Main targets of antiretroviral therapy. Can hiv infection be cured

I'll ask the question myself, and I'll answer it myself. :rolleyes: I think this is useful information
Replacement of antiretroviral therapy: why, when and how
As a rule, once started, antiretroviral therapy is not canceled. Often, its regimen has to be changed due to acute and long-term side effects, comorbidities, and inability to suppress HIV reproduction. However, in each individual case, the tactics depend on a number of circumstances, including why it is necessary to change the ART regimen, what antiretroviral drugs the patient has previously taken, and what treatment options remain. For example, if a drug in the first ART regimen caused a side effect, it is easy to replace it with another one. The situation is quite different in patients with advanced HIV infection, in whom a new regimen is required because many regimens have already been exhausted due to side effects, virological failure, and drug resistance. It describes the circumstances that require replacement of ART, data from clinical studies and tactics for switching to new regimens.
Acute side effects
Side effects of ART are common and sometimes lead to a drug change. They are rarely life threatening, but they can cause a lot of discomfort to patients, which negatively affects their desire to comply with the treatment regimen. A number of studies have shown that side effects cause changes in ART regimens more often than virological treatment failure. In these studies, the majority of drug changes due to drug intolerance occurred during the first 3 months of ART. The vast majority of patients in these studies received regimens based on protease inhibitors.
There are no unequivocal recommendations on when to change the ART regimen in case of side effects. Given that in many patients side effects improve within a few weeks of ART, doctors often prescribe short-term symptomatic treatments (eg, loperamide for diarrhea and prochlorperazine or metoclopramide for nausea). Efavirenz-induced CNS disturbances usually resolve on their own after a few weeks, and it is usually sufficient to explain this to the patient and reassure them. If an acute side effect occurs that is characteristic of a particular drug, that drug is usually replaced with another drug of the same class that does not cause such a side effect (for example, for gastrointestinal disorders caused by zidovudine, it is changed to abacavir or tenofovir).
The decision to switch antiretroviral drugs is based on the severity of side effects, the effectiveness of symptomatic therapy, options for substitution, and the associated risk. Side effects adversely affect adherence, and if a patient reports that they have started missing medications due to side effects, the doctor should consider changing the therapy regimen. According to available data, changing the initial ART regimen due to side effects does not lead to further virological treatment failure.
Long-term side effects
Some side effects develop months or even years after starting antiretroviral therapy. These include neuropathy, changes in body composition (lipodystrophy), and metabolic disorders that increase the risk of cardiovascular disease (particularly dyslipoproteinemia and insulin resistance). Therefore, when deciding which drug to replace with the development of long-term side effects, they rely on epidemiological data indicating the association of a side effect with a particular drug.
Lipoatrophy
Lipoatrophy (in particular, the loss of subcutaneous tissue on the face, limbs and buttocks) is one of the manifestations of lipodystrophy. A number of studies have shown that the use of thymidine analogues, especially stavudine, is a risk factor for lipoatrophy. Although the loss of adipose tissue is considered irreversible, a number of small studies have shown that replacing stavudine with zidovudine or abacavir can provide good results. Very notable are the results of one study in which patients with lipoatrophy were randomly divided into two groups: one group continued to receive stavudine or zidovudine, while in the other, thymidine analogues were replaced with abacavir. After 24 weeks, in patients treated with abacavir, computed tomography showed a statistically significant increase in subcutaneous tissue volume on the abdomen, and two-photon x-ray absorptiometry showed the same increase on the thigh. Although the changes that developed during this time were not clinically significant, follow-up over the next 2 years showed that the volume of adipose tissue increased even more. This suggests that such tactics are justified in patients who do not have contraindications to such substitutions, for example, a history of hypersensitivity to abacavir or confirmed resistance to it. In addition, in patients who have already received regimens with one or two nucleoside reverse transcriptase inhibitors, the risk of virological treatment failure when prescribing abacavir is increased, which may be due to the presence of mutations that cause resistance to drugs in this group, therefore it is undesirable to prescribe abacavir to such patients.
Observations show that protease inhibitors can exacerbate lipoatrophy that develops during treatment with nucleoside reverse transcriptase inhibitors. However, in general, substitution of a protease inhibitor with another drug is unlikely to result in clinically significant changes in adipose tissue volume, at least in the short term.
Trunk obesity
Epidemiological data link male-type obesity (increased visceral adipose tissue) with treatment with protease inhibitors. In one study in male-type obese patients, after replacing protease inhibitors with abacavir, nevirapine, adefovir, visceral fat volume decreased more than in the control group, who continued to receive protease inhibitors. However, in patients in whom protease inhibitors were replaced by other drugs, lipoatrophy increased. In a study of metabolic disorders in a large randomized trial 24 months after the replacement of protease inhibitors with abacavir, nevirapine or efavirenz, there was no marked improvement in the distribution of adipose tissue. In general, the benefit of replacing protease inhibitors with other drugs has not been proven, so such a replacement cannot be recommended as a treatment for visceral obesity. Today, other treatments for this condition are being actively explored.
Dyslipoproteinemia
Hypertriglyceridemia and hypercholesterolemia are clearly associated with certain protease inhibitors and may develop during the first weeks of treatment. These disorders can be eliminated if the drug that caused them is replaced with another protease inhibitor or drug of a different class. For example, in a small study, the replacement of ritonavir with nelfinavir or the combination of nelfinavir with saquinavir improved the plasma lipid profile. Nucleoside reverse transcriptase inhibitors can also cause dyslipoproteinemia in HIV-infected people. In two randomized controlled trials, stavudine (in combination with lamivudine and efavirenz or nelfinavir) affected lipid metabolism to a greater extent than zidovudine and tenofovir. In a number of studies, the replacement of stavudine with tenofovir reduced total cholesterol and LDL levels, but the effect of such a replacement on triglyceride levels was mixed.
Insulin resistance and diabetes
The effect of drug substitution on insulin resistance is less well understood than in the case of dyslipoproteinemia. Indinavir is well known to reduce insulin sensitivity in healthy, HIV-free volunteers. However, other protease inhibitors may have a direct or indirect effect on insulin sensitivity. There is evidence that replacing the protease inhibitor with abacavir, efavirenz, or nevirapine improves insulin resistance. Therefore, in patients with risk factors for diabetes mellitus (eg, obesity, family history of diabetes), substitution of the protease inhibitor with another drug is reasonable, although it is not clear to what extent this tactic helps to prevent diabetes mellitus. Since insulin resistance increases the risk of cardiovascular disease in general, reducing insulin resistance may reduce the risk of long-term complications.
Life-threatening side effects
Life-threatening side effects are rare but are an important reason for switching to ART. Severe toxidermia (eg, Stevens-Johnson syndrome or erythema multiforme exudative) is an absolute indication for ART replacement. Such toxidermia most often develops during the treatment of NNRTIs: delavirdine (rarely), efavirenz (0.1% of cases) and nevirapine (1% of cases). Lactic acidosis can be life threatening; it most often develops during treatment with stavudine, but it can be caused by any nucleoside reverse transcriptase inhibitors. Retrospective studies show that when clinical symptoms of hyperlactatemia and lactic acidosis appear, the suspected drug (usually stavudine or didanosine) can usually be replaced without any risk with another nucleoside reverse transcriptase inhibitor with similar virological activity, but with less pronounced mitochondrial toxicity (usually abacavir). , lamivudine or tenofovir). As a rule, before prescribing a new drug, they take a break in treatment so that unwanted symptoms disappear. Other life-threatening side effects are didanosine-induced pancreatitis and hypersensitivity to abacavir. When these complications occur, the drug that caused them is canceled and the patient is never prescribed again.
Switching ART in Viral Suppressed Patients
If viral replication is suppressed, it is important to consider how the patient was previously treated when considering changing ART for any of the reasons discussed above. If the patient has already experienced a virologic failure on NNRTI treatment (regardless of whether a drug resistance study has been performed or not), or if the isolated strain of the virus is confirmed to be resistant to this drug class, switching to nevirapine or efavirenz regimens is contraindicated in this patient. In addition, previous treatment with one or two nucleoside reverse transcriptase inhibitors increases the risk of virological failure when switching to abacavir due to the accumulation of mutations conferring resistance to the virus against nucleoside reverse transcriptase inhibitors. It is also important that when replacing protease inhibitors or NNRTIs with abacavir, a regimen with three nucleoside reverse transcriptases is usually prescribed, which, as an initial regimen, is inferior in virological activity to regimens based on efavirenz. When replacing protease inhibitors with abacavir, nevirapine, or efavirenz, the rate of virologic failure is increased. Thus, switching to a combination of three NRTIs without adding additional drugs is possible only in selected cases.
