a Academic Department of HIV/GU Medicine, The Guy's, King's and St Thomas' School of Medicine, Weston Education Centre, Cutcombe Road, King's College Hospital, London SE5 9RT; b St Stephen's Centre, Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK
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Abstract |
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Patients and methods: This was a retrospective cohort study based on two large HIV centres in London. Eligible patients received indinavir for at least 1 week between 1 December 1995 and 28 February 1999. Development of IRC was ascertained by case-note review. Multivariate logistic regression and Cox Proportional Hazard's model analysis were used to determine independent risk factors for the development of IRC.
Results: 781 patients were eligible. Median CD4 count and viral load at indinavir initiation were 117 x 106 cells/L and 47 332 copies/mL, respectively. Median indinavir exposure was 53 weeks (IQR: 2083). Many patients received other potentially nephrotoxic drugs during indinavir treatment: co-trimoxazole (46%), aciclovir (33%) or both (20%). Overall IRC incidence was 7.3% (6.7 per 100 person-years indinavir exposure). Cases presented with loin pain (58%), renal colic (42%) or dysuria (19%). Identified precipitating events (26%) included fluid depletion or altered indinavir regimen. In the majority of cases indinavir therapy was continued and there was no progressive rise in creatinine levels. In the multivariate analysis, for indinavir treatment >74 weeks there was a reduced risk of developing IRC (OR = 0.23, 95% CI 0.090.57, P = 0.001). Concomitant aciclovir increased the IRC risk (OR = 1.99, 95% CI 1.143.51, P = 0.016). Factors not associated with outcome were age, gender, ethnicity, baseline CD4 count and viral load, concomitant co-trimoxazole, or use of specific antiretrovirals.
Conclusion: An overall IRC incidence of 7.3% was identified. Concomitant aciclovir doubled the risk of IRC and we therefore recommend careful monitoring when prescribing aciclovir with indinavir. A precipitating event was identified in 26% of IRC cases, many of which could have been avoided.
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Introduction |
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The reported incidence of IRC based on data from approximately 2200 patients participating in clinical trials ranges from 2.6% to 5% in patients taking indinavir either alone or in combination, and up to 7% when doses exceed the recommended 2.4 g/day.7 However, clinical experience indicates that the true incidence may be much higher, and IRC has been an important reason for hospital admission among patients receiving indinavir. Other information about IRC is based on case reports, case series and a few cross-sectional or retrospective studies,10,11,18,19 but these studies have lacked a standardized case definition, which may account for their differing rates of ascertainment of IRC. Definitions of IRC used have ranged from a variety of clinical symptoms (flank pain, haematuria, dysuria, renal colic), a raised creatinine level (>20% above the normal maximum level)20 or the presence of indinavir crystals in the urine,9 which limits the comparability of findings from these studies. Only three small cohort studies (two retrospective20,21 and one prospective9) have examined for risk factors for IRC. However, the number of cases of IRC in these studies was small (n = 19, 17 and 20, respectively), and they also used different outcome definitions.
Our objectives were to determine the incidence of IRC and to identify independent risk factors for its development in a large cohort of patients who had received indinavir. The identification of such risk factors would allow patients at high risk to be targeted and monitored more effectively, and so potentially reduce the likelihood of developing IRC.
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Materials and methods |
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The study population was drawn from two large clinical HIV centres in London: King's College Hospital in southeast London, and Chelsea and Westminster Hospital in west London, both of which have large and wellestablished patient databases. Eligible patients were HIV-1-infected individuals who had received indinavir for at least 1 week during the period 1 December 1995 to 28 February 1999.
Data collection and case ascertainment
Data were collected on each patient using both computerized databases and review of the medical records. Information abstracted from the computerized database included demographic data, clinical stage of HIV disease (using the 1987 CDC diagnostic criteria22), CD4 cell count and viral load at initiation of indinavir, concomitant use of other antiretroviral drugs, and use of the following potentially nephrotoxic drugs: co-trimoxazole, aciclovir, ganciclovir, pentamidine and foscarnet.
