Application for Inclusion of indinavir/low dose ritonavir on who model List of E

*ZDV/3TC is listed as the initial recommendation for dual NsRTI component based on efficacy, toxicity, clinical experience and availability of fixed dose formulation. Other dual NsRTI components can be substituted including d4T/3TC, d4T/ddI and ZDV/ddI depending upon country-specific preferences. ZDV/d4T should never be used together because of proven antagonism.

** RTV-PI includes IDV/r, LPV/r, and SQV/r.
4. What is the evidence for the efficacy and toxicity of anti-retroviral drug combinations that include indinavir plus ritonavir? (Level 2 evidence)
Indinavir is a well studied and effective protease inhibitor. In full doses it has been included in a substantial number of trials that are the basis of submissions for other anti-retroviral drugs included in the agenda for the Expert Committee meeting (see for instance submissions for nelfinavir, stavudine, and zidovudine/lamivudine for ‘full dose’ indinavir trials).
However, in the conventional regimen indinavir is associated with certain disadvantages and toxicities. It needs to be taken with a low-fat, low-calorie, meal or at least 1 hour before, or 2 hours after, a meal. Dosing is three times per day. Toxicities include nephrolithiasis, which may be related to maximum plasma concentration (C_max).
Claimed advantages of dual Protease Inhibitor therapy: Synergistic antiretroviral activity has been demonstrated in vitro when ritonavir was combined with indinavir, saquinavir (both soft-gel and hard-gel formulations), and amprenavir. Ritonavir is a highly potent inhibitor of cytochrome P450 3A (CYP3A), and, to a lesser extent, CYP2D6; it may also inhibit the p-glycoprotein system.
In pharmacokinetic studies with healthy volunteers ritonavir was shown to decrease the Cmax of indinavir, increase its C_min and not alter its area under the curve (AUC) when administered simultaneously (Hsu 1998a-c²², Saah 1999²³, 2001²⁴). In studies in HIV-infected patients, similar pharmacokinetic characteristics were demonstrated (Bani-Sader²⁵ 2001, Burger 1999²⁶, Hugen 1999²⁷, 2000²⁸, Mallolas 2000a-b²⁹, van Heeswijk RPG 1999³⁰, van Rossum 2000³¹). In particular, the C_min of indinavir, when combined with low-dose ritonavir, has in most studies exceeded the therapeutic level needed to suppress HIV replication. It should be noted that in these studies in HIV-infected patients ritonavir does not reach therapeutic levels; its effect is due primarily to its inhibition of indinavir metabolism.
Inidinavir and low-dose ritonavir have been studied clinically in two dosage formulations, indinavir 800 mg + ritonavir 100-200 mg bid and indinavir 400 mg + ritonavir 400 mg bid.
These combinations are used in three different clinical settings: (1) as initial therapy, (2) as salvage therapy for patients failing highly active antiretroviral therapy and (3) as switch therapy to simplify regimens for patients on indinavir three times per day.
There is only one randomized controlled trial that has compared indinavir and low-dose ritonavir with full dose indinavir (Boyd, 2001)³². Boyd compared zidovudine and lamivudine + indinavir 800 mg + ritonavir 100 mg twice daily to zidovudine and lamivudine twice daily + indinavir 800 mg three times per day in nucleoside reverse-transcriptase-experienced patients. They found that viral suppression and immunologic improvement were equivalent between the two study arms at 48 weeks. Adverse events were slightly higher in the indinavir plus low-dose ritonavir arm, but permanent treatment discontinuation was equivalent between the arms.
In addition to this trial one non-randomized trial (Barreiro 2000)³³ and seven uncontrolled prospective studies (Burger 2000³⁴, Casado 2000³⁵, Estrada 2000³⁶, Kempf 2001³⁷, Mallolas 2000a-b²⁹, Moreno 2000³⁸, Workman 1999d³⁹, 1999f⁴⁰) measured virologic and/or immunologic endpoints.
Barreiro and colleagues compared the 800 mg/100 mg regimen of indinavir and ritonavir to the 400 mg/400 mg regimen but presented results for the two arms combined³³.
The prospective studies found significant decreases in HIV plasma viral load from baseline and significant increases in CD4 cell counts. The longest running of these studies (Workman 1999f⁴⁰) reported two patients at 2 years of therapy; the majority are in the 16 to 24 week range.
There are also two clinical series that reported high levels of viral suppression in antiretroviral therapy-naïve patients and patients switched from three times daily indinavir (Matthews 2000⁴¹) and the absence of, or resolution of, nephrotoxicity (Workman 1999 a-c⁴²). There were several different dosages used in all these studies (see table).
There is also a prospective cohort study, reported by Burger and colleagues (2001)⁴³, of Dutch patients who sent serum for antiretroviral level monitoring. This study was able to compare the 800 mg/100 mg regimen of indinavir and ritonavir to the 400 mg/400 mg regimen directly. In examining the subset of patients who switched from indinavir 800 mg three times per day, they found that viral suppression was equivalent (78% and 70% respectively by intention to treat analysis) and that rates and types adverse events were comparable.

