Antiretroviral Treatment And Prevention
HIV infection is treated with antiretroviral therapy , which involves the use of multidrug regimens to reduce HIV-associated morbidity, prolong the duration and quality of survival, and prevent HIV transmission.
As of January 2016, there are more than 25 available antiretroviral drugs in six major classes . Multiple comparative clinical trials have shown that combination therapy involving multiple drugs from different classes is most effective. However, eradication of HIV infection cannot be achieved with available ARV regimens, primarily because the pool of latently infected CD4 T cells is established during the earliest stages of acute HIV infection and persists with a long half-life.100
ARV drugs work by blocking the virus at various points in its seven-stage life cycle. The stages of the HIV life cycle and the classes of ARV drugs that block them are100,101:
In addition, two drugs are pharmacokinetic enhancers/boosters used solely to improve the pharmacokinetic profiles of some ARV. These are listed in Table 11-6.100
Therapy Initiation Recommendations
For most patients, ART is initiated soon after the initial diagnosis. However, several conditions increase the urgency for therapy for example, pregnancy, presence of HIV-related complications, opportunistic infections, chronic hepatitis B and C infection, acute symptomatic HIV infection, and CD4 200cells/µl, rapidly declining CD4 counts, and higher viral loads .100
Therapy Regimen Recommendations
Hiv Treatment In Infants And Children
While rates of mother to child transmission of HIV have fallen over the last decade, the Joint United Nations Programme on HIV/AIDS still estimates that as many as 1.8 million children under 15 years old worldwide were living with HIV in 2017. NIAID supports research to determine which drugs, doses, and formulations comprise the safest and most effective HIV treatment regimens for pediatric patients, whose age, size, and organ function can cause them to react differently to medication than adults. Read more about HIV treatment in children. .
Starting And Staying On Antiretroviral Treatment
Antiretroviral treatment has transformed HIV infection from an almost uniformly fatal infection into a manageable chronic condition. Starting daily antiretroviral therapy as soon as possible after diagnosis and staying on treatment are essential for keeping HIV under control, which benefits individual health and prevents HIV transmission to others. NIAID-supported research has played a key role in optimizing antiretroviral drug regimens and in establishing the importance of early treatment and strict adherence. .
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Rationale Of Antiretroviral Therapy
HIV causes progressive damage to the immune system largely through loss of CD4+ T lymphocytes. Immune activation in the chronic phase allows continued HIV entry and replication. As many as 1010 virions are produced and cleared every day. The half-life of circulating virions is estimated to be 1-2 hours.
Antiretroviral therapy interrupts crucial steps of the HIV life cycle. Certain combinations of antiretrovirals are so potent that plasma viral load is suppressed to undetectable levels by conventional assays. This has led to the concept of HAART, which literally means using very potent antiretroviral regimen to control HIV disease. In operational terms, therapy is HAART if sustained suppression of viral load to undetectability is achieved. As a result of viral suppression, immune damage is halted and in most cases reversed so that the CD4 count rises and immune capability is reconstituted. The virologic and immunologic benefits have been translated into decreased morbidity and mortality. With HAART, management of HIV disease has taken resemblance to other chronic medical conditions such as diabetes.
How Do Hiv/aids Medicines Work
HIV/AIDS medicines reduce the amount of HIV in your body, which helps by:
- Giving your immune system a chance to recover. Even though there is still some HIV in your body, your immune system should be strong enough to fight off infections and certain HIV-related cancers.
- Reducing the risk that you will spread HIV to others
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Basic Principles Of Antiretroviral Therapy
Before 1996, few antiretroviral treatment options for HIV-1 infection existed. The clinical management of HIV-1 largely consisted of prophylaxis against common opportunistic pathogens and managing AIDS-related illnesses. The treatment of HIV-1 infection was revolutionized in the mid-1990s by the development of inhibitors of the reverse transcriptase and protease, two of three essential enzymes of HIV-1, and the introduction of drug regimens that combined these agents to enhance the overall efficacy and durability of therapy. A timeline of antiretroviral drug development and approval for human use is described in Figure 1.
Timeline for FDA approval for current antiviral and antiretroviral drugs.
