Antiretroviral drug

Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. Different classes of antiretroviral drugs act at different stages of the HIV life cycle. Combination of several (typically three or four) antiretroviral drugs is known as Highly Active Anti-Retroviral Therapy (HAART).

Organizations such as the National Institutes of Health (Bethesda, Maryland, USA) recommend offering antiretroviral treatment to all patients with HIV-related symptoms. However, because of the complexity of selecting and following a regimen, the severity of the side effects, and the importance of compliance to prevent viral resistance, such organizations emphasize the importance of involving patients in therapy choices and recommend analyzing the risks and the potential benefits to patients without symptoms.

Combination therapy

The life cycle of HIV can be as short as about 1.5 days: from viral entry into a cell; through replication, assembly, and release of additional viruses; to infection of other cells. HIV lacks proofreading enzymes to correct errors made when it converts its RNA into DNA via reverse transcription. Its short life cycle and high error rate cause the virus to mutate very rapidly, resulting in a high genetic variability of HIV. 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 have a natural selection superiority to their parent and can enable them to slip past defenses such as the human immune system and antiretroviral drugs. The more active copies of the virus, the greater the possibility that one resistant to antiretroviral drugs will be made, so antiretroviral combination therapy defends against resistance by suppressing HIV replication as much as possible.

Combinations of antiretrovirals create multiple obstacles to HIV replication to keep the number of offspring low and reduce the possibility of a superior mutation. If a mutation arises that conveys resistance to one of the drugs being taken, the other drugs continue to 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, which limits the number of useful combinations. For example, ddI and AZT inhibit each other, so taking them together is less effective than taking either one separately. Other issues further limit some people's treatment options from antiretroviral drug combinations, including their complicated dosing schedules and often severe side effects.

Current treatment guidelines

Antiretroviral drug treatment guidelines have changed many times. Early recommendations attempted a "hit hard, hit early" approach. A more conservative approach followed, with a starting point somewhere between 350 and 500 CD4+ T cells/mm³. The current guidelines use new criteria to consider starting HAART, as described below. However, there remain a range of views on this subject and the decision of whether to commence treatment ultimately rests with the patient and their doctor.

The current guidelines for antiretroviral therapy (ART) from the World Health Organization reflect the 2003 changes to the guidelines and recommend that in resource-limited settings (i.e., developing nations), HIV-infected adults and adolescents should start ART when HIV infection has been confirmed and one of the following conditions is present ):

Clinically advanced HIV disease;
WHO Stage IV HIV disease, irrespective of the CD4 cell count;
WHO Stage III disease with consideration of using CD4 cell counts less than 350/µl to assist decision making;
WHO Stage I or II HIV disease with CD4 cell counts less than 200/µl.

The treatment guidelines in the USA are set by the United States Department of Health and Human Services (DHHS). The current guidelines for adults and adolescents were stated on October 6, 2005 :

All patients with history of an AIDS-defining illness or severe symptoms of HIV infection regardless of CD4+ T cell count receive ART.
Antiretroviral therapy is also recommended for asymptomatic patients with less than 200 CD4+ T cells/µl.
Asymptomatic patients with CD4+ T cell counts of 201–350 cells/µl should be offered treatment.
For asymptomatic patients with CD4+ T cell of greater than 350 cells/µl and plasma HIV RNA greater than 100,000 copies/ml, most experienced clinicians defer therapy but some clinicians may consider initiating treatment.
Therapy should be deferred for patients with CD4+ T cell counts of greater than 350 cells/µl and plasma HIV RNA less than 100,000 copies/mL.

The preferred initial regimens are either :

efavirenz + lamivudine or emtricitabine + zidovudine or tenofovir; or
lopinavir boosted with ritonavir + zidovudine + lamivudine or emtricitabine.

Because HIV disease progression in children is more rapid than in adults, and laboratory parameters are less predictive of risk for disease progression, particularly for young infants, treatment recommendations from the DHHS have been more aggressive in children than in adults, the current guidelines were published November 3, 2005 .

In 2005, the Centers for Disease Control and Prevention in the United States recommended a 28-day HIV drug regimen for those who have been exposed to HIV (HIV Postexposure Prophylaxis [PEP]). The drugs have demonstrated effectiveness in preventing the virus nearly 100% of the time in those who received treatment within the initial 24 hours of exposure. The effectiveness falls to 52% of the time in those who are treated within 72 hours; those not treated within the first 72 hours are not recommended candidates for the regimen.

Concerns

There are several concerns about antiretroviral regimens. The drugs can have serious side effects. Regimens can be complicated, requiring patients to take several pills at various times during the day, although treatment regimens have been greatly simplified in recent years. If patients miss doses, drug resistance can develop. Also, anti-retroviral drugs are costly, and the majority of the world's infected individuals do not have access to medications and treatments for HIV and AIDS.

Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance.

Limitations of antiretroviral drug therapy

If an HIV infection becomes resistant to standard HAART, there are limited options. One option is to take larger combinations of antiretroviral drugs, an approach known as mega-HAART or salvage therapy. Unfortunately, salvage therapy often increases the drugs' side-effects and treatment costs. Another is to take only one or two antiretroviral drugs, specifically ones that induce HIV mutations that diminish the virulence of the infection. The most common resistance mutation to lamivudine (3TC) in particular appears to do this. Thus, 3TC can be somewhat effective even alone and when the virus is resistant to it.

If an HIV infection becomes sufficiently resistant to antiretroviral-drugs, treatment becomes more complicated and prognosis may deteriorate. Treatment options continue to improve as additional new drugs enter clinical trials. However, the limited distribution of many such drugs denies their benefits to patients in the developing world.

