People with HIV/AIDS are often prescribed a combination of drugs that inhibit HIV at different steps in its life cycle. These are known as antiretroviral drugs. They are given in various combinations of three or four drugs, known as Highly Active Anti Retroviral Therapy or HAART, to inhibit HIV from mutating into forms that are resistant to the antiretroviral drugs.
HIV has a life span that can be as short as about 1.5 days from assembly by an infected, effectively hijacked cell through infection of another cell back to assembly by the newly infected cell. HIV lacks proofreading enzymes to correct errors made when it converts its RNA into DNA via reverse transcription. Since the life time of HIV is short and the DNA copies are wildly diverse due to a high error rate HIV mutates very rapidly. Most of the mutations either are inferior to the parent virus (often lacking the ability to reproduce at all) or convey no advantage, but some of them are superior to their parent and can enable HIV to slip past defenses such as the human immune system and antiretroviral drugs. The best defense against resistance is to suppress HIV as much as possible because the more active copies there are, the more chance that a superior one will be made. This is natural selection in action.
Combinations of antiretrovirals work by increasing the number of obstacles HIV has to mutate around and by reducing the chances of a superior mutation by keeping the number of offspring low. If a mutation arises that conveys resistance to one of the drugs being taken, the other drugs will help suppress reproduction of that mutation. With rare exceptions, no individual antiretroviral drug has been demonstrated to suppress an HIV infection for long; these agents must be taken in combinations in order to have a lasting effect. As a result the standard of care is to use combinations of antiretroviral drugs.
Combinations of antiretrovirals are subject to positive and negative synergies. This limits the total number of combinations that are available to use. For example, taking ddI and AZT together does less than taking either one separately since they inhibit each other.
There are other issues that further reduce the number of viable treatment combinations that can be derived from the available antiretroviral drugs. The often severe side effects from antiretrovirals further limit treatment options. The need to adhere to a complicated dosing schedule makes it impossible for some people to use the drugs properly.
In the event that a person's HIV infection becomes resistant to standard HAART there are only a few options. One option is to take larger combinations of antiretroviral drugs known as mega-HAART or salvage therapy unfortunately at the cost of increasing the drugs' side-effects. Another is to take only one or two antiretroviral drugs, specifically ones that have been demonstrated to induce HIV mutations which diminish the virulence of the infection somewhat.
Treatment interruptions (aka "drug holidays") where the antiretrovirals drugs are discontinued are also being studied as a method by which the sensitivity of HIV to the antiretroviral drugs can be increased by changing the selection pressure back from the drugs to being the human immune system again. This is an effort to breed virus which is more drug susceptible. Unfortunately, during the life-cycle of HIV the virus spends some time in a state where it is entirely composed of DNA which has been integrated into human DNA. Under certain conditions HIV can remain dormant in this state since CD4 T-cells also are dormant when they are not aroused due to the presence of detectable invading organisms. Once the antiretroviral drugs are re-introduced HIV emerging from the dormant state can include drug resistant strains.
Once HIV has mutated in a sufficiently antiretroviral-drug-resistant state the treatments become more fitful and and desperate. People are still dying of AIDS despite the improvements in therapy that allow so many to live.
Reverse Transcriptase Inhibitors inhibit activity of reverse transcriptase, a viral enzyme HIV needs to reproduce. Lack of this enzyme prevents HIV from building DNA based on its RNA. They come in three forms:
What Antiretroviral drugs are
Why there are so many of these drugs
Why it still isn't enough
Antiretroviral drugs include:
Reverse Transcriptase Inhibitors (RTIs)
Nucleoside Analog Reverse Transcriptase Inhibitors (NARTIs) or (NRTIs).
This was the first class of antiretroviral drugs developed.
First FDA-approved antiretroviral, originally developed in 1964 and tested against cancer in the 1970's but abandoned as ineffective and toxic. It was approved by the FDA on Mar 19, 1987 for AIDS and ARC (which is "AIDS Related Complex", a now-defunct medical term for a sort-of pre-AIDS illness) via the then-new FDA accelerated approval system. The unavailability of alternatives to treat AIDS altered the risk/benefit ratio, with the certain toxicity of HIV infection now outweighting the risk of drug toxicity. That this medication received rapid FDA approval is a measure of how desperate things were when it was tested and deployed.
