The HIV/AIDS management usually includes the use of some antiretroviral drugs in an effort to control HIV infection. There are several classes of antiretroviral agents that act at different stages of the HIV life cycle. The use of multiple drugs acting on different viral targets is known as highly active antiretroviral therapy ( HAART ). HAART lowers the total patient's HIV burden, maintains immune system function, and prevents opportunistic infections that often lead to death.
Treatment has been so successful that in many parts of the world, HIV has become a chronic condition where progression to AIDS is becoming increasingly scarce. Anthony Fauci, head of the National Institute of Allergies and Infectious Diseases of the United States, has written, "With today's collective and assertive action and firm commitment for years to come, AIDS-free generation is within reach." In the same paper, he noted that some 700,000 people were rescued in 2010 alone by antiretroviral therapy. As other comments in The Lancet noted, "Instead of dealing with acute and potentially life-threatening complications, doctors are now faced with managing chronic illnesses that in the absence of drugs will last for decades."
The US Department of Health and Human Services and the World Health Organization recommend to offer antiretroviral treatment to all patients with HIV. Due to the complexity of choosing and following a regimen, the potential side effects, and the importance of taking medication regularly to prevent viral resistance, the organization emphasizes the importance of involving patients in therapeutic options and recommends analyzing potential risks and benefits.
Video Management of HIV/AIDS
History
The first effective therapy against HIV is NRTIs, zidovudine (AZT). It was approved by the US FDA in 1987. Subsequently, some NRTIs were developed but even in combination it was not able to suppress the virus for long periods of time and the patient still had to die. To distinguish from this antiretroviral therapy (ART), the highly active term antiretroviral therapy (ART) is introduced. In 1996, Hammer and his colleagues and Gulick and colleagues described the great benefits of combining 2 NRTIs with a new class of antiretroviral drugs, protease inhibitors, indinavir. The concept of 3-drug therapy is rapidly incorporated into clinical practice and quickly demonstrates impressive benefits with a 60% to 80% reduction in AIDS, mortality and hospitalization rates.
As ART becomes widespread, dose combinations remain available to facilitate administration. Later, antiretroviral combination therapy (ART) has the support of some doctors as a more accurate name for the current era, not conveying to patients the wrong idea about the nature of therapy. Now, multidrug, a very effective regimen has long since the failure of ART, which is why they are often called ART instead of ART or cART. This retronymic process is linguistically proportional to the way that the words electronic computer and digital computers were initially required to make a useful difference in computational technology, but with later relevance of the differences, computer itself now includes its meaning. Thus because "all computers are now digital", so "all ART is a combination of current HAART." However, the name HAART and cART, reinforced by thousands of earlier mention in the medical literature are still frequently quoted, are also in use today.
Maps Management of HIV/AIDS
Drug classes
There are six classes of drugs, usually used in combination, to treat HIV infection. Antiretroviral drugs (ARVs) are widely classified by the retrovirus life cycle phases that inhibit the drug. Typical combinations include 2 Nucleoside reverse transcriptase inhibitors (NRTIs) as a "backbone" along with a Non-Nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI) or integrase inhibitor (also known as integrase nuclear strand transfer inhibitor or INSTIs) as a "base."
Inhibitor entry
The entry inhibitor (or fusion inhibitor) interferes with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. Maraviroc and enfuvirtide are the two agents currently available in this class. Maraviroc works by targeting CCR5, a co-receptor located in human helper T cells. Caution should be used when delivering this drug but because of the possible tropism shift that allows HIV to target alternative cooperative receptors such as CXCR4. In rare cases, the individual may have a mutation in the CCR5 delta gene that results in a nonfunctional CCR5 co-receptor and, in turn, means of slow disease resistance or progression. However, as mentioned earlier, this can be overcome if the HIV variant targeting CXCR4 becomes dominant. To prevent virus fusion by the host membrane, enfuvirtide may be used. Enfuvirtide is a peptide drug that must be injected and acts by interacting with the HIV gp41 heptad N-terminal heptad to form an inactive six-helix hetero bundle, thus preventing host cell infections.
