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Boosting alternatives
   Last updated: 25.08.04
Can PIs be boosted without ritonavir? by Megan Nicholson
The ritonavir (Norvir) US price hike announced by Abbott Laboratories in December last year was a PR disaster. Outraged HIV clinicians, researchers and non-government organisations called for a global boycott of Abbot products and Abbott was forced to review its initial price increase to protect treatment access for low-income Americans.

These days, ritonavir is rarely used as a sole protease inhibitor (PI). Instead it is now being used to boost - i.e. increase the amount of available drug - other PIs, most popularly in Abbott’s own Kaletra, which combines the PI lopinavir with a small dose of ritonavir in each orange capsule.

However, US price increase aside, there has been growing concern from both clinicians and people living with HIV regarding the increasing reliance of low-dose ritonavir to boost PI therapy. This is because the DAD study - a large international trial set up to monitor the risk of heart disease in people taking anti-HIV therapy - has shown that people receiving ritonavir and ritonavir-boosted PIs are significantly more likely to have elevated cholesterol and triglyceride levels than those taking other PIs.1 This is an important risk factor in the increasing incidence of heart disease and stroke now seen in HIV-positive people on HAART.

These elevated blood fats don’t take long to reach worrying levels, either. A Canadian study found that HIV-negative adults given a 100mg booster dose of ritonavir twice a day for just 14 days had significant increases in total cholesterol, triglycerides and LDL (“bad”) cholesterol, and a reduction in HDL (“good”) cholesterol.2


The search for PI boosting agents
PI boosting with low-dose ritonavir developed as a treatment strategy when drug monitoring showed that a proportion of people taking PIs did not have enough drug in their systems to block HIV effectively, particularly in the period prior to the next dose (the trough).

Utilising a favourable drug-drug interaction solved this problem. Ritonavir blocks key human enzymes (proteins) in the liver that limit drug absorption or accelerate the processing of other PIs (see ‘Understanding PI Boosting’ for details). Taking a small dose of ritonavir (e.g. 100mg) with another PI thus increases exposure to the PI and maintains adequate trough concentrations.
Boosting PI concentrations has many benefits including improved efficacy against both wild-type and drug-resistant virus, reduced pill burden, once- or, at most, twice-daily dosing, the removal of food restrictions and, depending where you are in the world, lower cost.

Ritonavir-boosted PIs are now the preferred standard of care for PI therapy in Europe and the US, and a lot of effort has gone into identifying safe and effective ritonavir-boosted dosages. In some circumstance, PIs are only recommended when boosted by ritonavir.

Given the current importance of ritonavir to PI therapy, can it easily be replaced by other drugs?
Several drugs have been used to boost PI levels, but at present no drug is a serious rival to ritonavir. According to Britain’s leading HIV pharmacologist, Professor David Back of the University of Liverpool, “There’s nothing, in terms of potency or being able to boost in same the way, that is equivalent to ritonavir”.

Ideally what is required is a drug which causes few side-effects but is a powerful PI booster. When looking for alternatives to ritonavir for PI boosting, several other drugs are known to inhibit the same liver enzyme. These include:

*other HIV protease inhibitors.
*the NNRTI, delavirdine.
*-azole antifungals e.g. ketoconazole, fluconazole.
*calcium channel blockers used to treat heart conditions.
*some macrolides (a type of antibiotic) e.g. troleandromycin, erythromycin.
*'SSRI' antidepressants e.g. Prozac.
*the antacid, cimetidine.
*concentrated grapefruit juice.

However, the search for PI-boosting agents needs to weigh the benefit of increased PI exposure against potential short- and long-term side-effects as well as dosing considerations.

How drugs interact also needs consideration. Generally, PI boosting increases total drug exposure and trough levels and extends drug half-life. A less desirable effect of boosting may be too much drug exposure or very high peak levels. These can cause or worsen adverse effects.

Given the risks attached to PI boosting, the British HIV Association guidelines recommend monitoring drug levels when boosting PIs with alternatives to ritonavir (e.g. with delavirdine), or when using ritonavir to boost two or more PIs (e.g. Kaletra and amprenavir).


Using another PI to boost PI concentrations
Low-dose ritonavir is able to dramatically increase PI concentrations. For instance, it increases total exposure to saquinavir by 20 fold, indinavir by 2-4 fold, nelfinavir by 1.5-2 fold and amprenavir by 2-3 fold.3.

Several PIs are known to modestly enhance exposure to other protease inhibitors. But generally they do not produce the substantial increases in steady exposure associated with ritonavir.


