients with NRTI resistance viral load is reduced by 0.6 log. The resistance data that will be discussed below and the data from the study above (as well as from early TDF monotherapy data) suggest the TDF viral load reduction is greater in patients with no prior HIV treatment. An ongoing study is comparing TDF to d4T in patients without prior experience in a regimen also consisting of efavirenz and 3TC. Although the final data is not yet available from this study, I expect that TDF will look at least as potently and safely as d4T.
In preclinical animal studies using doses of TDF much higher than that used in humans some bone abnormalities were seen but so far in 1-2 year studies there have been no abnormalities seen in human studies of HIV-infected patients. However, a large study is now ongoing looking intensively at this question and the results are not yet available. TDF is similar to adefovir whose development was discontinued in part due to kidney-related lab abnormalities and potential kidney toxicity. So far in 1 year studies these problems have not been observed in studies of TDF, but at ICAAC results from a 2-year study found slight grade 1-2 elevations in kidney-related lab abnormalities compared to the levels seen at 1 year. These changes may or may not be clinically relevant. But doctors and patients are encouraged to follow these lab evaluations for patients fairly closely, perhaps every few months.
Although the potential for TDF drug-drug interactions appear minimal, data from studies showed it increased ddI levels in blood, but added ddI side effects and toxicities were not seen. They did not explore TDF effect on ddI intracellularly. Intracellular levels may be related to NRTI toxicities. Since many HCV/HIV coinfected patients be taking ribavirin in combination with interferon for HCV, we need to explore potential interactions between TDF and ribavirin. Ribavirin has been shown to increase ddI levels in test tube studies. This creates a question around using ribavirin, TDF, and ddI in combination. It could increase DDI levels and related toxicities and may also have more potent antiviral activity against HIV.
There have been no studies yet showing the use of TDF as a substitute for a PI or NNRTI in first line regimen in patients without prior treatment experience. In speaking with several doctors they have told me they feel the convenience and apparent safety of TDF are adequate now for them to use TDF as a PI or NNRTI substitute in combination with 2 NRTIs for some patients. I presume they consider the initial tolerability of TDF and its convenience and ease of its which translates into perhaps improved adherence and quality of life. Research so far suggests resistance to TDF may develop slowly, but more data on this question is needed and hopefully will be available as we have more longterm experience using the drug.
Other doctors I have spoken with prefer to wait for more data on its use as a substitute for a PI or NNRTI in combination with 2 NRTIs for firstline therapy. They are considering this approach but prefer to wait for more data. Since TDF is effective for patients with extensive NRTI resistance, should it be saved for second and third line or perhaps salvage therapy? The good news emanating from this yearıs Retrovirus Conference is that there appears to be a number of new drugs (NNRTIs, protease inhibitors) and new classes of drugs for patients with resistant virus. So, one could speculate that if TDF were used in a firstline regimen with 2 NRTIs and if viral failure and resistance developed adequate therapies would perhaps be available. And getting patients who have difficulty adhering to adhere to their initial therapy by using a convenient and tolerable therapy is an approach that might be successful. However, what NRTI resistance will develop several years down the line after viral failure of a regimen containing TDF and 2 NRTIs? We donıt have an answer to that question yet.
Tenofovir Resistance
Michael Miller from Gilead Sciences reported in an oral presentation at the Retrovirus Conference (abstract 43) on TDF resistance from observations made in two large studies (902 and 907) in patients with extensive NRTI experience and resistance. This study looked at the genotypic resistance of a subset of 333 patients from these 2 studies of 535 patients, and at the phenotypic resistance in 204 patients; and evaluated the effect of preexisting NRTI resistance on the viral load response for patients from TDF. The average CD4 count in study 907 for all the 500 patients was 426, and the viral load was low (2,300 copies/ml). They had previously received about 5.4 years of previous HIV therapy. The 186 patients in 902 had an average CD4 count of 375, and also a low average viral load of 5,000 copies/ml. They had received 4.6 years of previous HIV therapy. When looking at 333 patients from the 2 studies, its clear they had extensive drug resistance: over 90% had at least one NRTI mutation, 70% had multiple NRTI mutations, over 60% had 3TC resistance, and about 60% had PI resistance; about 40% had NNRTI resistance; only about 2% had the K65R mutation which has been shown in the test tube to confer resistance to TDF. The NRTI mutations evaluated in this study were M41L, D67N, K70R, L210W, T215y/f, K219Q/E/N. These mutations have been associated with reduced viral load response to AZT and d4T and called TAMS (thymidine analogue mutations). These TAMS can confer cross-resistance to abacavir or ddI when the M184 3TC mutation is present; or perhaps resistance to abacavir from multiple NRTI mutations without 3TC can occur, this has not resolved yet.
