Side-effects

When it was first developed, there were fears that tenofovir (Viread) would cause serious kidney toxicity. In the case of adefovir (Hepsera), tenofovir’s sister compound, kidney toxicity became a problem during the first 48 weeks of treatment. However, throughout the development and testing of tenofovir, no cases of severe kidney toxicity were reported. Other side-effects of tenofovir treatment are less worrying, including nausea, diarrhoea and vomiting.

Several case reports have described cases of kidney toxicity in patients taking tenofovir, including a report of kidney stones.^{1 2 3 4 5} The majority of cases have manifested Fanconi syndrome, in which the small tubes in the kidneys that absorb electrolytes and minerals become damaged. In the context of antiretroviral therapy, this is thought to be a result of damage to mitochondria by tenofovir. Studies have consistently found that abnormal measures of kidney function indicating mild impairment, often without symptoms, are more frequent in patients taking the drug.^{6 7 8}

However, abnormal laboratory values (such as elevated creatinine levels, reduced creatinine clearance and reduced glomerular filtration rate (see Renal function tests in A to Z of tests) are not perfect indicators of clinical kidney damage. Many real-world clinical studies have confirmed that acute renal toxicity is rare, affecting only around 1 to 4% of patients.^{9 10} A number of studies have also failed to detect differences in the incidence of renal toxicity in patients on regimens using tenofovir versus a nucleoside reverse transcriptase inhibitor (NRTI).^11,12

One clinic-based study of 322 people taking tenofovir found that after six months, 7% had developed significant elevations in creatinine but most did not experience any symptoms of renal toxicity, and after one year, only 1% had stopped treatment due to kidney problems. In the same study, 3% of patients treated with abacavir also developed creatinine elevations that might be indicative of kidney damage.¹³ Other studies have found similar outcomes in treatment-experienced participants.^{14 8}

This is in contrast to a Canadian study of approximately 900 people with normal kidney function who started either tenofovir or abacavir (Ziagen), in which people who began tenofovir had more than twice the risk of creatinine elevation compared with those who started abacavir. Lower CD4 cell counts were also linked to increased risk of kidney toxicity. For every reduction in CD4 cell count of 100 cells/mm³, the risk of creatinine elevation increased 1.5 times.¹⁵

Studies have disagreed on whether tenofovir contributes to the risk of chronic kidney disease – defined as a persistent reduction in glomerular filtration rate (GFR) to less than 60 ml/min/1.73m² or presence of albumin in the urine. An analysis from the large EuroSIDA study found that people who take tenofovir appear more likely to develop chronic kidney disease. This prospective analysis, of 6843 EuroSIDA cohort participants followed for an average of about four years, found that people never exposed to tenofovir had an incidence rate of 0.7 per 100 person-years, whilst people with three or more years of exposure had an incidence rate of 2.4 per 100 person-years. Weaker associations were seen for indinavir (Crixivan), atazanavir (Reyataz) and (most weakly) lopinavir/ritonavir (Kaletra).¹⁶

Other studies have also found long-term declines in GFR in people treated with tenofovir.¹⁷ However, a large systematic review of 17 studies involving over 10,000 patients found that tenofovir was not associated with any increase in the risk of chronic kidney disease, or of end-stage kidney failure requiring long-term dialysis.¹⁸ This review did find that patients taking tenofovir had a small but significant increase in the risk of acute renal failure. Creatinine clearance and GFR were also generally poorer, but the review noted considerable differences between individual study findings.

More detailed analyses have concluded that tenofovir-associated kidney toxicity is more common in people who have pre-existing renal insufficiency or who are also taking other drugs that can damage the kidneys.^{14 19 20} Individuals who have been exposed to other drugs with proven toxicity to the kidneys, such as adefovir or amphotericin (Fungilin/Fungizone), may be at a higher risk of Fanconi syndrome, as may those with creatinine clearance below 50ml/min or baseline creatinine levels above 1.5mg/dl (132µM).

