Triple nucleoside combinations came under more scrutiny this week at the Eleventh Conference on Retroviruses and Opportunistic Infections, with still little consenus about why so many of these combinations are suboptimal. But the confusion has not prevented an ongoing trial of the experimental once-daily combination of AZT (zidovudine)/ 3TC (lamvudine)/ abacavir (Trizivir) with tenofovir (Viread) from continuing, despite only mediocre short-term results.
A review of data presented prior to this conference in this month’s AIDS Treatment Update concluded that several triple nucleoside combinations that included tenofovir should not be taken under any circumstance, and that Trizivir should only be used when alternative HAART is not possible. But why?
The researchers behind a study of tenofovir/ddI (didanosine, Videx / VidexEC)/3TC (lamivudine, Epivir), which was discontinued last June, felt that it was low potency that caused this combination to fail to achieve a viral load below 50 copies/ml in anyone on the trial.
Jemsek and colleagues reported on their 24-week pilot study to evaluate the potency and safety of a once-daily regimen of ddI 250mg, 3TC 300mg, and tenofovir 300mg in 22 treatment-naïve patients. Median viral load and CD4 count at baseline were 81,300 (range 2040 - 1,050,000) copies/ml and 133 (range 4 - 475) cells/mm3; 38% had a viral load above 100,000 copies/ml, and 58% had a CD4 cell count below 200 cells/mm3 at baseline.
Only two individuals actually completed the study, whereas 20 patients (91%) discontinued treatment early due to a suboptimal response. At week 12, only one person had a greater than 2 log10 reduction in viral load, whereas the other 21 had a median viral load of 80,000 copies/ml. Resistance testing (n = 20) showed the M184I/V mutation in all participants (100%), with ten of these (50%) also having the K65R mutation. Surprisingly, of the 19 participants who had phenotyping results available, all samples showed susceptibility to tenofovir, and five of ten patients with K65R showed reduced susceptibility to ddI.
The researchers concluded that since this was a once-daily regimen, it was potency that was the problem, but admitted under questioning from the audience that the dynamics were not fully understood.
However, the researchers behind the Tonus Study, which was the French version of the notorious ESS30009 trial – abacavir/lamivudine/tenofovir – felt that the reasons this particular combination failed was due to a “low genetic barrier to resistance”.
This pilot study of 38 antiretroviral-naïve participants received abacavir/3TC/tenofovir once daily for 12 months. At baseline, median CD4 cell count was 221 cells/mm3 (range 61 - 348) and median viral load was 79,400 log10 copies/ml (range 100 to 794,000). The trial was prematurely interrupted in June 2003 after the ESS30009 results were announced at the International AIDS Society meeting in Paris.
At week 24, 12/36 (33%) were classed a virological failures. All had baseline viral load above 100,000 copies/ml. Eleven of the twelve failures were found to have had adequate concentrations of all three study drugs at week 4, so it was surprising to find that eleven of twelve had both K65R and M184V mutations and one had the M184V mutation alone.
Of the two thirds who were not considered virological failures, 12/34 achieved a viral load below 50 copies/ml after 12 weeks, which increased to 17/26 at six months. However, baseline viral load was a very significant determinant of success: after twelve weeks, only 5/26 (19%) with a baseline viral load above 100,000 copies/ml achieved less than 50 copies, whereas 7/8 (88%) with a lower baseline viral load achieved less than 50 (p
Interestingly, 14 individuals had their intracellular metabolite concentrations of all drugs measured, and no major intracellular interaction between abacavir, 3TC and tenofovir was seen.
Given the previous presentations, the investigators behind the COL40263 trial – a pilot, open-label, multicentre study evaluating the efficacy and safety of once-daily Trizivir and tenofovir in antiretroviral naïve individuals with baseline viral loads greater than 30,000 copies/ml - were understandably nervous about the poor results of nucleoside regimens that included tenofovir, and so they provided interim results that suggested no lack of potency in this NNRTI- and PI-sparing combination.
The idea behind the study, which began enrolling in 2002, was that AZT could delay the appearance of the K65R mutation, which is associated with both abacavir and tenofovir resistance. This was based on an earlier study which saw the emergence of K65R in less than 2% in people on an abacavir combination that included AZT, compared to 10-40% without.
Analyses were performed on data from 88 out of 123 people currently enrolled in the study who had at least eight weeks of viral load measurements. At baseline, median viral load and CD4 cell count were 126,000 copies/ml and 226 cells/mm3, respectively. At week 24, 67% (36/54) achieved a viral load below 50 copies/ml. This percentage improved to 76% when a level of 400 copies/ml was used. When they compared these numbers to the ESS30009 study, the rate of virologic suppression seemed very favourable, particularly when looking at those with a baseline viral load above 100,000 copies/ml: 71% in their study versus 32% in ESS30009, and overall a 76% success rate versus 51%.
However, compared with the currently recommended initial regimens of efavirenz- or lopinavir/ritonavir (Kaletra)-based HAART (with a success rate of 75 - 90%), these results are still somewhat disappointing, especially in those with viral loads over 100,000 copies/ml. In fact, the researchers admitted that virological non-response appears to be associated with a baseline viral load over 100,000 copies/ml.
Nevertheless, they appeared to be right about AZT’s modulating effects – that even when dosed once-a-day, the resistance pattern to date included less K65R resistance (13% so far) and no-one with a single M184V mutation.
If there was a take-home message for people with HIV from these three confusing presentations, it was perhaps to avoid all NRTI-only HAART as first-line therapy if your baseline viral load is 100,000 copies/ml or above. The investigators, however, still have a long way to go before truly understanding why these combinations are problematic.
Further information on this website
More bad news on tenofovir/abacavir/3TC - news story
US treatment guidelines updated - news story
EMEA issues warning against use of abacavir/lamivudine/tenofovir - news story
Abacavir/3TC/tenofovir study stopped due to high failure rate - news story
Jemsek J et al. Poor Virologic Responses and Early Emergence of Resistance in Treatment Naive, HIV-infected Patients Receiving a Once Daily Triple Nucleoside Regimen of Didanosine, Lamivudine, and Tenofovir DF. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 51, 2004.
Landman R et al. Low Genetic Barrier to Resistance Is a Possible Cause of Early Virologic Failures in Once-Daily Regimen of Abacavir, Lamivudine, and Tenofovir: The Tonus Study. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francsico, abstract 52, 2004.
Elion R et al. COL40263: Resistance and Efficacy of Once-daily Trizivir and Tenofovir DF in Antiretroviral Naïve Subjects. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 53, 2004.