Tenofovir (Viread)

Tenofovir (Viread) is an antiviral drug that is approved for the treatment of HIV infection. It is able to reduce the amount of HIV in the blood, help prevent or reverse damage to the immune system and reduce the risk of AIDS-related illnesses. It is also an experimental treatment for hepatitis B[ix] [ix] [ix] [ix] [ix].

Tenofovir is made by Gilead Sciences Inc. and is marketed as Viread. During the early phase of development, tenofovir was known by the code-name GS 4331 and its chemical abbreviation bis(POC)PMPA or PMPA.

Tenofovir belongs to the nucleotide reverse transcriptase inhibitor (NtRTI) class of drugs. Like the nucleoside analogue reverse transcriptase inhibitors (NRTIs), NtRTIs inhibit an enzyme called reverse transcriptase, which is essential to the process of viral replication.

Tenofovir is also available in a fixed-dose combination tablet called Truvada. Truvada contains 300mg tenofovir and 200mg FTC (emtricitabine, Emtriva). It was approved in the United States in August 2004 and in the European Union in November 2004.

Tenofovir is also available in two triple-drug combination tablets Atripla, the first once-daily tablet containing a complete HIV treatment regimen, contains 600mg efavirenz, 200mg FTC, and 300mg tenofovir. It was approved in the United States in July 2006 and in late 2007 by the European Union. Eviplera is a fixed-dose tablet combining 25mg rilpivirine, 200mg FTC (emtricitabine), and 245mg tenofovir. It was licensed in the United States for use in HIV-positive adults in August 2011 and approved for use in the European Union in November 2011.

TAF as a replacement for tenofovir (TDF)

A new formulation of tenofovir, called tenofovir alafenamide (TAF), has been approved for use in combination with other antiretroviral drugs.

TAF is a prodrug of tenofovir disoproxil fumarate (TDF), the agent used in previous formulations. It is converted into active drug in the body and reaches higher concentrations in cells than TDF. As a result, a much smaller quantity of TAF is needed (25mg or 10mg).

TAF is now included in the following approved products:

  • Descovy (TAF/emtricitabine)
  • Genvoya (TAF/emtricitabine/elvitegravir/cobicistat)
  • Odefsey (TAF/rilpivirine)

There was no significant difference in virological or immunological response to TAF when compared to TDF in studies examining the use of either drug in combination with other antiretroviral agents.

Studies have shown consistently that people taking TAF had less kidney toxicity or bone loss than people taking TDF. It is unclear if these reductions in laboratory measurements of kidney function and bone density will translate into long-term reductions in kidney damage or fewer fractures.



Organ that removes waste products from the blood through urine.



A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.




Breakdown product of creatine phosphate in muscle, usually produced at a fairly constant rate by the body (depending on muscle mass). As a blood test, it is an important indicator of the health of the kidneys because it is an easily measured by-product of muscle metabolism that is excreted unchanged by the kidneys.


A single change in gene sequence. Some HIV mutations cause the virus to become resistant to certain antiretroviral (ARV) drugs.

Fewer people taking TAF discontinued treatment due to kidney injury than people taking TDF in two phase III studies, although the number of events was small (4 vs 0). The phase III studies of TAF in first-line treatment combined with elvitegravir and cobicistat also found a smaller reduction in bone mineral density in the first year after starting treatment in people taking TAF when compared to TDF.[ref]

People switched from TDF-containing regimens to TAF-containing regimens continued to maintain viral suppression at the same rate as people taking TDF-containing regimens in another 48-week phase III study, and showed modest improvements in kidney function and bone mineral density.[ref]


Tenofovir (Viread) is an effective antiviral agent that can reduce HIV viral load. As a first-line therapy in combination with other antiretrovirals (ARVs), tenofovir is equivalent to most nucleoside reverse transcriptase inhibitors (NRTIs). Despite the absence of long-term safety data, tenofovir is an attractive first-line option for HIV-positive patients.