Indinavir
Co-administration of indinavir and nelfinavir can modestly boost exposure to both drugs.3

The AIDS Clinical Trials Group ACTG 388 Study compared standard indinavir three times daily with either 1000mg or 1200mg indinavir plus nelfinavir twice daily. The study found that nelfinavir slowed clearance of indinavir.4

However, only the 1200mg indinavir/nelfinavir combination produced adequate trough concentrations of indinavir. The average trough concentration of indinavir in the 1200mg group was 146ng/ml (none of seven people had less than 10ng/ml) compared to an average that was below 10ng/ml in the 1000mg group.

Another study found that 1200mg indinavir and 1250mg nelfinavir twice daily were required to achieve adequate trough levels of both drugs.5

The danger with indinavir boosting is the risk of increasing kidney toxicities. When peak indinavir concentrations are boosted, there is greater risk of kidney stones or high bilirubin. This has been a key problem with ritonavir-boosted indinavir. Combining indinavir with other drugs which are associated with kidney toxicities, such as the new PI atazanavir, is also not recommended.


Nelfinavir/saquinavir
Nelfinavir/saquinavir is another mutually enhancing dual PI combination. Saquinavir exposure is boosted by 3-5 fold3, and trough levels of both drugs are substantially increased.6.

However, several randomised studies have used this combination and failed to find a clear-cut clinical benefit. In a long-term study, nelfinavir/saquinavir produced lower rates of viral suppression than soft-gel saquinavir after 48 weeks.7 In the SPICE study, four-drug therapy including nelfinavir/saquinavir was equivalent to triple therapy with saquinavir or nelfinavir, although it did extend the average time to viral rebound.8

The failure of the saquinavir/nelfinavir drug interaction to produce a clinical benefit may be due to the prevalence or severity of gastrointestinal side-effects associated with this combination.


Amprenavir
Pharmacokinetic studies of amprenavir plus protease inhibitors other than ritonavir have used mainly the original formulation of amprenavir. Co-administration of standard amprenavir with nelfinavir or indinavir can slow clearance and increase drug exposure and trough levels to some extent.9,10, 11 However, this formulation has been superseded by fosamprenavir - a pro-drug of amprenavir which achieves higher blood levels than the original formulation - and a new set of pharmacokinetic studies are required.


Atazanavir
In contrast to the mediocre PI boosting described above, more promising results have been reported using atazanavir. For instance, atazanavir and saquinavir interact to slow drug clearance, allowing once-daily dosing at a dose of 400/1200mg.12

Atazanavir and amprenavir also have a useful interaction which increases amprenavir exposure. A small dosing study found that 400mg atazanavir once daily combined with 600mg amprenavir twice daily produced amprenavir trough levels equivalent to those seen with ritonavir/amprenavir. Total exposure to amprenavir compared favourably with concentrations produced by ritonavir boosting.13

Unfortunately, atazanavir levels were not measured in this study, so it is not known whether participants were being exposed to adequate levels of atazanavir. Another limitation of this study was the use of tenofovir, which is known to lower atazanavir levels.

Studies are ongoing to assess atazanavir’s boosting potential with other PIs, which could be promising, although atazanavir itself is currently only approved in the EU when boosted with 100mg ritonavir.

The good news is that studies have found that atazanavir appears to counteract ritonavir’s lipid-raising effects, which means that ritonavir-boosted atazanavir appears to be the only boosted PI combination not associated with increased cholesterol and triglycerides.14, 15


Using other drugs to boost PIs: Delavirdine
Delavirdine was the first NNRTI to be developed, and although approved in the US, it is still not approved in the EU, although is it available to individuals in the UK if their HIV clinician requests it. Delavirdine is a weaker inhibitor of CYP3A4 than ritonavir but it is a more potent inhibitor of another enzyme (CYP2C19) which plays an important part in the metabolism of nelfinavir.

Several studies have combined delavirdine with PIs but it seems to be less effective in slowing the breakdown and clearance of PIs than ritonavir. Unlike ritonavir, delavirdine does not act on p-glycoprotein to maintain cellular PI concentrations. Other downsides to delavirdine are its weakness relative to the other NNRTIs and, at three pills twice daily, a relatively high pill count. Nevertheless, it has been suggested as a potential boosting agent in people with NNRTI resistance, and, in Brighton, for example, delavirdine is being used for this purpose in at least two individuals.

Pharmacokinetic studies with some PIs have been somewhat favourable, indicating that drug exposure to indinavir and amprenavir is increased when each is dosed with delavirdine.16, 17

Several salvage studies have also used delavirdine in combination with PIs. For instance, the ACTG 359 study randomised 277 people with indinavir resistance to one of six treatment arms including saquinavir/nelfinavir (800mg and 750mg three times a day) plus delavirdine. At 16 weeks, 46% of people in this arm had a viral load below 500 copies/ml.18


Using other drugs to boost PIs: Cimetidine
Cimetidine is an antacid which has been tested as a potential PI-boosting agent in twelve HIV-negative people. Participants took saquinavir soft gel 1200mg three times a day for 13 days and then switched to saquinavir soft gel 1200mg twice a day, with cimetidine 400mg twice a day from day 14 to 26.

