CIPLADOC - AIDS updates

This randomized study compared the efficacy of indinavir/ritonavir 800/100 bid versus nelfinavir 1250 bid both in combination with 2 NRTIs in patients failing or intolerant to an NNRTI-containing regimen. Patients were either PI-naïve or had previous PI exposure that did not result in virologic failure.

An interim analysis was conducted at 48 weeks as the study was ongoing, and hence a Data-As-Observed approach was used. 42 patients were enrolled in the indinavir/ritonavir arm, with a mean CD4 count of 424 cells/mm3 and mean viral load of 3.88 log10 copies/ml. 44 patients were enrolled in the nelfinavir arm, with a mean CD4 count of 338 cells/mm3 and mean viral load of 3.99 log10 copies/ml. Results are presented in Figures 3 and 4.

The overall adverse effect profile between the two groups was similar, with 37 of 42 patients (88%) in the indinavir/ritonavir group and 40 of 44 patients (90%) in the nelfinavir group reporting a clinical adverse event. 2 patients in the indinavir/ritonavir group had a serious drug-related adverse event and discontinued therapy, whereas no patient in the nelfinavir group had a serious drug-related adverse event. A greater number of patients receiving nelfinavir discontinued therapy due to lack of efficacy or withdrawal of consent.

Thus, the preliminary results of this study indicate that therapy with both indinavir/ritonavir 800/100 mg and nelfinavir 1250 mg and 2 NRTIs resulted in viral load suppression and improvement in CD4 counts in patients who failed or were intolerant to NNRTI therapy.

A study15 in thirteen HIV-1-infected men has shown that the addition of low-dose ritonavir (100 mg) resulted in a significant increase in the absolute concentrations of indinavir (800 mg bid) in seminal plasma and CSF. A correlation was found between serum C min and the concentrations of indinavir in seminal plasma (p<0.01) and CSF (p=0.01).

Ritonavir appears to influence indinavir concentrations in seminal plasma and CSF, independent from its effect on indinavir serum concentrations. This suggests that ritonavir can influence the blood-brain barrier or the blood-testis barrier, in which its effect on P-glycoprotein possibly plays a key role.

The 400/400 ritonavir/saquinavir regimen can be associated with hyperlipidemia, as well as frequent adverse events due to ritonavir. It may be poorly tolerated in many patients. In an effort to solve the problems of the 400/400 dose, O'Brien and colleagues devised a study in which patients already taking the regimen were randomized into 2 groups: one group continued on the 400/400 regimen, while the other was switched to 1,000 mg of saquinavir plus 100 mg of ritonavir, administered bid . Patients in this study had been previously treated with the 400/400 regimen for at least 6 months; the mean duration of treatment was 2.5 years. In all, 23 patients participated in the study and 11 were switched to the boosted 1,000/100 PI regimen. Two patients with pancreatitis in the 1,000/100 arm withdrew from the study (1 of the 2 had a history of alcoholism). One patient with high triglycerides in the 400/400 arm also withdrew.

Results showed that switching to the 1,000/100 dose was a safe and effective approach. Improved tolerability was noted in the patients who switched, and the therapy modification appeared to maintain HIV RNA suppression and CD4 counts. The median increase in saquinavir levels was 2-fold in the switch group, and very few adverse events were observed. Fasting triglycerides fell from 488 to 329 mg/dL (p=0.038) in the 1,000/100 arm, while cholesterol fell from 259 to 222 mg/dL (p=0.05) in that group.

Thus, this study has demonstrated that switching patients from the
400 mg/400 mg bid dose to the 1000/100 bid dose is an efficacious treatment option, with improved tolerability.

MaxCmin1 is the first head-to-head comparison of ritonavir-boosted PI therapies. This open-label, randomized, multicentre trial compared the efficacy of saquinavir/ritonavir 1,000 mg/100 mg bid with indinavir/ritonavir 800 mg/100 mg bid, both in combination with two NRTIs in PI-naïve and PI-experienced patients. Three hundred and six patients began the assigned treatment. At 48 weeks, virologic failure was seen in 43 (27%) of 158 and 37 (25%) of 148 patients in the indinavir/ritonavir and saquinavir/ritonavir groups, respectively. The time to virologic failure did not differ between study arms (p=0.76). When switching from randomized treatment was counted as failure, this was seen in 78 of 158 patients in the indinavir/ritonavir arm, versus 51 of 148 patients in the saquinavir/ritonavir arm (p=0.009). A switch from the randomized treatment occurred in 64 (41%) of 158 patients in the indinavir/ritonavir arm, versus 40 (27%) of 148 patients in the saquinavir/ritonavir arm (p=0.013). 64% of the switches occurred because of adverse events. A greater number of treatment-limiting adverse events were observed in the indinavir/ritonavir arm. The study concluded that ritonavir-boosted saquinavir and indinavir were found to have comparable antiretroviral effects in the doses studied.

