Protease Inhibitors

Protease inhibitors are a heterogeneous structure of antiviral agents that, unlike reverse transcriptase inhibitors, act in the final stage of HIV reproduction.

Viral protease is included in the work at the stage of reproduction of virions. Aspartate protease acts as a scissors, cutting strips of protein into mature viral particles, which then leave the infected HIV reproducing cell. Protease inhibitors bind the active site of the enzyme, preventing the formation of full-fledged virus particles that can infect other cells.

This class of antiretroviral drugs is currently considered to be the most active in relation to HIV infection. Treatment with these drugs leads to positive dynamics of surrogate markers of infection (increasing the number of C04 + cells and reducing the concentration of the virus in the blood, that is, the viral load), in addition, their use gives patients clinical advantages - reduces mortality and the frequency of clinical conditions that determine the diagnosis of AIDS. Protease inhibitors exhibit antiviral activity in both lymphocytes and monocyte cells. Their advantage is the activity with respect to HIV isolates. Resistant to zidovudine. To provide an antiviral effect, protease inhibitors, unlike nucleoside analogs, do not require intracellular metabolism, so they retain a lasting effect in chronically infected cells.

Currently, 4 HIV protease inhibitors, saquinavir (Invirase), indinavir (crysivan), nelfinavir (viracept), ritonavir (norvir) are used in the world practice.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]

Saquinavir

Saquinavir (Invorase; Hoffmann La-Roche) is the first of the protease inhibitors approved for use in HIV infection and is the most potent of them, suppressing in vitro generation of syncytia, improving the function of dendritic cells bearing the antigen, suggesting the ability of the drug to restore the immune status.

Saquinavir is metabolized by enzymes of the cytochrome P450 system. The enzyme inductors of this system, as well as rifampicin depressant activity. Saquinavir displays a pronounced antiviral activity in combination with AZT, zalcitabine (ddC), as well as lamivudine and stavudine. It is effective and well tolerated by patients who start therapy, and those who have already received nucleoside analogues. It was found that the combination of saquinavir, zidovudine and zalcitabine has synergistic activity in vitro, reduces the development of resistance to each of these drugs.

A study of the effectiveness of this protease inhibitor in 97 patients with triple therapy: retrovir200 mg x3 times a day, zalcitabine 750 mgx3 times a day, saquinavir 600 mg x 3 times a day showed the most favorable dynamics of triterapy compared with monotherapy and biotherapy. At the same time, there was an increase in the number of CD4 cells, a significant reduction in the viral load, and no significant signs of toxicity. It should be noted that, unlike retrovir, protease inhibitors, as well as most other reverse transcriptase inhibitors, penetrate poorly through the blood-brain barrier, and therefore retrovir is mandatory.

Saquinavir in the form of a gel (SYC), marketed under the name Fortovase, is highly bioavailable compared to the solid form of the drug (HGC). It is used in a dose of 1200 mgx3 times a day or 1600 mg2 times a day in combination with ritonavir 400 mg2 times a day. Simultaneous use of the combination saquinavir / ritonavir (400 mg / 400 mg) provides convenient dosing - 2 times a day, recommended for the first line of therapy. Special studies have found that with the use of retrovir, epivir and fortovase, the viral load decreases significantly more rapidly than when using crysvene.

In 1999, a new mode of dosing fortwarza was established. A new treatment regimen in which the Fortovase protease inhibitor (saquinavir) is administered once daily in combination with the lowest doses of ritonavir (another protease inhibitor) allows the maintenance of therapeutic concentrations of saquinavir during the entire 24-hour dosing interval. Fortovaz is prescribed in a dose of 1600 mg per day + ritonavir 100 mg per day.

