November 21, 2002
Gilead study 903 recruited over 600 patients to be randomly assigned to tenofovir (TDF, Viread)/3TC (lamivudine, Epivir)/efavirenz (EFV, Sustiva) and d4T (stavudine, Zerit) placebo or d4T/3TC/efavirenz and tenofovir placebo. The results of this study have been previously reported to have the highest rates of virological success of any clinical trial in HIV disease looking at HAART so far.
To recap, 87 percent of individuals in each arm, by the most strict analysis (i.e., intent-to-treat), had a viral load below 400 copies at 48 weeks. Eighty-two percent of patients in the tenofovir arm and 81 percent of patients in the d4T arm were undetectable by the 50-copy assay. CD4 count cell changes were similar in both arms. It is therefore difficult from this study to see any difference in efficacy between tenofovir and d4T when used in conjunction with 3TC, and efavirenz as regards virological or immunological efficacy.
However, it is important to remember that for effective and durable virological suppression, one must not only have powerful antiviral drugs, but also a regimen which is easy to comply with and which shows little long-term toxicity. In addition, in individuals who virologically fail a regimen, it is important to know the probability of sequencing to another effective regimen. Already presented is 903 toxicity data suggesting a reduction in potential mitochondrial-induced toxicity such as peripheral neuropathy and lipodystrophy and lower levels of cholesterol and triglycerides in the tenofovir arm.
The aim of this study was to describe the resistant mutations through to week 48 which occurred in both arms of the Gilead 903 study.
Of the 299 patients who were recruited to the tenofovir arm, and 301 to the d4T arm, 29 individuals who had received tenofovir were classified as virological failures and 25 who had received d4T. Patients underwent genotypic and phenotypic resistant testing. The results of the genotype tests are shown below:
|Development of Resistance Mutations Through Week 48 (ITT)|
|Number of Patients (percent)|
|Virological Failures||29 (9.7 percent)||25 (8.3 percent)||0.57|
|Any EFV-R:||161 (5.4 percent)||12 (4.0 percent)||0.44|
|EFV-R alone||52 (1.7 percent)||4 (1.3 percent)||0.75|
|EFV-R+ M184V/1||4 (1.3 percent)||6 (2.0 percent)||0.75|
|EFV-R+ K65R||2 (0.7 percent)||1 (0.3 percent)||0.62|
|EFV-R+ M184V/l +K65R||5 (1.7 percent)||1 (0.3 percent)||0.12|
|M184Vl alone||3 (1.0 percent)||1 (0.3 percent)||0.37|
|K65R alone||0 (0 percent)||0 (0 percent)||1.0|
|Wild type||103 (3.3 percent)||12 (4.0 percent)||0.82|
In individuals with virological failure on tenofovir, 24 percent developed the signature mutation to tenofovir (i.e., the K65R), while in the d4T arm, 8 percent developed K65R. No mention of thymidine analogue mutations were found in either arm. Interestingly, less than half the individuals virologically failing their regimen had the M184V mutation and only 50 percent had efavirenz-resistant mutations.
In individuals who developed the K65R mutation while on therapy, the VIRCO antivirogram suggested continuing susceptibility in all individuals to AZT/d4T and to some individuals continuing sensitivity to ddI (didanosine, Videx)/abacavir (ABC, Ziagen) and also tenofovir. In vitro phenotypic analysis revealed that the K65R mutation was associated with hypersensitivity to AZT/d4T, full sensitivity to abacavir if the M184V was not present and partial sensitivity if it was present. By virtual phenotype, five out of six individuals undergoing this test retained full sensitivity to tenofovir, three of whom also had the M184V mutation which is known in vitro to hypersensitize the virus to tenofovir.
The 903 study had remarkable results: high efficacy rates through to week 48 with less than 10 percent of patients in each arm undergoing virological failure. The high numbers of patients with wild type virus at the time of virological failure (35 percent in the tenofovir arm and 48 percent in the d4T arm) suggest that, in many cases, virological failure was not a true definition but may have been related to lack of adherence.
The evidence for poor compliance is increased with the low levels of non-nucleoside and 3TC resistance mutations in suggesting partial non-compliance within the regimen. Of the total number of patients entering the study on tenofovir, only 2.3 percent developed a K65R mutation, however, this was 24 percent of all patients who experienced virological failure.
Discounting patients with wild type virus who may well have been poor compliers suggests that the K65R mutation may occur at a relatively high level in patients failing tenofovir. This is a much higher rate than in previous studies and an easy explanation is not forthcoming. Whether the escaping virus within this regimen preferentially selects for the K65R mutation, may be one explanation that needs to be looked at further.
Interestingly, in individuals developing the K65R mutation who experienced virological failure, with a mean viral load decrease of 0.9 log from baseline, continued. By both virtual phenotype and true phenotype, patients with a K65R mutation were hypersensitive to AZT and d4T and had full or partial susceptibility to abacavir, and, in many cases -- based on the results of resistance test alone -- remained sensitive to tenofovir and ddI. Therefore it was not surprising that five of the seven patients experiencing failure with a K65R mutation, experienced virological success with a second regimen, two of which included tenofovir. Of the two patients who failed to respond to the second regimen, one was lost to follow up and one patient was known to be non-adherent.
The results of this study must not be taken out of context. In the Gilead 903 study, there were very few virological failures compared with any other study which has previously taken place, and clearly both regimens are highly effective. The study does suggest that tenofovir may select for the K65R mutation more readily than previously thought, and also it should not be discounted that no patient who experienced virological failure in the d4T arm selected thymidine mutations confirming a high barrier to resistance for d4T.
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