Tenofovir associated with fewer side-effect related switches compared to AZT or d4T in first-line treatment
Nathan Geffen, Community Media Trust
Medecins Sans Frontieres (MSF) have published the results of an analysis of a Lesotho cohort, comparing toxicity and regimen substitutions due to tenofovir versus AZT and d4T (stavudine). 
The findings of this nurse-managed community cohort study support the latest WHO guidelines that recommend the replacement of d4T with either tenofovir or AZT. This study confirmed available evidence because it showed that tenofovir has lower side effect rates. This coupled with easier dosing makes it a better option than either d4T or AZT.
Between January 2008 and December 2008, 1,185 adult patients (785 women) were enrolled into care and the records of 1,124 were analysed. All patients were prescribed 3TC and either nevirapine or efavirenz. Their third drug was tenofovir, AZT or d4T (at 40 mg BID dose). This period was chosen because there was overlapping use of the three drugs during this period, as d4T was phased out and tenofovir was phased in.
Nearly all patients initiated on tenofovir were given baseline renal function tests. Patients with low creatinine clearance were not initiated on tenofovir. Therefore 13 patients with severe renal insufficiency (CrCl <30 mL/min) were excluded from the analysis to avoid bias. From HAART initiation the endpoints were death, loss to follow-up or first toxicity-driven switch. Median age was 39 years. The authors noted that proportionately fewer women were initiated on tenofovir than AZT or d4T (53.5% v 89% v 78% respectively) due to misconceptions among health workers that tenofovir should not be initiated in pregnant women.
The study included 587 patients started on tenofovir, 255 on AZT and 282 on d4T with a similar median time on treatment of 483 days (IQR: 392-585), 493 days (IQR: 349580) and 480 days (IQR: 277610) respectively.
The overall mortality rate for the cohort was 6.5 per 100 person-years [95%CI: 5.3 to 7.9 per 100 person-years]. For patients on tenofovir, the mortality rate was 5.1 per 100 person-years [95%CI: 3.8 to 7.0), for those on AZT, 7.5 per 100 person-years [95%CI: 5.0 to 11.1] and for those on d4T, 8.3 per 100 person-years [95%CI: 5.8 to11.7]. None of these differences were significant.
The overall rate of switches due to toxicity was 8.0 switches per 100 person-years [95%CI: 6.7 to 9.6]. Based on the regimen that patients were on, this rate of switch differed significantly; for tenofovir the switch-rate was 3.0 switches per 100 patient-years [95CI%: 2.0 to 4.5]; for AZT it was 8.1 switches per 100 patient-years [95CI%: 5.4 to 12.1] and for d4T it was 18.8 switches per 100 patient-years [95CI%: 14.8 to 24.1].
The most common reason for switching regimens amongst patients on tenofovir (n=19) was renal toxicity (18 patients). For AZT (n=15) it was severe anaemia (11 patients) and for d4T (n=42) it was severe neuropathy (29 patients). Also in the d4T group 11 patients switched because of lipodystrophy and two because of severe lactic acidosis.
Tenofovir-associated renal toxicity was low and generally well managed. Of the 5% who developed toxicity, the majority had a creatinine drop of less than 10 mL/min, and all but 3 returned to normal on a subsequent measurement.
The authors conclude that their study indicates that in resource poor settings where the detection of lactic acidosis and the monitoring of neuropathy and lipodystrophy are difficult, the use of tenofovir as the first-line option is advised.
This study confirms expectations and adds further evidence to support the changes in WHO guidelines as well as by South Africa and other African countries in recent years.
But this study also allays a concern that renal toxicity rates from tenofovir might be unmanageably high in an African setting. In the US kidney disease is four times higher amongst African Americans than Caucasians.  Tenofovirs good side-effect profile was based in large part on its use in non-African settings, though there is no evidence that tenofovir is associated with lower GFR amongst people of African descent in the US and Europe. The Lesotho study is reassuring because it confirms that the drugs association with few side-effects can be expected in African populations as well.
- Bygrave H et al. Implementing a tenofovir-based first-line regimen in rural Lesotho: clinical outcomes and toxicities after two years. J Acquir Immune Defic Syndr. 2011 Mar 1;56(3):e75-8. PMID: 21164354
- National Kidney Disease Education Program. African Americans and Kidney Disease Fact Sheet.