In Study 903, over 600 people who had not previously used ART were randomised to receive tenofovir or d4T (stavudine; Zerit), plus 3TC (lamivudine, Epivir) and efavirenz (Sustiva). Intent-to-treat analysis showed that both arms had similar virological outcomes, with 76% of people in the tenofovir arm achieving viral load below 50 copies/ml as compared to 80% in the d4T arm. Equivalence was also demonstrated at weeks 96 and 144. At week 144, the mean increase in CD4 cell count was 263 cells/mm3 in the tenofovir arm and 283 cells/mm3 in the d4T arm.[ref]

Results from a study of treatment combinations containing tenofovir in treatment-experienced patients are also encouraging. After nine months’ follow-up, tenofovir was well tolerated with modest virological and immunological outcomes.[ref] This was supported by the findings of a cohort study based in two large United States clinics, showing efficacy of tenofovir-based treatment regimens in treatment-naive and highly experienced patients.[ref]

Several intensification studies have shown that adding tenofovir to an existing regimen can provide benefit in treatment-experienced people with detectable viral load. In Study 907, 550 treatment-experienced people with detectable viral load were randomised to add tenofovir or placebo to their treatment regimen.[ref]

In the tenofovir arm, 22% reached viral load below 50 copies/ml after 24 weeks, compared to 1% in the placebo group. After one year, the average viral load reduction was 0.57 log10 in the tenofovir arm. A similar study found that the addition of tenofovir to a failing regimen produced an average reduction in viral load of 0.62 log10. [ref] [ref]

Factors shown to be associated with an increased chance of virological failure in treatment-experienced patients taking combinations including tenofovir include advanced HIV disease, having a baseline viral load above 100,000 copies/ml, a CD4 cell count below 200 cells/mm3 and resistance to protease inhibitors, especially ritonavir-boosted lopinavir (Kaletra).[ref]

Tenofovir has also been investigated as a treatment to prevent HIV infection in people who are likely to be exposed to the virus, as pre-exposure prophylaxis (PrEP). While animal studies have shown promise, human studies have been difficult to carry out.[ref] [ref]

Tenofovir is also effective against hepatitis B. Use of tenofovir in HIV and hepatitis B co-infected people showed a significant drop in hepatitis B viral load and, in some cases, clearance of hepatitis B virus.[ref] [ref]

In also seems to be effective in people with hepatitis B virus that is resistant to 3TC.[ref] [ref] An analysis of a subset of patients enrolled in Study 903 showed that combination treatment with tenofovir and 3TC is more effective in treating hepatitis B virus than is 3TC alone.[ref] This was confirmed in another long-term study.[ref]

However, in July 2004, the United States Food and Drug Administration added a warning to tenofovir’s product label, stating that the drug’s safety for the treatment of HIV and hepatitis B co-infection has not yet been demonstrated. In contrast, the current guidelines of the British HIV Association continue to recommend tenofovir as a potential first-line treatment for co-infected patients, alongside 3TC.

A small observational study has suggested that tenofovir is eliminated from the body very slowly. Although it requires confirmation in a larger study, the investigators estimated that it takes around 7.5 days for half of the drug to be eliminated. This indicates a need for care when discontinuing the drug to avoid the risk of resistance while tenofovir levels fall. However, it may be reassuring for patients who have missed occasional doses of the drug, provided it is paired with other drugs with similarly slow rates of elimination, such as 3TC, FTC, and efavirenz.[ref]

Tenofovir reaches higher levels in the semen than in the blood, suggesting that it may have anti-HIV activity in the male genital tract.[ref]

Taking it

The standard dose of tenofovir (Viread) is one 200mg tablet once a day. Although taking tenofovir with food results in higher blood levels, this does not appear to affect the response to treatment. Labelling for tenofovir was amended in the United States in October 2003 to indicate that the drug does not have to be taken with food.

Patients who have difficulty taking tenofovir tablets can crush the pills and dissolve them in at least 100ml water, grape juice or orange juice.


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[ix][ix].

