The targeted spontaneous reporting methodology can increase reporting of suspected adverse reactions to a drug. |
Although the occurrence of renal toxicity associated with tenofovir is low, in a resource-limited setting where there is rapid scale-up of treatment and patients are initiated on a tenofovir regimen without initial screening, a monitoring programme for those that may develop renal toxicity should be put in place to encourage evidence-based decision making for improved patient safety. |
Having adopted and leveraged on existing structures in the STD/AIDS Control Program, a platform for collaboration with the National Pharmacovigilance Centre was created, hence strengthening pharmacovigilance activities. |
1 Introduction
2 Methodology
2.1 Implementation Design
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national referral
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regional referral
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district or general hospital
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health centre IV (Serves a county, should be able to admit patients having a senior medical officer and another doctor as well as a theatre for carrying out emergency operations)
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health centre III (Found in sub-county, runs an out-patient clinic, treating common diseases and offering antenatal care. Its led by a senior clinical officer and has a functioning laboratory)
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health centre II (serves a few thousand people, led by a registered nurse, runs an out-patient clinic treating common diseases and offering antenatal care)
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health centre I (structured as village health teams and working as a link between the community and the health facilities).
2.2 Site Selection
2.3 Monitoring of the Tenofovir-Based Regimen
2.4 Training and Support Supervision for the Targeted Spontaneous Reporting (TSR) Methodology
2.5 Data Collection
2.6 Ethical Considerations
3 Results
3.1 Background to the Sites
Study site | Number of patients on tenofovir |
---|---|
Masaka Region | |
Masaka Regional Referral hospital | 2,637 |
TASO Masaka | 1,759 |
Villa Maria hospital | 1,700 |
Lyantonde hospital | 740 |
Kalungu Health Centre IV | 63 |
Kitovu hospital | 40 |
Bukulula Health Centre IV | 348 |
Subtotal | 7,287 |
Mbale Region | |
Mbale Regional Referral hospital | 950 |
TASO Tororo | 1,615 |
St. Antony hospital Tororo | 158 |
Bududa hospital | 215 |
Sub-total | 2,938 |
Total | 10,225 |
3.2 Demographics of the Suspected Renal Toxicity Cases
3.3 Presenting Signs and Symptoms for the Suspected Renal Toxicity
Parameter | Number of patients (%) | Total (N) |
---|---|---|
Increased creatinine (>1.2 g/dL) | 43 (81) | 53 |
Creatinine clearance >90 mL/min | 43 (100) | 43 |
Creatinine levels not provided | 10 (19) | 53 |
Proteinuria | 25 (66) | 38 |
Glycosuria and proteinuria | 11 (44) | 25 |
Bone demineralisation | 5 (9) | 53 |
Bilateral pitting pedal oedema | 6 (11) | 53 |
Facial puffiness | 4 (8) | 53 |
Age | Sex | Duration on ART (months) | Regimen | Concomitant drugs | Presenting symptom/signs | Outcome and remarks | Serum creatinine (mg/dL) | Creatinine clearance (mL/min) | Regimen change |
---|---|---|---|---|---|---|---|---|---|
