Friday 3 February 2012

Treatment of HIV Infection


In the early 1980s when the HIV/AIDS epidemic began, people with AIDS were not likely to live longer than a few years. With the development of safe and effective drugs, however, people infected with HIV now have longer and healthier lives.

DRUGS FOR HIV/AIDS

Currently, there are 30 antiretroviral drugs approved by the Food and Drug Administration to treat people infected with HIV. These drugs fall into four major classes.
  1. Reverse transcriptase (RT) inhibitors interfere with the critical step during the HIV life cycle known as reverse transcription. During this step, RT, an HIV enzyme, converts HIV RNA to HIV DNA. There are two main types of RT inhibitors.
    • Nucleoside/nucleotide RT inhibitors are faulty DNA building blocks. When these faulty pieces are incorporated into the HIV DNA (during the process when the HIV RNA is converted to HIV DNA), the DNA chain cannot be completed, thereby blocking HIV from replicating in a cell.
    • Non-nucleoside RT inhibitors bind to RT, interfering with its ability to convert the HIV RNA into HIV DNA.
  2. Protease inhibitors interfere with the protease enzyme that HIV uses to produce infectious viral particles.
  3. Entry and fusion inhibitors interfere with the virus' ability to fuse with the cellular membrane, thereby blocking entry into the host cell.
  4. Integrase inhibitors block integrase, the enzyme HIV uses to integrate genetic material of the virus into its target host cell.
  5. Multidrug combination products combine drugs from more than one class into a single product.
Currently available drugs do not cure HIV infection or AIDS. They can suppress the virus, even to undetectable levels, but they cannot eliminate HIV from the body. Hence, people with HIV need to continuously take antiretroviral drugs.
Truvada DHHS
*NNRTI = Non-nucleoside reverse transcriptase inhibitors
NRTI = Nucleoside reverse transcriptase inhibitors
PI = Protease inhibitors (preferably boosted with ritonavir)


1.Reverse transcriptase inhibitor

Reverse transcriptase inhibitors (RTIs) are a class of antiretroviral drug used to treat HIV infection, tumors, and cancer. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.

Mechanism

When HIV infects a cell, reverse transcriptase copies the viral single stranded RNA genome into a double-stranded viral DNA. The viral DNA is then integrated into the host chromosomal DNA, which then allows host cellular processes, such as transcription and translation to reproduce the virus. RTIs block reverse transcriptase's enzymatic function and prevent completion of synthesis of the double-stranded viral DNA, thus preventing HIV from multiplying.

Types

RTIs come in three forms:
  • Nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)
  • Nucleotide analog reverse transcriptase inhibitors (NtARTIs or NtRTIs)
  • Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
The mode of action of NRTIs and NtRTIs is essentially the same; they are analogues of the naturally occurring deoxynucleotides needed to synthesize the viral DNA and they compete with the natural deoxynucleotides for incorporation into the growing viral DNA chain. However, unlike the natural deoxynucleotides substrates, NRTIs and NtRTIs lack a 3'-hydroxyl group on the deoxyribose moiety. As a result, following incorporation of an NRTI or an NtRTI, the next incoming deoxynucleotide cannot form the next 5'-3' phosphodiester bond needed to extend the DNA chain. Thus, when an NRTI or NtRTI is incorporated, viral DNA synthesis is halted, a process known as chain termination. All NRTIs and NtRTIs are classified as competitive substrate inhibitors.
In contrast, NNRTIs have a completely different mode of action. NNRTIs block reverse transcriptase by binding at a different site on the enzyme, compared to NRTIs and NtRTIs. NNRTIs are not incorporated into the viral DNA but instead inhibit the movement of protein domains of reverse transcriptase that are needed to carry out the process of DNA synthesis. NNRTIs are therefore classified as non-competitive inhibitors of reverse transcriptase.

Nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)

Nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs) compose the first class of antiretroviral drugs developed. In order to be incorporated into the viral DNA, NRTIs must be activated in the cell by the addition of three phosphate groups to their deoxyribose moiety, to form NRTI triphosphates. This phosphorylation step is carried out by cellular kinase enzymes.
Zidovudine 
Zidovudine, also called AZT, ZDV, and azidothymidine, has the trade name Retrovir. Zidovudine was the first antiretroviral drug approved by the FDA for the treatment of HIV.
Didanosine 
Didanosine, also called ddI, with the trade names Videx and Videx EC, was the second FDA-approved antiretroviral drug.
Zalcitabine 
Zalcitabine, also called ddC and dideoxycytidine, has the trade name Hivid. This drug has been discontinued by the manufacturer.
Stavudine 
Stavudine, also called d4T, has trade names Zerit and Zerit XR.
Lamivudine 
Lamivudine, also called 3TC, has the trade name Epivir.
Abacavir 
Abacavir, also called ABC, has the trade name Ziagen, is an analog of guanosine.
Emtricitabine 
Emtricitabine, also called FTC, has the trade name Emtriva (formerly Coviracil).
Apricitabine 
Apricitabine, also called ATC. As of 2009, this drug is undergoing Phase-III evaluation, and if successful may achieve FDA approval in 2011.

