17th Expert Committee on the Selection and Use of Essential Medicines Geneva, 2009

APPLICATION FOR LISTING OF ZIDOVUDINE/LAMIVUDINE/ABACAVIR FOR THE TREATMENT OF HIV-1 INFECTION ON THE WHO MODEL LIST OF ESSENTIAL MEDICINES

FEBRUARY 2009

zidovudine/lamivudine/abacavir – HIV infection 1 TABLE OF CONTENTS 1. Summary statement of proposal for inclusion, change, or deletion...... 3 2. Name of focal point in WHO submitting the application...... 3 3. Name of the organization(s) consulted and/or supporting the application ...... 3 4. International Nonproprietary Name (INN) ...... 3 5. Formulation proposed for inclusion...... 3 6. International availability ...... 3 7. Category of listing requested ...... 4 8. Information supporting the public health relevance ...... 4 8.1 Epidemiological information on disease burden...... 4 8.2 Assessment of current use...... 5 8.3 Target population...... 5 9. Treatment details...... 6 9.1 Dosage regimen ...... 6 9.2 Treatment duration...... 6 9.3 Reference to WHO and other clinical guidelines ...... 6 9.4 Need for special diagnostic or treatment facilities and skills ...... 6 10. Summary of comparative effectiveness...... 7 10.1 Identification of clinical evidence...... 7 10.1.1 Search strategy...... 7 10.1.2 Systematic reviews identified ...... 7 10.1.3 Selection/exclusion of particular data...... 7 10.2 Summary of available data...... 9 10.2.1 Appraisal of quality...... 9 10.2.2 Outcome measures...... 9 10.2.3 Summary of results –randomized trials ...... 10 10.2.4 Summary of results –non-randomized studies...... 14 10.3 Summary of available estimates of comparative effectiveness ...... 16 11. Summary of comparative evidence on safety ...... 17 11.1 Estimate of total patient exposure to date...... 17 11.2 Description of adverse effects/reactions ...... 17 11.3 Identification of variation in safety due to health systems and patient factors ...... 19 11.4 Summary of comparative safety against comparators ...... 20 12. Summary of available data on comparative cost and cost-effectiveness...... 20 12.1 Range of costs of the proposed medicine ...... 20 12.2 Comparative cost-effectiveness (presented as range of cost per routine outcome) ...... 21 13. Regulatory status...... 21 14. Availability of pharmacopoeial standards ...... 23 15. Proposed text for the WHO Model Formulary ...... 23 References...... 23 Attachment 1...... 26 Attachment 2...... 33

zidovudine/lamivudine/abacavir – HIV infection 2 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

zidovudine/lamivudine/abacavir fixed dose combination tablet for the treatment of HIV-1 infection

1. Summary statement of proposal for inclusion, change, or deletion The combination tablet of zidovudine/lamivudine/abacavir (AZT/3TC/ABC) is proposed for inclusion on the WHO Model List of Essential Medicines for the treatment of HIV infection. The principal reasons for requesting this inclusion are as follows: ƒ Modern anti-retroviral therapy (ART) mandates the use of three or more drugs and this can require a large number of tablets to be swallowed each day and used lifelong. ƒ The efficacy of current ART can be compromised with quite small reductions in adherence. ƒ Fixed dose combinations of appropriate antiretroviral drugs improve adherence and efficacy and may reduce the development viral resistance. ƒ The WHO guidelines for Antiretroviral Therapy for HIV Infection in Adults and Adolescents (WHO Guidelines) emphasise the need for a public health approach with simplification of treatment regimens, particularly the use of fixed dose drug combinations that enable once or twice daily dosing and also facilitates the programmatic & logistics aspects. The Guidelines also emphasise the selection of suitable combinations and consideration of price and cost-effectiveness. ƒ The WHO Guidelines recommend first line therapy with a dual nucleoside reverse transcriptase inhibitor (NRTI) and a non-nucleoside reverse transcriptase (NNRTI). The Guidelines identify a triple NRTI regimen as an alternative for first-line ART in situations where NNRTI options provide complications and to preserve the PI drugs for second-line treatment (eg in women with CD4 counts of 250-350 cells/mm3; coinfection with viral hepatitis or tuberculosis; severe adverse reactions to nevirapine or efavirenz; infection with HIV-2). The Guidelines recommend AZT/3TC/ABC as a triple NRTI combination, along with AZT/3TC/TDF.

2. Name of focal point in WHO submitting the application

3. Name of the organization(s) consulted and/or supporting the application

4. International Nonproprietary Name (INN) zidovudine/lamivudine/abacavir

5. Formulation proposed for inclusion Combination tablet comprised of zidovudine 300mg and lamivudine 150mg and abacavir 300mg.

6. International availability Section 13 (see Table 13.1) provides a list of countries in which AZT/3TC/ABC has regulatory approval and a list of the manufacturers. The drug manufactured zidovudine/lamivudine/abacavir – HIV infection 3 by GlaxoSmithKline has WHO pre-qualification status in all countries, while the versions manufactured by Ranbaxy and Hetero Drugs do not have WHO pre- qualification status.

7. Category of listing requested Listing is requested as a fixed dose combination of the antiretrovirals group, including three nucleoside reverse transcriptase inhibitors.

8. Information supporting the public health relevance 8.1 Epidemiological information on disease burden Current estimates indicate that 33 million people were living with HIV in 2007, with a total of 2.7 million new infections in 2007 (WHO 2008). Developing countries, in particular sub-Saharan African countries, are the most affected countries in the world, with 27 million people with HIV (82%). The majority of AIDS-related deaths occur in sub-Saharan Africa (1.5 million of the 2 million deaths in 2007) (UNAIDS 2008).

Table 8.1.1 summarises the number of people living with HIV, the number of AIDS deaths and the number of new infections world-wide in 2007.

Table 8.1.1: Summary of HIV infection and AIDS deaths in 2007 People living with HIV 2007 AIDS deaths 2007 Region (low-high estimate) (low-high estimate) Sub-Saharan Africa 27,000,000 1,500,000 (20,500,000-23,600,000) (1,300,000-1,700,000) South and 4,200,000 340,000 Southeast Asia (3,500,000-5,300,000) (230,000-450,000) East Asia 740,000 40,000 (480,000-1,100,000) (24,000-63,000) Latin America 1,700,000 63,000 (1,500,000-2,100,000) (49,000-98,000) North America 1,200,000 23,000 (760,000-2,000,000) (9,100-55,000) Western and 730,000 8,000 Central Europe (580,000-1,000,000) (4,800-17,000) Eastern Europe 1,500,000 58,000 and Central Asia (1,100,000-1,900,000) (41,000-88,000) Middle-east and 380,000 27,000 North Africa (280,000-510,000) (20,000-35,000) Caribbean 230,000 14,000 (210,000-270,000) (11,000-16,000) Oceania 74,000 1,000 (66,000-93,000) (<1,000-1,400) Total 33,000,000 2,000,000 (30,000,000-36,000,000) (1,800,000-2,300,000) Source: http://www.unaids.org/en/KnowledgeCentre/HIVData/GlobalReport/2008/2008_Global _report.asp

Table 8.1.2 provides the number of people receiving antiretroviral (ART) therapy in 2007 in low and middle income countries.

zidovudine/lamivudine/abacavir – HIV infection 4 Table 8.1.2: Summary of ARV treatment Number receiving ARV therapy ARV therapy Number requiring coverage Region December 2007 therapy 2007 December 2007 Sub-Saharan Africa 2,120,000 7,000,000 30% Latin America and 390,000 630,000 62% Caribbean East, South and 420,000 1,700,000 25% Southeast Asia Eastern Europe 54,000 320,000 17% and Central Asia Middle-east and 7,000 100,000 7% North Africa Total 2,990,000 9,700,000 31% Source: www.who.int/hiv/pub/towards_universal_access_report_2008.pdf

Although the proportion of people receiving ARV therapy of those requiring therapy in low and middle income countries has increased to 31% in 2007, from 24% in 2006 and 7% in 2003, the proportion treated in these countries remains low (WHO, UNAIDS and UNICEF 2008).

Given that successful therapy requires high levels of adherence, fixed dose combinations (FDCs), which eliminate high pill burden associated with combination therapy, assist in achieving successful therapy. The WHO Model List of Essential Medicines states that “In order to simplify treatment, facilitate storage and distribution, and improve patients’ adherence to the treatment plan, the Committee recommends and endorses the use of fixed- dose combinations and the development of appropriate new fixed-dose combinations”. The advantages of FDCs, combined with the recommendation of a triple NRTI regimen as alternate first-line therapy (WHO Guidelines) lead to this request to include AZT/3TC/ABC on the WHO Model List. Evidence demonstrating the efficacy and safety of AZT/3TC/ABC is provided in Sections 10.2 and 11.

8.2 Assessment of current use Combination treatment with zidovudine, lamivudine and abacavir is considered an alternate first-line treatment for HIV infection. A survey of use in resource-limited settings by the WHO in 2006 (Renaud-Thery et al., 2007) reported that fewer than 1% of patients were receiving alternate first- line regimens, either AZT+3TC+ABC or d4T+3TC+ABC. A second survey in 2007 (WHO, UNAIDS and UNICEF 2008) found that in the 30 countries which responded, 3% of patients were using an “other” first-line regimen. Given that it is estimated that up to 3 million individuals are taking antiretroviral therapy (WHO, UNAIDS and UNICEF 2008), this suggests that less than 100,000 will be using AZT/3TC/ABC.

