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

APPLICATION FOR LISTING OF ATAZANAVIR FOR THE TREATMENT OF HIV-1 INFECTION ON THE WHO MODEL LIST OF ESSENTIAL MEDICINES

FEBRUARY 2009

Atazanavir – 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 organisation(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 ...... 3 8. Information supporting the public health relevance ...... 3 8.1 Epidemiological information on disease burden...... 3 8.2 Assessment of current use...... 5 8.3 Target population...... 5 9. Treatment details...... 5 9.1 Dosage regimen ...... 5 9.2 Treatment duration...... 5 9.3 Reference to WHO and other clinical guidelines ...... 5 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...... 10 10.2.3 Summary of results – second-line treatment – randomized trials...... 11 10.2.4 Summary of results – second-line treatment – non-randomized studies ...... 16 10.3 Summary of available estimates of comparative effectiveness ...... 18 11. Summary of comparative evidence on safety ...... 18 11.1 Estimate of total patient exposure to date...... 18 11.2 Description of adverse effects/reactions ...... 19 11.3 Identification of variation in safety due to health systems and patient factors...... 21 11.4 Summary of comparative safety against comparators ...... 22 12. Summary of available data on comparative cost and cost-effectiveness...... 22 12.1 Range of costs of the proposed medicine ...... 22 12.2 Comparative cost-effectiveness (presented as range of cost per routine outcome) ...... 22 13. Regulatory status...... 24 14. Availability of pharmacopoeial standards ...... 24 15. Proposed text for the WHO Model Formulary ...... 24 References...... 24 Attachment 1...... 28 A1.1 Summary of results – first-line treatment – randomized trials...... 28 A1.2 Summary of results – first-line treatment – non-randomized studies ...... 31 Attachment 2...... 32 Attachment 3...... 35

Atazanavir – HIV infection 2 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION

Atazanavir capsules (100mg and 300mg) for the treatment of HIV-1 infection

1. Summary statement of proposal for inclusion, change, or deletion Atazanavir capsules (100mg and 300mg) are proposed for inclusion on the WHO Model List of essential medicines for the treatment of HIV infection. . 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) atazanavir

5. Formulation proposed for inclusion 100mg capsule and 300mg capsule.

6. International availability Section 13 (see Table 13.1) provides a list of the manufacturers. Atazanavir is available in six African countries and India. In these countries the 150mg capsule has WHO pre-qualification status.

7. Category of listing requested Listing is requested as an individual drug.

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)

Atazanavir – HIV infection 3 People living with HIV 2007 AIDS deaths 2007 Region (low-high estimate) (low-high estimate) 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.

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).

Another aspect of treatment that has been recognised as critical is the need in resource-limited countries to make second-line treatment regimens available (WHO 2007). An expert meeting was convened by the WHO in May 2007 to develop guidance for second-line drugs. The working group ranked atazanavir boosted with ritonavir as one of the highest priorities for the protease inhibitor (PI) component of second-line treatment (WHO 2007).

Atazanavir has a low pill burden and there is evidence of beneficial effects on

Atazanavir – HIV infection 4 lipid levels (see Section 10.2) which offers advantages for adherence and longer-term treatment. Thus, inclusion of atazanavir on the WHO Model Lists of Essential Medicines is sought. Evidence demonstrating the efficacy and safety of atazanavir is provided in Sections 10.2 and 11 and Attachments 1 and 2.

8.2 Assessment of current use Atazanavir combined with ritonavir (ATV/r) is currently used as an alternate to lopinavir combined with ritonavir (LPV/r) which is the dominant PI in low and middle income countries. The WHO estimated that approximately 180,000 patients will need second-line regimens in 2008. This estimate is also provided by Galarraga et al (2007) in their forecast of demand for antiretroviral drugs in low and middle-income countries in 2007-2008. Given that the switching rate from first to second line regimens is expected to increase, and also that the use of PIs in first-line regimens is expected to increase (WHO 2006), the use of ATV/r is expected to increase.

8.3 Target population Patients with HIV infection.

9. Treatment details 9.1 Dosage regimen For therapy-experienced patients the recommended dose is ATV 300mg with ritonavir 100mg, taken once daily with food. The dose remains the same if combined with an H2-receptor antagonist. If combined with tenofovir and an H2-receptor antagonist, the recommended dose is ATV 400mg with ritonavir 100mg. It is recommended that proton pump inhibitors should not be used in treatment-experienced patients receiving atazanavir.

For therapy-naive patients the recommended dose is ATV 300mg with ritonavir 100mg taken once daily with food if combined with either tenofovir, efavirenz, an H2-receptor antagonist or proton pump inhibitors. If taken alone, the recommended dose is ATV 400mg taken once daily with food.

9.2 Treatment duration Treatment duration is continuing or until treatment has to be changed because eof 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, 2006b) recommend a ritonavir-boosted PI as the core of a second-line regimen. As liponavir/ritonavir (LPV/r) is available as a fixed-dose combination it is a preferred choice, however the WHO Guidelines recommend that if LPV/r is not an option, ATV/r can be selected as a suitable replacement.

A WHO working group meeting in May 2007 was held to develop guidance

Atazanavir – HIV infection 5 for selection, prioritisation and planning for second-line antiretroviral (ARV) drugs. This meeting determined that of the PI component of treatment, LPV/r and ATV/r ranked as the highest priorities. Specifically, the following recommendations were made:

- for patients who initiated ARV therapy with thymidine-based analogues (first-line regimens containing zidovudine or stavudine), the second-line regimens should preferably comprise tenofovir + lamivudine, tenofovir + emtricitabine or abacavir + didanosine as the nucleoside background component associated with either liponavir + ritonavir or atazanavir + ritonavir. - for patients who initiated ARV therapy with non-thymidine-based analogues (first-line regimens containing tenofovir or abacavir) the second-line regimens should preferably comprise zidovudine + lamivudine associated with lopinavir + ritonavir or atazanavir + ritonavir.

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) list ATV/r as a preferred PI for treatment-naive patients, and is also recommended for treatment- experienced patients.

The British HIV Association Guidelines (Gazzard 2008) recommend that boosted PIs, including ATV/r, be reserved for ‘later’. The Guidelines state that the main advantages of boosted atazanavir are the once daily dosing and its limited effect on lipids. The main side effects are hyperbilirubinaemia with or without jaundice, but this has not been associated with liver enzyme changes and seldom results in the need to discontinue treatment. The Guidelines also note that a disadvantage of atazanavir is its interaction with acid-reducing agents, in particular proton-pump inhibitors. The Guidelines state that where alternative antacid strategies cannot be used, atazanavir should be avoided.

The Zambian HIV National Guidelines 2008 (http://www.zambiahivguide.org/drugs/antiretrovirals/atazanavir.html?conten tInstanceId=441414) recommend atazanavir 300mg plus ritonavir 100mg for treatment-experienced patients, and state this is also the preferred dose for treatment-naive patients.

9.4 Need for special diagnostic or treatment facilities and skills The WHO Guidelines (2006b) 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 ZDV 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.

Atazanavir – 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 ATV/r or unboosted atazanavir with other HIV regimens. The search terms used were: 1. atazanavir 2. 1 and randomized controlled trial 3. adverse events 4. toxicity 5. 2 and (3 or 4)

10.1.2 Systematic reviews identified No systematic reviews were identified. A recent review of the use of ATV/r in HIV therapy (von Hentig 2008) describes some ATV/r trials (all presented in Section 10.2 below), adverse events associated with atazanavir (see Section 11) and its use in the US and Europe.

10.1.3 Selection/exclusion of particular data Trials were included if they were randomized controlled trials of ATV/r, ATV/saquinavir or unboosted atazanavir, as part of a multi- drug regimen or sole treatment, compared to another HIV regimen. While the current WHO treatment Guidelines (2006) recommend that PI drugs be reserved for second-line treatment (ie following failure of first-line therapy), in order to provide an assessment of evidence across the use of atazanavir, trials in first-line therapy (ie treatment- naive patients) are also included. Results of the first-line trials are provided in Attachment 1. In addition to the available randomized comparative data, a number of non-randomized studies were also included to provide a broad perspective on the available data. Table 10.1.3.1 lists the selected trials and studies.

Table 10.1.3.1: Selected data Trial Design Second-line treatment – randomized controlled trials Cohen et al., 2005 •randomized, open-label comparison of unboosted ATV 400mg/day and LPV 400mg/r 100mg bd with two NRTIs in patients with one PI regimen failure Flammer et al., 2008 •randomized open-label comparison of current PI or unboosted ATV in patients with viral replication and fasting LDL-C >3mmol/L Gatell et al., 2007 •randomized, open-label trial in patients with virological suppression with current treatment but seeking regimen simplification. Trial compared ATV 400mg/day or ATV/r 300/100mg/day and current PI Haas et al., 2003 •randomized, dose-level blinded, otherwise open-label comparison of ATV 400mg or 600mg plus saquinavir 1200mg/day versus ritonavir 400mg/bd plus saquinavir 400mg/bd in patients who had failed ARV treatment •North America, South America, Europe

Atazanavir – HIV infection 7 Trial Design Johnson et al., 2005; 2005 Johnson et al., 2006; •randomized, open-label trial comparing ATV/r 300/100mg/day, Naeger and Struble 2006 ATV/s 400/1200mg/day and LPV/r 400/100mg/bd, each with tenofovir 300mg/day and a NRTI in patients who had failed two or more prior regimens •North America, South America, Europe 2006 •96 week results of 2005 trial above for ATV/r and LPV/r arms only Naeger and Struble •assessment of baseline genotype and phenotype on HIV response in patients in Johnson et al., 2005 Piketty et al., 2006 •randomized, open-label trial in patients with history of failure to at least two PIs and one NNRTI who were randomized to either their current regimen or replacement of PI with ATV/r 300/100mg/day. After two weeks, all patients received ATV/r, tenofovir 300mg/day plus a NRTI Soriano et al., 2008 •randomized, open-label trial in which patients receiving LPV/r- containing regimens and having plasma HIV-RNA <50 copies/mL for longer than 24 weeks were randomized to receive either the same therapy or switch to ATV 400mg/day (or if taking tenofovir, ATV/r 300/100mg/day) •Spain Winston et al., 2007 •randomized, open-label trial of SQV/RTV/ATV 1500/100/300mg/day without NRTIs in patients who had been treated with combination ARV therapy Wood et al., 2004 •open-label extension of randomized trial (Murphy et al., 2003) comparing ATV 400mg/day, ATV 600mg/day or nelfinavir 1250mg/bd plus lamivudine 150mg/bd and stavudine 30 or 40mg/bd Second-line treatment – non-randomized studies Chan-Tack et al., 2007 •retrospective review of FDA adverse event reporting system for cases of nephrolithiasis associated with ATV treatment •United States Colafigli et al., 2008 •open-label trial of patients switched to ATV-containing regimen •Italy Cuzin et al., 2008 •prospective cohort analysis of patients with viral load >400 copies/mL despite ARV treatment who received ATV/r de Mendoza et al., 2006 •retrospective review pf patients who experienced PI failure and were rescued with SQV/r, IDV/r, LPV/r, ATV/r, APV/r or TPV/r Karlstrom et al., 2007 •single arm study of ATV/r 300/100/day in patients without PI experience who had maintained viral load <20 copies/mL for a minimum of 12 months on conventional ARV treatment •Sweden Keiser and Nassar, 2008 •retrospective review comparing patients receiving H2-blockers versus those not while receiving ATV/r or LPV/r as part of their ARV regimen Santoro et al., 2008 •observational study of highly pre-treated patients receiving ATV/r 300/100mg/day or ATV 400mg/day Swindells et al., 2006 •open-label study of patients receiving at least two NRTIs plus at least one PI for at least 48 weeks who were switched to maintenance therapy with ATV/r 300/100mg/day alone •United States First-line treatment – randomized controlled trials Malan et al., 2008 •randomized, open-label trial comparing ATV/r 300/100mg/day and ATV 400mg/day plus 3TC and d4T in treatment-naive patients •North America, South America, Africa, Europe