Accompanying illnesses
Often the need to change ART is dictated by changes in the patient's condition. For example, some antiretroviral drugs are undesirable during pregnancy. Efavirenz has been shown to be teratogenic in animals, and few cases of human birth defects have been reported, so if pregnancy occurs, the drug should be substituted with nevirapine or the woman should be given an appropriate protease inhibitor regimen. Nevirapine should be used with caution in pregnant women, as they have an increased risk of fatal hepatitis. The risk of this complication is particularly high in women with higher CD4 counts, so women with a CD4 count of more than 250 microliters of nevirapine are generally not prescribed. Amprenavir solution for oral administration is contraindicated in pregnant women, as it contains a large amount of polyethylene glycol. Hyperbilirubinemia caused by atazanavir and indinavir is theoretically dangerous for the newborn.
Drugs that are used to treat comorbidities often have drug interactions with antiretrovirals. A prime example is the interactions of rifampicin (a first-line drug for the treatment of tuberculosis) with NNRTIs and protease inhibitors. To avoid these interactions, it is possible to replace nevirapine with efavirenz, change the dose of efavirenz, or, in the case of treatment with protease inhibitors, replace rifampicin with rifabutin. Other important drug interactions include interactions of lipid-lowering agents (HMG-CoA reductase inhibitors) with protease inhibitors, oral contraceptives with NNRTIs and protease inhibitors, and ergot alkaloids with protease inhibitors. The activity of tenofovir, emtricitabine, and lamivudine against hepatitis B virus prompts the inclusion of these drugs in ART regimens for patients with chronic hepatitis B.
Insufficient immunological response
Some patients on ART do not have a significant increase in the number of CD4 lymphocytes, despite the suppression of the reproduction of the virus. In a Swiss cohort study, 38% of participants who achieved suppression of HIV reproduction for more than 5 years on ART failed to achieve an increase in the number of CD4 lymphocytes even up to 500 µl. Usually the causes of this phenomenon remain unknown, as well as its clinical significance, although it causes concern to both the patient and the doctor. There is no indication that boosting the regimen (adding antiretrovirals) improves the immunological response when there is insufficient CD4 lymphocyte growth.
Complications of HIV infection
Patients in whom ART suppresses viral reproduction rarely develop complications such as opportunistic infections and AIDS-defining malignancies. Little is known about changing the ART regimen in the event of an AIDS-defining illness. Undoubtedly, the regimen should be changed if the patient is viraemic and if there is a good alternative for maximum suppression of HIV reproduction and restoration of immunity. Other infections, such as herpes recurrences, shingles, pneumonia, and human papillomavirus infection causing dysplasia and cancer of the cervix and anus, may develop in patients with persistent viral suppression and are not an indication for switching ART.
Clinical manifestations of HIV infection shortly after initiation of ART (within the first 3 months) should be interpreted with caution. During this period, patients with low CD4 counts (especially <100 μl) at the start of ART may develop an immune reconstitution syndrome characterized by unusual manifestations of opportunistic infections (particularly those caused by atypical mycobacteria and cytomegalovirus) and progressive multifocal leukoencephalopathy. . The syndrome develops as a result of an improved immune response to a latent infection; exacerbations of infections do not mean the ineffectiveness of therapy, so it is not necessary to change it. In such cases, antimicrobial therapy and, if necessary, symptomatic treatment (for example, the appointment of glucocorticoids and other anti-inflammatory drugs) is necessary.
Replacement of ART for virological treatment failure
Therapeutic guidelines suggest the following criteria for virological treatment failure: HIV RNA >400 copies/mL after 24 weeks of treatment, HIV RNA >50 copies/mL after 48 weeks of treatment, or resumption of viremia after successful viral suppression. A single rise in the level of viral RNA must be confirmed by a second measurement, because a separate rise (“splash”) develops in almost 40% of patients and does not indicate a virological failure of treatment. If the increase in viral load is repeated or stable, the risk of virological failure is increased.
Reasons for treatment failure
If the patient fails to suppress the reproduction of the virus, you need to find out what caused it. If noncompliance, toxicity, and pharmacokinetic causes can be ruled out, failure may be attributed to the ineffectiveness of the current regimen. In case of treatment failure, first of all, it is necessary to carefully analyze which antiretroviral drugs in which dosage forms and combinations the patient received, the duration of treatment of each of the previous regimens, their side effects and the dynamics of viral load and CD4 lymphocyte count. This information is needed to assess the likelihood of mutations conferring resistance to individual drugs or entire classes of drugs. It is important that the patient continue on their current regimen while the cause of treatment failure is being clarified, as discontinuation of ART - even if it is virologically ineffective - can lead to a rapid increase in viral load, a decrease in CD4 counts, and the onset of clinical manifestations of HIV infection.
Drug susceptibility testing
A susceptibility study provides information only on the predominant strains of the virus circulating in the blood at the time of blood sampling for testing. If the drug to which resistance has developed is withdrawn, the strain carrying the resistance mutation will no longer predominate and become more difficult to detect. Therefore, the study of resistance should be carried out against the background of treatment with a regimen that turned out to be virologically ineffective. In separate studies, an ART regimen based on genotypic and phenotypic testing was significantly more effective than a regimen based on drug history alone. Current clinical guidelines suggest testing resistance in all patients who fail ART, but whether genotypic, phenotypic, or both should be preferred is not clear. The combination of a detailed drug history and drug resistance testing provides the most complete assessment of current and archived resistance mutations and allows the best choice of next ART regimen.
Pharmacokinetics
Virological response to treatment depends on the concentration of drugs in the blood. In addition, drug concentration is an independent predictor of virological response. With a greater number of active drugs (to which resistance has not been identified) and higher drug concentrations in the blood, the virological response to treatment is better.
Sufficient concentrations of antiretroviral drugs, especially protease inhibitors, can be achieved without their monitoring. Ritonavir, being a potent inhibitor of cytochrome P450 isoenzymes, at low doses increases the concentrations of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, saquinavir and tipranavir, as well as new protease inhibitors that are still being tested. Because drug resistance is relative, increasing drug concentrations may be sufficient to overcome partial drug resistance. For example, in a study in 37 patients treated with the standard indinavir-based regimen 3 times daily for viremia, serum indinavir concentrations increased 6-fold after the addition of ritonavir, and in 58% of patients (21 of 36) viral load through 3 weeks decreased by 0.5 lg or more or fell below 50 copies per 1 ml. The authors concluded that the increased concentrations of indinavir due to ritonavir were sufficient to overcome resistance to this drug.
There is an indicator that reflects both the concentration of the drug and the sensitivity of the isolated strain of the virus to it - the so-called suppression coefficient (IQ, from the English inhibitory quotient). It is the ratio of drug concentration to drug sensitivity (for example, the concentration of a protease inhibitor sufficient to suppress 50% of virus strains isolated from a given patient). A number of retrospective studies have shown that in patients who switched ART regimens, a higher suppression ratio had a better virological response, and that this ratio was a more valuable predictor of response to treatment than drug concentration and data on drug resistance to the drug, taken separately.
Selecting the next scheme
How to choose a new ART regimen when treatment has failed virologically? Previously, the tactics were simple: they prescribed drugs that the patient had not yet taken. However, even the first clinical studies have shown that with such tactics, the maximum suppression of virus reproduction was achieved only in 30% of patients. The same studies identified factors that improved virological response: low viral load at the time of switching therapy, the use of 2 protease inhibitors in the new regimen instead of one, and the use of a drug from a new class (for example, NNRTIs). In the early studies that looked at drug resistance, it was concluded that for a new ART regimen to achieve a good virological response in patients with virological treatment failure, it must contain at least three active antiretroviral drugs (i.e., drugs that sensitivity to which was confirmed in the isolated strain).
In clinical practice, it is often necessary to change the ART regimen both in patients with suppressed reproduction of the virus and in patients in whom it was not possible to suppress the reproduction of the virus. If viral reproduction is suppressed, the goal of switching ART is usually to eliminate acute and long-term side effects and improve the patient's quality of life. However, switching to ART is usually safe if treatment history and other considerations are taken into account. The benefit of switching ART should be weighed against the risk of new side effects and virologic failure.