Nucleoside/nucleotide reverse transcriptase inhibitor
Nucleoside reverse transcriptase inhibitors (NRTIs) and nucleotide reverse transcriptase inhibitors (NtRTIs) are nucleoside and nucleotide analogs that inhibit inverted transcription. HIV is an RNA virus and therefore can not be integrated into DNA in the nucleus of human cells; it must be "upside down" transcribed into DNA. Since the conversion of RNA to DNA is not done in mammalian cells, it is done by a viral protein that makes it a selective target for inhibition. NRTIs are chain terminators as they have been incorporated, working by preventing other nucleosides from being incorporated into the DNA chains due to the absence of OH 3 'groups. Both act as competitive substrate inhibitors. Examples of NRTIs currently used include AZT, abacavir, lamivudine, emtricitabine, and tenofovir.
Non-nucleoside reverse transcriptase inhibitor
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit reverse transcriptase by binding to the allosteric site of the enzyme; NNRTIs act as non-competitive inhibitors of reverse transcriptase. NNRTIs affect substrate handling (nucleotides) by reverse transcriptase by binding near the active site. NNRTIs can be further classified into the first generation and second generation NNRTIs. First-generation NNRTIs include nevirapine and efavirenz. Second-generation NNRTIs are etravirine and rilpivirine. HIV-2 is naturally resistant to NNRTIs.
Integrase inhibitor
Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) inhibit the integrase of viral enzymes, which are responsible for the integration of viral DNA into the DNA of infected cells. There are several integrase inhibitors currently in clinical trials, and raltegravir became the first to receive FDA approval in October 2007. Raltegravir has two groups of metal binders that compete for a substrate with two Mg 2 ions on metal binding. site integrase. As early as 2014, two other clinically approved integrase inhibitors were elvitegravir and dolutegravir.
Protease inhibitor
Protease inhibitors block viral protease enzymes that are necessary to produce adult virions in buds from the parent membrane. In particular, it prevents protein splitting of gags and gag/pol precursors. Viral particles produced in the presence of protease inhibitors are damaged and most are not contagious. Examples of HIV protease inhibitors are lopinavir, indinavir, nelfinavir, amprenavir, and ritonavir. Darunavir and atazanavir are currently recommended as a first-line treatment option. Maturation inhibitors have the same effect as binding to vomiting, but the development of two experimental drugs in this class, bevirimat and vivecon, was discontinued in 2010. Resistance to some high protease inhibitors. Second-generation drugs have been developed that are effective against resistant variant HIV.
Combination therapy
The HIV life cycle can be as short as about 1.5 days from the entry of the virus into cells, through replication, assembly, and the release of additional viruses, to other cell infections. HIV does not have an enzyme proofreading to correct errors made when converting RNA into DNA via reverse transcription. Short life cycles and high error rates cause the virus to mutate very quickly, resulting in high HIV genetic variability. Most of the mutations are either lower than the parent virus (often lacking the ability to reproduce at all) or do not provide an advantage, but some of them have the advantage of natural selection for its mother and may allow them to sneak past defenses such as human immune systems and antiretroviral drugs. The more copies of the active virus, the more likely a person who is resistant to antiretroviral drugs will be made.
When antiretroviral drugs are used improperly, drug-resistant strains can become the dominant genotype very quickly. In the era before the double-drug class was available (pre-1997), reverse transcriptase inhibitors zidovudine, ddI, zalcitabine, stavudine, and lamivudine were used serially or in combination leading to the development of many drug-resistant mutations.
Antiretroviral combination therapy persists against resistance by suppressing HIV replication as much as possible, thereby reducing the potential for spontaneous resistance mutations.
Combination of antiretrovirals creates many barriers to HIV replication to keep the number of offspring low and reduce the likelihood of superior mutations. If a mutation indicates resistance to one of the drugs taken, then other drugs continue to suppress the reproduction of the mutation. With rare exceptions, no individual antiretroviral drugs have been shown to suppress old HIV infections; these agents must be taken in combination to have lasting effects. As a result, the standard of care is to use a combination of antiretroviral drugs. The combination usually consists of three drugs from at least two different classes. The combination of these three drugs is commonly known as a triple cocktail. Combinations of antiretrovirals are exposed to positive and negative synergies, which limit the number of useful combinations.
