SUMMARY OF AVAILABLE SAFETY DATA FOR NEVIRAPINE, STAVUDINE, ZIDOVUDINE AND TENOFOVIR

OCTOBER 2009

Safety review NVP, d4T, AZT, TDF 1 TABLE OF CONTENTS

Introduction...... 3 1. Nevirapine...... 5 2. Stavudine...... 20 3. Tenofovir...... 24 4. Zidovudine ...... 30 5. Additional reviews...... 33 References...... 36 Annex 1...... 44

Safety review NVP, d4T, AZT, TDF 2 Introduction

As part of the revision of the Who ARV Therapy (ART) Guidelines for Adults and Adolescents, a review of toxicity for four drugs was requested. The identified drugs and issues are:

1. Nevirapine (NVP) in HIV+ children, adolescents and adults with higher or unknown CD4, particularly regarding the risk of severe skin and hepatic reactions; 2. Stavudine (d4T) in HIV+ pregnant women, particularly regarding the risk of lactic acidosis; 3. Zidovudine (AZT) in HIV+ children, adolescents and adults, including pregnant women, particularly regarding anaemia and neutropenia; 4. Tenofovir (TDF) in HIV+ children, adolescents and adults, including pregnant women, particularly regarding renal toxicity (glomerular and tubular dysfunction) and osteopenia.

Medline, Embase and the Cochrane Library were searched to identify available data. The searches were reasonably broad, with the search terms including the drug name, toxicity and specific adverse events. Titles and abstracts of the articles identified by the searches were assessed to determine applicability to the issues listed above. All types of trials and studies were considered, including randomized controlled trials, observational studies, retrospective reviews, systematic reviews and case control studies. Studies addressing toxicity in resource-limited settings were a main focus of the review, however studies in other settings were included. A total of 554 potentially relevant articles were identified for nevirapine, 213 for stavudine, 333 for tenofovir and 762 for zidovudine.

It was requested that the dossiers be prepared in a GRADE style, however given the characteristics of the available data it was not feasible to use GRADE tables for all available data. GRADE tables are essentially comparative in nature, requiring entry of data for an intervention and control group. This is required even for the GRADE format of “should (intervention) be used for (health problem)”. Given that many of the available studies are non-comparative (eg single arm studies) there is no clear advantage to entering such data into a GRADE table which looks to calculate either a relative or absolute effect.

The wide range of available data dictated that it was not considered appropriate to meta-analyse the data given the differences in populations, outcomes, settings and comparators in the identified studies. For the same reasons there were very few cases were more than one study could be included in a GRADE table. Essentially the available data differs considerably in terms of the study populations, treatment regimens, study settings and outcomes assessed. As such it is difficult to reach general conclusions regarding the safety of each drug. Instead, the more conservative option would be to consider the safety of each drug relative to the characteristics of each study.

A recent systematic review by Chowers1 assessed the quality of reporting of adverse events in publications of randomized trials of highly active antiretroviral treatment, examining whether reporting quality impacts the effect estimates for adverse events

Safety review NVP, d4T, AZT, TDF 3 and whether sponsorship affects the quality and characteristics of adverse event reporting. The authors found that there was a large degree of variability and a lack of standardization in the reporting of adverse events, with highly selective reporting of severity grade, occurrence threshold and attribution to study drugs. Trials sponsored by industry usually reported all or Grade 2 to 4 adverse events above an arbitrary threshold. The authors state that this tends to overrepresent common and mild adverse events while serious events are filtered by the occurrence threshold. In comparison, non-profit-sponsored trials tended to report only serious adverse events without an occurrence threshold. The review calculated relative risks for discontinuations due to adverse events and compared pooled results, finding that reporting of adverse events by intention-to-treat rather than on-treatment was significantly associated with a benefit for the experimental arm. The comparison also found that adverse event definitions were reported more in trials showing a benefit for the intervention with regard to treatment discontinuations. The authors conclude that the variability of adverse event reporting and the influence of sponsor identity obstruct the ability to chose antiretroviral treatment based on currently published data.

While the evidence presented in the current report has not been assessed in terms of reporting quality or potential sponsor influence the findings of Chowers1 should be taken into consideration, particularly given the lack of homogenous data for the issues addressed in the report.

While there are considerable concerns with the suitability of the available data to the GRADE format there was still an attempt made to create GRADE tables where possible. The following issues were addressed using GRADE: - Comparison of patients with high (>250 cells/µL for women and >400 cells/µL for men) and low (<250 cells/µL for women and <400 cells/µL for men) CD4 cell count using NVP with outcomes assessed including hepatotoxicity in pregnant women, treatment-naive patients, treatment- experienced patients, stable virologically suppressed patients and occurrence of rash in stable virologically suppressed patients. - Occurrence of serious adverse events in patients taking NVP or abacavir- containing regimens. - Occurrence of treatment-limiting toxicity in patients taking NVP or nelfinavir- containing regimens. - Occurrence of hepatotoxicity in treatment-naive patients taking NVP or efavirenz-containing regimens. - Occurrence of hepatotoxicity in treatment-naive patients with CD4 cell counts >200 cells/µL taking NVP or efavirenz-containing regimens. - Occurrence of rash in treatment-naive patients with CD4 cell counts >200 cells/µL taking NVP or efavirenz-containing regimens. - Occurrence of rash in pregnant and non-pregnant women using NVP. - Occurrence of creatinine increase in patients taking TDF-containing regimens compared to other regimens. - Occurrence of proteinuria in patients taking TDF-containing regimens compared to other regimens. - Discontinuation due to serious adverse events in patients taking TDF- containing regimens compared to other regimens. - Occurrence of Grade 3 to 4 adverse events in patients taking TDF-containing regimens compared to other regimens.

Safety review NVP, d4T, AZT, TDF 4

Each table is footnoted describing the issues relevant to the included study. For AZT and d4T none of the available studies were entered into GRADE given that none provided comparative data. For these drugs, summary tables describing each study are provided along with conclusions. For NVP and TDF summary tables including all available data as well as the GRADE tables are provided.

Given that the GRADE software did not provide an assessment of relative effect (relative risk) for individual studies, post-hoc analyses were conducted for studies with available data. Results of these analyses are provided in Annex 1.

1. Nevirapine

A total of 554 potentially relevant articles were identified by the literature searches. Articles relevant to skin and hepatic reactions, particularly in regard to the relationship with CD4 cell count, were selected. A total of 30 articles were selected for inclusion and are summarised in Table 1.1 below.

Nevirapine is associated with hypersensitivity reactions, in particular skin rash, and hepatotoxicity. Both the FDA and the EMEA in 2005 issued warnings in the nevirapine product information recommending against the use of NVP in adult men with a CD4 cell count >400 cells/µL or in adult women with CD4 >250 cells/µL, except in situations where the benefits clearly outweigh the risks.

The results reported by the articles are somewhat conflicting, as some did not show differences in the occurrence of adverse events based on gender and CD4 cell count. For example, Knobel2 reported that more women and men with high CD4 cell counts experienced hepatotoxicity and skin rash compared to those with low CD4 cell counts. Knobel2 concluded that recommendations not to use NVP in drug-naïve patients on the basis of gender and CD4 cell count was not supported, however the study was based on a relatively small number of patients (n=142). Bonjoch3 reported no difference in occurrence of adverse events in females with high or low CD4 cell count and De Lazzari4 concluded that warning against NVP use in patients with high CD4 cell counts may not apply to virologically suppressed patients switching to NVP. Manfredi, in one trial with treatment naive and pre-treated patients5 (2006) and another trial with pregnant women6 (2007) found no increase in hepatotoxicity and skin rash in those with high CD4 cell count. Marazzi7 found lower occurrence of Grade 3-4 hepatotoxicity in patients with high CD4 cell count and concluded that NVP-containing regimens appear to be safe in pregnant women at all CD4 cell counts. Other trials showed increased occurrence of adverse events associated with high CD4 levels (eg, van Leth8; Mocroft9; Lyons10; Jamisse11; Hitti12).

The available evidence is largely based on retrospective reviews or open-label studies, with very few randomized controlled trials providing evidence. As such, all results should be interpreted with caution, taking into consideration the potential biases of such studies and analyses.

Finally, attention should be paid to studies based in resource-limited settings – while there is a good representation of studies in resource-limited settings described in the

Safety review NVP, d4T, AZT, TDF 5 table below, it appears that the key recommendations regarding use of NVP and CD4 cell count are based on trials in an industrialised population (eg van Leth8).

