Just half of a small cohort who commenced antiretroviral therapy for the first time with triple nucleoside/tide analogue combination of AZT/3TC (Combivir) with tenofovir (Viread) had an undectectable viral load after 18 months, according to the results of a small pilot, non-randomised, prospective study in the December 15th edition of the Journal of Acquired Immune Deficiency Syndrome. Although the French investigators argue that this combination appears to be more potent than other previously studied triple nucleoside/tide regimens, a high proportion of participants dropped out of the study, due to either the adverse effects of AZT or virological failure.
Shortly after the availability of tenofovir (Viread) in 2002, investigators from Hôpitaux Universitaires in Strasbourg, France initiated a prospective, open-label, single-site cohort study in order to assess the virologic and immunologic efficacy – as well as the safety and tolerability – of AZT (zidovudine, Retrovir), 3TC (lamivudine, Epivir) and tenofovir, dosed as Combivir twice daily and Viread once daily.
Despite reports emerging in 2003 that tenofovir/3TC in combination with abacavir (Ziagen) or ddI (didanosine, Videx/Videx EC) had a high rate of early virological failure the investigators note that “our preliminary results were encouraging and we decided to continue the enrolment of patients in our cohort study.”
A total of 129 patients began antiretroviral therapy at their clinic for the first time between April 2002 and March 2005. Of these, 51 (42 male and 9 female) mostly asymptomatic patients, with no contraindication to AZT or tenofovir use (based on baseline complete blood count, creatinine clearance, phosphate level, proteinuria, and lipid profile tests), volunteered to enter the pilot study.
At baseline, the median CD4 cell count was 230 cells/mm3 (range 23-425 cells/mm3), 20 (39%) had CD4 cell counts below 200 cells/mm3, median plasma viral load was 4.89 log (range 3.14 to >5.87 log), and 24 (47%) had a viral load greater than 5 logs.
The median age was 37 (range 22-73) years; 22 acquired HIV via sex between men; 16 through heterosexual sex; two via injecting drug use; and transmission route was unknown for eleven participants.
Median follow-up was twelve months (range one week to 38 months). During the study, 14 (27.5%) participants changed or stopped the study regimen. Nine were due to adverse effects; three due to virologic failure; one due to pregnancy; and one due to a structured treatment interruption. Another three participants were lost to follow-up. Consequently only 34 out of the original 51 (67%) participants remained on treatment throughout the study period.
Nevertheless, the investigators focus on their on-treatment analysis, which saw 89% (34/38) with a viral load below 50 copies/mL at month 6, 78% (21/27) at month 12, and 81% (13/16) after 18 months. The median CD4 cell count increase at month 18 was 142 cells/mm3. These results, they suggest, show that the regimen is efficacious.
However, intent-to-treat (missing = failure) results were a more realistic 72% (34/47), 56% (21/36) and 50% (13/25) having a viral load below 50 copies/mL at months 6, 12, and 18, respectively.
The investigators note that there was a rapid viral load decline on this combination – a median of -1.7 log (-0.54 to -2.48 log) at one to two weeks and -2.41 log (-1.23 to -3.4 log) at one month – and point out that the median time to reach a viral load below 50 copies/mL was three months (range, one week to six months) in the 38 participants who achieved an undetectable viral load on treatment, and that 86% (36/42) had a viral load below 1000 copies/mL at week 4.
Notably, however, five the six who did not reach a viral load below 1,000 copies/mL at week 4 had a baseline viral load greater than 5 logs. Although in the ITT analysis they found that “similar” proportions of participants with baseline viral loads above and below 5 logs had viral loads below 50 copies/ml at week 48 – 50% (8/16) and 60% (12 /20) respectively – and at week 72 – 54% (7/13) and 46% of (6/13), respectively – they note that “the small number of patients in each subgroup limits the power of the analysis”.
A total of 18% (9/51) of study participants experienced treatment-limiting adverse events. Four were due to GI intolerance to AZT within two weeks of starting treatment. A further two participants developed AZT-related anaemia within the first month, and another participant switched after 14 months due to AZT-related lipoatrophy. Another individual stopped all drugs due to rash, and there was one report of tenofovir-associated “mild” renal toxicity “without any decrease in creatinine clearance”. They note that one participant with “pre-existing moderate renal dysfunction...remained stable” taking tenofovir every other day “as directed by the creatinine clearance”.
In addition, a further 12% (6/51) experienced virologic failure, defined as two successive viral load results above 50 copies/ml after at least 24 weeks of treatment (three participants), or viral load level remaining above 50 copies/mL at 24 weeks (three participants). Three of the six switched to new combinations and all achieved an undetectable viral load on their second-line regimen; however three patients remained on the failing study regimen.
Surprisingly only 34 of the 51 participants underwent baseline genotype testing. One of the six virological failures had possible AZT-resistance due to TAMs at baseline; the investigators explain that, “the genotype result had been received after ARV was started.”
Of the remaining five virological failures, two had tenofovir’s signature K65R mutation (alone or associated with Y115F and M184V) and three had TAMs (two with M184V).
The investigators note that the “main limitations of our study are its conduct at a single site and the lack of a control group using a combination recommended by current guidelines.” Although they write that the study cohort patients were “similar to the whole cohort” at their clinic, they provide no results for comparison.
They suggest that their results are superior to AZT/3TC/tenofovir substudy of the DART trial from Uganda and Zimbabwe, and which found 55% had viral loads below 50 copies/mL at 48 weeks, and point out that a small pilot study in which participants switched to ZDV/3TC/tenofovir had also suggested that this combination was more potent than other triple nucleoside regimens. They also point out that compared with quadruple nucleoside/tide therapy (which also includes abacavir) combining AZT/3TC/tenofovir means “decreased cost and no potential for [abacavir] hypersensitivity”.
They conclude by stating that in this pilot non-randomised prospective study they found that AZT/3TC/tenofovir “induces a rapid and sustained HIV RNA decrease associated with a good immunologic response,” but note that although tenofovir was well tolerated “most adverse events were probably related to [AZT]. Despite recent recommendations not to use triple-NRTI drug combinations, the results of the current study suggest that this particular triple-NRTI combination needs to be evaluated further.”
Rey D et al. Virologic response of zidovudine, lamivudine, and tenofovir disoproxil fumarate combination in antiretroviral-naive HIV-1-infected patients. JAIDS 43 (5): 530-534, 2006.