Ascertainment of the development of IRC was by review of the medical records of all patients. Information collected included the clinical presentation, possible precipitating events, management and outcome. IRC was defined as the presence of loin pain, renal colic or dysuria, where infection had been excluded by a negative midstream urine culture. For those patients who had further investigations, results from urine microscopy (for haematuria or crystalluria), radiological investigations (abdominal X-ray, intravenous urogram and renal ultrasound) and abnormal creatinine levels were also recorded. Prescription data were used to calculate the total duration of indinavir exposure. If patients failed to receive further indinavir prescriptions, 30 days were added to the date of the most recent prescription to give the estimated duration of therapy, as it was assumed that they had discontinued treatment. Patients were censored at the date of IRC diagnosis, date of discontinuation of indinavir (as patients were no longer at risk of developing IRC), date of last follow-up or at the censorship date of 31 March 1999, whichever was sooner.
Statistical analyses
Time to development of IRC was calculated using Kaplan Meier methods, and potential risk factors for the development of IRC were examined using both logistic regression and Cox proportional hazards modelling. Risk factors investigated included demographic variables (age at initiation of indinavir, gender, HIV risk group, ethnicity), clinical stage of disease at initiation of indinavir, baseline CD4 cell count [analysed both as a continuous and categorical covariate (tertiles of 50, 51200 and >200 x 106 cells/L)], baseline viral load [analysed as a continuous and categorical covariate (quartiles of
500, 50120 000, 20 001150 000 and >150 000 copies/mL)], duration of indinavir therapy, concomitant antiretroviral therapy, and use of potentially nephrotoxic drugs. Interaction terms between the most frequently used potentially nephrotoxic drugs, co-trimoxazole and aciclovir, were examined for their impact on the development of IRC. Analyses were performed using the software packages SAS (version 6.12; SAS Institute, Inc., Cary, NC, USA) and Stata (version 6; StataCorp, College Station, TX, USA).
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Results |
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The most common nucleoside reverse transcriptase inhibitors (NRTI) prescribed with indinavir were lamivudine and stavudine (47%), zidovudine and lamivudine (22%), and stavudine and didanosine (14%). Of the potentially nephrotoxic drugs, 362 (46%) patients had received co-trimoxazole prophylaxis and 260 (33%) patients had received aciclovir (82% as herpes prophylaxis at a dose of 400 mg bd, and 7% for an acute episode of herpes at a total daily dose of 4 g) at some point during their indinavir treatment. One hundred and fifty-six (20%) patients had received both. Less than 10 patients received ganciclovir, foscarnet or pentamidine.
Incidence and clinical features of IRC
Fifty-seven of 781 patients (7.3%) developed IRC, or 6.7 per 100 person-years of indinavir exposure. The median time from initiation of indinavir to the onset of symptoms was 37 weeks (IQR: 1656), and the Figure shows a KaplanMeier plot of time to the development of IRC. The majority of cases (88%) occurred within 74 weeks of starting indinavironly seven cases developed after this time, at 77, 79, 86, 89, 98, 122 and 143 weeks.
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Of the 57 cases of IRC, a possible precipitating event was documented in 15 (26%) patients. The majority were events likely to result in fluid depletion, such as gastroenteritis (n = 5), long-haul airplane flights (n = 2), use of a sauna (n = 2) and excess alcohol intake (n = 1). Other possible precipitants included a change in indinavir dose frequency, from 800 mg tds to 1200 mg bd regimen (n = 4), and an inadvertent overdose (n = 1). No patients with IRC had a history of previous or pre-existing renal disease documented.