8.3 Target population Patients with HIV infection.

zidovudine/lamivudine/abacavir – HIV infection 5 9. Treatment details 9.1 Dosage regimen The recommended dose in adults is one tablet twice daily, giving a total daily dose of zidovudine 600mg, lamivudine 300mg and abacavir 600mg.

9.2 Treatment duration Treatment duration is continuing or until treatment has to be changed because of adverse effects, contraindications or the development of viral resistance.

9.3 Reference to WHO and other clinical guidelines The WHO “Antiretroviral Therapy for HIV Infection in Adults and Adolescents” Guidelines (WHO, 2006) recommend a triple NRTI regimen as alternate first-line therapy, for use when NNRTI options provide complications and to preserve the PI drugs for second-line treatment (eg in women with CD4 counts of 250-350 cells/mm3; coinfection with viral hepatitis or tuberculosis; severe adverse reactions to nevirapine or efavirenz; infection with HIV-2). The combination of zidovudine, lamivudine and abacavir is one of two triple NRTI regimens recommended by the WHO Guidelines.

The US Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, updated in November 2008, (Hammer et al., 2008) state that the combination of AZT/3TC/ABC is generally not recommended and should be used only when a preferred or an alternate NNRTI-based or a PI-based regimen is less desirable because of concerns about toxicities, drug interactions or regimen complexity.

In contrast to the WHO and American Guidelines, the British HIV Association Guidelines (Gazzard 2008) do not consider the use of triple nucleoside therapy in situations where NNRTI options provide complications or to preserve PI options, and instead state that currently no triple NRTI regimen can be recommended.

9.4 Need for special diagnostic or treatment facilities and skills The WHO Guidelines (2006) recommend that facilities be available to perform the following tests: confirmation of HIV infection status; measurement of CD4 (where possible); haemoglobin measurement if initiation of AZT is being considered; pregnancy test in women if initiation of efavirenz is being considered; screening for tuberculosis and malaria; and diagnostic testing for other co-infections and opportunistic diseases where clinically indicated.

zidovudine/lamivudine/abacavir – HIV infection 6 10. Summary of comparative effectiveness 10.1 Identification of clinical evidence 10.1.1 Search strategy Medline, Embase and the Cochrane Library were searched for relevant trials comparing AZT/3TC/ABC with other HIV regimens. The search terms used were: 1. zidovudine 2. lamivudine 3. abacavir 4. trizivir 5. (1 and 2 and 3) or 4 and randomized controlled trial 6. adverse events 7. toxicity 8. 5 and (3 or 4)

10.1.2 Systematic reviews identified One systematic review including AZT/3TC/ABC was identified (Bartlett et al., 2006). This review assessed triple combination therapy in antiretroviral-naïve HIV-infected adults. All trials presented in this application were included in the Bartlett review. The review found that NNRTI and ritonavir-boosted PI regimens were virologically superior to NRTI (including AZT/3TC/ABC) and PI regimens over 48 weeks.

There is a protocol for a review of Trizivir in the Cochrane Library, however it is dated 2005 and has not advanced beyond a protocol since that time.

10.1.3 Selection/exclusion of particular data Trials were included if they were randomized controlled trials of the fixed dose combination of AZT/3TC/ABC compared to another HIV regimen. Three non-randomized studies (two retrospective reviews and one open-label single arm study) were also included. Table 10.1.3.1 lists the selected trials and studies.

Table 10.1.3.1: Selected data Trial Design Randomized controlled trials Bonjoch et al., 2005 •randomized, open-label, multicentre, noninferiority trial comparing coformulatedAZT/3TC/ABC (Trizivir) and coformulated AZT/3TC (Combivir) plus NVP in HIV-1-infected patients receiving successful HAART •Spain Fischl et al., 2003 •randomized, open-label comparison of AZT/3TC/ABC (Trizivir) and AZT/3TC (Combivir) plus ABC in treatment-experienced patients •US Gulick et al., 2004 •randomized, double-blind trial comparing AZT/3TC/ABC and AZT/3TC plus EFV and AZT/3TC/ABC plus EFV in treatment- naive patients •US

zidovudine/lamivudine/abacavir – HIV infection 7 Trial Design Katlama et al., 2003 •randomized, open-label comparison of AZT/3TC/ABC and current treatment (two NRTIs plus a PI or a NNRTI or triple NRTI treatment) in patients receiving successful HAART treatment •Europe Katlama et al., 2003b •substudy of Katlama et al (2003) assessing patients previously treated with NNRTI who were randomized to AZT/3TC/ABC or to continue current treatment •Europe Kumar et al., 2006 •randomized, open-label trial comparing AZT/3TC/ABC, AZT/3TC plus NVP or d4T 40mg + 3TC 150mg + NFV 1250mg/bd in treatment-naive patients •US, Central America Kumar et al., 2006b •randomized, open-label trial comparing AZT/3TC/ABC and AZT/3TC plus ATV in treatment-naive patients •US Lafeuillade et al., 2003 •substudy of Katlama et al (2003) assessing changes in metabolic abnormalities and clinical lipodystrophy •Europe Markowitz et al., 2005 •randomized, open-label trial in treatment-naive patients. Following 48 week induction phase of treatment with AZT/3TC/ABC plus EFV patients were randomized to continue AZT/3TC/ABC plus EFV or simplify to AZT/3TC/ABC •US Non-randomized studies Berenguer et al., 2006 •retrospective case series study of patients treated with AZT/3TC/ABC (76% treated with fixed dose combination tablet, 13% treated with fixed dose AZT/3TC plus ABC, 11% treated with separate components) •Spain Nassar et al., 2003 •retrospective review of an HIV database comparing treatment- naive patients treated with AZT/3TC/ABC or AZT/3TC plus EFV •US Srikantiah et al., 2007 •open-label, single arm study of tuberculosis/HIV-co-infected patients treated with AZT/3TC/ABC •Uganda AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; NVP=nevirapine; EFV=efavirenz; NFV=nelfinavir; ATV=atazanavir; HAART=highly active antiretroviral treatment

Only one study, an open-label single arm study set in Uganda of tuberculosis and HIV co-infected patients (Srikantiah et al., 2007) was set in a resource-poor country. One trial (Kumar et al., 2006) included centres in resource-poor countries (Central America), while all other trials were based in the US or Europe. None of the available trials specifically assessed the comparative efficacy and safety of AZT/3TC/ABC in populations identified by the WHO Guidelines as those for whom a triple NRTI regimen is an alternative (those in whom NNRTI options provide additional complications, eg women with CD4 cell counts between 250 and 350 cells./mm3, patients with viral hepatitis coinfection, tuberculosis coinfection, severe reactions to NVP or EFV and HIV-2 coinfection. The Srikantiah et al (2007) study did assess tuberculosis-co-infected patients, however this was a single-arm, open-label study that does not provide comparative results.

As such, the trial results should be interpreted with caution when

zidovudine/lamivudine/abacavir – HIV infection 8 considering use in resource-poor countries. While drug efficacy is likely to be similar across settings (Lawn et al., 2005; Ivers et al., 2005), programmatic factors such as the availability and accessibility of services will influence treatment success.

10.2 Summary of available data 10.2.1 Appraisal of quality The table below provides an assessment of the trial quality of the randomized trials included in this application. Non-randomized studies are not included in this assessment.

Table 10.2.1.1: Assessment of quality of randomized trials presented in the application Generation allocation ITT Description Objective Trial Blinding sequences analysis withdrawals outcomes Bonjoch 2005 open-label not reported 9 9 9 Fischl 2003 open-label not reported 9 9 9 Gulick 2004 double-blind not reported 9 9 9 Katlama 2003 open label not reported 9 9 9 Katlama open-label not reported 9 9 9 2003b Kumar 2006 open-label not reported 9 9 9 Kumar 2006b open-label not reported 9 9 9 Lafeuillade open-label not reported 9 9 9 2003 Markowitz open-label not reported 9 9 9 2005 Nassar 2003 open-label not reported 9 9 9

All trial were open-label except one (Gulick et al., 2004). All trials used objective outcomes and all used intent-to-treat (ITT) analyses. Overall, the trials are of reasonable quality. A GRADE profile of the trials is provided in Attachment 1.

10.2.2 Outcome measures Table 10.2.2.1 provides the primary outcome measures used in the selected trials.

Table 10.2.2.1: Outcome measures used in the selected trials Trial/study Primary outcomes Randomized controlled trials Bonjoch 2005 •proportion of patients with HIV RNA <200 copies/mL at week 48 Fischl 2003 •proportion of patients who maintained <0.5 log10 increase from baseline in HIV RNA (virologic success) Gulick 2004 •virologic failure, defined as two successive HIV RNA values of ≥200 copies/mL at least 16 weeks after randomization Katlama 2003 •treatment failure, defined as either virological failure (viral load ≥0.5400 copies/mL on two consecutive occasions) or premature discontinuation of randomized study treatment Katlama 2003b •proportion of patients with HIV RNA <50 copies/mL Kumar 2006 •change from baseline in LDL-C Kumar 2006b •proportion of patients with HIV RNA <50 copies/mL Lafeuillade 2003 •occurrence of clinical lipodystrophy Markowitz 2005 •proportion of patients with HIV RNA <50 copies/mL •time to treatment failure

zidovudine/lamivudine/abacavir – HIV infection 9 Trial/study Primary outcomes Non-randomized studies Berenguer 2006 •treatment failure, defined as reduction in viral load <1 log during first 112 weeks of treatment; failure to achieve a viral load < lower limit of quantification; rebound to two consecutive viral loads ≥ lower limit of quantification after achieving viral load < lower limit of quantification Nassar 2003 •time to virologic failure, defined as two consecutive viral load >400 copies/mL Srikantiah 2007 •virological suppression (<400 copies/mL; <50 copies/mL) and CD4 cell response

10.2.3 Summary of results –randomized trials

Following are presented the key results of the randomized trials assessing the effectiveness of the fixed dose combination of AZT/3TC/ABC.