Second FDA-approved antiretroviral on Oct 9, 1991 and again, as a reformulation in 2000. Didanosine was developed using tax dollars but since the government cannot market a product it awarded Bristol-Myers Squibb (BMS) with a ten-year patent-like arrangement to exclusively market and sell ddI as Videx® tablets. At the end of the ten-year period BMS re-formulated Videx® as Videx EC® and patented that. Didanosine is easily damaged by stomach acid; the original formula used chewable tablets that included a buffering compound to neutralize stomach acid. The chewable tablets were not only large and fragile, they also were foul-tasting and the buffering compound would cause diarrhea. The new formulation is a smaller capsule containing coated microspheres instead. It is also FDA approved for once-a-day dosing. Although the FDA had not approved the original formulation for once-a-day dosing it was possible for some people to take it that way.
Third antiretroviral to be approved by FDA, on Jun 19, 1992 as a monotherapy and again in 1996 for use in combination with AZT. Using combinations of NTRIs was in practice prior to the second FDA approval and the triple drug combinations with dual NRTIs and a PI were not far off by this time. Zalcitabine is the least powerful of all antiretroviral drugs.
Approved by the FDA in Jun 24, 1994 for adults and in Sep 6, 1996 for pediatric use and again as an extended-release version for once-a-day dosing in 2001. Fourth antiretroviral drug on the market.
Approved by the FDA in Nov 17, 1995 for use with AZT and again in 2002 as a once-a-day dosed medication. Fifth antiretroviral drug on the market, last NRTI for three years while approval process switched to protease inhibitors.
Approved by the FDA December 18, 1998, fifteenth approved antiviral. Most powerful NRTI, and one of the most deadly due its ability to trigger to hypersensitivity reactions that lead to sudden death in certain individuals.
Not approved by the FDA. In November 1999, an expert panel advised the FDA not to approve the drug due to concerns about possible kidney damage. The manufacturer, Gilead, discontinued HIV research in December 1999 in the US but continues to develop the drug in the US for Hepatitis B and continues to develop it for HIV but not in the US.
Approved by the FDA July 2, 2003.
NonNucleoside Reverse Transcriptase Inhibitors (NNRTIs)
This is the third class of antiretroviral drugs that were developed.
First NNRTI (tenth antiretroviral) approved by the FDA Jun 21, 1996 for adults and Sep 11, 1998 for pediatrics.
Approved by the FDA Apr 4, 1997, eleventh approved antiretroviral.
Approved by the FDA Sep 21, 1998, fourteenth approved antiretroviral.Nucleotide Analog Reverse Transcriptase Inhibitors (NtARTIs) or (NtRTIs)
Normally nucleoside analogs are converted into nucleotide analogs by the body. Taking them directly allows conversion steps to be skipped, causing less toxicity.
Approved by the FDA October 26, 2001Protease inhibitors (PIs)
Protease inhibitors inhibit the activity of protease, an enzyme used by HIV to cleave nacent proteins for final assembly of new HIV virons, and so prevent viral replication. This was the second class of antiretroviral drugs developed.
First FDA-approved protease inhibitor (sixth antiretroviral) in December 6, 1995, as Invirase®, a poorly-absorbed hard gel capsule which quickly led to viral resistance in many of the pioneer patients and again as Fortovase®, a soft gel capsule reformulated for improved bioavailablity in Nov 7, 1997. It appears that the manufacturer, Roche, rushed Invirase® to market, but again the conditions that prevailed at the time were very bad and there was a lot of pressure to produce products quickly.
FDA approved March 1, 1996, seventh approved antiretroviral. Exceptional in that this is the only antiretroviral that inhibits a liver enzyme that that body normally uses to metabolize away protease inhibitors, Cytochrome P450-3A4 (CYP3A4). The drug's molecular structure inhibits CYP3A4, so a low dose can be used to enhance any other protease inhibitors. This effect does come with a price: it also affects the strength of numerous other medications, making it difficult to know how to administer them concurrently. In addition it can cause a large number of side-effects on its own.