Nucleotide analog reverse transcriptase inhibitors (NtARTIs or NtRTIs)

Normally, nucleoside analogs are converted into nucleotide analogs by the body. Taking nucleotide analog reverse transcriptase inhibitors (NtARTIs or NtRTIs) directly allows conversion steps to be skipped.
Tenofovir 
Tenofovir, also known as tenofovir disoproxil fumarate, has the trade name Viread.
Adefovir 
Adefovir, also known as bis-POM PMPA, has trade names Preveon and Hepsera. It is not approved by the FDA for treatment of HIV.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the third class of antiretroviral drugs that were developed. In all cases, patents remain in force until beyond 2007. This class of drugs was first described at the Rega Institute for Medical Research (Belgium)

2.Protease inhibitor

Protease inhibitors (PIs) are a class of medications used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of HIV-1 protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new virons.

Antiretrovirals

Protease inhibitors were the second class of antiretroviral drugs developed. In all cases, patents remain in force until 2010 or beyond.

Name
Notes
It was the first protease inhibitor approved by the FDA (December 6, 1995).
-
-
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The FDA approved it April 15, 1999, making it the sixteenth FDA-approved antiretroviral. It was the first protease inhibitor approved for twice-a-day dosing instead of needing to be taken every eight hours. The convenient dosing came at a price, as the dose required is 1,200 mg, delivered in eight very large gel capsules. Production was discontinued by the manufacturer December 31, 2004, as it has been superseded by fosamprenavir.
Is only marketed as a combination, with ritonavir.
The FDA approved it on June 20, 2003. Atazanavir was the first PI approved for once-daily dosing. It appears to be less likely to cause lipodystrophy and elevated cholesterol as side effects. It may also not be cross-resistant with other PIs.
Is a pro-drug of amprenavir. The FDA approved it October 20, 2003. The human body metabolizes fosamprenavir in order to form amprenavir, which is the active ingredient. That metabolization increases the duration that amprenavir is available, making fosamprenavir a slow-release version of amprenavir and thus reduces the number of pills required versus standard amprenavir.
Also known as tipranavir disodium
It was approved by the Food and Drug Administration (FDA) on June 23, 2006. Prezista is an OARAC recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents[3].

3.Binding, Fusion, Entry Sequence Inhibitors

HIV entry into human cells requires the following steps in sequence:
  1. The binding of HIV surface protein gp120 to the CD4 receptor
  2. A conformational change in gp120, which both increases its affinity for a coreceptor and exposes gp41
  3. The binding of gp120 to a coreceptor either CCR5 or CXCR4
  4. The penetration of the cell membrane by gp41, which approximates the membrane of HIV and the T cell and promotes their fusion
  5. The entry of the viral core into the cell
Entry inhibitors work by interfering with one aspect of this process.

Approved agents

  • Maraviroc binds to CCR5, preventing an interaction with gp120. It is also referred to as a "chemokine receptor antagonist" or a "CCR5 inhibitor."
  • Enfuvirtide binds to gp41 and interferes with its ability to approximate the two membranes. It is also referred to as a "fusion inhibitor."

Investigation / experimental agents

Other agents are under investigation for their ability to interact with the proteins involved in HIV entry and the possibility that they may serve as entry inhibitors.
  • TNX-355, a monoclonal antibody that binds CD4 and inhibits the binding of gp120
  • PRO 140, a monoclonal antibody that binds CCR5
  • BMS-488043, a small molecule that interferes with the interaction of CD4 and gp120
  • Plerixafor was being developed to interfere with interaction between HIV and CXCR4, but showed little useful antiviral activity in recent trials.
  • Epigallocatechin gallate, a substance found in green tea, appears to interact with gp120 as do several other theaflavins.
  • Vicriviroc, similar to maraviroc, is currently undergoing clinical trials for FDA approval.
  • Aplaviroc, an agent similar to maraviroc and vicriroc. Clinical trials were halted in 2005 over concerns about the drug's safety.
  • b12 is an antibody against HIV found in some long-term nonprogressors. It has been found to bind to gp120 at the exact region, or epitope, where gp120 binds to CD4. b12 seems to serve as a natural entry inhibitor in some individuals. It is hoped that further study of b12 may lead to an effective HIV vaccine.
  • Griffithsin, a substance derived from algae, appears to have entry inhibitor properties.
  • "Next generation fusion inhibitors" are being developed in an attempt to overcome the shortcomings of enfuvirtide. The most promising candidate to date is TRI-1144, in development by Trimeris.
  • DCM205, is a small molecule based on L-chicoric acid which is capable of directly inactivating HIV-1 in vitro. DCM205 is thought to act primarily as an entry inhibitor and represents a promising new microbicide candidate for the prevention of HIV-1/AIDS.

