A switch from protease inhibitor-based therapy to Trizivir in people with no history of monotherapy or dual therapy with nucleoside analogues appears to be just as effective as continued therapy with an existing PI or NNRTI-containing regimen, according to the results of the Trizal study published in the April 2003 edition of HIV Medicine.
Trizal is likely to provide further reassurance that the strategy is safe in terms of controlling viral load, leads to signficant reductions in total cholesterol and does not result in a higher failure rate due to abacavir hypersensitivity reactions.
Trizal was sponsored by GlaxoSmithKline, which is keen to promote a strategy of switching from more complex regimens to the compact, one tablet twice a day regimen of Trizivir (AZT/3TC/abacavir) after viral load is controlled on a multi-class regimen.
Trizal was an open label 48 week study conducted in nine European countries. The study evaluated the strategies of maintaining treatment with a PI-containing or NNRTI-containing regimen, or switching to Trizivir .
Participants had viral load below 400 copies and CD4 cell counts above 100 cells/mm3, and had received at least six months of antiretroviral treatment at the time of randomisation. 219 participants were enrolled, with a median CD4 cell count of 482 cells/mm3 in the group randomised to Trizivir, and 504 in the Continued therapy group.
The intent to treat analysis evaluated all patients who received at least one dose of study drug, with treatment failure classified as either viral load measurements above 400 copies/ml on two consecutive occasions or discontinuation of randomised treatment.
Equal proportions of patients in each group experienced treatment failure during the 48 week follow-up (22%). Ten per cent (n=11) of abacavir-treated patients experienced possible hypersensitivity reactions, and all but one patient discontinued abacavir treatment as a result. Other treatment-limiting adverse events were haematologic (2), gastrointestinal (1), malaise/fatigue (1) and hyperamylasemia (1). In contrast, the treatment limiting adverse events in patients who continued their existing therapy were: lipodystrophy (7), gastrointestinal (3), d4T-associated neuropathy (2), indinavir-associated renal colic (1), grade 4 neutropenia (1), depression (1), miscarriage (1).
A switch to Trizivir resulted in a significantly greater reduction in total cholesterol levels (-0.8mmol/L vs -0.44mmol/L, p
The investigators also evaluated the extent of body fat changes (lipodystrophy) in each group, and found that manifestations of lipodystrophy appeared to diminish in the Trizivir-treated group after 48 weeks, as well as being significantly lower than in the Continued treatment group. However, these findings, first presented amid considerable controversy at the Third International Workshop in Adverse Drug Reactions and Lipodystrophy in HIV Infection in Athens, 2001, highlight a number of issues about the reporting of lipodystrophy, and subsequent marketing claims made on the basis of such data.
The study methodology does not describe how fat wasting or fat alterations were measured, beyond noting `evaluated by clinician`. Given that Trizal was an open label study, an element of investigator bias where lipodystrophy was attributed to prior PI or NRTI treatment choices must be suspected in the absence of objective measures.
The lipodystrophy definition used in the Trizal study included dry skin, ingrown toe nails, body hair loss, loss of libido and erectile dysfunction, none of which would be classed as lipodystrophic according to the recent case definition published by Andrew Carr and colleagues in February.
The authors report that 40% of the switch group and 50% of the continued therapy group had at least one clinical symptom of lipodystrophy at baseline (non-significant difference). The proportion with at least one symptom fell from 40% to 28% in the switch group, and also fell from 50% to 42% in the continued therapy group (a significant difference, pTrizivir group too.
Adherence as assessed by 7-day adherence scores and a questionnaire about factors associated with adherence did not differ between the two arms, remaining above 98% in both arms throughout the study. The authors report that when assessed on eight unspecified items associated specifically with the regimen, Trizivir recipients showed significantly better adherence scores (p
Does Trizal support simplification to Trizivir-containing regimens?
Trizal did not show that the switch–maintenance approach to long-term HIV therapy, as it has been dubbed by GlaxoSmithKline, is superior to continuation of existing therapy. However, another larger study, EfaVIP, conducted in Spain, found that whilst abacavir-treated switchers had no greater likelihood of sustained viral load suppression than people who switched from PI-containing regimens to either efavirenz or nevirapine, fewer abacavir-treated patients discontinued treatment due to adverse events, and fewer had elevated cholesterol levels 48 weeks after switching.
The authors note that it is difficult to make comparisons between studies of switching therapy, because the populations have differed. Important differences include:
- Prior NRTI exposure: the Trizal study included very few people with prior NRTI exposure, in contrast to the study conducted by Milos Opravil and colleagues in Switzerland and Italy, which showed a trend towards a higher virologic failure rate in patients who simplified to Trizivir.
- The EfaVip study looked at switchers from PI-based therapy to a PI-sparing regimen, and had no continued therapy control arm
- The Trizal study evaluated switching from either NNRTI or PI, but was not large enough (nor designed) to show whether a difference in outcome existed between those who switched from a protease inhibitor and those who switched from an NNRTI.
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Reference
Katlama C, et al. TRIZAL study: switching from successful HAART to Trizivir (abacavir-lamivudine-zidovudine combination tablet): 48 weeks efficacy, safety and adherence results. HIV Medicine 4: 79-86, 2003.