Risk factors for the development of IRC
Table 1 compares the characteristics at initiation of indinavir of the 57 patients who developed IRC, and the remaining 724 without IRC. In the univariate analysis we found no statistically significant differences between the two groups in either demographic, baseline laboratory or clinical characteristics (Table 1
). However, the duration of indinavir therapy was significantly associated with the likelihood of developing IRC. If patients tolerated indinavir for more than 74 weeks, there was a reduced risk of developing IRC (OR = 0.32, 95% CI 0.130.76, P = 0.01), when compared with patients who had <30 weeks of exposure. Concomitant use of aciclovir (mainly at a prophylactic dose of 400 mg bd) with indinavir was also significantly associated with IRC, with nearly a two-fold increased risk (OR = 1.76, 95% CI 1.023.03, P = 0.043). However, we found no significant association between the duration of aciclovir treatment or concomitant use of co-trimoxazole and IRC.
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Thirty-six (63%) of the 57 cases of IRC resulted in a hospital admission, and 14 of these (39%) were referred for urological assessment. Five (9%) required stent insertion, and three (5%) had lithotripsy. Only seven (12%) required permanent cessation of indinavir, and in five cases (9%) the dose was modified (from a twice daily to a thrice daily regimen). Twenty (35%) cases experienced recurrence of symptoms on at least one further occasion, and seven (12%) on three or more occasions, often requiring hospital admission.
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Discussion |
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We identified two independent risk factors for the development of IRC: duration of indinavir therapy and concomitant use of aciclovir. If indinavir was tolerated for >74 weeks, there was a reduced risk of developing IRC. In contrast, Boubaker et al.20 found that the longer the duration of therapy, the greater the risk of IRC (as defined by elevated serum creatinine levels >20% above normal). They found that the greatest risk was after 54 weeks of indinavir exposure with a seven-fold increased risk (OR = 7.1, 95% CI 1.827.7, P < 0.05). Other studies have not examined duration of indinavir as a risk factor, but have simply described the median or mean duration of therapy at the time of developing IRC, which has varied between 3 and 43 weeks.9,11,20,21
The other striking association we found was that concomitant use of aciclovir with indinavir significantly increased the risk of IRC by two-fold. Furthermore, there was a trend, with the risk of IRC increasing the longer the duration of aciclovir therapy. This is not unexpected as aciclovir is known to cause crystalluria, and it is postulated that indinavir may precipitate around these crystals.17 It is noteworthy that patients on chronic aciclovir treatment were in fact excluded from the original clinical trials of indinavir because of this potential interaction. This new finding warrants further investigation and confirmation in other cohort studies. It is noteworthy that co-trimoxazole, which in common with other sulfa-containing drugs, also forms urinary crystals, did not show a statistically significant association with the development of IRC, nor was an association apparent among long-term users of co-trimoxazole. This again is in contrast to the findings of Boubaker et al.,20 who found that the use of co-trimoxazole was associated with a four-fold increased risk of IRC. The one other risk factor for IRC that has been described is hepatitis C infection.21 From clinical trial data, it is known that patients with mild to moderate hepatic insufficiency and clinical evidence of cirrhosis have reduced metabolism and an increased half-life of indinavir,7 which could potentially influence the development of IRC. A study by Brodie et al.21 found that patients with hepatitis C infection (mainly haemophiliacs and intravenous drug users) had an increased incidence of IRC (37% in patients with hepatitis C versus 13% in uninfected patients, P = 0.02).
In summary, this represents the largest cohort study evaluation of IRC to date. We identified an overall incidence of IRC of 7.3%, with most episodes occurring within 74 weeks of starting indinavir therapy. Although the majority of patients were hospitalized, mainly for intravenous hydration and analgesia, only 14% required urological intervention. In most patients, indinavir treatment was continued, and there was no progressive rise in their serum creatinine levels. Concomitant use of aciclovir significantly increased the risk of IRC by approximately two-fold. Finally, a significant proportion of cases identified precipitating events, many of which could have been avoided.
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Acknowledgements |
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Notes |
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References |
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Received 20 September 2000; returned 27 February 2001; revised 2 May 2001; accepted 21 May 2001