Bonjoch et al (2005) In the Bonjoch et al (2005) trial patients with suppressed viral load and receiving a first-line treatment of containing two NRTIs plus PIs or NNRTIs were randomized to receive AZT/3TC/ABC (n=68) or AZT/3TC plus NVP (n=66). Treatment duration was 48 weeks. Table 10.2.3.1 provides key trial results.

Table 10.2.3.1: Results of Bonjoch et al (2005) at 48 weeks ATZ/3TC/ABC ATZ/3TC + NVP Outcome (n=68) (n=66) Difference (95% CI) p value Proportion with HIV 71% 73% -2.1% 0.783 RNA <200 copies/mL (-17.4%, 13.1%) Proportion with HIV 65.1% 63.2% 0.01 0.897 RNA <50 copies/mL (-0.123, 0.214) CD4 cell count change +96 cells/µL +43 cells/µL NR NR from baseline AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; NVP=nevirapine; NR=not reported

There was no statistically significant difference between AZT/3TC/ABC and AZT/3TC plus NVP in the maintenance of viral suppression (HIV RNA <200 copies/mL) at 48 weeks. The authors conclude that the fixed dose combination of AZT/3TC/ABC is non- inferior to AZT/3TC plus NVP. The authors also state that patients receiving effective first-line PI or NNRTI-based HAART can safely simplify treatment with AZT/3TC/ABC or AZT/3TC plus NVP, as long as their likelihood of harbouring nucleoside analogue-associated resistance mutations (NAMS) is low.

zidovudine/lamivudine/abacavir – HIV infection 10 Fischl et al (2003) The Fischl et al (2003) trial sought to establish the clinical equivalence of the fixed dose combination of AZT/3TC/ABC with AZT/3TC combined plus ABC. Antiretroviral-experienced patients were randomized to treatment with AZT/3TC/ABC (n=97) of AZT/3TC plus ABC (n=98) for 24 weeks. Clinical equivalence of treatments was established if the lower 95.1% confidence limit (LCL) for the difference in proportion of virologic success was –0.12 or greater. Table 10.2.3.2 provides the results of the trial.

Table 10.2.3.2: Results of Fischl et al (2003) ATZ/3TC/ABC ATZ/3TC + ABC Outcome (n=97) (n=98) 95.1% LCL Virologic successa 80/97 (83%) 75/98 (77%) -0.026 HIV RNA <400 copies/mL 82/83 (99%) 77/83 (93%) 0.021 HIV RNA <50 copies/mL 74/83 (89%) 64/83 (77%) 0.038 a <0.5 log10 increase from baseline in HIV RNA through week 24 AZT=zidovudine; 3TC=lamivudine; ABC=abacavir

All outcomes demonstrated clinical equivalence of treatments. As such, the fixed dose combination of AZT/3TC/ABC can be substituted with AZT/3TCV plus ABC to simplify treatment and reduce pill burden.

Gulick et al (2004) The Gulick et al (2004) trial compared three PI-sparing regimens in antiretroviral-naive patients, the triple nucleoside regimen of AZT/3TC/ABC, a NNRTI combined with two NRTIs (AZT/3TC plus EFV) and a NNRTI combined with three NRTIs (AZT/3TC/ABC plus EFV). The trial was randomized, double-blind, with a median follow- up of 32 weeks. The two efavirenz groups were combined for comparison with the AZT/3TC/ABC group. Table 10.2.3.3 provides the trial results.

Table 10.2.3.3: Results of Gulick et al (2004) ATZ/3TC/ABC EFV groups Outcome (n=382) (n=765) Virologic failure 82/382 (21%) 85/765 (11%) HIV RNA <200 copies/mL 74% (95% CI: 65, 83) 89% (85, 93) HIV RNA <50 copies/mL 61% (95% CI: 50,72) 83% (78, 88) CD4 change from baseline 174 (95% CI: 151, 197) 173 (95% CI: 152, 194) (cells/mm3) AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; EFV=efavirenz

The time to virologic failure (two successive HIV RNA values <200 copies/mL at least 16 weeks after randomisation) was significantly shorter in the AZT/3TC/ABC group (p<0.001). While changes in CD4 cell counts did not differ significantly between groups, there was an advantage for the combined EFV group on other outcomes, and AZT/3TC/ABC was virologically inferior to a regimen containing EFV and two or three nucleosides. The AZT/3TC/ABC arm of the trial was halted in 2002 due to meeting the prespecified stopping guidelines. An update of the Gulick et al (2004) trial was provided in 2007 (Ribaudo et al., 2007). This analysis reported the unpooled comparison and zidovudine/lamivudine/abacavir – HIV infection 11 found at 48 weeks of follow-up that 98 of 382 AZT/3TC/ABC patients had virologic failure compared with 50 of 383 patients in the AZT/3TC/ABC plus EFV group (HR=2.21; 97.5% CI: 1.32, 3.7) and with 60 of 382 in the AZT/3TC plus EFV group (HR=1.85; 95% CI: 1.14, 3.01). The authors conclude that the analysis confirms the findings and that the triple nucleoside regimen was virologically inferior to the four drug and standard care three drug regimens.

Katlama et al (2003) In the Katlama et al (2003) trial, treatment-experienced patients were randomized to either continue their current treatment (n=103) or switch to AZT/3TC/ABC (n=106). Table 10.2.3.4 provides the results of the trial.

Table 10.2.3.4: Results of Katlama et al (2003) AZT/3TC/ABC Continued treatment Difference Outcome (n=106) (n=103) (95% CI) Virologic failure a 23/106 (22%) 23/103 (22%) 1.2% (-10.1, 12.5) HIV RNA <50 copies/mL 79/106 (75%) 71/103 (69%) NR CD4 increase from 26 cells/µL 26 cells/µL NS baseline a viral load ≥400 copies/mL or premature discontinuation of study drug AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; NR=not reported; NS=not significant

Time to treatment failure was similar between the groups (HR=0.97; 95% CI: 0.54, 1.72). There was a statistically significant reduction in cholesterol and triglyceride levels observed in the AZT/3TC/ABC group. The authors conclude that switching to AZT/3TC/ABC offers a simplified regimen with equivalent efficacy and significant improvement in lipid levels compared to continued triple therapy.

Katlama et al (2003b) This paper reported a subgroup analysis of the Katlama et al (2003) trial, focusing on patients who had previously been treated with NNRTI. The forty patients who previously been treated with NNRTI were randomized to remain on current treatment (n=20) or switch to AZT/3TC/ABC (n=20). Table 10.2.3.5 provides the results of this subgroup analysis.

Table 10.2.3.5: Results of Katlama et al (2003b) ATZ/3TC/ABC Continued NNRTI Outcome (n=40) (n=40) p value HIV RNA <50 copies/mL 15/40 (75%) 13/40 (65%) 0.49 Change in TC -1.35mmol/L -0.41mmol/L26 cells/µL <0.001NS AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; NR=not reported; NS=not significant

Kumar et al (2006) The Kumar et al (2006) paper focused on lipid and metabolic effects, comparing antiretroviral-naive patients treated with AZT/3TC/ABC (n=85), AZT/3TC plus NFV (n=88 and d4T plus 3TC plus NFV (n=81). Virological outcomes were also assessed. Results following 96 weeks treatment are provided in Table 10.2.3.6.

zidovudine/lamivudine/abacavir – HIV infection 12 Table 10.2.3.6: Results of Kumar et al (2006) D4T/3TC/NFV AZT/3TC+NFV AZT/3TC/ABC Outcome (regimen 1) (regimen 2) (regimen 3) Comparisons Change in TC +53mg/dL +38mg/dL +12mg/dL 1vs. 3: <0.001; 2 vs. 3: <0.001 Change in LDL-C +29mg/dL +19mg/dL -8mg/dL Change in HDL +5mg/dL +4mg/dL +5mg/dL NS Change in TG +101mg/dL +72mg/dL +75mg/dL NS HIV RNA <50 27/41 (66%) 34/47 (72%) 35/45 (78%) NS copies/mL HIV RNA 36/41 (88%) 42/47 (89%) 41/45 (91%) NS <400copies/mL Change CD4 +289 cells/µL +270 cells/µL +265 cells/µL NS AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; NFV=nevirapine; d4T=stavudine; TC=total cholesterol; LDL-C=low density lipoprotein cholesterol; HDL=high density lipoprotein; TG=triglycerides; NS=not significant

In this trial, AZT/3TC/ABC demonstrated similar virological efficacy to the comparators, with significantly less of an increase in LDL-C.

Kumar et al (2006b) In the Kumar et al (2006b) trial, antiretroviral-naive patients were randomized to 48 week treatment with AZT/3TC/ABC (n=139) or AT/3TC plus atazanavir (ATV) (n=140). Table 10.2.3.7 provides the results of the trial.