Plays an important role. It is prescribed only by a qualified doctor based on tests, other clinical and laboratory studies, as well as the general condition of the patient. Of course, it is impossible to cure the disease completely with its help. But to alleviate the patient's condition and significantly extend his life - completely. Antiretroviral therapy is most commonly used for HIV infection. It implies an impact on several problems at once, which are carried by the immunodeficiency virus. When is such treatment used, and what types does it consist of?

HIV infection, ART therapy: general information

Therapy for AIDS has been developed for several decades. To date, it is high antiretroviral that is recognized as the most effective. Before describing its effectiveness and direction, it is necessary to find out when such treatment is started and for whom it is needed. It is known that antiretroviral therapy for HIV infection is not applied immediately after diagnosis. It would seem that an infected person should be treated immediately. But it's not. With such a diagnosis, it is very important not to harm the body with strong drugs. It is worth noting that approximately thirty percent of all those infected are carriers of the virus. They do not have an acute stage of the disease, and the incubation period immediately turns into a latent one, which lasts for decades. In such people, a terrible illness is diagnosed, as a rule, by chance, for example, in preparation for a planned operation, medical examination, and so on.

Taking HIV therapy in this case is considered inappropriate. Since the body does not respond to the presence of an infectious agent in it. The use of strong drugs can cause a weakening of the immune system. In some cases, this can backfire. Then a person from a carrier of the virus will turn into an infected person with all the accompanying symptoms. AIDS therapy is not used even in the asymptomatic stage. We are also talking about patients in whom the acute stage appears "in all its glory." Treatment in their case directly depends on how the infected organism behaves.

Throughout the latent stage, such patients regularly visit a doctor and take tests. The decision on whether antiretroviral therapy for HIV is necessary in each case is made by a specialist based on some research. What is taken into account when making such a decision? viral load. With regular sampling of tests in an infected patient, the viral load per milliliter of blood is determined. While it is within the normal range, the asymptomatic stage continues. An organism with strong immunity manages to produce the right amount of antibodies that resist the virus. In this case, therapy for HIV infection is not needed.