Atazanavir – HIV infection 8 Trial Design Molina et al., 2008 •randomized, open-label trial comparing ATV/r 300/100mg/day and LPV/r 400/100mg/bd in combination with tenofovir/emtricitabine 300/200mg/day •Africa, Asia, Europe, North America, South America Murphy et al., 2003 •randomized, dose-blinded comparison of ATV 400mg or 600mg/day and nelfinavir 1250mg/bd, plus 3TC and d4T in treatment-naive patients •Africa, Asia, Europe, North America, South America Sanne et al., 2003 •randomized, dose-blinded study comparing ATV 200, 400 or 500mg/day with nelfinavir 750mg/td in treatment-naive patients Smith et al., 2008 •randomized, open-label trial comparing FPV/r 1400/100mg/day and ATV/r 300/100mg/day in treatment-naive patients •United States Squires et al., 2004 •randomized, double-blind trial comparing ATV 400mg/day plus ZDV and 3TC with efavirenz placebo and efavirenz 600mg/day plus ZDV and 3TC and ATV placebo in treatment-naive patients •North America, South America, Europe, Asia, South Africa First-line treatment – non-randomized studies Elton et al., 2008 •single-arm, open-label study of treatment-naïve patients receiving ATV/r 300/100mg/day plus tenofovir/emtricitabine 300/200mg/day Elton et al., 2008(b) •open-label study of treatment-naive patients receiving ABC/3TC 600/300mg/day and ATV/r 300/100mg/day ATV/r=atazanavir/ritonavir; 3TC=lamivudine; ZDV=zidovudine; SQV=saquinavir; RTV=ritonavir; IDV=indinavir; NRTI=nucleoside reverse transcriptase inhibitor; bd=twice daily

While there are a number of randomized, comparative trials available, in both first-line and second-line therapy, none of the trials are set in resource-poor countries. Of the trials that identified trial centres, only four trials included African centres and six trials included South American centres. All other trials were based in the US and/or Europe. While the paucity of published data from resource-poor settings confirms the concern highlighted by Cooke (2007) regarding the lack of data to inform antiretroviral policy, the available comparative evidence does provides some insight into the efficacy and safety of atazanavir.

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. As the assessment focuses on characteristics of randomized trials, the non-randomized studies are not included.

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 Second-line treatment Cohen 2005 open-label not reported 9 9 9 Flammer 2008 observer blind not reported 9 not reported 9 Gatell 2007 open-label not reported 9 9 9 Haas 2003 dose level 1:1:1 permuted block 9 9 9 design Johnson 2005; open-label 1:1:1 central 9 9 9

Atazanavir – HIV infection 9 Generation allocation ITT Description Objective Trial Blinding sequences analysis withdrawals outcomes Johnson 2006; randomization Naeger and Struble 2006 Piketty 2006 open-label not reported 9 9 9 Soriano 2008 open-label not reported 9 9 9 Winston 2007 open-label not reported 9 9 9 Wood 2004 dose levela not reported evaluable 9 9 First-line treatment Malan 2008 open-label not reported 9 9 9 Molina 2008 open-label 1:1 computer- 9 9 9 generated centralised schedule Murphy 2003 dose level not reported 9 9 9 Sanne 2003 dose level 1:1:1 permuted block 9 9 9 design Smith 2008 open-label not reported 9 9 9 Squires 2004 double-blind 1:1:1 central 9 9 9 randomization NR=not reported a dose level unblinded upon entry into rollover/switch study following 48 weeks of treatment

Of the second-line trials, one was observer blind (Flammer et al., 2008), two were blinded to dose level (Haas et al., 2003; Wood et al., 2004) and the remainder were open-label trials. All trials assessed objective outcomes and all trials except Wood et al (2004) used intent- to-treat (ITT) analyses of efficacy data. Overall, the trials are of reasonable quality.

10.2.2 Outcome measures Table 10.2.2.1 provides the primary outcome measures used in the randomized trials and the non-randomized studies.

Table 10.2.2.1: Outcome measures used in the trials and studies Trial/study Primary outcomes Second-line treatment – randomized trials Cohen 2005 •change from baseline in HIV RNA level and fasting LDL-C level Flammer 2008 •endothelial function assessed by flow-mediated vasodilation (FMD) of brachial artery; change from baseline in lipid levels Gatell 2007 •proportion of patients experiencing virologic rebound, defined as HIV RNA ≥50 copies/mL Haas 2003 •change from baseline to 48 weeks in HIV-1 RNA levels, CD4 cell counts and proportion of patients achieving virologic response, defined as decrease of at least 1.0 log10 copies/mL in HIV-1 RNA copies/mL from baseline or HIV-1 RNA level <400 copies/mL at week 48 Johnson 2005; •magnitude and durability of reduction in plasma HIV RNA from baseline based on time-averaged difference through week 48 Johnson 2006; •magnitude and durability of reduction in plasma HIV RNA from baseline based on time-averaged difference through week 96 Naeger and •HIV RNA response according to presence or absence of baseline PI Struble 2006 mutations Piketty 2006 •change from baseline in viral load Soriano 2008 •change from baseline in viral rebound, CD4 cell count, lipid levels Winston 2007 •virologic failure; occurrence of adverse events Wood 2004 •virologic response; change from baseline in CD4 cell count and

Atazanavir – HIV infection 10 Trial/study Primary outcomes percentage change from baseline to week 12 in total cholesterol level Second-line treatment – non-randomized studies Chan-Tack 2007 •cases of nephrolithiasis Colafigli 2008 •change from baseline in lipid levels and cardiovascular risk score Cuzin 2008 •failure of the regimen defined as either viral load >400 copies/mL at week 24 or treatment interruption before week 24 de Mendoza 2006 •rate of virologic response; number of baseline protease resistance mutations and relationship to response Karlstrom 2007 •number of patients completing 72 weeks of therapy without experiencing virological failure, defined as 2 consecutive plasma HIV-1 RNA samples above limit of detection (>20 copies/mL) Keiser and •time to virological failure; proportion of patients not experiencing Nassar, 2008 virological failure Santoro 2008 •time to virologic success (viral load <500 copies/mL) Swindells 2006 •risk of virologic failure (2 consecutive plasma HIV-1 RNA levels ≥200 copies/mL) through 24 weeks First-line treatment – randomized trials Malan 2008 •proportion of patients with HIV RNA <400 copies/mL at week 48 Molina 2008 •proportion of patients with HIV RNA <50 copies/mL at week 48 Murphy 2003 •mean change from baseline in HIV-1 RNA at week 48 Sanne 2003 •time-averaged difference in change from baseline in HIV RNA levels over 48 weeks Smith 2008 •proportion of patients with plasma HIV-1 RNA levels <50 copies/mL at week 48 Squires 2004 •proportion of patients with HIV RNA levels <400 copies/mL through 48 weeks First-line treatment – non-randomized studies Elton et al., 2008 •proportion achieving HIV-1 RNA <50 copies/mL at week 48; change from baseline in CD4 cell count; change from baseline in lipid levels Elton et al., •proportion achieving HIV-1 RNA <50 copies/mL at week 48; treatment 2008(b) discontinuation due to study drugs

10.2.3 Summary of results – second-line treatment – randomized trials

Following are presented the key results of the randomized trials assessing the effectiveness of atazanavir in second-line treatment. Results of the first-line trials are provided in Attachment 1.

Cohen et al (2005) In the Cohen et al (2005) trial, patients with prior PI failure were randomized to treatment with unboosted ATV 400mg (n=144) or LPV/r 400/100mg (n=146). Table 10.2.3.1 provides key trial results.

Table 10.2.3.1: Results of Cohen et al (2005) at 48 weeks ATV 400mg LPV/r 400/100mg Outcome (n=144) (n=146) p value Change from baseline in HIV-1 -1.59 -2.02 <0.001 RNA log10 copies/mL log10 copies/mL Change in lipid levels from baseline (%) LDL-C -6% +3% <0.05 TC -2% +12% <0.05 TG +1% +53% <0.05 ATV=atazanavir; LPV/r=liponavir/ritonavir; LDL-C=low density lipoprotein cholesterol; TC=total cholesterol; TG=triglycerides

Atazanavir – HIV infection 11

Significantly greater viral suppression was observed with LPV/r compared to unboosted atazanavir, however atazanavir-treated patients demonstrated a better lipid profile.

Flammer et al (2008) In the Flammer et al (2008) trial, which sought to assess whether endothelial function improves after switching from another PI to atazanavir, patients on stable therapy including one PI (not atazanavir) were randomized to either continue current PI treatment or switch to unboosted atazanavir 400mg. Twenty patients switched to atazanavir and 19 continued their current PI. Table 10.2.3.2 provides the baseline and change from baseline scores for the outcome variables.

Table 10.2.3.2: Results of Flammer et al (2008) ATV 400mg Current PI 24 p 24 p p Outcome Baseline weeks value Baseline weeks value value N(%) HIV RNA <50 20 10 0.15 19 15 0.32 0.30 copies/mL (100%) (100%) (100%) (78.9%) HIV RNA log10 0.03 0.17 0.15 0.32 0.58 0.32 0.30 copies/mL CD4 cell count 539 543 0.14 520 489 0.61 0.38 cells/µL Brachial artery 4.60 4.56 0.90 4.68 4.74 0.78 NR diameter mm FMD 4.0 3.4 0.40 3.9 3.3 0.37 NR TC mmol/L 6.5 5.5 <0.001 6.5 5.8 0.007 0.048 LDL-C mmol/L 4.0 3.3 <0.001 4.2 3.8 0.02 0.13 HDL mmol/L 1.2 1.3 0.03 1.2 1.2 0.77 0.07 TG mmol/L 3.2 2.0 0.003 2.3 2.0 0.13 0.03 NR=not reported; ATV=atazanavir; FMD=flow mediated vasodilation; TC=total cholesterol; LDL-C=low density lipoprotein cholesterol; HDL=high density lipoprotein; TG=triglycerides

There was no statistically significant difference between patients who switched to ATV and those who remained on their current PI in HIV RNA levels. There was no statistically significant change in endothelial function in ATV-treated patients compared to those remaining on their current PI, although there were significant improvement in lipid levels.

Gatell et al (2007) In the Gatell et al (2007) trial, patients who were receiving stable PI- based regimens were randomized to switch to atazanavir (n=278), either unboosted 400mg or combined with ritonavir (300/100mg) or continue their current regimen (n=141).

At week 48, the proportion of patients who experienced virologic rebound (HIV RNA ≥50 copies/mL) was statistically significantly lower for those who switched to ATV treatment, with 19 of 278 (7%) compared to 22 of 141 (16%) of patients who continued to receive their current PI regimen (p=0.004). Patients who switched to ATV also experienced significantly fewer lipid elevations (p<0.001).

Atazanavir – HIV infection 12

Haas et al (2003) The Haas et al (2003) trial compared atazanavir combined with saquinavir to ritonavir plus saquinavir in treatment-experienced patients. All patients had used a NRTI, over 80% had used a PI and 19% to 30% had used a NNRTI in first-line therapy. None of the patients had previously used atazanavir. Table 10.2.3.3 provides the results of the trial at 48 weeks.

Table 10.2.3.3: Results of Haas et al (2003) at 48 weeks ATV/SQV ATV/SQV RTV/SQV 400/1200 600/1200 400/400 Outcome (n=34) (n=28) (n=23) p value Change from baseline -1.28 ± 0.20 -1.11 ± 0.20 -1.50 ± 0.31 NS in HIV-1 RNA log10 copies/mL log10 copies/mL log10 copies/mL Virological response 41% 29% 35% NS CD4 cell count change 109 × 106 cells/L 55 × 106 cells/L 149 × 106 cells/L NR from baseline LDL-C change from -0.6% -6.7% +23.2% <0.05 baseline TC change from +1.0% -5.1% +10.7% NS baseline TG change from -4.8% -27.1% +93.0% <0.001 baseline ATV=atazanavir; SQV=saquinavir; RTV=ritonavir; NS=not significant; NR=not reported

Once daily atazanavir, combined with saquinavir, showed similar efficacy to twice daily ritonavir plus saquinavir. There were decreases in lipid levels associated with atazanavir treatment, compared to increases associated with ritonavir treatment.

