What are Antiretroviral Drugs?

Acquired immunodeficiency syndrome (AIDS, AIDS) is a serious infectious disease caused by the human immunodeficiency virus (HIV). HIV is a retrovirus. The reverse transcription process is the process of synthesizing proviral DNA using viral RNA as a template under the action of viral reverse transcriptase. Antiretroviral drugs are a class of drugs used to treat retroviral (mostly HIV) infections.

Acquired immunodeficiency syndrome (AIDS, AIDS) is a serious infectious disease caused by the human immunodeficiency virus (HIV). HIV is a retrovirus. The reverse transcription process is the process of synthesizing proviral DNA using viral RNA as a template under the action of viral reverse transcriptase. Antiretroviral drugs are a class of drugs used to treat retroviral (mostly HIV) infections.

Drug Name

Antiretroviral drugs

Whether prescription drugs

prescription

Main indications

HIV and other reverse infections

Dosage form

injection

Antiretroviral drugs

Antiretroviral drugs are a class of drugs used to treat retroviral (mostly HIV) infections. The combination of several (usually three or four) antiretroviral drugs is called Highly Active Anti-Retroviral Therapy (HAART) ^[1] . The National Institutes of Health (NIH) and some other organizations recommend that patients with AIDS-related symptoms be treated with antiretroviral drugs. However, due to the complex combination and administration of the drug, the possible serious side effects, and more importantly the resistance of the virus to the drug, these organizations also emphasize the need to analyze the risks that this treatment poses to asymptomatic patients And benefits to choose a treatment. Different types of antiretroviral drugs work at different stages of the HIV life cycle.

Antiretroviral drugs 2. Common drugs and classification

At present, there are more than 30 drugs (including complex preparations) in 6 major categories, which are divided into nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), Integrase inhibitors (raltegravir), fusion enzyme inhibitors (FIs), and CCR5 inhibitors ^[2] .

1. Nucleoside reverse transcriptase inhibitors (NRTIs)

The chemical structure of NRTIs is similar to that of natural nucleosides. Active metabolites are generated after intracellular phosphorylation. By competitively inhibiting the binding of natural nucleosides to HIV1 reverse transcriptase, they inhibit HIV cDNA production and thereby inhibit HIV replication. The existing NRTIs in China are zidovudine, lamivudine, didanosine, stavudine, abacavir, tenofovir, emtricitabine.

(1) Abakawe

Since 1989, abacavir has been used in the prevention and treatment of AIDS with other antiretroviral drugs. About 5% of first-time patients will have a hypersensitivity reaction after 2 weeks of use, causing fever, general weakness, and gastrointestinal discomfort. Then a rash appeared, and some patients could easily cause fatal adverse reactions if they were given abacavir again.

(2) Stavudine

Stavudine (d4T) is metabolized into stavudine triphosphate (d4T-TP) in the body to produce antiviral activity. Changes in the level of d4T-TP in the cell may lead to changes in the efficacy and toxicity of stavudine. Studies have shown that thymidylate synthase (TS) gene polymorphism can affect the intracellular concentration of d4T-TP. In patients with low expression of TS, d4T-TP in peripheral blood mononuclear cells is significantly increased. At the same time, Increased risk of lipid abnormalities.

2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

NNRTIs bind to HIV1 reverse transcriptase non-competitively, hinder virus replication and produce antiviral effects. These drugs are mainly biotransformed by the cytochrome P450 enzymes of the liver and intestinal wall. Therefore, NNRTIs are prone to drug interactions when combined with other drugs. The current domestic NNRTIs include nevirapine, efavirenz, and travirin.

(1) Efaviren Efaviren is one of the most widely used NNRTIs in the world and is often used in combination with two other NRTIs to treat AIDS. CYP2B6 is the main metabolic enzyme for hydroxylation of efavirenz, and participates in 77% to 92% of efavirenz metabolism. Studies have shown that CYP3A4, CYP3A5, CYP2A6 and UGT2B7 are also involved in the metabolism of efavirenz. Other cytochromes may also be involved in the metabolism of efavirenz, including CYP2D6, CYP2C9, CYP2C19, and CYP2C8, but the role of these enzymes is not fully understood. Genetic polymorphisms of metabolic enzymes may lead to large differences in pharmacokinetic parameters of efavirenz among individuals. At present, the research on the changes of efavirenz blood concentration caused by CYP2B6 gene polymorphism is the most in-depth. It has been found that more than 30 alleles of CYP2B6, some alleles can cause the weakening or loss of CYP2B6 function. The widely studied single nucleotide polymorphism site (SNP) is CYP2B6516G> T. This mutation can cause slow metabolism of efavirenz and nevirapine, increase its plasma concentration level, strengthen antiviral ability, and may also cause Adverse reactions occurred. In addition, CYP2B6983C> T, 785A> G, 136A> 6, 1172T> A, 499C> G, 593T> C, 1132C> T may also cause slow metabolism of efavirenz [3], and CYP2B618492T> C and efavirenz Related to fast metabolism.

