Antiretroviral Therapy

The decision to initiate antiretroviral therapy should be taken together by the doctor and the patient. Before the appointment of antiretroviral therapy in each case, it is necessary to perform a clinical and laboratory examination of the patient, determine the clinical indications and contraindications, evaluate the laboratory parameters and, based on the data obtained, develop an acceptable treatment regimen. It is extremely important to conduct psychological training with the patient in order to ensure strict compliance with the chosen regime.

[1], [2], [3], [4], [5], [6],

Antiretroviral therapy: indications

Antiretroviral therapy should begin on the basis of laboratory indications, and its changes should be based on monitoring parameters such as plasma HIV RNA level (viral load) and CD4 + T-cell count in peripheral blood. These tests are the most important in assessing viral replication, the patient's immune status and the risk of disease progression. Initially, the viral load was determined only for the purpose of prognosis of the disease, at present it also serves as a test for evaluating the results of treatment of patients. Numerous observations indicate an improvement in clinical outcomes (reduction in mortality and progress toward AIDS) with a reduction in viral load.

The international AIDS community held a special meeting in the United States on antiretroviral therapy in adults, taking into account the December 1999 consensus. This meeting, compared with the recommendations adopted in 1995, provided more extensive information on monitoring in the treatment process, taking into account the definition of resistance.

In addition, the emergence of new antiretroviral drugs, in particular, efavirenz, abacavir and amprenavir, was taken into account, which gave grounds for reconsidering previous recommendations. In accordance with the revised recommendations, antiretroviral therapy is indicated to patients:

• with HIV RNA levels above 30,000 copies / ml,
• the level of CD4 lymphocytes is 350 / mL,
• treatment can also be recommended for patients with HIV RNA from 5000 to 30,000 copies / ml and a CD4 count of lymphocytes between 350 and 500 x 10 ⁶ / L,
• therapy can also be considered shown if CD4 lymphocytes are above 500 x 10'7l, and HIV RNA is from 5000 to 30,000 copies / ml, taking into account the possible progression of the disease in patients with high viral load.

Antiretroviral therapy should begin only after treatment of serious opportunistic diseases.

In 2002, antiretroviral therapy (APT) for patients with HIV infection was prescribed more severely (Antiretroviral therapy quidelines, International AIDS society JAMA, 2002, V. 288). In accordance with these recommendations, the onset of APT in previously untreated patients is recommended when:

• symptomatic of HIV infection,
• asymptomatic HIV infection in CD4 cells below 200 per ml of blood,
• asymptomatic HIV infection with CD4 above 200 in cases of rapid reduction or high viral load, higher than 50000-100000 RNA copies / mL.

This takes into account the risk of individual toxicity, drug interactions, and their pharmacokinetics. Great importance is attached to the patient's interest in attraction and the ability to be committed to therapy.

Indications for the onset of APT are acute HIV infection and stages III AB and B, laboratory indications are: a decrease in CD4 lymphocytes below 0.3x109 with an increase in the concentration of HIV RNA in the blood of more than 60,000 kop / ml. If these indicators are identified for the first time, repeated studies with an interval of at least 4 weeks are required to resolve the APT problem, with antiretroviral therapy in the form of mono- or di-therapy assigned to stage 3A (2B in the 1999 classification). Antiretroviral therapy is recommended for CD4 below 0.2x107L (below 200 in ml). In IV (V stage according to the classification of 1999) APT is not assigned.

Quantitative measurement of HIV RNA level in plasma is recommended to be performed just before antiretroviral therapy is administered and after 4-8 weeks of treatment, which allows estimating the initial efficacy. In most patients, a rapid decrease in the viral load (0.5-0.7 log, 0, or approximately 3-5 times) occurs during this time, and after 12-16 weeks it decreases below the detection level (<500 copies of RNA / ml plasma). The rate of decrease in viral load is individual and depends on many factors: the initial level of viral load and the number of CB4GG cells. Presence of previous therapy of its duration, as well as the presence of opportunistic infections and the patient's adherence to the chosen regimen}.

Subsequent measurements of viral load should be performed every 3 to 4 months. If after 6 months of treatment twice measured viral load remains more than 500 copies of RNA / ml of plasma, antiretroviral therapy should be changed.

More sensitive methods of determining the viral load (up to 50 copies of RNA / ml) have now been developed. Clinical data confirm that a decrease in the level of HIV PIU below 50 copies / ml is associated with a more complete and prolonged viral suppression than with a decrease in HIV RNA to 50-500 copies / ml of plasma.

It is not recommended to measure viral load within 4 weeks after the end of treatment for any intercurrent infection, symptomatic disease or after immunization.