Table 10.2.3.7: Results of Kumar et al (2006b) ATZ/3TC/ABC AZT/3TC + ATV Outcome (n=139) (n=140) Virologic failure 13% 12% HIV RNA <50 copies/mL 62% 59% HIV RNA <50 copies/mL if baseline viral load 39% 60% <100,000 copies/mL AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; ATV=atazanavir

The authors conclude that AZT/3TC/ABC was non-inferior to AZT/3TC plus ATV, however the limit of non-inferiority was not mentioned in the report.

Lafeuillade et al (2003) This paper reported a substudy of Katlama et al (2003), assessing the occurrence of clinical lipodystrophy (LD) and metabolic abnormalities in patients who switched to AZT/3TC/ABC or remained on current treatment. Table 10.2.3.8 provides the trial results.

Table 10.2.3.8: Results of Lafeuilllade et al (2003) AZT/3TC/ABC Continued treatment Outcome (n=106) (n=103) p value Proportion with at least one LD 28% 42% 0.03 symptom Median number of LD symptoms per 2 4 0.016 participant Median change in blood glucose +2.00mg/dL +0.50mg/dL 0.492 Change in TC -.080mmol/L -0.44mmol/L <0.001 Change in TG -0.17mmol/L +0.01mmol/L 0.006 AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; LD=lipodystrophy; TC=total cholesterol; TG=triglycerides

zidovudine/lamivudine/abacavir – HIV infection 13 Lafeuillade et al (2003) demonstrated that a switch to AZT/3TC/ABC was associated with an improvement in clinical lipodystrophy and lipid abnormalities.

Markowitz et al (2005) In the Markowitz et al(2005) trial, antiretroviral-naive patients were treated with AZT/3TC/ABC plus EFV for an induction phase of 48 weeks. Patients were then randomized to either continued treatment with AZT/3TC/ABC plus EFV or a simplified regimen of AZT/3TC/ABC for a 48 week maintenance phase. Results of the maintenance phase are provided in Table 10.2.3.9 below.

Table 10.2.3.9: Results of Markowitz et al (2005) AZT/3TC/ABC AZT/3TC/ABC + EFV Outcome (n=141) (n=141) Comparison Virologic failure a 16/141 (11%) 8/141 (6%) P=0.134 HIV RNA <50 copies/mL 108/141 (77%) 111/141 (79%) 95% CI: -8.6%, 5.7%; p=0.70 CD4 increase +42 cells/mm3 +30 cells/ mm3 NR a viral load ≥400 copies/mL or premature discontinuation of study drug AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; EFV=efavirenz; NR=not reported

At week 96, 99.8% of patients in the AZT/3TC/ABC group reported perfect adherence, compared to 79.6% in the AZT/3TC/ABC plus EFV group. The authors concluded that simplification to AZT3TC/ABC following induction including EFV maintained virologic control and improved adherence.

10.2.4 Summary of results –non-randomized studies

Following are presented the key results of the non-randomized studies assessing the efficacy of AZT/3TC/ABC.

Berenguer et al (2006) The Berenguer et al (2006) study was a retrospective database review designed to assess the efficacy and safety of AZT/3TC/ABC in the treatment of HIV infection in patients not included in clinical trials. The authors state that selection bias is a limitation of clinical trials because of the tendency to include motivated and medication-adherent patients. While there may be some validity to this argument, the randomization and blinding of controlled clinical trials allows for a more unbiased assessment of the comparative efficacy of treatments, in contrast to retrospective reviews which remain susceptible to selection bias, as well as a number of sources of other sources of bias, including reporting bias and hindsight bias.

The Berenguer et al (2006) study reviewed 730 antiretroviral-naive patients treated with AZT/3TC/ABC, of which 76% were treated with fixed dose combination, 13% were treated with AZT/3TC fixed dose combination plus separate ABC, and 11% were treated with each of the three drugs administered separately. The paper does not report results for these differing treatment types separately. Table 10.2.4.1 provides the number and proportion of patients experiencing treatment failure. zidovudine/lamivudine/abacavir – HIV infection 14

Table 10.2.4.1: Results of Berenguer et al (2006) Treatment failure N (%) ITT analysis of observed dataa Total with treatment failure 105 (14.40%) Viral load reduction <1log after 12 weeks 21 (2.9%) Detectable viraemia after 24 weeks 46 (6.3%) Viral rebound 38 (5.2%) Event × 100 person years (95% CI) 13.53 (10.20, 15.40) ITT analysis assuming lost to follow-up failed therapyb Total with treatment failure 165 (22.92%) Adverse event 104 (14.2%) Voluntary abandonment 27 (3.7%) Virologic failure 18 (2.5%) ART intensification 6 (0.8%) Structure treatment interruptions 5 (0.7%) Other reasons 5 (0.7%) Event × 100 person years (95% CI) 22.92 (19.42, 26.42) a loses to follow-up or treatment switches not necessarily considered treatment failures if there were no virologic failures. Data from patients lost to follow-up censored at last visit AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; ART=antiretroviral therapy b loses to follow-up or treatment switches classified as failures AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; ART=antiretroviral therapy

A multivariate Cox proportional hazards regression analysis found the following variables independently associated with treatment failure: <90% adherence some time during the first year of therapy (HR=4.248; 95% CI: 2.640, 6.833); methadone use (HR=2.116; 95% CI: 1.180, 3.797); baseline viral load (HR=1.651 per log (95% CI: 1.190, 2.292); and the presence of AIDS defining condition prior to treatment (HR=1.639; 95% CI: 1.009, 2.662). The authors conclude that treatment with AZT/3TC/ABC is a reasonable option for antiretroviral- naïve patients with a viral load <100,000 copies/mL in whom preferred regimens are not advisable.

Nassar et al (2003) In Nassar et al (2003) a retrospective database review assessed virologic failure with fixed dose combination AZT/3TC/ABC (n=229) and AZT/3TC/EFV (n=250) in antiretroviral-naive patients. Table 10.2.4.2 provides results for time to virologic failure.

Table 10.2.4.2: Results of Nassar et al (2003) AZT/3TC/ABC AZT/3TC/EFV Outcome (n=229) (n=250) p value Time to virologic failure 441 days 1220 days <0.001 Time to virologic failure baseline viral 729 days 1056 days 0.02 load <100,000 copies/mL Time to virologic failure baseline viral 148 days 802 days 0.001 load >100,000 copies/mL AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; EFV=efavirenz

There was a shorter time to virologic failure for patients treated with AZT/3TC/ABC compared to those treated with AZT/3TC/EFV (1220 days; p<0.001) for all patients, with results not differing for those with baseline viral load greater than or less than 100,000 copies. The

zidovudine/lamivudine/abacavir – HIV infection 15 authors conclude that AZ/3TC/EFV is superior to AZT/3TC/ABC in antiretroviral-naive patients. While the results indicate greater efficacy for efavirenz combined with AZT and 3TC compared to the fixed dose combination of AZT/3TC/ABC, the study was not randomized and thus results should be interpreted with caution, given the potential for bias.

Srikantiah et al (2007) In the Srikantiah et al (2007) study, 34 patients co-infected with tuberculosis and HIV were treated with open-label AZT/3TC/ABC for 24 weeks. Table 10.2.4.3 provides the study results.

Table 10.2.4.3: Results of Srikantiah et al (2007) AZT/3TC/ABC Outcome (n=34) HIV RNA <400 copies at 12 weeks 29 (85%) HIV RNA <400 copies at 24 weeks 31 (91%) HIV RNA <50 copies at 24 weeks 26 (76%) Median change from baseline in CD4 cell count 81 cells/µL AZT=zidovudine; 3TC=lamivudine; ABC=abacavir

The authors claim that the virologic suppression rate of (<50 copies/mL) of 76% compares to suppression rates of 66% to 88% observed in studies of efavirenz or nevirapine-based antiretroviral therapy in Thailand and South Africa. The authors conclude that nucleoside-based regimens represent an option fir select populations, such as those co-infected with tuberculosis who may be unable to tolerate NNRTI. The authors acknowledge that their study has limited sample size, however they state the data suggest that the development and continued evaluation of such regimens for tuberculosis/HIV co- infection is warranted.

10.3 Summary of available estimates of comparative effectiveness The available evidence provides conflicting results regarding the efficacy of AZT/3TC/ABC. The Gulick et al (2004) trial demonstrated that AZT/3TC/ABC was virologically inferior to regimens including efavirenz, such that the AZT/3TC/ABC arm of the trial was halted. The Nassar et al (2003) retrospective database review comparing AZT/3TC/ABC and AZT/3TC/EFV concluded that AZT/3TC combined with EFV was superior to AZT/3TC/ABC. The Bartlett et al (2006) review found that triple NRTI regimens including AZT/3TC/ABC were virologically inferior to NNRTI and ritonavir-boosted PI-based regimens.

All other trials presented indicated that AZT/3TC/ABC was non-inferior to the comparator regimen.

A recent review of AZT/3TC/ABC (Keiser and Nassar, 2007) stated that compared to efavirenz-based regimens, AZT/3TC/ABC has not performed well, however it is being considered for maintenance strategies, as switching a patient to AZT/3TC/ABC has been shown to have similar virologic efficacy as continuing PI or efavirenz-based regimens.

zidovudine/lamivudine/abacavir – HIV infection 16 While one of the studies (Srikantiah et al (2007) assessed the efficacy and safety of AZT/3TC/ABC in patients co-infected with tuberculosis, this was a single-arm, open-label study that does not provide a comparative assessment, and may be open to bias. None of the remaining trials specifically assessed AZT/3TC/ABC in populations whom NNRTI regimens may prove complicated (women with CD4 cell counts between 250 and 350 cells/mm3, patients with viral hepatitis coinfection, tuberculosis coinfection, severe reactions to NVP or EFV and HIV-2 coinfection).