Drug holidays (or "structured treatment interruptions"), are intentional discontinuations of antiretroviral drug treatment. Studies of such interruptions attempt to increase the sensitivity of HIV to antiretroviral drugs. The interruptions attempt to change the selection pressure from the drug resistance back toward resistance to the human immune system, thus breeding a more drug-susceptible virus. Unfortunately, HIV spends some of its life-cycle in a state where its DNA is entirely integrated into human DNA. Under certain conditions, drug-resistant strains of the virus can remain dormant in this state, since CD4 T-cells also are dormant when not aroused by invading organisms. The resistant strain can then reemerge when antiretroviral drugs are re-introduced.

Intermittent therapy is an experimental approach designed to reduce exposure to antiretroviral 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. Studies of such approaches include schedules of Week-on, week-off (a.k.a. "wowo") and Five-days-on, two-days-off (a.k.a. "foto"), which skips treatment on weekends. They also seek to determine what kinds of patients are best suited for this approach. However, initial data suggest that intermittent therapy is ineffective and results in drug resistance.

It is still unclear whether suppressing or even eliminating HIV will be adequate to restore normal immune function in the long term, since HIV can damage the ability of the thymus to produce normally diverse T-cells. Also, rapid suppression of HIV and partial restoration of the immune system sometimes produces a dangerous hypersensitivity reaction, immune reconstitution inflammatory syndrome. Research continues in these areas.

Classes of antiretroviral drugs

Antiretroviral drugs are broadly classified by the phase of the retrovirus life-cyle that the drug inhibits. There are thus three broad classifications of antiretroviral drugs:

Reverse transcriptase inhibitors (RTIs) target construction of viral DNA by inhibiting activity of reverse transcriptase.
Protease inhibitors (PIs) target viral assembly by inhibiting the activity of protease, an enzyme used by HIV to cleave nascent proteins for final assembly of new virons.
Fusion inhibitors block HIV from fusing with a cell's membrane to enter and infect it.

Fixed dose combinations

Fixed dose combinations are multiple antiretroviral drugs combined into a single pill.

Combivir®: Combivir® = AZT + 3TC. The FDA approved it September 26, 1997, making it the thirteenth approved antiretroviral. It is marketed by GlaxoSmithKline.
Trizivir®: Trizivir® = abacavir (ABC) + AZT + 3TC. The FDA approved it November 15, 2000, making it the eighteenth approved antiretroviral drug. It is marketed by GlaxoSmithKline.
Kaletra®: 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. The FDA approved it September 15, 2000, making it the seventeenth approved antiretroviral drug. It 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, its patent will expire in the United States on 2016- 06-26.
Epzicom®: Epzicom® (also Kivexa®) = ABC + 3TC. The FDA approved it August 2, 2004 for once-a-day dosing. It is marketed by GlaxoSmithKline.
Truvada®: Truvada® = emtricitabine + tenofovir. The FDA approved it August 2, 2004 for once-a-day dosing. It is 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: Hydroxyurea (HU) is an older medication (an antimetabolite) used for sickle-cell anemia and some other hematologic disorders. It 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 similarity, 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: Resveratrol (RV) is a natural product extracted from certain plants. It 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: Mycophenolic acid is an inosine monophosphate dehydrogenase ( IMPDH)-inhibitor. It 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: Grapefruit juice is a common natural plant extract. The enzyme CYP3A4, a member of the Cytochrome P450 enzyme family, is present mostly in the liver but also in the lining of the gastrointestinal (GI) tract. One of the functions of CYP3A4 is to metabolise, or break down, foreign chemicals including many drugs used to treat HIV. Such enzymes present in the GI tract 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 liver. By pre-treating with grapefruit juice prior to taking protease inhibitors the GI intake and therefore the bioavailabity is increased. The effect, however, is unreliable and results may vary greatly, therefore it is not a standard recommended practice.
Ritonavir: Ritonavir has the trade name Norvir®. It enhances other protease inhibitors through the inhibition of CYP3A4, a liver enzyme. While ritonavir is a protease inhibitor, it cannot be used to inhibit HIV significantly by itself at the low doses required to enhance other protease inhibitors.
Leflunomide: Leflunomide has the trade name Arava®. It enhances AZT through depleting a dNTP analogous to HU, RV and mycophenolic acid.

Adverse Effects

Adverse effects of antiretroviral drugs vary by drug, by ethnicity, and by individual, and by interaction with other drugs, including alcohol. Hypersensitivity to some drugs may also occur in some individuals. The following list is not complete, but includes several of the common adverse effects experienced by patients taking some antiretroviral drugs:

Abdominal pain
Alopecia
Anemia
Asthenia
Diarrhea
Dizziness (Vertigo)
Fanconi syndrome
Flatulence
Headache
Hepatitis
Hyperbilirubinemia
Hypercholesterolemia (Dyslipidemia, Hyperlipidemia, high cholesterol)
Hyperpigmentation (of nails, palms, or soles)
Ingrown nails
Insomnia
Jaundice
Liver failure
Malaise
Mental confusion
Myalgia
Myalgic Encephalomyelitis (chronic fatigue syndrome)
Myopathy
Nausea
Neutropenia
Nightmares
Oral ulcers
Pancreatitis
Paresthesia (numbness)
Peripheral neuropathy
Rash
Renal failure or insufficiency
Somnolence (drowsiness)
Stevens-Johnson syndrome
Change in taste perception
Vomiting
Xeroderma (dry skin)
Xerostomia (dry mouth)