In order to obtain more reliable results, the definition of a viral load should be carried out under the same conditions in view of the existing differences among commercial tests.

Antiretroviral therapy of the first line: therapy should be carried out by a combination of drugs with high antiviral activity and good tolerability. The first scheme should leave strategic options for the future, i.e. Include drugs that give the least cross-resistance.

Recommended schemes: AZT + 3TC + IDV, AZT + 3TC + EFV. Nelson recommends instead of AZT + 3TC-DDKD4T.

Currently, there is a transition to a new concept of APT, based on a variety of drugs, to create simpler treatment regimens, including those when one can take medications once a day. Recommended schemes: EFV-DDH3TC, F.FV + D4T + 3TC. The use of simple and effective schemes for first-line therapy can prolong the period of its effectiveness, i.e. Reduce the need for a second-line HAART.

[7], [8], [9], [10], [11],

Antiretroviral therapy in patients with asymptomatic HIV infection

To date, there has been convincing evidence that antiretroviral therapy provides success and is indicated to all patients with symptomatic HIV infection, regardless of viral load and CD4 + T-cell counts, but for individuals with asymptomatic HIV infection with CD4 + -T cells> 500 / ml, we can only talk about the theoretically anticipated success of using antiretroviral agents because of the lack of data on sufficiently long observations.

The combinations of antiretroviral agents currently used have a pronounced antiviral effect, but all of them are capable of causing side effects, complications and interacting with other drugs, so the decision to prescribe treatment for patients with chronic asymptomatic HIV infection should be based on a comparison of a number of factors that determine the risk and the benefits of treatment.

Serious arguments influencing the decision to start therapy are: a real or potential opportunity to achieve maximum suppression of viral replication; preservation of immune functions; improvement of quality and prolongation of life; reducing the risk of drug resistance due to early suppression of viral replication; minimal toxic effects and drug interactions.

Negative factors in the early administration of treatment such as antiretroviral therapy include: potential adverse drug effects; potential risk of developing early drug resistance; Potential limitation of the choice of therapy in the future, etc.

When deciding whether to prescribe therapy for asymptomatic patients, the patient's desire to start therapy, the degree of existing immunodeficiency determined by the number of CD4 + T cells, the risk of progression of HIV infection, determined by plasma HIV RNA level, the potential benefit and risk of initial therapy, the patient's adherence probability prescribed regime.

In the case of the appointment of therapy, it is necessary to use powerful combinations to achieve a reduction in viral load to an undetectable level. Overall, antiretroviral therapy is indicated to all patients with a C04 + T cell count of <500 / mm3 or a viral load> 10,000 KonHU (bDNA), or> 20,000 copies of PNK (RT-PCR) in 1 ml of plasma.

However, for patients with asymptomatic HIV infection, antiretroviral therapy currently has two sets of approaches: the first is therapeutically more aggressive, when most patients should be treated early in the course of the illness, given that HIV infection is almost always progressing; the second is a therapeutically more cautious approach, allowing a later onset of antiretroviral therapy in view of the degree of presumed risk and benefit.

The first approach is based on the principle of early initiation of therapy before the development of significant immunosuppression and achieving an undetectable level of viral load. Thus, all patients with a C04 + T cell count of less than 500 / ml, as well as those with a CD4 T cell count greater than 500 / ml, but a viral load of more than 10,000 copies (bDNA) or 20,000 copies (RT-PCR) in 1 ml of plasma, should start antiretroviral therapy. Early antiretroviral therapy can help preserve immunocompetent cells and develop a proper immune response, so it is recommended that all patients with a primary infection, if possible, have antiretroviral therapy.

With a more conservative approach, patients with a low viral load and a small risk of occupational HIV disease with CD4 + T-cells less than 500 / ml, antiretroviral therapy is not prescribed. In such cases, patients are monitored and monitored.

If antiretroviral therapy is initiated in patients who have not previously taken antiretroviral drugs, then it should begin with regimens that involve reducing the viral load to undetectable.

Based on the experience of using antiretroviral agents, antiretroviral therapy is recommended with two nucleoside RT inhibitors and one potent protease inhibitor (PI). Other alternative modes are possible. They include two PIs, for example ritonavir and saquinavir (with one or two NRTIs) or nevirapine instead of IP. Dual PI-antiretroviral therapy with ritonavir and saquinavir without NRTI suppresses viremia below the detection limit and is convenient for taking twice daily, but the reliability of this combination is not fully established, so it is recommended that at least one NRTI is added if antiretroviral therapy starts with two PIs.