In recent years, drug companies have worked together to incorporate this complex regimen into a simpler formula, called a fixed-dose combination. For example, there are now several options that combine 3 or 4 drugs into one pill taken once a day. This greatly enhances the ease with which they can take, which in turn improves consistency with the drugs taken (adherence), and thus their effectiveness over the long term. Not taking regular anti-retroviral drugs is a cause of resistance development in people who have started taking them before. Patients taking regular medication may continue to use one regimen without developing resistance. It greatly increases life expectancy and leaves more medicine available to individuals if needed.
Fixed-dose combinations
Fixed-dose combinations are some of the antiretroviral drugs that are combined into a single pill.
Additional treatments
Although antiretroviral therapy has helped improve the quality of life of people living with HIV, there is still a need to explore other ways to cope with the burden of disease further. One potential strategy under investigation is to add interleukin 2 as an adjunct to antiretroviral therapy for adults with HIV. The Cochrane review includes 25 randomized controlled trials conducted in six countries. The researchers found that interleukin 2 boosts CD4 immune cells, but does not make a difference in terms of death and other infectious events. In addition, there may be an increase in adverse events with interleukin 2. The findings of this review do not support the use of interleukin 2 as an adjunctive treatment for antiretroviral therapy for adults with HIV.
Maintenance guidelines
Guidelines for treatment of antiretroviral drugs have changed over time. Prior to 1987, no available antiretroviral drugs and treatment consisted of treating complications from opportunistic infections and malignancies. Once antiretroviral drugs are introduced, most doctors agree that HIV positive patients with low CD4 cell counts should be treated, but no consensus is established for whether to treat patients with high CD4 cell counts.
In April 1995, Merck and the National Institute of Allergies and Infectious Diseases began recruiting patients for trials that examined the combined effects of three indinavir protease inhibitor drugs and two nucleoside analogues. described the great benefits of combining 2 NRTIs with a new class of anti retroviral, protease inhibitor, indinavir. Later that year David Ho became an advocate of this "hitting hard, hitting early" approach with aggressive treatment with many antiretroviral drugs early in the course of the infection. Later reviews in the late 90s and early 2000s noted that the approach of "hitting hard, hitting early" posed a significant risk of adverse side effects and the development of multi-drug resistance, and this approach was largely abandoned. The only consensus is to treat patients with advanced immunosuppression (CD4 count less than 350/L). Treatment with ARVs is expensive at the time, ranging from $ 10,000 to $ 15,000 per year.
The timing of when to start therapy continues to be a core controversy in the medical community, although recent research has led to more clarity. The NA-ACCORD study looked at patients who started either antiretroviral therapy at less than 500 CD4 cell counts compared to less than 350 cells/mm 3 and showed that patients starting ART at lower CD4 cell counts had a 69% increase in risk of death. By 2015, the START and TEMPRANO studies show that patients live longer if they start antiretrovirals at the time of their diagnosis, rather than waiting for their CD4 cell count to fall to the prescribed level.
Another argument for the start of previous therapy is that people who start therapy later prove less restored to their immune system, and higher CD4 cell counts are associated with fewer cancers.
Treatment as prevention
A separate argument for starting antiretroviral therapy that is increasingly recognized is its effect on HIV transmission. ART reduces the amount of virus in the blood and genital secretions. This has been shown to lead to dramatically reduced HIV transmission when one partner with a suppressed viral load (& lt; 50 copies/ml) has sex with an HIV negative partner. In clinical trials, HPTN 052,1763 serodiscordant heterosexual couples in 9 countries were planned to be followed for at least 10 years, with both groups receiving education to prevent HIV and condom transmission, but only one group received ART. This study was discontinued earlier (after 1.7 years) for ethical reasons when it became clear that antiviral treatment provided significant protection. Of the 28 couples in whom cross infection occurred, all but one occurred in the control group consistent with a 96% reduction in the risk of transmission while on ART. Single transmission in the experimental group occurs early after starting ART before viral load tends to be suppressed. The term "Pre-Exposure Prophylaxis (PrEP)" refers to the concept of providing HIV-individuals with drugs - in conjunction with safe sex education and regular HIV/STI screening - to reduce the risk of contracting HIV. In 2011, the journal Science awarded Breakthroughs of the Year for treatment as a precaution.