In addition to the viral load, the immune status is also taken into account. We are talking about the quantitative composition of CD-4 cells. It is also determined through blood sampling. There are cases when the immune status and viral load are normal, but the patient gradually begins to show signs of secondary manifestations. This includes both comorbidities and opportunistic infections. In these cases, antiviral and retroviral therapy for HIV is necessary. And the sooner treatment begins, the better the prognosis. It is important to take into account that when deciding on the appointment of certain drugs, the doctor necessarily looks at the dynamics of the immune status and viral load. The specialist needs to analyze how the patient's condition changes over several months.

Based on the monitoring of the state of the immune system, a decision is made on what kind of therapy for HIV-infected people is necessary at this stage of the course of the disease. Only a doctor should prescribe treatment. After all, for each patient, it is selected depending on the characteristics of the body and the results of the tests.

HIV - therapy regimens: antiviral, immune and clinical orientations

It should be noted that HAART therapy used in HIV has several goals at once. It has a virological, general strengthening immune and clinical focus. Each of them should be considered in more detail. Antiretroviral drugs for HIV are taken in combination. The doctor prescribes several medicines to the patient at once. Usually we are talking about three or four drugs. Virological agents for HIV and AIDS are prescribed as a therapy that pursues not only the goal of suppressing the immunodeficiency virus itself.

As a rule, antiviral drugs are also needed in order to reduce the impact on the body of concomitant diseases, if they have already manifested themselves. If the doctor decides to use such drugs even at the asymptomatic stage, then the patient needs a powerful course of medications that suppress infected cells. Most often, such a need arises when the viral load significantly exceeds the norm. In this case, one cannot do without treatment, which implies such AIDS therapy.

So, the main task of the antiviral effect on the body of an infected person is to reduce the production of infected cells and reduce their spread. The course of such antiviral therapy for HIV lasts, as a rule, from sixteen to twenty-four weeks. In this case, the effect of suppression can be observed as early as the sixth week.

Immunological initiation therapy for HIV is necessary in order to restore the immune system. She suffers greatly with an increase in viral load. The immune status at the same time does not correspond to the norm. Taking drugs that restore the immune system allows you to increase the number of CD-4 cells to normal.

Clinical ART therapy for HIV includes drugs that can extend the life of infected patients not by a year or two, but by decades. At times, the risk of developing AIDS, which, as you know, quickly ends in death, is reduced. With this HIV treatment, HAART makes it possible for infected partners to conceive a child relatively safely. The risk of transmitting the virus through blood or through sexual contact is also reduced.

The initiation and side effects of HIV therapy are closely related

It is the specialist who decides when to start therapy for HIV, therefore, immediately after the diagnosis, you need to go to a specialized hospital. However, the effectiveness of treatment largely depends on the person's lifestyle and adherence to medical prescriptions, and, of course, on what kind of therapy is prescribed for HIV. Here are a few helpful tips to help infected individuals start the treatment prescribed by their doctor:

It should be remembered once again that adherence to HAART for HIV infection is one of the important components of successful treatment.

Side effects and consequences of HIV therapy

HAART is a highly effective treatment, with the help of which the latent period of the immunodeficiency virus can last for decades, and AIDS does not develop at all. However, this approach to maintaining and restoring an infected organism, unfortunately, is not ideal. All drugs, the use of which he implies, are toxic. Of course, this affects the internal organs and vital systems of the human body. That is why, before AIDS-preventing antiretroviral therapy is prescribed, the patient must undergo a lot of examinations and pass the necessary tests. This is necessary so that the attending physician can choose the most appropriate scheme. Regular visits to a specialist and a clear clinical picture will help the patient successfully balance the line between suppressing the virus and the harm that drugs can cause.

Doctors, when prescribing therapy for HIV, always warn the patient about possible side effects. This is extremely important, if only so that the patient can distinguish the consequences of taking drugs with dangerous symptoms that can occur if the effectiveness of the treatment decreases. It is important to note here that antiretroviral therapy for HIV-infected patients is a treatment that is well tolerated by most patients. Although it is often compared to chemotherapy, side effects from its use are much less frequent and much easier.

Nausea and vomiting are the most common signs of a reaction to HAART. They can haunt the patient constantly or appear only occasionally. As a rule, nausea and vomiting appear in the first weeks of treatment. The doctor should warn the patient about this when it will be necessary to start therapy for HIV.

Another common side effect is diarrhea. It occurs due to the fact that drugs for the treatment of the immunodeficiency virus disrupt the flora in the intestine. That is why, in HIV therapy, the effects on the intestines should be eliminated by taking prebiotics. On the part of the gastrointestinal tract during the use of such drugs, there may also be anorexia, pain in the epigastric region. If the patient had an undiagnosed ulcer, then such treatment can cause stomach bleeding.

Side effects of HIV therapy can also be observed in the central nervous system. This is a rather rare phenomenon, which occurs in only five percent of those infected.

There are a number of contraindications for HAART. So, for example, alcohol should not be taken at least a few days before it starts. It is not used in acute renal failure or gastric bleeding. ART therapy for HIV should only be initiated with fever if it is a consequence of one of the comorbidities. If this symptom manifested itself due to a disease that is not related to the immunodeficiency virus, then it should be eliminated before starting treatment.

Gene therapy for HIV 2016: effective or not?

Gene therapy for the immunodeficiency virus has been developed relatively recently. In 2016, it was adopted by some clinics in our country. Such HIV therapy is expensive in Russia, while its effectiveness is little trusted by some specialists qualified in the treatment of the immunodeficiency virus. Perhaps the reason is that not too much research has been done on the new method. Whether gene therapy helps with HIV is a question that is still difficult to answer.

It is based on the use of enzymes that remove infected tissue from the body. Some scientists believe that such a method of treatment can cause irreversible consequences. After all, intervention in the body at the gene level is always unpredictable. Which is better to drink HAART therapy for HIV infection should be decided by a qualified specialist.

Physiotherapy for HIV Infection and Other Alternative Therapies

Physio-methods are not used as a treatment for the immunodeficiency virus. This type of therapy can be used to alleviate the symptoms of diseases caused by damage to the central nervous system.

Psychotherapy for HIV infection brings tangible results. Some patients need it, because it is extremely difficult to live with such a diagnosis. Much depends on the psychological state of the patient, including how HAART will affect his body.

Some private clinics today offer a service such as ozone therapy for HIV infection. Qualified specialists consider it insufficiently effective.