Replacing PIs with nevirapine or using only two NRTIs does not reduce the viral load below the detection threshold, as when two NRTIs + PIs are combined, so these combinations should only be used if more severe treatment is not possible. However, some experts are discussing the choice of triterapy, which includes either PIs or nevirapine for patients who have not previously taken anirretroviral agents.

Other regimens using two PIs or PIs + NNRTIs as initial therapy are now undergoing clinical trials. Clinical studies of two approved NNRTIs, confirmed by the results of measuring the viral load, revealed the advantage of nevirapine with supadavirdine.

It should be taken into account that, although ZTS is a strong NRTI in combination with other NRTIs, there may be situations in which complete viral suppression is not achieved, and then viral resistance rapidly develops to ZTS. Therefore, the optimal use of this drug in combination of three or more antiretroviral agents is recommended. In such regimens, other antiretroviral agents, such as NNRTIs - nevirapine and delavirdine - should be used, and resistance develops rapidly.

In recent years, antiretroviral therapy has been proposed in new variants. It includes efavirenz (sestiva), zidovudine and lamivudine (possibly combivir), another option: indinavir, zidovudine and lamivudine, as well as efavirenz, d4T, ZTS).

The use of antiretroviral agents as monotherapy is not indicated, except when there is no other choice, or in pregnant women for the prevention of perinatal infection.

With the beginning of therapy, all drugs should be taken synchronously, in a full dose, but with the use of ritonavir, nevirapine and the combination of ritonavir with saquinavir, the doses of the drugs should be changed. Particular attention should be paid to the drug interactions of IPs with other drugs.

[12], [13], [14], [15], [16], [17], [18], [19], [20]

Antiretroviral therapy in patients with advanced HIV infection

The stage of HIV infection in patients with opportunistic infections, vascular syndrome or malignant tumors is regarded as advanced. All patients with advanced HIV infection should receive antiretroviral therapy, but certain characteristics must be considered. If the patient has an acute opportunistic infection or other complication of HIV infection, when deciding to start therapy, it is necessary to carefully select the antiviral regimens taking into account the drug toxicity, the acceptability of the selected therapy, drug interactions and laboratory changes. Initial antiretroviral therapy should include the most intensive regimens (two NRTIs: one PI). Initiated antiretroviral therapy should not be interrupted during an acute opportunistic infection or malignant process unless it is associated with drug toxicity, intolerance, or drug interactions.

In patients with AIDS progressing to HIV, who receive complicated combinations of antiretroviral agents, multiple drug interactions are possible, so the choice should be made taking into account all potential interactions and cross-drug toxicity. For example, the use of rifampin for the treatment of active forms of tuberculosis is problematic in patients taking protease inhibitors. Which negatively affect the metabolism of rifampin, but, at the same time, are necessary for effective suppression of viral replication in patients with advanced HIV infection. Conversely, rifampin reduces the concentration of PIs in the blood, which can make the chosen regimen suboptimal. However, despite the fact that rifampin is contraindicated or not recommended for joint use with all protease inhibitors, the possibility of its use in reduced doses is discussed.

Other factors complicating the course of advanced HIV infection are depletion and anorexia nervosa, the presence of which in a patient may impair the absorption of certain PIs and reduce the effectiveness of treatment such as antiretroviral therapy.

Bone marrow suppression associated with AZT, as well as neutropenia caused by ddC, d4T and ddl, can exacerbate the direct effects of HIV, which can lead to their drug intolerance.

Hepatotoxicity associated with certain PIs may limit the use of these drugs, especially in patients with liver dysfunction.

The absorption and half-life of certain drugs can be altered by the simultaneous use of antiretroviral agents, especially PI and NNRTI, whose metabolism involves the enzymes of the cytochrome P450 system: ritonavir, indipavir, saquinavir, nelfinavir and delavirdine-inhibit, nevirapine-induces. Inhibitors of the P450 cytochrome system have the potential to increase the concentration of certain drugs that have similar metabolic pathways. By adding an inhibitor of the cytochrome P450 system, it is sometimes possible to improve the pharmacokinetic profile of selected agents (eg, by adding ritonavir to saquinavir) and their antiviral effect, but these interactions can lead to life-threatening consequences, so patients should be informed of all possible consequences, and the decision to prescribe such combinations should be agreed with the patient.

Strong antiretroviral therapy is often associated with some degree of recovery of immune functions. Therefore, in patients with advanced HIV infection and the subclinical course of opportunistic infections (atypical mycobacteriosis or CMV), new immune responses in response to the pathogen can develop and, consequently, new symptoms associated with a change in the immune and / or inflammatory response may appear. These phenomena should not be regarded as failure of antiretroviral therapy. In such cases, it is necessary to treat opportunistic infections in parallel with antiretroviral therapy and simultaneously monitor the level of viral load.