(2) Nevirapine

Nevirapine is mainly metabolized by CYP2B6 and CYP3A4. A large number of studies have shown that CYP2B6516G> T mutation is associated with increased plasma concentrations of nevirapine, but this effect has certain ethnic differences. In the first few weeks after taking nevirapine, 5% of patients can cause hypersensitivity reactions, such as rash, liver damage, allergies, etc., especially female patients who use nevirapine for the first time and CD4 + T cells> 250 / mm3. The study found that the immune system is involved in the occurrence of hypersensitivity reactions, and human leukocyte antigen (HLA) gene polymorphisms can be used as predictors of nevirapine adverse reactions. A recent study found that HLA-DRB1 * 0102 and HLA-B * 5801 may be risk factors for nevirapine liver injury in South African populations. Despite racial differences, identifying HLA phenotypes in susceptible populations will lay the foundation for the development of optimal treatments.

3. Protease inhibitors (PIs)

PIs competitively block the binding of HIV proteases to their natural substrates and inhibit late HIV1 replication. The current domestic PIs are indinavir, ritonavir, lopinavir, tilanavir, and darunavir.

(1) Lopinavir / ritonavir (LPV / r)

LPV / r is a commonly used PIs antiretroviral drug, and is often used in the clinic as a first-line anti-AIDS drug. Affected by the first-pass effect of cytochrome P450 and the drug transporter P-glycoprotein, lopinavir has low oral bioavailability and is often used clinically with the potentiator ritonavir. CYP3A4 is the main metabolic enzyme of protease inhibitors (PIs). At the same time, PIs are competitive inhibitors of CYP3A4. Low-dose ritonavir competitively binds to CYP450 and P-glycoprotein in the small intestine and liver, which can reduce the first-pass effect of lopinavir and increase its plasma concentration. Organic anion transport peptide (OATP / SLCO) is a transporter specifically distributed on the basement membrane of hepatocytes, which is closely related to the liver uptake of many endogenous or exogenous substances in the body.

4. Integrase inhibitor

The only domestic integrase inhibitor is latiravir.

(1) Latiravir

Latiravir is the first integrase inhibitor approved by the FDA for clinical use and exerts antiviral effects by inhibiting covalent binding of viral DNA to the host genome. The main metabolic enzyme of lativavir is UDP glucuronyltransferase 1A1 (UGT1A1), so it is speculated that UGT1A1 gene polymorphism may affect the pharmacokinetic parameters of lativavir. UGT1A1 * 28 alleles have been shown to reduce UGT1A1 activity, but two studies exploring the relationship between UGT1A1 gene polymorphisms and latiravir blood concentrations in two healthy populations have not found any effect on latiravir blood The effect of concentration. The study found that studies in patients and healthy subjects found that UGT1A9 * 3 may explain some differences in individual plasma concentrations of lativavir.

Antiretroviral drugs III. Treatment options

The guidelines for antiretroviral therapy have changed many times. It is recommended to use the "hit hard, hit early" method in the early stage. A more conservative approach followed, starting at 350 to 500 CD4 + T cells per milliliter. Recent guidelines have considered the use of (cocktail therapy) HAART therapy with new standards ^[1] .

Currently, the World Health Organization's antiretroviral therapy (ART) guidelines recommend use in developing countries. Adults and adolescents with HIV infection should be used after HIV infection has been confirmed and meets any of the following conditions:

Advanced HIV disorders: Stage IV of HIV as specified by the WHO does not consider CD4 cell counts; Stage III of HIV as specified by the WHO assists in making decisions based on CD4 cell counts less than 350 / micron; Stages I and II of HIV as prescribed by the WHO, CD4 cell count is less than 200 / & micro; l. Treatment guidelines in the United States are developed by the United States Department of Health (DHHS). The latest guidance program for teens and adults was launched on October 6, 2005.

