Antiretroviral therapy

The decision to initiate antiretroviral therapy should be made jointly by the physician and the patient. Before antiretroviral therapy is prescribed in each case, it is necessary to conduct a clinical and laboratory examination of the patient, determine clinical indications and contraindications, evaluate laboratory parameters and, taking into account the data obtained, develop an acceptable treatment regimen. It is extremely important to conduct psychological preparation with the patient in order to ensure strict compliance with the selected regimen.

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

Antiretroviral therapy: indications

Antiretroviral therapy should be initiated based on laboratory findings, and changes in therapy should be based on monitoring of parameters such as plasma HIV RNA (viral load) and peripheral CD4+ T-cell counts. These tests are essential in assessing viral replication, the patient's immune status, and the risk of disease progression. Viral load was initially determined only for prognostic purposes; today, it also serves as a test for assessing patient outcomes. Numerous observations indicate improved clinical outcomes (reduction in mortality and progression to AIDS) with decreased viral load.

The International AIDS Society 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 1995 recommendations, provided more detailed information on monitoring during treatment, 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 provided grounds for revising the previous recommendations. According to the revised recommendations, antiretroviral therapy is indicated for patients:

• with HIV RNA levels above 30,000 copies/ml,
• CD4 lymphocyte level 350/mL,
• treatment can also be recommended for patients with HIV RNA from 5,000 to 30,000 copies/ml and CD4 lymphocyte levels between 350 and 500 x 10 ⁶ /l,
• therapy can also be considered indicated if CD4 lymphocytes are above 500 x10'7L and HIV RNA is from 5000 to 30000 copies/ml, taking into account possible disease progression in patients with a high viral load.

Antiretroviral therapy should be initiated only after treatment of serious opportunistic infections.

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

• symptomatic HIV infection,
• asymptomatic HIV infection with CD4 cells below 200 per ml of blood,
• asymptomatic HIV infection with CD4 above 200 in cases of rapid decline or high viral load, higher than 50,000-100,000 RNA copies/ml.

In this case, the risk of individual toxicity, drug interactions, and their pharmacokinetics are taken into account. Great importance is attached to the patient's interest in the drug and the ability to adhere to therapy.

Indications for starting ART are acute HIV infection and stages III A-B and C, laboratory indications are: decrease in CD4 lymphocytes below 0.3x109 with an increase in the concentration of HIV RNA in the blood of more than 60,000 cop/ml. If these indicators are detected for the first time, then to decide on ART, repeated studies are necessary at intervals of at least 4 weeks, while in stage 3 A (2B according to the 1999 classification) antiretroviral therapy is prescribed in the form of mono- or ditherapy. Antiretroviral therapy is recommended for CD4 below 0.2x107L (below 200 in ml). In IV (stage V according to the 1999 classification) ART is not prescribed.

Quantitative measurement of plasma HIV RNA levels is recommended immediately before initiation of antiretroviral therapy and after 4-8 weeks of treatment to assess the initial efficacy. Most patients experience a rapid decline in viral load (0.5-0.7 log,0, or approximately 3-5 times) during this time, with viral load becoming undetectable (<500 RNA copies/mL plasma) after 12-16 weeks. The rate of viral load decline is individual and depends on many factors, including the initial viral load and the number of CB4H cells, the presence of previous therapy (its duration), the presence of opportunistic infections, and the patient's adherence to the chosen regimen.

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

More sensitive methods for determining viral load (up to 50 RNA copies/ml) have now been developed. Clinical data confirm that a decrease in the HIV RNA level below 50 copies/ml is associated with 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 completion of treatment for any intercurrent infection, symptomatic illness, or after immunization.

To obtain more reliable results, viral load determination should be performed under the same conditions due to the existing differences among commercial tests.

First-line antiretroviral therapy: therapy should be carried out with a combination of drugs with high antiviral activity and good tolerability. The first regimen should leave strategic options for the future, i.e. include drugs that provide the least cross-resistance.