Johnson et al (2005); Johnson et al (2006) The Johnson et al (2005) trial compared ATV/r 300/100mg, (n=119) ATV/SQV 400/1200mg (n=110) and LPV/r 400/100mg (n=118) in patients who had failed two or more prior regimens. A total of 34% of the patients had taken a PI and 60% had taken a NNRTI as part of their previous regimen prior to randomisation. Median prior exposures to any PI, NNRTI or NRTI were 2.5, 1.5 and 5.1 years, respectively. The Johnson et al (2005) paper reports 48 week results of the trial, while the Johnson et al (2006 paper reports 96 week results of the trial. Table 10.2.3.4 summarises the 48 and 96 week results.

Table 10.2.3.4: Results of Johnson et al (2005) and Johnson et al (2006) ATV/r ATV/SQV LPV/r Outcome 300/100 400/1200 400/100 Week 48 results Reduction in HIV RNA from baseline -1.93 -1.55 -1.87 log10 copies/mL log10 copies/mL log10 copies/mL TAD for HIV RNA reduction ATV/r vs. 0.13 (97.5% CI: -0.12, 0.39) LPV/r TAD for HIV RNA reduction 0.33 (97.5% CI: 0.07, 0.60) ATV/SQV vs. LPV/r Increase in CD4 cell count 110 × 106 cells/L 72 × 106 cells/L 121 × 106 cells/L

Atazanavir – HIV infection 13 ATV/r ATV/SQV LPV/r Outcome 300/100 400/1200 400/100 TAD for CD4 reduction ATV/r vs. -17.5 (95% CI: -45.6, 10.6) LPV/r TAD for HIV RNA reduction -47.6 (95% CI: -79.2, -16.q) ATV/SQV vs. LPV/r Week 96 results ATV/r 300/100 LPV/r 400/100 Reduction in HIV RNA from baseline -2.29 log10 copies/mL -2.08 log10 copies/mL TAD for HIV RNA reduction ATV/r vs. 0.14 (97.5% CI: -0.13, 0.41) LPV/r ATV=atazanavir; SQV=saquinavir; LPV=lopinavir; r=ritonavir: TAD=time-averaged difference

At 48 weeks, ATV/r was demonstrated to be non-inferior to LPV/r, with the time-averaged difference (TAD) estimate (0.13; 97.5% CI: - 0.12, 0.39) meeting the criteria for non-inferiority. The response to ATV/SQV was significantly lower than that to LPV/r (TAD 0.33; 97.5% CI: 0.07, 0.60). At 96 weeks, the non-inferiority of ATV/r and LPV/r was maintained (TAD 0.14; 97.5% CI: -0.13, 0.41).

Naeger and Struble (2006) The Naeger and Struble (2006) paper reported on virologic response of patients in the Johnson et al (2005) trial based on presence of baseline PI mutations. Table 10.2.3.5 provides the results.

Table 10.2.3.5: Results of Naeger and Struble (2006) ATV/r LPV/r PI mutation % of patients <400 copies/mL % of patients <400 copies/mL Overall response 64/110 (56%) 67/113 (59%) D30N 6/8 (75%) 4/7 (57%) M361/V 20/38 (53%) 25/42 (60%) M461/L/T 5/20 (25%) 7/25 (28%) 154V/L/T/M/A 5/15 (33%) 5/17 (29%) A71V/T/1/G 14/35 (40%) 18/38 (47%) G73S/A/C/T 2/7 (29%) 3/8 (38%) V771 20/32 (63% 16/29 (55%) V82A/F/T/S/1 10/25 (40%) 11/31 (35%) 184V/A 1/8 (13%) 2/7 (29%) N88D 6/9 (67%) 4/6 (67%) L90M 7/23 (23%) 17/34 (50%) 1-2 PI mutations 36/48 (75%) 40/61 (66%) >3 PI mutations 14/43 (32%) 17/46 (37%) <4 PI mutations 54/82 (66%) 57/82 (70%) >4 PI mutations 10/28 (36%) 10/31 (32%) ≥5 PI mutations 0/9 (0%) 5/18 (28%) ATV=atazanavir; SQV=saquinavir; RTV=ritonavir;

Response rates were less than 30% for ATV/r if mutations at M46, G73, I84 or L90 were present for ATV/r-treated patients, while response was less than 30% if there were mutations at M46, I54 or I84 for LPV/r. Response rates were similar between ATV/r and LPV/r if 0 to 4 PI mutations were present, however if greater than 5 mutations were present, the response rate was 0% for ATV/r and 28% for LPV/r.

Atazanavir – HIV infection 14 Piketty et al (2006) In the Piketty et al (2006) trial a total of 53 patients with a history of failure to at least two PIs and one NNRTI were randomized to either continue their current regimen or replace the PI with ATV/r 300/100mg for two weeks. Following the initial two week period, all patients then received ATV/r plus tenofovir 300mg plus optimised NRTIs. Table 10.2.3.6 provides the key results of the trial.

Table 10.2.3.6: Results of Piketty et al (2006) Outcome ATV/r Unchanged regimen Change from baseline in -0.1 log10/mL -0.1 log10/mL viral load at week 2 All patients Change from baseline in -0.2 log10/mL viral load at week 26 ATV=atazanavir

The combination of ATV/r plus tenofovir demonstrated relatively low antiretroviral activity.

Soriano et al (2008) In the Soriano et al (2008) trial, patients receiving LPV/r and having undetectable plasma HIV-RNA for longer than 24 weeks were randomized to continue on the same therapy or switch to atazanavir. All treatment arms received the PI plus two NRTIs. Of 189 patients who were receiving LPV/r, 102 switched to ATV/r, 49 on ATV 400mg and 53 on ATV/r 300/100mg, and 87 continued LPV/r. Table 10.2.3.7 presents the key results of the trial.

Table 10.2.3.7: Results of Soriano et al (2008) Outcome LPV/r ATV ATV/r (n=87) (n=49) (n=53) Virological failure 9 (10%) 5 (10%) 7 (13%) Change from baseline in CD4 cell count 42 cells/mm3 46 cells/mm3 Median ATV plasma trough concentration - 0.234µg/mL 0.822µg/mL ATV=atazanavir; LPV=liponavir; r=ritonavir

Virological failure was similar across all three groups. There was a statistically significant decrease in total cholesterol and triglycerides for patients switched to atazanavir. The authors conclude that the replacement of LPV/r by atazanavir provides a significant reduction in lipids without increased risk of virological failure.

Winston et al (2007) In the Winston et al (2007) trial, 25 patients currently treated with combination therapy were switched to saquinavir plus ritonavir plus atazanavir for 48 weeks. Patients were randomized to receive an initial change in SQV formulation (200mg to 500mg) or a change in combination therapy to SQV/ATV/r. All patients then received SQV/ATV/r for 48 weeks, without NRTIs.

A total of three patients (12.5%) experienced virologic failure over 48

Atazanavir – HIV infection 15 weeks. The mean increase in CD4 cell count was 63 cells/µL over 48 weeks, which was statistically significant (p=0.012). The authors concluded that a regimen of SQV/ATV/r demonstrated sustained virologic efficacy and was associated with significant increases in CD4 cell count.

Wood et al (2004) The Wood et al (2004) trial is an open-label, rollover/switch study following the Murphy et al (2003) trial compared ATV 400mg, ATV600mg and nelfinavir 1250mg. Of the 178 patients treated with ATV 400mg in Murphy et al (2003), 139 entered the Wood trial. For ATV 600mg, 144 of 195 treated in Murphy et al (2003) entered the rollover trial, and 63 of 91 nelfinavir-treated patients switched to ATV. Table 10.2.3.8 provides the key results of the trial.

Table 10.2.3.8: Results of Wood et al (2004) ATV 400mg ATV 600mg Nelfinavir switch to ATV Outcome (n=139) (n=144) (n=63) Proportion with HIV RNA 83% 85% 87% <400 copies/mL Proportion with HIV RNA 60% 56% 60% <50copies/mL Increased CD4 cell count -44 cells/mm3 43 cells/mm3 29 cells/mm3 ATV=atazanavir

There were minimal changes in lipid levels for patients remaining on ATV treatment, however for patients switching from nelfinavir to ATV there were statistically significant reductions in total cholesterol (- 16%), LDL-C (-20%) and triglycerides (-25%).

10.2.4 Summary of results – second-line treatment – non-randomized studies

Table 10.2.4.1 provides results from the non-randomized studies of atazanavir in second-line treatment.

Table 10.2.4.1: Results of the non-randomized studies in second-line treatment Study Results Chan-Tack •from December 2002 to January 2007, 30 cases of nephrolithiasis were 2007 reported in the Adverse Event Reporting System of the FDA in HIV patients taking ATV •12 cases had confirmed ATV by infrared spectrophotometry •authors conclude that ATV can be associated with nephrolithiasis Colafigli •in 197 treatment-experienced patients switched to ATV, TC decreased 6.5% 2008 (p<0.001), HDL decreased 1.7% (p=0.029), TG decreased 8.6% (p<0.001). •crude cardiovascular risk score decreased from 3.43% to 3.38% (p=0.51); when normalized by age the reduction was statistically significant (3.43 to 3.14%, p<0.001) Cuzin 2008 •424 patients with viral replication despite treatment received ATV/r for 24 weeks •36% of patients experienced treatment failure, 24% with viral load >400 copies/mL and 12% due to treatment interruption. •Female gender, previous use of LPV, number of new drugs and active drugs in the regimen and baseline viral load were independently related with treatment failure •authors conclude ATV/r can be a useful strategy as long as patients did not

Atazanavir – HIV infection 16 Study Results suffer previous LPV failures de Mendoza •patients who had experienced PI failure were rescued with SQV/r (n=139), IDV/r 2006 (n=35), LPV/r (n=129), APV/r (n=35), ATV/r (n=29) and TPV/r (n=22). •5 mutations was best threshold to predict chance of virological response •total number of protease resistance mutations was associated with lower virological response (OR=0.77; 95% CI: 0.68, 0.87; p<0.001). •for patients with 5 protease resistance mutations, the rates of virological response (>1 log reduction in plasma HIV RNA or to < 50 copies/mL at week 24) were 64% with TPV/r, 47% with LPV/r, 46% with SQV/r, 33% with ATV/r, 25% with IDV/r and 16% with APV/r Karlstrom •patients taking triple ARV therapy with HIV RNA <20 copies/mL were switched 2007 to ATV/r 300/100mg. •5 cases of virologic failure (2 consecutive plasma HIV RNA samples >20 copies/mL) occurred when 15 of planned 30 patients had been recruited, thus study was halted according to study protocol. •authors conclude that ritonavir-boosted ATV as maintenance monotherapy may not be as potent as conventional ART. Keiser and •data from 267 ATV/r-treated patients and 670 LPV/r-treated patients was Nassar, available. 2008 •approximately 10% of the ATV/r group and 20% of the LPV/r group received concurrent H2-blockers. •no statistically significant difference between patients treated with ATV/r or LPV/r, with or without concurrent H2-blockers, in time to virological failure •at 750 days following initiation, proportion of patients not experiencing virological failure was 56% on the ATV/r + HR-blocker group, 48% in the ATV/r along group, 42% in the LPV/r + H2-blocker group and 45% in the LPV/r along group. Santoro •200 patients received ATV/r 300/100mg and 154 received ATV 400mg 2008 •median time to virological success (viraemia <500 copies/mL) was 8 weeks in ATV/r group and 13 weeks in ATV group •proportion achieving virological success at week 12 was 66% in ATV/r group and 47% in ATV group. •proportion achieving virological success at week 48 was 86% in ATV/r group and 64% in the ATV group. •receiving ATV/r was independently associated with increased probability of achieving virological success (adjusted HR: 1.57; 95% CI: 1.19, 2.06). •authors conclude antiviral efficacy of ATV is greater when boosted with ritonavir. Swindells •34 patients receiving combination ARV therapy with HIV RNA <50 copies/mL 2006 were switched to simplified maintenance therapy with ATV/r 300/100mg plus NRTI for 6 weeks followed by ATV/r alone for 24 weeks •virological success (absence of failure defined as two consecutive plasma HIV RNA measurements of >200 copies/mL) occurred in 91% of patients •authors conclude simplified maintenance with ATV/r alone may be efficacious in maintaining virologic suppression in carefully selected patients. ATV=atazanavir; LPV=liponavir; SQV=saquinavir; IDV=indinavir; TPV=tipranavir; r=ritonavir

While the non-randomized studies provide evidence of the efficacy of atazanavir, there are some conflicting results. The Karlstrom et al (2007) study, in which patients on successful ARV treatment were switched to a simplified regimen of ATV/r, was halted due to virological failure. In contrast, the Swindells et al (2006) study, in which patients were switched to ATV/r plus NRTI for 6 weeks, followed by ATV/r alone, virological success was observed in 91% of patients. The differing results of these two studies indicate a need to examine the issue of switching to a simplified maintenance regimen in

Atazanavir – HIV infection 17 a larger, randomized controlled trial.

