Ways to Stop the Spread
There is no definite cure for HIV. Although, there are treatments that slow down the spread of the virus inside the body, which can increase life expectancy by decades. These treatments manipulate the complex life cycle of HIV by interfering in one of the steps which stops the entire cycle. Unfortunately because this virus enters the CD4 cells any chemicals used to fight against it may have the ability to damage our own cells. HIV is treated using a combination of HIV medicines (called an HIV Regimen) . This is called antiretroviral therapy (ART). The HIV medicines are grouped into six classes based on which part of the life cycle they interfere with;
1. Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTI's/NtRTI's)
2. Non-nucleoside reverse transcriptase inhibitors (NNRTI's)
3. Protease Inhibitors
4. Fusion Inhibitors
5. Integrase strand transfer inhibitors (INSTI)
NRTI/NtRTI's
The enzyme reverse transcriptase (RT) is essential to the life cycle of HIV and its ability to manipulate cell machinery to make more copies of itself(10). Enzymes are a type of protein, proteins are made up of polypeptide chains built from amino acids.The HIV-1 RT is made up of two molecular subunits; p66 and p51(3). The antiviral affect of either of these drugs is essentially the same as they are both analogues of naturally occurring deoxynucleotides which are the monomers of nucleic acids. These natural deoxynucleotides are needed to create the viral DNA(3). The analogue nucleotides compete with the natural nucleotides in order to be incorporated into the growing chain of viral DNA(10). However, unlike the natural nucleotides the analogues do not have a free 3' hydroxyl group. Due to this whenever a NRTI or NtRTI is incorporated into the viral DNA no more nucleotides can be added to form the 5'-3' phospodiester bonds. Thus, DNA synthesis comes to a halt also known as chain termination(10).
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NNRTI
This antiviral drug also acts by affecting RT but in a more direct way. NNRTI work by binding to the enzyme itself and causing a conformational change in the structure of the enzyme(11). This affects the catalytic activity of the enzyme and blocks the replication of the DNA by inhibiting the polymerase active site of the RT's p66 subunit. The overall change in enzyme structure also reduces its ability to bind to nucleotides(11).
Protease Inhibitor
HIV protease cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV particle. Without effective HIV protease, HIV virions remain uninfectious(12). These drugs prevent cleavage of HIV gag and pol polyproteins that include essential structural and enzymatic components of the virus. This prevents the transition of non-infectious HIV particles into their viral form. Protease inhibitors were designed to mimic the transition state of the protease's actual substrates. A peptide linkage consisting of –NH-CO- is replaced by an hydroxyethylen group (-CH2-CH(OH)-) which the protease is unable to cleave(12).
Fusion/Entry Inhibitors
This class of drugs interferes with the binding, fusion and entry portion of the HIV life cycle. An example of one of these drugs is Fuzeon, in this case a chemical binds to the gp41 protein and interferes with its ability to fuse the two membranes together thus ending the cycle right there and halting the infection of that cell(13). A second example would be Maraviroc which works by binding to the CCR5 preventing it from interacting with the gp120 protein on the HIV virus(13).
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INSTI
Integrase is a viral enzymes that integrates the viral HIV DNA into the host cell's DNA. The two most important co-factors in this process are Mg2+ and Mn2+. If they are inactivated these critical co-factors can cause functional impairment of the integrase enzymes (14). These co-factors can be inactivated by chelation therapy which is also used to treat certain heavy-metal poisoning. Chelation therapy is a chemical process in which a synthetic solution-EDTA (ethylenediaminetetraacetic acid)-is injected into the bloodstream to remove heavy metals from the body(14).This concept is applied in INSTI's, as most attack the same way by binding to the active site of Mg2+ ions. Competitive inhibitors compete with the viral DNA directly by binding to the enzyme itself and inhibit its function(14). This is done as the active site is blocked from binding to the target DNA(14).