Table 1.1: Summary of NVP toxicity Author Design Location/population Results Ananworanich •Post-hoc •Thailand •incidence of rash was 20% with 200513 analysis of •treatment-naive EFV, 21% with NVP twice daily, patients in adult patients 38% with NVP once daily, 67% randomized trial (n=202) with EFV + NVP (2NN) •multivariate analyses showed assessing females with CD4 cell count ≥250 incidence, ×106 cell/l, high body mass index, severity and rise in CD4 and ALT ≥34U/l at treatment of week 4 to be risk factors for rash rash and risk factors that may predict occurrence of rash Bonjoch 20063 MC, OBS •Spain •no difference in occurrence of •patients receiving adverse events and evolution of NVP-containing liver enzymes in females with regimen for at least 2 CD4 cell counts >250 cells/µL and years (n=613) <250 cells/µL •males with CD4 cell counts >400 cells/µL showed a statistically significant difference in GGT levels than those with CD4 cell counts <400 cells/µL •liver toxicity was infrequent and generally mild Boulle 200714 RET •South Africa •7.6% substituted off NVP due to •treatment-naive toxicity, with most changes adults receiving ART occurring in first few months of (n=2679) therapy and related to hypersensitivity (rash and transaminitis) DART 200815 R, DB •Uganda •2.0% of abacavir patients and •comparison of •treatment-naive 4.7% of NVP patients experienced safety and adults with CD4 <200 adverse events related to tolerability of cells/mm3 (n=600) treatment nevirapine and •2.0% of abacavir and 4.3% of abacavir in NVP patients experienced HSR combination 4.7% of abacavir and 10.0% of with zidovudine/ NVP-treated patients discontinued lamivudine due to toxicity Authors conclude there was a trend toward lower rate of serious adverse reactions in Ugandan adults with low CD4 starting ART regimens with abacavir compared to NVP De Lazzari 20084 MA •4 trials with a pooled •risk of hepatotoxicity in first 3 •meta-analysis total of 410 patients months was 2% in the low CD4 of randomized included group and 4% in the high CD4 studies in which group (OD=1.46; 95% CI: 0.43, virologically 4.98; p=0.54) and risk of suppressed hepatotoxicity at any point in trials patients was similar with HR=0.8 (95% CI:

Safety review NVP, d4T, AZT, TDF 6 Author Design Location/population Results switched to 0.3, 2.5; p=0.80) NVP-containing •authors conclude that current regimen with a warning against NVP use in follow-up ≥3 patients with high CD4 cell counts months. CD4 may not apply to virologically cell counts were suppressed patients switching to considered high NVP; however sample size was if >400 cells/µL small thus results should be for males and > interpreted with caution 250 cells/µL for females Hitti 200412 R, OL •United States •toxicity observed in 5% of •comparison of •treatment-naive nelfinavir-treated patients and NVP or pregnant women 29% of NVP-treated patients nelfinavir (n=38) •all adverse events among women combined with with CD4 cell count >250 cells/µL zidovudine plus were associated with NVP lamivudine •trial suspended due to greater than expected toxicity of NVP Ho 199816 RET •China •5 of 8 patients (62.5%) •adult patients developed NVP-related rash receiving NVP (n=8) resulting in discontinuation of treatment •small number of patients Jamisse 200711 OL •Mozambique •severe hepatotoxicity more •pregnant women common in women with higher receiving NVP, CD4 cell count, 6% vs. 0% for lamivudine and CD4 >250 cells/µL and <250 stavudine or cells/µL, respectively zidovudine (n=146) •rates of skin toxicity, anaemia and peripheral neuropathy did not differ by CD4 cell count group Joao 200617 RET •Brazil •toxicity occurred in 5.6% of •pregnant women patients (n=11) and led to receiving NVP discontinuation in 7 patients (n=197) •no serious liver toxicity except for one case of grade 4 cholestasis •median CD4 was 344 in women without toxicities and 298 in women with toxicities •hepatitis C infection was only significant factor associated with toxicity (OR=15.61; p=0.001) Kiertiburanakul CC •Thailand •history of drug allergy, body 200818 •treatment naive- weight, CD4 cell count and AIDS- patients initiated on defining illness were statistically NVP at low CD4 cell significantly associated with rash counts (n=357) Kondo 200719 RET •Brazil 4 of 31 women with CD4 cell •pregnant women count <250 cells/µL (12.9%) and using NVP (n=133) 23 of 102 women with CD4 cell counts >250 cells/µL developed adverse events •baseline CD4 cell counts, viral loads and transaminases were similar in women who developed skin rashes or liver function abnormalities •no correlation between high CD4

Safety review NVP, d4T, AZT, TDF 7 Author Design Location/population Results cell counts and adverse events for both cutaneous and hepatic reactions Knobel 20082 RET •Spain •142 patients included, 62 in the •patients •drug-naive men and high group and 81 in the low divided into women taking NVP group high CD4 (n=142) •hepatotoxicity developed in (women 4.92% in high group (95% CI: >250cells/µL; 1.79%, 13.50%) and in 6.17% men >400 (955 CI: 2.73%, 13.66%) in low cells/µL) and group (p=1.0) low CD4 (<250 •skin rash developed in 6.56% in and 400 high group (95% CI: 2.67%, cells/µL, 15.70%) and 14.81% of low group respectively) (95% CI: 8.72%, 24.17%) with p=0.18 •authors conclude that recommendations not to use NVP in drug-naive patients on basis of gender and CD4 cell count not supported, however only a small number of patients in study Kumarasamy 20 OL •India •liver enzymes did not significantly 2007 •treatment •treatment- change from time of initiating EFV experienced experienced male to change to NVP and at end of patients using and female patients 12-month follow-up EFV-based with elevated CD4 HAART with cell count (n=36) median CD4 cell count 463 cells/µL switch to NVP- containing HAART Littera 200621 OL •Sardinia •46% of NVP-sensitive patients •assessment of •adult patients had HLA-Cw8 and HLA-B14(65) whether higher treated with NVP antigens compared with 5% of incidence of (n=49) patients tolerant to NVP HSR in Sardinian patients could be linked to HLA antigens Lyons 200610 RET •Ireland •8 of 123 women developed •pregnant women significant hepatotoxicity taking NVP as part of •women who developed combination therapy hepatotoxicity had higher pre- (n=123) treatment CD4 cell counts (median 493 cells/µL compared to 310 cells/µL; p=0.01) Manfredi 200522 OL, OBS •Italy •hepatotoxicity characterised by at •male and female least 2-fold increase of treatment-naive transaminases versus baseline patients (n=623) was significantly linked with NVP, while there was a reduction in hepatotoxicity in EFV group •authors conclude NVP-based HAART may be more hepatotoxic than EFV-based HAART and a

Safety review NVP, d4T, AZT, TDF 8 Author Design Location/population Results role is played by chronic liver disorders Manfredi 20065 OL •Italy •female gender and CD4 cell •comparison of •treatment-naive; count >250 cells/µL did not patients treated patients treated with increase risk of hepatotoxicity with either 2-10 previous ART NVPO of lines; patients on efavirenz-based salvage therapy HAART (n=742) Manfredi 20076 OL •Italy •no increase in liver toxicity, •sub-group •pregnant women cutaneous rash in pregnant analysis of who were either women with high CD4 levels pregnant treatment naive, women taking treated with 2-4 prior NVP in 2006 ART lines or on study salvage therapy (n=27) Manosuthi 200523 RET •Thailand •receiving fluconazole was not •patients receiving predictive of clinical hepatitis, fluconazole for elevated aminotransferase or skin cryptococcal rashes prophylaxis (n=686) •authors conclude that initiation of NVP-based ART among Thai patients with advanced HIV receiving fluconazole is safe and well-tolerated Marazzi 20067 RET •Africa •Grade 3-4 hepatotoxicity •pregnant women occurred in 9.4% of women with treated with fixed- CD4 cell counts <250 cells/µL and dose combinations of 5.9% with CD4 >250 cells/µL NVP-containing •overall incidence of skin rash was regimen (n=703) 2.4% and hepatotoxicity 6.5% •authors conclude that NVP- containing regimens, in pregnant women at all CD4 cell count levels appear to be safe Mocroft 20079 RET •Europe •significantly lower risk of •treatment- discontinuation of NVP in group experienced and with high CD4 cell count and treatment-naive adult treatment-experienced compared patients (n=1,571) to those with high CD4 cell count and treatment-naive (RH=0.56; 95% CI: 0.34, 0.94; p=0.027) •authors conclude that NVP may be safer to initiate in treatment- experienced patients compared to treatment-naïve patients with high CD4 cell counts Phanuphak RET •Thailand •hepatotoxicity occurred in 15.6% 200724 •adult patients of all patients and rash occurred including pregnant in 16.1% of all patients women receiving •gender and baseline CD4 cell NVP-containing count were not associated with HAART (n=409) risk of hepatotoxicity or rash •pregnant women receiving HAART for prevention of mother- to-child transmission of HIV had significantly higher rate of hepatotoxicity than pregnant