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

Currently, a transition to a new concept of APT is planned, based on a variety of drugs to create simpler treatment regimens, including those where drugs can be taken once a day. Recommended regimens: EFV-DDH3TC, F.FV+D4T+3TC. The use of simple and effective regimens for first-line therapy can extend the period of its effectiveness, i.e. reduce the need for second-line HAART.

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

Antiretroviral therapy in patients with asymptomatic HIV infection

To date, there is convincing evidence that antiretroviral therapy is successful and indicated for 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-cell counts > 500/ml, we can only talk about the theoretical success of using antiretroviral agents due to the lack of data on sufficiently long-term observations.

Currently used combinations of antiretroviral agents have a pronounced antiviral effect, however, all of them can cause side effects, complications and interact with other drugs, therefore the decision to prescribe treatment to patients with chronic asymptomatic HIV infection should be based on a comparison of a number of factors that determine the risk and benefit of treatment.

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

Negative factors for early administration of such treatment as antiretroviral therapy may include: potential adverse drug effects; potential risk of developing early drug resistance; potential limitation of future therapy choices, etc.

When deciding on therapy for asymptomatic patients, the patient's desire to initiate therapy, the degree of existing immunodeficiency determined by the number of CD4+ T cells, the risk of HIV progression determined by the level of HIV RNA in plasma, the potential benefit and risk of initial therapy, and the likelihood of patient adherence to the prescribed regimen should be taken into account.

If therapy is prescribed, it is necessary to use powerful combinations to achieve a reduction in viral load to an undetectable level. In general, antiretroviral therapy is indicated for all patients with a CD4+ T-cell count of <500/mm3 or a viral load level of >10,000 KonHU(bDNA), or >20,000 copies of RNA (RT-PCR) in 1 ml of plasma.

However, for patients with asymptomatic HIV infection, antiretroviral therapy currently has two approaches to administration: the first is a therapeutically more aggressive approach, when most patients should be treated at early stages of the disease, given that HIV infection is almost always progressive; the second is a therapeutically more cautious approach, allowing for a later start of antiretroviral therapy, taking into account the degree of expected risk and benefit.

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

In a more conservative approach, patients with a low viral load and a low risk of developing HIV disease with a CD4+ T-cell count of less than 500/ml are not prescribed antiretroviral therapy. In such cases, monitoring and observation of patients continues.

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

Based on experience with antiretroviral agents, antiretroviral therapy with two nucleoside RT inhibitors and one strong protease inhibitor (PI) is recommended. Other alternative regimens are possible. They include two PIs, such as ritonavir and saquinavir (with one or two NRTIs) or nevirapine instead of a PI. Dual PI-antiretroviral therapy with ritonavir and saquinavir without NRTIs suppresses viremia below the limit of detection and is convenient for twice-daily dosing; however, the reliability of this combination is not well established, so it is recommended to add at least one NRTI if antiretroviral therapy is initiated with two PIs.

Replacing a PI with nevirapine or using two NRTIs alone does not reduce viral load below detection thresholds as well as two NRTIs plus a PI, so these combinations should be used only when more stringent treatment is not possible. However, some experts are discussing the choice of triple therapy, including either a PI or nevirapine, for patients who have not previously taken antiretroviral agents.

Other regimens using two PIs or PIs and NNRTIs as initial therapy are currently in clinical trials. Clinical studies of two approved NNRTIs, supported by viral load measurements, have shown a benefit of nevirapine over delavirdine.

It should be noted that although 3TS is a potent NRTI in combination with other NRTIs, situations may arise in which complete viral suppression is not achieved and viral resistance to 3TS develops rapidly. Therefore, optimal use of this drug in combination with three or more antiretroviral agents is recommended. Such regimens should also include other antiretroviral agents, such as the NNRTIs nevirapine and delavirdine, to which resistance develops rapidly.

In recent years, new antiretroviral therapies have been proposed. These include efavirenz (Sustiva), zidovudine, and lamivudine (possibly Combivir), another option: indinavir, zidovudine, and lamivudine, as well as efavirenz, d4T, ZTC).

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.