Regardless of CD4-positive T cell counts, all patients with a history of AIDS or with severe symptoms of HIV infection can be treated with antiretroviral drugs. . Asymptomatic patients but the number of CD4-positive T cells below 200 / & micro; l, antiretroviral drugs are still recommended. Asymptomatic patients with CD4-positive T-cell numbers between 201-350 / micron should receive this treatment. In patients with CD4 positive T cells greater than 350 / micron and HIV RNA in plasma greater than 100,000 / ml, many experienced physicians will postpone treatment, but some physicians will consider starting treatment. When the number of CD4 positive T cells in the patient is greater than 350 / micron and the HIV RNA in the plasma is less than 100,000 / ml, the treatment may be delayed. Any of the following preferred methods:

efavirenz + lamivudine or emtricitabine + zidovudine or tenofovir; or lopinavir assisted ritonavir + zidovudine + lamivudine or emtricitabine because HIV progresses faster in children than in adults, laboratory parameters cannot predict the danger of the disease, especially for infants, the US Department of Health More aggressive treatments are recommended for children. A new treatment plan for children was launched on November 3, 2005.

In 2005, the United States Department of Infectious Disease Prevention (Centers for Disease Control and Prevention in the United States) recommended that people exposed to the HIV virus use 28-day anti-HIV drugs for prevention. The effectiveness of the drug in preventing the virus from exposure to the first 24 hours of the person reached 100%, and the effectiveness of taking the drug within 72 hours dropped to 52%.

In September 2012, U.S. researcher Deborah Persaud discovered that a baby had received high doses of antiretroviral drugs and had not received medication for five months. After a comprehensive inspection, the baby was found to be free of HIV, and the results of this study were subsequently published in March 2013, attracting media attention.

Antiretroviral drugs

In just 1.5 days, the HIV virus completed the process of entering cells, replicating genetic material, assembling new viruses, and releasing infection to other cells. The HIV virus lacks the enzymes that correct errors during reverse transcription from RNA to DNA. The high error rate in this short cycle makes the mutation of the virus very fast, which brings the high genetic mutation rate of the HIV virus. Most mutations have no advantage over the parental virus, but some mutations inherit the parental advantage, making it easier for the virus to resist the body's immune system and antiretroviral drug defenses. The higher the activity of the virus, the stronger the resistance to antiretroviral drugs. Therefore, the combination of antiretroviral drugs is very important for suppressing the reproduction of HIV virus and resisting the virus.

If antiretroviral drugs are used improperly, these resistant strains can quickly become the dominant genotype. Incorrect use of reverse transcription inhibitors, such as zidoyudine, didanosine, zalcitabine, stayudine, and lamivudine, can cause multiple drug resistance mutations. These mutations include V75I, F77L, K103N, F116Y, Q151M, and M184V mutations. These mutations were discovered before proteaseinhibitor was widely used, and these mutations are sensitive to the early protease inhibitor saquinavir, and they are also sensitive to the rarely used reverse transcription inhibitor foscarnet.

The combination of antiretroviral therapy is designed to suppress HIV replication as much as possible.

The combination of antiretroviral drugs creates multiple obstacles to HIV replication, which can keep the number of offspring low and reduce the possibility of dominant mutations. If a mutation becomes resistant to a drug, other drugs can continue to suppress virus replication and mutation. Antiretroviral drugs alone (with few exceptions) cannot fight HIV infection for long periods of time; therefore, multiple drugs must be used in combination to achieve sustained results. Therefore, the current standard treatment is to use antiretroviral combination therapy. Drug combinations usually use two RTIs plus one NRI or proteaseinhibitor. The combination of these three drugs is called triplecocktail.

The combination of antiretroviral drugs has synergistic positive and negative effects, which limits the number of combinations. For example, ddl and AZT inhibit each other, so taking both at the same time is less effective than taking one alone. Other issues have limited the use of antiretroviral drugs, including complex dosing schedules and severe adverse reactions.

In recent years, pharmaceutical companies have worked together to transform these complex formulations into simpler forms known as fixed-dose combinations. For example, multiple antiretroviral drugs are combined to form a pill (pill), which is taken daily to greatly increase convenience and long-term efficacy.

Antiretroviral drugs V. Limitations

If an HIV-infected person develops resistance to standard HAART, options are limited. One option is to use a combination of antiretroviral drugs called mega-HAART or remedial therapy. But remedial treatment usually increases the adverse reactions of the drug and increases the cost of treatment. Another option is to use only one or two antiretroviral drugs, which can direct the virus to mutate in a direction that reduces its virulence. The most common resistance mutation to lamivudine (3TC) appears to be this. Therefore, 3TC alone can have some effects when the virus is resistant.