Safety review NVP, d4T, AZT, TDF 9 Author Design Location/population Results women receiving HAART for therapy •authors conclude results support continued use of NVP-containing regimens as first-line treatment in developing countries, although pregnant women with high CD4 cell counts may have higher rates of hepatotoxicity Phillips 200725 RET •Canada •66 of 685 patients (9.6%) met •assessment of •treatment-naive definition for HSR hypersensitivity adult patients •no variables identified as risk reaction in receiving NVP- factors using univariate logistic patients containing regimens regression analysis receiving NVP (n=685) •patients with HSR and hepatitis C co-infection had higher risk of death compared to those without HSR or hepatitis C Pitche 200526 RET •France •13.86% developed cutaneous •adults receiving reactions attributable to NVP HAART regimens •multivariate analysis showed containing NVP female gender and plasma HIV (n=101) RNA load >10,000 copies/mL were associated with rash Taiwo 200627 REV •review of NVP •description of occurrence of rash toxicity across world and hepatotoxicity with NVP •concludes that women with CD4 cell count >250 cells/mm3 have increased susceptibility to NVP toxicity Tansuphaswadikul RET •Thailand •incidence of NVP toxicity was 200728 •adult patients 1.09/11 person-months treated with NVP •history of drug allergy and NVP (n=206) toxicity were significantly associated (p=0.006) •concurrent anti-tuberculosis drugs significantly increased risk of NVP associated liver toxicity (p=0.001) Timmermans RET •Netherlands •NVP-related hepatotoxicity 200529 •pregnant women occurred more often in pregnant receiving nelfinavir or women than non-pregnant case NVP (n=372) control group •risk of NVP-associated rash was not increased in pregnant women •no major adverse events occurred and nelfinavir and NVP were well-tolerated during pregnancy Torti 200730 RET •Italy •hepatitis C virus reactivity was •adults receiving associated with 3-fold increase in NVP for first time, risk of developing liver majority (79%) were transaminase elevations (95% CI: treatment- 1.75, 5.3; p<0.001) while gender experienced (n=905) and CD4 cell count did not impact significantly •authors conclude most of the excess rates of raised transaminase levels in patients

Safety review NVP, d4T, AZT, TDF 10 Author Design Location/population Results treated with NVP could be attributed to hepatitis C co- infection van Leth 20058 •Post-hoc •Asia/Australia, North •incidence of rash significantly analysis of America, South higher in female patients with patients in America, South higher CD4 cell counts randomized trial Africa, Europe (2NN) (n=1216) comparing regimens including NVP, EFV or both Wit 200831 RET •Netherlands •patients with undetectable viral •analysis of •male and female load at start of NVP therapy had a patients who patients treated with reduced risk of developing an had NVP in ATHENA HSR discontinued cohort who had •pre-treated patients with low pre- NVP-based discontinued NVP ART and high CD4 cell counts therapy due to due to and detectable VL when switching hypersensitivity hypersensitivity to NVP had significantly higher reactions reactions (n=231) risk of HSR compared with treatment-naive patients who started NVP with low CD4 cell counts •pretreated patients with high CD4 cell counts and undetectable VL did not have an increased risk of developing an HSR •authors conclude that treatment- experienced patients who start NVP with low pre-ART and high CD4 cell counts and undetectable VL have similar likelihood of discontinuing NVP due to HSR as treatment-naive patients with low CD4 cell counts. •However these conclusions were based on a sample of 231 patients NA=not applicable; R=randomized; DB=double-blind; OL=open label; RET=retrospective review; REV=review; MA=meta-analysis; CC=case control; MC=multicentre; OBS=observational; GGT=-glutamyltransferase; HSR=hypersensitivity reaction

The following issues could be addressed using the GRADE format and tables including the GRADE assessment of quality and summary of findings are provided below: - Comparison of patients with high (>250 cells/µL for women and >400 cells/µL for men) and low (<250 cells/µL for women and <400 cells/µL for men) CD4 cell count using NVP with outcomes assessed including hepatotoxicity in pregnant women, treatment-naive patients, treatment- experienced patients, stable virologically suppressed patients and occurrence of rash in stable virologically suppressed patients. - Occurrence of serious adverse events in patients taking NVP or abacavir- containing regimens. - Occurrence of treatment-limiting toxicity in patients taking NVP or nelfinavir- containing regimens.

Safety review NVP, d4T, AZT, TDF 11 - Occurrence of hepatotoxicity in treatment-naive patients taking NVP or efavirenz-containing regimens. - Occurrence of hepatotoxicity in treatment-naive patients with CD4 cell counts >200 cells/µL taking NVP or efavirenz-containing regimens. - Occurrence of rash in treatment-naive patients with CD4 cell counts >200 cells/µL taking NVP or efavirenz-containing regimens. - Occurrence of rash in pregnant and non-pregnant women using NVP.

Safety review NVP, d4T, AZT, TDF 12 Table G1: Question: Should NVP be used in patients with high or unknown CD4? Summary of findings Quality assessment No of patients Effect Relative Importance No of Other Low High Quality Design Limitations Inconsistency Indirectness Imprecision (95% Absolute studies considerations CD4 CD4 CI) hepatotoxicity (follow-up median 39 weeks; standard assays1) 2 observational serious2 no serious no serious serious3 none 90 fewer studies inconsistency indirectness per 1000 5/79 6/67 RR 0 (0 (from 90 IMPORTANT (6.3%) (9%) to 0) fewer to 90 fewer) hepatotoxicity in pregnant women 2 observational serious4 no serious no serious no serious none 59 fewer studies inconsistency indirectness imprecision per 1000 12/160 40/676 RR 0 (0 5 6 (from 59 IMPORTANT (7.5%) (5.9%) to 0) fewer to 59 fewer) hepatotoxicity in treatment- naïve patients 1 observational serious7 no serious no serious no serious none 0 fewer per studies inconsistency indirectness imprecision 3/81 0/61 RR 0 (0 1000 (from 8 9 IMPORTANT (3.7%) (0%) to 0) 0 fewer to 0 fewer) hepatotoxicity in stable virologically suppressed patients (follow-up mean 3 months) 4 randomized no serious no serious no serious no serious none 43 fewer trials10 limitations inconsistency indirectness imprecision per 1000 3/133 12/277 RR 0 (0 ÅÅÅÅ 8 9 (from 43 IMPORTANT (2.3%) (4.3%) to 0) HIGH fewer to 43 fewer)11 rash in stable virologically suppressed patients 4 randomized no serious no serious no serious no serious none 101 fewer 10 17/133 28/277 RR 0 (0 ÅÅÅÅ trials limitations inconsistency indirectness imprecision 8 9 per 1000 IMPORTANT (12.8%) (10.1%) to 0) HIGH (from 101

Safety review NVP, d4T, AZT, TDF 13 fewer to 101 fewer)12 1 for the Jamisse11 study, the hepatotoxicity was defined as ALT or AST equal to or greater than 2.5 times the upper limit of normal 2 non-randomized, non-comparative studies, hence are susceptible to bias 3 as the studies were not designed to examine differences between patients with regard to CD4 cell count and the occurrence of adverse events, the results should be interpreted with caution 4 Both the Marazzi7 and Kondo19 studies were retrospective analyses of clinical files, thus open to bias 5 This is the patient group with CD4 cell count less than or equal to 250 cells/uL 6 This is the patient group with CD4 cell count greater than or equal to 250 cells/uL 7 The Knobel 20082 study is a retrospective study and the authors note that this limits it, as well as the small number of patients (n=142) and consequent limited power 8 this is the group with low CD4 cell count, which was <250 cells/uL for women and <400 cells/uL for men 9 this is the group with high CD4 cell count, which was >250 cells/uL for women and >400 cells/uL for men 10 this reports a meta-analysis of 4 randomized trials of patients who switched to an NVP-containing regimen 11 the between-group difference was not statistically significantly different 12 combined odds ratio for hepatotoxicity, rash or death was 1.17 (95% CI: 0.56, 2.42; p=0.680) indicating no difference between low and high CD4 cell count groups

Although the results vary in that in some studies there was a numerically greater occurrence of hepatotoxicity in patients with low CD4 cell count and in other studies there was a greater occurrence in patients with high CD4 cell count, the meta-analysis (De Lazzari et al., 20084) found no statistically significant difference between those with high and low CD4 cell count in occurrence of hepatotoxicity. However, these results are based on stable virologically suppressed patients and may not extend to other patient groups.

Safety review NVP, d4T, AZT, TDF 14 Table G.2: Occurrence of serious adverse events in patients using NVP compared to abacavir Summary of findings Quality assessment No of patients Effect Importance No of Other Relative Quality Design Limitations Inconsistency Indirectness Imprecision NVP abacavir Absolute studies considerations (95% CI) serious adverse events (follow-up mean 24 weeks) 1 randomized no serious no serious no serious no serious none 20 fewer per trials limitations inconsistency indirectness imprecision 14/300 6/300 RR 0 (0 1000 (from ÅÅÅÅ IMPORTANT (4.7%) (2%) to 0) 20 fewer to HIGH 20 fewer)

Safety review NVP, d4T, AZT, TDF 15 Table G.3: Occurrence of treatment-limiting toxicity in pregnant women using NVP or nelfinavir Summary of findings Quality assessment No of patients Effect Relative Importance No of Other Quality Design Limitations Inconsistency Indirectness Imprecision NVP nelfinavir (95% Absolute studies considerations CI) treatment-limiting toxicity (follow-up median 38 weeks) 11 randomized no serious no serious no serious serious2 none 48 fewer trials limitations inconsistency indirectness per 1000 5/17 1/21 RR 0 (0 ÅÅÅO (from 48 IMPORTANT (29.4%) (4.8%) to 0) MODERATE fewer to 48 fewer)3 1 both NVP and nefinavir were co-administered with AZT and 3TC 2 Although the trial is randomized it was open-label and also had a very small N, with 21 patients treated with nelfinavir and 17 with NVP 3 This represents fewer adverse events associated with nelfinavir compared to NVP. The trial was halted due to greater than expected toxicity and changes in NVP prescribing information.