Kidney toxicity

Several case reports have described cases of kidney toxicity in patients taking tenofovir, including a report of kidney stones.[ref] [ref] [ref] [ref] [ref] The majority of cases have manifested Fanconi syndrome[ix], 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[ix] 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.[ref] [ref] [ref]

However, abnormal laboratory values (such as elevated creatinine[ix] levels, reduced creatinine clearance[ix] and reduced glomerular filtration rate[ix] 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.[ref] [ref] 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).[ref][ref]

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.[ref] Other studies have found similar outcomes in treatment-experienced participants.[ref] [ref]

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.[ref]

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[ix] 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).[ref]

Other studies have also found long-term declines in GFR in people treated with tenofovir.[ref] 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.[ref] 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.[ref] [ref] [ref] Individuals who have been exposed to other drugs with proven toxicity to the kidneys, such as adefovir [ix]or amphotericin [ix](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.[ref]

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.[ref]

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.

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.[ref]

Tenofovir appears to have much milder metabolic side-effects than d4T (stavudine, Zerit)[ix] [ix]. 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.[ref] Furthermore, switching from d4T to tenofovir has been shown to reduce blood lipid levels, particularly cholesterol levels.[ref] 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.[ref]

Tenofovir is less likely to be associated with mitochondrial toxicity than NRTIs.[ref] 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.[ref]

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.[ref]

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

Findings from animal studies have raised concerns about a possible deleterious effect of tenofovir on bone mineral density[ix], which was confirmed in one clinical trial.[ref] 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.[ref] Fanconi syndrome[ix] 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.[ref] [ref]

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.[ref] 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.[ref]


As with all other anti-HIV drugs, strains of HIV that are resistant to tenofovir (Viread) may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug[ix] [ix].

Tenofovir does not appear to select new resistance mutations in the vast majority of people who add the drug to a failing regimen. Genotypic analysis from the 907 study found that only 3% of the patients with detectable viral load had developed a K65R mutation, which has been associated with tenofovir resistance in test-tube studies.[ref] [ref] [ref] [ref]

The 902 and 907 studies, in which some participants have taken tenofovir for up to 48 weeks, showed that some resistance mutations in the reverse transcriptase gene did not undermine the activity of tenofovir, including D67N, K70R, T215Y/F and K219Q/E/N. However, the thymidine analogue mutations (TAMs) M41L and L210W did reduce the response to tenofovir in these studies.[ref]

Tenofovir is also active against virus with the ddI (didanosine, Videx / VidexEC) resistance mutation L74V and the ddC (zalcitabine, Hivid) resistance mutation T69D. In addition, laboratory studies suggest that virus which is resistant to NRTIs with the Q151M multidrug resistant mutation will still be sensitive to tenofovir. Multi-NRTI resistant virus with a T69S double insertion mutation may exhibit reduced susceptibility to tenofovir, although it may remain sensitive to tenofovir if the M184V mutation, which is associated with prior 3TC (lamivudine, Epivir) treatment, is also present.[ref] In general, the presence of the M184V mutation in the context of other drug resistance mutations seems to improve sensitivity to tenofovir.[ref]

This has led some researchers to suggest that it may be appropriate to maintain 3TC or abacavir (Ziagen) treatment in treatment-experienced people commencing tenofovir in order to preserve this mutation. Furthermore, tenofovir seems to have a high barrier to resistance as well as being effective against HIV with NRTI resistance, making it an attractive candidate for first- and second-line treatment.

Drug interactions

Tenofovir (Viread) has an important interaction with the nucleoside reverse transcriptase inhibitor ddI (didanosine, Videx / VidexEC), in three ways:

  • Combining the drugs results in increased exposure to ddI.[ref] This can lead to a greater risk of ddI-related side-effects such as lactic acidosis, pancreatitis and peripheral neuropathy, which have been fatal in some cases.[ref] [ref] [ref] [ref] Research suggests that reducing the once-daily dose of ddI from 400 to 250mg should result in acceptable exposure to ddI when taken with the standard dose of tenofovir daily, although there have been reports of lactic acidosis even with this reduced dose of ddI.[ref] [ref]
  • The combination of ddI and tenofovir has also been linked to falls in CD4 cell counts in treatment-experienced patients who switch to the drugs as well as patients who are taking tenofovir as part of their first treatment regimen.[ref] [ref] However, this may be prevented by using a lower dose of 250mg ddI in patients taking tenofovir.[ref]
  • The combination of ddI and tenofovir with nevirapine (Viramune) or efavirenz (Sustiva) may also be problematic due to a higher risk of virologic failure.[ref] [ref] [ref]

Gilead and ddI’s manufacturer Bristol-Myers Squibb issued ‘Dear Doctor’ letters in November 2004 and March 2005 warning healthcare providers not to prescribe tenofovir and ddI together unless absolutely necessary, because of the risks of side-effects and treatment failure.

When a patient is taking tenofovir as well as other medicines that are known to cause kidney toxicity, there may be an increased risk of kidney side-effects. If co-administration with drugs such as ganciclovir (Cymevene), foscarnet (Foscavir), pentamidine (Pentacarinat), amphotericin (Fungilin / Fungizone), vancomycin (Vancocin), interleukin-2, cidofovir (Vistide) or the aminoglycosides cannot be avoided, weekly monitoring of kidney function is recommended. ddI can also increase the risk of kidney toxicity, possibly through damaging the mitochondria in the kidney.[ref]

Tenofovir levels are also slightly increased when dosed with ritonavir-boosted lopinavir (Kaletra) or atazanavir (Reyataz). Although some studies have reported no negative effects of tenofovir on lopinavir concentrations in treatment-experienced patients, significant reductions in lopinavir and ritonavir minimum concentrations have been seen.[ref] [ref] Tenofovir also decreases atazanavir levels.[ref] When the two drugs are taken together, it is recommended that atazanavir be boosted with ritonavir (Norvir).


Tenofovir (Viread) is only approved for use in adults over 18 years of age[ix] [ix]. A small study of 18 children with substantial treatment experience found that tenofovir-containing antiretroviral treatment regimens brought about modest declines in viral loads and increases in CD4 cell counts. However, a third of the children needed to stop tenofovir after experiencing falls in bone density.[ref] This was seen in previous studies of infant monkeys.[ref]

In contrast, a small study of HIV-infected children switching from an effective d4T (stavudine, Zerit)-containing regimen to one containing tenofovir found no effect on the bone.[ref] Further studies are required to determine whether reduced bone density is related to the children’s state of health.


The safety of tenofovir (Viread) in pregnant women has not been demonstrated, but one study of tenofovir in pregnant monkeys found some evidence that infant size, weight, and bone porosity were reduced in infants exposed to tenofovir. Circulating levels of insulin-like growth factor were also significantly lower in the exposed infants.[ref]

An analysis of data submitted to the Antiretroviral Pregnancy Registry found no indication that tenofovir (Viread) use by HIV-positive pregnant women, either during the first trimester or later in pregnancy, was associated with an increased risk of birth defects. The registry collects reports from healthcare providers worldwide about adverse outcomes amongst infants born to women taking anti-HIV drugs during pregnancy. Tenofovir use was found in approximately 10% of the roughly 10,000 cases for which there was adequate outcomes information. The majority of women had asymptomatic HIV disease, but about 20% had serious immune deficiency.

In the US, the overall rate of birth defects is 2.7%, the same percentage that was found in infants exposed to antiretroviral drugs during gestation. Looking specifically at tenofovir, birth defects were found in 2.3% of infants exposed to any tenofovir-containing regimen during the first trimester and in 1.5% exposed during the second or third trimester. None of the five infants born to women who had used the fixed-dose combination of tenofovir, efavirenz, and emtricitabine (the three drugs in Atripla) had any abnormalities. Further, no congenital abnormalities were reported amongst women taking tenofovir who had induced abortions, miscarriages, or stillbirths, indicating that the drug did not cause problems leading to early pregnancy loss.[ref]

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