[21], [22], [23], [24], [25], [26],

Antiretroviral therapy for acute HIV infection

According to available information, at least 50%, and possibly up to 90% of people with acute HIV infection, have at least some symptoms of the so-called "acute retroviral syndrome," therefore, they are candidates for early therapy. Data on the immediate effect of treatment on the magnitude of viral load and the number of C04 + T cells have been obtained, but the remote clinical results of antiretroviral therapy for primary HIV infection are unknown. The clinical trials that have been completed so far have been limited to a small sample size, a short follow-up period, and often such treatment regimens that, according to modern ideas, have insufficiently optimal antiviral activity. Nevertheless, these studies generally support the view of the need for antiretroviral therapy at the stage of acute HIV infection. Current clinical studies are studying the long-term clinical efficacy of more powerful therapeutic regimens.

The theoretical justification for early intervention is argued as follows:

• it is necessary to suppress the initial "explosion" of viral replication and to reduce the degree of dissemination of the virus in the body;
• it is necessary to reduce the severity of the acute phase of the disease;
• possibly, antiretroviral therapy will affect the initial localization of the virus, which, in the final analysis, can reduce the rate of progression of the disease;
• it is possible that the treatment will reduce the rate of mutation of viruses due to the suppression of their replication.

Many specialists agree with the treatment of acute HIV infection, based on theoretical justifications and limited data from clinical trials that speak for it, as well as the experience gained by clinicians involved in HIV infection. However, the physician and the patient should clearly understand that the treatment of primary HIV infection is based on theoretical considerations and the potential benefits described above need to be correlated with the possible risk that includes:

• side effects in relation to the quality of life associated with the toxic effects of drugs and the features of their administration;
• the likelihood of developing drug resistance if initial antiretroviral therapy does not lead to effective suppression of viral replication, which will limit the choice of therapy in the future;
• the need for treatment with an indefinite duration.

Antiretroviral therapy is recommended for all patients with laboratory signs of acute HIV infection, which include the presence of HIV RNA in plasma determined by the sensitive PCR method or bDNA, in combination with serological diagnosis of HIV infection (HIV antibodies). Although the determination of HIV RNA in plasma is the preferred method of diagnosis, if this is not possible, it may be appropriate to test the p24 antigen.

Once the doctor and patient have decided to carry out antiretroviral therapy for primary HIV infection, they should aim to suppress the concentration of HIV RNA in the plasma to below the detection threshold. The accumulated experience suggests that antiretroviral therapy for acute HIV infection should include a combination of two NRTIs and one potent IP. It is possible to use the same drugs that are used to treat already developed HIV infection.

Because the:

• the ultimate goal of therapy is suppression of viral replication below the detection threshold,
• The benefits of therapy are mainly based on theoretical considerations and
• the long-term clinical effect is not yet proven, any scheme that is not expected to lead to maximum suppression of viral replication is not acceptable for people with acute HIV infection. To further study the role of antiretroviral therapy in primary infection, additional clinical studies are required.

Determination of HIV RNA in plasma and the number of CD4 + cells, as well as monitoring of toxic phenomena in the acute phase of HIV infection should be carried out according to the usual rules, that is, at the beginning of treatment, after 4 weeks, and then every 3-4 months. Some experts believe that it is not necessary to determine HIV RNA in the fourth week to evaluate the effectiveness of therapy for acute infection, because the viral load may decrease (in comparison with the peak) even in the absence of treatment.

Many experts also believe that, in addition to patients with acute HIV infection. Treatment is also necessary for persons with confirmed seroconversion in the previous 6 months. Although the initial "explosion" of viremia in infected adults usually disappears within two months, treatment at this time is justified by the fact that replication of the virus in the lymphoid tissue in the first 6 months after infection is still not maximally suppressed by the immune system.

[27], [28], [29], [30], [31], [32],

Antiretroviral therapy and interruptions

Sometimes, for some reason (intolerable adverse effects, drug interactions, lack of drugs, etc.), antiretroviral therapy is interrupted. Reliable information about how many days, weeks or months you can safely cancel one drug or the entire combination, no. If there is a need for interruption of antiretroviral therapy for a long time, it is theoretically better to cancel all drugs than to continue therapy with one or two antiretroviral drugs. This approach allows to minimize the risk of the emergence of resistant strains of the virus.

A break in antiviral therapy is also recommended by domestic authors. However, a break is possible only when monitoring the level of CD4 cells and viral load.