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Factors that Affect HIV Regimen
Antiretroviral therapy (ART) is treatment for people infected with human immunodeficiency virus (HIV) using anti-HIV drugs. The standard treatment consists of a combination of at least three drugs that suppress HIV replication. Three drugs are used in order to reduce the likelihood of the virus developing resistance. ART has the potential both to reduce mortality and morbidity rates among HIV-infected people, and to improve their quality of life. There are many factors that are taken into consideration when choosing an HIV regimen such as;
- Current and lowest-ever CD4 cell count
- Viral load
- Pre-existing drug resistance
- Potential Interactions with other drugs
- Ability to achieve good adherence
- Cost
- Possible side effects
Drug Resistance
One of the issues with these regimens is that they may not be as effective due to the fact that the HIV virus mutates very easily. Specific strains can develop resistance against some of the HIV drugs. Drug resistance can lead to failure in treatment and, due to cross resistance (when a mutant strain is resistant to more than one drug), elimination of other HIV drugs. Studies have found transmitted drug resistance in anywhere from 6 to 16% of treatment in naive patients(16). Most critical is the detection of low-level NNRTI-resistance. One study found that the prevalence of primary drug resistance was over 11% in patients with chronic HIV infection(16). Antiretroviral treatment chosen on the basis of resistance testing resulted in similar efficacy rates between patients with primary drug resistance and those with wild-type virus(16). The “wild type” virus is the most common form of HIV. Anything different from the wild type is considered a mutation(15). The more that HIV multiplies, the more mutations show up. These mutations happen by accident. The virus doesn’t “figure out” which mutations will resist medications. Just one mutation can make HIV resistant to some drugs which is true for non-nucleoside reverse transcriptase inhibitors (NNRTIs)(15). However, HIV has to go through a series of mutations to develop resistance to other drugs, such as most protease inhibitors(15). Mutations that code for alterations of the conformational shape facilitate resistance of HIV to protease inhibitors(12). The locations of these mutations are primarily in the active site of the HIV protease enzyme as well as outside of the active site, including those at protease cleavage sites in the Gag-Pol polyprotein precursors(12).In an analysis of 3130 blood samples from newly diagnosed, ART-naive individuals, drug resistance mutations were found in over 10% of the samples(16). NRTI resistance was found in 4% and NNRTI resistance in 6% of samples 2.5% of patients had PI resistance(16).
Side Effects
Most drugs cause some side effects in some patients, but individual patients vary in their ability to tolerate them. For example, while one person might prefer to deal with mild nausea compared to insomnia, the opposite could be true for someone else(16). The risk of drug-related side effects also varies from person to person. For example, people with a specific genetic variation should not use some NRTI's due to the risk of hypersensitivity, while those with a history of pre-existing psychiatric problems are advised to avoid some NNRTI's(16). Side effects themselves can be divided into short term and long term. Short term effects include nausea, vomiting, diarrhea, headaches and fatigue. Often, these symptoms are worse soon after starting therapy and diminish after the body adjusts to a drug(16). Some side-effects associated with antiretroviral therapy worsen rather than improve over time. Retrovir (an NNRTI) has a harmful effect on bone marrow, potentially leading to anemia and low white blood cell counts (neutropenia). Other long term effects specific to "d-drugs"(special class of HIV drugs) include lipoatrophy (fat loss in the face and limbs), peripheral neuropathy( breakdown of the nerve endings or axons that send sensations to the brain), pancreatitis(inflammation of the pancreas) and elevated lactic acid in the blood(16). These issues appear to be due to mitochondrial toxicity. Mitochondria are small organelles in our cells(17). They are the cell’s power plant. They use oxygen, fat and sugar to produce adenosine triphosphate (ATP) via a process of complex oxidation-reduction reactions. This process is called “cellular respiration.” When the cell needs energy, it breaks down molecules of ATP to release the stored energy. Mitochondrial toxicity is damage that decreases the number of mitochondria. Mitochondria have an enzyme that helps them multiply(17). This enzyme is called DNA polymerase gamma, or “pol gamma.” It is very similar to HIV’s reverse transcriptase enzyme(17). Unfortunately, this also means that some drugs we use to inhibit reverse transcriptase can also inhibit pol gamma(17). When this happens, fewer new mitochondria may be produced.
Controlling Infection
The chain of infection consists of six steps; microorganism, reservoir, exit point, mode of transmission, entry point and susceptible host. The spread of this disastrous disease can be stopped by breaking this chain. In terms of breaking the chain at the first step, it should be recognized as early as possible, the earlier it is detected the better the response from the treatment. The main reservoir for this disease is humans and breaking the chain of infection here is through basic hygiene and wound care. In terms of exit point, anyone that has this disease should inform their sexual partners and practice safe sex or abstinence. This infection has a direct mode of transmission and can be stopped by basic hand washing, using condoms, and avoid contaminated needles.
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