In July 2016, a consensus document was created by the Prevention Access Campaign which has been supported by more than 400 organizations in 58 countries. The consensus document states that the risk of HIV transmission from a person living with HIV undetected for at least 6 months can be ignored until none, with little to say as 'very small or unimportant not worth considering'. Chairman of the British HIV Association (BHIVA), Chloe Orkin, stated in July 2017 that 'there can be no doubt about a clear and simple message that a person with a steady and undetectable level of HIV virus in their blood can not transmit HIV to a sexual partner. '
Furthermore, the PARTNER study, which runs from 2010 to 2014, enrolled 1166 serodiscordant couples (in which one partner was HIV positive and the other negative) in a study that found an estimated rate of transmission through unprotected HIV-positive sex. couples taking ART with a viral load less than 200 copies/ml were zero.
In short, as the WHO HIV treatment guidelines state, "Current ARV regimens are available, even in the poorest countries, safer, simpler, more potent, and more affordable than ever."
There is a consensus among experts who, once started, antiretroviral therapy should not be stopped. This is because selection pressure from incomplete suppression of viral replication in the presence of drug therapy causes more sensitive drug strains to be selectively inhibited. This allows drug-resistant strains to become dominant. This in turn makes it harder to treat infected individuals as well as others they infect. One trial in which ART therapy was discontinued periodically had higher rates of opportunistic infections, cancer, heart attack and death in patients who interrupted their ART.
Guide Source
There are several treatment guidelines for HIV-1-infected adults in developed countries (ie, countries with access to all or most of the therapy and laboratory tests). In the United States there is the International AIDS Society-USA (IAS-USA) (501 (c) (3) non-profit organization in the US) as well as the US Department of Health and Human Services guidelines. In Europe there are guidelines for the European AIDS Clinical Society.
For resource-limited countries, most of the national guidelines follow World Health Organization guidelines.
Current guide
Current guidelines use new criteria to consider starting ART, as described below. However, there are still views on this and the decision whether to start treatment ultimately depends on the patient and his doctor.
The current US DHHS guidelines (published April 8, 2015) state:
- Antiretroviral therapy (HAART) is recommended for all people infected with HIV to reduce the risk of disease progression.
- ART is also recommended for people infected with HIV for the prevention of HIV transmission.
- Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence. Patients may choose to delay therapy, and providers, on a case-by-case basis, may choose to delay therapy based on clinical and/or psychosocial factors.
The latest World Health Organization guidelines (dated September 30, 2015) now agree and state:
- Antiretroviral therapy (ART) should be initiated in all people living with HIV at any CD4 count
Resistance baseline
Initial resistance is the presence of resistance mutations in previously untreated patients for HIV. In countries with high initial resistance levels, resistance testing is recommended before initiation of treatment; or, if treatment initiation is urgent, the "best guess" treatment regimen should start, which is then modified based on resistance testing. In the UK, there was 11.8% medium to high resistance at baseline for the combination of efavirenz zidovudine lamivudine, and 6.4% medium to high resistance to lamivudine nevirapine stavudine. In the US, 10.8% of one group of patients who had never taken antiretroviral therapy before had at least one resistance mutation in 2005. Surveys in different parts of the world have shown an increased or stable base rate of resistance as an effective HIV era. therapy continues. With the initial resistance test, effective combination antiretroviral drugs can be adjusted for each patient.
Regimen
Most current ART regimens consist of three drugs: 2 NRTIs ("backbone") of a PI/NNRTI/INSTI ("base"). Early regimens used "first-line" drugs with high efficacy and low side effects.