In occasion of breaks in treatment there is a big discussion. Some authors suggest intermittent therapy, others consider it advisable to take breaks in treatment. Intermittent antiretroviral therapy is recommended for those patients whose HIV RNA drops below 500 copies per ml, interruptions are considered possible from 3 to 6 months. The most promising is to hold this break for those patients who have a viral load below 50 copies per ml, and CD4 is above 300 in mm3. Dybul M et al., 2001 recommend the following pattern of intermittent therapy: zerit and lamivudine, indinavir for 7 days, 7 days for a break and this treatment continues throughout the year. The authors reported a positive result of using this scheme. According to Faussi, 2001, patients with intermittent therapy had less lipodystrophy syndrome, and a decrease in total triglycerides and cholesterol was observed.

Subsequently, Dybul et al. Analyzed the results of treatment of 70 patients who received treatment for 8 weeks and 4 weeks without treatment (intermittent antiretroviral therapy). During each drug withdrawal, the level of viral load increased by approximately 20%. Unessentially, but the number of CD4 cells decreased. The level of lipids in the blood was also decreasing. According to the latest recommendations, with a viral load of more than 30-50 copies of RNA in ml and CD4 cells below 400, antiretroviral therapy is recommended for a long time, but breaks are possible, but only when there is persistent suppression of viral replication and a significant improvement in immunological parameters. Patients who had a history of CD4 below 200 and who had opportunistic infections registered should be systematically treated with medication without any interruption.

Special Swiss-Spanish studies have shown that intermittent antiretroviral therapy in patients with HIV RNA levels below 400 copies per ml and CD4 above 300 in mm ³ who received highly active antiretroviral therapy with four cycles of 8 weeks of treatment and 2 weeks of interruptions was successful. Treatment was stopped after 40 weeks and patients did not receive therapy until 52 weeks inclusive, however, antiretroviral therapy was prescribed if plasma HIV RNA levels increased over 5000 copies per ml.

In multicenter studies conducted by C. Fagard (2000), Lori et al. (2000-2002) in the cities of Italy and the United States, the possibility and promise of interruptions in antiretroviral therapy was demonstrated. The use of a complex of 3-4 antiviral agents may, with HAART in chronic patients with HIV infection, have a temporary effect, but may be accompanied by a ricochet increase in viral load and a decrease in CD4 lymphocytes. In view of this, it is proposed to use during the period of treatment interruptions drugs that increase the cellular immune HIV of a specific Th1 T cell and the level of gamma-interferon.

Consequently, antiretroviral therapy with interruptions is justified, expedient. However, they require control definitions of CD4 and viral load, at least monthly or better 2 weeks after the abolition of HAART.

[33], [34], [35],

Change in ineffective regimens of antiretroviral therapy

Antiretroviral therapy may not be effective. It arises because of many circumstances, such as initial viral resistance to one or more agents, altered absorption or metabolism of drugs, adverse effects of drug pharmacokinetics on the level of therapeutic agents, and others.

The main parameter in assessing the therapeutic outcome is the viral load. Clinical complications and changes in the number of CD4 + T cells can complement the viral load test in evaluating the response to therapy.

In the case of therapeutic failure, the criteria for changing antiretroviral therapy are:

• the decrease in HIV RNA in plasma after 4-8 weeks from the start of treatment is less than 0.5-0.7 log | n;
• the inability to reduce the viral load to an undetectable level within 4-6 months from the start of therapy;
• Renewal of the virus definition in plasma after initial suppression to an undetectable level, which confirms the development of resistance;
• triple or more increase in HIV RNA in plasma;
• undiagnosed viremia in patients receiving combination therapy from two NRTIs (patients receiving two NRTIs achieving the goal of undetectable viral load have the option of continuing with this regimen or changing it to a higher priority regimen.) Previous experience shows that the majority of patients who have remained on a double NRTI -therapy, in the end, suffer a virological failure compared to patients using priority regimens);
• a persistent decrease in the number of C04 + T cells, confirmed by at least two separate studies;
• clinical deterioration.

Antiretroviral therapy should be changed in three categories of patients:

• persons taking one or two NRTIs with a detectable or undetectable viral load:
• persons who are on powerful combination therapy, including IP. With renewed niremia, a note of initial suppression to undetectable levels;
• persons who are on powerful combination therapy, including AI. At whom the viral load never decreased to an undetectable level.

The changed regimen in all patients should suppress viral activity as much as possible, however, for the first category of individuals, the choice of new combinations is much wider, since they did not take IP.

Discussion of alternative regimens should take into account the forces of the substitution regime, tolerability of drugs and the patient's adherence to this regime.