When initiating therapy, all drugs should be taken simultaneously, at full dose, but when using ritonavir, nevirapine and the combination of ritonavir and saquinavir, the doses of the drugs should be adjusted. Particular attention should be paid to drug interactions of IP 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, wasting syndrome, or malignancies is considered advanced. All patients with advanced HIV infection should receive antiretroviral therapy, but some special considerations should be taken. If a patient has an acute opportunistic infection or other complication of HIV infection, the decision to initiate therapy should carefully select antiretroviral regimens based on drug toxicity, acceptability of the selected therapy, drug interactions, and laboratory abnormalities. 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 malignancy unless this is due to drug toxicity, intolerance, or drug interactions.

In patients with HIV infection progressing to AIDS receiving complex combinations of antiretroviral agents, multiple drug interactions are possible, so the choice should be made taking into account all potential interactions and cross-toxicity of drugs. For example, the use of rifampin for the treatment of active forms of tuberculosis is problematic in patients receiving 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 blood concentrations of PIs, which may make the chosen regimen suboptimal. However, although rifampin is contraindicated or not recommended for concomitant use with all protease inhibitors, its use in reduced doses is under discussion.

Other factors that complicate the course of advanced HIV infection include wasting syndrome and anorexia, the presence of which in a patient can impair the absorption of certain PIs and reduce the effectiveness of treatments such as antiretroviral therapy.

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

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

Absorption and half-life of some drugs may be altered by concomitant use of antiretroviral agents, especially PIs and NNRTIs, whose metabolism involves cytochrome P450 enzymes: ritonavir, indipavir, saquinavir, nelfinavir and delavirdine inhibit it, nevirapine induces it. Cytochrome P450 inhibitors have the potential to increase concentrations of some drugs that have similar metabolic pathways. Adding a cytochrome P450 inhibitor can sometimes improve the pharmacokinetic profile of selected agents (e.g. 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.

Potent antiretroviral therapy is often associated with some degree of immune recovery. In this regard, patients with advanced HIV infection and subclinical opportunistic infections (atypical mycobacterioses or CMV) may develop new immune responses to the pathogen and, accordingly, may develop new symptoms associated with changes in the immune and/or inflammatory response. These phenomena should not be regarded as failures of antiretroviral therapy. In such cases, it is necessary to treat opportunistic infections in parallel with antiretroviral therapy and simultaneously monitor the viral load.

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

Antiretroviral therapy for acute HIV infection

It is estimated that at least 50% and possibly as many as 90% of individuals with acute HIV infection have at least some symptoms of the so-called "acute retroviral syndrome" and are therefore candidates for early therapy. Although there is evidence of short-term treatment effects on viral load and CD4+ T-cell counts, the long-term clinical outcomes of antiretroviral therapy for primary HIV infection are unknown. Clinical trials completed to date have been limited by small sample sizes, short durations of follow-up, and often by regimens that are currently thought to have suboptimal antiviral activity. However, these studies generally support the view that antiretroviral therapy is necessary during acute HIV infection. Ongoing clinical trials are examining the long-term clinical efficacy of more potent regimens.

The theoretical rationale for early intervention is argued as follows:

• it is necessary to suppress the initial “explosion” of viral replication and 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;
• It is possible that antiretroviral therapy will affect the initial localization of the virus, which may ultimately reduce the rate of disease progression;
• It is possible that the treatment will reduce the rate of mutation of viruses by suppressing their replication.

Many experts agree with treatment of acute HIV infection based on theoretical justifications, limited clinical trial data in its favor, and the experience of HIV clinicians. However, the physician and patient must be clear that treatment of primary HIV infection is based on theoretical considerations and the potential benefits described above must be weighed against the possible risks, which include:

• side effects on quality of life associated with the toxic effects of drugs and the characteristics of their administration;
• the possibility of developing drug resistance if initial antiretroviral therapy does not effectively suppress viral replication, limiting future treatment options;
• the need to carry out treatment of indefinite duration.

Antiretroviral therapy is recommended for all patients with laboratory evidence of acute HIV infection, which includes the presence of HIV RNA in plasma, as determined by a sensitive PCR assay, or bDNA, in combination with HIV serology (HIV antibodies). Although plasma HIV RNA is the preferred diagnostic method, p24 antigen testing may be appropriate if this is not available.