US DHHS preferred initial regimen for adults and adolescents in the United States, as of April 2015, is:
- tenofovir/emtricitabine and raltegravir (integrase inhibitor)
- tenofovir/emtricitabine and dolutegravir (integrase inhibitor)
- abacavir/lamivudine (two NRTIs) and dolutegravir for patients who had tested negative for HLA-B * 5701 gene alleles
- tenofovir/emtricitabine, elvitegravir (integrase inhibitor) and cobicistat (inhibiting metabolism in the former) in patients with good renal function (gfr & gt; 70)
- tenofovir/emtricitabine, ritonavir, and darunavir (both protease inhibitors)
In the case of a protease inhibitor-based regimen, ritonavir is used at low doses to inhibit p450 cytochrome enzymes and "boost" other protease inhibitor levels, not for immediate antiviral effects. This boost effect allows them to be taken less frequently throughout the day. Cobicistat is used with elvitegravir for a similar effect but has no direct antiviral effect.
WHO's initial preferred regimen for adults and adolescents on June 30, 2013 is:
- tenofovir lamivudine (or emtricitabine) efavirenz
Custom population
Acute infection
In the first 6 months after infection, HIV viral load tends to increase and people are more symptomatic than latent latent phase in the future. There may be particular benefits for starting antiretroviral therapy early during this acute phase, including lowering viral loads or early viral loads, reducing viral mutation rates, and reducing the size of virus reservoirs (see section below on virus reservoirs). The SPARTAC trial compared 48 weeks of treatment vs 12 weeks vs. no treatment of acute HIV infection and found that 48 weeks of treatment delayed the time to decrease CD4 cell counts below 350 cells per ml at 65 weeks and maintained a much lower viral load even after treatment had stopped. Since viral load is usually very high during acute infection, this period carries the risk of transmission 26 times higher. By treating acutely infected patients, it is suspected that it could have a significant impact on the overall decline in HIV transmission rates because lower viral loads are associated with lower transmission risk (see section on treatment as prevention). But the overall benefits have not been proven and must be balanced with the risk of HIV treatment. Therapy during acute infection brings the recommendation of BII grade from US DHHS.
Children
HIV can be very dangerous for infants and children, with one study in Africa showing that 52% of untreated children born with HIV have died by age 2. With five years, the risk of illness and death due to HIV begins to approach young adults. WHO recommends treating all children under 5 years of age, and initiating all children older than 5 years with stage 3 or 4 disease or CD4 & lt; 500 cells/ml. DHHS guidelines are more complicated but recommend starting all children less than 12 months and children of all ages who have symptoms.
For what ARVs are used, this is complicated by the fact that many children born to mothers with HIV are given single dose of nevirapine (NNRTI) at birth to prevent transmission. If this fails then it can lead to NNRTI resistance. Also, a large study in Africa and India found that PI-based regimens were superior to NNRTI-based regimens in children younger than 3 years who had not been exposed to NNRTIs in the past. Thus WHO recommends PI-based regimens for children less than 3.
WHO recommends for children less than 3 years:
- abacavir (or zidovudine) lamivudine lopinivir ritonivir
and for children 3 years to less than 10 years and teenagers & lt; 35 kilograms:
- abacavir lamivudine efavirenz
US DHHS Guidelines are similar but include PI-based options for children & gt; 3 years.
A systematic review assessed the effect and safety of abacavir-containing regimens as first-line therapy for children between 1 month and 18 years when compared to other NRTI regimens. This review included two trials and two observational studies with nearly eleven thousand HIV-infected children and adolescents. They measured virological suppression, death, and side effects. The authors found that there was no significant difference between abacavir-containing regimens and other NRTI-containing regimens. The evidence of its quality is low to moderate and therefore it is possible that future research may alter these findings.
Pregnant women
The goal of treatment for pregnant women includes the same benefits to the mother as in other infected adults as well as the prevention of transmission to her child. The risk of mother-to-child transmission is proportional to maternal plasma viral load. Mothers not treated with viral load & gt; 100,000 has a transmission risk of more than 50%. Risk of viral load & lt; 1000 copies/ml less than 1%. ART for mothers both before and during labor and for mothers and infants after delivery is recommended to reduce the risk of transmission substantially. The mode of delivery is also important, with the planned cesarean section having a lower risk than vaginal delivery or emergency cesarean section. HIV can also be detected in breast milk of infected mothers and is transmitted through breastfeeding. WHO balances the risk of low transmission through breast-feeding from mothers on ART with the benefit of breastfeeding against diarrhea, prakitonia and malnutrition. It is also highly recommended that breastfeeding infants receive prophylactic antiretroviral therapy. In the US, DHHS recommends against women with HIV who breastfeed.