In the next study in this series, MaxCmin2, saquinavir/ritonavir 1000/100 mg twice daily (n=163) was compared with lopinavir/ritonavir 400/100 mg twice daily (n=163). The results of a preliminary 24-week analysis show that both regimens appear to be highly effective and well-tolerated.18

The study by Hall et al assessed the efficacy of salvage therapy containing ritonavir 400 mg bid and saquinavir 400 mg bid after failure of indinavir- or nelfinavir-containing regimens. Thirteen (56.5%) of 23 patients who failed indinavir responded to salvage therapy (HIV RNA < 400 copies/ml). This response persisted to a median of 37 weeks of follow-up. Among six patients failing nelfinavir, four responded to salvage therapy with a median durability of 47.5 weeks, with three demonstrating durable responses exceeding one year. These patients had been on nelfinavir-containing regimens for a median of 34 weeks and had demonstrated virologic failure for a median 20.5 weeks. Thus, this retrospective analysis revealed that 17 out of 29 patients failing therapy with either indinavir or nelfinavir had durable responses to salvage therapy containing ritonavir/saquinavir. Salvage therapy is more likely to succeed when it is initiated in failure at low viral loads.

This was a 48-week, open-label, multicentre study of 152 antiretroviral-naïve patients with HIV RNA ≥ 5000 copies/ml. Patients were randomized to receive either saquinavir 1600 mg/ritonavir 100 mg od (Arm A) or efavirenz 600 mg od (Arm B), each in combination with 2 nucleoside analogs. The median viral load and CD4 count at baseline for Arm A is 4.70 log10 copies/ml with 322 cells/ m l, and Arm B is 4.77 log10 copies/ml with 326 cells/ m l. The results are depicted in Table 4.

Table 4: Results at week 48
Regimen	Arm A	Arm B
HIV RNA < 400 (ITT)	59% (n=75)	73% (n=77)
HIV RNA < 400 (OT)	83% (n=53)	93% (n=60)
Mean log10 change	-2.72	-2.86
Mean CD4 change	+236	+191
Mean change from baseline in triglycerides (mg/dL)	51.23	71.43
Mean change from baseline in total cholesterol (mg/dL)	35.43	36.52

The most frequently reported adverse events with at least moderate intensity in Arm A are gastrointestinal while those in Arm B are CNS effects. The authors feel that the GI differences in Arm A could be due to the SGC formulation of saquinavir, and that a switch to the HGC formulation may reduce the incidence of these adverse events.

Conclusion

Ritonavir has been used to successfully boost indinavir- and saquinavir-containing regimens. A range of dosage regimens have been investigated, in different clinical situations.

All current guidelines recommend ritonavir-boosted saquinavir or indinavir as an option for first-line as well as subsequent therapy. Dosages of ritonavir that have been employed for boosting purposes are in the 100-400 mg range. The 100 mg strength is increasingly preferred, as it adequately boosts levels of the other PI, whilst minimizing the toxicities associated with ritonavir.

Ritonavir should be stored in a refrigerator between 2-8 degrees Celsius. Refrigeration by the patient is recommended but not required if used within 30 days and stored below 25 degrees Celsius.

Currently, both the WHO Guidelines21 and the European Committee for Proprietary Medicinal Products22 recommend saquinavir/ritonavir at a dose of 1000 mg/100 mg bid. Either the hard or soft gel preparation of saquinavir can be used when combined with ritonavir. Most recently, the US FDA has also approved of this regimen. 23

Data suggest that saquinavir-HGC/ritonavir provides therapeutic levels of saquinavir and has a better tolerability profile than saquinavir-SGC/ritonavir. If used, liver function tests should be carefully monitored. It is recommended that saquinavir/ritonavir be taken with or within 2 hours after food ingestion.

A 1600/100 mg od regimen has also achieved promising results.24

The combination of indinavir and ritonavir allows once- or twice-daily dosing of both drugs with food. Doses of indinavir/ritonavir that have been investigated are 800/200 mg, 800/100 mg and 400/400 mg all given twice daily25 or 1200/200 mg given once daily. The 800/100 bid dose is currently in clinical use. Ensuring adequate hydration is important.26

Warning

CO-ADMINISTRATION OF RITOMUNE WITH CERTAIN NON-SEDATING ANTIHISTAMINES, SEDATIVE HYPNOTICS, ANTIARRHYTHMICS, OR ERGOT ALKALOID PREPARATIONS MAY RESULT IN POTENTIALLY SERIOUS AND/OR LIFE-THREATENING ADVERSE EVENTS DUE TO POSSIBLE EFFECTS OF RITOMUNE ON THE HEPATIC METABOLISM OF CERTAIN DRUGS. SEE CONTRAINDICATIONS AND PRECAUTIONS SECTIONS.