For all antiretroviral drug classes, drug resistance has been documented in patients failing therapy as well as in therapy-naïve patients infected with transmitted, drug-resistant viruses. Resistance testing is therefore recommended before initiating HAART in therapy-naïve patients as well as when reoptimizing antiretroviral therapy after treatment failure. Given the number of agents and distinct classes of antiretroviral drugs available today, most patients, even those with a history of failure, can be successfully treated. However, as the virus continues to evolve and escape, with even the most effective therapies, new HIV-1 treatments will always be needed.
Classification Of Antiretroviral Agents
Category: Antiviral agents
Antiretroviral agents are synthetic antiviral agents that have antiviral activity against human immunodeficiency virus and are used in the management of HIV infection. There currently are 5 different classes of antiretroviral agents commercially available: nucleoside reverse transcriptase inhibitors , HIV protease inhibitors, nonnucleoside reverse transcriptase inhibitors , nucleotide reverse transcriptase inhibitors, and HIV fusion inhibitors.
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Choosing The Appropriate Antiretrovirals For The Treatment
Once the decision to initiate treatment is made, an appropriate regimen is designed after evaluating the following:
HIV-2 is not susceptible to NNRTI and T20
Primary drug resistance – this is quickly becoming a problem in developed countries as more viruses are being transmitted from patients who have been treated. It is useful to determine the resistance before starting treatment, although the absence of resistance does not guarantee success as resistant viruses may have been overgrown by wild type virus.
Patient profile, including age, sex, allergy history, current CD4 count, pregnancy, etc. A relatively high CD4 count is a contraindication to use nevirapine a woman’s desire to conceive in the future should also be known, as should any life style factors that may impede adherence. Food restrictions, pill burden and frequency of administration have to be evaluated for their impact on a patient’s lifestyle.
Coexisting hepatitis B and C– TDF , FTC , and 3TC are active against both HIV and hepatitis B. A combination of TDF + FTC/3TC is preferred as the nucleoside backbone in those who require treatment for both diseases. On the other hand, they should be avoided for treating HBV if HIV does not yet require treatment, for fear of development of HIV resistance. In untreated hepatitis C, ddI is best avoided as the standard treatment will include ribavirin.
‘Preparing’ the patient and adherence
Recommendations For Elite And Viremic Controllers
Definition of Elite and Viremic Controllers
A small percentage of persons naturally control their HIV without medications and are considered “elite controllers” of HIV. These individuals have a unique immunologic response to HIV that results in persistent control of plasma HIV RNA levels to levels consistently below the limit of quantitation. These individuals also usually maintain long-term control of CD4 cell count levels above 500 cells/mm3. Similarly, a larger, but still small subset of individuals with HIV, referred to as “viremic controllers”, have the ability to naturally maintain plasma HIV RNA at very low, but not undetectable, levels. The viremic controllers also usually have high CD4 cell counts, but typically have less stable and lower CD4 cell counts than elite controllers.
Management of Elite and Viremic Controllers
The optimal antiretroviral management of elite controllers and viremic controllers has generated controversy since, without antiretroviral therapy, these individuals naturally control HIV RNA levels and theoretically would pose minimal risk of transmitting HIV to others. These individuals, however, may still have increased risk of non-AIDS-related morbidity from immune activation and a significant proportion will eventually lose their immunologic control of HIV and have disease progression. The Adult and Adolescent ARV Guidelines make the following key recommendations for “elite controllers”:
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When Is It Time To Start Taking Hiv Medicines
People with HIV should start taking HIV medicines as soon as possible after an HIV diagnosis. It is especially important for people with AIDS-defining conditions or early HIV infection to start HIV medicines right away.
Women with HIV who become pregnant and are not already taking HIV medicines should also start taking HIV medicines as soon as possible.
How Is Hiv Treated
Although there is no cure for HIV, medications can dramatically slow the progression of the disease and people can live a relatively infection-free life. Few people die of AIDS these days thanks to effective treatments.Medications used to treat HIV are called antiretrovirals . Most people with HIV take combination ART every day. ART also reduces the risk of HIV transmission. Approved ARV treatments are grouped into seven drug classes as follows:
- Nucleoside reverse transcriptase inhibitors
- Non-nucleoside reverse transcriptase inhibitors
- Protease inhibitors
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Mode Of Action Entry Inhibitors
Entry Inhibitors interfere with the receptor-mediated entry of the virus into a cell. Two subclasses known as fusion inhibitors and CCR5 antagonists, are new classes of antiretroviral drugs used in combination therapy for the treatment of HIV infection.
