| Clinical Use|
Regimens consisting of 2 nucleoside analogues and ritonavir have been found to provide potent suppression of viral load in previously untreated patients, but side effects are significant.(1) A number of regimens containing ritonavir in combination with another protease inhibitor have also been found to be effective, and allow lower doses of both of the protease inhibitors than when either is used alone. For example, the efficacy of saquinavir + ritonavir or lopinavir + ritonavir in combination with nucleoside analogues compares favorably with that of other potent combination regimens.(2,3) In some cases, combination with ritonavir also allows less frequent dosing or fewer dietary restrictions than single-protease inhibitor use. In current practice, ritonavir is used almost exclusively at subtherapeutic doses solely to maintain therapeutic serum levels of other protease inhibitors used in combination, ie, as a pharmacokinetic enhancer of other protease inhibitors.
Ritonavir may be combined with any of the other protease inhibitors, although optimal dosing information for combination with certain protease inhibitors has not been fully determined. Lopinavir is available only as a coformulation with low-dose ritonavir and both tipranavir and darunavir must be used in combination with ritonavir. The addition of low-dose ritonavir may boost amprenavir,(4) atazanavir,(5) fosamprenavir,(6) or saquinavir (7) to therapeutic levels when any of these protease inhibitors is used in combination with efavirenz.
Ritonavir is a potent inhibitor of cytochrome P450 3A (CYP3A) and CYP2D6, as well as an inducer of other hepatic enzyme systems. Coadministration with ritonavir therefore causes clinically significant alterations in serum levels not only of other antiretrovirals, but also of a variety of drugs including certain calcium channel blockers, cholesterol-lowering agents, antiarrhythmics, sedative-hypnotics, erectile dysfunction agents, oral contraceptives, recreational substances, and others.
Information on drug interactions should be consulted, as dose adjustments are frequently required, and some combinations are clearly contraindicated.
| Use in Initial vs Subsequent Therapy|
Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services include combinations of low-dose ritonavir with atazanavir or darunavir as "preferred" components of antiretroviral regimens for initial treatment of HIV infection, and include low-dose ritonavir in combination with several other protease inhibitors as "alternative" components. Because of the persistent and long-term side effects of full-dose ritonavir, regimens containing ritonavir as the only protease inhibitor are not recommended.
Failure of a regimen containing ritonavir may decrease the likelihood that subsequent protease inhibitor-containing regimens will succeed (see "Resistance," below).
Regimens incorporating combinations of ritonavir with other protease inhibitors may be effective subsequent to virologic recurrence on initial treatment regimens.(8,9)
| Factors Affecting Adherence|
Common symptomatic side effects of ritonavir include weakness, diarrhea, abdominal discomfort, and nausea. Less-frequent effects include numbness around the mouth or in the extremities, and abnormal taste sensation. Abnormalities of liver function are common, as is hyperlipidemia. As with other protease inhibitors, ritonavir is associated with abnormalities of glucose metabolism and body fat distribution. Capsules require refrigeration. The oral solution should not be refrigerated, and it is usually characterized as unpleasant in taste.
Resistance to ritonavir is associated with the selection of 1 or more of several resistance mutations.
| Implications of ritonavir resistance for treatment with other antiretrovirals|
Resistance mutations selected by ritonavir frequently confer or contribute to resistance against other protease inhibitors. Different mutations are associated with cross-resistance to different drugs. For example, M46I is associated with cross-resistance to indinavir, nelfinavir, and fosamprenavir (but not to saquinavir); V82A,F,T,S alone is associated with cross-resistance to indinavir, but in combination with other mutations also confers resistance to nelfinavir, fosamprenavir, and saquinavir; and I84V contributes to resistance against all available protease inhibitors. Although no single one of these mutations is associated with full resistance to lopinavir, each contributes partial resistance, and the presence of several mutations together can confer resistance.
Response to indinavir is unlikely in the setting of resistance to ritonavir.
Genotypic or phenotypic testing may be useful in predicting the likelihood of response to other protease inhibitors following failure of a regimen containing ritonavir.
| Implications of resistance to other antiretrovirals for ritonavir treatment|
Response to ritonavir is unlikely in the setting of resistance to indinavir.
Following failure of a regimen containing a single protease inhibitor or NNRTI, patients may respond to regimens containing the combination of low-dose ritonavir and another protease inhibitor (a "boosted" protease inhibitor).
Genotypic or phenotypic testing may be useful in predicting the likelihood of response to ritonavir following failure of regimens containing other protease inhibitors.
| Special Uses|
Because of its strong inhibitory effect on CYP3A (see "Combinations") ritonavir at doses below the normal therapeutic dosage is frequently combined with other protease inhibitors to achieve therapeutic levels of the second protease inhibitor while reducing the number of pills required, the dosing frequency, or both.
Coadministration of low-dose ritonavir may also be used to compensate for drug interactions that tend to decrease levels of a protease inhibitor metabolized by CYP3A (for example, in the case of fosamprenavir combined with efavirenz).
|| || Notermans DW, Jurriaans S, de Wolf F, Foudraine NA, de Jong JJ, Cavert W, Schuwirth CM, Kauffmann RH, Meenhorst PL, McDade H, Goodwin C, Leonard JM, Goudsmit J, Danner SA. Decrease of HIV-1 RNA levels in lymphoid tissue and peripheral blood during treatment with ritonavir, lamivudine and zidovudine. Ritonavir/3TC/ZDV Study Group. AIDS 1998;12:167-73.|
|| || Kirk O, Katzenstein TL, Gerstoft J, Mathiesen L, Nielsen H, Pedersen C, Lundgren JD. Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial. AIDS 1999;13:F9-16.|
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|| ||Piscitelli S, Bechtel C, Sadler B, Falloon J. The Addition of a Second Protease Inhibitor Eliminates Amprenavir-Efavirenz Drug Interactions and Increases Plasma Amprenavir Concentrations. Abstract 78. 7th Conference on Retroviruses and Opportunistic Infections. January 30 - February 2, 2000; San Francisco.|
|| ||Tackett D, Child M, Agarwala S, Geiger M, Geraldes M, Laura B, O'Mara E. Atazanavir: A Summary of Two Pharmacokinetic Drug Interaction Studies in Healthy Subjects 10th Conference on Retroviruses and Opportunistic Infections, Boston, February 10-14, 2003. Abstract 543|
|| || Wire MB, Ballow C, Preston SL, Hendrix CW, Piliero PJ, Lou Y, Stein DS. Pharmacokinetics and safety of GW433908 and ritonavir, with and without efavirenz, in healthy volunteers. AIDS. 2004 Apr 9;18(6):897-907. |
|| ||Hendrix CW, Fiske WD, Fuchs EJ, Redpath EC, Stevenson DL, Benedek IH, Kornhauser DM. Pharmacokinetics of the Triple Combination of Saquinavir, Ritonavir, and Efavirenz in HIV-Positive Patients. Abstract 79. 7th Conference on Retroviruses and Opportunistic Infections. January 30 - February 2, 2000; San Francisco.|
|| || Tebas P, Patick AK, Kane EM, Klebert MK, Simpson JH, Erice A, Powderly WG, Henry K. Virologic responses to a ritonavir--saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS 1999;13:F23-8.|
|| || Zolopa AR, Shafer RW, Warford A, Montoya JG, Hsu P, Katzenstein D, Merigan TC, Efron B. HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed. Ann Intern Med 1999;131:813-21.|