Antiretroviral Therapy (ARVT) and Hepatotoxicity: The Dangers Your Liver Exposes

Original article in English http://www.aidsmeds.com/articles/Hepatotoxicity_7546.shtml
Translation: Demyanuk A.V. http://u-hiv.ru/hiv_livehiv_arv-hepatotoxity.htm

Introduction
The liver is one of the largest and most important organs in the human body. It is located behind the lower right ribs and performs many functions that help our body stay healthy. Here are some of its many features:

Preservation of important nutrients from food;
The formation of chemicals necessary for the body to maintain health;
Destruction of harmful substances such as alcohol or other chemical compounds;
Removal of by-products from the blood.

For HIV-positive people, the liver is critical because it is responsible for making new proteins needed by the immune system to help the body fight infection and process drugs used to treat HIV and AIDS-related infections. Unfortunately, these same drugs can also destroy the liver, preventing it from doing what it needs to do, and eventually leading to its destruction.

Hepatotoxicity- the official name for the process of destruction of the liver under the influence of drugs and other chemicals. This course is designed to help readers better understand the phenomenon of hepatotoxicity, including how drugs destroy the liver, factors that increase your risk of developing hepatotoxicity, and some of the ways you can control and protect your liver health. If you have concerns or questions about hepatotoxicity, especially with the antiretroviral (ARV) drugs you are taking, feel free to discuss them with your healthcare provider.
How can antiretrovirals damage the liver?
Even though HIV drugs are meant to improve health, the liver recognizes them as toxic compounds. In addition, they are not substances naturally produced by the body and contain certain chemicals that are potentially harmful to the body. Together with the kidneys and other organs, the liver processes drugs, reducing their harmfulness. When processing, the liver can be “overloaded”, which leads to its destruction.
HIV drugs can produce liver damage mainly in two ways:
1. Direct destruction of liver cells
Liver cells, called hepatocytes, play an extremely important role in the functioning of the entire organ. If these cells are under heavy stress due to the removal of chemicals from the blood, or if they are harmed by infections (for example, the hepatitis C virus), abnormal chemical reactions can begin in them, leading to destruction. This can happen for three reasons:

Overdose. If you take an overdose of an ARV or other drug (i.e., take a large number of pills instead of the prescribed one or two), this can lead to very rapid, sometimes quite severe, destruction of liver cells. An overdose of almost any drug can cause a destructive effect of this type in the liver.

Taking the usual dose of the drug for an extended period of time. If you take medication regularly for a long time, you are also at risk of destroying your liver cells. This effect may appear if you take certain medicines for several months or years. Protease inhibitors can cause destruction of liver cells if taken for a long time.
Allergic reaction. When we hear the expression "allergic reaction" we usually imagine itchy skin or watery eyes. However, an allergic reaction is also present in the liver. If you are allergic to any drug, your immune system, reacting to the interaction of major liver proteins with the drug, causes an inflammatory process in it. If you do not stop taking the drug, inflammation increases, thereby destroying the liver. Two anti-HIV drugs are known to cause a similar allergic reaction (sometimes called “hypersensitivity”) in HIV-positive people: Ziagen (abacavir) and Viramune (nevirapine). Such an allergic reaction usually appears within a few weeks or months from the start of the drug and may also be accompanied by other allergic symptoms (for example, fever or rash).
Non-allergic destruction of the liver. Some drugs can cause liver damage unrelated to an allergic reaction or overdose. The specific anti-HIV drugs Aptivus (tipranavir) and Prezista (darunavir) can cause severe liver damage, albeit in a small group of people, namely those with hepatitis B virus (HBV) or hepatitis C virus (HCV).
2. Lactic acidosis
Nucleoside reverse transcriptase inhibitors (NRTIs) are not processed by the liver, they are removed from the blood and from the body by the kidneys. Therefore, many experts consider it unlikely that they have a damaging effect on the liver. However, it is also known that drugs can cause the destruction of "cellular mitochondria" - intracellular "power plants" that convert nutrients into energy. As a result, the level of lactic acid, a by-product of cell activity, rises. With an excessively high level of lactate, a disease called lactic acidosis occurs, which results in various problems in the functioning of the liver, including an increase in the level of fatty tissue, inflammatory processes in the liver and adjacent departments.
How to identify the destructive effect on the liver of antiretroviral drugs?
The best indicator for the presence of hepatotoxicity is an elevated level of certain liver enzymes in the blood. The most important enzymes are: AST (aspartate aminotransferase), ALT (alanine aminotransferase), alkaline phosphatase and bilirubin. The level of these four enzymes is included in the standard set of parameters of the "chemical panel" - a test, most likely ordered by your doctor every time you have a blood for CD4 cells and viral load.
If you or your doctor have any reason to suspect that you have drug-related liver damage, a blood test should be done. Early detection of hepatotoxicity always prevents further deterioration and promotes liver healing.

In most cases, hepatotoxicity develops over several months or years and usually begins with a mild increase in AST or ALT levels that progresses over time. In general, you can tell if your AST or ALT is elevated but not more than five times normal (for example, AST over 43 IU/L but below 215 IU/L or ALT over 60 IU/L but below 300 IU/L), you have mild or moderate hepatotoxicity. If you have an AST level above 215 IU/L or an ALT level above 300 IU/L, the hepatotoxicity is severe and can subsequently lead to permanent liver damage and serious problems.

Fortunately, as mentioned above, the vast majority of physicians routinely order a blood chemistry test (every three to six months) and can usually detect mild to moderate hepatotoxicity (which is most often reversible) before it progresses to a severe form. However, an allergic reaction in the liver to some of the drugs, such as Ziagen (abacavir) and Viramune (nevirapine), can lead to a sharp increase in enzyme levels soon after the start of treatment. In turn, it is very important that your doctor checks your enzyme levels every two weeks for the first three months of taking one of these drugs.

Elevated enzyme levels rarely make themselves felt. In other words, you may not experience any physical symptoms even if your enzyme levels are elevated. Therefore, it is very important that you and your doctor monitor your enzyme levels regularly with blood tests. On the other hand, people with severe hepatotoxicity develop symptoms similar to those of viral hepatitis (eg, B or C). The symptoms of hepatitis are as follows:

anorexia (loss of appetite);
discomfort (feeling unwell);
nausea;
vomit;
discolored stool;
atypical fatigue/weakness;
stomach or abdominal pain;
jaundice (yellowing of the skin and whites of the eyes);
loss of addiction to cigarettes.