Once the physician and patient have decided to initiate antiretroviral therapy for primary HIV infection, they should aim to suppress plasma HIV RNA levels below the detection threshold. Current experience suggests that antiretroviral therapy for acute HIV infection should include a combination of two NRTIs and one potent PI. The same drugs used to treat established HIV infection may be used.

Because:

• the ultimate goal of therapy is to suppress viral replication below the detection threshold,
• the benefits of therapy are based mainly on theoretical considerations and
• Because long-term clinical benefit has not yet been demonstrated, any regimen that is not expected to result in maximal suppression of viral replication is not acceptable for individuals with acute HIV infection. Additional clinical trials are needed to further explore the role of antiretroviral therapy in primary infection.

Plasma HIV RNA and CD4+ cell counts, as well as monitoring of toxicities in the acute phase of HIV infection, should be performed according to the usual guidelines, i.e., at the start of treatment, after 4 weeks, and then every 3–4 months. Some experts believe that it is not necessary to measure HIV RNA at week 4 to assess the effectiveness of therapy for acute infection, because the viral load may decrease (compared to 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 individuals with confirmed seroconversion in the previous 6 months. Although the initial "burst" of viremia in infected adults usually resolves within two months, treatment at this time is justified by the fact that viral replication in 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 breaks

Sometimes, for one reason or another (unbearable side effects, drug interactions, lack of a drug, etc.), antiretroviral therapy is interrupted. There is no reliable information on how many days, weeks, or months one drug or the entire combination can be stopped without consequences. If there is a need to interrupt antiretroviral therapy for a long period, then theoretically it is better to stop all drugs than to continue therapy with one or two antiretroviral drugs. This approach allows to minimize the risk of emergence of resistant strains of the virus.

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

There is a lot of discussion about treatment breaks. 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, breaks are considered possible from 3 to 6 months. It is most promising to take these breaks for those patients whose viral load is below 50 copies per ml, and CD4 is above 300 per mm3. Dybul M et al., 2001 recommend the following intermittent therapy regimen: zerit and lamivudine, indinavir for 7 days, 7 days of break, and this treatment continues for a year. The authors reported a positive result of using this regimen. According to Faussi, 2001, patients on intermittent therapy had less pronounced 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 viral load level increased by approximately 20%. The number of CD4 cells decreased, but not significantly. The level of lipids in the blood also decreased. According to the latest recommendations, with a viral load above 30-50 copies of RNA per ml and CD4 cells below 400, antiretroviral therapy is recommended for a long time, however, interruptions are possible, but only in a situation where there is a stable suppression of viral replication and a significant improvement in immunological parameters. Patients who have a history of CD4 below 200 and have registered opportunistic infections should be systematically on drug therapy without any interruptions.

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 per mm ³, who received highly active antiretroviral therapy in four cycles of 8 weeks of treatment and 2 weeks of breaks, was successful. Treatment was stopped after 40 weeks and patients did not receive therapy up to and including 52 weeks, however, antiretroviral therapy was prescribed if the plasma HIV RNA level increased above 5000 copies per ml.

Multicenter studies conducted by C. Fagard (2000), Lori et al. (2000-2002) in cities of Italy and the USA demonstrated the possibility and prospects of breaks in antiretroviral therapy. The use of a complex of 3-4 antiviral agents can provide a temporary effect in HAART in chronic patients with HIV infection, but can be accompanied by a rebound increase in viral load and a decrease in CD4 lymphocytes. In view of this, it is proposed to use drugs that increase cellular immune HIV-specific Th1 T-cells and the level of gamma interferon during breaks in treatment.

Therefore, antiretroviral therapy with interruptions is justified and advisable. At the same time, they require control determinations of CD4 and viral load at least monthly or better after 2 weeks after discontinuation of HAART.

[ 33 ], [ 34 ], [ 35 ]

Modifying ineffective antiretroviral therapy regimens

Antiretroviral therapy may be ineffective. It occurs due to 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, etc.