Table. Uncontrolled clinical trials of indinavir and low-dose ritonavir

Study	Patients	N	IDV dose	RTV dose	Proportion with undetectable HIV RNA
Barreiro (2000)^33	HAART failures	51	800	100	22% at 24 weeks
			400	400
Burger (2001)^43	Mixed	9	1200	400	67% at 1 month
Casado (2000)^35	HAART failures	59	800	100	38% at 24 weeks
Estrada (2000)^36	Mixed	56	800	100	43% at 12 weeks
Havlir (2000)^44 Hsu (2001)^45 Kempf (2001)^37 Shulman (2000)^46	IDV switch	35	400	400	53% at 16 weeks (on-treatment analysis)
Mallolas (2000a, 2000b)	Naïve	27	800	200	94% at 32 weeks
Moreno (2000)	HAART failure	32	Mixed	Mixed	1.8 log10 decrease in HIV RNA at 6 months
Rockstroh (1998, 1999a, 1999b, 2000)	Naïve	90	400	400	71% at 24 weeks
Workman (1999d, 1999f)	Naïve	33	400	400	93% at 12 weeks (on-treatment analysis)

HAART, highly active antiretroviral therapy; IDV, indinavir; RTV, ritonavir

There is an ongoing trial comparing indinavir and low-dose ritonavir to efavirenz listed in AIDSTRIALS (U.S. National Library of Medicine). AIEDRP AI-07-001 is examining the safety and antiviral activity of a stavudine + didanosine + indinavir 800 mg + ritonavir 100 mg regiment to a protease-sparing stavudine + didanosine + efavirenz regimen in patients with acute and early HIV infection.

9. Comparative evidence on safety (See Attachment 1 for results from clinical studies of indinavir and low dose ritonavir):
a) ritonavir (Note: these are adverse events as reported with a 600 mg BID dose)
Adverse effects/reactions: fatigue, nausea, diarrhoea, vomiting, anorexia, abdominal pain, taste perversion, circumoral and peripheral parasthesias.
Laboratory abnormalities (Grade 3 or 4): anaemia, neutropaenia, lymphocytopaenia; elevated cholesterol, triglycerides, CPK, AST, ALT.
b) indinavir (Note: these are adverse events as reported with a 800 mg q8h dose)
Adverse effects/reactions: nausea, abdominal pain, vomiting, nephrolithiasis/ urolithiasis, headache, taste perversion, acid regurgitation, anorexia, dizziness, diarrhoea, pruritus, fatigue, somnolence, malaise, dyspepsia, dysuria, jaundice, fever, anaemia, cough, rash, dyspnoea.
Laboratory abnormalities (Grade 3 or 4): neutropaenia, anaemia, thrombocytopaenia; elevations in total serum bilirubin, ALT, AST, amylase, glucose, creatinine.
Warnings:
Nephrolithiasis/Urolithiasis: Nephrolithiasis/urolithiasis has occurred with indinavir therapy. The frequency of nephrolithiasis, as reported in clinical trials, is substantially higher in paediatric patients (29%) than in adult patients (9.3%). However in adults nephrolithiasis has been reported in up to 43% of recipients of full dose indinavir⁴⁷. In some cases, nephrolithiasis/urolithiasis has been associated with renal insufficiency or acute renal failure. If signs or symptoms of nephrolithiasis/urolithiasis occur, (including flank pain, with or without haematuria or microscopic haematuria), temporary interruption (e.g., 1-3 days) or discontinuation of therapy may be considered.
Also, although the early reports of indinavir with low dose ritonavir didn’t report nephrolithiasis, the BEST study found nephrolithiasis in 20% of the ind/rit BID arm vs. 7% of the ind q8H arm⁴⁸
Pancreatitis: pancreatitis has been observed in patients receiving ritonavir, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to ritonavir has not been established, marked triglyceride elevation is a risk factor for the development of pancreatitis. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk of recurrence during ritonavir therapy. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and ritonavir and/or other antiretroviral therapy should be suspended as clinically appropriate.
Diabetes: New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycaemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycaemic agents for treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycaemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
Haemolytic anaemia: Acute haemolytic anaemia, including cases resulting in death, has been reported in patients treated with indinavir. Once a diagnosis is apparent, appropriate measures for the treatment of haemolytic anaemia should be instituted, including discontinuation of indinavir.
Precautions:
Hepatic impairment and toxicity: Ritonavir is principally metabolized by the liver. Therefore, caution should be exercised when administering this drug to patients with hepatic impairment. Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at risk of developing further transaminase elevations.
Hepatitis: Hepatitis, including cases resulting in hepatic failure and death, has been reported in patients treated with indinavir. Because the majority of these patients had confounding medical conditions and/or were receiving concomitant therapy(ies), a causal relationship between indinavir and these events has not been established
Lipid elevations: Treatment with ritonavir has resulted in large increases in the concentration of total cholesterol and total triglycerides. Cholesterol and triglyceride testing should be performed prior to initiating treatment with ritonavir at a periodic intervals during therapy.
Haemophilia: There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis, in patients with haemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship has not been established.
Redistribution/accumulation of body fat: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement, peripheral wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving protease inhibitors. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Hyperbilirubinaemia: Indirect hyperbilirubinaemia has occurred frequently during treatment with indinavir and has infrequently been associated with increases in serum transaminases. It is not known whether indinavir will exacerbate the physiologic hyperbilirubinaemia seen in neonates

