Risk of kidney problems similar for tenofovir and alternative drugs

Michael Carter
Published: 25 August 2009

Treatment with tenofovir does not involve a greater risk of kidney problems compared to alternative NRTI drugs, US investigators report in the online edition of AIDS. They found that regardless of whether a patient took tenofovir or an alterative drug as part of their initial antiretroviral therapy, there was a modest decline in kidney function, but that this soon stabilised. However, the research did show that taking tenofovir in combination with a ritonavir-boosted protease inhibitor could have an adverse effect on the health of the kidneys.

Tenofovir (Viread, also in the combination pills Truvada and Atripla) is one of the drugs recommended for first-line HIV treatment. It has a powerful anti-HIV effect, is easy to take, and is generally very safe.

The drug is excreted by the body using the kidneys. There was no evidence in the clinical trials which were conducted during the development of tenofovir that it caused kidney dysfunction. However, after the drug’s approval there were reports of kidney toxicity including acute tubular necrosis and Fanconi syndrome. Some observational studies have also found an association between treatment with tenofovir and kidney dysfunction, and there have been suggestions that the risk may be higher for patients who take the drug in combination with a ritonavir-boosted protease inhibitor.

Investigators from Johns Hopkins University in Baltimore looked at the kidney function of patients starting HIV treatment for the first time who took a combination of drugs that included either tenofovir or an alternative drug from the nucleoside reverse transcriptase inhibitor (NRTI) class.

Kidney function was monitored by testing estimated glomerular filtration rate. Tests were performed before patients started HIV treatment, and changes in kidney function were regularly checked during the first two years of antiretroviral therapy.

The study involved patients who started HIV treatment after 2002. A total of 201 individuals were treated with tenofovir and 231 with an alternative drug (57% AZT; 37% abacavir; 37% d4T; and 6% ddI). There were no baseline differences between these treatment groups.

Kidney function declined in all patients during the first six months of therapy, regardless of whether they were treated with tenofovir or an alternative NRTI. Moreover, there was no difference in the magnitude of the change in estimated glomerular filtration rate between the tenofovir and NRTI-treated patients. Kidney function then stabilised in both groups of patients during the next 18 months of HIV treatment.

Furthermore, similar proportions of patients taking these tenofovir and an alternative NRTI experienced a decline in their estimated glomerular filtration rate of 25% or 50% during the first two years of HIV treatment.

Statistical analysis showed that there was no significant difference in the risk of experiencing a 25% or 50% decline in kidney function between the tenofovir and NRTI-treated patients. This remained the case when the investigators controlled for baseline factors such as age, race, baseline kidney function, diabetes, high blood pressure or CD4 cell count.

The significant factors associated with declines in kidney function were age over 45 years (HR = 2.31; 95% CI: 1.44-3.69); a baseline CD4 cell count below 200 cells/mm3 (HR = 2.66; 95% CI: 1.65-4.29); high blood pressure (HR = 1.56; 95% CI: 1.00-2.45); and use of a ritonavir-boosted protease inhibitor (HR = 2.14; 95% CI: 1.37-3.34).

When the investigators looked at these results in greater detail, they noticed that patients taking tenofovir with a ritonavir-boosted protease inhibitor had greater declines in kidney function at six (p = 0.01) and 24 months (p = 0.008) than did those taking tenofovir with a non-nucleoside reverse transcriptase inhibitor (NNRTI). By contrast, patients taking an alternative NRTI with a boosted-protease inhibitor had similar kidney function to those taking an alternative NRTI with an NNRTI.

“We observed a modest initial decline in estimated glomerular filtration rate among antiretroviral-naïve patients starting both tenofovir and an alternative NRTI as part of their initial antiretroviral regimen, with no significant difference between the two groups”, comment the investigators.

They add, “these results emphasise the importance of always including a control group that receives an alternative NRTI when studying the effect of tenofovir on renal function, as the decline in renal function could have otherwise been attributed to tenofovir.”

However, the investigators note that patients who combined tenofovir with a ritonavir-boosted protease inhibitor had significantly poorer kidney function than those who took the drug with an NNRTI.

Levels of tenofovir are increased by up to 30% when combined with a ritonavir-boosted protease inhibitor, note the investigators, providing one possible explanation for this finding. Alternatively, the investigators suggest that ritonavir could block excretion of tenofovir.

The investigators conclude that their results “support the use of tenofovir as part of an initial antiretroviral regimen”. They suggest that kidney function should be closely monitored “in older patients, patients with hypertension, patients with baseline CD4 cell counts less than 200 cells/mm3, and when a ritonavir-boosted protease inhibitor is used.”

Reference

Gallant JE et al. Renal function with the use of tenofovir-containing initial antiretroviral regimen. AIDS 23 (online edition), 2009.

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