Given the lack of specific evidence and the varying trial results, the efficacy of AZT/3TC/ABC in the population recommended in the WHO Guidelines cannot be ascertained, however the evidence indicating non-inferiority does suggest AZT/3TC/ABC may have a role as an alternate treatment.

11. Summary of comparative evidence on safety 11.1 Estimate of total patient exposure to date

The most recent survey of antiretroviral use in resource-limited settings (WHO, UNAIDS and UNICEF 2008) reported that 3% of patients were using an “other” first-line regimen. Given that it is estimated that 3 million individuals in these countries are using antiretroviral treatment, less than 100,000 will have been exposed to AZT/3TC/ABC.

11.2 Description of adverse effects/reactions

The Product Information for the fixed dose combination of AZT/TC/ABC contains the following black box warnings:

Hypersensitivity reactions: serious and sometimes fatal hypersensitivity reactions have been associated with abacavir. Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in two or more of the following groups: fever; rash; gastrointestinal (including nausea, vomiting, diarrhoea, abdominal pain); constitutional (including general malaise, fatigue or achiness); respiratory (including dyspnoea, cough or pharyngitis). It is recommended that patients discontinue AZT/3TC/ABC as soon as a hypersensitivity reaction is suspected and patients are to permanently discontinue AZT/3TC/ABC if hypersensitivity cannot be ruled out. The Product Information states that patients are never to restart AZT/3TC/ABCor any other abacavir-containing product.

Haematologic toxicity: Zidovudine has been associated with haematology toxicity including neutropenia and severe anaemia. Prolonged use of AZT has been associated with symptomatic myopathy.

Lactic acidosis and severe hepatomegaly: The use of NRTIs, alone or in combination, has been associated with the occurrence of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases.

Hepatitis B exacerbations: In patients co-infected with hepatitis B, the discontinuation of lamivudine has been associated with exacerbations of hepatitis B.

zidovudine/lamivudine/abacavir – HIV infection 17 A recent paper (DAD Study Group, 2008) reported an excess incidence of myocardial infarction in patients treated with abacavir. This finding was based on a cohort of over 30,000 HIV-infected patients in the US, Europe and Australia. Whether the findings apply to other populations is unknown.

Tables 11.2.1 to 11.2.5 provide a summary of the comparative adverse event data for AZT/3TC/ABC available in the selected trials.

Table 11.2.1: Adverse events reported in the Bonjoch et al (2005) trial ATZ/3TC/ABC ATZ/3TC + NVP Adverse event (n=68) (n=66) Discontinuation due to toxicity 13/68 (19%) 14/66 (21%) Grade 3 or 4 toxicity 1/68 (1.5%) 4/66 (6.1%) Decrease in proportion of patients with hypercholesterolaemia Baseline 55.6% 68.9% Week 48 30.5% 42.2% p value 0.019 0.019 Decrease in proportion of patients with elevated LDL-C Baseline 60% 59.3% Week 48 20.6% 41.7% p value 0.003 <0.05 AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; NVP=nevirapine

There was no difference between the treatment groups in the occurrence of adverse events. There was a statistically significantly greater change in the proportion of patients with elevated LDL-C, with a greater decrease in those treated with AZT/3TC/ABC.

Table 11.2.2: Adverse events reported in Gulick et al (2004) trial ATZ/3TC/ABC Combined EFV groups Adverse event (n=382) (n=765) Suspected hypersensitivity 27 (7%) 59 (8%) Grade 3 toxic effects 37 (10%) 95 (13%) Grade 4 toxic effects 9 (2%) 17 (2%) AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; EFV=efavirenz

Occurrence of adverse events was similar between treatment groups in the Gulick et al (2004) trial.

Table 11.2.3: Adverse events reported in Katlama et al (2003) trial ATZ/3TC/ABC Current regimen Adverse event (n=111) (n=108) Hypersensitivity 11 (10%) 0 (0%) Discontinuation due to adverse 16 (15%) 17 (16%) events Grade 3 or 4 clinical chemistry 13(12%) 15 (14%) abnormalities Change in TC -0.80mmol/L -0.44mmol/L Change in TG -0.17mmol/L +0.01mmol/L At least one clinical lipodystrophy 27 (28%) 42 (42%) manifestation Median clinical lipodystrophy 4 2 symptoms AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; TC=total cholesterol; TG=triglycerides

zidovudine/lamivudine/abacavir – HIV infection 18 There were statistically significantly greater decreases in lipid levels, and statistically significantly fewer clinical lipodystrophy events and symptoms in the AZT/3TC/ABC group compared to those remaining on their current regimen.

Table 11.2.4: Drug-related adverse events reported in the Kumar et al (2006) trial AZT/3TC/ABC AZT/3TC+NFV d4T/3TC/NFV Outcome (n=87) (n=91) (n=83) Gastrointestinal Diarrhoea 5 (6%) 46 (51%) 40 (48%) Nausea 26 (30%) 29 (32%) 14 (17%) Vomiting 14 (16%) 6 (7%) 2 (2%) Abdominal pain 7 (8%) 10 (11%) 6 (7%) Abdominal discomfort 2 (2%) 4 (4%) 4 (5%) Non-site-specific Fatigue 13 (15%) 14 (15%) 5 (6%) Anorexia 5 (6%) 4 (4%) 2 (2%) Suspected hypersensitivity 3 (3%) 0 (0%) 0 (0%) Neurology Headache 12 (14%) 11 (12%) 9 (11%) Blood and lymphatic Decreased white cell 4 (5%) 8 (9%) 1 (1%) Anaemia 2 (2%) 8 (9%) 0 (0%) AZT=zidovudine; 3TC=lamivudine; ABC=abacavir; NFV=nevirapine; d4T=stavudine

Suspected abacavir hypersensitivity occurred in 3% of the AZT/3TC/ABC- treated patients. Diarrhoea was more frequent in the nelfinavir-treated patients (51% for AZT/3TC/NFV and 48% for d4T/3TC/NFV) compared to 6% in AZT/3TC/ABC-treated patients.

Table 11.2.5: Adverse events reported in Berenguer et al (2006)

Adverse event N (%) All adverse events 104 (14.25%) Suspected hypersensitivity reaction to ABC 36 (4.93%) Haematologic 30 (4.10%) Gastrointestinal 21 (2.88%) Hepatic 6 (0.82%) Malaise 4 (0.55%) Mitochondrial toxicity 3 (0.41%) Myopathy 1 (0.14%) Migraine 1 (0.14%) Fever 1 (0.14%) Rash 1 (0.14%)

After a median follow-up of 50.5 weeks, 104 patients (14.25%) discontinued treatment because of adverse events. The most frequent adverse event was suspected hypersensitivity to ABC, which occurred in 36 patients (4.93%). The median time to occurrence of a hypersensitivity reaction was 4 weeks (IQR:1 to 9 weeks).

11.3 Identification of variation in safety due to health systems and patient factors While it has been reported that the rate of abacavir hypersensitivity may be lower in Africa than industrialized countries due to race and lower pre- treatment CD4 (Brothers et al., 2006), a recent randomized, double-blind trial

zidovudine/lamivudine/abacavir – HIV infection 19 of prospective screening for HLA-B*5701 prior to abacavir treatment (Mallal et al., 2008) reported that the association between HLA-B*5701 and hypersensitivity to abacavir appears to be generalizable across racial groups.

11.4 Summary of comparative safety against comparators

Across the trials, suspected hypersensitivity reactions occurred more frequently in the AZT/3TC/ABC treatment groups. This is not unexpected given the known association between abacavir and hypersensitivity. Other adverse events occurred at a similar rate in AZT3TC/ABC-treated patients compared to the different comparator regimens used in the trials. Reduction in lipid levels was greater for AZT/3TC/ABC-treated patients.

12. Summary of available data on comparative cost and cost-effectiveness 12.1 Range of costs of the proposed medicine Table 12.1.1 provides the median transaction prices of AZT/3TC/ABC as reported in the October 2008 report from the Global Price Reporting Mechanism (http://www.who.int/hiv/amds/gprm/en/) of the WHO.

Table 12.1.1: Median transaction prices for AZT/3TC/ABC 2008 2008 price per patient per year (US$) Lower-middle Upper-middle Drug/dose Tablets Low income income income AZT/3TC/ABC 2 $852 $3256 NR (300/150/300mg)

The cost of AZT/3TC/ABC is almost 4 times as great in lower-middle income countries compared to low income countries.

zidovudine/lamivudine/abacavir – HIV infection 20 12.2 Comparative cost-effectiveness (presented as range of cost per routine outcome)

Trueman et al (2000) assessed the cost-effectiveness of AZT/3TC/ABC compared to AZT/3TC in the treatment of HIV in the UK. This analysis used a Markov model, with clinical data derived from the Fischl et al (2006) trial (see Section 10.2.3) and other published data. The analysis was conducted from a UK public finance perspective. The incremental cost per QALY was estimated to be between £10,072 to £16,168. The model predicted that triple nucleoside therapy extended life expectancy by an additional 1.2 years compared to dual nucleoside therapy with an incremental cost per life year saved of £8,419. These results cannot be assumed to be applicable to resource-poor settings, however they do demonstrate cost-effectiveness for ATV/3TC/ABC in the UK setting.