This class of drugs interferes with the binding, fusion and entry process of HIV into a human cell.
Antiretroviral Drug Discovery And Development
NIAID plays a role in many stages of the antiretroviral drug discovery and development process. The search for new drugs remains a priority due to the development of resistance against existing drugs and the unwanted side effects associated with some current drugs. NIAID supports basic research to identify novel strategies to prevent HIV from taking hold and replicating in the body, as well as preclinical research to formulate antiretroviral drugs that can be tested in people. In addition, NIAID supports the largest networks of HIV therapeutic clinical trial units in the world. .
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What Is The Treatment For Hiv
The treatment for HIV is called antiretroviral therapy . ART involves taking a combination of HIV medicines every day.
ART is recommended for everyone who has HIV. ART cannot cure HIV, but HIV medicines help people with HIV live longer, healthier lives. ART also reduces the risk of HIV transmission.
Other Considerations In The Use Of Haart
Interruption of therapy
Although STI as a strategy of treatment is inadvisable, HAART may need to be interrupted because the patient undergoes surgery, develops intercurrent illness or manifests significant toxicity. It is also not uncommon that a patient develops medication ‘fatigue’ and demands a drug holiday. All interruptions and subsequent re-start should be supervised by a specialist in HIV medicine, as there are risks involved. For example, after stopping an NNRTI-regimen, the prolonged half-lives of NVP and EFV will maintain their concentrations above the IC95 level for up to 3 weeks, greatly increasing the chance of resistance. Stopping TDF, 3TC, or FTC in a patient co-infected with hepatitis B may also cause a flare-up of hepatitis B. It has been reported that viral rebound upon discontinuation of therapy can result in the acute retroviral syndrome.
Tolerability and convenience
Although it is cost effective, HIV infection has become the costliest disease to treat. Drugs alone average between HK$8,000 to 12,000 per month for the lifetime of a patient. Few societies will be able to sustain this cost if the rate of new infections remains unchanged. It will be prevention, not treatment, which constitutes the most effective response to the epidemic.
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How Do Antiretroviral Agents Work
Antiretroviral agents are a class of drugs used to help controlhuman immunodeficiency virus infection. Although they do not cure HIV, they may decrease the chances of developing acquired immunodeficiency syndrome and HIV-related illnesses such as serious infections or cancer. They reduce the number of HIV particles in the body , thus causing the immune system to work better and improving the quality of life.
HIV depletes the immune cells, CD4 T cells that the body needs for an effective immune response. Thus, the body’s ability to fight diseases reduces, leaving it vulnerable to an ever-widening range of opportunistic infections. For HIV to replicate, it must go through various stages of its life cycle:
- Attach to and enter a hostcell
- Translate its viral RNA into DNA
- Integrate its genetic coding into the host cell’s nucleus
- Create the building blocks by which new viruses are formed
- Start churning out copies of itself
The World Health Organization recommends that all adults and adolescents with HIV commence ARV treatment when their CD4 cell counts reach or fall below 350 cells/mm3.
A combination of “cocktails” of at least two of them is called ART. The following are the different categories of the antiretroviral drug:
- Nucleoside reverse transcriptase inhibitors
ARVs work in the following ways:
This DNA moves into the cell nucleus where it is incorporated into the human DNA strand by viral integrase.
Enhancing Healthcare Team Outcomes
Currently, the standard of care for a treatment-naïve patient with HIV-1 is a three-drug, highly active antiretroviral therapy regimen that is started as soon as possible after a patient tests positive for HIV. A foundation of HAART is the administration of drugs that inhibit HIV viral replication at several stages in the lifecycle through different mechanisms to prevent viral resistance to any single agent. However, the selection of these drugs and the life-long treatment of a patient with HIV can be complex. Management of a HAART regimen is a multifaceted process that should be administered by, or in consultation with, a provider with specific training as defined by the HIV-Medicine Association of the Infectious Diseases Society of America. This approach is crucial to optimize patient care as studies have demonstrated provider experience positively correlates with improved patient outcomes.
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What Hiv Medicines Are Included In An Hiv Treatment Regimen
There are many HIV medicines available for HIV treatment regimens. The HIV medicines are grouped into seven drug classes according to how they fight HIV.