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 assessing the response to therapy.

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

• reduction in HIV RNA in plasma after 4-8 weeks from the start of treatment by less than 0.5-0.7 log|n;
• inability to reduce the viral load to an undetectable level within 4-6 months from the start of therapy;
• resumption of virus detection in plasma after initial suppression to undetectable levels, confirming the development of resistance;
• threefold or more increase in HIV RNA in plasma;
• undetectable viremia in patients receiving dual NRTI combination therapy (patients receiving dual NRTIs who achieve the goal of undetectable viral load have the choice of continuing that regimen or changing to a higher-priority regimen. Previous experience shows that more patients remaining on dual NRTI therapy eventually experience virologic failure compared to patients using higher-priority regimens);
• persistent decline in CD4+ T cell counts confirmed by at least two separate studies;
• clinical deterioration.

Antiretroviral therapy should be changed in three categories of patients:

• individuals taking one or two NRTIs with detectable or undetectable viral load:
• persons on potent combination therapy, including IP, with recurrent neuremia after initial suppression to undetectable levels;
• people on powerful combination therapy, including AIs, whose viral load has never dropped to undetectable levels.

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

Discussion of alternative regimens should take into account the strength of the replacement regimen, drug tolerability, and patient adherence to the regimen.

Recommendations for modification of therapy (Guidelines for the Treatment of HIV Infection in Adults and Adolescents, U.S. Department of Health, May 1999).

Recommendations for changes in therapy vary according to the indications for changes. If the desired reduction in viral load has been achieved but the patient develops toxicity or intolerance, the offending agent should be replaced by another agent from the same class of agents with a different toxicity and tolerability profile. At the Seventh European Symposium on HIV Therapy "For Life", Budapest, 1-3 February 2002, the following issues in HIV therapy were relevant: what to do after the first failure, how to choose second-line therapy, trying to find a regimen that can suppress HIV RNA to <50 copies as much as possible. In this case, it is recommended to carry out:

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

If the desired viral load reduction has been achieved but the patient has been receiving a non-priority regimen (two NRTIs or monotherapy), the therapy started can be continued under careful monitoring of the viral load level, or another drug can be added to the current regimen according to intensive therapeutic regimens. Most experts believe that the use of non-intensive regimens ends in failure and recommend priority regimens. 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 characteristic of the PI class. It is obvious that viral strains that have become resistant to one of the PIs become less sensitive to most or all PIs. Thus, the success of a PI + two NNRTI combination may be limited, even if all components differ from the previous regimen, in which case a change to two PIs is possible. Possible combinations of two PIs are currently under active study.

Changing the regimen because of therapeutic failure should ideally involve replacing all components with drugs not previously used by the patient. Typically, two new NRTIs and one new PI, two PIs with one or two new NRTIs, or a PI in combination with an NNRTI are used. Dose adjustments may be required due to drug interactions when protease inhibitors or PIs+NNRTIs are used.

Different antiviral therapy regimens are substantiated. Antiretroviral therapy - monotherapy with domestic drugs - timazid 0.2x3 times, phosphazid 0.4x3 times a day is recommended in the initial stages of HIV infection with a 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 ineffectiveness of monotherapy, taking into account the CD4 cell count and the viral load level. However, the authors consider it possible to prescribe combination therapy only according to clinical indications in the absence of laboratory data.

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

However, firstly, long-term, 3-year clinical studies cast doubt on the effectiveness of the treatment. Secondly, the cost of combination therapy for a year is quite expensive. Thirdly, studies including convenience, toxicity, pharmacological interactions, resistance and lack of effect require new ideas for antiretroviral therapy.

[ 36 ], [ 37 ], [ 38 ]

Compliance with HIV treatment regimen

Highly active antiretroviral therapy has necessitated adherence to the treatment regimen to achieve good results. The consequence of non-adherence to the prescribed treatment regimen is the risk that the drug 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 drug resistance and negative consequences in terms of disease progression and death. Factors that influence the accuracy of drug intake by the patient are:

• stage of the disease, the patient must be aware of the danger posed by the disease and believe that compliance with 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 proposed to him;
• the relationship between the patient and the health care professional, the physician must monitor the need to consistently adhere to the prescribed course of treatment in view of the benefit to the patient and the course of the disease.