There are no available assessments of the cost-effectiveness of AZT/3TC/ABC in resource-poor settings. Cost-effectiveness analyses in resource-poor settings have largely focused on a comparison of antiretroviral therapy to no therapy (Cleary et al., 2004; Badri et al., 2006; Badri et al., 2006b; Goldie et al., 2006) or prevention, care and support (Creese et al., 2002). Given that AZT/3TC/ABC is, at best, non-inferior to comparator antiretroviral regimens, it may be difficult to demonstrate cost-effectiveness.

13. Regulatory status

Table 13.1 provides the regulatory status and WHO pre-qualification status of AZT/3TC/ABC as recorded in the WHO Drug Regulatory Status Report (http://www.who.int/hiv/amds/patents_registration/drs/).

Table 13.1 – Regulatory status as based on WHO Drug Regulatory Status Report Country Dose Manufacturer WHO pre-qualified Argentina 300mg+150mg+300mg Laborotorios No Richmond S.A.C.I.F Armenia 300mg+150mg+300mg GSK Yes Azerbaijan 300mg+150mg+300mg GSK Yes Bahamas 300mg+150mg+300mg GSK Yes Bangladesh 300mg+150mg+300mg GSK Yes Barbados 300mg+150mg+300mg GSK Yes Belize 300mg+150mg+300mg GSK Yes Bhutan 300mg+150mg+300mg GSK Yes Bolivia 300mg+150mg+300mg GSK Yes Botswana 300mg+150mg+300mg GSK Yes Burundi 300mg+150mg+300mg Hetero Drugs Ltd. No Cambodia 300mg+150mg+300mg GSK Yes Cameroon 300mg+150mg+300mg GSK Yes Cape Verde 300mg+150mg+300mg GSK Yes Colombia 300mg+150mg+300mg Ranbaxy Ltd. No Comoros 300mg+150mg+300mg GSK Yes Congo 300mg+150mg+300mg Hetero Drugs Ltd. No Cote d’Ivoire 300mg+150mg+300mg GSK Yes Democratic 300mg+150mg+300mg GSK Yes People’s Republic of Korea

zidovudine/lamivudine/abacavir – HIV infection 21 Country Dose Manufacturer WHO pre-qualified Democratic 300mg+150mg+300mg GSK Yes Republic of Timor- Leste Equatorial Guinea 300mg+150mg+300mg GSK Yes Eritrea 300mg+150mg+300mg GSK Yes Ethiopia 300mg+150mg+300mg GSK Yes Gambia 300mg+150mg+300mg GSK Yes Hetero Drugs Ltd. No Georgia 300mg+150mg+300mg GSK Yes Ghana 300mg+150mg+300mg GSK Yes Guinea-Bissau 300mg+150mg+300mg GSK Yes Guyana 300mg+150mg+300mg GSK Yes Haiti 300mg+150mg+300mg GSK Yes India 300mg+150mg+300mg GSK Yes Ranbaxy Ltd. No Indonesia 300mg+150mg+300mg GSK Yes Kenya 300mg+150mg+300mg GSK Yes Kiribati 300mg+150mg+300mg GSK Yes Kyrgyzstan 300mg+150mg+300mg GSK Yes Lao People’s 300mg+150mg+300mg GSK Yes Democratic Republic Liberia 300mg+150mg+300mg GSK Yes Madagascar 300mg+150mg+300mg GSK Yes Malawi 300mg+150mg+300mg Hetero Drugs Ltd. No Maldives 300mg+150mg+300mg GSK Yes Mongolia 300mg+150mg+300mg GSK Yes Mozambique 300mg+150mg+300mg GSK Yes Myanmar 300mg+150mg+300mg Ranbaxy Ltd. No Namibia 300mg+150mg+300mg GSK Yes Nepal 300mg+150mg+300mg GSK Yes Nigeria 300mg+150mg+300mg GSK Yes Hetero Drugs Ltd. No Pakistan 300mg+150mg+300mg GSK Yes Papua New Guinea 300mg+150mg+300mg GSK Yes Paraguay 300mg+150mg+300mg GSK Yes Peru 300mg+150mg+300mg Ranbaxy Ltd. No Philippines 300mg+150mg+300mg GSK Yes Rwanda 300mg+150mg+300mg GSK Yes Samoa 300mg+150mg+300mg GSK Yes Sao Tome and 300mg+150mg+300mg GSK Yes Principe Sierra Leone 300mg+150mg+300mg GSK Yes Solomon Islands 300mg+150mg+300mg GSK Yes South Africa 300mg+150mg+300mg GSK Yes Sri Lanka 300mg+150mg+300mg GSK Yes Sudan 300mg+150mg+300mg GSK Yes Suriname 300mg+150mg+300mg GSK Yes Swaziland 300mg+150mg+300mg GSK Yes Syrian Arab 300mg+150mg+300mg GSK Yes Republic Tajikistan 300mg+150mg+300mg GSK Yes Turkmenistan 300mg+150mg+300mg GSK Yes Tuvalu 300mg+150mg+300mg GSK Yes Uganda 300mg+150mg+300mg GSK Yes United Republic of 300mg+150mg+300mg GSK Yes Tanzania Uzbekistan 300mg+150mg+300mg GSK Yes

zidovudine/lamivudine/abacavir – HIV infection 22 Country Dose Manufacturer WHO pre-qualified Vanuatu 300mg+150mg+300mg GSK Yes Vietnam 300mg+150mg+300mg GSK Yes Yemen 300mg+150mg+300mg GSK Yes Zambia 300mg+150mg+300mg GSK Yes Zimbabwe 300mg+150mg+300mg GSK Yes GSK=GlaxoSmithKline Ltd.

14. Availability of pharmacopoeial standards Zidovudine, lamivudine and abacavir tablets are included in the International Pharmacopoeia but are not included in the US Pharmacopoeia.

15. Proposed text for the WHO Model Formulary The proposed text for the WHO Model Formulary is provided in Attachment 2.

References

Badri M, Maartens G, Mandalia S, Bekker LG et al. Cost-=effectiveness of highly active antiretroviral therapy in South Africa. PloS Med 3(1): 0048-56. Badri M, Cleary S, Maartens G, Pitt J et al. When to initiate highly active antiretroviral therapy in sub-Saharan Africa? A South African cost- effectiveness study. Antiviral Therapy 2006b; 11: 63-72. Bartlett JA, Fath MJ, DeMasi R, Hermes A et al. An updated systematic review of triple combination therapy in antiretroviral-naïve HIV-infected adults. AIDS 2006; 20: 2051-64. Berenguer J, Perez-Elias MJ, Bellon JM, Knobel H et al. Effectiveness and safety of abacavir, lamivudine, and zidovudine in antiretroviral therapy=naïve HIV- infected patients. J Acquir Immune Defic Syndr 2006; 41: 154-59. Bonjoch A, Paredes R, Galvez J, Miralles C et al. Antiretroviral Treatment Simplification With 3 NRTIs or 2 NRTIs Plus Nevirapine in HIV-1-Infected Patients Treated With Successful First-Line HAART. J Acquir Immun Defic Syndr 2005; 39: 313-316. Brothers C, Wannamaker P, Sutherland-Phillips D, Hernandez J. Lower reported rate of suspected hypersensitivity reaction (HSR) to abacavir (ABC) among black patients. 46th Interscience Conference On Antimicrobial Agents and Chemotherapy, San Francisco 2006; Abstract H-1065. Cleary S, Boulle A, McIntyre D, Coetzee D. Cost-effectiveness of HIV/AIDS interventions in Africa: a systematic review of the evidence. Available at http://www.hst.org.za/uploads/files/arv_cost.pdf Creese Q, Floyd K, Alban A, Guinness L. Cost-effectiveness of HIV/AIDS interventions in Africa: a systematic review of the evidence. Lancet 2002; 359: 1635-42. D*A*D Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 2008; 371:1417-26. Fischl MA, Burnside AE Jr, Farthing CE, Thompson MA et al. Twice-Daily Trizivir versus Combivir-abacavir in antiretroviral-experienced adults with human immunodeficiency virus-1 infection: a formulation-switch trial. Pharmacotherapy 2003; 23(11): 1432-40. Gazzard BG. British HIV Association Guidelines for the treatment of HIV-10- infected adults with antiretroviral therapy 2008. HIV Medicine 2008; 9: 563-