According to AVKravchenko et al., 2002, combination therapy with antiretroviral drugs Fortovaza / Norvir + Nikavir + Videx of HIV-infected patients was effective for 24 weeks: the level of HIV RNA was reduced by 2.01 log / l, and 63% of patients were below the test system (400 copies / ml), the median CD4 count increased by 220 cells per 1 mm%, the immunoregulatory ratio (CD4 / 8 ratio) increased significantly. The authors showed that the use of the enhanced HIV protease inhibitor (Fortovaz / Norvir combination) for 6 months in the therapeutic scheme in minimal daily dosages has practically no effect on lipid metabolism parameters. The use of Fortovaz together with a single capsule of Norvir per day allows to reduce the daily dose of fortovase to 8 capsules (instead of 18), to reduce the frequency of intake of an HIV protease inhibitor up to 1 time per day (instead of 3) and to almost halve the monthly cost of a protease inhibitor. The scheme, including Fortovaz / Norvir, Nikavir and Videx, may be recommended as first-line therapy for the treatment of HIV-infected patients.

Nelfinavir

Nelfinavir (viracept, Roche-Agouion Pharmaceuticals) - antiretroviral drugs, are recommended for the treatment of HIV infection in both adults and children. It is active in relation to both HIV-1 and HIV-2.

These antiretroviral drugs are available in the following dosage forms: 250 mg tablets, coated tablets 250 mg, powder for ingestion 50 mg / 1 g.

Recommended doses for adults are 750 mgx3 times a day. Or 1250 mg twice a day, for children - 20-30 mg / kg body weight x 3 times a day. Bioavailability of nelfinavir for oral administration is up to 80%.

A high therapeutic effect was obtained in the combination of nelfinavir with zidovudine, lamivudine and stavudine, a joint application with other nucleoside RT inhibitors, in particular, with abacavir, protease inhibitors - saquinavir, indinavir, ritonavir, amprenamir and NNIO'G - delavirdine, nevirapine, lorivid, Efavirenz.

Controlled clinical studies of nelfinavir (virasept) in combination with other antiviral drugs lasting at least 1 year have demonstrated a persistent decrease in plasma HIV-1 RNA levels and an increase in the number of CD4 cells in previously untreated and previously treated HIV-1 infected patients.

Nelfinavir inhibits the cytochrome P450 system, therefore, simultaneous administration of other most common drugs that use the cytochrome system for metabolism, including terfenadine, cipradin, triazolam, rifampin, etc., is not recommended at the same time. Carbamazepine, phenobarbital, feniotion can reduce the concentration of nelfinavir in plasma, in contrast, indinavir , saquinavir, rigonavir can increase it. When co-administered with didanosine, nelfinavir should be taken two hours before or one hour after taking didanosine.

In monotherapy with nelfinavir, viral resistance is rapidly developed, but, in combination with nucleoside analogues, the appearance of resistance may be delayed. For example, of 55 patients who took nelfinavir alone, or in combination with AZT and ZTS, resistance appeared in 56% of recipients of one nelfinavir and 6% of recipients of combination therapy. Resistance to nelfinavir may not cause cross-resistance with other protease inhibitors.

Most of the side effects observed in clinical trials were poorly expressed. The most common side effect of using nelfinavir in the recommended doses was diarrhea. Other possible side effects: a rash, flatulence, nausea, a decrease in the number of neutrophils, increased activity of cretekinase and ALT / AST.

Nelfinavir is metabolized and excreted mainly by the liver. Therefore, care must be taken when administering the drug to patients with impaired liver function.

The benefits of using Viracept (Nelfinavir) in the first line HAART regimens:

• mutation in codon D30N
• Primary in the therapy of nelfinavir,
• D30N leads to a decrease in the viability of the virus and does not cause cross-resistance with other PIs,
• in patients who previously received nelfinavir, the use of other PIs in the schemes of the 2nd line is effective.

Ritonavir

Ritonavir (Norvir, Abbott Laboratories) showed the best efficacy when used at a dose of 600 mg x 2 times a day. These antiretroviral drugs can be used for monotherapy or in combination with nucleoside analogues. Studies by Danner et al., 1995, demonstrated a dose-dependent reduction in viral load and an increase in the number of CD4 + cells treated with ritonavir for 16-32 weeks. Cameron etal., 1996, presented the results of extensive clinical trials demonstrating a slowdown in the progression of the disease and a reduction in mortality in AIDS patients who received ritonavir for standard therapy with nucleoside analogues. Preliminary data showed that ritonavir can be used for initial therapy concomitantly with retrovir and zalcitabine (ddC) or lamivudine. Mellors et al., Molla et al. Demonstrated a high effectiveness of joint use of ritonavir and saquinavir, while the level of viral load was significantly reduced and the number of CD4 cells increased.