Composition

Ritonavir Capsules
Each soft gelatin capsule contains
Ritonavir ……..100 mg

Description

Ritomune is an inhibitor of HIV protease with activity against the Human Immunodeficiency Virus (HIV).

Indications

Ritomune is indicated in combination with other antiretroviral agents for the treatment of HIV-infection.

Dosage and Administration

It is recommended that Ritomune be taken with meals if possible.

Adults

Recommended dosage: The recommended dosage of ritonavir is 600 mg twice daily by month. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily.

Concomitant therapy: If saquinavir and ritonavir are used in combination, the dosage of saquinavir should be reduced to 400 mg twice daily. The optimum dosage of ritonavir (400 mg or 600 mg twice daily), in combination with saquinavir, has not been determined; however, the combination regimen was better tolerated in patients who received ritonavir 400 mg twice daily.

General Dosing Guidelines

Patients should be aware that frequently observed adverse events, such as mild to moderate gastrointestinal disturbances and paraesthesias, may diminish as therapy is continued. In addition, patients initiating combination regimens with Ritomune and nucleosides may improve gastrointestinal tolerance by initiating Ritomune alone and subsequently adding nucleosides before completing two weeks of Ritomune monotherapy.

Contraindications

Ritomune is contraindicated in patients with known hypersensitivity to ritonavir or any of its ingredients.

Ritomune should not be administered concurrently with the drugs listed in Table 1 because competition for primarily CYP3A by ritonavir could result in inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening reactions such as cardiac arrhythmias, prolonged or increased sedation, and respiratory depression.

Post-marketing reports indicate that co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities.

Warnings and Precautions

Drug Interactions

Ritonavir is an inhibitor of cytochrome P4503A (CYP3A) both in vitro and in vivo . Ritonavir also inhibits CYP2D6 in vitro , but to a lesser extent than CYP3A. Co-administration of ritonavir and drugs primarily metabolized by CYP3A or CYP2D6 may result in increased plasma concentrations of other drugs that could increase or prolong its therapeutic and adverse events, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A as well as other enzymes, including glucuronosyl transferase, CYP1A2, and possibly CYP2C9.

Table 1: Drugs that are contraindicated with ritonavir use
Drug Class	Drugs Within Class that are Contraindicated with Ritonavir
Antiarrhythmics	Amiodarone, bepridil, flecainide, propafenone, quinidine
Antihistamines	Astemizole, terfenadine
Ergot derivatives	Dihydroergotamine, ergotamine, ergonovine, lergonovine
Sedative/hypnotics	Midazolam, triazolam
GI motility agent	Cisapride
Neuroleptic	Pimozide

Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed both in Tables 1 and 2. Clinical recommendations based on drug interaction studies are listed in Table 3.

When co-administering ritonavir with calcium channel blockers, immunosuppressants, some HMG-CoA reductase inhibitors, some steroids, or other substrates of CYP3A, or most antidepressants, certain antiarrhythmics and some narcotic analgesics which are partially mediated by CYP2D6 metabolism, it is possible that substantial increases in concentrations of these other agents may occur, possibly requiring a dosage reduction (> 50%); examples are listed in Table 4.

When co-administering ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted. With some agents, the metabolism may be induced, resulting in decreased concentrations (see Table 5).

Cardiac and neurologic events have been reported with ritonavir when co-administered with disopyramide, mexiletine, nefazodone, fluoxetine and beta blockers. The possibility of drug interaction cannot be excluded. Particular caution should be used when prescribing sildenafil in patients receiving ritonavir. Co-administration of ritonavir with sildenafil is expected to substantially increase sildenafil concentrations (11-fold increase in AUC) and may result in an increase in sildenafil-associated adverse events, including hypotension, syncope, visual changes, and prolonged erection (see Table 3).

Concomitant use of ritonavir with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including ritonavir, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g. atorvastatin or cerivastatin). The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including ritonavir are used in combination with these drugs.

Concomitant use of ritonavir and St Johns wort ( Hypericum perforatum ) or products containing St. Johns wort is not recommended. Co-administration of protease inhibitors including ritonavir with St. Johns wort is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of ritonavir and lead to loss of virologic response and possible resistance to ritonavir or to the class of protease inhibitors.

Table 2: Drugs that should not be co-administered with Ritonavir
Drug Class: Drug Name	Clinical Comment
Antiarrhythmics: amiodarone, bepridil, flecainide, propafenone, quinidine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antihistamines: astemizole, terfenadine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Ergot Derivatives: dihydroergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.
GI motility agent: cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John's wort (hypericum perforatum)	May lead to loss of virologic response and possible resistance to Ritonavir or to the class of protease inhibitors.
HMG-CoA Reductase Inhibitors: lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: pimozide	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnotics: midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.