Safety review NVP, d4T, AZT, TDF 16 Table G.4: Question: Occurrence of hepatotoxicity and rash in patients using NVP or efavirenz? Summary of findings Quality assessment No of patients Effect Relative Importance No of Other Quality Design Limitations Inconsistency Indirectness Imprecision NVP efavirenz (95% Absolute studies considerations CI) hepatotoxicity (follow-up 18 months) 1 observational serious2 no serious no serious no serious none 204 studies1 inconsistency indirectness imprecision fewer per 1000 147/299 66/324 RR 0 (0 (from 204 IMPORTANT (49.2%) (20.4%) to 0) fewer to 204 fewer)3 hepatotoxicity and CD4 cell count 1 randomized serious5 no serious no serious no serious none 198 trials4 inconsistency indirectness imprecision fewer per 1000 148/607 79/400 RR 0 (0 ÅÅÅO 6 7 (from 198 IMPORTANT (24.4%) (19.8%) to 0) MODERATE fewer to 198 fewer) rash and CD4 cell count 1 randomized serious5 no serious no serious no serious none 95 fewer trials inconsistency indirectness imprecision per 1000 76/607 38/400 RR 0 (0 (from 95 ÅÅÅO 6 IMPORTANT (12.5%) (9.5%) to 0) fewer to MODERATE 95 fewer)8 1 the publication does not indicate what other treatments were used in combination with NVP or efavirenz. In addition, some patients were completely treatment-naive and others had received previous ARV treatment but were naive to NVP or efavirenz. 2 open-label observational study thus open to bias 3 indicates there were fewer cases of hepatotoxicity (AST/ALT levels equal to or greater than 2 times the upper limit of normal) observed in patients treated with efavirenz

Safety review NVP, d4T, AZT, TDF 17 4 post-hoc analysis of 2NN trial 5 as this is a post-hoc analysis conducted to investigate which level of CD4 and pVL the risk for subsequent virologic failure was increased and whether there were differences in virologic efficacy between NVP and efavirenz, there is some potential for bias given the post-hoc nature. In addition, toxicity outcomes were not the primary outcomes of the analysis. 6 these results are for patients with CD4 cell count >200 7 there were fewer efavirenz-treated patients with elevated liver enzymes. The paper indicates that increased liver enzymes were associated with CD4 cell count for NVP but there was no clear relationship between this outcome and CD4 cell count for efavirenz 8 there were fewer efavirenz-treated patients reported skin rash. The paper stated that the association between CD4 cell count and rash differed significantly between NVP and efavirenz-treated patients.

Safety review NVP, d4T, AZT, TDF 18 Table G.5: Occurrence of rash and hepatotoxicity in pregnant and non-pregnant women using NVP1 Summary of findings Quality assessment No of patients Effect Relative Importance No of Other Non- Quality Design Limitations Inconsistency Indirectness Imprecision Pregnant (95% Absolute studies considerations pregnant CI) rash 1 observational serious2 no serious no serious no serious none 105 fewer studies inconsistency indirectness imprecision per 1000 5/58 10/95 RR 0 (0 (from 105 3 4 IMPORTANT (8.6%) (10.5%) to 0) fewer to 105 fewer)5 hepatotoxicity 1 observational serious2 no serious no serious no serious none 42 fewer studies inconsistency indirectness imprecision per 1000 11/58 4/95 RR 0 (0 3 4 (from 42 IMPORTANT (19%) (4.2%) to 0) fewer to 42 fewer)6 1 this study compared pregnant and non-pregnant women using NVP or nelfinavir, however it did not directly compare these groups across the two drugs, hence only results for NVP are provided 2 retrospective cohort study and therefore open to bias 3 this refers to pregnant women 4 this refers to non-pregnant women 5 pregnant women experienced numerically fewer cases of rash compared to non-pregnant women, however the difference was not statistically significantly different 6 this indicates pregnant women experienced statistically significantly more cases of hepatotoxicity than non-pregnant women

Safety review NVP, d4T, AZT, TDF 19

2. Stavudine

A total of 213 potentially relevant articles were identified by the literature searches. Articles addressing the use of d4T in women, particularly pregnant women, were selected for a review. Additional articles addressing lactic acidosis in non-pregnant women and males were also included. A total of 14 articles addressing the occurrence of lactic acidosis in patients using stavudine (d4T) are summarised in Table 2.1 below. A summary of case reports is provided in Table 2.2. As none of the studies provided data suitable to the GRADE format, ie non-comparative single-arm studies, the data was not entered into GRADE.

Only 4 articles and 3 case reports are based in resource-limited settings. As such, the applicability of the results of the remaining articles should be considered.

Bolhaar32, Geddes33 and Osler34, all in South African settings, report that the incidence of lactic acidosis is greater in female patients. This concurs with findings from industrialised countries. Laurent et al (2008), on the basis of a study comparing d4T and zidovudine in combination with nevirapine and lamivudine, recommended that given the observed toxicity with d4T there is support for recommendations calling for a gradual switch from d4T to zidovudine.

Only one of the articles (Wade35) focused on pregnant women, as well as 2 of the case reports. As such, no conclusions can be drawn regarding the occurrence of lactic acidosis in pregnant women using d4T.

Given that all articles were either retrospective reviews or open label trials, the biases associated with these types of studies should be taken into consideration when interpreting the results.

Table 2.1: Summary of toxicity for d4T – lactic acidosis Author Design Location/population Results Arenas-Pinto REV •USA, western •90 published cases of lactic 200336 •systematic Europe, Australia acidosis were selected review of lactic (n=90) •51 of 83 patients (61%) were acidosis taking d4T •using data on numbers of HIV- infected individuals in US, risk of lactic acidosis could be 2.5 times greater for women than men •authors conclude nucleoside reverse transcriptase inhibitors and female gender appear to be risk factors for development of lactic acidosis Blanco 200337 RET •NR •percentage of patients with lactate concentration ≥2mmol/L significantly higher in patients receiving d4T plus ddl (71%) compared to those receiving AZT plus 3TC (10%)

Safety review NVP, d4T, AZT, TDF 20 Author Design Location/population Results Bolhaar 200732 RET •South Africa •23 of 1735 patients experienced •adult patients taking lactic acidosis HAART with lactate •overall incidence was 10.6 cases levels ≥4.5mmol/L per 1000 patient-years, with (n=1735) incidence 16.1 case per 1000 patient-years in females and 1.2 cases/1000 patient-years in males •of patients experiencing lactic acidosis and hyperlactatemia, 66 of 67 were receiving d4T Boubaker 200138 RET •Switzerland •use of d4T with or without ddl •adult patients was a risk factor for increased receiving ART serum lactate levels Geddes 200633 OBS •South Africa •in 891 patients taking HAART, 14 •adult patients taking cases of lactic acidosis were HAART (n=891) reported, giving incidence rate of 19 cases per 1000 person-years •all cases were female •all cases were in patients taking d4T, 3TC and one non-NRTI Hocqueloux RET, CC NR •patients with increased lactic acid 200339 concentrations were more likely than controls to receive d4T or ddl Huynh 200340 OL NR •elevated lactic acid levels in 178 patients out of 848 (21%) receiving HAART •significant correlation between d4T or RTV-based regimen and occurrence of hyperlactatemia John 200141 OL •Australia •risk of hyperlactatemia •patients taking significantly associated with d4T HAART Lactic Acidosis RET, CC •10 countries •lactic acidosis associated with International (unspecified) exposure to ddl in all categories of Study Group ‘•adult patients taking exposure duration but most 200742 ART (n=330) strongly associated with exposure <12 months after adjustment for age, gender, CD4 cell count •apart from exposure to d4T or ddl, age above 40 years, female gender and advanced immunosuppression were independent associations with lactic acidosis Laurent 200843 OL •Cameroon •incidence rates of adverse events •assessment of •adult patients were 49.1/100 person-years in efficacy and receiving first-line patients treated with d4T and safety of ARV treatment 41.7/100 person-years in patients patients (n=169) treated with AZT receiving NVP •elevated ananine and 3TC plus aminotransferase activity more d4T or AZT frequent in d4T group (85 vs. 2%) •5 patients developed peripheral neuropathy and 1 lipodystrophy syndrome, all were treated with d4T •authors suggest that in view of d4T toxicity, there is support for recommendations calling for

Safety review NVP, d4T, AZT, TDF 21 Author Design Location/population Results gradual switch from d4T to AZT- based regimens Makinson 200844 REV •worldwide •authors recommend initiating or •review of toxic switching to less toxic nucleoside effects of d4T, analogues when possible, or particularly in lowering d4T dose to 30mg/bd resource-limited settings Osler 200934 CC •South Africa •Female gender (OR=23.4; 95% CI: 4.0–136.6), a baseline weight between 60 and 75kg (OR=4.5; 95% CI: 1.4–14.1) or ≥75kg (OR=19.4; 95% CI: 4.1–82.5) at ART initiation and gaining ≥6 kg in the first 3 months on therapy (OR=3.5; 95% CI: 1.3–9.5) were independent risk factors identifying patients who may subsequently develop symptomatic hyperlactatemia and lactic acidosis Tien 200745 RET •USA •women demonstrated decreases •women taking d4T in weight and body circumference (n=1432) measurements over time whether continuing or discontinuing d4T treatment Wade 200435 OL •USA •no toxicities in women or their •pregnant women infants which required receiving d4T and discontinuation or modification of lamivudine d4T NA=not applicable; NR=not reported; OL=open label; RET=retrospective review; REV=review; CC=case control; OBS=observational; HAART=highly active antiretroviral therapy

