Antiretroviral drugs are medications for the treatment of infection by the retrovirus HIV. Different antiretroviral drugs act at various stages of the HIV life cycle. Various combinations of three or four drugs are known as HAART or Highly Active Anti Retroviral Therapy.

Treatment guidelines are changing constantly. First came "hit hard, hit early", then came a more conservative approach with a starting point somewhere between 350 and 500 CD4+ T cells/mm3. The latest guidelines use 200 to 350 cells/mm3 as the range to consider starting HAART.

Antiretroviral regimens are complex, have serious side effects, pose difficulty with adherence, and carry serious potential consequences from the development of viral resistance because of nonadherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic decisions are critical. Treatment should usually be offered to all patients with symptoms ascribed to HIV infection. Recommendations for offering antiretroviral therapy among asymptomatic patients require analysis of real and potential risks and benefits. Panel on Clinical Practices for Treatment of HIV. September 2002 (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=12617573&dopt=Abstract)

Combination therapy

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.

Limitations of antiretroviral drug therapy

In the event that a person's HIV infection becomes resistant to standard HAART there are limited options. One option is to take larger combinations of antiretroviral drugs known as mega-HAART or salvage therapy. Unfortunately, salvage therapy will often increase the drugs' side-effects as well as the cost of the treatment. 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. The most common resistance mutation to 3TC in particular appears to do this, meaning that 3TC can be somewhat effective even as monotherapy and even where the virus is resistant to it.

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.

Intermittent Therapy is an experimental approach designed to reduce exposure to antiretrovirals drugs in an effort to mitigate side-effects. Intermittent Therapy differs from treatment interruptions in that it involves using a much shorter cycle of switching on and off the antiviral drugs. Week-on, week-off (wowo) or Five-days-on, two-days-off (foto), which involves being off on weekends, are being studied. Exactly what kinds of patients are best suited for this approach are still being studied. However, initial data suggests that this approach is ineffective and results in the development of drug resistance.

Once HIV has mutated in a sufficiently antiretroviral-drug-resistant state the treatments become more complicated and prognosis may deteriorate. Nevertheless, treatments continue to improve with a number of new drugs in clinical trials. In the twenty-first century it is rare for anyone in a developed country to die from AIDS.

However, in the developing world, limited access to treatments mean infections and deaths continue at an alarming rate.

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®, analog of thymidine

First FDA-approved antiretroviral, originally developed in 1964 and tested against cancer in the 1970s 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 outweighing 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®, analog of adenosine

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.

• zalcitabine: also called ddC, dideoxycytidine, trade name: Hivid®, analog of pyrimidine

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 NRTIs 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, is inconvenient to take and has serious side effects. For these reasons it is now rarely used.

• stavudine: also called d4T, trade names: Zerit®, Zerit XR®, analog of thymidine

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.

• lamivudine: also called 3TC, trade name: Epivir®, analogue of cytidine

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®, analog of guanosine

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. However, a genetic test is now available that, while not perfect, has reasonable accuracy in predicting whether an individual will be hypersensitive. Over 90% of patients can safely take abacavir.

• emtricitabine: also called FTC, trade name: Emtriva®, (formerly Coviracil), analogue of cytidine,

Approved by the FDA July 2, 2003. It is very similar to 3TC and cross-resistance between the two is near-universal.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

This is the third class of antiretroviral drugs that were developed.

• nevirapine: trade name: Viramune®

First NNRTI (tenth antiretroviral) approved by the FDA Jun 21, 1996 for adults and Sep 11, 1998 for pediatrics.

• delavirdine: trade name: Rescriptor®

Approved by the FDA Apr 4, 1997, eleventh approved antiretroviral.

• efavirenz: trade names: Sustiva®, Stocrin®

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: also known as tenofovir disoproxil fumarate, trade name: Viread®

Approved by the FDA October 26, 2001, tenofovir is marketed by Gilead Sciences.

• adefovir: also known as bis-POM PMPA, trade names: Preveon®, Hepsera®

Not approved by the FDA for HIV. In November 1999, an expert panel advised the FDA not to approve the drug due to concerns about possible kidney damage. Gilead Sciences discontinued development for HIV in December 1999 but continued to develop the drug for Hepatitis B, where it is effective with a much lower dose. FDA approval for use in the treatment of Hepatitis B was granted on September 20, 2002, and adefovir is sold for this indication under the brand name Hepsera.

