Low CD4 predicts earlier onset of creatinine elevation on HAART

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Creatinine elevations during abacavir or tenofovir treatment are more likely in patients with lower CD4 cell counts, according to a review of British Columbia patients presented yesterday at the Second International AIDS Society Conference on HIV Pathogenesis and Treatment in Paris.

Creatinine elevation is an indicator of kidney damage, a rare potential side effect of tenofovir treatment.

476 patients who began tenofovir treatment during 2002 were compared with 430 abacavir-treated patients in the British Columbia state database, which tracks all patients receiving antiretroviral therapy in the Canadian province. Laboratory measurements were available for 322 tenofovir-treated patients and 430 abacavir treated patients. Creatinine elevation was defined as 1.5x upper limit of normal (ULN), a different definition from that used in US Food and Drug Administration-mandated analysis of tenofovir clinical trials.

Glossary

creatinine

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.

relative risk

Comparing one group with another, expresses differences in the risk of something happening. For example, in comparison with group A, people in group B have a relative risk of 3 of being ill (they are three times as likely to get ill). A relative risk above 1 means the risk is higher in the group of interest; a relative risk below 1 means the risk is lower. 

multivariate analysis

An extension of multivariable analysis that is used to model two or more outcomes at the same time.

Food and Drug Administration (FDA)

Regulatory agency that evaluates and approves medicines and medical devices for safety and efficacy in the United States. The FDA regulates over-the-counter and prescription drugs, including generic drugs. The European Medicines Agency performs a similar role in the European Union.

p-value

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

Tenofovir-treated patients had significantly greater duration of antiretroviral exposure (P<0.001), lower viral load and higher cd4 cell count (230 vs 190 cells/mm3, p<0.001), and were older (p<0.001). creatinine levels were similar (80 vs 82umol/l) and similar proportions had mild elevations >133 umol/l (3.1 vs 3.7%). Approximately one-third of each group had a prior AIDS diagnosis.

Six tenofovir treated patients (1.3%) discontinued the drug due to creatinine elevations during the follow-up period, compared to no abacavir-treated patients. Elevations were observed in 7.1% of tenofovir-treated patients compared to 3.1% of abacavir treated patients after six months of therapy (p=0.003).

Multivariate analysis showed a relative risk of 2.54 for creatinine elevation associated with tenofovir treatment when compared with abacavir treatment, and a relative risk of 1.4 for creatinine elevation with every 100 cell decrement in CD4 cell count.

The authors concluded that in those with normal renal function at baseline, those with lower CD4 cell counts are at greater risk of creatinine elevation when compared to abacavir-treated patients.

This study could not capture the known risk factor of previous history of nephrotoxic drug use, and did not analyse concomitant antiretroviral use that might have elevated tenofovir levels.

It was also unable to capture the prevalence of HIV nephropathy (direct kidney damage caused by HIV), that might potentially predispose to the development of creatinine elevations on tenofovir.

Of note, the background rate seen in abacavir-treated patients was 3.1% after six months of treatment. Using a different measurement, Gilead Sciences data on file shows that 0.3% of French patients receiving tenofovir in the expanded access programme prior to licensing developed grade III or IV creatinine elevations.

References

Harris M et al. Increases in creatinine during therapy with tenofovir DF. Antiviral Therapy 8 (Suppl 1): S197 (abstract 55), 2003.