If you have any of these symptoms, it is very important to tell your doctor or other health care provider.
Do all patients taking antiretroviral ARV drugs develop hepatotoxicity?
No, not everyone. A number of studies have been conducted that determined the percentage of patients who developed hepatotoxicity as a result of taking various ARV drugs. One detailed study, conducted by the National Institutes of Health, measured the number of cases of hepatotoxicity in 10,611 HIV-positive people who took part in government-funded clinical trials conducted from 1991 to 2000. As a result, 6.2% of clinically tested participants developed severe hepatotoxicity. Among patients taking one of the non-nucleoside reverse transcriptase inhibitors together with two nucleoside analogues, severe hepatotoxicity occurred in 8.2% of cases. Among participants who took protease inhibitors concomitantly with two nucleoside analogs, 5% developed severe hepatotoxicity.

Unfortunately, clinical studies do not always reflect the real state of affairs. In many of the clinical studies, participants were followed up for one year, while HIV-positive patients need to take these drugs for many years, which increases the risk of hepatotoxicity. Moreover, for most of the studies, participants were selected who did not have other diseases that could increase the risk of developing hepatotoxicity. For example, it is believed that women and people over 50 are more likely to develop hepatotoxicity. Weight and alcohol abuse also increase the possibility of hepatotoxicity. With a high degree of probability, hepatotoxicity will be affected by HIV-positive people who are also infected with hepatitis B or C than those with only HIV.
I have HIV and hepatitis C. Can I take ARVs?
Yes. If you have chronic hepatitis B or C—two types of viral infections that cause liver inflammation and destruction—you can take anti-HIV drugs. However, it is important to understand that you are at greater risk of liver damage than if you were taking antiretrovirals and had only one of these infections.

Despite the fact that a fairly large number of studies have been conducted to determine the proportion of cases of hepatotoxicity in patients co-infected with HIV and hepatitis B or C, taking anti-HIV drugs, often the results are conflicting. For example, one study conducted by the Community Health Network, San Francisco, showed that the only anti-HIV drug that significantly increased the risk of heptotoxicity in patients with HIV and one of the hepatitis B or C was Viramune (nevirapine). But there are also studies showing that Viramune causes hepatotoxicity to the same extent as other anti-HIV drugs. It is still important to monitor the increase in liver enzyme levels during the first three months of treatment with Viramun.

There have also been several studies with protease inhibitors showing that Norvir (ritonavir) is most likely to cause hepatotoxicity in HIV-positive patients also infected with hepatitis B or C. However, Norvir is rarely given at the approved dose (600 mg twice daily). ). A much lower dose (100 or 200 mg twice daily) is usually used because the drug is most commonly prescribed to increase blood levels of other proteinase inhibitors. This, in turn, probably reduces the risk of hepatotoxicity in patients infected with HIV alone or infected with both HIV and hepatitis B or C. It is recommended that Aptivus or Prezista be used with extreme caution in patients with HIV or hepatitis C, especially if they already have even moderate liver damage.

What is clear is that patients infected with both HIV and hepatitis C or B must work closely with their physician to develop a safe and effective treatment regimen. For example, many experts now believe that if you have HIV and hepatitis C, you should start treatment for hepatitis C while your CD4 count is still high, before taking the course of treatment needed for HIV. Successful treatment or control of hepatitis C appears to be the best way to reduce the risk of hepatotoxicity once antiretroviral therapy has been started.

It is equally important to carefully monitor the state of the liver throughout the course of treatment with ARV drugs. You should check your liver enzyme levels before starting anti-HIV treatment. Even if it is higher than normal due to the presence of hepatitis B or C, you can more carefully monitor this indicator throughout the course of treatment.
Are there ways to restore liver function or prevent hepatotoxicity?

(See also: Alcohol contributes to the development of HIV infection)

Liver and diet
The liver is not only responsible for processing drugs, it must also process and detoxify the food and fluids we eat and drink on a daily basis. In fact, 85% to 90% of the blood that moves from the stomach and intestines contains nutrients derived from the fluids and foods we consume for further processing in the liver. Thus, a carefully balanced diet is a wonderful way to help the liver relieve stress and keep it healthy. Take into account a few tips:

Eat plenty of fruits and vegetables, especially dark green leafy vegetables and orange and red fruits.
Cut down on fats that put a lot of stress on the liver, such as those found in dairy products, processed vegetable oils (hydrogenated fats), heavily fried foods, stale or rancid foods, canned foods, and fatty meats.
Focus on eating the “right fats,” which contain essential fatty acids. Such as are found in cold-pressed vegetable oils from seeds, avocados, fish, flaxseed, raw nuts, seeds, legumes. It is believed that the right fats are not only easily processed by the liver, they are also involved in the construction of complete cell membranes around liver cells.
Try to avoid artificial chemicals and toxins such as insecticides, pesticides, artificial sweeteners (especially aspartame) and preservatives. Also, be careful when drinking coffee. Many nutritionists recommend no more than two cups of coffee a day, brewed from real coffee, not instant coffee powders. Recent studies also suggest that moderate coffee consumption actually has positive effects on the liver.
Eat a variety of proteins with grains, raw nuts, seeds, legumes, eggs, seafood and, if desired, plenty of chicken, fresh lean red meat. If you are a vegetarian, please note that the diet should be supplemented with vitamin B12 and carnitine to boost metabolism and avoid fatigue.
Drink plenty of fluids, in particular water, at least eight glasses. This is a must, especially if you are taking ARVs.
Be careful with raw fish (sushi) and shellfish. Sushi can harbor bacteria that can harm the liver, and shellfish can contain the hepatitis A virus, which causes severe liver damage in people who are not vaccinated against the disease. Avoid eating wild mushrooms. Many types of forest mushrooms contain toxins that cause severe liver damage.
Be careful with iron. Iron, a mineral found in meats and fortified cereals, can be toxic to the liver, especially in patients with hepatotoxicity or infectious diseases that can cause hepatitis. Foods and kitchen utensils - like iron pans - high in iron should be used wisely.
Vitamins and minerals are shown for the health of your liver. Many nutritionists recommend looking in grocery stores for the following types of foods:
Vitamin K. Leafy vegetables and sprouted alfalfa are rich sources of this vitamin.
Arginine. Sometimes it is difficult for the liver to cope with the processing of proteins. This can cause an increase in the level of ammonia in the blood. Arginine, found in beans, peas, lentils and seeds, helps cleanse the body of ammonia.
Antioxidants. Antioxidants neutralize active destructive compounds called free radicals, which are produced in excess by highly active organs (such as the liver, especially if it processes drugs daily). Antioxidant-rich fruits and vegetables such as carrots, celery, beets, dandelions, apples, pears and citrus fruits. Another powerful antioxidant, selenium, is found in brazil nuts, brewer's yeast, seaweed, brown rice, liver, molasses, seafood, sprouted wheat, whole grains, garlic, and onions.
Methionine. A detoxifying agent found in beans, peas, lentils, eggs, fish, garlic, onions, seeds and meat.