Older adults
With an increase in HIV therapy, several studies now estimate that patients undergoing treatment in high-income countries can expect a normal life expectancy. This means that a higher proportion of people living with HIV are now older and research is ongoing into unique aspects of HIV infection in older adults. There is data that parents with HIV have a blunted CD4 response to therapy but are more likely to achieve undetectable viral load levels. However, not all studies have seen differences in response to therapy. The current guidelines do not have separate treatment recommendations for older adults, but it is important to consider that older patients are more likely to take some non-HIV drugs and consider drug interactions with potential HIV drugs. There is also an increase in HIV levels related to non-AIDS conditions (HANA) such as heart disease, liver disease and dementia which are multifactorial complications of HIV, related behaviors, co-infection such as hepatitis B, hepatitis C and human papilloma virus (HPV) as well as HIV treatment.
Adult with depression
Many factors can contribute to depression in adults living with HIV, such as viral effects on the brain, infections or other tumors, antiretroviral drugs and other medical treatments. Severe depression rates are higher in people living with HIV than in the general population, and this can negatively affect antiretroviral therapy. In a systematic review, Cochrane researchers assess whether administering antidepressants in adults living with HIV and depression can improve depression. Ten trials, of which eight were conducted in high-income countries, with 709 participants involved. The results suggest that antidepressants may be better at correcting depression than with placebo, but low evidence quality and future research will likely have an impact on findings.
Worries
There are some concerns about antiretroviral regimens that should be addressed before starting:
- Intolerance: Drugs can have serious side effects that can cause harm and keep patients from taking medication regularly.
- Resistance: Not taking drugs consistently can lead to low blood levels that promote drug resistance.
- Costs: WHO maintains a world-class cost of ART that has dropped dramatically in the last few years as more and more first-line drugs are not patents. One pill, once-daily combination therapy has been introduced in South Africa for just $ 10 per patient per month. One recent study estimated overall cost savings for ART therapy in South Africa because of reduced transmission. In the United States, a new patent regimen can cost up to $ 28,500 per patient, per year.
- Public health: Individuals who fail to use ARV as directed may develop drug-resistant strains that can be passed on to others.
Response to therapy
Virologic response
Suppressing viral load to undetectable levels (& lt; 50 copies per ml) is the primary goal of ART. This should occur 24 weeks after starting combination therapy. Viral load monitoring is the most important predictor of response to treatment with antiretroviral therapy. A higher rate of 200 copies per ml is considered virological failure, and should encourage further tests for possible viral resistance. Lack of suppression of viral load on ART is called virological failure.
Immunological response
CD4 cell count is another key measure of immune status and effectiveness of antiretroviral therapy. CD4 cell count should increase from 50 to 100 cells per ml in the first year of therapy. There is substantial fluctuation in CD4 cell counts up to 25% by time or concurrent infection. In one long-term study, the majority of CD4 cell count increases were within the first two years after starting ART with a slight increase thereafter. The study also found that patients starting ART at lower CD4 cell counts continued to have lower CD4 cell counts than those who started with higher CD4 cell counts. When viral suppression of antiretroviral therapy is achieved but no corresponding increase in CD4 cell count can be called nonresponse immunology or immunological failure. While this is a poor predictor of the outcome, there is no consensus on how to adapt therapy to immunological failure and whether switching therapy is beneficial. The DHHS guidelines do not recommend replacing stressful regimens.
