Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as highly active antiretroviral therapy, or HAART. The American National Institutes of Health and other organizations recommend offering antiretroviral treatment to all patients with AIDS. 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, however, such organizations emphasize the importance of involving patients in therapy choices, and recommend analyzing the risks and the potential benefits to patients without symptoms.[1]
There are different classes of antiretroviral drugs that act at different stages of the HIV life-cycle.
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Antiretroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits.
Fixed dose combinations are multiple antiretroviral drugs combined into a single pill.
Synergistic enhancers either do not possess antiretroviral properties alone or are inadequate or impractical for monotherapy, but when they are taken concurrently with antiretroviral drugs they enhance the effect of one or more of those drugs (often by altering the metabolism of antiretrovirals). These include ritonavir, which is an antiretroviral drug that belongs to the class of protease inhibitors. It can, however, be administered at a "baby" dosage to reduce the liver metabolism of other antiretroviral drugs. This principle was first exploited in the drug Kaletra (Abbott), which is a combination of ritonavir with the protease inhibitor lopinavir at a ratio (v/v) of 1:4. Ritonavir is also used as an enhancer of other protease inhibitors such as saquinavir and atazanavir, and of the investigational integrase inhibitor, GS-9137. Other synergistic enhancers are being investigated for this purpose.
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.[11] 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 that conveys resistance to one of the drugs being taken arises, 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 usually comprise two nucleoside-analogue RTIs and one non-nucleoside-analogue RTI or protease inhibitor.[12] This three drug combination is commonly known as a triple cocktail.[13]
[14] Combinations of antiretrovirals are subject to positive and negative synergies, which limits the number of useful combinations. For example, Didanosine 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.
In recent years, drug companies have worked together to combine these complex regimens into simpler formulas, termed fixed-dose combinations. For instance, two pills containing two or three medications each can be taken twice daily. This greatly increases the ease with which they can be taken, which in turn increases adherence, and thus their effectiveness over the long-term. Lack of adherence is a primary cause of resistance development in medication-experienced patients. Patients able to adhere at this rate and higher can maintain one regimen for up to a decade without developing resistance. This greatly increases chances of long-term survival, as it leaves more drugs available to the patient for longer periods of time.
The most important two considerations for HAART are
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 (that is, developing nations), HIV-infected adults and adolescents should start ART when HIV infection has been confirmed and one of the following conditions is present [15]:
The treatment guidelines specifically for 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 [16]:
In countries with a high rate of baseline resistance, resistance testing is recommended prior to starting treatment; or, if the initiation of treatment is urgent, then a "best guess" treatment regimen should be started, which is then modified on the basis of resistance testing. In the UK, there is 11.8% medium to high-level resistance at baseline to the combination of efavirenz + zidovudine + lamivudine, and 6.4% medium to high level resistance to stavudine + lamivudine + nevirapine.[17]
Most current HAART regimens consist of three(3) drugs: 2 NRTIs + a PI/NNRTI. Initial regimens use "first-line" drugs with a high efficacy and low side-effect profile. A typical regimen would be: tenofovir(TDF) + lamivudine(3TC) + efavirenz(EVZ).
The treatment guidelines for HIV-1 infected adults in the developed world (that is, those countries with access to all or most therapies and laboratory tests) have been set by the International AIDS Society-USA(IAS-USA) since 1996. The IAS-USA is a 501(c)(3) not-for-profit organization in the USA (and is not related to the worldwide International AIDS Society or IAS). The IAS-USA guidelines for antiretroviral therapy are developed by a volunteer panel of experts. Its last update was published in August 2008 in the Journal of the American Medical Association [18] . In this update, the panel recommends that therapy be initiated before the CD4+ cell count declines to below 350/uL and be individualized for the particular patient's situation and comorbidities. For initial therapy, it recommends 2 NRTIs with either an NNRTI or a ritonavir-boosted PI. In antiretroviral therapy failure, the goal of subsequent treatment is suppression of HIV-1 RNA to below detection; the treatment should ideally have 3 new drugs to which the patient's virus is susceptible. Therapy in selected clinical situations is also described. The IAS-USA also sponsors the development of guidelines for the use of drug resistance testing in patients with HIV-1 infection [19]
The preferred initial regimens are[20]:
Because HIV disease progression in children is more rapid than in adults, and laboratory parameters are less predictive of risk for disease progression, in particular 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 [21].