The Santoro et al (2008) study, in which 200 highly pre-treated patients received ATV/r 300/100mg and 154 received ATV 400mg, indicates that the efficacy of atazanavir is greater when boosted with ritonavir.

10.3 Summary of available estimates of comparative effectiveness The available evidence demonstrates that atazanavir, when boosted with ritonavir, is non-inferior to liponavir boosted with ritonavir in both second- line (Johnson et al., 2005; Johnson et al., 2006; Soriano et al., 2008; de Mendoza et al., 2006; Keiser and Nassar, 2008) and first-line treatment (Molina et al., 2008).

Unboosted ATV has been demonstrated to be less efficacious than LPV/r (Cohen et al., 2005) as significantly greater viral suppression was observed with LPV/r. A non-randomized comparison of unboosted ATV and boosted ATV in second-line treatment (Santoro et al., 2008) showed that ATV/r was associated with an increased probability of achieving virological success. As such, in second-line treatment, boosted ATV appears more efficacious.

Treatment with atazanavir resulted in improvement in lipid levels in all trials and studies that reported lipid outcomes. The Soriano et al (2008) trial demonstrated that replacement of LPV/r by ATV or ATV/r provided a significant reduction in lipids without increased risk of virological failure.

While there is considerable evidence demonstrating the virological efficacy of ATV, as well as benefits on lipid levels, none of the trials were based in resource-poor countries and only a few trials included centres in such settings. As such, there is limited direct evidence of the efficacy of ATV in populations in resource-poor countries. A meta-analysis of antiretroviral treatment programs in resource-poor settings (Ivers et al., 2005) found efficacy rates similar to those reported for developed countries. While the studies included in this meta-analysis did not assess second-line treatment, it may be reasonable to conclude that the efficacy of atazanavir is likely to be similar across developed and resource-poor countries. As Lawn et al (2005) point out, drug efficacy is likely to be similar across settings, but programmatic factors such as the availability and accessibility of services will influence treatment success.

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

Estimates of total patient exposure to date are not available. As stated in Section 8.2, ATV/r is currently used as an alternate to LPV/r which is the dominant PI in low and middle income countries. The WHO estimated that approximately 180,000 patients will need second-line regimens in 2008.

Atazanavir – HIV infection 18 11.2 Description of adverse effects/reactions

Atazanavir is considered to be well tolerated (Shibuyama et al., 2006; Busti et al., 2004). Hyperbilirubinaemia has been observed to be associated with atazanavir (Shibuyama et al., 2006; Busti et al., 2004). The most common event observed is an indirect unconjugated elevation of bilirubin, which is believed to be related to inhibition of UDP-glucuronosyl transferase. This event is reversible and is considered to have little clinical significance (Shibuyama et al., 2006; Haas et al., 2003; Busti et al., 2004).

Chan-Tack et al (2007) conducted a retrospective review of the FDA adverse event reporting system for cases of nephrolithiasis associated with ATV treatment. The authors reported that from December 2002 to January 2007 30 cases of nephrolithiasis were reported in the FDA system and that 12 of these cases had confirmed ATV by infrared spectrophotometry. The authors concluded that ATV can be associated with nephrolithiasis.

Atazanavir has not been associated with clinically relevant increases in lipid levels (Cahn et al., 2004), with its favourable effects on dyslipidaemia well- documented (Haas et al., 2003; Cahn et al., 2004; Busti et al., 2004; Bergersen 2005; Flammer et al., 2008).

The effect of atazanavir on lipid outcomes is included in trial results presented above in Sections 10.2.3 to 10.2.4 and in Attachment 1. In all of the trials presenting lipid outcomes, atazanavir was associated with significantly lower increases in lipid levels compared to other PIs. Cahn et al (2004) re-analyzed lipid data from the Sanne et al (2003) and Murphy et al (2003) trials and concluded that ATV does not lead to dyslipidaemia in ARV- naive patients, and may limit the need for lipid-lowering strategies to reduce the risk of cardiovascular disease. In the Flammer et al (2008) trial (see Section 10.2.3) assessing endothelial function, there was a significant improvement in lipid levels for patients who switched to atazanavir from another PI.

Colafigli et al (2007) assessed whether the impact of atazanavir on lipid profile could translate into a reduction in cardiovascular risk. When patients where switched from current treatment to atazanavir there were significant reductions in lipid levels and a statistically significant reduction in age- normalized cardiovascular risk score (see Table 10.2.4.1).

Tables 11.2.1 to 11.2.3 provide a summary of the comparative adverse event data for atazanavir used in second-line treatment. Adverse event data based on first-line treatment is provided in Attachment 2.

Table 11.2.1: Adverse events reported in the Haas et al (2003) trial ATV/SQV 400/1200 ATV/SQV 600/1200 RTV/SQV 400/400 Adverse event (n=32) (n=27) (n=23) Diarrhoea 10 (31%) 2 (7%) 11 (48%) Infection 13 (41%) 12 (44%) 10 (43%) Nausea 6 (19%) 7 (26%) 10 (43%) Abdominal pain 8 (25%) 5 (19%) 8 (35%)

Atazanavir – HIV infection 19 ATV/SQV 400/1200 ATV/SQV 600/1200 RTV/SQV 400/400 Adverse event (n=32) (n=27) (n=23) Peripheral neuropathy 6 (19%) 5 (19%) 5 (22%) Headache 5 (16%) 6 (22%) 4 (17%) Fatigue 5 (16%) 5 (19%) 4 (17%) Flatulence 3 (9%) 1 (4%) 4 (17%) Hypertriglyceridaemia - - 4 (17%) Cough 5 (16%) 4 (15%) 3 (13%) Rash 6 (19%) 4 (15%) 3 (13%) Accidental injury 5 (16%) 4 (15%) 2 (9%) Fever 5 (16%) 2 (7%) 2 (9%) Vomiting 4 (13%) 7 (26%) 2 (9%) Jaundice 4 (13%) 4 (15%) - Elevated 7 (22%) 12 (44%) - hyperbilirubinaemia Grade 3-4 laboratory abnormality Neutropenia 1 (3%) 1 (4%) - Thrombocytopenia 1 (3%) 1 (4%) - Elevated AST 1 (3%) 3 (11%) 5 (23%) Elevated ALT 1 (3%) 4 (15%) 5 (23%) Elevated bilirubin 7 (22%) 13 (48%) 1 (5%) ATV=atazanavir; SQV=saquinavir; RTV=ritonavir; ALT=alanine aminotransferase; AST=aspartate aminotransferase

The Haas et al (2003) paper also reported that the proportion of patients discontinuing treatment because of adverse events that were possibly related to study medication was greater in the RTV/SQV group (26%) than either the ATV 400 or 600mg group (12 and 11%, respectively). The paper also reported that the Grade 3 to 4 elevations in total bilirubin values in the atazanavir groups were not related to grade 3 to 4 elevations in transaminase values, and that the hyperbilirubinaemia in the atazanavir groups was predominantly unconjugated, reversible, asymptomatic and dose-related.

Table 11.2.2: Adverse events reported in the Johnson et al (2006) trial ATV/r 300/100 LPV/r 400/100 Adverse event (n=119) (n=118) p value AEs leading to discontinuation 10 (8%) 9 (8%) NS Serious AEs 16 (13%) 13 (11%) NS Grade 2-4 AEs ≥3% Diarrhoea 3% 13% <0.01 Nausea 3% 2% NS Jaundice 7% 0% <0.01 Scleral icterus 3% 0% NS Myalgia 4% 0% NS Lipodystrophy 3% 3% NS Grade 3-4 laboratory abnormalities ALT elevation 5% 3% NS AST elevation 3% 4% NS Total bilirubin elevation 53% <1% <0.0001 Neutropenia 8% 10% NS Thrombocytopenia 5% 5% NS ATV=atazanavir; LPV=liponavir; r=ritonavir; AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; NS=not significant

There was statistically significantly greater occurrence of jaundice and bilirubin elevation in ATV/r-treated patients compared to those treated with

Atazanavir – HIV infection 20 LPV/r. The grade 3 to 4 elevations in bilirubin were not associated with increases in hepatic transaminase levels.

Table 11.2.3: Adverse events reported in Wood et al (2004) ATV 400mg ATV 600mg Nelfinavir switch to ATV Adverse event (n=139) (n=144) (n=63) Treatment-emergent adverse events n(%) Total 94 (68%) 107 (74%) 50 (79%) Infection 41 (29%) 46 (32%) 22 (35%) Headache 13 (9%) 9 (6%) 12 (19%) Lipodystrophy 13 (9%) 14 (10%) 6 (10%) Diarrhoea 5 (4%) 5 (3%) 1 (2%) Rash 6 (4%) 8 (6%) 5 (8%) Jaundice 4 (3%) 8 (6%) 4 (6%) Grade 3-4 laboratory abnormalities observed/evaluable (%) Total bilirubin 35/137 (26%) 64/144 (44%) 8/63 (13%) ALT/SGPT 2/137 (1%) 3/144 (2%) 0/63 (0%) AST/SGOT 0/137 (0%) 0/144 90%) 0/63 (0%) ATV=atazanavir; ALT=alanine aminotransferase; AST=aspartate aminotransferase; SGPT=serum glutamic-pyruvic transaminase; SGOT=serum glutamic-oxaloacetic transaminase

The overall occurrence of adverse events was similar between treatment groups. The greater occurrence of elevated bilirubin in the ATV groups was predominantly of the indirect and unconjugated type and no patients had concurrent Grade 3 or 4 elevations in bilirubin and aminotransferases.

11.3 Identification of variation in safety due to health systems and patient factors It has been recognized that coadministration of atazanavir with proton pump inhibitors (PPIs) or H2 receptor blockers may lead to inadequate absorption of ATV. A retrospective review of medical records in 10 American HIV clinics by Khanlou and Farthing (2005) found that PPIs and H2 blockers do interact negatively when used with standard ATV dosing and that boosting with ritonavir does not result in adequate levels. The atazanavir product information (PI) was updated in December 2007 to include information on administering atazanavir with acid-reducing therapies. For treatment- experienced patients the PI recommends:

- PPIs should not be used in treatment-experienced patients receiving atazanavir. - the H2-receptor–antagonist dose should not exceed the dose-equivalent of twice-daily 20-mg famotidine. Atazanavir and ritonavir should be administered simultaneously with, or at least 10 hours after, the H2- receptor antagonist. The recommended dose of atazanavir with ritonavir depends on whether the patient is also taking tenofovir. If a patient’s regimen does not include tenofovir, 300 mg of atazanavir should be given with 100 mg of ritonavir, both once daily (all as a single dose with food). If a patient’s regimen does include tenofovir, 400 mg of atazanavir should be given with 100 mg of ritonavir, both once daily (all as a single dose with food).

Atazanavir – HIV infection 21 11.4 Summary of comparative safety against comparators

The available evidence indicates that atazanavir is associated with greater incidence of elevated bilirubin levels compared to other PIs. These elevated levels are generally not associated with elevated transaminase levels, are reversible and are considered to have little clinical significance (Shibuyama et al., 2006; Haas et al., 2003; Busti et al., 2004).