Overall patients achieved a mean reduction in viral load of 0.6 log which was durable for the 48 weeks of the study. But Miller reported there were differences in response based on the type and amount of preexisting NRTI resistance. This information may be useful in selecting a regimen for a patient based on their previous NRTI experience and genotypic and phenotypic resistance profiles.
They used an ITT analysis for these data and the differences were statistically significant. When there were no TAMS detected patients had a viral load reduction of 0.8 log. No matter whether patients had 1, 2, 3, or 4 TAMS viral load reduction was the same, about 0.7 log. When there were 1 or 2 TAMS the viral load reduction was almost 0.7 log. Miller reported that patients with 3 or or more TAMS also had a 0.7 log reduction, when there was no M41L or L210W present. But when patients had 3 TAMS or more which included the M41L or the L210W the viral load reduction was significantly reduced to 0.25. So the L210W or the M41L mutation has to be present for TDF resistance significantly reducing viral load response.
In a further analysis, Miller reported that only 11% of patients in their study had these 3 TAMS (M41L, L210W, T215Y), and 7% had these 4 or more TAMS (M41L, D67N, L210W, T215Y). The L210W was always found with the T215Y (>98%) or the M41L (>94%). Miller said the when the L210W is present there should be 3 or more TAMS present including the M41L or the L210W. Miller concluded the presence of the L210W mutation is the strongest single marker of reduced responses.
Using the Virco Antivirogram test for phenotypic resistance, Miller reported that 4 or more fold resistance to TDF was associated with a 0.2 log reduction (n=19), concluding that about a 4.0 fold reduction in phenotypic resistance was associated with little viral load reduction and can be considered the clinical cutoff for phenotypic resistance with this test.
Patients with 1 or less fold reduced susceptibility to TDF (n=78) had a 0.8 log reduction in viral load. Patients with 1 to <3 fold reduced TDF susceptibility had a 0.6 log reduction (n=66). But patients with 3 to <4 fold TDF resistance had less viral load reduction, a 0.4 log reduction.
In trying to further refine the understanding of viral load response to TDF as it related to phenotypic resistance and to establish phenotypic cutoffs, Miller reported results on using an analysis called Recursive Partitioning. Using this technique, Miller found that patients achieved a 0.77 log viral load reduction if they had 1.4 fold or less resistance ; and 50% of the patients (n=102) had <1.4 baseline phenotypic resistance. For patients with 1.4 fold to <3.8 fold TDF resistance, viral load reduction was 0.47 (n=80); 39% of the patients had 1.4 to 3.8 fold resistance. And for patients with 3.8 or greater phenotypic resistance (n=22) the viral load reduction was 0.24 log, and only 11% of the patients had 3.8 or greater fold TDF resistance. The genotypic resistance of the patients with 3.8 or greater fold TDF resistance had a mean 3.6 TAMS .
Tenofovir For HBV
I two pilot studies of Tenofovir in HBV/HIV coinfected patients, TDF was very effective in reducing HBV viral load in patients with and without 3TC resistance. About a 5 log reduction was seen in HBV/HIV coinfected patients (5.38 log without 3TC resistance and about 4 to 4.5 log for patients with 3TC resistance. To read more details about these studies, see NATAP HBV Retrovirus Report:
www.natap.org/2002/9retro/day22.htm
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