Initial antiretroviral therapy should be carefully selected taking into account the patient's wishes and lifestyle. The involvement 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 to be taken per day, the possibility of choosing convenient treatment options, the necessity of observing intervals between doses, dietary requirements and dietary restrictions. It is especially important to consider adverse reactions, as well as the possibility of drug interactions (see appendices). It is also necessary to take into account the limitations of drug storage conditions. Some drugs are stored in special conditions, which should be taken into account for those who take drugs outside the home. Some patients have difficulty swallowing, for whom drugs in liquid form should be selected.

One of the most important aspects is the alliance between the patient and the healthcare professional, based on respect for the parties and 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 specific patient, explain the prescribed instructions and provide reminders on adherence to the regimen and treatment schedule. It is advisable to check what the patient has remembered after each consultation. During subsequent observations, it is advisable to have close contact with the patient, the possibility of visiting or calling the patient to clarify difficulties in taking medications and adhering to the treatment regimen. It is necessary to follow the rule: provide the best medicine for a given patient, taking into account his or her lifestyle. A pharmacist, discussing with the patient all issues related to the medication taken, can play an important role and help the HIV-infected person achieve the best treatment outcome.

Reasons for low adherence to APT:

• the problem of the patient's psychological adequacy (depression, drug addiction, psychotropic side effects of drugs),
• a significant number of tablets to take daily (sometimes about 40),
• multiple doses of medications per day,
• difficult conditions for taking medications associated with:
  • time of day,
  • the presence, nature and time of food intake,
  • taking other medications,
  • the particularities of administration (for example, indinavir must be washed down with at least 1.5 liters of liquid, which, with 3 doses, is 4.5 liters every day),
  • large size of tablets and capsules,
  • unpleasant taste of drugs (ritonavir, for example, tastes like a mixture of alcohol and castor oil),
  • severe adverse reactions (especially from the central nervous system, lygudystrophy, hyperglycemia, lactic acidosis, hyperlipidemia, bleeding, osteoporosis, rash, etc.),
  • continued drug use.

Low adherence to therapy leads to:

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

Insufficient adherence to treatment is the main reason for the decrease in the effectiveness of ART. The most common reasons for poor adherence are: patients are very busy or forgetful (52%), being away from home (46%), lifestyle changes (45%), depression (27%), lack of medication (20%), etc. That is, the prevalence of violations of the prescribed treatment regimen ranges from 23% to 50%. A real way to improve adherence is to use simpler drug regimens, preferably with once-daily administration, for example, ddl (videx) 400 mg, lamivudine (epivir) 300 mg, zerit (stavudine) 1.0 per day, etc.

The once-daily regimen, as shown by N. Nelson (2002), is effective and well tolerated. Reducing the number of tablets facilitates administration, 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), class-specific side effects (characteristic for a class of drugs) and those characteristic for specific drugs within a class are distinguished.

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

Class-specific side effects of IPs include gastrointestinal disorders, hyperlipidemia, lipodystrophy, and decreased sensitivity of peripheral tissues to insulin. Metabolic disorders caused by IPs correlate with the duration of their use. Lipid metabolism disorders may be a risk factor in the development of cardiovascular diseases.

Approaches to reducing the side effects of APT: selection of drug combinations with minimal side effects, optimization of drug doses (use of monitoring), the possibility of a break in treatment, later initiation of therapy or alternating administration of different regimens, use of new, less toxic drugs or less toxic dosage forms.

The use of protease inhibitors has led to the development of lipodystrophy syndrome, which is characterized by a redistribution of fat deposits: loss of fat tissue in the face and fat deposition in the abdomen and neck (Buffalo hump) with breast enlargement, as well as diabetes and the risk of cardiovascular diseases. Reverse transcriptase inhibitors are less involved in this syndrome. The author provides a description of this syndrome taking into account other literature data. Physical and metabolic disorders in lipodystrophy syndrome

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

1. Reduction or loss of fat on the face, arms, legs.
2. Accumulation of fat on the abdomen, back of the neck (“Buffalo hump”), and chest in women.
3. Dry skin and lips.

