Tenofovir, Lamivudine and Zidovudine Combination Therapy Results in Surprisingly Low Rate of Treatment Failure

In a retrospective study, published in the current issue of AIDS (January 3, 2005), German and Spanish researchers suggest that the triple combination of the nucleoside analogues zidovudine (AZT; Retrovir) plus lamivudine (as Combivir) with the nucleotide analogue tenofovir (Viread) results in a low rate of treatment failure.

In theory, the combination of three nucleoside reverse transcriptase inhibitors (NRTI) seems to be a promising strategy with respect to a low pill burden, a low potential for drug interactions, and the option of sparing other antiretroviral classes for later regimens.

However, triple NRTI regimens combining tenofovir (Viread), lamivudine (3TC; Epivir) and abacavir (Ziagen) or didanosine (ddI; Videx) have recently shown unexpectedly high rates of virological failure, raising serious concerns about this strategy.

Of note is the fact that high failure rates were observed not only in antiretroviral-naive patients (1, 2), but also in patients with long-term suppressed HIV-1 plasma viremia who changed their regimens for treatment simplification (3).

Virological failure was mostly associated with the emergence of the K65R mutation (associated with resistance to tenofovir, lamivudine, didanosine, abacavir) and the M184V/I mutation (lamivudine, didanosine, abacavir).

These findings suggested that the combination of tenofovir, lamivudine and abacavir or didanosine provides a low genetic barrier to resistance. In-vitro data and a retrospective analysis from a large outpatient cohort appear to support this hypothesis (4, 5)

In contrast, there is some evidence from the same studies suggesting that the inclusion of zidovudine (AZT; Retrovir) in tenofovir-containing regimens may be protective against virological failure and the selection of K65R. Clinical data on a triple NRTI regimen combining tenofovir, lamivudine and zidovudine have not been reported so far.

To evaluate this, researchers in Germany and Spain collected data retrospectively from all consecutive patients who were ever prescribed antiretroviral therapy consisting of tenofovir (245 mg once a day) and lamivudine plus zidovudine (150/300 mg twice a day co-formulated as Combivir) in each of the four participating HIV centers. In total, 40 patients were identified by computed database analysis and chart review.

All patients were pretreated at the time of switching to tenofovir, lamivudine and zidovudine, which was considered as the baseline. In 27 patients, the HIV-1-RNA level was undetectable (<50 copies/ml), whereas 13 patients had a detectable HIV-1-RNA level (range 11 200-398 000 copies/ml) at baseline.

At the time of the analysis all patients had completed at least 24 weeks after initiation of treatment.

At week 24, the HIV-1-RNA level was less than 50 copies/ml in 23 out of 27 patients who were switched with an undetectable HIV-1-RNA level, and in eight out of 13 patients with a detectable HIV-1-RNA level at baseline.

The median CD4 cell counts in both subgroups increased from 415 cells/μl (range 125-1232 cells/μl) to 595 cells/μl (range 128-1070 cells/μl, P = 0.014, Wilcoxon test) and from 354 cells/μl (range 21-766 cells/μl) to 407 cells/μl (5-615 cells/μl, P = 0.036, Wilcoxon test), respectively.

All patients who showed a virological failure on tenofovir, lamivudine and zidovudine were analyzed in more detail. Samples from all patients with detectable HIV-1-RNA levels before baseline or after week 24 were genotyped for resistance.

Two patients with a detectable HIV-1-RNA level at baseline who showed virological failure admitted to not having taken their medication regularly. The HIV-1 resistance genotype was available in seven patients with a detectable viral load at week 24.

All had an M184V mutation that was combined with the T215Y mutation in six out of seven patients (specific for zidovudine). Other mutations detected were M41L (n = 5), K70R (n = 3), D67N (n = 3), L210S (n = 1), and K219Q (n = 2) (all specific for zidovudine). The K65R mutation was only found in one patient who had a D67N mutation in addition.

Of note is the fact some of the pretreated patients who switched to tenofovir, lamivudine and zidovudine, while having a detectable plasma viremia, showed a sustained virological response despite the presence of zidovudine or lamivudine-associated mutations such as T215Y (n = 1) or M184V (n = 2) at baseline. No resistance mutation specific for tenofovir was present in these patients.

This observational cohort study of a heterogeneous patient population revealed an acceptable efficacy of a triple NRTI regimen combining tenofovir, lamivudine and zidovudine.

Although limited by retrospective design and small size, these results are encouraging compared with the worrisome results reported from other studies evaluating triple NRTI regimens containing tenofovir without zidovudine.

In patients with resistance mutations, so far only mutations with substantial activity against zidovudine/lamivudine (n = 5) or tenofovir (n = 1) were detected, but no combinations of mutations active against both agents were found.

These findings may support the observation that the common zidovudine mutations outlined above are disadvantageous for HIV-1 in vitro and in vivo when combined with the K65R mutation by rendering HIV-1 susceptible to zidovudine again [5].

The authors conclude, “Taken together, our preliminary data indicate that triple NRTI regimens including zidovudine and tenofovir may be more effective than other triple NRTI combinations, as reported previously. These data may warrant further controlled studies.”

01/14/05

Source
S Mauss and others. Low rate of treatment failure on antiretroviral therapy with tenofovir, lamivudine and zidovudine (Correspondence). AIDS 19(1): 101-102. January 3, 2005.

References
1. Gallant JE, Rodriguez AE, Weinberg W, Young B, Berger D, Lim ML, et al. Early non-response to tenofovir DF (TDF) + abacavir (ABC) and lamivudine (3TC) in a randomized trial compared to efavirenz (EFV) + ABC and 3TC: ESS30009 unplanned interim analysis. In: 43rd Interscience Conference on Microbial Agents and Chemotherapy. Chicago, 14-17 September 2003 [Abstract H-1722a].

2. Jemsek J, Hutcherson P, Harper E.; 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. In: 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, 8-11 February 2004 [Abstract 51].

3. Hoogewerf M, Regez RM, Schouten WE, Weigel HM, Frissen PH, Brinkman K. Change to abacavir-lamivudine-tenofovir combination treatment in patients with HIV-1 who had complete virological suppression. Lancet 2003; 362:1979-1980.

4. MacArthur RD, Crane LR, Alvarez D, Fairfax M, Richmond D, Curtis G. Factors associated with selection of the K65R mutation: a retrospective chart review. In: Program and Abstracts of the 2nd International AIDS Society Conference on Pathogenesis and Treatment. Paris, 13-16 July 2003 [Abstract 835].

5. Parikh U, Koontz D, Sluis-Cremer N, Hammond J, Bacheler L, Schinazi R, et al. K65R: a multinucleoside resistance mutation of increasing prevalence exhibits bi-directional phenotypic antagonism with TAM. In: 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, 8-11 February 2004 [Abstract 54].