UK-CAB 20 – London HIV commissioning – renal toxicity – Gilead

26 January 2007

Programme for the meeting
Background reading
Background to speakers

Programme

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Background reading

Renal toxicity

The following article is a report from the last year’s conference in Glasgow. Originally it was published at: HIV and Hepatitis.
http://www.hivandhepatitis.com/2006icr/glasgow/docs/112806_a.html

Risk Factors for Kidney Toxicity in Patients Taking Tenofovir

By Liz Highleyman

Kidney toxicity is a concern for individuals receiving tenofovir (Viread), since this side effect has been observed in patients taking the related drugs cidofovir (Vistide, used to treat CMV retinitis) and — at higher doses — adefovir (Hepsera, used at lower doses to treat chronic hepatitis, but never approved for HIV).

Tenofovir can build up in the renal tubules of the kidneys, which filter waste products and reabsorb nutrients from the blood. Signs of kidney toxicity may include impaired creatinine clearance, reduced glomerular filtration rate (GFR), low phosphate levels (hypophosphatemia), and protein in the urine; in severe cases, it may progress to Fanconi’s syndrome and acute kidney failure.

Kidney toxicity was not observed more frequently among individuals taking tenofovir compared with placebo in clinical trials, but elevated creatinine levels were observed in the pre-approval tenofovir expanded access programs (EAPs), which included some patients with pre-existing kidney disease.

Several presentations at the 8th Congress on Drug Therapy in HIV Infection, held this month in Glasgow, looked at kidney impairment in patients taking tenofovir as part of an antiretroviral regimen.

Predictors of Kidney Toxicity

In a late-breaker oral session, M. Harris reported on risk factors that predicted kidney toxicity in 1182 HIV positive adults in British Columbia who started tenofovir between January 2003 and May 2005.

The median age was 42 years, 85% were men, 22% had a previous AIDS diagnosis, and 16% were antiretroviral-naive. The average CD4 cell count was 220 cells/mm³, HIV viral load was 24,500 copies/mL, creatinine level was 83 mmol/L (normal is abut 70-120 for men or 50-100 for women), and the GFR was 92.2 mL/minute/173m² (90 is considered the lower limit of normal). In addition to tenofovir — which was used for an average of 12.2 months — 34% were taking ddI (Videx) and 82% were taking boosted protease inhibitors.

Results

• Over a median follow-up period of 1 year, 7.5% of patients had at least 1 measurement showing a 30% or greater increase in creatinine levels from baseline, and 4.3% had 2 or more such measurements.
• 20% of patients discontinued tenofovir-containing regimens, and 3% stopped tenofovir only.
• 66 patients (5.6%) died.
• In a multivariate analysis, factors associated with elevated creatinine were:
  • concomitant use of ddI (OR 2.14; P = 0.015);
  • lower baseline CD4 count (OR 1.59 per 100 cell decrement; P < 0.0001);
  • female sex (OR 2.33; P = 0.029).
• Factors associated with tenofovir discontinuation were:
  • ddI use (OR 2.21; P < 0.0001);
  • lower baseline CD4 count (OR 1.22 per 100 cell decrement; P < 0.0001);
  • previous antiretroviral exposure (OR 0.89 per 12 months; P < 0.0001).

The researchers concluded that, Among patients taking tenofovir, creatinine elevation and tenofovir discontinuation are associated with concomitant use of ddI (but not boosted PIs), and with lower CD4 [counts].

Other Studies

Among the other tenofovir kidney toxicity data presented in Glasgow:

• F. Tordato and colleagues reported on a study of 316 Italian patients (41% men, mean age 41 years, median CD4 count 404 cells/mm³, nadir CD4 count 203 cells/mm³, 93% on antiretroviral therapy), 31% of whom were taking tenofovir. 23% had abnormal GFR. Female sex, older age, and larger differences between nadir and current CD4 counts were associated with decreased GFR, but no significant association was observed between antiretroviral use and GFR impairment.
• S. Rocha and colleagues studied 219 Portuguese patients on tenofovir who had normal baseline kidney function. Overall, GFR declined significantly (by 12.7%) from baseline during the first year on tenofovir. 85 patients (38.8%) developed kidney impairment, of whom 81 (95.2%) experienced GFRs of 60-90 mL/min (mild impairment), 2 (2.4%) developed GFRs of 30-60 mL/min (moderate impairment), and 2 (2.4%) had GFRs below 30 mL/min (severe impairment).
• C. Davies and colleagues presented a case series of 20 patients (all men, median age 46 years, median CD4 count 501 cells/mm³, 30% treatment-naive, mean 2.3 years of tenofovir use) referred to a specialist renal clinic due to tenofovir-related kidney toxicity. Of the 17 men with pre-tenofovir creatinine data, all had normal levels. Upon presentation at the clinic, 19 men had at least mildly impaired GFR and/or elevated creatinine, 19 had protein in their urine, and 8 had confirmed Fanconi’s syndrome. 9 were taking other potentially nephrotoxic drugs; 5 were on ddI. Proximal tubular dysfunction was confirmed by kidney biopsies in 3 patients. Kidney impairment partially reversed after stopping tenofovir, but function did not completely return to normal.
• C. Smith and colleagues studied 868 patients at 3 clinics in the U.K. who were taking HAART regimens that included either tenofovir (n = 610) or abacavir (Ziagen; n = 358). Individuals taking tenofovir were significantly more likely to have kidney impairment, as indicated by reduced GFR, elevated creatinine, and/or elevated alkaline phosphatase. Similar results were observed when analyzing only patients who were treatment-naive when starting tenofovir or abacavir. The researchers concluded that, “[Tenofovir] was associated with increased creatinine levels and reduced GFR, although this was of a small magnitude.”
• F. Gutierrez and colleagues studied 749 Spanish patients starting tenofovir plus ddI (73% men, mean age 43 years, mean baseline CD4 count 412 cells/mm³). After a median follow-up of 9 months, there was no significant change in mean GFR among patients who started tenofovir/ddI (usually a switch due to virological failure or for treatment simplification). However, over 943 person-years of follow-up, 5 individuals — all of whom had impaired GFR at baseline — stopped taking tenofovir/ddI due to kidney-related side effects, and 1 died due to kidney failure.
• I. Cassetti and colleagues assessed kidney toxicity in a 4-year extension of Gilead Study 903, in which 172 treatment-naive patients were randomly assigned to receive either tenofovir or d4T (Zerit), along with 3TC (Epivir) plus efavirenz (Sustiva). Among 86 participants in Brazil, Argentina, and the Dominican Republic who took the tenofovir-containing regimen throughout the study period (62% men, mean age 33 years, mean baseline CD4 count 299 cells/mm³), GFR did not change significantly over 5 years, and none discontinued due to renal adverse even
• F. Wolf and colleagues, who compared 500 patients taking tenofovir (for a median of 22 months) and 100 control patients on antiretroviral regimens without tenofovir, found that the tenofovir group had significantly lower mean creatinine clearance, but were no more likely to have mildly elevated creatinine levels. In the tenofovir group, 25% experienced mild kidney impairment (compared with 21% in the tenofovir-sparing group), and 4% developed moderate to severe impairment (compared with none in the tenofovir-sparing group). A majority of patients (41%) with reduced creatinine clearance while on tenofovir had pre-existing kidney impairment. What’s more, 72% of patients taking tenofovir were also taking other drugs that could potentially cause kidney toxicity, compared with just 12% in the tenofovir-sparing group.
• G. Madeddu and colleagues analyzed 754 Italian patients taking tenofovir in the prospective observational SCOLTA Project, of whom 354 had available creatinine data (67% men, mean age 40 years, mean CD4 cell count 363 cells/mm³). During a mean follow-up period of about 20 months, 9 individuals (2.5%) had significantly elevated creatinine — usually mild — for an overall incidence rate of 1.6 per 100 person-years; no Grade 4 (severe) toxicities were reported. Patients who experienced kidney toxicity were older, had lower CD4 counts, and were more likely to be men and to be coinfected with hepatitis C virus. The researchers concluded that, “Renal injury in patients receiving [tenofovir] seems associated with the presence of co-morbidities and with advanced HIV infection.”
• Finally, S. Staszewski and colleagues looked at creatinine levels among patients in Gilead Study 903 and Study 934, in which participants received either tenofovir or d4T or AZT (Retrovir), in combination with efavirenz plus either 3TC or emtricitabine (Emtriva). They analyzed data from 87 patients taking tenofovir and 92 on tenofovir-sparing regimens who had either mild pre-existing kidney impairment (n = 57) or a history of high blood pressure and/or diabetes mellitus (n = 122), both risk factors for kidney dysfunction. After 96 weeks, patients taking tenofovir were not significantly more likely to experience reduced GFR (though patients taking the other drugs experienced slight GFR improvement). No subjects in either study developed Fanconi’s syndrome, and none withdrew due to kidney toxicity.

Summary Conclusion

Taken together, these results indicate that kidney impairment is uncommon among patients taking tenofovir (less than 5%), occurring at about the same rate or only slightly more often than among individuals taking other nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).

However, studies consistently find that the risk of tenofovir kidney toxicity is higher among patients with a history of pre-existing kidney impairment. Female sex, older age, lower CD4 cell count, and use of other kidney-toxic drugs are also consistent risk factors.

Given these results, patients should have their kidney function assessed before starting tenofovir and monitored regularly during treatment.

28 November 2006

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Background to speakers

Mark Creelman

Mark Creelman has worked in the HIV sector since qualifying as a social worker in 1995, firstly as a specialist social worker and then managing a multi-disciplinary health and social care team for people living with HIV. Moved into commissioning in 2004 locally in Islington, before taking up his present role as North West Sector Lead for HIV. Mark holds an MA in Health and Social Care Management, Advanced Award in Social Work and is an accredited social work practice teacher

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