Recommendations for modification of therapy ("Guidelines for the treatment of HIV infection in adults and adolescents," US Department of Health, May 1999).

Recommendations for changes in therapy vary according to the indications for change. If the desired reduction in viral load is achieved, but the patient develops toxicity or intolerance, it is necessary to replace the drug that caused adverse effects with another of the same class of agents with an excellent toxicity profile and tolerability. At the Seventh European Symposium on HIV Treatment "For the Rest of Life", Budapest, February 1-3, 2002, the following issues on HIV therapy were topical: what to do after the first failure, how to choose the second line therapy, try to find a scheme , to the maximum extent capable of suppressing HIV RNA up to <50 copies. It is recommended that:

• Analysis of medical history - the choice of an antiretroviral drug based on expert opinion and treatment standard considerations
• Resistance analysis: genotypic and / or phenotypic, cross-resistance.
• Thorough assessment of tolerability / toxicity.
• Determination of the concentrations of drugs in the body should be taken into account:
  • adherence to treatment;
  • drug interactions - IP, in combination with their enhanced ritonavir, taking into account toxicity and, in particular, mitochondrial hypertoxicity;
  • monitoring of drug concentrations;
  • pharmacokinetics of drugs.

If the desired reduction in viral load has been achieved, but the patient has received a non-priority treatment (two NRTIs or monotherapy), one can continue the initiation of therapy under close monitoring of the level of viral load, or add another drug to the current regimen according to intensive therapeutic regimens. Most experts believe that the use of non-intensive schemes ends in failure, and recommend priority regimes. There is evidence confirming the failure of therapeutically potent regimens including PIs, due to the development of cross-resistant HIV strains, especially if viral replication has not been completely suppressed. Such phenomena are most typical for the IP class. Obviously, viral strains that have become resistant to one of the PIs become less sensitive to the majority or to all PIs. Thus, the success of a combination of PI + two NNRTIs may be limited, even if all components differ from the previous regimen, in which case a replacement for two PIs is possible. The possible combinations of the two IPs are currently being actively studied.

Modification of the regimen due to therapeutic failure ideally should involve a complete replacement of all components for drugs previously not used by the patient. Usually, two new NRTIs and one new PI are used, two PIs with one or two new NRTIs, or PIs in combination with NNRTIs. Dosage changes due to drug interactions may be required when protease inhibitors or PI + NNRTIs are used.

Different schemes of antiviral therapy are substantiated. Antiretroviral therapy - monotherapy with domestic preparations - thymazid 0.2x3 times, phosphazide 0.4x3 times a day is recommended in the initial stages of HIV infection with CD4 count below 500 and / or with a viral load of 20,000 to 100,000 copies of HIV RNA. Bi-antiretroviral therapy using reverse transcriptase inhibitors is indicated in the presence of clinical manifestations and in the inefficiency of monotherapy, taking into account the number of CD4 cells and the level of viral load. However, the authors consider it possible to prescribe combination therapy only on clinical indications in the absence of laboratory data.

The leading scientist on this problem, B.Gazzard (1999), draws a pessimistic picture of the future therapy of HIV infection. Standard high-activity antiretroviral therapy, including 2 NRTIs in combination with protease inhibitors or NNRTIs, reduces the viral load to undetectable levels by the most sensitive methods. Such antiretroviral therapy is the standard for the treatment of patients who have not previously received antiretroviral therapy.

However, firstly, long-term clinical studies for 3 years allow us to doubt the effectiveness of treatment. Secondly, the cost of combined therapy during the year is quite expensive. Third, studies, including convenience, toxicity, pharmacological interactions, resistance and lack of effect, require new ideas for antiretroviral therapy.

[36], [37], [38]

Compliance with the treatment regimen for HIV infection

Highly active antiretroviral therapy caused the need for adherence to the treatment regimen for good results. The consequence of non-compliance with the prescribed treatment regimen is the risk that the medicine will not have an effect. The main danger is that an insufficient dose of an antiretroviral drug due to non-adherence to the treatment regimen can lead to an increase in the amount of DNA in the plasma, the development of resistance to drugs and the negative consequences in terms of disease progression and death. Factors affecting the accuracy of the patient's medication are:

• the stage of the disease, the patient should be aware of the danger that the disease brings and believe that adherence to the treatment regimen will reduce this danger;
• The treatment regimen must imply that the patient understands the complexity. Duration, safety and cost of the treatment regimen offered to him;
• the relationship between the patient and the health worker, the physician should monitor the need to consistently observe the prescribed course of treatment because of the benefits to the patient and the course of the disease.