Table 2.2: Summary of case reports of lactic acidosis and hyperlactatemia associated with d4T use Author Design Location/population Results Falco 200346 CR, REV NR •female gender, pregnancy and higher body mass index were significantly associated with greater risk of developing severe hyperlactatemia Gerard 200047 CR NR •14 adult patients developed hyperlactatemia and all were receiving d4T Johri 200048 CR •women receiving •describes occurrence of lactic d4T and lamivudine acidosis in 3 women receiving (n=3) d4T and 3TC, 2 of whom died. Lonergan 200349 CR NR •10 patients treated with d4T reported hyperlactatemia Mandelbrot 200350 CR •France •case reports of two women •pregnant women receiving d4T who developed receiving d4T and ddl lactic acidosis (n=2) •authors conclude that the mitochondrial tendencies of nucleoside analogues should be considered when choosing

Safety review NVP, d4T, AZT, TDF 22 Author Design Location/population Results treatment regimens Nelson 200851 CR •Kenya •patient had Fanconi syndrome •woman with and concurrent lactic acidosis advanced HIV taking •authors conclude that d4T and regimen including 3TC should be added to list of d4T and 3TC (n=1) ARVs that can induce Fanconi syndrome Sarner 200252 CR •Uganda •patients developed lactic acidosis •pregnant woman and died treated with d4T and •authors conclude that it is unclear didanosine (n=2) whether pregnancy is a risk factor for lactic acidosis Songa 200753 CR •Uganda •24 patients had documented •patients receiving lactic acidosis combination therapy •all were receiving combination who developed therapy that included d4T hyperlactatemia •835 of patients were female Tripuraneni 200454 CR; REV •USA •zidovudine associated with •patients with lactic higher lactate levels and mortality acidosis (n=58) than d4T and 3TC; association of zidovudine with increased mortality confounded with effect of time REV=review; CR=case report; HAART=highly active antiretroviral therapy

Safety review NVP, d4T, AZT, TDF 23 3. Tenofovir

A total of 333 potentially relevant articles were identified by the literature searches. For this summary 18 articles were selected for review and are provided in Table 3.1 below. There are relatively few articles addressing the renal toxicity of tenofovir used in patients in resource-limited settings, with only two relevant publications. Three of the studies were suitable for entry into GRADE tables, see below following the overall summary.

A review of tenofovir safety by Sax55 stated that the cumulative incidence rate of nephrotoxicity associated with the use of tenofovir is 1% to 4%, with estimated rate of Fanconi syndrome being 0.5% to 2%. Gender, age and race are have not been demonstrated to be associated with tenofovir-induced nephrotoxicity. Roling56 et al (2006) state that severe tubular dysfunction seems to be rare and decreases in glomerular filtration rate have not been clinically significant, particularly in treatment- naive patients. However, given the relative lack of trials and/or reviews addressing toxicity of tenofovir in resource-limited settings, no conclusions can be drawn regarding whether the observed effects in industrialised settings occur in a similar manner in resource-limited settings.

A 2007 report of all postmarketing adverse drug reactions up to April 2005 for 10,343 patients in developed countries (Nelson57) using tenofovir reported that renal serious adverse events were observed in 0.5% of patients and graded elevations of serum creatinine were observed in 2.2% of patients. Risk factors for increased serum creatinine were concomitant nephrotoxic medications, elevated serum creatinine, low body weight, advanced age and lower CD4 cell count. Based on post-marketing data for 455,392 person-years of exposure to tenofovir the most commonly reported serious adverse events were renal events. The authors conclude that the data demonstrate a favourable safety profile for tenofovir and that risk factors for nephrotoxicity can be identified and may be useful in managing patients at risk.

A recent publication by Gallant and Moore58 (2009) described renal outcomes in patients who initiated treatment with tenofovir or an alternate NRTI. The authors report no difference between tenofovir and NRTI-treated patients in estimated glomerular filtration rate and conclude that the evidence is consistent with clinical trials which show no indication of renal toxicity when tenofovir is used as part of an initial regimen.

The studies listed in the table below, with the exception of the Squires59 trial, are either open-label or observational studies. As such, there is potential for bias and results should be interpreted with caution. The Arribas60, Fux61, Moreno62 and Squires59 are reasonably-sized studies, while the remainder have small n’s. There is only one paper assessing the use of tenofovir in pregnant women (Nurutdinova et al., 200863). This paper found that tenofovir was well-tolerated in a population of pregnant women. However the population was small (n=15) thus results may not apply to a wider population.

Table 3.1: Summary of articles addressing toxicity of tenofovir Author Design Location/population Results

Safety review NVP, d4T, AZT, TDF 24 Author Design Location/population Results Ananworanich OL •Thailand •significant reduction in lipids and 200864 •patients •patients with full HIV lactate, but no change in liver treated with RNA suppression enzymes for patients switched to d4T/ddl were treated with d4T/ddl TDF/3TC switched to (n=35) •reversal of lipoatrophy TDF/3TC while receiving saquinavir/ ritonavir Arribas 200860 R, OL •USA •more patients in the AZT/3TC •comparison of •adult treatment- arm discontinued therapy TDF, FTC and naive patients because of adverse events (11% EFV with (n=511) vs. 5%; p=0.01) 3TC/AZT and •no patients discontinued because EFV of renal events Cassetti 200765 OL •Brazil, Argentina, •no patient discontinued due to •extension Dominican Republic renal adverse events study of (n=86) •no patient developed Fanconi randomized, syndrome or renal tubulopathy double-blind during double-blind or extension trial comparing phases TNF to d4T in combination with 3TC and EFV in treatment-naive patients Cirino 200666 RET •USA •40 patients identified from (n=40) individual safety reports who developed hypokalemia associated with the use of TDF •risk factors included RTV or ddl use, lower weight and length of TDF use Elion 200867 OL, MC •USA •6 patients discontinued due to •assessment of •adult treatment- adverse events ATV/r and naive patients •Grade 4 hyperbilirubinemia TDF/FTC (n=100) occurred in 5% of patients Fux 200861 OL •Switzerland •statistically significant association Adult patients between TDF and increased initiating, re-initiating serum alkaline phosphatise. This or discontinuing ARV indicates stimulated bone treatment with and turnover, and when considered without TDF along with TDF-related renal (n=1091) phosphate loss raises concerns that TDF use could result in osteomalacia with a loss of bone mineral density Gupta 200868 RET •USA •case series of 164 patients who (164) had Fanconi syndrome •majority (83%) received PIs plus TDF Hazra 200569 OL •USA •>6% decrease in bone mineral 6-day course of •treatment- density in 5 of 15 patients, for TDF experienced children which 2 patients discontinued monotherapy aged >4 and <18 therapy followed by years (n=18) •during monotherapy 2 patients combination developed Grade 3 hepatic regimen transaminase elevations and were

Safety review NVP, d4T, AZT, TDF 25 Author Design Location/population Results including TDF removed from the study Irizarry-Alvarado CR USA •report of 3 patients who 200970 (n=3) developed Fanconi syndrome and nephrogenic diabetes insipidus with an ARV regimen including TDF and ddl Mauss 200571 CSect, OL •Germany •24 patients on TDF (30%) had •comparison of (n=174) proteinuria >130mg/day compared TDF-treated to 5 (5%) of control patients patients with (p<0.001) patients on •patients on TDF showed lower ARV therapy mean glomerular filtration rate never treated estimated by creatinine clearance with TDF or cystatin C clearance compared to control patients (p<0.05) •impaired GFR based on creatinine clearance in 46% of TDF patients compared to 32% of control patients (p=0.04) Moreno 200662 OBS, MC •Spain •5 patients (0.39%) experienced •observational •treatment- renal dysfunction and study to identify experienced adult discontinued TDF treatment the most patients (n=1286) Authors conclude that risk of frequently- developing nephrotoxicity related occurring to TDF leading to discontinuation toxicities with is rare and usually occurs when NRTI treatment other risk factors exist Nelson 200757 RET •Europe, Australia, •renal serious adverse events North America observed in 0.5% of patients (n=10,343) •serum creatinine elevations reported in 2.2% of patients •based on post-marketing safety data the most commonly reported serious adverse event were renal events •authors conclude data demonstrates a favourable safety profile for TDF Nurutdinova RET •USA •11 women (73%) had abnormal 200863 •pregnant women laboratory results using tenofovir as •GFR remained above part of HAART 90mL/min/1.73m2 in all women (n=15) except one •no mother-to-child transmission of HIV Padilla 200572 RET, CC •US •serum creatinine elevations (n=316) occurred in 4.1% of patients treated with a tenofovir-containing regimen compared to 0.5% treated with other ARV regimens •2 patients discontinued TDF treatment due to creatinine elevation Pozniak 200673 R, OL •US •two treatment groups had •comparison of •treatment-naive comparable renal safety TDF, FTC and patients •decreases in GFR in both EFV versus (n=517) treatment groups at week 96 3TC, AZT and •no confirmed creatinine EFV abnormalities and no cases of