zidovudine/lamivudine/abacavir – HIV infection 23 608. Goldie SJ, Yazdanpanah Y, Losina E, Weinstein MC et al. Cost-effectiveness of HIV treatment in resource-poor settings – the case of Cote d’Ivoire. NEJM 2006; 355: 1141-53. Gulick RM, Ribuado HJ, Shikuma CM, Lustgarten S et al. Triple—Nucleoside Regimens versus Efavirenz-Containing Regimens for the Initial Treatment of HIV-1 Infection. NEJM 2004; 350(18): 1850-61. Hammer SM, Eron Jr JJ, Reiss P et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society USA Panel. JAMA 2008; 300(5): 555-70. Ivers LC, Kendrick D, DoucetteK. Efficacy of antiretroviral therapy programs in resource-poor settings: A meta-analysis of the published literature. Clin Infect Diseases 2005; 41: 217-24. Katlama C, Fenscke S, Gazzard B, Lazzarin A et al. TRIZAL study: switching from successful HAART to TrizivirTM (abacavir-lamivudine-zidovudine combination tablet): 48 weeks efficacy, safety and adherence results. HIV Medicine 2003; 4: 79-86. Katlama C, Gazzard B, Mallolas J, Schürmann D et al. Comparison of metabolic abnormalities 48 weeks after switching from highly active antiretroviral therapy containing a non-nucleoside reverse transcriptase inhibitor to Trizivir versus continued highly active antiretroviral therapy. (Katlama 2003b for the purposes of this document) AIDS 2003; 17: 1853-1856. Keiser P, Nassar N. Abacavir sulfate/lamivudine/zidovudine fixed combination in the treatment of HIV infection. Expert Opin on Pharmacotherapy 2007; 8(4): 477-83. Kumar PN, Rodriguez-French A, Thompson MA, Tashima KT et al. A prospective, 96-week study of the impact of Trizivir ®, Combivir®/nelfinavir, and lamivudine/stavudine/nelfinavir on lipids, metabolic parameters and efficacy in antiretroviral-naïve patients: effect of sex and ethnicity. HIV Medicine 2006; 7: 85-98. Kumar PN, Patel P, Salvato et al. ACTION Study: efficacy and safety of abacavir/lamivudine/zidovudine [ABC/3TC/ZDV] BID versus lamivudine/zidovudine [3TC/ZDV] BID + atazanavir [ATV] QD in ART-naive HIV-1 infected subjects. In: Program and abstracts of the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract H-1058. (Kumar et al 2006b for the purposes of this document). Lafeuillade A, Clumeck N, Mallolas J, Jaeger H et al. Comparison of metabolic abnormalities and clinical lipodystrophy 48 weeks after switching from HAART to Trizivir versus continued HAART: the Trizal study. HIV Clin Trials 2003; 4(1): 37-43. Lawn SD, Myer L, Wood R. Efficacy of antiretroviral therapy in resource-poor settings: Are outcomes comparable to those in the developed world? Clin Infect Diseases 2005; 41: 1683. Mallal S, Phillips E, Carosi G, Molina JM et al. HLA-B*5701 screening for hypersensitivity to abacavir. NEJM 2008; 358(6):568-79. Markowitz M, Hill-Zabala C, Lang J, DeJesus E et al. Induction with abacavir/lamivudine/zidovudine plus efavirenz for 48 weeks followed by 48-week maintenance with abacavir/lamivudine/zidovudine alone in antiretroviral-naive HIV-1-infected patients. J Acquir Immune Defic Syndr 2005; 39(3):257-64. Nassar N, Armas L, Smillie J, Moreno S et al. An observational cohort comparison of Zidovudine-Lamivudine-Efavirenz to Zidovudine-Lamivudine-Abacavir in

zidovudine/lamivudine/abacavir – HIV infection 24 antiretroviral-naive individuals. Antivir Ther 2003; 8 (Suppl.1): abstract no. 554. Renaud-Thery F, Nguimfack BD, Vitoria M, Lee E et al. Use of antiretroviral therapy in resource-limited countries in 2006: distribution and uptake of first = and second-line regimens. AIDS 2007; (suppl 4): S89-S95. Ribaudo HJ, Kuritzkes DR, Gulick RM. A comparison of three =initial antiretroviral AIDS regimens. NEJM 2007; 357 (10):1056-57. Trueman P, Youle M, Sabin CA, Miners AH, Beck EJ. The cost-effectiveness of triple nucleoside analogue therapy antiretroviral regimens in the treatment of HIV in the United Kingdom. HIV Clin Trials 2000; 1(1): 27-35. WHO 2006: http://www.who.int/hiv/pub/guidelines/artadultguidelines.pdf WHO 2006b: http://www.who.int/hiv/pub/guidelines/artadultguidelines.pdf WHO 2007: http://www.who.int/hiv/pub/meetingreports/Second_Line_Antiretroviral.pdf WHO, UNAIDS and UNICEF 2008. Towards universal access. Scaling up priority HIV/AIDS interventions in the health sector, progress report 2008. Accessed at: www.who.int/hiv/pub/towards_universal_access_report_2008.pdf

zidovudine/lamivudine/abacavir – HIV infection 25 Attachment 1

GRADE profile

A GRADE profile of the efficacy and safety of AZT/3TC/ABC using the available trials and studies was conducted, using GRADEpro and Reference Manager (RevMan 5.0). As the available trials vary in terms of the comparator used (EFV-based regimens, PI-based regimens, current treatment), the population assessed (antiretroviral-naive, treatment-experienced) and the outcomes assessed (virological failure, virological success, HIV RNA levels, safety outcomes) it is not possible to provide pooled comparisons using all of the available trials. The only comparisons that were possible are as follows:

- AZT/3TC/ABC versus EFV-using regimens: two trials (Gulick et al., 2004; Markowitz et al., 2005) with results for virological failure and HIV RNA <50 copies/mL. The definition of virological failure was different between the trials. - AZT/3TC/ABC versus PI-using regimens: two trials (Kumar et al., 2006; Kumar et al., 2006b) were available, using different PIs (nelfinavir and atazanavir). Results for HIV RNA <50 copies/mL available for each trial. - AZT/3TC/ABC versus all comparators: four trials in antiretroviral-naive patients and lumping all comparators together. This is not ideal, as the different comparators may have different results and/or characteristics. Results were available for HIV RNA <50 copies/mL and occurrence of abacavir hypersensitivity.

Tables A1.1 to A1.3 provide the GRADE assessment of quality and summary of findings. Table A1.4 provides the characteristics of the trials used in the application in the RevMan 5.0 format.

zidovudine/lamivudine/abacavir – HIV infection 26

Table A1.1: GRADE review for AZT/3TC/ABC versus EFV-based regimens Summary of findings Quality assessment No of patients Effect Importance No of Other Relative Quality Design Limitations Inconsistency Indirectness Imprecision AZT/3TC/ABC EFV Absolute studies considerations (95% CI) virological failure 2 randomized very serious no serious no serious none 98/523 93/906 See 69 more trial serious1 indirectness imprecision VERY CRITICAL (18.7%) (8.4%) comment per 1,000 LOW HIV RNA<50 copies/mL 2 randomized serious2 serious3 no serious no serious none 227/336 440/537 See 121 fewer CRITICAL trial indirectness imprecision (67.6%) (80.9%) comment per 1,000 LOW 1 the Gulick 2004 trial reported virological inferiority for AZT/3TC/ABC while the Markowitz 2005 trial reported non-inferiority 2 the Gulick 2004 trial combined two EFV arms, one receiving AZT/3TC+EFV and the other AZT/3TC/ABC+EFV, while the Markowitz 2005 trial used AZT/3TC/ABC+EFV. Thus, the comparator groups are not the same. 3 the Gulick 2004 trial reported virological inferiority for AZT/3TC/ABC while the Markowitz trial reported non-inferiority

zidovudine/lamivudine/abacavir – HIV infection 27 Table A1.2: GRADE review for AZT/3TC/ABC versus PI-based regimens Summary of findings Quality assessment No of patients Effect Importance No of Other Relative Quality Design Limitations Inconsistency Indirectness Imprecision AZT/3TC/ABC PI Absolute studies considerations (95% CI) HIV RNA <50 copies 2 randomized serious1 no serious no serious no serious none 121/184 117/187 See 32 more IMPORTANT trial inconsistency indirectness imprecision (65.8%) (65.8%) comment per 1,000 MODERATE 1 the two included trials used different PIs, with nelfinavir used in Kumar 2006 and atazanavir in Kumar 2006b. The appropriateness of combining results based on these two PIs has not been assessed.

zidovudine/lamivudine/abacavir – HIV infection 28 Table A1.3: GRADE review for available trials in antiretroviral-naive patients, combining all comparators Summary of findings Quality assessment No of patients Effect comparators Importance No of Other Relative Quality Design Limitations Inconsistency Indirectness Imprecision AZT/3TC/ABC in naive Absolute studies considerations (95% CI) patients HIV RNA <50 copies/mL 4 randomized very serious2 no serious no serious none 348/520 557/724 See 45 fewer trial serious1 indirectness imprecision VERY IMPORTANT (66.9%) (75.5%) comment per 1,000 LOW hypersensitivity 3 randomized very serious4 no serious no serious none 3 See 0 more trial serious indirectness imprecision 41/578 (7.1%) 59/961 (0%) VERY IMPORTANT comment per 1,000 LOW 1 combines trials that use EFV in the comparator arm (Gulick 2004 and Markowitz 2005) with trials that use PI in the comparator arm (Kumar 2006 and Kumar 2006b). 2 the Gulick 2004 trial demonstrated virological inferiority for AZT/3TC/ABC compared to the EFV arms, while the other three trials demonstrated non- inferiority of AZT/3TC/ABC to the comparators 3 trials may not be comparable, as two are in antiretroviral-naive patients (Gulick 2004; Kumar 2006) and one in treatment experienced patients ((Katlama 2003). In addition, all trials have different comparator arms. 4 The Gulick (2004) trial, which demonstrated virological inferiority for AZT/3TC/ABC had a higher rate of hypersensitivity in the EFV groups, while the Kumar (2006) and Katlama (2003) trials had a higher hypersensitivity rate for AZT/3TC/ABC-treated patients.

zidovudine/lamivudine/abacavir – HIV infection 29 Below are the characteristics of the included trials, in RevMan 5.0 format. This does not include trials which were substudies of included trials (eg Lafeuillade et al., 2003).