Congenital lymphoid cells (ILC) are another class of immune cells that are depleted during HIV infection. However, if ART begins before this depletion in about 7 days post infection, ILC levels can be maintained. While CD4 cell count usually fills after effective antiretroviral therapy, ILC depletion can not be altered with antiretroviral therapy starting after depletion despite viremia suppression. Because one of the roles of ILCs is to regulate the immune response to commensal bacteria and maintain an effective intestinal barrier, it has been hypothesized that irreversible ILC depletion plays a role in weak intestinal obstruction of HIV patients even after successful HAART..
rescue therapy
In patients who have a fixed viral load detected while on ART, tests may be performed to investigate whether there is drug resistance. The most commonly sequenced genotypes are comparable to databases of the HIV viral genotype and other resistance profiles for predicting response to therapy. If there is extensive resistance, phenotypic tests of the patient's virus on various drug concentrations can be performed, but are expensive and may take several weeks, so genotypes are generally preferred. Using information from genotypes or phenotypes, a 3-drug regimen of at least 2 classes is built that will have the highest probability of suppressing the virus. If a regimen can not be constructed from a recommended first-line agent it is called rescue therapy, and when 6 or more drugs are needed it is called a mega-HAART.
Structured interruptions of treatment
A drug holiday (or "structured treatment interruption") is the cessation of intentional antiretroviral treatment. As noted above, randomized controlled studies of structured disorders have shown higher rates of opportunistic infections, cancer, heart attacks and death in patients taking drugs. With the exception of post-exposure prophylaxis, current treatment guidelines do not require interruption of drug therapy once it is started.
Adverse effects
Each class and individual antiretroviral brings unique risks of adverse side effects.
NRTI
NRTIs can interfere with mitochondrial DNA synthesis and cause high levels of lactate and lactic acidosis, liver steatosis, peripheral neuropathy, myopathy, and lipoatrophy. Current first-line NRTIs such as lamivudine/emtrictabine, tenofovir, and abacavir are less likely to cause mitochondrial dysfunction.
NNRTI
NNRTIs are generally safe and well tolerated. The main reason for the cessation of efavirenz is the neuro-psychiatric effect including the idea of ​​suicide. Nevirapine can cause severe hepatotoxicity, especially in women with high CD4 cell counts.
Protease inhibitor
Protease inhibitors (PIs) are often administered with ritonavir, a powerful inhibitor of the cytochrome P450 enzyme, leading to various drug-drug interactions. They are also associated with lipodystrophy, elevated triglycerides and an increased risk of heart attack.
Integrase inhibitor
Integrase inhibitors (INSTIs) are among the most tolerated of antiretrovirals with excellent short and medium term outcomes. Given its relatively recent development, its long-term security data is lacking. They are associated with elevated creatinine kinase levels and rarely myopathy.
post-exposure prophylaxis (PEP)
When people are exposed to body fluids from HIV positive infections through skin pricking, contact with mucous membranes or contact with damaged skin, they are at risk of contracting HIV. The collected estimates provide transmission risk with 0.3% puncture exposure and 0.63% mucosal membrane exposure. The US guidelines state that "dirt, nasal secretions, saliva, sputum, sweat, tears, urine, and vomit are not considered potentially infectious unless they look bloody." Given the rare nature of this incident, rigorous studies on ARV protective capabilities are limited but suggest that taking antiretrovirals may prevent transmission. It is not known whether three drugs are better than two. Faster after exposure to antiretroviral therapy started better, but after what period they became ineffective is unknown, with the US Public Health Service Guidelines recommending starting prophylaxis for up to a week after exposure. They also recommend treatment for a period of four weeks based on animal studies. The recommended regimen was emtricitabine tenofovir raltegravir (an INSTI). The reason for this regimen is that the drug is "tolerable, strong, and easily administered, and has been associated with minimal drug interactions." HIV exposed individuals should have advanced HIV testing at six, 12, and 24 weeks.
Planning pregnancy
Women with HIV have been shown to have decreased fertility that may affect the choice of reproduction available. In cases where the woman is HIV negative and the man is HIV positive, the main assisted reproductive method used to prevent HIV transmission is sperm leaching followed by intrauterine insemination (IUI) or in vitro fertilization (IVF). Preferably this is done after the man achieves an undetectable viral load. In the past there was a case of HIV transmission to an HIV-negative partner through artificial insemination, but a large modern series of 741 couples followed in which the man had a stable viral load and semen samples were tested for HIV-1, no cases of HIV transmission.
For cases where the woman is HIV positive and the man is HIV negative, the usual method is artificial insemination. With appropriate treatment the risk of mother-to-child infection can be reduced to below 1%.
