Three-NRTI regimens

Despite their lower potency, some experts have proposed that NRTI-only regimens might be strong enough for some individuals just starting therapy, especially those with a low pre-treatment viral load. Because NRTIs/NtRTIs are less expensive and require less expertise to manage drug interactions and short-term side-effects, NRTI-only regimens have been more commonly used in resource-limited settings .

Some early studies found that regimens consisting of three NRTIs could suppress viral load over the short term, and performed as well as two-class combinations containing an unboosted protease inhibitor.^{1 2} These promising short-term outcomes were attributed to the greater convenience and tolerability of NRTI-only regimens, leading to better adherence.

However, when studies categorised patients according to pre-treatment virus levels, those with a high viral load (above 100,000 copies/ml) were less likely to achieve viral suppression. Further, longer-term results showed that people taking NRTI-only regimens were more likely to experience eventual viral breakthrough.

The ACTG 5095 study, which included more than 1000 patients new to treatment, found that people who commenced treatment with AZT/3TC/abacavir – regardless of viral load – were more likely to experience treatment failure by week 48 (26%) than those who started on AZT/3TC/efavirenz (16%) or the four-drug combination of AZT/3TC/abacavir/efavirenz (13%).³ The triple-NRTI arm was prematurely discontinued due to the better responses in the other groups.

The ACTION study found that 62% of patients taking AZT/3TC/abacavir achieved a viral load below 50 copies/ml at 48 weeks, compared with 59% of those taking ATZ/3TC plus unboosted atazanavir. Yet while the response rate was similar in the atazanavir arm regardless of pre-treatment viral load, in the NRTI-only arm it fell to 39% for those with a baseline viral load above 100,000 copies/ml.⁴

Most NRTI-only trials have looked at AZT/3TC/abacavir, coformulated in the convenient Trizivir combination pill, but other studies have shown inferior results for d4T/ddI/3TC and d4T/ddI/abacavir compared with standard two-class HAART regimens. Regardless of efficacy, these regimens would not be favoured today due to the toxicity of the d4T/ddI combination.

On the other hand, in the African DART study, which included 300 patients with a CD4 cell count below 200 cells/mm³ and a median viral load approaching 300,000 copies/ml, a triple regimen consisting of AZT/3TC/tenofovir proved more promising. After 48 weeks, 61% of participants had a viral load below 50 copies/ml and the average CD4 cell increase was 127 cells/mm³. But 24% still had a viral load above 1000 copies/ml, and most of these patients developed resistance mutations.⁵

Triple-NRTI combinations that do not include AZT may be particularly problematic. In 2003, the European drug agency issued a warning against the use of tenofovir/3TC/abacavir as first-line therapy following poor results in the ESS30009 trial. Nearly half of patients taking this regimen did not achieve a substantial viral load decrease after twelve weeks, likely due to the rapid development of drug resistance.^{6 7} Similarly, in October 2003, Gilead warned against using tenofovir/3TC/ddI because of poor efficacy and increased risk of side-effects.⁸

Triple nucleoside analogue therapy is generally not recommended because of its inferior performance compared with regimens containing a protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or an agent from one of the newer drug classes.