In this 72-week randomized comparison of hematologic, metabolic, renal, and neurologic toxicities of the three most commonly used first-line ARV regimens worldwide, we demonstrated that short-term d4T use for 24 weeks before switching to AZT did not result in greater toxicities compared to the other two regimens. In contrast, after 24 weeks of treatment, d4T-treated patients had a significantly higher Hb level than that seen in the AZT arm, and had a larger CD4 count increase than that observed in both the AZT and TDF arms. These changes could be pertinent in settings where patients start ART with low CD4 counts, since the magnitude of CD4 count rise following treatment is associated with improved clinical outcomes in patients with low nadir CD4 counts [13
]. Our findings may have important implications for treatment programs in resource-limited settings where patients generally start treatment late and anemia is frequent. The benefit of this treatment strategy may even be greater for HIV-infected patients in malarious areas with high burden of anemia. As expected, we noted lower Hb levels in patients treated with AZT. More neuropathic signs were identified in patients treated with AZT compared to those on TDF; but, unexpectedly, the frequency of neuropathic signs was not greater for the d4T arm compared to the other arms. Virologic suppression did not differ among arms.
Our data concur with a meta-analysis of 6 prospective, randomized, comparative studies identifying a greater negative impact on hematologic parameters with AZT-based relative to d4T-based ARV regimens [14
]. The use of d4T is being phased out globally because of long-term risks of peripheral neuropathy and lipoatrophy. In our study, we did not observe an increased risk of d4T-related neuropathic signs or neuropathy. In fact, in both ITT and PP analyses a higher proportion of subjects in the AZT arm had abnormal neurologic examinations compared to either the d4T or TDF arms. This suggests that there is a low risk for neuropathy with short-term use of d4T in patients carefully screened to not have neuropathic signs or symptoms before initiation of the medication. Our ongoing study to quantify epidermal nerve fiver density before and after ART in this cohort may shed some light on why neuropathic signs were more common with AZT than with d4T.
After 24 weeks of treatment, clinical lipoatrophy was not seen in patients on d4T and the peripheral fat mass was similar across arms. However, treatment with 24 weeks of d4T is likely too short a duration to cause significant changes in fat. In the GS-903 and GS-934 studies, clinical lipodystrophy and peripheral fat mass loss were observed in patients treated with three years of d4T compared to those on TDF or AZT [15
]. Unexpectedly, we identified trends toward lower peripheral fat mass at week 72 in the d4T lead-in arm when compared to the AZT and TDF arms despite transition off d4T at 24 weeks. The peripheral fat mass loss in the d4T switched arm was small with differences in fat mass loss among arms being around 500g or less, which is not likely to be clinically relevant. The GS-903 study reported a 2.9 Kg difference in peripheral fat mass between d4T and TDF arms at three years. The lack of standardized DEXA criteria to diagnose lipodystrophy further limits our ability to identify the clinical impact of such findings [17
Similar to other reports, the increase in total cholesterol was less with TDF than observed with AZT or d4T [15
]. In contrast to the GS-903 study [15
], we saw a more favorable HDL cholesterol profile with d4T than TDF. The HDL cholesterol increase was also higher with d4T than with AZT in our study. Other studies have not identified differences in the HDL cholesterol profile when participants on d4T were compared to those on AZT [18
]. These findings need to be confirmed by larger studies.
AZT- and TDF-based first-line regimens are currently recommended in resource-limited settings including Thailand [1
]. We found TDF to be a safe and well tolerated drug. Some studies have reported an unexpectedly high early virologic failure rate of 25-43% with TDF plus 3TC or FTC plus NVP regimen [20
], especially in patients with high baseline plasma HIV RNA, but these findings were not found by others [22
]. Our study was not powered to compare virologic efficacy between treatment arms. Nevertheless, treatment failures were uncommon in all arms. We saw a small but non-significant decline in eGFR with TDF that is consistent with previous reports [15
]. Acute renal failure after TDF, particularly in patients with advanced HIV disease has been reported [6
]. It is possible that in such patients, short-term d4T could be used as the initial NRTI before switching to TDF to lessen such risk. Thus, with the expanded use of TDF in developing countries, regular and long-term monitoring of renal function is necessary.
Our study was designed and powered to test short-term outcomes associated with a d4T lead-in strategy so our ability to comment on less common toxicities, such as lactic acidosis, and hepatic steatosis, or those that occur after long-term ART is limited due to a small sample size and short duration of follow up. In addition, our patients who were mostly well, lacked neuropathic signs and had nadir CD4 counts close to 200 cells/mm3 may not represent the majority of patients in developing countries who because of advanced disease may be at greater risk for ARV-related toxicities. Nevertheless, we included equal proportions of female and male participants, which more closely reflects the patient population needing treatment in developing countries, and the prospective, systematic and detailed evaluation of ARV-related toxicities in subjects randomly assigned to one of three commonly used NRTIs strengthens the validity of our findings.
In summary, we demonstrated that initiating ART with d4T for 6 months before switching to AZT was safe among subjects without neuropathic signs, and resulted in greater initial CD4 count and Hb rise when compared to initiating treatment with AZT. TDF was also safe, and resulted in higher Hb and lower neuropathic signs than observed with AZT; however, its higher cost may limit its scale up in resource-limited settings. Our results provide important information which, if confirmed in a larger study, will be useful for the refinement and further development of existing global recommendations for initiating ART.