FDA approved March 13, 1996, eighth approved antiretroviral. Indinavir was much more powerful than any prior antiretroviral drug; using it with dual NRTIs set the standard for treatment of HIV/AIDS and raised the bar the design and introduction of subsequent antiretroviral drugs. Protease inhibitors changed the very nature of the AIDS epidemic from one of a terminal illness to a somewhat managable one. Unfortunately, indinavir wears off quickly after dosing and therefor requires dosing very precisely every eight hours in order to thwart HIV from forming drug resistant mutations including resistances to other protease inhibitors. It has restrictions on what sorts of food may be eaten concurrently. It can cause kidneys stones and metabolic abnormalities including hyperlipidemia which is cholesterol elevations, triglyceride elevations and bizarre alterations in body shape know as lipodystrophy in addition to other side-effects.
FDA approved March 14, 1997, twelth approved antiretroviral.
FDA approved April 15, 1999, sixteenth FDA-approved antiretroviral. First protease inhibitor approved for twice-a-day dosing instead of needing to be taken every eight hours. This came at a price as the dose required is 1,200mg which is delivered in eight very large gel capsules.
FDA approved June 20, 2003
FDA approved October 20, 2003. This is a substance that the human body metabolizes in order to form another drug, amprenavir, which is the active ingrediant. The intention is to increase the duration that amprenavir available since it has the effect of be a slow-release version of amprenavir. This reduces the amount of pills required versus standard amprenavir.
(not yet FDA approved)Fusion Inhibitors
Fusion inhibitors inhibit fusion (entry) of HIV with the cell membrane, preventing infection of uninfected cells.
FDA approved March 15, 2003Fixed Combinations
Fixed Combinations are multiple drugs in a single pill
FDA approved Sep 26, 1997, thirteenth approved antiviral.
FDA approved November 15, 2000, eighteenth approved antiretroviral drug.
FDA approved Sep 15, 2000, seventeenth approved antiretroviral drug. This is the first multi-drug capsule that contains a drug not available individually.Synergistic enhancers
While most of these substances do not possess any antiretroviral properties, when they are taken concurrently with antiretroviral drugs they enhance the effect of that drug. One of these is an over-the-counter nutritional supplement and another two of these have been FDA approved (for other indications) and are thus readily available for treatment use on an off-label basis.
Enhances ddI, and to a lesser extent AZT and ddC. One possible explaination is that HU causes cells to spend more time in the "S" phase checkpoint of cellular growth which allows ddI, AZT and ddC into the cell more. In addition HU inhibits ribonucleotide reductase, an enzyme used to breakdown certain proteins to form the building blocks of DNA called dNTPs. When dNTPs are depleted the cell tries to absorb more but if ddI, AZT or ddC is present it absorbs that due to the simlarity, the net effect is more ddI, AZT or ddC enters the cell. There are warnings that using HU with ddI can increase the risk of pancreatitis. The Health and Human Services (HHS) panel in the US is recommending against the use of HydroxyUrea although some doctors are still using it for various reasons.
Enhances ddI, and to a lesser extent AZT and ddC in vitro. Like HU, RV also causes cells to spend more time in the "S" phase checkpoint of cellular growth and also inhibits ribonucleotide reductase. RV is generally better tolerated than HU and has fewer side-effects.
Enhances abacavir but reduces the effect of AZT and d4T. Works analogous to HU and RV only the enzyme inhibited is IMPDH which leads to depletion of the dNTP named dGTP which causes cells to take up more abacavir. Mycophenolic acid is currently approved for used in organ transplantation as mycophenolate mofetil, trade name: CellCept®.
The liver enzyme CYP3A4 is secreted into the gastrointestinal (GI) tract as well as the blood stream. The GI secretions are a first line defense against toxic substances; this allows the body to metabolize away many chemicals before they enter the bloodstream. Grapefruit juice can neutralize CYP3A4 in the GI tract but not significantly in the bloodstream. By pre-treating with grapefruit juice prior to taking protease inhibitors the GI intake and therefor the bioavailabity is increased.
enhances other protease inhibitors through the inhibition of CYP384, a liver enzyme. While ritonavir is a protease inhibitors, it cannot be used to inhibit HIV significantly by itself at the low doses required to enhance other protease inhibitors.
enhances AZT through depleting a dNTP analogous to HU, RV and mycophenolic acid.
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