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

Attachment 2

Overview of p1rotease inhibitor-based regimens including two nucleoside analogue reverse transcriptase inhibitors:

Advantages	Disadvantages
*potent, durable antiretroviral activity	* adherence difficult with original TID dosing regimens; addition of ritonavir can reduce dosing to BID or QD.
* clinical benefit established, confirming validity of surrogate marker improvement	* adverse events associated with long-term antiretroviral use, but a causal relationship has yet to be established

Characteristics of individual drugs

Non-proprietary name	Cost p.a. US $	Advantages	Disadvantages
Nelfinavir	$2585 including 15% rebate in kind (Roche USA) to $2924 (Aurobindo, India)	* well-tolerated; * resistance profile may allow 2^nd line PI regimen; * twice-daily dosing; * active against Group O subtypes;	*mild to moderate diarrhoea in ca 30% of patients; *high level resistance usually confers cross-resistance with other protease inhibitors; * high pill burden (10 tablets daily); * cannot be used with rifampin:
Indinavir	$600 (Merck, US) to $985 (Hetero, India)	* active against Group O subtypes; *only PI to penetrate blood/brain barrier;	* dosing regimen every 8 hours, empty stomach or with fat-free, very low protein snack; *extra hydration, at least 2 litres, required daily; *nephrolithiasis reported in 9 - 43% of users; * moderate pill burden (6 capsules daily); * cannot be used with rifampin; * multiple potential drug interactions *high level resistance usually confers cross-resistance with other protease inhibitors
Indinavir + ritonavir	cost variable, depending on dose see above	*combination reduces cost; * allows for twice-daily dosing; * can be taken with food; * reduces hydration requirement; * active against GroupO subtypes	*optimal dosing not established; *limited clinical data on combination available; * nephrolithiasis incidence may be increased; * cannot be used with rifampin; * multiple potential drug interactions;
Saquinavir soft-gel capsule	$814 (including 100% rebate in kind) Roche USA	*well-tolerated; * twice daily dosing; *active against Group O subtypes; *low level resistance to saquinavir-sgc with only one gene mutation will often allow successful switching to another protease inhibitor combination therapy	* mild to moderate diarrhoea in ca 20% of patients; *high pill burden (16 capsules daily); *soft-gel capsules must be stored in refrigerator in warm climates; 3 month shelf-life at room temperature (25C or lower); *cannot be used with rifampin; *high level resistance usually confers cross-resistance with other protease inhibitors
Saquinavir soft-gel capsule + ritonavir	N/A	*combination reduces cost; * allows twice-daily dosing (400 mg SQV-sgc + 100 mg RTV); * allows once daily dosing (1600 mg SQV-sgc + 100 mg RTV);	*optimal once-daily dose not established; *limited clinical data on once-daily dosing; *soft-gel capsules must be stored in refrigerator in warm climates; 3 month shelf-life at room temperature (25C or lower); *cannot be used with rifampin;
Ritonavir (only as low dose ‘boost’ therapy with other PI drugs)	$650 (Abbott US) to $3504 (Hetero, India) (full dose therapy – see above for costs of boosted treatment)	*twice-daily dosing; *active against group O subtypes	*adverse events mostly GI-related, can be severe; * cannot be used with rifampin; *multiple potential drug interactions; *both capsule and liquid formulations contain alcohol; *capsules must be stored in refrigerator; *liquid has 30 day shelf-life at room temperature 20-25C; *high level resistance usually confers cross-resistance with other protease inhibitors

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