B. Metabolic disorders

Hyperlipidemia is a specific effect of PIs. The duration of PI treatment is a significant risk factor for the development of metabolic disorders. Hypercholesterolemia develops in 26% of patients who took PIs for 1 year, in 51% after 2 years, and in 83% after 3 years. Lipodystrophy develops in more than 60% of patients who took PIs (Saag M.. 2002). Such patients have an increased risk of cardiovascular diseases. Symptoms are not a reason to discontinue protease inhibitors. It is necessary to decide on switching to naefavirenz or prescribing the protease inhibitor atazanavir, which does not cause lipopolydystrophy and is even able to correct the syndrome.

Drugs for the treatment of dyslipidemia:

• Statins - suppress cholesterol synthesis.

Fibrates - stimulate the activity of LP-lipase. Bile-adsorbing resins - increase the removal 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 carboxymethylcellulose and magnesium stearate.

Lipostat belongs to the class of HMG-CoA reductase inhibitors, new hypolipidemic agents that reduce cholesterol biosynthesis. These agents are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme 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 component of intervention to address multiple risk factors in individuals at increased risk of atherosclerotic vascular disease due to hypercholesterolemia.

Lipostat should be used in addition to a diet restricted in saturated fat and cholesterol in cases where the response to diet and other non-drug treatments is insufficient.

Method of administration and dosage. Before starting treatment with lipostat, the patient should be prescribed a standard diet to lower cholesterol. During treatment with the drug, the patient should continue to follow this diet. The recommended dose of lipostat is 10 to 40 mg, once a day before bedtime. The usual initial dose is 10-20 mg. If the serum cholesterol concentration is significantly elevated (for example, total cholesterol is more than 300 mg / dL), the initial dose can be increased to 40 mg per day. Lipostat can be taken regardless of meal time, and the daily dose can be divided into several doses. Since the maximum effect of the prescribed dose is manifested within four weeks, lipid levels should be regularly determined during this period and the dose should be adjusted accordingly, taking into account the patient's response to the drug and the established treatment rules.

Serious complications include osteopenia, osteoporosis and osteoneurosis. Patients with bone or joint pain are recommended to undergo X-ray examinations. Treatment is carried out using calcium-phosphorus and vitamin preparations. Surgical treatment is indicated for osteonecrosis and pathological fractures.

Guidelines for the integrated use of drugs

1. Expect deviations from the treatment regimen. Always assume that the treatment regimen will not be followed.
2. Consider treatment from the patient's perspective. Healthcare providers should understand the situation of each individual patient. The physician should be aware of the patient's expectations, goals, feelings, and views regarding the disease and treatment.
3. Develop a partnership between the patient and the physician. Responsibility for decisions made should be equally shared between the patient and the physician. This means that the patient should receive accessible, understandable information to be able to make adequate decisions regarding therapy.
4. Take a patient-oriented position. Patient satisfaction is the main criterion. The patient's questions, wishes and feelings should form the starting point of therapy. Any deviations should be discussed.
5. Individualize treatment. All aspects of therapy, all necessary aids for therapy should be discussed individually. Universal solutions should be avoided.
6. Involve family in joint work. Family and close friends should be involved in the treatment process for support. The patient should be helped not to abandon the social environment while fighting the disease.
7. Ensure duration and availability. The patient must be absolutely sure of the duration and availability of therapy.
8. Consider the services of other social and health professionals. A doctor can only provide one part of the professional help in combating the disease. Other specialists must be involved.
9. Repeat everything. Efforts to achieve collaboration within the therapeutic relationship must be made continuously throughout treatment.
10. Don't give up. The issue of compliance is extremely complex and multifaceted. The attitude towards illness and death is a fundamental theme in life, especially in the relationship between doctor and patient. Only in close and constant cooperation can doctor and patient achieve success.

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