The clinical trial evidence indicates that atazanavir is well-tolerated, with occurrence of adverse events similar or of a lower frequency than comparator PIs. There is also evidence of favourable effects of atazanavir on dyslipidaemia compared to other PIs, which are associated with increases in lipid levels (Haas et al., 2003; Cahn et al., 2004; Busti et al., 2004; Bergersen 2005; Flammer et al., 2008).

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 atazanavir, as well as the price for the boosting dose of ritonavir, 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 atazanavir 2008 Lower-middle Upper-middle Low income income income Tablets/ 2008 2008 2008 capsules price per patient price per patient price per patient Drug/dose per day year (US$) year (US$) year (US$) Atazanavir 150mg 2 NR $4315 $5110 Atazanavir 200mg 2 NR $4351 $4010 Ritonavir 100mg 2 $85 ($83-$91) $313 ($97-$870) $584 ($489-$679) NR=not reported

Second-line treatment is eight to thirteen times more expensive than first-line treatment in low and middle income countries (GPRM 2008). There are no prices available for atazanavir in low income countries, and the reported prices in low-middle income countries are four times greater than the prices for LPV/r. The Global Price Reporting Mechanism does not provide a price for the 300mg capsule of atazanavir. A US source (John Hopkins HIV Guide) states that the average wholesale price of atazanavir 300mg capsule is $USD34.28 (http://www.hopkins- hivguide.org/drug/antiretrovirals/protease_inhibitor/atazanavir__atv_.html).

The 2008 Global Price Reporting Mechanism Report notes that the largest price reduction for second-line therapy from 2004 to 2008 was observed for a fixed-dose combination (FDC) of lopinavir and ritonavir. It is anticipated that a similar FDC for atazanavir and ritonavir may also result in a lower price for ATV/r.

12.2 Comparative cost-effectiveness (presented as range of cost per routine

Atazanavir – HIV infection 22 outcome)

Simpson et al (2007) assessed the comparative cost-effectiveness of ATV/r versus LPV/r in ARV-experienced patients in the US. This analysis used 48 week efficacy data from Johnson et al (2005), which reported 58% of LPV/r- treated patients and 56% of ATV/r-treated patients with HIV RNA <400 copies/mL and 46% of LPV/r-treated patients and 36% of ATV/r-treated patients with HIV RNA <50 copies/mL. Although analysis of the data in the Johnson et al (2005) paper demonstrated that ATV/r was non-inferior to LPV/r, Simpson et al (2007) claimed less efficacy for ATV/r compared to LPV/r and with the greater drug cost for ATV/r compared to the fixed dose combination of LPV/r the cost-effectiveness analysis found LPV/r to be dominant, ie more effective and cheaper than ATV/r. The same model used in this analysis was updated with 2006 cost estimates for the UK, Spain, Italy and France (Simpson et al., 2007b). This analysis found a significant advantage for LPV/r compared to ATV/r, with incremental cost-effectiveness ratios ranging from dominant for Spain to €11,856 per QALY for Italy. Whether the parameters used in the Simpson et al (2007 and 2007b) models are representative of the efficacy of ATV/r is debatable. More importantly, the results may not necessarily be applicable to resource-poor countries, given that the structure of the model, in regard to costing of healthcare resources, and the actual costs used will be considerably different than those in resource-poor settings.

While there have been some attempts to assess the cost-effectiveness of ARV therapy in resource-poor countries (Creese et al., 2002; Cleary et al., 2004), there are no analyses that specifically assess the cost-effectiveness of second- line atazanavir treatment in these settings. Cleary et al (2004) conducted a cost-utility analysis comparing ARV treatment and no ARV treatment in adult HIV patients with CD4 cell counts of <200 cells/µL. The treatment scenario used in the analysis included second-line therapy with LPV/r. The incremental cost per QALY gained was estimated to be 13,621 Rand. The authors concluded that ARV therapy is efficient in economic terms.

Freedberg et al (2007) assessed the cost-effectiveness of ARV therapy in India, including the impact of a second-line PI-based regimen. This regimen was comprised of ritonavir-boosted indinavir, didanosine and lamivudine. The per patient annual cost used in the model of this regimen was $US1435. The use of second-line therapy had an incremental cost effectiveness ratio of $US1880 per year of life saved.

The cost-effectiveness estimates generated by these models are dependent upon the structure of the models and the parameters used, which are highly content-specific. Thus, it is likely that the results are not directly applicable to the use of atazanavir in second-line treatment in resource-poor settings. Beck et al (2008) outlines the need to recognize cost and cost-effectiveness as important information for countries scaling up HIV services, and offers an overview of how such strategic information can be collected, stored and used within a country’s HIV monitoring and evaluation system. Application of required resources for data collection, management and analysis will provide

Atazanavir – HIV infection 23 a basis upon which to more accurately assess cost-effectiveness of specific agents and treatment regimens in resource-poor settings.

13. Regulatory status

Table 13.1 provides the regulatory status and WHO pre-qualification status of atazanavir as recorded in the WHO Drug Regulatory Status Report (http://www.who.int/hiv/amds/patents_registration/drs/). The 100mg and 300mg capsules have regulatory approval in the US and India. Neither of these formulations have WHO pre-qualification.

Table 13.1 – Regulatory status as based on WHO Drug Regulatory Status Report Country Dose Manufacturer WHO pre-qualified Burundi 150mg BMS Yes 200mg BMS No Democratic 150mg BMS Yes Republic of Congo 200mg BMS No Ghana 150mg BMS Yes 200mg BMS No India 100mg Emcure No 150mg Emcure No 200mg Emcure No Kenya 150mg BMS Yes 200mg BMS No Malawi 150mg BMS Yes 200mg BMS No Namibia 150mg BMS Yes 200mg BMS No USA 100mg BMS No 100mg Emcure No 150mg BMS Yes 150mg Emcure No 200mg BMS No 200mg Emcure No 300mg BMS No

14. Availability of pharmacopoeial standards Atazanavir is not currently included in the International Pharmacopoeia, US Pharmacopoeia, British Pharmacopoeia or the European Pharmacopoeia.

15. Proposed text for the WHO Model Formulary The proposed text for the WHO Model Formulary is provided in Attachment 3.

References

Beck EJ, Santas XM, DeLay PR. Why and how to monitor the cost and evaluate the cost-effectiveness of HIV services in countries. AIDS 2008; 22 (suppl 1): S75- S85. Bergersen BM. Cardiovascular risk in patients with HIV infection: impact of antiretroviral therapy. Drugs 2006; 66(15): 1971-87.

Atazanavir – HIV infection 24

Busti AJ, Hall RG, Margolis DM. Atazanavir for the treatment of human immunodeficiency virus infection. Pharmacotherapy 2004; 24(12): 1732-47. Cahn PE, Gatell JM, Squires K, Percival LD et al. Atazanavir – a once-daily HIV protease inhibitor that does not cause dyslipidemia in newly treated patients: results from two randomized clinical trials. J Int Assoc Phys AIDS Care 2004; 3: 92-98. Chan-Tack KM, Truffa MM, Struble KA, Birnkrant DB. Atazanavir-associated nephrolithiasis: cases from the US Food and Drug Administration’s Adverse Event Reporting System. AIDS 2007; 21(9): 1215-18. 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 Cohen C, Nieto-Cisneros L, Zala C, Fessel WJ et al. Comparison of atazanavir with lopinavir/ritonavir in patients with prior protease inhibitor failure: a randomized multinational trial. Curr Med Res and Opin 2005; 21(10): 1683-92. Colafigli M, Giambenedetto SD, Bracciale L, Tamburrini e et al. Cardiovascular risk score change in HIV-1-infected patients switched to an atazanavir-based combination antiretroviral regimen. HIV Med 2008; 9: 172-79. Cooke GS. Evolution of adult antiretroviral therapy for programmatic delivery in Africa and the potential role for new therapeutic approaches. Therapy 2007; 4(6): 767-74. 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. Cuzin L, Flandre P, Pugliese P, Duvlvier C et al. Atazanavir in patients with persistent viral replication despite HAART: results form the French prospective NADIS cohort. HIV Clin Trials 2008; 9(3): 147-51. de Mendoza C, Valer L, Ribera E, Barreiro P et al. Performance of six different ritonavir-boosted protease inhibitor regimens in heavily antiretroviral-experienced HIV-infected patients. HIV Clin Trials 2006; 7(4): 163-71. Elton R, Cohen C, Ward D, Ruane P et al. Evaluation of efficacy, safety, pharmacokinetics, and adherence in HIV-1-infected, antiretroviral naïve patients treated with ritonavir-boosted atazanavir plus fixed-dose tenofovir DF/emtricitabine given once daily. HIV Clin Trials 2008; 9(4): 213-24. Elton R, DeJesus E, Sension M, Berger D et al. Once-daily abacavir/lamivudine and ritonavir-boosted atazanavir for the treatment of HIV-1 infection in antiretroviral naive patients: a 48 week pilot study. HIV Clin Trials 2008b; 9(3): 152-63. Flammer AJ, Vo NTT, Ledergerber B, Hermann f et al. Effect of atazanavir versus other protease inhibitor-containing antiretroviral therapy on endothelial function in HIV-infected persons: randomized controlled trial. Heart 2008. Freedberg KA, Kumarasamy N, Losina E, Cecelia AJ, Scott CA et al. Clinical impact and cost-effectiveness of antiretroviral therapy in India: starting criteria and second-line therapy. AIDS 2007; 21 (suppl 4):S117-S128. Galarraga O, O’Brien ME, Gutierrez JP, Renaud-Thery F, Nguimfack D et al. Forecast of demand for antiretroviral drugs in low and middle-income countries: 2007-2008. AIDS 2007 21(suppl 4): S97-S103. Gatell JM, Salmon-Ceron D, Lazzarin A, Van Wijngaerden e et al. Efficacy and safety of atazanavir-based highly active antiretroviral therapy in patients with virologic suppression switched from a stable, boosted or unboosted protease

Atazanavir – HIV infection 25 inhibitor regimen: the SWAN Study (A1424-097) 48 week results. Clin Infect Dis 2007; 44(11): 1484-92. Gazzard BG. British HIV Association Guidelines for the treatment of HIV-10- infected adults with antiretroviral therapy 2008. HIV Medicine 2008; 9: 563-608. Haas DW, Zala C, Schrader S, Piliero P et al. Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial. AIDS 2003; 17: 1339-49. 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. Johnson M, Grinsztejn B, Rodriguez C, Coco J et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS 2005; 19: 685-94. Johnson M, Grinsztejn B, Rodriguez C, Coco J et al. 96-week comparison of once- daily atazanavir/ritonavir and twice daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS 2006; 20: 711-18. Khanlou H, Farthing C. Co-administration of atazanavir with proton-pump inhibitors and H2 blockers. J Acquir Immun Defic Syndr 2005; 39(4): 503. Karlstrom O, Josephson F, Sonnerborg A. Early virologic rebound in a pilot trial of ritonavir-boosted atazanavir as maintenance monotherapy. J Acquir Immune Defic Syndr 2007; 44: 417-22. Keiser PH, Nassar N. time to virological failure with atazanavir/ritonavir and lopinavir/ritonavir, with or without an H2-receptor blocker, not significantly different in HIV observational database study. Int J STD and AIDS 2008; 19(8): 561-62. 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. Malan DR, Krantz E, David N, Wirtz V, Hammond J, McGrath D for the 089 Study Group. Efficacy and safety of atazanavir, with or without ritonavir, as part of a once-daily highly active antiretroviral therapy regimens in antiretroviral-naive patients. J Acquir Immune Defic Syndr 2008; 47:161-67. Molina JM, Villanueva JA, Echevarria J, Chetchotisakd P et al. Once-daily atazanavir/ritonavir versus twice daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naïve HIV-1- infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 2008; 372: 646-55. Murphy RL, Sanne I, Cahn P, Phanuphak P et al. Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naïve subjects: 48 weeks results. AIDS 2003; 17: 2603-14. Naeger LK, Struble KA. Effect of baseline protease genotype and phenotype on HIV response to atazanavir/ritonavir in treatment-experienced patients. AIDS 2006; 20: 847-53. Piketty C, Gerard L, Chazallon C, Marcelin AG et al. Salvage therapy with atazanavir/ritonavir combined to tenofovir in HIV-infected patients with multiple treatment failures: randomized ANRS 107 trial. Antiviral Therapy 2006; 11(2): 213-21.