Liver and Dietary Supplements and Herbs

Some Complementary and Alternative Therapies (CAMS) are offered to prevent and control liver damage. Milk thistle (Sylibum marianum) is the most commonly used and studied adjunctive therapy for liver disease, but studies have not yet conclusively shown that it can prevent, halt, or reverse liver damage in patients with hepatitis. According to the National Center for Complementary and Alternative Medicine (NCCAM) of the US National Institutes of Health (NIH), there is insufficient evidence that milk thistle can be recommended for the treatment of hepatitis C or other diseases that cause liver damage. HCV Advocate, a non-profit organization for people with hepatitis C, speaks about the safety of the drug and recommends milk thistle, provided that the patient taking the drug informs the attending physician and is aware of the possible interaction with other drugs, and also does not use it as a replacement therapy for hepatitis C .

N-acetyl-cysteine ​​(NAC) is another adjuvant commonly used to treat liver toxicity due to acetaminophen (Tylenol) overdose. Again, there are no conclusive studies on the use of NAC to treat other types of liver damage.

It must be remembered that the mere fact that complementary therapies can be obtained without a prescription does not mean that they are always safe to use. Some of the additional medicines may have certain side effects. Also, consumer advocacy organizations that have performed spot checks on various herbs and supplements have found that they often contain much more or less active ingredients than what is listed on the packaging. Check with your healthcare professional before starting any additional therapy.

Some of the herbs that have been linked to liver damage and should be avoided are blue-green algae, borage (Borago officianalis), boletus, chaparral (Larrea tridentata), comfrey (Symphytum officinale and S. uplandicum), angelica (Angelica polymorpha), dubrovnik (Eucrium chamaedrys), sawtooth club moss (Lycopodium serratum), kava, mistletoe (Phoradendron leucarpum and viscum album), pennyroyal (Mentha pulegium), sassafras (Sassafras albidum), shark cartilage, broadleaf skullcap (Scutellaria lateriflora) and valerian. This is a partial list of herbs with known or suspected liver toxicity.

HIV nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine, phosphazid, stavudine, didanosine, zalcitabine, abacavir

Non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs): nevirapine, ifavirenz

HIV protease inhibitors (PIs): saquinavir, indinavir, ritonavir, nelfinavir, amprenavir

Combination drugs (lamivudine/zidovudine)

Mechanism of action. NRTIs block HIV reverse transcriptase and selectively inhibit viral DNA replication. NNRTIs block RNA- and DNA-dependent polymerase. PIs block the active site of the HIV protease.

Pharmacokinetics.

Table 26.13. Pharmacokinetic characteristics of some ARPs

A drug	Bioavailability, %		Metabolism	breeding
Zidovudine			Liver (P450)
Ifavirenz			Liver (inductor P450)
indinavir			Liver (P450 inhibitor)

Unwanted reactions. Poor tolerability of ARP is one of the most important reasons for low therapy compliance and high rate of ARP withdrawal. For NRTIs, mitochondrial toxicity, lactic acidosis, peripheral neuropathy, and bone marrow depression are more common; for NNRTIs - CNS lesions; for IP - lipodystrophy, hyperlipidemia, nephrolithiasis.

drug interactions. You can not prescribe drugs from the NRTI group, which are analogues of the same nucleotide. It is necessary to pay attention to whether ARP is an inducer, inhibitor or substrate of the cytochrome P450 system.

Indications. Treatment and prevention of HIV infection.

Contraindications. Hypersensitivity, breast-feeding, pregnancy, renal, hepatic insufficiency.

Features of clinical use in various categories of patients. The appointment of zidovudine to pregnant women infected with HIV significantly reduces the risk of infection of the child. Zidovudine, didanosine, stavudine, abacavir, nelfinavir, ritonavir, ifavirenz, amprenavir, zalcitabine, saquinavir are approved for use in children.

Chemoprophylaxis of parenteral HIV infection

It is used when medical workers receive injuries with an instrument contaminated with HIV. If more than 72 hours have passed since the moment of possible infection, chemoprophylaxis is considered inappropriate. The scheme is chosen depending on the characteristics of the patient-source of HIV infection.

Basic mode: zidovudine 0.6 g/day in 2-3 divided doses + lamivudine 0.15 g every 12 hours

Advanced mode: one of the basic regimens + indinavir 0.8 g every 8 hours or nelfinavir 0.75 g every 8 hours or 1.25 g every 12 hours or ifavirenz 0.6 g once a day or abacavir 0.3 g every 12 hours.

26.3. Antifungal drugs Indications for use in dentistry

In dental practice, antifungal drugs are most often used topically for the treatment of oral candidiasis, which refers to superficial candidiasis. The latter are characterized by damage to the mucous membranes (oral cavity, esophagus, vagina) and skin. With impaired immunity, the infection acquires a chronic course, and can go into a systemic form with damage to internal organs. The most severe form is invasive candidiasis. For systemic lesions other than C. albicans pathogens such as Aspergillus spp ., Rhizopus spp. , Fusarium spp . and other mushrooms.

Yeast fungi of the genus Candida are permanent residents of the oral cavity. Against the background of the use of antibiotics and immune disorders (diabetes mellitus, cancer, taking immunosuppressive drugs, HIV infection), they can cause oral candidiasis, which manifests itself in the form of aphthous stomatitis, candidal leukoplakia, "prosthetic" stomatitis, drug-induced stomatitis and mucocutaneous forms of injury. Cadidal stomatitis may be a manifestation of a systemic fungal infection.

Classification

Antifungal drugs, depending on the chemical structure, are divided into several groups that differ in the spectrum of activity, pharmacokinetics, tolerability and indications for use (see tab. 26.14).

