In the setting of HIV infection, renal dysfunction is not uncommon. It usually develops in the setting of pre-existing renal disease (most accurately measured by the glomerular filtration rate, or GFR, rather than the serum creatinine), the co-administration of known nephrotoxic agents (such as non-steroidal anti-inflammatory agents or NSAIDs) or the presence of co-morbid conditions (such as hypertension, diabetes mellitus or active viral hepatitis, mostly hepatitis B and/or hepatitis C).

It is unclear whether the use of highly active antiretroviral therapy (HAART) may improve or worsen renal dysfunction and under what circumstances this might be significant. Dr. Marianne Harris of the British Columbia Center for Excellence was among the first to report cases of life-threatening renal dysfunction in patients who were taking tenofovir (TDF, Viread). She presented a comprehensive review of the renal effects of HIV therapy at IAS.

In general terms, Harris noted that the use of HAART reduces renal disease in several ways:

• by directly treating HIV-associated nephropathy,

• by improving an individual's general state of health, or

• by reducing the potential effects of co-morbid conditions (such as fungal infections or their treatments).

There are some exceptions, though. Indinavir (IDV, Crixivan) is known to promote nephrolithiasis and renal dysfunction. However, ensuring proper hydration and, failing this, the use of other effective agents can almost always circumvent this problem.

Tenofovir has also been implicated in the causation of renal disease, almost by association with its "ancestor" adefovir (Hepsera), which was removed from the market (at least in terms of the doses required to treat HIV infection) for this very reason.

We are first struck by the fact that in all the clinical trials that have been done (by the drug's manufacturer as well as by other sponsors) in over 2,400 patients, no difference in renal function was seen between patients who were receiving tenofovir and those in the control arms of the protocols. This extends to the recent 934 study (presented at this meeting), in which 255 drug-naive patients were exposed to tenofovir in combination with emtricitabine (FTC, Emtriva) and efavirenz (EFV, Sustiva, Stocrin) for 48 weeks.

However, in patients with extensive prior exposure to antiretroviral therapy who were receiving tenofovir through Canadian expanded access programs, Harris' group reported alarming increases in serum creatinine levels in 11/563 (2%) patients. In 9 cases where this was done, renal biopsies revealed acute tubular injury. Renal function returned to normal when tenofovir was discontinued. The same group did a retrospective analysis of patients receiving similar HAART regimens that included either abacavir (ABC, Ziagen) or tenofovir as the nucleoside/tide reverse transcriptase inhibitor -- all in the context of significant prior treatment -- and seems to have demonstrated an association of serum creatinine elevations with tenofovir use (RR = 2.86).

Further analysis showed that the risk is limited to individuals with a baseline GFR of less than 90 mL/min. The CHORUS database (n = 1625) further suggests that renal dysfunction in patients taking tenofovir may occur in the context of pre-existing renal disease or an abnormal baseline GFR.

In another study, a group from Johns Hopkins University, led by Joel Gallant, compared 344 individuals on tenofovir to 301 patients receiving other NRTIs. They were able to show (and publish¹) that in long-term follow-up, there was a 4% decrease in renal function in patients taking tenofovir. This was not felt to be clinically significant, however, and it neither required discontinuation of therapy nor warranted any additional monitoring of patients on therapy.

In the 934 study mentioned above, creatinine clearance decreased by 1.3 mL/min in those on tenofovir, compared to a slight increase (6.2 mL/min) in those on zidovudine/lamivudine (AZT/3TC, Combivir) and efavirenz. This seems to confirm the findings of Gallant that the effect of tenofovir on renal function in previously drug-naive patients with normal renal function is not of clinical significance, at least in the short term.

The group at Chelsea and Westminster Hospital, led by Brian Gazzard, demonstrated and published² that in over 4,000 patients on HAART there was a progressive improvement in renal function, with the most significant improvements seen in those on tenofovir. It appears that, for the most part, the beneficial effects of tenofovir (on the patient's clinical condition as well as on renal function) far outweigh any risk associated with its use.

However, it still remains that, from a mechanistic perspective, tenofovir does reduce GFR. It has been proposed that tenofovir would exert its nephrotoxic effects via interactions with ritonavir (RTV, Norvir) (which could impair the export of tenofovir from proximal renal tubular cells) or didanosine (ddI, Videx) (which could act with tenofovir to cause mitochondrial toxicity).

It is quite reassuring that other NRTIs (such as zidovudine [AZT, Retrovir], abacavir, lamivudine [3TC, Epivir] and emtricitabine), as well as all non-nucleoside reverse transcriptase inhibitors (NNRTIs) have not been linked in any way to renal toxicity.

So, how can we put all of this information together? First, it is important to remember that tenofovir is NOT adefovir. This is not a drug that is being removed from the market due to its nephrotoxicity. This being said, it is correct to say that it has been associated with proximal renal tubular dysfunction (a Fanconi-like syndrome) in as many as 20 cases reported in the literature. This is associated with hypophosphatemia and decreased GFR, but is largely reversible upon discontinuation of the drug.

In the vast majority of cases where elevations of serum creatinine have occurred in patients on tenofovir, another etiology has been identified. The vast majority of leading authorities (including the American AIDS Clinical Treatment Group) do NOT recommend additional monitoring of renal function in patients on tenofovir.

It is also important to remember that tenofovir is an important part of many of the simple, potent HAART regimens that are so effective today, and that seem to, on the whole, be associated with improvements in renal function. In patients with more advanced immune disease, on complex regimens and with other risk factors for renal disease, agents such as tenofovir and indinavir should be used with caution with careful prospective monitoring of GFR, perhaps more so in combinations including didanosine and/or ritonavir. Otherwise, the benefits of therapy far outweigh any possible risk to the kidneys.

Footnotes

1. Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis. April 15, 2005;40(8):1194-1198.

2. Jones R, Stebbing J, Nelson M, et al. Renal dysfunction with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy regimens is not observed more frequently: a cohort and case-control study. JAIDS. December 1, 2004;37(4):1489-1495.