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.

Kidney toxicity

Several case reports have described cases of kidney toxicity in patients taking tenofovir, including one report of kidney stones^{[1][2][3][4][5]}. The majority of cases have manifested as Fanconi syndrome, where 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. At least three studies have also found abnormal measures of kidney function indicating mild impairment, often without symptoms in patients taking the drug^[6][7][8].

Despite these isolated observations, most clinical studies of the drug have failed to find an elevated risk. For example, nearly 300 individuals exposed to tenofovir in the 903 Study, which was sponsored by tenofovir’s manufacturer, for over 144 weeks showed similar low levels of kidney toxicity to a group taking d4T^[9][10][11]. This was confirmed in a clinic-based study that confirmed the low incidence of renal toxicity among 322 people taking tenofovir. 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^[12]. Similarly, analysis of patients in Baltimore found that tenofovir use and a low CD4 cell count were the only factors linked to kidney damage in over 650 patients after almost a year^[13].

More recent real-world studies have confirmed that renal toxicity is rare, affecting only around 1 to 4% of patients^[14][15]. A number of studies have also failed to detect differences in the incidence of renal toxicity between patients taking treatment containing tenofovir and a nucleoside reverse transcriptase inhibitor (NRTI)^[16][17].

More detailed analyses have concluded that tenofovir-associated kidney toxicity is reversible and more common in people taking tenofovir who have pre-existing renal insufficiency or who are taking other drugs that can damage the kidneys^[18][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). Both the United States and European Union drug regulators recommend that individuals with creatinine levels greater than this should not commence tenofovir treatment, while those with creatinine clearance below 50ml/min should increase the dosing interval to 48 hours or longer. 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].

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 is 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 low muscle mass.

Indeed, Gilead issued a ‘Dear Health Care Professional’ letter in March 2006 reminding doctors of their recommendations for monitoring 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.

Other side-effects

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^[22].

Tenofovir appears to have much milder metabolic side-effects than d4T (stavudine, Zerit). In study 903, for example, triglyceride levels did not rise in people who took tenofovir for up to 144 weeks, and cholesterol levels rose by a significantly greater amount among people taking d4T compared to those taking tenofovir^[23]. Furthermore, switching from d4T to tenofovir has been shown to reduce blood lipid levels, particularly cholesterol levels^[24]. 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^[25].

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^[27].

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^[28].

Rash was observed in 7% of people taking tenofovir in the 907 study, compared with 1% in the placebo arm^[29]. One case of red, itchy rash has also been reported in a man co-infected with HIV and hepatitis B virus^[30].

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^[31]. 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^[32]. Fanconi syndrome can lead to bone disease due to a lack of resorption of substances such as calcium, which are essential for bone maintenance.

Low potassium levels in the blood have also been found in 40 patients taking tenofovir. Although rare, four of these patients died, although two thirds recovered after tenofovir was stopped^[33]. Further studies are needed to determine whether tenofovir caused the condition, which can cause muscle, heart and nervous system disorders.

Tenofovir is unlikely to cause liver damage, and this was not seen in a yearlong study involving 142 patients, 66 of whom had hepatitis C^[34].