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Three Cohorts See No RNA Disadvantage With Abacavir/Lamivudine
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9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow
Mark Mascolini
US antiretroviral guideline writers moved abacavir/lamivudine (ABC/3TC) off its "preferred" list of nucleoside backbones [1], partly because of fears over cardiotoxicity with abacavir [2,3], and partly because an AIDS Clinical Trials Group (ACTG) study found a feebler response to ABC/3TC than to tenofovir/emtricitabine (TDF/FTC) in people starting their first regimen with a viral load above 100,000 copies [4]. But three cohort studies unveiled at the Glasgow meeting produced evidence countering the second part of that rationale. Using different outcome measures, the three groups found no major virologic response difference between these two nucleoside pairs, even in people with six-digit starting viral loads [5-7].
At the August International AIDS Conference, ACTG 5202 investigators reported that time to virologic failure was twice faster with ABC/3TC than with TDF/FTC when previously untreated people with a viral load above 100,000 began one of those nucleoside pairs as part of their first regimen [4].
German STAR Cohort investigators compared 24-week virologic response in 113 previously untreated people starting a combination containing ABC/3TC and 563 starting TDF/FTC [5]. Everyone in this analysis took lopinavir/ritonavir with their coformulated nucleosides. The two groups did not differ significantly in gender, age, or pretreatment CD4 count. Median starting viral load was significantly higher in people taking ABC/3TC than in those starting TDF/FTC (189,500 versus 125,500 copies, P = 0.01). Although a higher proportion of people taking ABC/3TC had a pretreatment load above 100,000 copies (68% versus 55%), that difference did not reach statistical significance.
Among cohort members starting therapy with more than 100,000 HIV RNA copies, the 24-week 50-copy response was statistically equivalent with the two regimens in a discontinuation-equals-failure analysis (57% with ABC/3TC and 51% with TDF/FTC). Nor did the on-treatment sub-50 rate differ significantly between the two regiments (57% and 54%). Response rates at 24 weeks were also statistically equivalent for people with fewer than 100,000 HIV RNA copies when starting, by either intent-to-treat or on-treatment reckoning. An analysis that factored in pretreatment viral load and CD4 count found an equivalent time to reaching a sub-50 load with ABC/3TC and TDF/FTC. CD4 gains were similar with the two regimens.
Clinicians in Manchester, UK compared 120 people starting ABC/3TC with 140 starting TDF/FTC [6]. About 56% in each group had no antiretroviral experience when they began one of these double-nuke medications, and about 80% took a nonnucleoside. Among previously untreated people, a substantially higher proportion starting TDF/FTC had a viral load above 100,000 copies (56% versus 18%).
A 48-week missing-data-excluded analysis for treatment-experienced people showed little difference in sub-50-copy rates between the two fixed-dose nucleoside pairs--96.3% with TDF/FTC and 93.0% with ABC/3TC. In a missing-data-equals failure analysis, TDF/FTC had a wider advantage over ABC/3TC, but one that still lacked statistical significance (86.7% versus 75.5%, P = 0.13).
Among people starting their first antiretroviral regimen, a missing-data-excluded analysis found similar 48-week sub-50 rates with the two double nucleosides. In a missing-data-equals-failure analysis of previously untreated people, significantly more starting TDF/FTC had a 48-week load under 50 copies (93.8% versus 76.1%, P = 0.002) because of high loss to follow-up in antiretroviral-naive people starting ABC/3TC: 11 of 53 people in this group (21%) stopped coming back for visits. The investigators counted 2 virologic failures with TDF/FTC in previously untreated people (4%), compared with 3 in the previously untreated ABC/3TC group (4%).
At London's Chelsea and Westminster Hospital, clinicians analyzed 6-month outcomes in 87 previously untreated people starting coformulated ABC/3TC or TDF/FTC with efavirenz (n = 53), nevirapine (n = 6), atazanavir/ritonavir (n = 9), lopinavir/ritonavir (n = 6), or some other protease inhibitor (n = 13) [7]. They split this group into three strata based on pretreatment viral load: above 100,000, 10,000 to 100,000, and below 10,000.
The investigators spelled out virologic responses for 33 people who started ABC/3TC and 53 who started TDF/FTC. Overall 6-month sub-50 rates were 91% with ABC/3TC and 83% with TDF/FTC. Respective sub-50 rates for people with more than 100,000 copies before treatment were 91% and 80%, for those with 10,000 to 100,000 copies 90% and 91%, and for those with fewer than 10,000 copies 91% and 83%. None of these differences reached statistical significance. Apparently these are on-treatment analyses since the investigators did not define an intent-to-treat approach.
Although results of uncontrolled studies like these can be confounded by variables the researchers do not anticipate or analyze, the findings indicate that ABC/3TC performed well in these clinics as first-line or later therapy, regardless of pretreatment viral load.
References
1. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. November 3, 2008 (http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf).
2. D:A:D Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study. Lancet. 2008;371:1417-1426.
3. The SMART/INSIGHT and the D:A:D Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS. 2008;22:F17-F24.
4. Sax P, Tierney C, Collier A, et al. ACTG 5202: shorter time to virologic failure with ABC/3TC than TDF/FTC in treatment-naive subjects with HIV RNA >100,000. XVII International AIDS Conference. August 3-8, 2008. Mexico City. Abstract THAB0303.
5. Wolf E, Trein A, Schmidt W, et al. Similar virologic response rates for ART-naive subjects starting KVX + LPV/4 or TVD + LPV/4: data from the prospective observational STAR cohort. 9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow. Abstract P7.
6. Eccleston KJ, Bambumba A, Babu CS, et al. Efficacy and safety of tenofovir/emtricitabine compared to abacavir/lamivudine in HIV-1 infected patients in clinical setting: the TEAL study. 9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow. Abstract P79.
7. Daniels RH, Gazzard BG, Holmes P, et al. Comparing the efficacy of Truvada and Kivexa combination therapy in HAART-naive individuals with different viral loads. 9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow. Abstract P14.
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