Towards healing
People living with HIV today can expect to live a normal life span if they achieve durable viral suppression of combination antiretroviral therapy. However this requires lifelong treatment and will still suffer from higher cardiovascular, kidney, liver, and neurological diseases. This has led to further research into healing for HIV.
"Berlin patients"
So far only one adult (so-called "Berlin patient") has been potentially cured and has been out of treatment since 2006 without a detectable virus. This is achieved through two bone marrow transplants that replace their immune system with donors that do not have CCR5 cell surface receptors, which are required for some HIV variants to enter the cell. Bone marrow transplantation carries significant risks including the potential for death and is only pursued because it is needed to treat the blood cancer it has. Attempts to replicate this have not been successful and given the risks, costs and scarcity of CCR5 negative donors, bone marrow transplantation is not seen as the primary choice. This has inspired research into other methods to try to block CCR5 expression through gene therapy. Finger-zinc nuclease have been used in Phase I trials in 12 humans and lead to an increase in CD4 cell count and a decrease in viral load when taking antiretroviral therapy.
After the "Berlin patient", two additional patients (who had HIV and cancer) had no HIV virus tracked after successful stem cell transplantation, as announced July 17, 2016 by virology Annemarie Wensing of University Medical Center Utrecht during a speech entitled "Cell Transplantation Alogenic Mother in HIV-1-Infected People EpiStem Consortium ", presented during 2016 Towards the HIV Cure Symposium in Durban, South Africa. However, both patients reported by EpiStem Consortium are still on antiretroviral therapy that is not so for Berlin patients. Therefore, it is not known whether both patients recover from HIV infection. The drug can be confirmed if therapy is stopped and there is no viral load increase.
Viral reservoir
The main constraint of conventional antiretroviral therapy that eliminates HIV infection is that HIV can integrate itself into host cell DNA and rest in latent state, while antiretrovirals only actively attack HIV replication. The cells in which HIV is dormant are called virus reservoirs, and one of the major sources is considered as a central memory and CD4 cell T4 transition memory. A recent report on the cure of HIV in two infants may be due to the fact that treatment begins within hours of infection, preventing HIV from forming a deep reservoir. Currently there is work being done to try to activate the reservoir cells into replication so that the virus is forced out of latency and can be attacked by ARV and host immune system. Targets include histone deacetylase (HDAC) that represses transcription and if inhibited may cause increased cell activation. The HDAC inhibitors of valproic acid and vorinostat have been used in human trials with only preliminary results so far.
Immune activation
Even with all latent viruses disabled, it is thought that a strong immune response needs to be induced to clear all remaining infected cells. Current strategies include using cytokines to restore CD4 cell counts and therapeutic vaccines for prime immune response. One such vaccine candidate is Tat Oyi, developed by Biosantech. The vaccine is based on HIV protein tat. A brief report of their I/II phase clinical trials reported safe and well-tolerated in 48 HIV-positive patients. Animal models have demonstrated the generation of neutralizing antibodies and lower levels of HIV viral load.
Drug ads
Direct advertising for consumers and other advertising for HIV drugs in the past has been criticized because they use a healthy and glamorous model rather than typical HIV patients and by presenting patients in unrealistically heavy activities, such as mountain climbing. The US FDA reprimanded some pharmaceutical manufacturers for publishing the advertisement in 2001 because misleading advertising harms consumers by implying unproven benefits and failing to disclose important information about the drug.
See also
- Antiviral drugs
- Invention and Development of HIV Protease Inhibitors
- Invention and Development of Non-Nucleoside Reverse Transcriptase Inhibitors
- The discovery and development of nucleoside and nucleotide reverse transcriptase inhibitors
References
External links
- AIDSinfo - Comprehensive resource for HIV/AIDS treatment and clinical trial information from the US Department of Health and Human Services
- ASHM - Australian comment on HHS Guidelines for the use of Antiretroviral Agents in Adult and HIV-Infected Adults
- The origin of combination antiretroviral therapy
- Viral Load research papers, including the effectiveness of ART to reduce viral load
- The current status of gene therapy strategies for treating HIV/AIDS
Source of the article : Wikipedia
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