Safety review NVP, d4T, AZT, TDF 26 Author Design Location/population Results Fanconi syndrome Riordan 200974 RET UK and Ireland •12 (7.5%) experienced serious •HIV-infected adverse events and stopped TDF children (n=159) treatment •5 had renal toxicity Squires 200359 R, DB, PC, MC •North America, •incidence of Grade 3 or 4 Europe, Australia adverse events was similar for •adult patients with TDF (13%) and placebo (14%) detectable viral groups. replication despite •laboratory abnormalities higher in current therapy placebo group (n=552) •no evidence of TDF-related toxicity •no withdrawals due to serum creatinine or phosphorous level Young 200975 CS •USA (n=19) •median 12-month change in •change in renal estimated creatinine clearance profile in from baseline of -0.3 mL/min patients with (range, -32.2 to +23.6) and the pre-existing median change in GFR of -0.1 renal mL/min/1.73 m2 (range, -49.8 to dysfunction +29.5) treated with •confirmed worsening of kidney TDF disease in 5 of 19 patients (26.3%) •authors conclude TDF use can be considered in patients with pre- existing or current renal dysfunction and can be closely monitored for worsening of renal function NA=not applicable; R=randomized; DB=double-blind; OL=open label; RET=retrospective review; REV=review; CC=case control; CS=cohort study; CSect=cross-sectional; MC=multicentre; OBS=observational; PI=protease inhibitor; GFR=glomerular filtration rate

The following issues could be addressed using the GRADE format and tables including the GRADE assessment of quality and summary of findings are provided below: - Occurrence of creatinine increase in patients taking TDF-containing regimens compared to other regimens. - Occurrence of proteinuria in patients taking TDF-containing regimens compared to other regimens. - Discontinuation due to serious adverse events in patients taking TDF- containing regimens compared to other regimens. - Occurrence of Grade 3 to 4 adverse events in patients taking TDF-containing regimens compared to other regimens.

Safety review NVP, d4T, AZT, TDF 27 Table G.6: Occurrence of adverse events in patients using TDF-containing regimens compared to other regimens Summary of findings Quality assessment No of patients Effect TDF- other Relative Importance No of Other Quality Design Limitations Inconsistency Indirectness Imprecision containing ARV (95% Absolute studies considerations regimens regimens CI) creatinine increase 1 observational serious1 no serious no serious no serious none 5 fewer per studies inconsistency indirectness imprecision 5/122 1/194 RR 0 (0 1000 (from 5 2 IMPORTANT (4.1%) (0.5%) to 0) fewer to 5 fewer) proteinuria 1 observational serious3 no serious no serious serious4 none 54 fewer per studies inconsistency indirectness 24/82 5/92 RR 0 (0 1000 (from 54 IMPORTANT (29.3%) (5.4%) to 0) fewer to 54 fewer) discontinuation due to adverse events 15 randomized no serious no serious no serious no serious none 125 fewer per trials limitations6 inconsistency indirectness imprecision 12/231 29/232 RR 0 (0 1000 (from ÅÅÅÅ IMPORTANT (5.2%) (12.5%) to 0) 125 fewer to HIGH 125 fewer) Grade 3 or 4 adverse events 17 randomized no serious no serious no serious no serious none 137 fewer per trials limitations inconsistency indirectness imprecision 49/368 25/182 RR 0 (0 1000 (from ÅÅÅÅ IMPORTANT (13.3%) (13.7%) to 0) 137 fewer to HIGH 137 fewer)8 1 retrospective case control study (Padilla et al., 2005), thus open to bias. Also, a relatively small n, thus results should be interpreted with caution 2 statistically significant difference in occurrence of elevated creatinine levels between tenofovir -treated patients and those on other regimens (p=0.018) 3 The Mauss et al (2005) trial was a cross-sectional study pharmacokinetic comparing patients treated with TDF to those never treated with TDF 4 As the Mauss study was a PK study with assessments taken after 24 hours, it may not represent the effects of TDF over a longer time period 5 Comparison of TDF with FTC and EFV versus AZT plus 3TC and EFV in treatment-naive patients (Arribas et al., 2008) 6 The Arribas et al (2008) trial, while randomized, was open-label and thus susceptible to bias

Safety review NVP, d4T, AZT, TDF 28 7 Squires et al (2003), a randomized, double-blind trial comparing TDF and placebo in patients with detectable viral replication despite current ARV therapy 8 There was no significant difference between patients receiving TDF and those receiving placebo in the occurrence of serious adverse events

While the Arribas et al (2008)60 study indicated that there was greater discontinuation in tenofovir-treated patients, the Squires et al (2003)59 trial found no significant difference in the occurrence of Grade 3 or 4 adverse events between patients taking tenofovir as part of their ARV regimen or other regimens. However, it should be noted that these trials are in different populations (Arribas et al (2008)60 in treatment-naive patients and Squires et al (2003)59 in treatment-experienced patients).

Safety review NVP, d4T, AZT, TDF 29 4. Zidovudine

A total of 762 potentially relevant articles were identified by the literature searches and of these, 14 were selected for review and are included in the table below.

Lower body mass and lower CD4 cell count appear to be factors related to risk of developing anaemia (Ssali76; Isaakidis77). A trial assessing the prevention of mother- to-child HIV transmission (Sperling et al., 199878) reported that anaemia was significantly more common in infants receiving AZT compared to those receiving placebo (19% versus 8%; p=0.001) however the authors concluded that the trial did not identify any problems that would alter the recommendations for the routine use of AZT for the prevention of mother-to-child HIV transmission. No other trials specifically addressed the occurrence of anaemia in pregnant women using AZT. A greater decrease in haemoglobin levels in patients using AZT and also being treated for hepatitis C has resulted in the recommendation that AZT is not used in patients receiving treatment for hepatitis C79.

Table 4.1: Summary of occurrence of adverse events associated with zidovudine in resource-limited settings Author Design Location/population Results Alvarez 200580 RET •USA •mean decrease in haemoglobin •HIV and hepatitis C was significantly greater for those co-infected patients using AZT compared to those not (n=217) taking AZT (p<0.0001) •use of AZT associated with an increased risk of anaemia Aurpibul 200881 RET •Thailand •following switch from d4T to AZT •children aged •children receiving in children there were statistically 2-15 years HAART (n=78) significant decreases in receiving haemoglobin level, WBC count HAART with and ANC, but decreases were not NVP or EFV clinically significant as no patient plus 3TC and had clinical symptoms of d4T and had anaemia, leukopenia or switched from neutropenia d4T to AZT Bae 200882 NC •Botswana •21.7% of HAART-exposed •nested cohort •infants who had or infants were neutropenic within had not been compared to 5.5% of infants randomized exposed to maternal exposed to AZT (p<0.01) controlled trial HAART in Mashi indicating that in-utero exposure to compare study (n=69) to HAART was associated with toxicities in increased risk of neutropenia infants who had •neutropenia no longer associated or had not been with antenatal exposure to exposed to HAART after 1 month of age maternal •postnatal exposure to HAART not HAART associated with haematologic or hepatic toxicities Curkendall 200783 RET •USA •incidence of anaemia was 24.3 •AZT-naive patients per 100 person-years for patients (n=1649) initiating AZT compared to 8.1 per 100 person-years for those using a regimen not including AZT •patients initiating treatment with

Safety review NVP, d4T, AZT, TDF 30 Author Design Location/population Results AZT at greater risk of anaemia than those initiating treatment excluding AZT Huffam 200784 RET, OBS •Asia-Pacific region •anaemia occurred in 57 of 433 •analysis of •adult patients in (13%) of patients treated with AZT factors TAHOD (TREAT in first 6 months of treatment associated with Asia HIV •baseline anaemia was strongest anaemia and Observational predictive factor for subsequent time to Database) cohort anaemia and anaemia reported discontinuation taking ART less frequently in those on AZT of treatment in containing 3 or more who had prior ART experience patient agents (n=433) •patients who commenced commencing treatment with AZT more likely to AZT or stop within first 9 months of switching from treatment than those who d4T commenced d4T Idoko 200285 OL •Nigeria •two patients (5%) withdrew due •non- •adult patients with to adverse events comparative CD4 cell count •one patient reported anaemia, trial of triple between 100-500 but did not withdraw regimen cells/mm3 (n=40) including nelfinavir, zalcitabine and zidovudine Isaakidis 200877 RET, OBS •Cambodia •within one year of switch, 21.9% •adults •adults receiving of patients developed anaemia systematically d4T-based HAART Grades 1 to 4 and 7.1% switched from (n=527) developed severe anaemia d4T to AZT- Grades 3 to 4 based HAART •low body mass index and low CD4 cell count <200 cells/µL were factors associated with anaemia •authors conclude switch to AZT led to satisfactory clinical outcomes however there was increased burden of anaemia Moh 200586 R, OL •Cote d’Ivoire •118 of 498 patients had Grade 3- •pre- •adult treatment- 4 neutropenia (56.3/100 person- randomisation naive patients years), 23 had Grade 3-4 phase of trial in (n=498) anaemia (9.6/100 person-years) which patients •one patient discontinued AZT received due to neutropenia and 11 continuous discontinued due to anaemia standard •authors note that almost all of the HAART severe neutropenia disappeared regimen after cotrimoxazole was stopped, including AZT. which suggests an accentuated All patients also interaction between cotrimoxazole received and AZT cotrimoxazole Moyle 200487 MA •randomized trials •haemoglobin levels decreased comparing AZT and with AZT treatment and increased d4T in triple-therapy with d4T treatment regimens •all grades of anaemia and (n=6 trials) neutropenia were more common with AZT-based regimens compared to d4T-based regimens •the occurrence of Grade 1 to 4