Cimetidine boosted saquinavir exposure by an average of 120%. However, although it doubled saquinavir peak levels, trough concentrations did not differ significantly.19 Professor Back comments that this increase of 120% is inferior to the 1000% rise in saquinavir levels seen when saquinavir is boosted with ritonavir.


Using other drugs to boost PIs: Antifungals
The class of drugs known as -azoles – fluconazole, itraconazole, ketoconazole – are antifungal agents commonly used to treat HIV-associated conditions such as thrush and cryptococcosis. They are known to inhibit the P450 enzymes and several have been tested as PI boosting agents.

A small pharmacokinetic study of fluconazole and saquinavir found that, when saquinavir was taken at the standard dose of 1200mg three times daily over eight days, and fluconazole was taken at 400mg on day 2 and 200mg on days 3 to 8, total exposure to saquinavir was doubled.20

Ketoconazole is also known to boost blood plasma concentrations of saquinavir and amprenavir. However, the increases are generally modest and do not approach the levels of boosting produced by ritonavir.21, 22

However, side-effects are a concern with the -azoles – they can cause severe liver toxicity and lower testosterone levels. This makes them a poor option for PI boosting, according to David Back. “The -azoles just won’t work [as PI boosters] because of their toxicity,” he says.


Using other drugs to boost PIs: Grapefruit juice
A boosting strategy from the early days of saquinavir was the use of concentrated grapefruit juice. David Back and his colleagues at Liverpool University tested five components of grapefruit juice, and found that naringin, 6', 7'-dihydroxybergamottin and bergamottin inhibit and downregulate CYP3A4 and modulate P-glycoprotein, producing higher levels of saquinavir as well as slower clearance by the liver.23

However, according to Professor Back, five years on it is clear that grapefruit juice is neither a viable nor a reliable method of boosting saquinavir. “It works,” Prof. Back says, “but there’s a lot of variability between brands of grapefruit juice.”

Unless a concentrated grapefruit juice pill were formulated to exacting standards, it would be very difficult to ensure that one is consuming appropriate levels of the active constituents. Additionally, simply eating half a grapefruit at breakfast or drinking a small amount of regular strength juice will not adequately boost saquinavir levels because the active chemicals are mainly found in the skin of the grapefruit.

Another downside with grapefruit juice is that it does not appear to boost concentrations of other PIs, 24 although it does affect the metabolism of many other medicines.25


A new drug?
Ritonavir is not simply an imperfect boosting drug due to its association with higher lipids. The current formulation of ritonavir is not heat-stable, which means that, once dispensed, it can only be stored out of the fridge for up to a month as long as the room temperature is below 25 degrees C. This has major implications in resource-limited nations. Although the NNRTI class is currently the major component of HAART, there will soon be a demand for second-line and salvage regimens as first-line NNRTI therapies fail. Since boosted PIs are the gold standard in these cases, finding an alternative to ritonavir that does not require refrigeration appears to be rather urgent.

Although Abbott has said that one of the justifications for its ritonavir price increase is to fund research into a heat-stable formulation, this is likely to be several years away, and still does not address ritonavir’s lipid-raising issues. Furthermore, it is likely that even at greatly reduced cost, ritonavir will be too expensive for many resource-limited nations.

It might be considered, then, that the best long-term option would be to develop a new drug aimed at inhibiting cytochrome P450 and P-glycoprotein. Professor Back believes that any such drug development is likely to come out of a research centre. However, funding such a project may be difficult.

Another key issue is the need to investigate the long-term adverse effects of any new agent. This would require the lengthy and costly procedure of drug development. Additionally, any new drug which inhibits P450 and P-glycoprotein may have unwanted effects on other bodily processes. For instance, P450 has a role in the production of steroids and thus a drug which inhibits P450 may cause unwanted effects related to steroid activity.

“So, in a sense,” Professor Back says, any new drug “has to be developed from an existing drug in order to circumvent the whole process of long-term drug development. That’s a problem. So ritonavir is with us for the foreseeable future. There’s no doubt. There is absolutely no doubt.”
Nevertheless, Professor Back notes that scientists do have the ability to develop a new drug. “Normally the way you would do it is to take a drug such as ritonavir, and make some structural modifications,” he said. These modifications would be aimed at reducing the known negative features of ritonavir. However, this approach would likely involve breaching the patent on ritonavir and might trigger legal and commercial wrangling.

“Funding and motivation have got in the way until now,” Professor Back concludes. “However, I think that we’re at a situation where if there was enough will, a programme could be developed.”