In 2005, the Centers for Disease Control and Prevention in the United States recommended a 28-day HIV drug regimen for those that have been exposed to HIV (HIV Postexposure Prophylaxis [PEP])[22]. The WHO recommendations on treatment are that the minimum that should be used is dual NRTIs for 28 days, with triple therapy (dual NRTIs plus a boosted PI) being offered where there is a risk of resistance [23]. The effectiveness of this intervention has never been precisely ascertained, but it is believed to be most effective the sooner the drugs are administered, and useless if treatment is delayed too long; hence it is not usually recommended that it be started on the basis of an exposure more than 76 hours prior to starting therapy.
The use of antiretrovirals is also recommended for the prevention of mother-to-child transmission of HIV-1. The current WHO recommended regimen is as follows: where the pregnant woman does not yet need to start ART for therapeutic reasons, she should start Zidovudine (AZT) from 28 weeks or as soon as possible thereafter, be provided with single-dose Nevirapine (NVP) when entering labour, and be given AZT+3TC for one week following delivery. Meanwhile, whether the mother was on the above or standard ART, the child should be given single dose Nevirapine immediately after delivery and daily Zidovudine until one week old.[24] Complementary measures that may also be used include caesarian section and formula feeding; in some settings, the combination of providing all these measures has succeeded in reducing the risk of infection from 25% to about 1%.[25]
There are several concerns about antiretroviral regimens. The drugs can have serious side-effects.[26] 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.[1] Also, providing anti-retroviral treatment is costly and resource-intensive, and the majority of the world's infected individuals cannot access treatment services.
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.
Other means of simplifying adherence is the use of internet and smartphone tools such as email and Text/SMS reminders.
As people age, their bodies are not able to repair and rebuild damaged cells, organs or tissues as rapidly as those of younger people. Diseases like HIV that attack and destroy the body's defenses can exacerbate this slowing and increase the risk of developing additional medical problems like diabetes and high blood pressure, and more physical limitations than younger adults with HIV. In the early years of the HIV epidemic (before HAART), older adults' health deteriorated more rapidly than that of younger individuals - regardless of CD4 count. Several studies found that older adults had lower CD4 counts at diagnosis, faster progression to an AIDS diagnosis, more opportunistic infections, and a shorter survival rate than younger adults, regardless of when they were first diagnosed with HIV.
Recent studies have found that a person's age does not interfere with the ability of HAART to reduce viral load, but there may be differences between younger and older people in how well the immune system responds to treatment. A study published in AIDS (2000) by Roberto Manfredi and Francesco Chiodo examined the effect of HAART on older people (defined as 55 or older) compared to younger people (35 or younger). The study included 21 older people (8 women, 13 men) and 84 younger people (29 women, 55 men). The researchers found that both groups responded to HAART, especially in reducing viral load. However, CD4 counts did not increase as much in the older people relative to the younger ones. On average, CD4 counts increased from 212 to 289 for older adults after one year of HAART. During the same period, CD4 counts rose from 231 to 345 for younger people.
Some people may have a very low CD4 count even though they have an undetectable viral load. This may be related to decreased activity in the thymus (the gland where CD4 cells are made). A 2001 study in AIDS conducted by researchers in Los Angeles included 80 HIV-positive veterans (13 were over 55 and 67 were younger). Although both groups of veterans showed dramatic reductions in viral load once they were on treatment, the researchers found significant differences in CD4 levels at 3, 9, 15, and 18 months. After one year on HAART, average CD4 counts increased by 50 for the older men, compared to increases of 100 for the younger ones. This difference was not related to baseline HIV viral load, coinfection with hepatitis C, or the race/ethnicity of participants. These studies represent an important first step in understanding how their age may affect older adults' response to HIV treatment, but more studies are needed to understand the long-term effects of age on HAART in older adults.
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. 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. 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 (also known as "wowo") and five-days-on, two-days-off (also known as "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.
Adverse effects of antiretroviral drugs vary by drug, by ethnicity, 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: [27]
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