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

Attachment 1: Results of indinavir plus low-dose ritonavir (IDV/r) trials

AUTHOR	METHODS		BENEFITS		TOLERABILITY AND ADVERSE EFFECTS
	PATIENTS	DETAILS	IDV/r regimen	Comparator regimen	IDV/r regimen	Comparator regimen
Barreiro et al 2000^33	PI experienced, HAART failures	Non randomized NRTIs plus IDV 800 mg + RTV 100 mg bid IDV 400 mg + RTV 400 mg bid N=51	HIV RNA undetectable at 24 weeks		Discontinuation of therapy <3 months
			IDV/r (both arms) 22% (ITT), 75% on-treatment analysis	No comparison arm	22 (43%) Nausea/vomiting 15 Dyspepsia 3 Diarrhea 2 Elevated LFTs 1 Renal stones 1	No comparison arm
			Increase in CD4 cells/ml at 6 months (patients with successful viral suppression only)
			IDV/r (both arms) 199 ± 89	No comparison arm
Boyd et al 2001^32	NRTI experienced (≥3 months ZDV at entry) N=104	RCT Open ZDV+3TC and IDV 800 mg tid IDV 800 mg/RTV 100 mg bid	Virologic response at 48 weeks		Drug interruptions/dose reductions
			Decrease in log10 HIV RNA: IDV/r 1.6 (0.3-2.6) (NS) % of patients with VL < 50 copies IDV/r 66% (NS)	IDV tid 2.0 (0.4- 2.) IDV tid 70%	IDV/r 20/50 (40%) (p=0.09) Adverse events: Nausea IDV/r 68% (p=0.04) Dry mouth IDV/r 46% (p=0.02). Hyperbilirubinaemia (>2.5*ULN) IDV/r 34% (p=0.09) Nephrolithiasis (± flank/back pain ± haematuria ± dysuria) was seen in 20 patients IDV/r 17% (p=0.08).	IDV tid 14/54 (26%) IDV tid 48% IDV tid 24% IDV tid 20% IDV tid 22%
			Increase in CD4+ cells/ml		Permanent treatment discontinuation
			IDV/r 70 (-11-128)	57 (-1-128)	IDV/r 8/50 (16%)	IDV tid (9/54) 17%

Burger et al 2001^26	Registry of Dutch patients on HAART who sent serum for drug monitoring N=132 Questionnaire response rate 72% in 400/400 group and 77% in 800/100 group	Cohort study 1. IDV 800 mg + RTV 100 mg (N=100, 10% ART naïve) 2. IDV 400 mg + RTV 400 mg (N=32, 17% ART naïve)	HIV RNA below limit of detection among those who switched from IDV 800 mg tid		Discontinuation of therapy for side effects among those who switched from IDV 800 mg tid
			N=41 (2 had HIV-2) IDV/r 800/100 78% (ITT) Among patients in whom HIV RNA undetectable before switch 24/26 (92%) Among patients in whom HIV RNA detectable before switch 8/15 (53%)	N=10 IDV/ r 400/400 70% (ITT) Among patient s in whom HIV RNA undetectable before switch 6/6 (100%) Among patients in whom HIV RNA detectable before switch 1/4 (25%)	N=43 IDV/r 800/100 23%	N=10 IDV/r 400/400 40%
					Side effects reported by >5% (all patients responding to questionnaire)
					IDV/R 800/100 N=77 Nausea/vomiting 22% Nephrotoxicity 14% Lipodystrophy 13% Hyperbilirubinemia 12% Skin reaction 13%	IDV/R 400/400 N=23 Nausea/vomiting 35% Nephrotoxicity 9% Lipodystrophy 4%
Burger et al 2000^34 PIPO	6/9 pretreated and failed, 2/9 ART naïve, 1/9 pretreated and suppressed. N=9	Uncontrolled IDV 1.2 gm + RTV 400 mg plus existing NRTIs and NNRTIs	HIV RNA at 1 month <500 copies/ml (baseline 89,000 copies/ml)		Subtherapeutic concentrations only in patients using concurrent NVP or EFV. “Regimen well tolerated with no signs of renal toxicity except slight increase in serum creatinine level, which stabilize after 3 months.”
			IDV/r 67% (2/2 ART naïve, 4/6 treatment experienced)	No comparison arm
			CD4 cells/ml at 3 months (baseline 70 cells/ml)
			IDV/r 170	No comparison arm

Casado et al 2000^35	HAART experienced, failing therapy (mean duration 44 months; ,78% and 39% had failed regimens with IDV or RTV) N=59	Uncontrolled2 NRTIs plus IDV 800 mg bid + RTV 100 mg bid	Virologic response at 24 weeks		Nephrolitiasis, hematuria, or flank pain 13/59 (22%) Premature discontinuation 6/59 (10%).
			Decrease in HIV RNA >1 log10 IDV/r 61% HIV RNA <50 copies/ml 38%	No comparison arm
			IDV Cmin plasma levels (mg/L)
			Median 1.75 mg/L, (IQR 1.07-2.57)	No comparison arm
Estrada et al 2000^36	26/56 (46%) HAART experienced and failing therapy 24/56 (43%) ART naïve 6/56 (11%) IDV switch to bid N=56	Uncontrolled 2 NRTIs plus IDV 800 mg + RTV 100 mg bid	HIV RNA <400 copies/ml at 12 weeks		“32 patients (57%) discontinued IDV/R 2.92 months after initiation (range 1-10). Main reasons for discontinuation were digestive intolerance in 18 cases (56%) and nephrolithiasis in 6 (18%).”
			IDV/r 43% ART naïve 58% HAART failure 19%	No comparison arm
			Increase in CD4 cells/ml at 3 months
			IDV/r +66 ART naïve +148 HAART failure +7
Havlir et al 2000^44 Hsu 2001^45 Kempf 2001^49 Shulman 2000^46 M98-985	HAART experienced, IDV tid switch N=35	Uncontrolled2 NRTIs plus IDV 400 mg + RTV 400 mg bid	HIV RNA <50 copies/ml at week 16 (on-treatment analysis)		“12 of 17 discontinuations at wk 36 were due to drug-related AEs. The most commonly reported AE of at least moderate severity and probable or possible relationship to drug was diarrhea (16 of 37 patients). 22 of 37 patients had Grade 3/4 cholesterol or triglyceride elevations.” (Hsu 2001)
			IDV/r 9/17 (53%)
			IDV Cmin levels µg/ml
			IDV/r 0.54 with no change in AUC