Initial antiretroviral therapy should be carefully selected in accordance with the wishes of the patient and his lifestyle. In this case, the participation of a pharmacologist who has detailed pharmacological characteristics of the drug is extremely important. The pharmacist should discuss with the patient the number of tablets taken per day, the choice of convenient treatment options, the compulsion to meet the intervals between doses, the requirements for diet and nutrition restrictions. It is especially important to take into account side reactions, as well as the possibility of drug interactions (see annexes). It is also necessary to take into account the limitations in the storage of medicines. Some of the medicines are stored under special conditions, which should be taken into account for those taking medication outside the home. Some patients have difficulties with swallowing, for them it is necessary to choose preparations that are produced in liquid form.

One of the main points is the union between the patient and the medical worker, based on the respect of the parties and the honest exchange of information (understanding - "compliance"). To improve adherence to the treatment regimen, it is necessary to take into account the individual needs of each individual patient, explain the prescribed instructions and provide a reminder for compliance with the treatment schedule and schedule. It is advisable to check what the patient remembered after each counseling. In subsequent observations, it is advisable to have close contact with the patient, the possibility of visiting or calling the patient to find out the difficulties in taking medication and adherence to the treatment regimen. It is necessary to follow the rule: to provide the best medicine for this patient, taking into account his own way of life. The pharmacist, discussing with the patient all the questions connected with the medicine, can play an important role and help the HIV-infected person in achieving the best result of treatment.

The reasons for the low adherence to APT:

• the problem of psychological adequacy of the patient (depression, drug addiction, psychotropic side effects of drugs),
• a significant number of tablets for everyday intake (sometimes around 40),
• multiple intake of drugs per day,
• complex conditions for taking medications associated with:
  • time of day,
  • presence, nature and time of food intake,
  • reception of other drugs,
  • reception characteristics (for example, indinavir should drink at least 1.5 liters of fluid, which with a 3-time admission is 4.5 liters every day),
  • large size of tablets and capsules,
  • unpleasant taste of drugs (ritonavir, for example, has a taste of a mixture of alcohol and castor oil),
  • pronounced adverse reactions (especially from the side of the central nervous system, lygdystrophy, hyperglycemia, lactic acidosis, hyperlipidemia, bleeding, osteoporosis, rash, etc.)
  • continued use of drugs.

Low adherence to therapy leads to:

• the growth of viral load, deterioration of the state and increase in mortality,
• development of resistance,
• a sharp decrease in its effectiveness.

Inadequate adherence to treatment is the main reason for the decline in the effectiveness of APT. The most frequent reasons for unsatisfactory adherence are: greater employment or forgetfulness of patients (52%), being away from home (46%), lifestyle changes (45%), depressed state (27%), lack of drug (20%), etc. That is, the prevalence of violations of the prescribed treatment regimen ranges from 23% to 50%. The real way to increase adherence is to use simpler drug regimens, preferably once a day, for example ddl (videix) 400 mg, lamivudine (epivir) 300 mg, zerit (stavudine) 1.0 per day, and others.

The regimen of drugs once a day, as shown by N. Nelson (2002), is effective and well tolerated. Decreasing the number of tablets facilitates reception, improves adherence, and therefore has potential therapeutic success.

[39], [40], [41], [42], [43], [44],

Antiretroviral therapy: side effects

According to the classification (Antiretroviral quidelines, 2002), there are class-specific side effects (characteristic for the class of drugs) and specific for specific drugs in the class.

Class-specific side effects of NRTIs: hyperlactatemia with possible steatosis of the liver, in rare cases, lipodystrophy (Lenzon, 1997).

Class-specific side effects of PI - GI disorders, hyperlipidemia, lipodystrophy, decreased sensitivity of peripheral tissues to insulin. Metabolic disorders caused by PIs correlate with the duration of their admission. Disorders of lipid metabolism can be a risk factor in the development of cardiovascular diseases.

Approaches to reducing the side effects of APT: choosing combinations of drugs with minimal side effects, optimizing the doses of drugs (using monitoring), the possibility of interruption in treatment, later initiation of therapy, or alternate administration of different regimens, the use of new, less toxic drugs or less toxic dosage forms.

The use of protease inhibitors led to the appearance of lipodystrophy syndrome, which is characterized by a redistribution of body fat: loss of fat in the face and fat deposition in the abdomen and neck ("Buffalo" hump) with breast enlargement, as well as diabetes and risk of cardiovascular diseases. Inhibitors of reverse transcriptase are less involved in this syndrome. The author gives a characterization of this syndrome, taking into account other information of the literature. Physical and metabolic disorders in the syndrome of lipodystrophy

A. One or more of the following symptoms when taking protease inhibitors.

1. Reduction or loss of fat on the face, arms, legs.
2. Accumulation of fat on the abdomen, posterior region of the neck ("Buffalo hump"), breasts in women.
3. Dry skin and lips.