Ritonavir inhibits the enzymes of the cytochrome P450 system and changes the plasma concentrations of many drugs, so some drugs must be eliminated, and for others, the doses should be changed when combined with ritonavir.

The intake of ritonavir may be accompanied by the appearance of undesirable manifestations, such as allergic reactions, nausea, vomiting, diarrhea, anorexia, paresthesia, asthenia, changes in hepatic tests, and diabetes, characteristic of all approved protease inhibitors.

Resistance to ritonavir often causes the emergence of resistance to indinavir, less often - to nelfinavir.

Indinavir

Indinavir (Merck) has an advantage over saquinavir and iritonavir: due to its low binding to proteins, it reaches higher concentrations in plasma, tissues and penetrates the CNS. The recommended dose is 2400 mg / day. (800 mg x 3 r.), Indinavir is taken on an empty stomach 1 hour before or 2 hours after ingestion, oral bioavailability is 65%. The possibility of using the drug in children is being studied.

Indinavir significantly reduces the level of viral load and increases the number of CD4 + cells when used alone or in combination with nucleoside analogues. However, many studies confirm the greatest effect of cryptan in combination therapy.

Resistance to indinavir develops quite rapidly, but to a lesser extent in those patients who started taking indinavir in combination with other antiretroviral agents and have not previously received anti-HIV therapy. Indinavir-resistant strains of HIV-1 are able to show a pronounced resistance to other protease inhibitors - ritonavir, nelfinavir, and less - to saquinavir.

Indinavir inhibits cytochrome P450, so it should be avoided sharing it with other drugs that use the cytochrome P450 system for metabolism. Didanosine reduces the absorption of indinavir, therefore, it is recommended that these two drugs be taken separately at an interval of 1 hour. Ketoconazole inhibits the metabolism of indinavir, which is why the dose of indinavir should be reduced to 600 mg x 3 times a day. In turn, indinavir inhibits the metabolism of rifabutin, which requires a 50% reduction in the dose of rifabutin.

When taking indinavir, such undesirable complications as diabetes, hemolytic anemia, as well as nephrolithiasis and dysuria, which are associated with the ability of indinavir to form crystals in the urine, can be noted.

The newest potential inhibitors of the HIV-1 and HIV-2 protease

Amprenavir (141W94) - antiretroviral drugs, the newest potential HIV-1 and HIV-2 protease inhibitors, developed by GlaxoSmithKline, are approved for use in RP. Has a good oral bioavailability (> 70%), characterized by a long half-life (about 7 hours), given in a dose of 1200 mg 2 times a day, regardless of food intake. Metabolized, like other protease inhibitors, by the cytochrome P450 system. Has a good therapeutic effect with trituration with AZT and ZTS. Combinations with other protease inhibitors (fortovase, indinavir, nelfinavir) were studied - in all cases, a significant reduction in the viral load (AIDS Clinical Care) was noted. Scheme of amprenavir and ritonavir: Amprenavir 600 mg + ritonavir 200 mg 2 times a day for patients with an unsuccessful combination of 3 drugs. Amprenavir and ritonavir were given with two or three other antiviral drugs. Decreased doses of amprenavir and ritonavir due to their combination reduced the toxic effect of each of the drugs and was effective in clinical and laboratory data (a 2-fold reduction in viral load compared to baseline after 2.5 months from 4.86 x 1010 log to 2.95 x 1010 log, an increase in CD4 from 187 to 365 x 106 log / L. Among the small side effects of minor diarrhea, increased cholesterol and triglycerides.

The company Boehringer Ingelheim represents a new protease inhibitor - tapranavir. Tipranavir is currently in Phase II development. These are the first antiretroviral drugs from a new class of non-peptide protease inhibitors. Clinical trials show that the main side effects of the drug are gastrointestinal manifestations, especially diarrhea, which is usually successfully treated.