Safety review NVP, d4T, AZT, TDF 31 Author Design Location/population Results neutropenia ranged from 26% to 43% in the AZT trials and 15% to 31% in the d4T trials Nunez 200879 OL •Spain •mean decrease in haemoglobin •patients co-infected from baseline to week 4 with HIV and significantly greater in patients hepatitis C (n=389) receiving AZT compared to other drugs (-3.09 vs. -2.3g/dL; p<0.001) •lower baseline haemoglobin and greater haemoglobin drops during first 4 weeks of therapy were independent predictors of moderate anaemia •authors advise that given the availability of other antiretrovirals, it is advised to avoid AZT treatment while receiving hepatitis C treatment Sperling 199878 R, DB •USA, France •anaemia significantly more •assessment of •pregnant women common in infants receiving AZT safety of with CD4 cell counts (19%) compared to those maternal-infant >200×106/l and no receiving placebo (8%), p=0.001 AZT regimen maternal indications •no association between AZT use for antiretroviral and newborn structural therapy (n=424) abnormalities Ssali 200676 •post-hoc •Uganda •219 patients (6.6%) developed analysis of •treatment-naive Grade 4 anaemia by week 48 patients using adult patients with •female patients and those with AZT in DART CD4 cell count <200 lower haemoglobin, lower CD4 trial cells/mm3 (n=3,314) cell count and lower body mass index at baseline were at significantly higher risk (p<0.05) for anaemia •authors conclude rate of anaemia is higher than that observed in studies from industrialised countries, likely due to population characteristics and higher rate of concurrent HIV-related clinical events Violari 200888 R, OL •South Africa •22 of 377 children (total) had •infants were •infants 6 to 12 neutropenia (13%) and 7 (4%) randomized to weeks of age with had anaemia receive HIV infection (n=377) •4 children switched from AZT to lopinavir- d4T due to neutropenia or ritonavir, anaemia zidovudine and lamivudine therapy as early therapy for 96 weeks or 40 weeks or as deferred therapy Willig 200989 CS •Peru •baseline weight <60kg was found •determine •treatment-naive to more than double risk of early factors adult patients discontinuation of AZT-containing associated with (n=546) regimens (HR=2.52; 95% CI:

Safety review NVP, d4T, AZT, TDF 32 Author Design Location/population Results abbreviated first 1.46, 4.35) regimen •discontinuation rates increased durability with lower baseline weights, with •determine 14% discontinuation for 70kg, factors 16% for 60-70kg, 26% for 50-59k associated with and 44% for 50kg toxicity-related •AZT rather than ddl/d4T as part discontinuation of an NRTI backbone was found of AZT to increase risk of discontinuation up to 120 days (adjusted HR=2.09; 95% CI: 1.22, 3.57) however after 120 days use of AZT was found to decrease risk of regimen discontinuation compared to ddl/d4T (adjusted HR=0.52; 95% CI: 0.28, 0.95) NA=not applicable; NR=not reported; MA=meta-analysis; OL=open label; R=randomized; DB=double-blind; RET=retrospective review; REV=review; CC=case control; OBS=observational; CR=case report; CS=cohort study; HAART=highly active antiretroviral therapy; NC=nested cohort

5. Additional reviews

There are a number of reviews of the use of ARVs and associated toxicity in limited- resource settings. These reviews are not particular to a specific drug, but instead cover a range of drugs. They are relevant in that they address the occurrence of adverse events in populations in resource-limited settings. The key results and conclusions of the reviews are summarised in the table below.

Table 5.1: Additional reviews Author Design Key results/conclusions Calmy 200690 •assessment of efficacy •NVP responsible for discontinuation for 42 and safety of generic of 655 patients, due to initiation of fixed dose combination rifampicin-based antituberculosis treatment ARV treatment in (n=15), skin toxicity (n=12), liver toxicity resource-poor settings (n=11) or unknown (n=4). •observational cohort •9 patients discontinued due to d4T toxicity using fixed dose – 5 for severe neuropathy, 2 for combination of 3TC, d4T lipodystrophy and 2 for unknown reason and NVP Forna 200791 •assessment of clinical •toxicities developed in 411 (40%) of toxicity in patients patients receiving ART in Uganda •peripheral neuropathy 36%, rash 6%, as part of a home-based hypersensitivity reaction 2%, acute AIDs care program hepatitis, anaemia, pancreatitis or lactic •treatment consisted of acidosis ≤0.5% and other 13% d4T plus 3TC plus NVP •no patients discontinued treatment due to (96% of patients) or EFV toxicity (4%). Kumarasamy •report of adverse events •most common adverse events following 3 200892 occurring with generic months treatment were rash (15.2%), HAART treatment in a peripheral neuropathy (9.0%), clinically population in southern significant anaemia (5.4%), hepatitis (3.4%). India •women were significantly more likely to experience lactic acidosis •in patients with 1 year follow-up, NVP was

Safety review NVP, d4T, AZT, TDF 33 Author Design Key results/conclusions associated with development of rash and d4T associated with development of peripheral neuropathy Manosuthi •assessment of mortality •hyperlactatemia was associated with d4T 200893 rate and risk factors after in 114 (91.2%) of patients, 5 (4.0%) using hyperlactatemia in d4T+ddl, 4 (3.2%) using ZDV+ddl and patients receiving ART 2(1.6%) using ddl •retrospective review of •patients with low body weight and high patients who were serum lactate level were at a higher risk of diagnosed with mortality symptomatic hyperlactatemia Murphy 200794 •review of adverse events •key events identified are lactic acidosis, associated with ART and lipoatrophy, pancreatitis, peripheral how to deal with these neuropathy, hyperlipidaemia, anaemia, events in resource-limited hypersensitivity, hepatotoxicity, fat settings accumulation, insulin resistance, Nuesch 200695 •retrospective review of •over 3.7 years there were 142 Grade 3-4 randomized controlled toxicities in 101 patients (24.2%). Hepatic trials of ART in Thailand, toxicity occurred in 33 (7.9%), assessing toxicity of ART hypercholesterolaemia in 57 (13.7%) and anaemia in 16 (3.8%) •ARVs used included ZDV, d4T, ddl, EFV, SQR, RTV, IDV Palacios •observational study of •all patients (n=1391) had developed 200596 toxicity of ARV treatment ≥adverse events that justified including d4T, AZT, 3TC, discontinuation of treatment with the ddl and ABC associated drug •drugs with highest discontinuation rates were d4T (65.7%) and AZT (12.7%) •most frequent adverse events were lipoatrophy and peripheral neuropathy •lipoatrophy most commonly associated with d4T (480 of 550 cases) and anaemia most commonly associated with AZT (70 of 77 cases) Siegfried •systematic review of •rash leading to temporary or permanent 200697 d4T, 3TC and NVP withdrawal of drug reported to be 12.3% for combination therapy NVP once daily, 6.5% for NVP twice daily, (Cochrane review) 3.8% with EFV, 13.9% for NVP+EFV Grade 3-4 liver toxicity occurred in 13.6% on NVP once daily, 8.3% on NVP twice daily, 4.5% on EFV, 9.1% on NVP+EFV Subbaraman •review of research on •spectrum of adverse events related to 200798 adverse effects of drugs HAART in developing countries may differ used in resource- from that in developed countries due to high constrained regions prevalence of conditions such as anaemia, malnutrition and tuberculosis and initial presentation with advanced disease. The severity of adverse effects may vary due to host genetics and delays attributable to inadequate laboratory monitoring. •article reviews current knowledge about toxicities related to HAART in resource- limited regions •authors conclude that initiating HAART before advance immunosuppression, titrating doses in fixed dose combinations to differences in patient weight, providing more

Safety review NVP, d4T, AZT, TDF 34 Author Design Key results/conclusions laboratory monitoring and providing access to less toxic drugs may decrease incidence of toxicities related to HAART in resource- limited settings van •evaluation of ART •76% of patients reported at least one Oosterhout results in resource-poor adverse event 200599 setting in Malawi •rash occurred in 45 (26%) of patients •drug used was fixed •no statistically significant difference in dose combination of d4T, occurrence of adverse events between men 3TC and NVP and women

Safety review NVP, d4T, AZT, TDF 35 References

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Safety review NVP, d4T, AZT, TDF 42 in Blantyre, Malawi. Tropical Medicine & International Health 2005;10(5):464-70.