B. Metabolic disorders

Hyperlipidemia is a PI-specific effect. The duration of IP treatment is an important risk factor for the development of metabolic disorders. Hypercholesterolemia develops in 26% of patients who took IP within 1 year, 51% after 2 years and 83% after 3 years. Lipodystrophy develops in more than 60% of patients taking IP (Saag M .. 2002). In such patients, the risk of cardiovascular diseases is increased. Symptoms are not grounds for abolishing protease inhibitors. It is necessary to decide whether to transfer to efavirenz or to prescribe an inhibitor of protease atazanavir, which does not cause lipopolidystrophy and is even able to correct the syndrome.

Drugs for the treatment of dyslipidemia:

• Statins - suppress the synthesis of cholesterol.

Fibrates - stimulate the activity of LP-lipase. Resins that adsorb bile - increase the excretion of cholesterol and lipids from the body.

Lipostat (pravastatin sodium). Each tablet contains 10 or 20 mg of pravastatin sodium. Excipients: lactose, povidone, microcrystalline cellulose, sodium carboxymethyl cellulose and magnesium stearate.

Lipostat belongs to the class of inhibitors of HMG-CoA reductase, new lipid-lowering agents that reduce biosynthesis of cholesterol. These agents are competitive inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the initial stage of cholesterol biosynthesis, namely the conversion of HMG-CoAm to mevalonate, which determines the rate of the process as a whole.

Treatment with Lipostat should be considered as one of the components of the impact on multiple risk factors in people at increased risk of atherosclerotic vascular disease caused by hypercholesterolemia.

Lipostat should be used in addition to a diet with a restriction on saturated fats and cholesterol in those cases where the response to diet and other non-pharmacological treatments is inadequate.

Method of administration and dose. Before starting treatment with lipostat, the patient should be prescribed a standard diet to lower cholesterol. During treatment with the drug, the patient must continue to follow this diet. The recommended dose of the drug lipostat is 10 to 40 mg, once a day before bedtime. Usually the starting dose is 10-20 mg. If the concentration of serum cholesterol is significantly increased (eg, total cholesterol is more than 300 mg / dl), the initial dose can be increased to 40 mg per day. Lipostat can be taken without regard to the time of food intake, and the daily dose can be divided into several receptions. Since the maximum effect of the prescribed dose is manifested within four weeks, during this period, the lipid content should be regularly determined and, accordingly, the dose adjustment should be carried out taking into account the patient's response to the drug and established treatment rules.

A serious complication is osteopenia, osteoporosis and osteoneurosis. Patients who have pain in the bones or joints are shown radiographic examinations. Treatment is carried out using calcium-phosphorus and vitamin preparations. In osteonecrosis and pathological fractures, surgical treatment is indicated.

Guidelines for the integrated use of drugs

1. Expect deviations from the treatment regimen. Always proceed from the fact that the treatment regimen will not be respected.
2. Consider treatment from the perspective of the patient. The medical staff should understand the situation of each individual patient. The physician should be aware of the patient's expectations, goals, sensations and views regarding the illness and treatment.
3. Develop a partnership between the patient and the doctor. Responsibility for the decisions made should be equally distributed between the patient and the doctor. This means that the patient must obtain accessible, understandable information in order to be able to make adequate decisions regarding therapy.
4. Take a position oriented to the patient. Satisfaction of the patient is the main criterion. Questions, wishes and feelings of the patient should form the starting point of therapy. All deviations must be negotiated.
5. Individualize treatment. All the moments of therapy, all for the therapy, the necessary aids must be negotiated individually. Universal solutions should be avoided.
6. Bring the family to work together. The family and circle of close friends should be involved in the treatment process for support. The patient needs help in the fight against the disease not to abandon the social environment.
7. Ensure duration and availability. The patient should be absolutely sure of the duration and availability of therapy.
8. Take into account the services of other professionals in the social and healthcare fields. A doctor can provide only one part of professional assistance in the fight against the disease. It is necessary to involve other specialists.
9. Repeat all. Efforts to achieve collaborative work within the framework of therapeutic relationships should be applied continuously throughout the treatment.
10. To not give up. The problem of the complex is extremely complex and multifaceted. Relation to illness and death is a fundamental topic in life, especially in the relationship between the doctor and the patient. Only in close and constant cooperation can the doctor and patient succeed.

[45], [46], [47], [48], [49],