Drug Interactions:
Ritonavir is a potent inhibitor of the P450 isozyme CYP3A. Coadministration of ritonavir and drugs primarily metabolized by CYP3A or CYP2D6 may result in increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects.
Drugs that must not be coadministered with indinavir + ritonavir: flecainide, propafenone, astemizole, terfenadine, ergot derivatives, midazolam, triazolam, cisapride, pimozide, lovastatin, simvastatin, rifampin, St. John's wort (Hypericum perforatum) or St. John's wort-containing products.
Drugs which require a dose reduction when coadministered with indinavir + ritonavir: A dose of at least 75% of the usual 300 mg/day dose of rifabutin (i.e., maximum rifabutin dose of 150 mg every other day or three times a week) is necessary if ritonavir and rifabutin are co-administered. Further reductions in rifabutin dose may be required.
Co-administration of sildenafil with ritonavir may increased sildenafil concentrations (11-fold increase in AUC) and may result in an increase in sildenfil-associated adverse events, such as hypotension, syncope, visual changes and prolonged erection.
Drugs which may require a dose increase when coadministered with ritonavir: methadone, atovaquone.
Drugs which require careful monitoring when coadministered with ritonavir:

ritonavir increases plasma concentrations of dihydropyridine calcium channel blockers (felodipine, nifedipine, nicardinpine) and HMG-CoA reductase inhibitors (atorvastatin and cerivastatin).

Other potentially clinically significant drug interactions with ritonavir + indinavir: carbamazepine, phenobarbital, phenytoin, and dexamethasone may decrease indinavir plasma concentrations. Plasma concentrations of estrogen-based hormonal contraceptives are decreased by ritonavir; alterative or additional contraceptive measures should be used.
Coadministration of ritonavir with other antiretrovirals:
Dosing of didanosine and ritonavir should be separated by 2.5 hours in order to avoid formulation incompatibility.
c) Variation in safety due to health systems and patient factors:
Antiretroviral therapy cannot be successfully introduced in a healthcare system vacuum. However, facilities and personnel infrastructure can be expanded in parallel with the implementation of antiretroviral agent delivery programmes. Health care provider and patient education, an essential health care package, and the ability to do at least limited clinical and laboratory monitoring are all necessary to try to insure programmatic success. [WHO Draft Antiretroviral Guidelines for Resource Limited Settings, p. 2.]
It is well established that the introduction of any antimicrobial therapy for an infectious disease is association with the induction and spread of drugs resistance as an inevitable consequence. Although an obvious concern, this is not a reason to delay introduction of large-scale antiretroviral therapy programmes. Rather, education of providers and patients, attention to drug adherence, monitoring the population for drug resistance, and institution of strategies to try to limit drug resistance are the components of an appropriate response. It is possible that the risk of the spread of resistant viral strains in the population may be balanced by the potential for the reduction of HIV transmission by the introduction of antiretroviral therapy. [WHO Draft Antiretroviral Guidelines for Resource Limited Settings, p. 15.]

10. Summary of available data on comparative cost and cost-effectiveness within the pharmacological class or therapeutic group:
No fixed dose combinations of indinavir and low dose ritonavir are available. Based on the most recent data from MSF the costs of ‘typical’ regimens will be:

IDV 800mg BD (Merck) + RTV 100mg BD (Abbott) $US 508/ year

IDV 800mg BD (Merck) + RTV 200mg BD (Abbott) $US 617/ year

IDV 400mg BD (Merck) + RTV 400mg BD (Abbott) $US 633/ year

In comparison:

‘Full dose’ IDV (2400mg/day) costs $US 600/ year

and full dose RTV (1200mg/day) costs $US 650/ year

The prices quoted here are the cheapest for the relevant drugs. Availability of protease inhibitors from generics suppliers is limited and prices tend to be higher than those from ‘originator’ companies.

11. Summary of regulatory status of the medicine (in country of origin and preferably in other countries as well): TBA
12. Availability of pharmacopoieal standards: TBA


Attachment 1: Results of trials of indinavir + low dose ritonavir

(Pages 18 – 23)