The choice of an HIV treatment regimen depends on a person’s individual needs. When choosing an HIV treatment regimen, people with HIV and their health care providers consider many factors, including possible side effects of HIV medicines and potential drug interactions.
Nucleoside Reverse Transcriptase Inhibitors
NRTIs are the most effective form of ART. When HIV enters a healthy cell, it attempts to make copies of itself by using an enzyme called reverse transcriptase. NRTIs work by blocking that enzyme so HIV can’t make new copies of itself.
NRTIs are the first class of antiretroviral drugs to be approved by the FDA. Many NRTIs are used in combination with other drugs that rapidly reduce the HIV retrovirus.
Different NRTI drugs include:
Many of these drugs must be taken as a combination drug, or if they are taken on their own, they should be taken with another type of HIV medication to complete the antiretroviral therapy.
Currently, ritonavir is prescribed as a booster in treatment. This means that it is utilized as an additional treatment in addition to other medication.
Indinavir, nelfinavir, and saquinavir are less commonly prescribed because they have more side effects, including nausea, headache, diarrhea, vomiting, weakness, and kidney stones.
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Regimen Choice And Laboratory Monitoring
TDF/emtricitabine is the recommended PrEP agent TDF/lamivudine, TAF/emtricitabine, or TDF alone are not recommended for PrEP at this time . TDF-based PrEP is not recommended for persons with creatinine clearance below 60 mL/min/1.73 m2 . Glomerular dysfunction may occur with therapy, particularly in individuals older than 50 years. The dysfunction is usually reversible, and rechallenge with PrEP is often possible.140 Such patients should have more frequent creatinine clearance monitoring .
A combination HIV antigen-antibody assay should be performed within 7 days before initiation of TDF/emtricitabine PrEP to exclude HIV infection . An HIV RNA assay may be needed to exclude acute HIV infection in high-risk populations. A1-month follow-up visitis recommended to assess adherence and tolerability and to ensure the absence of primary HIV infection .141 Subsequent follow-up is recommended every 3 months to allow for STI screening and HIV testing . HCV serologic testing should be performed atleast annually and more frequently in high-risk individuals or those with elevated transaminase elevels .PrEP prescription should not exceed 90 days without interval testing for HIV infection .
Choosing Nrti Backbone In Regimen
The Adult and Adolescent ARV Guidelines include four different NRTI backbone combinations: abacavir-lamivudine, tenofovir alafenamide-emtricitabine, tenofovir DF-emtricitabine, and tenofovir DF-lamivudine.Abacavir has been associated with increased cardiovascular risk, and although data is conflicting about this association, many experts would avoid abacavir in the setting of known cardiovascular disease risk factors. Tenofovir DF is linked to increased risk of renal dysfunction and loss of bone mineral density accordingly, tenofovir DF is not recommended for patients with renal disease or osteoporosis. Tenofovir alafenamide has a less favorable lipid profile than tenofovir DF.
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Hiv Entry And Entry Inhibitors
The initial step in the HIV life cycle involves a complex interaction between HIV envelope spikes and host surface proteins. The HIV envelope consists of two structural components: surface envelope glycoprotein and transmembrane envelope glycoprotein . The surface of HIV is studded with approximately 14 envelope spikes, with each spike consisting of a trimer of three gp120 and gp41 subunits . Both gp120 and gp41 play an essential role in HIV entry into the host cell.
- gp120: The gp120 subunit is the component of the envelope that interacts with the host receptors and coreceptors these interactions involve the gp120 CD4 binding site on the outermost surface of gp120 and the more internal variable 3 region of gp120. The gp120 V3 region plays a major role in determining the coreceptor tropism of HIV.
- gp41: The gp41 subunit consists of three domains: ectodomain , the transmembrane domain , and the cytoplasmic tail . The gp41 ectodomain has several functional components that include the N-terminal hydrophobic region and the N-terminal heptad repeat region 1 and the heptad repeat region 2 . Prior to cell binding, the HIV gp41 exist in a conformation in which the gp41 is folded back on itself in an energy loaded state.
HIV Entry Inhibitors
The FDA-approved HIV entry inhibitors includes three subclasses: CD4 postattachment inhibitor, CCR5 coreceptor antagonists, and fusion inhibitors each one of these subclasses of entry inhibitors has one FDA-approved drug.