New antiretroviral drugs are offered - lotshavir, which is a protease inhibitor and clearly reduces the level of viral load. Lopinavir, in combination with another protease inhibitor, ritonavir, is called caletra. Kaletra is the first combination drug from the class of HIV protease inhibitors produced by Abbott Laboratories. The combination in one Kaletra capsule 133.3 mg of lopinavir and 33.3 mg of ritonavir (80 mg of lopinavir and 20 mg of ritonavir in 1 ml of the oral solution) allows achieving high, long-lasting concentrations of lopinavir in the blood plasma, which provide a powerful antiviral effect drug when taken in a dose of 400/100 mg 2 times a day.

When Kaletra was prescribed in combination with 2 NRTIs (d4T and 3TC) for patients who had not previously received antiretroviral drugs, after 144 weeks of treatment, a reduction in HIV RNA of less than 400 copies in 1 ml of plasma was noted in 98% (RT analysis). Moreover, an increase in the number of CD4 cells in patients with initially low CD4 lymphocyte counts (less than 50 cells per mm1) was significant in the group of patients receiving Kaletra-265 cells (nelfinavir group-198 cells).

In patients previously treated with at least one HIV protease inhibitor (Study 765), after 144 weeks of Kaletra therapy in combination with nevirapip and 1 NRTI in 86% and 73% of cases, a decrease in HIV RNA of less than 400 and 40 copies in 1 ml of plasma was recorded, respectively (RT analysis).

Interaction with other drugs:

• an increase in the dose of calytes to 533 mg / 133 mg (4 capsules or 6.5 ml) 2 times a day during meals with the drug with nevirapine or efavirenz is done in patients who have a clinically predictable decrease in the sensitivity of the virus to lopinavir (according to the results of treatment or laboratory data).
• dosage of other PIs should be reduced when taken with calyx. Based on a limited number of observations, the dosage of amprenavir is 750 mg 2 times a day, indinavir 600 mg 2 times a day, saquinavir 800 mg 2 times a day when taking these drugs with calyx. The optimal doses of other PIs in combination with the kaletra, given their safety and efficacy, are not determined.
• it is recommended to reduce the daily dose of rifabutin (300 mg per day) to 75% (maximum dose of 150 mg every other day or 150 mg 3 times a week). When assigning such a combination, careful monitoring of the development of undesirable phenomena is necessary. It may be necessary to further reduce the dose of rifabutin.
• careful monitoring is required when concomitant administration of calf and inhibitors of HMG-CoA reductase: pravastatin, fluvastatin, or minimal doses of atorvastatin and cerivastatin.

In a study 863, in the treatment of calyces, 9% of patients had an increase in cholesterol (> 300 mg / dL) and triglyceryl (> 750 mg / dL).

If hepatitis B or C is present in patients with HIV infection, it is necessary to appoint kaletra with caution, since there are data that after 60 weeks of treatment, ALT level increased in 12% of cases (in 3% of patients without viral hepatitis), which was is completely comparable with the frequency of increase in ALT level in patients with HIV infection and chronic hepatitis B and C who received nelfinavir - the safest antiretroviral drugs from the class of HIV protease inhibitors - 17%.

Against the background of admission kaletra observed the development of pancreatitis. In some cases, increased triglyceride levels were noted. Despite the fact that the causal relationship between caletra and pancreatitis has not been proven, an increase in triglyceride levels in the blood may indicate an increased risk of pancreatitis. If the patient complains of nausea, vomiting, abdominal pain, and if serum levels of amylase or lipase are elevated, treatment with calyx and / or other antiretroviral drugs should be suspended. Patients receiving PI treatment report cases of hyperglycemia, diabetes mellitus, and increased bleeding (in patients with hemophilia).

Kaletra should be used with caution in liver lesions, including viral hepatitis B, C, and with increased levels of aminotransferases.