Combining tenofovir with the anti-HIV drugs ritonavir (Norvir), ritonavir-boosted lopinavir (Kaletra) atazanavir (Reyataz) or ddI (didanosine, Videx / VidexEC) may also be a risk factor for kidney damage.²¹

Reports have suggested that tenofovir-related kidney impairment is reversible, with renal function returning to normal soon after tenofovir therapy is stopped. However, an Australian study found that, in Australian men who discontinued tenofovir due to kidney toxicity as measured by impaired glomerular filtration rate (GFR), over 40% still had evidence of impaired kidney function 13 months after tenofovir was stopped. Acute changes in kidney function were less likely to lead to long-term problems than slow, gradual declines in renal function.²²

Although kidney damage is now regarded as a rare side-effect of tenofovir, anyone on tenofovir who begins to experience symptoms of extreme thirst, frequent urination, confusion, or muscular weakness should report these symptoms to their doctor immediately.

Experts have emphasised the importance of regular monitoring of blood levels of creatinine and electrolytes in patients receiving tenofovir. Current European guidelines suggest that this should be done every four weeks, or more frequently in those with kidney insufficiency. It is probably better to assess creatinine clearance rather than serum creatinine levels, since the latter may not reflect the adequacy of clearance in patients with more advanced disease and/or low muscle mass.

British and US treatment guidelines advise starting tenofovir use cautiously by first obtaining an estimated glomerular filtration rate and baseline urinalysis. Gilead issued a ‘Dear Health Care Professional’ letter in March 2006 reminding doctors of their recommendation to monitor kidney function in patients taking tenofovir. The letter states that kidney function should be tested before starting tenofovir, every four weeks during the first year, and every three months thereafter using creatinine clearance and serum phosphate measurements.

Side-effects commonly experienced by people taking tenofovir in combination with other antiretrovirals include nausea, vomiting, diarrhoea and flatulence, dizziness, and a decrease in the amount of phosphate in the blood.²³

Tenofovir appears to have much milder metabolic side-effects than d4T (stavudine, Zerit) . In study 903, over 144 weeks, triglyceride levels did not rise in people who took tenofovir and cholesterol levels rose by a significantly greater amount among people taking d4T compared to those taking tenofovir.²⁴ Furthermore, switching from d4T to tenofovir has been shown to reduce blood lipid levels, particularly cholesterol levels.²⁵ A safety analysis of tenofovir based on data from several studies found that most metabolic markers were not significantly affected by tenofovir after 24 weeks of treatment.²³

Tenofovir is less likely to be associated with mitochondrial toxicity than NRTIs.²⁶ For example, the uptake of tenofovir into polymerase gamma, the mitochondrial enzyme negatively affected by NRTIs, is 100-fold lower than the uptake of d4T. The rate of mitochondrial-related side-effects in study 903 after 144 weeks was 6% among people taking tenofovir compared to 28% among those taking d4T.²⁴

The risk of body fat changes associated with antiretroviral therapy may also be lower among people on tenofovir. Again, in a comparison with d4T, 3% of people taking tenofovir developed lipodystrophy compared with 19% of patients taking d4T.²⁴

Rash was observed in 7% of people taking tenofovir in the 907 study, compared with 1% in the placebo arm.²⁷ One case of red, itchy rash has also been reported in a man co-infected with HIV and hepatitis B virus.²⁸

Findings from animal studies have raised concerns about a possible deleterious effect of tenofovir on bone mineral density, which was confirmed in one clinical trial.²⁴ However, one study in patients taking tenofovir found no significant change in bone mass after 48 weeks by dual energy X-ray absorptiometry (DEXA) scan.⁴ Fanconi syndrome can lead to bone disease due to a lack of resorption of substances such as calcium, which are essential for bone maintenance.

Giving patients on tenofovir-containing regimens supplemental vitamin D helped reduce parathyroid hormone (PTH) levels, a hormone that can cause calcium loss from bones. Vitamin D is essential for bone metabolism. A study of over 1000 HIV-infected patients seen at King's College Hospital found insufficient levels in 91%. It is uncertain what the clinical significance of this finding is or whether vitamin D supplementation for patients taking tenofovir, or all patients with HIV infection, will reduce bone mineral loss; however, it seems to be a promising avenue for further investigation.^{29 30}

Low potassium levels in the blood have also been found in 40 patients taking tenofovir. Two-thirds of these patients recovered after tenofovir use was stopped, but four died.³¹ Further studies are needed to see if there is an association between tenofovir use and potassium deficiency, as the latter can result in muscle, heart, and nervous system disorders.

Tenofovir is unlikely to cause liver damage, and this idea was borne out by one year-long study of 142 patients on tenofovir, 66 of whom had hepatitis C.³²