Atazanavir – HIV infection 26 Sanne I, Piliero P, Squires K, Thiry A, Schnittman S for the A1424-007 Clinical Trial Group. Results of a Phase 2 clinical trials at 48 weeks (A1424-007): A dose- ranging, safety and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naïve subjects. JAIDS 2003; 32: 18-29. Santoro M, Bertoli A, Lorenzini P, Lazzarin A et al. Viro-immunologic response to ritonavir-boosted or unboosted atazanavir in a large cohort of multiply treated patients. The CARe Study. AIDS Patient Care and STDS 2008; 22(1):7-16. Shibuyama S, Gevorkyan A, Yoo U, Tim S et al. Understanding and avoiding antiretroviral adverse events. Current Pharm Design 2006; 12: 1075-90. Simpson KN, Jones WJ, Rajagopalan R, Dietz B. Cost effectiveness of lopinavir/ritonavir compared with atazanavir plus ritonavir in antiretroviral- experienced patients in the US. Clin Drug Invest 2007; 27(7): 443-52. Simpson KN, Jones WJ, Rajagopalan R, Dietz B. Cost effectiveness of lopinavir/ritonavir compared with atazanavir plus ritonavir in antiretroviral- experienced patients in the UK, France, Italy and Spain. Clin Drug Invest 2007; 27(12): 807-17. Smith KY, Weinberg WG, DeJesus E, Fischl et al. Fosamprenavir or atazanavir once daily boosted with ritonavir 100mg, plus tenofovir/emtricitibane, for the initial treatment of HIV infection: 48 weeks results of ALERT. AIDS Res and Therapy 2008; 5:5. Soriano V, Garcia-Gasco P, Vispo E, Ruiz-Sancho A et al. Efficacy and safety of replacing lopinavir with atazanavir in HIV0-infected patients with undetectable plasma viraemia: final results of the SLOAT trial. J Antimicrobial Chemo 2008; 61(1): 200-05. Squires K, Lazzarin A, Gatell JM, Powderly WG et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with JIV. J Acquir Immune Defic Syndr 2004; 36: 1011-19. Swindells S, DiRienzo AG, Wilkin T et al. Regimen simplification to atazanavir- ritonavir alone as maintenance antiretroviral therapy after sustained virologic suppression. JAMA 2006; 296(7): 806-14. von Hentig N. Atazanavir/ritonavir: a review of its use in HIV therapy. Drugs of Today 2008; 44(2): 103-32. WHO 2006: http://www.who.int/hiv/pub/guidelines/artadultguidelines.pdf WHO 2006: Report on WHO/UNAIDS meeting on forecasting ARV needs up to 2010: Draft January 2006; Geneva. 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 Winston A, Mallon PW, Satchell C, MacRae K et al. The safety, efficacy, and pharmacokinetic profile of a switch in antiretroviral therapy to saquinavir, ritonavir and atazanavir alone for 48 weeks and a switch in the saquinavir formulation. Clin Infect Dis 2007; 44(11); 1475-83. Wood R, Phanuphak P, Cahn P, Pokrovskiy V et al. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. J Acquir Immune Defic Syndr 2004; 36: 684-92

Atazanavir – HIV infection 27 Attachment 1

Summary of results for first-line treatment

A1.1 Summary of results – first-line treatment – randomized trials

Malan et al (2008) In the Malan et al (2008) trial, antiretroviral naive patients with HIV RNA levels ≥2000 copies/mL were randomized to ATV/r 300/100mg (n=95) or ATV 400mg (n=105), both in combination with lamivudine and an investigational extended release formulation of stavudine. Table A1.1.1 summarises the key trial results.

Table A1.1.1: Results of Malan et al (2008) at week 48 ATV/r ATV Outcomes (n=95) (n=105) HIV RNA <400 copies/mL n(%) 82 (86%) 89 (85%) HIV RNA <50 copies/mL n(%) 71 (75%) 73 (70%) Change from baseline in CD4 cell 174 cells/mm3 213 cells/mm3 count LDL-C increase of at least 1 NCEP 16% 11% category TC increase of at least 1 NCEP 46% 48% category TG increase of at least 1 NCEP 30% 18% category ATV=atazanavir’ r=ritonavir; NCEP=National Cholesterol Education Program

ATV/r met the criteria for non-inferiority to ATV 400mg for both virologic response at <400 copies/mL and <50 copies/mL. There was no statistically significant difference in change in CD4 cell count. There were greater changes in lipid levels for patients treated with ATV/r compared to ATV alone, however the paper does not report whether the between-group differences are statistically significantly different.

Molina et al (2008) In the Molina et al (2008) trial, antiretroviral naive patients were randomized to receive ATV/r 300/100mg (n=440) or LPV/r 400/100mg (n=443), both in combination with tenofovir/emtricitabine 300/200mg. Table A1.1.2 provides the results for the primary outcome, proportion of patients with HIV RNA <50 copies/mL at week 48.

Table A1.1.2: Results of Molina et al (2008) at week 48 ATV/r-LPV/r Outcome ATV/r LPV/r (95% CI) HIV RNA <50 copies/mL 343/440 (78%) 338/443 (76%) 1.7% (-3.8, 7.1) Increase in CD4 cell 203 cells/µL 219 cells/µL -16.4 (-35.9, 3.1) count Virological failure 25/440 (6%) 26/443 (6%) NR ATV=atazanavir; LPV=liponavir; r=ritonavir; NR=not reported

For the primary outcome, proportion of patients with HIV RNA <50

Atazanavir – HIV infection 28 copies/mL at week 48, ATV/r met the criterion for non-inferiority with LPV/r. There were no differences between treatment groups in change in CD4 cell count or occurrence of virological failure. The authors concluded that ATV/r has similar antiviral efficacy to LPV/r.

Murphy et al (2003) In the Murphy et al (2003) trial, antiretroviral naive patients were randomized to ATV 400mg/day (n=181, ATV 600mg/day (n=195 or nelfinavir 1250mg twice daily (n=91), each combined with lamivudine and stavudine. Table A1.1.3 provides the key results of the trial.

Table A1.1.3: Results of Murphy et al (2003) at week 48 Outcome ATV 400mg ATV 600mg NFV 1250mg Change from baseline -2.51 -2.58 -2.31 HIV RNA log10 copies/mL log10 copies/mL log10 copies/mL Proportion HIV RNA 116/181 (64%) 130/195 (67%) 48/91 (53%) <400 copies/mL Proportion HIV RNA <50 63/181 (35%) 71/195 (36%) 31/91 (34%) copies/mL Change from baseline in +234 × 106 cells/L +243 × 106 cells/L +211 × 106 cells/L CD4 cell count % change from baseline 5.1% 5.9% 24.6% in TC % change from baseline 5.2% 7.1% 23.2% in LDL-C % change from baseline 7.2% 7.6% 49.5% in TG ATV=atazanavir; NFV=nelfinavir

There was a statistically significant advantage for ATV 600mg compared to nelfinavir in change in HIV RNA and proportion with HIV RNA <400 copies/mL, as well as statistically significantly lower changes in lipid levels for both doses of ATV compared to nelfinavir. The authors concluded that atazanavir is an effective PI with low pill burden.

Sanne et al (2003) In the Sanne et al (2003) trial, antiretroviral naive patients were randomized to ATV 200mg/day (n=104), ATV 400mg/day (n=103), ATV 500mg (110) or nelfinavir 750mg three times daily (n=103) for 2 weeks, after which all patients received didanosine and stavudine. Table A1.1.4 provides the trial results.

Table A1.1.4: Results of Sanne et al (2003) Outcome ATV 200mg ATV 400mg ATV 500mg NFV 750mg Change from baseline HIV RNA -1.41 -1.41 -1.39 -1.51 at week 2 log10 copies/mL log10 copies/mL log10 copies/mL log10 copies/mL Change from baseline HIV RNA -2.57 -2.42 -2.53 -2.33 at week 48 log10 copies/mL log10 copies/mL log10 copies/mL log10 copies/mL Proportion HIV RNA 61% 64% 59% 56% <400 copies/mL Proportion HIV RNA 28% 36% 42% 39%

Atazanavir – HIV infection 29 Outcome ATV 200mg ATV 400mg ATV 500mg NFV 750mg <50 copies/mL Change in CD4 cell 220 cells/mm3 221 cells/mm3 208 cells/mm3 185 cells/mm3 count % change from 7.2% 6.8% 8.0% 27.8% baseline in TC % change from 3.7% -7.1% 2.6% 31.1% baseline in LDL-C % change from -1.1% 1.5% 6.8% 42.2% baseline in TG ATV=atazanavir; NFV=nelfinavir

Mean change in HIV RNA, the proportion of patients with HIV RNA <400 copies/mL and <50 copies/mL and increase in CD4 cell count were comparable across all treatment groups. The mean change from baseline in LDL-C was significantly less in the atazanavir groups compared to nelfinavir (p<0.0001).

Smith et al (2008) In the Smith et al (2008) trial, antiretroviral naive patients were randomized to treatment with fosamprenavir/ritonavir 1400/100 (n=53 or ATV/r 300/100mg (n=53), with both treatments combined with tenofovir/emtricitabine 300/200mg. Trial results are provided in Table A1.1.5 below.

Table A1.1.5: Results of Smith et al (2008)) Outcome ATV/r 300/100mg FPV/r 1400/100 Change from baseline HIV RNA at week 4 -2.2 -2.2 log10 copies/mL log10 copies/mL Proportion HIV RNA <400 copies/mL 87% 79% Proportion HIV RNA <50 copies/mL 83% 75% Change from baseline in CD4 cell count +183 cells/mm3 +170 cells/mm3 ATV=atazanavir; FPV=fosamprenavir

The paper did not report mean change from baseline in HIV RNA at week 48, however it did state that maximum reduction (seen at week 12, also not reported) did not diminish through week 48. There were no statistically significant differences between treatment groups on any efficacy outcomes.

Squires et al (2004) In the Squires et al (2004) trial, antiretroviral naive patients were randomized to ATV 400mg/day (n=404) or efavirenz 600mg/day (n=401), both in combination with zidovudine plus lamivudine. Table A1.1.6 provides a summary of trial results.

Table A1.1.6: Results of Squires et al (2004) at week 48 Outcome ATV 400mg EFV 600mg Proportion HIV RNA <400 copies/mL 70% 64% Proportion HIV RNA <50 copies/mL 32% 37% Change from baseline HIV RNA -2.7 -2.7 log10 copies/mL log10 copies/mL Change from baseline in CD4 cell count (median) +176 cells/mm3 +160 cells/mm3 ATV=atazanavir; FPV=fosamprenavir

Atazanavir – HIV infection 30

There were no statistically significant differences between treatment groups in proportion with HIV RNA <400 or <50 copies/mL, nor in change in HIV RNA or CD4 cell count. Patients in the efavirenz group demonstrated significant increases in lipid levels, while patients in the atazanavir group did not. The authors concluded that ATV plus zidovudine and lamivudine is as efficacious as efavirenz plus zidovudine and lamivudine.

A1.2 Summary of results – first-line treatment – non-randomized studies

Table A1.2.1 provides the results of the non-randomized studies in first-line treatment using atazanavir.