43 | F | 5 | TDF/3TC/NVP | Cotrimoxazole | Raised serum creatinine | Expected but not serious | 1.36 | 52.0 | No |
30 | F | 12 | TDF/3TC/NVP | Cotrimoxazole | Increased serum creatinine glucose: nil Proteins: + | Life-threatening but expected | 1.47 | 58.2 | No |
51 | M | 5 | TDF/3TC/NVP | Cotrimoxazole | Raised serum creatinine | Expected but not serious; urinalysis has been normal since May 2014 | 1.47 | 47 | No |
62 | M | 12 | TDF/3TC/NVP | None reported | Urine RBCs: nil Pus cells: + Epithelial cells: ++ Urine protein: ++ Glucose: nil. | Reaction expected and was life-threatening. Improved | 1.52 | 32.8 | Changed from TDF to AZT |
64 | M | 6 | TDF/3TC/EFV | Cotrimoxazole | Raised serum creatinine Urine protein: + Urea: 8.3 mg/dL | Cotrimoxazole stopped due to neutropenia. Patient improved. Reaction expected | 1.35 | 54.4 | Changed from TDF to ABC |
62 | F | 84 | TDF/3TC/NVP | None reported | Raised serum creatinine Urine protein: +++ Glucose: + | Reaction was serious but expected | 1.36 | 37.2 | No |
30 | F | 4 | TDF/3TC/NVP | Cotrimoxazole | Increased creatinine levels Glucose: nil Proteins: nil | Reaction was expected but not life-threatening. Patient recovered | 1.75 | 37.5 | No |
45 | M | 19 | TDF/3TC/NVP | Cotrimoxazole | Raised serum creatinine | Reaction was expected but not life-threatening. Patient recovered | 1.42 | 60 | No |
42 | F | 6 | TDF/3TC/NVP | Cotrimoxazole | Raised serum creatinine | No co-morbidities reported, patient died | 1.80 | 71.0 | No |
68 | M | 10 | TDF/3TC/NVP | Cotrimoxazole | Raised serum creatinine | Reaction was expected but not life-threatening. Patient recovered | 1.57 | 57.0 | No |
52 | M | 9 | TDF/3TC/EFV | Cotrimoxazole | Raised serum creatinine | Reaction was expected and life-threatening but resolved | 1.47 | 53.0 | No |
41 | F | TDF/3TC/lopinavir | Dapsone | Generalised oedema, progressive anuria | Dapsone has an effect on renal function. The patient was allergic to cotrimoxazole. The reaction was expected and life-threatening but it resolved | 2.3 | 21.0 | TDF changed to AZT | |
28 | M | 24 | TDF/3TC/EFV | None reported | Renal tubular necrosis, raised serum creatinine Urine glucose: nil Proteins: + | Good viral suppression at 381 copies Patient recovered. Reaction was expected | Actual results not seen | TDF changed to ABC | |
33 | M | 12 | TDF/3TC/NVP | Cotrimoxazole | Increased creatinine | Reaction was expected. Patient has normal urinalysis | Results not seen | No | |
38 | F | 48 | TDF/3TC/EFV | Cotrimoxazole | Raised serum creatinine | AZT had been changed to TDF after 2 months of treatment. Follow-up urinalysis on TDF regimen indicated protein +. The reaction was expected and serious | 2.57 | 27.0 | No |
29 | F | 24 | TDF/3TC/NVP | Ibuprofen for 5 days and vitamin B complex for 2 weeks | Increased creatinine: 1.65 mg/dL. Follow-up value was 1.3 mg/dL | The patient was reported to also have lumbago. Reaction was serious and expected but resolved | 1.65 | 58.0 | No |
37 | M | 84 | TDF/3TC/NVP | Cotrimoxazole | Increased creatinine | Very poor adherence with very poor immunological outcome. The suspected renal abnormality is also resolving | 10.91 | 6.2 | No |
45 | M | 36 | TDF/3TC/NVP | Carvedilol, spironolactone | Oedema, polyuria, raised serum creatinine protein 3+ and a known hypertensive | Reaction expected and patient is recovering | 4.6 | 24.4 | TDF changed to AZT |
