Data from a large study into the safety of
anti-HIV drugs suggest that the antiretrovirals tenofovir (Viread, also in Truvada, Atripla and Eviplera), atazanavir (Reyataz) and
lopinavir/ritonavir (Kaletra) each have an independent association with a decline in
kidney function. The study is published in the online edition of the Journal of Infectious Diseases.
also suggest that kidney function improved after therapy with these drugs was
stopped. The authors of an editorial accompanying the study stress the
importance of monitoring the renal health of people treated with
anti-HIV drugs regularly and that physicians should keep an open mind about the potential causes of kidney problems.
Improvements in HIV treatment and care mean
that the prognosis of many people living with HIV is now approaching normal. Non-AIDS-related
diseases are an increasingly important cause of serious illness in people
with HIV, and one such cause is chronic kidney disease.
The exact reasons for the elevated rates of
renal dysfunction observed in people living with HIV are unclear. However, there
are accumulating data suggesting that certain antiretroviral drugs may have a
But the results of earlier research looking
at the incidence and risk factors of kidney dysfunction are limited because – for the most part – they did not account for the presence of
renal disease before the initiation of antiretroviral drugs.
Investigators from the D:A:D study designed
research involving 22,603 people with a view to addressing this limitation.
To be eligible for inclusion in the D:A:D
analysis, patients were required to have normal kidney function at baseline.
This was defined as an estimated glomerular filtration rate (eGFR) of 90ml/min or above. Patients were followed-up at regular intervals. Individuals who had two
consecutive test results showing a decline in eGFR to below 70ml/min were
diagnosed as having kidney impairment; those with two consecutive measurements
indicating a fall in eGFR to below 60ml/min were defined as having chronic
The starting date for the study was January
2004, when measurement of eGFR became routine in the D:A:D cohort. The majority
of the patients were white gay men and their median age was 39 years.
Patients were followed for a median of 4.5
years and each contributed a median of twelve eGFR measures.
A total of 468 patients (2%) had a fall in
eGFR to below 70ml/min, an incidence of 4.78 per 1000 person years. Some 131
individuals (0.6%) developed chronic kidney disease, giving an incidence rate
of 1.33 per 1000 patient-years.
People with a current eGFR in the region
of 60-70ml/min were more likely to discontinue therapy with tenofovir than
any other anti-HIV drug (adjusted incidence rate ratio [aIRR], 1.72; 95% CI,
1.38-2.14). The authors believe this shows that physicians are aware of the possible
kidney toxicities of the drug.
The investigators also found that cumulative
exposure to tenofovir (aIRR, 1.18; 95% CI, 1.12-1.25 per year) and ritonavir-boosted
atazanavir (aIRR, 1.19, 95%
CI, 1.09-1.32 per year) were both associated the development of kidney
Cumulative exposure to lopinavir/ritonavir was associated with the diagnosis
of renal impairment (aIRR, 1.11; 95% CI, 1.05-1.17 per year) and the diagnosis
of kidney dysfunction (aIRR, 1.22; 95% CI, 1.16-1.28 per year).
“Given the relatively short length of
follow-up (< 5 years) these declines were substantial compared to the
expected age-related decline of 1 ml/min/year,” write the authors.
An association between tenofovir and
atazanavir therapy and kidney dysfunction has been identified in earlier
However, the finding that treatment with Kaletra led to renal dysfunction and
chronic kidney disease was novel. But the authors of the editorial recommend that
this finding should be treated with caution and may simply be because the Kaletra-treated patients had been living with HIV for longer and suffered more extensive renal damage before
initiating therapy with what is now an older drug largely used in second-line treatment.
Encouragingly, there was some evidence that
kidney function recovered after discontinuing therapy with the drugs associated
with renal side-effects. “A study with the specific aim of assessing the
reversibility of declining renal function among persons experiencing chronic
renal impairment while on antiretroviral therapy is currently being designed,”
note the investigators. They conclude, “use of tenofovir, atazanavir/ritonavir
and lopinavir/ritonavir were independently associated with adverse chronic
kidney impairment…the incidence of chronic renal impairment associated with
these ARVs decreased after their discontinuation.”
The authors of the editorial stress the
importance of regularly monitoring kidney function in patients taking antiretroviral drugs. They
recommend that eGFR should be used in conjunction with a number of other tests.
They also stress that antiretroviral drugs are far from being the only cause of
renal impairment, so “an evaluation of other causes is usually appropriate.”