Table A1.2.1: Results of the non-randomized studies in first-line treatment Study Results Elton 2008 •100 antiretroviral naive patients were treated with ATV/r 300/100mg plus tenofovir/emtricitabine 300/200mg. •81% achieved HIV RNA <50 copies/mL •median CD4 cell count increase was 217 cells/mm3. •median increase in TC, LDL-C and TG were 11,2 and 5 mng/dL, respectively Elton •112 antiretroviral naive patients received abacavir/lamivudine 600/300mg/day 2008(b) and ATV/r 300/100mg/day •proportion achieving HIV RNA <50 copies/mL at week 48 was 77% •median change from baseline in lipids was 28mg/dL for TC, 39mg/dL for TG, 14mg/dL for HDL and 8mg/DL for LDL-C.

Both of the non-randomized studies demonstrated that ATV/r in combination with either tenofovir/emtricitabine or abacavir/lamivudine in antiretroviral naive patients was effective, with little impact on lipid levels.

Atazanavir – HIV infection 31 Attachment 2 Summary of adverse events observed in first-line treatment

Tables A2.1 to A2.6 provide a summary of the adverse event data for atazanavir used in first-line treatment.

Table A2.1: Adverse events reported in Malan et al (2008) ATV/r ATV 400 Adverse event (n=95) (n=104) Serious AEs 14 (15%) 17 (16%) Discontinuation attributable to AEs 8 (8%) 1 (<1%) All Grade 2-4 treatment-related AEs 41 (43%) 35 (34%) Grade 2-4 treatment-related AEs 3% Jaundice 3 (3%) 1 (<1%) Headache 2 (2%) 4 (4%) Rash 2 (2%) 4 (4%) Clinically relevant Grade 3-4 laboratory abnormalities Total bilirubin elevation 56 (59%) 21 (20%) ALT elevation 6 (6%) 3 (3%) AST elevation 3 (3%) 3 (3%) ATV=atazanavir; r=ritonavir; ALT=alanine aminotransferase; AST=aspartate aminotransferase

Table A2.2: Adverse events occurring with greater frequency in ATV-treated patients reported in Molina et al (2008) Adverse event ATV/r LPV/r Total bilirubin elevation 146/435 (34%) 1/431 (<1%) ALT elevation 8/435 (2%) 6/431 (2%) AST elevation 9/435 (2%) 2/430 (<1%) ATV=atazanavir; LPV=liponavir; r=ritonavir; ALT=alanine aminotransferase; AST=aspartate aminotransferase

Table A2.3: Adverse events reported in the Murphy et al (2003) trial ATV 400 ATV 600 NFV 1250 Adverse event (n=178) (n=195) (n=91) Diarrhoea 36 (20%) 29 (15%) 51 (56%) Infection 75 (42%) 107 (55%) 44 (48%) Headache 45 (25%) 52 (27%) 24 (26%) Peripheral neuropathy 32 (18%) 42 (22%) 19 (21%) Rash 39 (22%) 34 (17%) 17 (19%) Nausea 38 (21%) 35 (18%) 16 (18%) Abdomen pain 33 (19%) 43 (22%) 12 (13%) Flu syndrome 30 (17%) 25 (13%) 9 (10%) Cough increased 27 (15%) 28 (14%) 8 (9%) Hyperbilirubinaemia 43 (24%) 62 (32%) 3 (3%) Jaundice 20 (11%) 39 (20%) - Grade 3-4 laboratory abnormality Elevated AST 5/177 (3%) 6/195 (3%) 5/91 (5%) Elevated ALT 8/177 (5%) 10/195 (5%) 7/91 (8%) Elevated bilirubin 73/177 (41%) 113/195 (58%) 4/91 (4%) ATV=atazanavir; SQV=saquinavir; RTV=ritonavir; ALT=alanine aminotransferase; AST=aspartate aminotransferase

Table A2.4: Adverse events reported in the Sanne et al (2003) trial ATV 200 ATV 400 ATV 500 NFV 750 Adverse event (n=102) (n=101) (n=107) (n=100)

Atazanavir – HIV infection 32 ATV 200 ATV 400 ATV 500 NFV 750 Adverse event (n=102) (n=101) (n=107) (n=100) Any event 92 (90%) 93 (92%) 100 (93%) 93 (93%) Infection 47 (46%) 53 (52%) 64 (60%) 53 (53%) Headache 22 (22%) 26 (26%) 22 (21%) 19 (19%) Flu syndrome 12 (12%) 10 (10%) 25 (23%) 19 (19%) Nausea 25 (225%) 35 (35%) 32 (30%) 18 (18%) Diarrhoea 23 (23%) 25 (25%) 32 (30%) 61 (61%) Abdomen pain 25 (25%) 31 (31%) 24 (22%) 23 (23%)( Vomiting 15 (15%) 20 (20%) 21 (20%) 19 (19%) Peripheral neurologic 25 (25%) 23 (23%) 21 (20%) 19 (19%) symptoms Rash 12 (12%) 22 (22%) 22 (21%) 14 (14%) Grade 3-4 laboratory abnormality Elevated AST 4 (4%) 14 (14%) 8 (8%) 4 (4%) Elevated ALT 7 (7%) 14 (14%) 8 (8%) 6 (6%) Elevated bilirubin 20 (20%) 41 (41%) 51 (49%) 1 (1%) ATV=atazanavir; NFV=nelfinavir; ALT=alanine aminotransferase; AST=aspartate aminotransferase

Table A2.5: Adverse events reported in the Squires et al (2004) trial ATV 400 EFV 600 Adverse event (n=404) (n=401) Grade 2-4 events Total 165 (41%) 182 (45%) Nausea 57 (14%) 51 (13%) Rash 25 (6%) 41 (10%) Headache 23 (6%) 25 (6%) Jaundice 21 (5%) 0 (0%) Vomiting 17 (4%) 27 (7%) Dizziness 8 (2%) 24 (6%) Scleral icterus 6 (1%) 0 (0%) Diarrhoea 5 (1%) 10 (2%) LAS/SHL 0 (0%) 1 (<1%) Grade 3-4 laboratory abnormalities ALT/SGPT 15 (4%) 10 (3%) AST/SGOT 7 (2%) 8 (2%) Total bilirubin 131 (33%) 2 (<1%) ATV=atazanavir; EFV=efavirenz; ALT=alanine aminotransferase; AST=aspartate aminotransferase; SGPT=serum glutamic-pyruvic transaminase; SGOT=serum glutamic- oxaloacetic transaminase; LAS/SHL=lactic acidosis syndrome/symptomatic hyperlactataemia

Table A2.6: Adverse events reported in the Smith et al (2008) trial FPV/r ATV/r Adverse event (n=53) (n=53) Diarrhoea 28 (53%) 13 (25%) Blood bilirubin increased 0 (0%) 16 (30%) Nausea 8 (15%) 6 (11%) Rash 8 (17%) 5 (9%) Fatigue 6 (11%) 7 (13%) Headache 5 (9%) 3 (6%) Hyperbilirubinaemia 0 (0%) 8 (15%) Cough 4 (8%) 3 (6%) Nasopharyngitis 3 (6%) 4 (8%) Upper respiratory tract infection 2 (4%) 4 (8%) Arthralgia 0 (0%) 5 (9%) Insomnia 2 (4%) 3 (6%) Ocular icterus 0 (0%) 5 (89%)

Atazanavir – HIV infection 33 FPV/r ATV/r Adverse event (n=53) (n=53) Syphilis 5 (9%) 0 (0%) Depression 3 (6%) 1 (2%) Herpes zoster 1 (2%) 3 (6%) Dizziness 3 (6%) 0 (0%) Jaundice 0 (0%) 3 (6%) Paresthesia 3 (6%) 0 (0%) ATV=atazanavir; FPV=fosamprenavir; r=ritonavir

As observed with adverse event data in second-line treatment, there is a greater occurrence of jaundice and bilirubin elevation associated with ATV treatment.

Atazanavir – HIV infection 34

Attachment 3 Proposed text for the WHO Model Formulary

The following is based on Product Information for atazanavir sulphate capsules.

Description: Atazanavir sulfate is an azapeptide inhibitor of HIV-1 protease. The compound selectively inhibits the virus specific processing of viral gag-pol proteins in HIV-1 infected cells, thus preventing formation of mature virions and infection of other cells.

How Supplied: Capsules, for oral administration in strengths containing the equivalent of 100 mg, or 300 mg of atazanavir as atazanavir sulfate and the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain gelatin and titanium dioxide, and are coloured with indigo carmine CI73015. The 300 mg capsule shell also contains red iron oxide, black iron oxide and yellow iron oxide.

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

Contraindications: - Hypersensitivity to atazanavir or to any of the excipients. - Patients with severe hepatic insufficiency. Atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment. - Atazanavir should not be used in combination with rifampicin. - Patients taking atazanavir should not use medicinal products that are substrates of the CYP3A4 isoform of cytochrome P450 and have narrow therapeutic windows. Coadministration may result in competitive inhibition of the metabolism of these medicinal products and create the potential for serious and/or life threatening adverse events such as cardiac arrhythmia (e.g. cisapride, pimozide), prolonged sedation or respiratory depression (e.g. midazolam, triazolam), or other events (e.g. ergot derivatives). - Atazanavir should not be administered with proton pump inhibitors due to an important reduction in atazanavir exposure. - Atazanavir should not be used in combination with products containing St John's wort (Hypericum perforatum).

Drug interactions. Atazanavir is an inhibitor of CYP3A4 and UGT (UDP-glucuronyl transferase) 1A1. Coadministration of atazanavir and drugs primarily metabolised by CYP3A4 (e.g. calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and phosphodiesterase inhibitors) or UGT1A1 (e.g. irinotecan) may result in increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects. Atazanavir is also an inhibitor of CYP1A2 and CYP2C9 with potential for drug-drug interactions. Atazanavir is metabolised in the

Atazanavir – HIV infection 35 liver by the cytochrome P450 enzyme system. Coadministration of atazanavir and drugs that induce CYP3A4, e.g. rifampin, may decrease atazanavir plasma concentrations and reduce its therapeutic effect. Coadministration of atazanavir and drugs that inhibit CYP3A4 may increase atazanavir plasma concentrations.

Atazanavir solubility decreases as pH increases. Do not administer atazanavir (with or without ritonavir) concomitantly with a proton pump inhibitor due to the substantial reduction in atazanavir exposure levels. When atazanavir/ ritonavir 300 mg/100 mg was coadministered with omeprazole in healthy subjects, a 76% reduction in atazanavir AUC resulted. In the absence of specific data, the recommendation against coadministration with atazanavir is extended to other proton pump inhibitors. Reduced plasma concentrations of atazanavir are also expected if antacids, buffered medications and H2-receptor antagonists are administrated with atazanavir.

Atazanavir has the potential to prolong the PR interval of the electrocardiogram in some patients. Caution should be used when coadministering atazanavir with medicinal products known to induce PR interval prolongation (e.g. atenolol, diltiazem).

Drugs that are contraindicated or not recommended for coadministration with atazanavir are included in Table 7. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. Please refer to table 7.

Atazanavir – HIV infection 36

Precautions:

Hyperbilirubinaemia and jaundice. Most patients taking atazanavir experience asymptomatic elevations in indirect (unconjugated) bilirubin, and this may be associated with scleral icterus and jaundice in some patients. This isolated hyperbilirubinaemia is reversible upon discontinuation of atazanavir.

Atazanavir – HIV infection 37 Hyperbilirubinaemia was related to atazanavir plasma concentrations and not generally associated with elevation of serum transaminases. Preclinical studies suggest that elevation in bilirubin was not associated with haemolysis and was related to inhibition of UDP-glucuronosyl transferase (UGT) by atazanavir. Hepatic transaminase elevations that occur with hyperbilirubinaemia should be evaluated for alternative aetiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin > 5 times upper limit of normal (ULN). Alternative antiretroviral therapy to atazanavir may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established.

Cardiac effects. Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (A-V) conduction were asymptomatic and generally limited to first degree A-V block. There have been rare reports of second degree A-V block and other conduction abnormalities and no reports of third degree A-V block (see Overdosage). In clinical trials, asymptomatic first degree A-V block was observed in 5.9% of atazanavir treated patients (n = 920), 5.2% of lopinavir/ ritonavir treated patients (n = 252), 10.4% of nelfinavir treated patients (n = 48) and in 3.0% of efavirenz treated patients (n = 329). In study AI424-045, asymptomatic first degree A- V block was observed in 5% (6/118) of atazanavir/ ritonavir treated patients and 5% (6/116) of lopinavir/ ritonavir treated patients who had on-study electrocardiogram measurements. Because of limited clinical experience, Atazanavir should be used with caution in patients with pre-existing conduction system disease (e.g. marked first degree A-V block or second or third degree A-V block).