Safety review NVP, d4T, AZT, TDF 43 Annex 1 Post-hoc relative risk analyses

Given that the GRADE software did not provide an assessment of relative effect (relative risk), post-hoc analyses were conducted for studies with available data. The questions and the outcomes from the GRADE tables were used to form the basis of these comparisons. Two of the GRADE questions were excluded: 1) hepatotoxicity in treatment-naive patients using NVP – this could not be calculated given no response in patients with high CD4 cell count; and 2) hepatotoxicity and rash in stable virologically suppressed patients using NVP – did not calculate relative risk for these values as data in GRADE table was based on a meta-analysis which provided odds ratio results (see Table 1.1 above for summary of results).

The relative risk results for the comparisons are provided below in Table 1 for the NVP studies and Table 2 for the TDF studies. A meta-analysis combining the Marazzi7 and Kondo19 NVP studies in pregnant women was conducted given the similarity in outcomes and patient populations. There was not statistically significant heterogeneity, which indicates it is reasonable to combine these two studies.

For all analyses, the relative risk results concur with the results reported by the studies in terms of statistical significance or non-significance. However, the results presented below should be interpreted with caution, given that the analyses are post-hoc and the majority of studies are not randomised, double-blind trials but instead are retrospective reviews or of other study design which leaves them open to potential sources of bias.

Table 1: Results of RR analyses – NVP studies Question Trial Comparison RR (95% CI) Should NVP be used in patients with high or Low CD4 High CD4 unknown CD4? (NVP) (NVP) Hepatotoxicity •Jamisse 200711 5/79 (6.3%) 6/67 (9.0%) 0.707 •pregnant women (0.24, 2.10) receiving NVP-based regimens •open-label •Mozambique •RR=0.707 (0.24, 2.10) which indicates no significant difference in hepatotoxicity between those with low and high CD4 cell count •results correspond to publication, which found no significant difference in hepatotoxicity (p=0.55). However, 6% of patients with high CD4 cell count had severe hepatotoxicity compared to none (0%) with low CD4 cell count (p=0.02). These results should be interpreted with caution, given small n and open-label nature of the study. Hepatotoxicity in •Marazzi 20067 and Kondo 12/160 40/676 1.04 pregnant women 200719 (*7.5%) (5.9%) (0.22, 4.93) •pregnant women Cochran receiving NVP-based Q=1.64 regimens p=0.20 •retrospective reviews •Brazil (Marazzi) and Africa (Kondo)

Safety review NVP, d4T, AZT, TDF 44 Question Trial Comparison •RR=1.04 (0.22, 4.93) indicates no significant difference between pregnant women with low and high CD4 cell count in the occurrence of hepatotoxicity. •results of meta-analysis concur with results of both studies. Marazzi et al (2006)7 had concluded that NVP-containing regimens, in pregnant women at all CD4 cell count levels appear to be safe. Serious AEs in patients using NVP vs. abacavir NVP Abacavir Serious AEs •DART 200815 14/300 6/300 2.33 •treatment-naive adults (4.7%) (2.0%) (0.94, 5.81) with CD4 <200 cells/mm3 •randomized, double-blind trial comparing NVP and ABC both in combination with ZDV and 3TC •Uganda •RR=2.33 (0.94, 5.81) indicates no significant difference between patients receiving NVP or abacavir-based regimens in the occurrence of serious AEs. •results concur with publication which indicated no significant difference in serious AEs between NVP and abacavir (HR=0.42; 95% CI: 0.16, 1.09; p=0.06) Treatment-limiting toxicity in pregnant women NVP Nelfinavir using NVP or nelfinavir Treatment-limiting •Hitti 200412 5/17 (29.4%) 1/21 (4.8%) 6.18 toxicity •treatment-naive pregnant (1.08, 38.07) women •open-label study comparing NVP and nelfinavir both in combination with ZDV and 3TC •USA •RR=6.18 (1.08, 38.07) indicates significantly more treatment-limiting toxicity occurred in pregnant women using NVP compared to those using nelfinavir. However results should be interpreted with caution given the small n and wide confidence intervals. •the publication did not report a p value, however the study was halted due to greater than expected toxicity and changes in NVP prescribing information. Hepatotoxicity and rash in NVP vs. efavirenz NVP Efavirenz Hepatotoxicity •Manfredi 200522 147/299 66/324 2.41 •treatment-naive patients (49.2%) (20.4%) (1.90, 3.09) •NVP and EFV-based regimens •open-label, observational study •Italy •RR=2.41 (1.90, 3.09) indicates significantly more patients treated with NVP-based regimens developed hepatotoxicity compared o those treated with EFV-based regimens •the publication reported that hepatotoxicity characterized by at least a 2- fold increase in serum transaminase levels compared to baseline values was significantly linked with NVP compared to EFV (p<0.00001). Hepatotoxicity •van Leth 20058 148/607 79/400 1.23 •post-hoc analysis of (24.4%) (19.8%) (0.97, 1.57)

Safety review NVP, d4T, AZT, TDF 45 Question Trial Comparison Rash patients in 2NN trial 76/607 38/400 1.32 comparing regimens (12.5%) (9.5%) (0.92, 1.90) containing NVP and EFV •Asia/Australia, North America, South America, South Africa, Europe •RR=1.23 (0.97, 1.57) and 1.32 (0.92, 1.90) indicate no significant difference between NVP and EFV-based regimens in occurrence of hepatotoxicity or rash •publication reports that women with a CD4 cell count >200 × 106 cells/l had a significantly greater risk to develop rash compared to men with the same high CD4 cell count (OR=2.0; 95% CI: 1.2, 3.4). Rash and hepatotoxicity in pregnant vs. non- Pregnant Non- pregnant women using NVP (NVP) pregnant (NVP) Rash •Timmermans 200529 5/58 (8.6%) 10/95 0.82 •pregnant women (10.5%) (0.30, 2.16) Hepatotoxicity receiving NVP or NFV 11/58 4/95 (4.2%) 4.50 •retrospective review (19.0%) (1.59, 12.91) •Netherlands •RR=0.82 (0.30, 2.16) indicate no significant difference between pregnant and non-pregnant women receiving NVP in occurrence of rash. •results concur with publication, which reported that risk of NVP-associated rash was not increased in pregnant women. •RR=4.50 (1.59, 12.91) indicates a significant difference in pregnant and non-pregnant women receiving NVP. •results concur with publication which reported that NVP-related hepatotoxicity occurred more often in pregnant women than non-pregnant case control group. •relative risk results should be interpreted with caution given retrospective nature of the study and potential for bias, as well as post-hoc nature of the analysis.

Table 2: Results of RR analyses – TDF studies Question Trial Comparison RR (95% CI) Adverse events in patients using TDF-based TDF Other regimens versus other regimens regimens Creatinine increase •Padilla 200572 5/122 (4.1%) 1/194 (0.5%) 7.95 •comparison of TDF- (1.25, 50.99) containing regimens and other ARV regimens •retrospective review •USA •RR=7.95 (1.25, 50.99) indicates that more patients treated with TDF- based regimens experienced creatinine increase compared to those treated with other regimens. Results should be interpreted with caution given retrospective nature of the study, post-hoc analysis and the wide confidence intervals. Proteinuria •Mauss 200571 24/82 5/92 (5.4%) 5.39 •comparison of TDF- (29.3%) (2.25, 13.20) treated patients and those treated with other regimens •cross-sectional •Germany

Safety review NVP, d4T, AZT, TDF 46 Question Trial Comparison •RR=5.39 (2.25, 13.20) indicates a significantly greater proportion of TDF- treated patients experienced proteinuria >130mg/day compared to those treated with other regimens. •results concur with publication, which reported significant difference in proportion of TDF-treated patients with proteinuria >130mg/day (p<0.001) compared to those treated with other regimens. •results should be interpreted with caution given small n and the cross- sectional design of the study. Discontinuation due •Arribas 200860 12/231 29/232 2.41 to AEs •comparison of TDF, FTC (5.2%) (12.5%) (1.28, 4.56) and EFV with 3TC/AZT and EFV in adult treatment-naive patients •randomized, open-label •USA •RR=2.41 (1.28, 4.56) indicates a significantly greater proportion of patients treated with 3TC/AZT and EFV compared to those treated with TDF, FTC and EFV discontinued treatment dues to AEs. •results concur with publication which reported that significantly more patients in the AZT/3TC arm discontinued therapy because of adverse events (p=0.01). Grade 3 or 4 AEs •Squires 200359 49/368 25/182 0.97 •randomized, double-blind (13.3%) (13.7%) (0.62, 1.52) comparison of TDF or placebo added to existing ARV regimens •North America, Europe, Australia •RR=0.97 (0.62, 1.52) indicates that there was no significant difference in the proportion of patients reporting Grade 3 or 4 AEs in those adding TDF to their regimen compared to placebo. •results concur with publication, which concluded that there was no evidence of TDF-related toxicity in the trial.

Safety review NVP, d4T, AZT, TDF 47