Protease inhibitors (PIs)

Protease inhibitors inhibit the activity of protease, an enzyme used by HIV to cleave nascent 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 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.

• ritonavir: trade name: Norvir®

FDA approved March 1, 1996, seventh approved antiretroviral. Exceptional in that this is the only antiretroviral that inhibits a liver enzyme that the 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.

• indinavir: trade name: Crixivan®

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 manageable 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. Increasingly, it is being replaced by newer drugs that are more convenient to take and less likely to promote resistant virus, such as Kaletra or Atazanavir.

• nelfinavir: trade name: Viracept®

FDA approved March 14, 1997, twelfth approved antiretroviral.

• amprenavir, trade name: Agenerase®

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. Production of Agenerase® was discontinued by the manufacturer December 31, 2004.

• lopinavir: only marketed as a combination, see Kaletra® below.
• atazanavir: trade name: Reyataz®

FDA approved June 20, 2003. Atazanavir is the first PI approved for once-daily dosing, and also appears to be less likely to cause lipodystrophy and elevated cholesterol as side effects. It may also not be cross-resistant with other PIs. When boosted with ritronavir it is of equivalent potency to Kaletra for use in 'salvage' therapy in patients with a degree of drug resistance.

• fosamprenavir, trade name: Lexiva® pro-drug of amprenavir

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 ingredient. 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.

• tipranavir

Tipranavir disodium is a nonpeptidic protease inhibitor. Tiprinavir is currently undergoing clinical trials and has not yet been approved by the FDA. Nelfinavir is the only FDA approved nonpeptidic protease inhibitor.

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. This makes it inconvenient to take, and it is also very expensive. Accordingly it is usually reserved for 'salvage' therapy in patients with multi-drug resistant HIV.

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. Marketed by GlaxoSmithKline.

• Trizivir® = ABC + AZT + 3TC

FDA approved November 15, 2000, eighteenth approved antiretroviral drug. Marketed by GlaxoSmithKline.

• Kaletra® = lopinavir (for its HIV protease enzyme inhibition), with 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, seventeenth approved antiretroviral drug. This is the first multi-drug capsule that contains a drug not available individually. It has been demonstrated to be extremely potent and is often used in 'salvage' therapy for patients with some level of drug resistance. Some studies have suggested Kaletra is potent enough to be used as monotherapy and is also suitable for once-daily dosing, although neither is currently recommended. Marketed by Abbott Laboratories.

• Epzicom® (also Kivexa®) = ABC + 3TC

FDA approved August 2, 2004 for once-a-day dosing. Marketed by GlaxoSmithKline.

• Truvada® = emtricitabine + tenofovir

FDA approved August 2, 2004 for once-a-day dosing. Marketed by Gilead Sciences.

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.

• Hydroxyurea, (abbreviated HU) an older medication (an antimetabolite) used for sickle-cell anemia and some other hematologic disorders.

Enhances ddI, and to a lesser extent AZT and ddC. One possible explanation 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. HU can result in bone marrow suppression, and 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.

• Resveratrol (abbrevated RV), a natural product extracted from certain plants.

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.

• mycophenolic acid, an inosine monophosphate dehydrogenase (IMPDH)-inhibitor

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®. There is some evidence it may also be active against Hepatitis C, making it of particular interest in treatment of HIV-HCV co-infected patients.

• grapefruit juice, a common natural plant extract.

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 therefore the bioavailabity is increased.

• ritonavir: trade name: Norvir®

enhances other protease inhibitors through the inhibition of CYP3A4, 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.

• Leflunomide: trade name: Arava®

enhances AZT through depleting a dNTP analogous to HU, RV and mycophenolic acid.

External links

• Drug Chart (http://www.aidsmeds.com/lessons/DrugChart.htm)
• Further drug information (http://www.aidsmeds.com/)
• NIH web site (http://www.AIDSinfo.nih.gov/)
• Ten Texts on Saquinavir (http://www.aidsinfonyc.org/tag/tx/saquinavirten.html)
• The Synergistic Inhibition of HIV-1 With Nucleoside Analogs Combined With A Natural Product, Resveratrol (http://www.retroconference.org/2000/abstracts/509.htm)
• AZT resistance may be reversed by rheumatic drug (http://www.aidsmap.com/news/newsdisplay2.asp?newsId=2161)
• Saquinavir Mesylate - Invirase (warning: commerical product web page) (http://www.inviraseinfo.com)
• Origins of antiretroviral combination therapy (http://www.aegis.com/pubs/atn/1993/ATN17001.html)