Table 26.14. Classification of antifungal drugs

		REPRESENTATIVES
		Nystatin
		Natamycin
		Amphotericin B Liposomal Amphotericin B
	For systemic use	Ketoconazole
		Fluconazole
		Itraconazole
	For topical application	clotrimazole Miconazole
		Bifonazole
Allylamines		Terbinafine
		Naftifin
Echinocandins		Caspofungin

The value of drugs such as potassium iodide, griseofulvin, chlornitrophenol, flucytosine has now significantly decreased.

Indications for starting ART include:

the presence of clinical symptoms of secondary diseases, which indicates the presence of immunodeficiency;

decrease in the number of CD4-lymphocytes in the blood;

the presence of active HIV replication, assessed by the level of HIV RNA in blood plasma.

In the absence of clinical symptoms of secondary diseases, the main criterion for initiating ART in patients with chronic HIV infection is the number of CD4-lymphocytes. Almost all experts are unanimous in their opinion that when the number of CD4-lymphocytes is less than 200/µl, treatment should be started immediately.

Almost all recommendations specifically emphasize that the patient must be ready to start treatment, understand its goals and be committed to therapy, i.e. take the medicines prescribed by the doctor in the indicated dosage, at certain time intervals, and also in accordance with the recommendations for taking food, liquids and other drugs and nutritional supplements (possible drug interactions). Treatment is prescribed only after the patient signs the voluntary informed consent form.

In addition to the presence of clinical symptoms of secondary diseases, a decrease in the number of CD4-lymphocytes less than 350/ml, the criterion for ART prescription is a high level of viral load (HIV RNA over 100,000 copies/ml).

Doctors face particular difficulties when deciding whether to prescribe ARVT to a patient who has been diagnosed with acute HIV infection. Currently, there is no consensus among experts on the advisability of using ARVT in the acute period of HIV infection.

In accordance with Russian recommendations, treatment for patients in the acute period of HIV infection is indicated if the patient has a decrease in the number of CD4-lymphocytes less than 1200/ml (stages 2A and 2B) or if the stage of HIV infection is 2B (acute HIV infection with secondary diseases) and at the same time, the number of CD4-lymphocytes was reduced to less than 350/µl. The duration of antiretroviral therapy in patients with acute HIV infection is usually 6 to 12 months.

1. First line arvt regimens

The basic regimen is the regimen that is prescribed to most patients. Alternative regimens include ART regimens used for special categories of patients due to the inability to assign them a basic regimen due to contraindications. First-line ARVT regimens are regimens given to patients who have not previously received ART. Second-line regimens are ART regimens used in case of failure of the first-line therapeutic regimen.

Most of the existing recommendations suggest that the preferred first-line ART regimen should include 2 drugs from the group of nucleoside HIV reverse transcriptase inhibitors (NRTIs) and 1 boosted HIV protease inhibitor (PI) or non-nucleoside HIV reverse transcriptase inhibitor (NNRTI - efavirenz or nevirapine). Regarding the combination of NRTIs, almost all experts advise the use of combination drugs that include 2 NRTIs. Doctors currently have 3 drugs containing 2 NRTIs in their arsenal: Combivir (zidovudine + lamivudine), Kivexa (lamivudine + abacavir) and Truvada (tenofovir + emtricitabine).

The advantages of these combined drugs include taking 1 capsule 1 time per day, regardless of food intake, and no effect on hematopoiesis. The most significant undesirable effect when using Kivexa is the development of a delayed-type hypersensitivity reaction (DTH) to abacavir.

Given the above data, the optimal choice for the initial combination of two NRTIs in Russia is Combivir (zidovudine + lamivudine), which is prescribed 1 tablet 2 times a day. In the presence of anemia or neutropenia, phosphazide or stavudine in combination with lamivudine can be used instead of zidovudine.

When using other combinations of drugs from the NRTI group, the presence of drug interactions between drugs should be taken into account:

With the simultaneous administration of didanosine and stavudine, the risk of developing lactic acidosis increases significantly. The combination of these drugs is contraindicated in pregnant women;

If a patient has polyneuropathy, the combination of didanosine and abacavir leads to a significant increase in it;

The combination of tenofovir and didanosine significantly increases the concentration in the blood of the latter, which leads to an increased risk of developing pancreatitis and peripheral polyneuropathy. In addition, this combination of drugs leads to a weak immunological response to ART;

Combinations of zidovudine (or phosphazide) + stavudine and lamivudine + emtricitabine should not be used because these drugs are thymidine and cytidine nucleoside analogs, respectively. With the simultaneous use of these drugs, the effectiveness of treatment is reduced, since they compete with each other for intracellular enzymes that carry out the process of drug phosphorylation.

Experts suggest including either an NNRTI drug or a ritonavir-boosted PI as the third drug in the ART regimen. Among the drugs from the NNRTI group, it is recommended to include nevirapine or efavirenz in the first-line ARVT regimen, with efavirenz being preferred. A significant limitation in the use of nevirapine is the high content of CD4-lymphocytes (more than 250/ml in women and 400 in men), which significantly increases the incidence of severe hepatotoxicity. Efavirenz is not recommended for pregnant women and women planning a pregnancy due to the increased likelihood of developing fetal pathology (especially when using the drug in the first trimester of pregnancy).

ART regimens differ in their safety profile, i.e. the frequency and severity of certain adverse events. It is this indicator that can be decisive in the preparation of a therapeutic regimen for a particular patient. In addition, the convenience of taking drugs, the presence of concomitant diseases or conditions, as well as possible drug interactions between ARVs and drugs that the patient is taking, are also taken into account. From the point of view of the optimal combination of efficacy and ease of administration, an ARVT regimen that includes tenofovir, emtricitabine, and efavirenz has a certain advantage. The combination drug Atripla contains all these three drugs in 1 tablet, which the patient takes 1 time per day, regardless of food and liquid intake.

In Russian recommendations, one of the main criteria for choosing a preferred first-line ART regimen is the cost of the ART regimen. When choosing a basic first-line ARVT regimen, Russian specialists took into account, in addition to cost, effectiveness, safety, tolerability, ease of administration, as well as the presence of this regimen in foreign recommendations. According to Russian guidelines, the preferred ART regimen is Combivir (zidovudine + lamivudine) and efavirenz (2 NRTIs + NNRTIs). The patient needs to take 1 tablet in the morning and 2 tablets in the evening, while the cost of such an ART regimen, under the National Project, is less than 1800 US dollars per year.