BERENGUER 2006 Methods retrospective review Participants antiretroviral-naive Interventions AZT/3TC/ABC Outcomes treatment failure hypersensitivity Notes Risk of bias table Item Judgement Description Allocation concealment? No retrospective review

BONJOCH 2005 Methods randomized, open-label Participants treatment-experienced Interventions AZT/3TC/ABC AZT/3TC+NVP Outcomes HIV RNA <200 copies/mL HIV RNA <50 copies/mL Notes Risk of bias table Item Judgement Description Allocation concealment? No open-label, unblinded

FISCHL 2003 Methods randomized, open-label Participants treatment-experienced Interventions AZT/3TC/ABC AZT/3TC+ABC Outcomes virological success HIV RNA <400 copies/mL HIV RNA <50 copies/mL Notes Risk of bias table Item Judgement Description Allocation concealment? No open-label, unblinded

GULICK 2004 Methods randomized, double-blind Participants antiretroviral-naive Interventions AZT/3TC/ABC AZT/3TC+EFV and AZT/3TC/ABC+EFV Outcomes virological failure HIV RNA <200 copies/mL HIV RNA <50 copies/mL hypersensitivity Notes AZT/3TC/ABC arm stopped due to meeting criteria for stopping rule; AZT/3TC/ABC virologically inferior to EFV-based regimens

zidovudine/lamivudine/abacavir – HIV infection 30 Risk of bias table Item Judgement Description Allocation concealment? No

KATLAMA 2003 Methods randomized, open-label Participants treatment-experienced Interventions AZT/3TC/ABC current ARV regimen Outcomes treatment failure HIV RNA <50 copies/mL change in CD4 hypersensitivity Notes Risk of bias table Item Judgement Description Allocation concealment? Yes open-label, non-blinded

KUMAR 2006 Methods randomized, open-label Participants antiretroviral-naive Interventions AZT/3TC/ABC AZT/3TC+NFV Outcomes HIV RNA <400 copies/mL HIV RNA <200 copies/mL virological failure CD4 cell count change hypersensitivity Notes Risk of bias table Item Judgement Description Allocation concealment? Yes open-label, unblinded

KUMAR 2006B Methods randomized, open-label Participants antiretroviral-naive Interventions AZT/3TC/ABC AZT/3TC+ATV Outcomes HIV RNA <50 copies/mL change in CD4 cell count Notes Risk of bias table Item Judgement Description Allocation concealment? Yes open-label, unblinded

MARKOWITZ 2005 Methods randomized, open-label Participants antiretroviral-naive Interventions AZT/3TC/ABC AZT/3TC+EFV Outcomes HIV RNA <50 copies/mL Notes

zidovudine/lamivudine/abacavir – HIV infection 31 Risk of bias table Item Judgement Description Allocation concealment? Yes open-label, unblinded

NASSAR 2003 Methods retrospective database review Participants antiretroviral-naive Interventions AZT/3TC/ABC AZT/3TC+EFV Outcomes time to virologic failure Notes Risk of bias table Item Judgement Description Allocation concealment? No database review

SRIKANTIAH 2007 Methods open-label, single arm Participants HIV and tuberculosis co-infected, antiretroviral-naive Interventions AZT/3TC/ABC Outcomes HIV RNA <400 copies/mL HIV RNA <50 copies/mL change in CD4 cell count Notes Risk of bias table Item Judgement Description Allocation concealment? No single arm, open-label

zidovudine/lamivudine/abacavir – HIV infection 32 Attachment 2 Proposed text for the WHO Model Formulary

The following is based on Product Information for the fixed dose combination (Trizivir) of ATZ/3TC/ABC.

Description: Abacavir, lamivudine and zidovudine are all nucleoside analogue reverse transcriptase inhibitors. Abacavir is a selective antiretroviral agent against HIV-1 and HIV-2, including HIV-1 isolates that are resistant to zidovudine, lamivudine, zalcitabine, didanosine or nevirapine. Zidovudine is an inhibitor of the in vitro replication of some retroviruses including HIV, whereas lamivudine is a potent, selective inhibitor of HIV-1 and HIV-2 replication in vitro. Lamivudine has been shown to be replication of HIV in cell culture.

How Supplied: Trizivir tablets are blue/green capsule-shaped film-coated tablets, engraved with “GX LL1” on one tablet face. Each tablet contains abacavir 300mg, lamivudine 150mg and zidovudine 300mg.

Use: For the treatment for HIV-1 infection in adults.

Contraindications: - in patients with known hypersensitivity to Trizivir or any of its components (abacavir, lamivudine or zidovudine), or to any of the excipients of trizivir tablets. - in patients with hepatic impairment. - due to the active ingredient zidovudine, TRIZIVIR is contraindicated in patients with abnormally low neutrophil counts (<0.75 x 109/L), or abnormally low haemoglobin levels (<7.5g/dL or 4.65 mmol/L)

Precautions: In clinical studies approximately 5% of subjects given abacavir developed a hypersensitivity reaction, which in rare cases has proved fatal. Over 28,000 patients received Trizivir in clinical trials up to 30 June 2000. In this period there were 7 cases in which the fatal outcome may have been due to hypersensitivity.

Patients developing signs or symptoms of hypersensitivity MUST contact their doctor immediately for advice. If a hypersensitivity reaction is suspected therapy with TRIZIVIR MUST cease immediately. TRIZIVIR, OR ANY OTHER MEDICINAL PRODUCT CONTAINING ABACAVIR (IE KIVEXA, ZIAGEN), MUST NEVER BE RESTARTED FOLLOWING A HYPERSENSITIVITY REACTION, AS MORE SEVERE SYMPTOMS WILL RECUR WITHIN HOURS AND MAY INCLUDE LIFE-THREATENING HYPOTENSION AND DEATH.

Fat redistribution: Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial

zidovudine/lamivudine/abacavir – HIV infection 33 wasting, breast enlargement, elevated serum lipid and blood glucose levels have been observed either separately or together in some patients receiving combination antiretroviral therapy

Lactic acidosis and severe hepatomegaly with steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues either alone or in combination, including abacavir, lamivudine and zidovudine. A majority of these cases have been in women.

Clinical features which may be indicative of the development of lactic acidosis include generalised weakness, anorexia, and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnoea and tachypnoea).

Caution should be exercised when administering Trizivir to any patient, and particularly to those with known risk factors for liver disease. Treatment with Trizivir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Immune Reconstitution Syndrome: In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary.

Patients co-infected with hepatitis C virus: Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. Therefore, the co- administration of ribavirin and zidovudine is not advised and consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This is particularly important in patients with a known history of zidovudine induced anaemia.

Haematological Effects: Therapy with zidovudine preparations is commonly associated with haematologic toxicity including granulocytopenia and severe anaemia requiring transfusions particularly in patients with advanced HIV disease

Pancreatitis: Cases of pancreatitis have occurred rarely in patients treated with abacavir, lamivudine and zidovudine. However it is not clear whether these cases were due to the medicinal products or to the underlying HIV disease. Treatment with TRIZIVIR should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.

Renal Impairment: In patients with moderate to severe renal impairment, the terminal plasma half-life of lamivudine exposure is increased due to decreased clearance. Dosage adjustment in these patients is better controlled using individual

zidovudine/lamivudine/abacavir – HIV infection 34 abacavir, lamivudine and zidovudine preparations as the dose frequency of lamivudine may need to be reduced.

Hepatic impairment or disease: TRIZIVIR should be used with caution in patients with HIV and chronic hepatitis B virus infection. Clinical trial and marketed use of lamivudine have shown that some patients with chronic hepatitis B virus (HBV) disease may experience clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. If TRIZIVIR is discontinued in a patient with HIV and HBV co-infection, periodic mfunction tests and markers of HBV replication should be considered.

Drug interactions: Clinical studies have shown that there are no clinically significant interactions between abacavir, zidovudine, and lamivudine. As Trizivir contains abacavir, lamivudine and zidovudine, any interactions that have been identified with these agents individually may occur with Trizivir. Based on the results of in vitro experiments and the known major metabolic pathways of abacavir, the potential for P450 mediated interactions with other medicinal products involving abacavir is low. The likelihood of interactions with lamivudine is low due to limited metabolism and plasma protein binding and almost complete renal clearance. Similarly zidovudine has limited protein binding but is eliminated primarily by hepatic conjugation to an inactive glucuronidated metabolite.

Adverse effects: Adverse events have been reported during therapy for HIV disease with abacavir, lamivudine and zidovudine, administered separately or in combination. For many of these adverse events it is unclear whether they are related to abacavir, lamivudine,zidovudine, or to the wide range of medicinal products used in the management of HIV disease or are as a result of the underlying disease process.

Information regarding the safety of TRIZIVIR, abacavir, zidovudine or lamivudine in combination with other antiretroviral drugs is limited. Physicians should refer to the complete product information for the respective antiretroviral therapy for a description of the known associated adverse reactions.

As TRIZIVIR contains abacavir, lamivudine and zidovudine, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no evidence of added toxicity following concurrent administration of the three compounds.

Dosage and administration: The recommended dose of TRIZIVIR in adults is one tablet twice daily, giving a total daily dose of 600mg abacavir, 300mg lamivudine and 600mg zidovudine.

zidovudine/lamivudine/abacavir – HIV infection 35