Forms of issue:

• Soft gelatin capsules: the recommended adult dose is 3 capsules 2 times a day with meals, each calyx capsule contains 133.3 mg of lopinavir and 33.3 mg of ritopavir.
• Solution for oral administration: the recommended dose of a solution of oral cavity for adult patients is 5 ml 2 times a day during meals, the recommended dose for children from 6 months to 12 years is determined in accordance with the child's body surface area.
• Each 5 ml contains 400 mg of lopinavir and 100 mg of ritonavir. It is easy to take the caletra: there are no restrictions on the diet, there are no requirements for the amount of liquid consumed.

In pediatric practice, children are recommended to appoint caletra (lopinavir and ritonavir) simultaneously with nevirapine.

In a study reported at a conference in Glasgow Julio Montaner, a scheme involving two protease inhibitors is activated: indinavir 1200 mg and ritonavir 100 mg or indinavir 800 mg 4 ritonavir 200 mg; either saquinavir 1600 mg, ritonavir 100 mg + efavirenz600 mg 1 time per day, or capetra.

The pharmacokinetic profile made it possible to develop the first IP for taking once a day (2 capsules of 200 mg) of atazanavir. Under these conditions of intake, the concentration of atazanavir (visival) remains in the range of values exceeding 1С90 for long periods. Atazanavir has a favorable side effect profile, rarely causes the formation of resistant forms, is safe and effective for more than 48 weeks, does not cause lipid and triglyceride elevations (M. Fleip, The Seventh European Symposium on HIV Treatment "For the Rest of Life," Budapest , 1-3 February 2002).

Thus, atazanavir:

• powerful, safe and well tolerated,
• on antiviral activity is close to nelfinavir,
• can be combined with all basic NRTIs,
• the smallest number of tablets taken in comparison with other PIs,
• unlike other PIs. Does not cause an increase in lipid levels,
• The profile of resistance, not identical to the profile of other PIs.

New candidates capable of replacing protease inhibitors are AVT 378 and tipranavir.

Tipranavir is a new class of non-peptide HIV-1 protease inhibitors. These protease inhibitors have shown excellent activity against a variety of laboratory HIV-1 strains and isolates from patients, including nucleoside reverse transcriptase resistant HIV zidovudine and delavirdine. Previous experiments have shown that the combination of tipranavir and ritonavir additionally exhibits a moderate synergistic antiviral effect against HIV isolates sensitive to ritonavir, and strong synergy arises with respect to isolates. Resistant to ritonavir.

Tipranavir maintained a consistent antiviral activity against clinical isolates of HIV that are multidrug-resistant to protease inhibitors and may be useful for combinations with other antiretroviral drugs in treatment regimens for patients in whom the use of therapy containing protease inhibitors has proved ineffective.

Another powerful nucleoside is adefovir, to which many strains resistant to nucleosides are sensitive.

The role of immunostimulants, such as interleukin 2, in the reconstruction of the immune system, requires further study.

The high efficacy of a new non-nucleoside reverse transcriptase inhibitor (NNRTI) - TMS 125 is shown by these studies. These antiretroviral drugs are derivatives of diazyl-pyrimidine. Its great advantage is the ability to impact on HIV strains having key mutations to NNRTIs - K103NL1001. TMS 125 exerts a marked suppression on HIV, significantly suppressing the replication of the virus with minor side effects. A 7-day monotherapy course was conducted for patients who had not previously been treated. Side effects of TMS 125:

• Dyspepsia - (8.3%)
• Headache - (8.3%)
• Rash - (8.3%)
• The increase in ALT (125-250 units) - (8.3%)
• Bilirubinemia (22-31 μmol / l) - (8.3%)

Potentially inhibitory fusions are active. Antiretroviral drugs T-20 (Enfuvirtide) are in clinical trials. Possible benefits of fusion inhibitors: efficacy, safety, lack of cross-resistance. Possible disadvantages: parenteral administration, antibody formation, high cost. T-20 fuses with gp 41 - the surface marker of HIV - and, thereby, makes it impossible for HIV to be connected to cells. Having a CD4 receptor. It is important to note that T-20 (enfuvirtide) is synergistic in its action with nucleoside and non-nucleoside inhibitors of reverse transcriptase, as well as with protease.