If an HIV-infected person is very resistant to antiretroviral drugs, then his treatment will become very complicated and his condition will worsen. Treatments continue to improve drugs into clinical trials, but the limitations of the introduction of such drugs have prevented patients in many developing countries from benefiting.

Medication holidays, or planned intermittent treatment, are intentional intermittent antiretroviral treatments. The purpose of this intermittent treatment is to increase the sensitivity of the HIV virus to antiretroviral drugs. Intermittent treatment attempts to change the selective pressure of drug resistance, thereby breeding viruses that are more sensitive to drugs. Unfortunately, there is a stage in the life cycle of HIV in which DNA is fully integrated with near-human DNA. At this stage, the resistant strains are dormant under certain conditions. During this period, CD4T cells are dormant when the body is not invaded. When antiretroviral drugs intervene again, those resistant strains will reappear.

Intermittent therapy

It is used to reduce the use of antiretroviral drugs, thereby reducing adverse reactions. Intermittent treatment is different from the treatment terminal. Intermittent treatment is the use or withdrawal of antiviral drugs in a short cycle. Treatment options include "week-on, week-off (" wowo ") and" five-days-on, two-days-off, "which skips the weekend foto "). Researchers are looking for the best solution for different patients. However, the raw data are clear, intermittent treatment has no effect, and has led to drug tolerance.

The HIV virus can impair the ability of the thymus to produce normal different kinds of T cells, so whether long-term suppression or even elimination of HIV can restore normal immune function is unclear. In addition, rapid suppression of HIV and partial recovery of the immune system can sometimes produce dangerous hypersensitivity reactions and immune-reconstructed inflammatory syndromes. Research in these areas is ongoing.

Antiretroviral drugs

Taking antiretroviral drugs may cause several adverse reactions. These drugs can cause serious side effects. Taking these drugs requires taking different drugs at different times and in different doses. In recent years, with the emergence of new drugs, the administration method has been slightly simplified. If the patient forgets to take the medication, resistance to the virus develops. Antiretroviral drugs are also very expensive, so most people living with HIV in the world do not get effective medication ^[3] .

Common adverse reactions

Systemic adverse reactions such as discomfort and fatigue; nervous system such as headache, dizziness, inattention, peripheral neuritis; digestive system such as nausea, vomiting, abdominal pain, bloating, diarrhea, liver damage; blood system such as reduced blood cells, anemia, and Stomatitis, rash, drug rash, and allergies, etc. In addition, there are still myalgia, inflammatory edema, kidney stones, hyperbilirubinemia, etc. Some of the symptoms are similar to those of HIV infection and AIDS itself. Differentiating and general treatment should be given according to the time of symptom onset and the time of medication. In severe cases, antiretroviral drugs should be suspended.

2. Special adverse reactions

Mainly are metabolic disorders, lipid metabolism disorders account for 49.0%, glucose metabolism disorders account for 20.0%, followed by bone metabolism disorders. Lipid metabolism disorders are manifested as fat redistribution and hyperlipidemia, and hyperlactic acidemia with liver steatosis is also listed here. (1) Fat redistribution or abnormal distribution

Including fat consumption, fat accumulation (such as fat and thin limbs), mixed fat distribution, lipoatrophy.

(2) Hyperlipidemia

The existing hypertriglyceridemia and hypercholesterolemia have the adverse effect of increasing the risk of coronary heart disease. IDV in protease inhibitors is easy to cause. Other five protease inhibitors and some nucleoside reverse transcriptase inhibitors can be used. Causes lipid metabolism disorders.

(3) Impaired glucose metabolism

Presented with insulin resistance, hyperinsulinemia, and possibly pancreatitis. There is an increased risk of causing diabetes.

(4) Hyperlactic acidemia

Most patients have mild hyperlactic acid after cocktail therapy.

(5) Abnormal bone metabolism

The existing osteopenia, osteoporosis and ischemic osteonecrosis occur in only a small number of patients.The time of occurrence is when the virus begins to be suppressed and CD4 cells have improved. Some people have speculated that it is related to immune reconstruction after HAART .

(6) Liver damage

Nearly 10% of patients treated with cocktail therapy had severe elevation of transaminase, which had nothing to do with the treatment. All three enzyme inhibitors can cause it. To avoid alcoholism, especially patients with hepatitis C, if possible, treat hepatitis C first, and then treat HIV infection and AIDS.