42 | F | 84 | TDF/3TC/NVP | Cotrimoxazole | Increased creatinine: 1.3 then 1.1 mg/dL | Reaction expected and patient is recovering | 1.3 | 51.6 | No |
49 | F | 48 | TDF/3TC/NVP | Cotrimoxazole | Neuropathy and increased creatinine Glucose: nil Proteins: + | Reaction expected and patient recovered | 10.0 | 7.2 | TDF changed to ABC |
61 | M | 36 | TDF/3TC/NVP | Cotrimoxazole | Increased creatinine | Reaction expected and patient recovered | Results not seen | No | |
33 | M | 12 | TDF/3TC | Atazanavir | Increase creatinine, facial puffiness, high urea level Glucose: nil Protein: nil | Reaction expected and patient recovered | 10.9 | 10.6 | No |
55 | M | TDF/3TC/NVP | None reported | Raised serum creatinine Glucose: nil Proteins: nil | Reaction expected and patient recovered | 1.5 | 44.2 | No | |
47 | F | 24 | TDF/3TC/NVP | Insulin | Increased serum creatinine Glucose: + Proteins: + | Known to be hypertensive and have diabetes mellitus. Reaction expected and patient recovering | Results not seen | TDF changed to ABC | |
49 | M | 12 | TDF/3TC | Alluvia and cotrimoxazole | Increased creatinine levels Glucose: nil Proteins: nil | History of TB treatment immediately before starting ART. Reaction expected and patient recovering | 1.66 | 27.8 | No |
53 | M | 12 | TDF/3TC/NVP | Cotrimoxazole | Facial puffiness, increased serum creatinine Proteinuria: +++ Glucose: + | Signs of treatment failure. The reaction was expected | Results not seen | TDF withdrawn, changed to ABC | |
50 | F | 24 | TDF/3TC/NVP | None reported | Increased creatinine Glucose: nil Proteins: + | Had lactic acidosis with high LDH levels. Reaction expected | Results not seen | No | |
48 | F | 5 | TDF/3TC | EFV | Increased creatinine levels | Reaction expected and patient recovering | 1.76 | 30.7 | No |
29 | F | 36 | TDF/3TC/NVP | Cotrimoxazole | Increased creatinine levels Urea: 51 mg/dL | Reaction expected and patient recovering | 1.74 | 47.8 | No |
28 | F | 24 | TDF/3TC/NVP | Cotrimoxazole | Raised serum creatinine, proteinuria Urine protein: 3+++ Glucose: nil | Reaction expected and patient recovered | 1.43 | 58.3 | Changed from TDF to AZT regimen |
25 | F | 12 | TDF/3TC/NVP | Cotrimoxazole | Fanconi syndrome Urine protein: 3+++ Urine glucose: + Random blood sugar: 6.1 mmol | Raised amylase, raised AST. Outcome is not yet known, patient still being monitored | 1.79 | 34.0 | ART stopped |
22 | F | 48 | TDF/3TC/EFV | Cotrimoxazole | Raised serum creatinine | Urinalysis was normal during follow-up. Reaction expected and patient recovering | 1.45 | 36.0 | No |
52 | M | 2 | TDF/3TC/EFV | Cotrimoxazole | Raised creatinine Glucose: nil Proteins: nil | Had a Kaposi’s sarcoma lesion as well. Urinalysis results returned to normal. Reaction expected and patient recovering | 1.30 | 54.3 | From NVP to EFV |
45 | M | 60 | TDF/3TC/NVP | Captopril, nifedipine | Increased creatinine, known hypertension Glucose: + Proteins: + | Known hypertensive. Reaction expected and patient recovering | 1.79 | 61.9 | No |
38 | F | 24 | TDF/3TC/EFV | Atorvastatin | Increased serum creatinine | Started ART (AZT/3TC/EFV) in 2006, substituted AZT with TDF due to lipodystrophy Reaction expected and patient recovered. Serum creatinine reduced to 1.39 mg/dL | 1.43 | 53.4 | No |
