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Management of HIV/AIDS

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What Antiretroviral drugs are

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.

Why there are so many of these 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.

In the event that a person's HIV infection becomes resistant to standard HAART there are a few options. One option is to take larger combinations of antiretroviral drugs known as mega-HAART or salvage therapy. Another is to take only one or two antiretroviral drugs, or to take a complete "drug holiday" to end the selection pressure that leads to selective reproduction of resistant strains of HIV, in the hope that sensitive strains will result and can then be treated.

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.

Antiretroviral drugs include:

Reverse Transcriptase Inhibitors (RTIs)

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:

Nucleoside Analog Reverse Transcriptase Inhibitors (NARTIs) or (NRTIs).

This was the first class of antiretroviral drugs developed.

  • zidovudine: also called AZT, ZDV, zidovudine, azidothymidine, trade name: Retrovir®
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.
  • didanosine: also called didanosine, ddI, trade names: Videx®, Videx EC®
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. The original formula's major debility was that it had to be taken with a buffer to neutralize stomach acid: this made the foul tasting, chewable tablets very large and also increased the probability that they would cause diarrhea. The new formula was also 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.
  • zalcitabine: also called ddC, dideoxycytidine, trade name: Hivid®
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 this FDA approval and the triple drug combinations with dual NRTIs and a PI were not far off by this time.
  • stavudine: also called d4T, trade names: Zerit®, Zerit XR®
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.
  • abacavir: also called ABC, trade name: Ziagen®
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.
  • adefovir: also known as bis-POM PMPA, trade name: Preveon®
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.
  • emtricitabine: also called FTC, trade name: Emtriva®, (formerly Coviracil)
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.

  • tenofovir: trade name: Viread®, Tenofovir DF, tenofovir disoproxil fumarate
Approved by the FDA October 26, 2001

Protease 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.

  • saquinavir: trade names Fortovase® (soft gel capsule), Invirase® (hard gel capsule)
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 reformulated soft gel capsule in Nov 7, 1997.
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 of can 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.
FDA approved March 13, 1996, eighth approved antiretroviral.
FDA approved March 14, 1997, twelth approved antiretroviral.
FDA approved April 15, 1999, sixteenth FDA-approved antiretroviral.
  • lopinavir: only marketed as a combination, see Kaletra® below.
  • atazanavir: trade name: Reyataz®
FDA approved June 20 2003
(not yet FDA approved)
(not yet FDA approved)

Fusion Inhibitors

Fusion inhibitors inhibit fusion (entry) of HIV with the cell membrane, preventing infection of uninfected cells.

  • enfuvirtide: trade name: Fuzeon®, also called T-20. Available only in injectable form since it is a peptide and would not survive digestion.
FDA approved March 15, 2003

Fixed Combinations

Fixed Combinations are multiple drugs in a single pill

  • Combivir® = AZT + 3TC
FDA approved Sep 26, 1997, thirteenth approved antiviral.
  • Trizivir® = ABC + AZT + 3TC
FDA approved November 15, 2000
  • Kaletra® = lopinavir (for its HIV protease enzyme inhibition) and ritonavir included to boost serum levels of lopinavir through inhibition of CYP3A4, a liver enzyme that metabolizes many other substances.
FDA approved Sep 15, 2000

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. Two of these have been FDA approved (for other indications) and are thus readily available for treatment use on an off-label basis.

  • HydroxyUrea, an old medication used for sickle-cell anemia and some other hematologic disorders.
enhances ddI, and to a lesser extent AZT and ddC
  • Resveratrol, a natural product extracted from certain plants.
enhances ddI, and to a lesser extent AZT and ddC
  • mycophenolic acid, an inosine monophosphate dehydrogenase (IMPDH)-inhibitor
enhances abacavir
  • ritonavir: trade name: Norvir®
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.


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