4.Integrase inhibitor

Integrase inhibitors are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, blocking it can halt further spread of the virus. Integrase inhibitors were initially developed for the treatment of HIV infection, but they could be applied to other retroviruses.
The first integrase inhibitor approved by the U.S. Food and Drug Administration (FDA) was
Raltegravir (brand name Isentress), approved on October 12, 2007. Research results published in the New England Journal of Medicine on July 24, 2008, concluded that "raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks."
Since integrase inhibitors target a distinct step in the retroviral life cycle, they may be taken in combination with other types of HIV drugs to minimize adaptation by the virus. They are also useful in salvage therapy for patients whose virus has mutated and acquired resistance to other drugs.

Drugs under development

  • Elvitegravir (GS 9137 or JTK-303), licensed by Gilead Sciences from Japan Tobacco, is currently undergoing Phase 2 clinical trials. GS 9137 is a low-molecular-weight, highly selective integrase inhibitor that shares the core structure of quinolone antibiotics.

5. HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) COUNTERS DRUG RESISTANCE

As HIV reproduces itself, variants of the virus emerge, including some that are resistant to antiretroviral drugs. Therefore, doctors recommend that people infected with HIV take a combination of antiretroviral drugs known as highly active antiretroviral therapy, or HAART. This strategy, which typically combines drugs from at least two different classes of antiretroviral drugs, has been shown to effectively suppress the virus when used properly. HAART has revolutionalized how people infected with HIV are treated. HAART works by suppressing the virus and decreasing the rate of opportunistic infections.

HIV TRANSMISSION AND ANTIRETROVIRAL DRUGS

Although the use of HAART has greatly reduced the number of deaths due to HIV/AIDS, and possibly the transmission of HIV/AIDS as well, this powerful combination of drugs cannot suppress the virus completely. Therefore, people infected with HIV who take antiretroviral drugs can still transmit HIV to others through unprotected sex and needle-sharing.

ANTIRETROVIRAL DRUG EFFECTS ON OPPORTUNISTIC INFECTIONS AND AIDS-ASSOCIATED CO-INFECTIONS

People infected with HIV have impaired immune systems that can leave them susceptible to opportunistic infections (OIs) and AIDS-associated co-infections, caused by a wide range of microorganisms such as protozoa, viruses, fungi, and bacteria. One example of an associated co-infection is hepatitis C virus infection, which can lead to liver cancer.
Potent HIV therapies such as HAART, however, have produced dramatic responses in patients. These therapies often allow the immune system to recover, sustain, and protect the body from other infections. Hence, antiretroviral drugs provide a way for the immune system to remain effective, thereby improving the quality and length of life for people with HIV.

SIDE EFFECTS OF ANTIRETROVIRAL DRUGS

People taking antiretroviral drugs may have low adherence to complicated drug regimens. Current recommended regimens involve taking several antiretroviral drugs each day from at least two different classes, some of which may cause unpleasant side effects such as nausea and vomiting. In addition, antiretroviral drugs may cause more serious medical problems, including metabolic changes such as abnormal fat distribution, abnormal lipid and glucose metabolism, and bone loss.

DOWN THE ROAD: NEW DRUGS IN THE PIPELINE

The Pharmaceutical Research and Manufacturers Association of America maintains a database of new drugs in development to treat HIV infection. They include new protease inhibitors and more potent, less toxic RT inhibitors, as well as other drugs that interfere with entirely different steps in the virus' lifecycle. These new categories of drugs include
  • Entry inhibitors that interfere with HIV's ability to enter cells
  • Integrase inhibitors that interfere with HIV's ability to insert its genes into a cell's normal DNA
  • Assembly and budding inhibitors that interfere with the final stage of the HIV life cycle, when new virus particles are released into the bloodstream
  • Cellular metabolism modulators that interfere with the cellular processes needed for HIV replication
  • Gene therapy that uses modified genes inserted directly into cells to suppress HIV replication. These cells are designed to produce T cells that are genetically resistant to HIV infection.
In addition, scientists are exploring whether immune modulators help boost the immune response to the virus and may make existing anti-HIV drugs more effective. Therapeutic vaccines also are being evaluated for this purpose and could help reduce the number of anti-HIV drugs needed or the duration of treatment.

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