31 | F | 24 | TDF/3TC/NVP | Nifedipine, atenolol | Renal tubular necrosis, raised serum creatinine Glucose: nil Protein: + | Right-sided hemiparesis of a known hypertensive Reaction expected and patient recovered | 4.28 | 14.1 | From TDF to ABC |
56 | F | 66 | TDF/3TC/NVP | Cotrimoxazole | Facial puffiness, easy fatigue, raised creatinine levels Urea: 240 mg/dL | Reaction expected and patient recovering | 7.26 | 7.7 | Changed TDF to ABC |
56 | M | 24 | TDF/3TC/NVP | Cotrimoxazole | Raised creatinine, urea (92 mg/dL) Glucose: + Proteins: ++ | Patient had pancytopaenia and he died | 3.15 | 17.2 | No |
44 | F | 24 | TDF/3TC | NVP | Facial puffiness, increased creatinine levels | Not known | Results not seen | No | |
40 | M | 2 | TDF/3TC/NVP | None reported | Renal toxicity with bilateral pedal oedema Glucose: + Proteins: + | Had a history of TB of the kidneys. Reaction was expected | 16.52 | 3.9 | Drug stopped |
39 | M | 48 | TDF/3TC/NVP | Cotrimoxazole | Increased creatinine | Reaction was expected and the patient recovered | Results not seen | TDF substituted for ABC |
Age | Sex | ART regimen | Duration on ART (months) | Concomitant drugs | Presenting symptom/signs | Outcome and remarks |
---|---|---|---|---|---|---|
30 | F | TDF/3TC/EFV | 48 | Ciprofloxacin 500 mg | Blood in urine Urine protein: + (30 g/dL) White blood cells: 2+ Glucose: nil Urinary tract infection that did not improve on ciprofloxacin 500 mg twice daily for 1 week | Regimen changed from TDF to ABC and the patient recovered |
29 | M | TDF/3TC/NVP | 1.2 | Dapsone, prednisone | Bilateral pedal oedema Urine protein: 3+ Red blood cells: 2+ Pus cells: 2+ | Patient died |
52 | F | TDF/3TC/NVP | 28 | Cotrimoxazole, ciprofloxacin 500 mg | Urine protein: 2++ Pus cells: ++ Epithelial cells: ++ CD4: 15 | Patient improved on ciprofloxacin 500 mg. Regimen was maintained |
47 | F | TDF/3TC/NVP | 36 | Anti-TB drugs for 6 months | Paraesthesia of both limbs Glucose: ++ Protein: ++ Pale | Had just completed TB treatment 1 week ago, TDF was changed to ABC and recovered |
38 | M | TDF/3TC/EFV | 1 | None | Bilateral pedal oedema Anaemia (haemoglobin 6.6 g/dL) Protein: + Ultrasound revealed bilateral hydronephrosis | Patient died |
34 | M | First on AZT/3TC/NVP, then TDF/3TC/NVP | 24 | Cotrimoxazole | Bone demineralisation on left head of femur Glucose: nil Proteins: nil | Developed hyperpigmentation of the nails and was substituted to TDF on request |
43 | F | TDF/NVP/3TC | 36 | None | Bone demineralisation Glucose: + Proteins: ++ | TDF substituted with ABC and recovered |
46 | F | TDF/3TC/NVP | 24 | None | Severe bone pains and unstable gait | Outcome and new regimen could not be readily established |
60 | F | TDF/3TC/NVP | 5 | Cotrimoxazole | Osteomalacia, reduced bone density of femur Glucose: nil Proteins: + | TDF substituted with AZT |
39 | F | TDF/3TC/EFV | 12 | Cotrimoxazole | Bone demineralisation Reduced bone density of the right and left femur Glucose: nil Proteins: nil | TDF substituted to ABC and recovered |
3.4 Causality Assessment
3.5 Reporting Trends for Suspected Adverse Drug Reactions
Source of reports | Period | ||||||
---|---|---|---|---|---|---|---|
Before TSR pilot study | After start of TSR | ||||||
2010 | 2011 | Total | 2012 | 2013 | 2014 | Total | |
Study sites | 17 | 27 | 44 | 142 | 46 | 181 | 369 |
Uganda VigiBase® reports | 60 | 518 | 578 | 42 | 239 | 687 | 968 |
Percentage | 8 % (44/578) | 38 % (369/968) |