Mallolas et al 2000a^29 Mallolas et al 2000b^29	ART naïve N=27	Uncontrolled Initial therapy with ZDV + 3TC + IDV 800 mg bid + RTV 100 mg bid. Switch at W8: 1. IDV/r 1000/100 qd (N=9) 2. IDV/r 800/200 qd (N=7) Group 1 switched to 800/200 qd at W12	HIV RNA <5 copies/ml at 32 weeks		11/27 (40%) discontinued in first 4 weeks due to clinical progression (N=3) or grade 1-2 RTV-related side effects (N=8)
			IDV/r 800/200 qd 15/16 (94%)	No comparison arm
			IDV Cmin <0.1 µg/ml (trough level inconsistent with viral suppression)
			IDV/r 800/200 qd 1/16 (6%)	IDV/r 1000/100 qd 4/9 (44%)
Matthews 2000^41	30/96 (31%) ART naïve, 22/96 (23%) IDV tid switch, 44/96 (46%) HAART failures N=96	Clinical series IDV/r in different regimens (66% IDV 800 mg + RTV 100 mg)	HIV RNA <500 copies/ml (<50 copies/ml) at 6 months (ITT)		“Only 6 patients stopped due to virological failure (all in SA [salvage] grp), 24 (25%) stopped due to R[TV] intolerance. Only 1 patient developed nephrolithiasis. Median chol rise was >1.6 mmol in all groups. Doses > 100 mg were stopped twice as often as 100 mg.”
			ART naïve 81% (71%) Switch 86% (86%) HAART failure 45% (30%)	No comparison arm

Moreno 2000^38 NIVELPROT	HAART failure 29/32 (91%) and 20/32 (63%) had prior IDV and RTV therapy N=32	UncontrolledNNRTI (EFV [N=25] or NVP [N=7]) plus IDV/r (different doses, 800/100 [N=11] or 400/400 [N=13] most common)	Decrease in HIV RNA at 6 months		“Drug-related adverse events appeared in 20 patients (63%), mainly due to gastrointestinal disturbance secondary to RTV liquid formulation, leading to withdrawal in 8 cases (25%). Dose adjustement was necessary in 15 cases (47%), mostly requiring a change from the 400/400 regimen to the 100/800 (8 cases, p = 0.02).”
			IDV/r 1.8 log10 (+0.2 to -3)	No comparison arm
			IDV Cmin
			1.70 µg/ml (range 0.06-4.74)	No comparison arm
Rockstroh 1998^50 Rockstroh 1999a^51 Rockstroh 1999b^52 Rockstroh 2000^53	ART naïve N=90	Uncontrolled Open 2 NRTIs plus IDV 400 mg + RTV 400 mg bid	HIV RNA <500 copies/ml (<80 copies/ml) at 24 weeks		“The quadruple therapy was well tolerated except for mild diarrhoea, initial nausea and increased triglyceride levels. Treatment was stopped in seven (7.7%) patients because of adverse events and three (3.3%) were lost to follow-up.”
			IDV/r 87% (71%)	No comparison arm
Workman 1997^54	12/36 (33%) ART naïve, 12/36 (33%) IDV and RTV naïve, 12/36 (33%) suppressed on SQV/r N=36	Controlled trial? IDV/r (dosage not stated)	No results in abstract		No results in abstract
Workman 1999a^42 Workman 1999b^42 Workman 1999c^42	On IDV/r therapy, mean 45 weeks, median 40 weeks N=57	Clinical series IDV 400 mg + RTV 400 mg bid	No efficacy data in abstract		“No cases of nephrolithiasis, haematuria, flank pain or other urinary or renal AEs [adverse events] were found. No patients experienced creatinine elevations of >20% of baseline values; no patients had sustained elevations of creatinine beyond the normal range.”

Workman 1999d^39 Workman 1999f*^40	ART naïve N=33	Uncontrolled Open 3TC/d4T plus IDV 400 mg + RTV 400 mg bid	Virologic response <400 copies/ml (except at 12 weeks, <1000 copies/ml; on treatment analysis)		“No cases or urinary or renal adverse events occurred.”
			At W12: IDV/r 25/27 (93%) At W24: IDV/r 23/24 (96%) At W52: 14/14 (100%) At Wk 104: 2/2 (100%)	No comparison arm
			Increase in CD4 cells/ml
			At W 12: IDV/r 166 At W24: IDV/r 204 At W52: IDV/r 287	No comparison arm

Key: 3TC, lamivudine; ART, antiretroviral therapy; AUC, area under the curve; bid, twice daily; C_min, trough concentration of drug; HAART, highly active antiretroviral therapy (≥2 drugs from ≥2 classes); IDV, indinavir; IDV/r, indinavir plus low-dose ritonavir (100-400 mg bid); ITT, intention-to-treat analysis; LFT, liver function tests; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; qd, daily; RTV, ritonavir; SQV, saquinavir; ULN, upper limit of normal; ZDV, zidovudine