In a pharmacokinetic study between atazanavir 400 mg once daily and diltiazem 180 mg once daily, a CYP3A4 substrate, there was a twofold increase in the diltiazem plasma concentration and an additive effect on the PR interval. When used in combination with atazanavir, a dose reduction of diltiazem by one-half should be considered and electrocardiographic monitoring is recommended. In a pharmacokinetic study between atazanavir 400 mg once daily and atenolol 50 mg once daily, there was no substantial additive effect of atazanavir and atenolol on the PR interval. When used in combination with atazanavir, there is no need to adjust the dose of atenolol.

Pharmacokinetic studies between atazanavir and other drugs that prolong the PR interval, including beta-blockers (other than atenolol), verapamil and digoxin, have not been performed. An additive effect of atazanavir and these drugs cannot be excluded; therefore, caution should be exercised when atazanavir is given concurrently with these drugs, especially those that are metabolised by CYP3A4 (e.g. verapamil).

Rash. In controlled clinical trials (n = 1,597), rash (all grades, regardless of causality) occurred in 21% of patients treated with atazanavir. Rashes are usually mild to moderate maculopapular skin eruptions that occur within the first three weeks of initiating therapy with atazanavir. In most patients, rash resolves within two weeks while continuing atazanavir therapy. The discontinuation rate for rash in clinical trials was 0.4%. atazanavir should be discontinued if severe rash develops.

Atazanavir – HIV infection 38 Haemophilia. There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses, in type A and B haemophiliac patients treated with protease inhibitors. In some patients additional factor VIII was given. In most reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship between protease inhibitor therapy and these events has not been established. Haemophiliac patients should be made aware of the possibility of increased bleeding.

Fat redistribution. Redistribution/ accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and `cushingoid appearance' have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Diabetes mellitus/ hyperglycaemia. New onset diabetes mellitus, hyperglycaemia and exacerbation of existing diabetes mellitus have been reported during postmarketing surveillance in HIV infected patients receiving protease inhibitors. In some of these, the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions, some of which required therapy with agents that have been associated with development of diabetes or hyperglycaemia.

Immune reconstitution syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (e.g. Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP) or tuberculosis), which may necessitate further evaluation and treatment.

Lactic acidosis. Cases of lactic acidosis, sometimes fatal, and symptomatic hyperlactataemia have been reported in patients receiving atazanavir in combination with nucleoside analogues, which are known to be associated with increased risk of lactic acidosis. In studies where didanosine and stavudine were administered with atazanavir to patients without prior antiretroviral therapy, lactic acidosis/ symptomatic hyperlactataemia was observed in 2.2% of subjects. Female gender and obesity are known risk factors for lactic acidosis. The contribution of atazanavir to the risk of development of lactic acidosis has not been established.

Rare lactose/ galactose metabolic conditions. Patients with rare hereditary problems of galactose intolerance, glucose/ galactose malabsorption or the Lapp lactase deficiency should not take atazanavir.

Impaired hepatic function. Atazanavir should be used with caution in patients with mild to moderate hepatic insufficiency. atazanavir is primarily hepatically metabolised and increased plasma concentrations were observed in patients with hepatic impairment. Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation.

Atazanavir – HIV infection 39 Carcinogenesis, mutagenesis, impairment of fertility. Carcinogenicity studies with atazanavir were conducted in mice and rats. Mice were administered doses of 20, 40 and 80 mg/kg/day in males and 40, 120 and 360 mg/kg/day in females. In female mice, there was an increase in the incidences of benign hepatocellular adenomas at the highest dose. The exposure in female mice at the high dose is approximately seven times exposure in humans given atazanavir 400 mg once daily. No increase in the incidence of tumours was observed in female mice at nontumorigenic doses or male mice at any dose. Exposures in male and female mice at nontumorigenic doses are approximately four times human exposure at 400 mg/day. In rats administered doses of 100, 350 and 1,200 mg/kg/day, there was no increased incidence of any tumour type. Exposures in rats at the highest dose are approximately two (males) and six (females) times the exposure in humans given atazanavir 400 mg daily. The increased incidence of benign hepatic adenomas in high dose female mice was likely the result of increased hepatocellular proliferation secondary to cytotoxic liver changes (single cell necrosis) and is considered unlikely to have clinical relevance at human therapeutic exposures.

Atazanavir was negative in reverse mutation assays in bacteria and in in vivo micronucleus and ex vivo DNA repair tests in rats. In an in vitro primary human lymphocyte cytogenetic assay, atazanavir increased the frequency of chromosome aberrations at cytotoxic concentrations in the absence and presence of metabolic activation. However, atazanavir did not induce chromosome aberrations in the absence and presence of metabolic activation at concentrations that were approximately 3 and 22 times the Cmax, respectively, and 12 and 98 times the average steady state concentration, respectively, in humans given the recommended dose. In in vivo studies in rats, atazanavir did not induce micronuclei in bone marrow, DNA damage in duodenum (comet assay) or unscheduled DNA repair in liver at plasma and tissue concentrations exceeding those that were clastogenic in vitro.

Atazanavir produced no effects on mating, fertility or early embryonic development in rats at doses that provided exposures equivalent to (males) and at least two times (females) exposure in humans given 400 mg once daily. Altered oestrus cycles were observed in female rats treated with oral doses resulting in similar estimated systemic drug exposures (AUC).

Use in pregnancy. (Category B2) There are no adequate and well controlled studies in pregnant women. Atazanavir should be given during pregnancy only after special consideration of the potential benefits and risks.

There are limited data from the use of atazanavir in pregnant women. In clinical trials, fatal cases of lactic acidosis have occurred in pregnant women receiving atazanavir in combination with nucleoside analogues, which are known to be associated with increased risk of lactic acidosis.

Hyperbilirubinaemia (predominantly unconjugated) occurs frequently during treatment with atazanavir. It is not known whether atazanavir administered to the mother during pregnancy will exacerbate physiological hyperbilirubinaemia and lead to kernicterus in neonates. In the prepartum period, additional monitoring and alternative therapy to atazanavir should be considered.

Atazanavir – HIV infection 40

No teratogenic effects were observed in rabbits exposed to a comparable human dose of 400 mg daily. No teratogenic effects were observed in rats exposed to the human equivalent of 800 mg daily. In the prenatal and postnatal development assessment of rats, transient weight loss or suppression of weight gain occurred in the offspring at maternally toxic doses. Offspring were unaffected at a lower dose which produced maternal exposure equivalent to that observed in humans given 400 mg twice daily.

Use in lactation. It is not known whether atazanavir and/or its metabolites are excreted in human milk. Studies in rats revealed that atazanavir and/or its metabolites are excreted in the milk. Transient reductions in offspring bodyweights were observed in a prenatal and postnatal development study in rats, at a dose that resulted in a systemic drug exposure (AUC) that was approximately twofold higher than that expected in humans given the recommended dose.

Because of both the potential for HIV transmission and the potential for serious adverse reactions in breastfeeding infants, mothers should be instructed not to breastfeed if they are receiving atazanavir.

Adverse effects:

Treatment emergent adverse events in all atazanavir treated patients. Among patients who received 400 mg once daily or 300 mg with ritonavir 100 mg once daily, the only adverse events of any severity reported very commonly with at least a possible relationship to regimens containing atazanavir and one or more NRTIs were nausea (24%), headache (10%) and jaundice (10%). Among patients receiving atazanavir 300 mg with ritonavir 100 mg, the frequency of jaundice was 17%. In the majority of cases, jaundice was reported within a few days to a few months after the initiation of treatment.

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients, including loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

Combination antiretroviral therapy has been associated with metabolic abnormalities, e.g. hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia, and hyperlactataemia.

Adult patients. The following adverse events of moderate intensity or greater with at least a possible relationship to regimens containing atazanavir and one or more NRTIs have also been reported. The frequency of adverse reactions listed below is defined using the following convention: very common (greater than or equal to 1/10), common (greater than or equal to 1/100, < 1/10), uncommon (greater than or equal to 1/1,000, < 1/100), rare (greater than or equal to 1/10,000, < 1/1,000) or very rare (< 1/10,000). Immune system disorder. Uncommon: allergic reaction.

Metabolism and nutrition disorders. Uncommon: anorexia, appetite increased, weight decreased, weight gain.

Atazanavir – HIV infection 41

Psychiatric disorders. Uncommon: anxiety, depression, sleep disorder.

Nervous system disorders. Common: headache, insomnia, peripheral neurological symptoms. Uncommon: abnormal dream, amnesia, confusion, dizziness, somnolence. Rare: abnormal gait.

Eye disorders. Common: scleral icterus.

Cardiac and vascular disorders. Uncommon: hypertension, syncope. Rare: oedema, palpitation.

Respiratory, thoracic and mediastinal disorders. Uncommon: dyspnoea.

Gastrointestinal disorders. Common: abdominal pain, diarrhoea, dyspepsia, nausea, vomiting. Uncommon: dysgeusia, flatulence, gastritis, pancreatitis, stomatitis aphthous. Rare: abdominal distension.

Hepatobiliary disorders. Common: jaundice. Uncommon: hepatitis. Rare: hepatosplenomegaly.

Skin and subcutaneous tissue disorders. Common: rash. Uncommon: alopecia, pruritus, urticaria. Rare: eczema, vasodilatation, vesiculobullous rash.

Musculoskeletal and connective tissue disorders. Uncommon: arthralgia, muscle atrophy, myalgia. Rare: myopathy.

Renal and urinary disorders. Uncommon: haematuria, nephrolithiasis, frequency of micturition, proteinuria. Rare: kidney pain.

Reproductive system and breast disorders. Uncommon: gynaecomastia.

General disorders and administration site conditions. Common: lipodystrophy syndrome, asthenia, fatigue. Uncommon: chest pain, fever, malaise.

In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.

Laboratory abnormalities: The most frequently reported laboratory abnormality in patients receiving regimens containing atazanavir and one or more NRTIs was elevated total bilirubin (84% grade 1, 2, 3 or 4). Grade 3 or 4 elevation of total bilirubin was noted in 33% (28% grade 3, 5% grade 4, reported predominantly as elevated indirect (unconjugated) bilirubin). Among patients treated with atazanavir 300 mg once daily with ritonavir 100 mg once daily for a median duration of 95 weeks, 53% had grade 3 to 4 total bilirubin elevations.

Atazanavir – HIV infection 42 Dosage and administration: Adults. Capsules. The recommended dose of atazanavir is 300mg combined with ritonavir 100 mg once daily taken with food. The recommended dose for unboosted atazanavir is 400mg once daily taken with food.

Concomitant therapy. Efavirenz. When coadministered with efavirenz, it is recommended that atazanavir 300 mg and ritonavir 100 mg be given with efavirenz 600 mg (all as a single daily dose with food). Atazanavir without ritonavir should not be coadministered with efavirenz.

Didanosine. When coadministered with didanosine, atazanavir should be given (with food) two hours before or one hour after didanosine.

Tenofovir disoproxil fumarate. When coadministered with tenofovir, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). Atazanavir without ritonavir should not be coadministered with tenofovir.

Patients with renal impairment. No dosage adjustment is needed.

Patients with hepatic impairment. Atazanavir should be used with caution in patients with mild to moderate hepatic insufficiency. A dose reduction to 300 mg once daily should be considered for patients with moderate hepatic insufficiency (Child-Pugh class B). Atazanavir should not be used in patients with severe hepatic insufficiency (Child-Pugh class C). Atazanavir in combination with ritonavir has not been studied in subjects with hepatic impairment and should be used with caution in patients with mild hepatic impairment. Atazanavir with ritonavir is not recommended for patients with moderate to severe impairment.

Atazanavir – HIV infection 43