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Highly active antiretroviral therapy

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Highly active antiretroviral therapy

"HAART" redirects here. For UK estate agency Haart, see Spicerhaart.

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs in an attempt to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death.

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, such organizations emphasize the importance of involving patients in therapy choices and recommend analyzing the risks and the potential benefits to patients with low viral loads.[1]

History

The advent of HAART has been dated to the 11th International Conference on AIDS in Vancouver, British Columbia, July 7–16, 1996. During that Conference, David Ho, MD, of the Aaron Diamond AIDS Research Center, New York, NY, and George Shaw, MD, PhD, of the University of Alabama at Birmingham School of Medicine, presented viral dynamics data showing that the average person with HIV infection produced 10 billion virions/day, bringing into sharp focus the fact that this was a viral infection that required antiviral treatment.[2] The conference was followed by sequential publications in The New England Journal of Medicine by Hammer and colleagues and Gulick and coinvestigators illustrating the substantial benefit of indinavir-based HAART. This concept of 3-drug therapy was quickly incorporated into clinical practice and rapidly showed impressive benefit with a 60% to 80% decline in rates of AIDS, death, and hospitalization.

Classes of drugs

There are several classes of drugs, which are usually used in combination, to treat HIV infection. Use of these drugs in combination is generally termed ARTs or Anti-Retroviral Therapy. Anti-retroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits. Typical combinations include 2 NRTIs (Nucleoside Reverse Transcriptase Inhibitors) + 1 PI (Protease Inhibitor) or 2 NRTIs + 1 NNRTI (Non-Nucleoside Reverse Transcriptase Inhibitor)[3]

  • Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. Maraviroc and enfuvirtide are the two currently available agents in this class. Maraviroc works by targeting CCR5, a co-receptor located on human helper T-cells. Caution should be used when administering this drug however due to a possible shift in tropism which allows HIV to target an alternative co-receptor such as CXCR4. In rare cases, individuals may have a mutation in the CCR5 delta gene which results in a nonfunctional CCR5 co-receptor and in turn, a means of resistance or slow progression of the disease. However as mentioned previously, this can be overcome if an HIV variant that targets CXCR4 becomes dominant.[4] To prevent fusion of the virus with the host membrane, Fuzeon (T20) can be used. Fuzeon is a peptide drug that must be injected and acts by interacting with the N-terminal heptad repeat of gp41 of HIV to form an inactive hetero six-helix bundle, therefore preventing infection of host cells.[5]
  • Nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide reverse transciptase inhibitors (NtRTI) are nucleoside and nucleotide analogues which inhibit reverse transcription. NRTIs are chain terminators such that once incorporated, work by preventing other nucleosides from also being incorporated because of the absence of a 3’ OH group. ; they both act as competitive substrate inhibitors. Examples of NRTIs include deoxythymidine, zidovudine, stavudine, didanosine, zalcitabine, abacavir, lamivudine, emtricitabine, and tenofovir.[6]
  • Non-Nucleoside reverse transcriptase inhibitors (NNRTI) inhibit reverse transcriptase by binding to an allosteric site of the enzyme; NNRTIs act as non-competitive inhibitors of reverse transcriptase. NNRTIs affect the handling of substrate (nucleotides) by reverse transcriptase by binding near the active site and causing “molecular arthritis”. NNRTIs can be further classified into 1st generation and 2nd generation NNRTIs. 1st generation NNRTIs are more rigid in structure and resistance can quickly be developed against them. Because 2nd generation NNRTIs have a more flexible structure, they can adjust more readily and resist mutation more effectively. NNRTIs, for example, include nevirapine, delavirdine, efavirenz, and rilpivirine.[6]
  • Integrase inhibitors inhibit the enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. There are several integrase inhibitors currently under clinical trial, and raltegravir became the first to receive FDA approval in October 2007. Raltegravir has two metal binding groups that compete for substrate with two Mg2+ ions at the metal binding site of integrase. Another clinically approved integrase inhibitor is Elvitegravir.[7]
  • Protease inhibitors block the viral protease enzyme necessary to produce mature virions upon budding from the host membrane. Particularly, these drugs prevent the cleavage of gag and gag/pol precursor proteins.[8] Virus particles produced in the presence of protease inhibitors are defective and mostly non-infectious. Examples of HIV protease inhibitors are Lopinavir, Indinavir, Nelfinavir, Amprenavir and Ritonavir. Maturation inhibitors have a similar effect by binding to gag, but development of two experimental drugs in this class, Bevirimat and Vivecon, was halted in 2010.[9] Resistance to some protease inhibitors is high. Second generation drugs have been developed that are effective against otherwise resistant HIV variants.[8]

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.[10] 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.

When antiretroviral drugs are used improperly, these multi-drug resistant strains can become the dominant genotypes very rapidly. Improper serial use of the reverse transcriptase inhibitors zidovudine, didanosine, zalcitabine, stavudine, and lamivudine can lead to the development of multi-drug resistant mutations. The mutations can include the V75I, F77L, K103N, F116Y, Q151M, and the M184V mutation. These mutations were observed before protease inhibitors had come into widespread use. The mutants retained sensitivity to the early protease inhibitor saquinavir. These mutants were also sensitive to the rarely used reverse transcriptase inhibitor foscarnet.[11]

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] Combinations of antiretrovirals are subject to positive and negative synergies, which limits the number of useful combinations.[14]

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 cause of resistance development in medication-experienced patients. Patients who maintain proper therapy can stay on one regimen without developing resistance. This greatly increases life expectancy and leaves more drugs available to the individual should the need arise.

Fixed-dose combinations

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

Brand Name Drug Names (INN) Date of FDA Approval Company
Combivir zidovudine + lamivudine September 26, 1997 GlaxoSmithKline
Trizivir abacavir + zidovudine + lamivudine November 15, 2000 GlaxoSmithKline
Kaletra lopinavir + ritonavir September 15, 2000 Abbott Laboratories
Epzicom (in USA)
Kivexa (in Europe)
abacavir + lamivudine August 2, 2004 GlaxoSmithKline
Truvada tenofovir/emtricitabine August 2, 2004 Gilead Sciences
Atripla efavirenz + tenofovir/emtricitabine July 12, 2006 Gilead Sciences and
Bristol-Myers Squibb
Complera rilpivirine + tenofovir/emtricitabine August 10, 2011 Gilead Sciences and
Tibotec (Johnson & Johnson)
Stribild elvitegravir + cobicistat + tenofovir/emtricitabine August 27, 2012 Gilead Sciences

The preferred initial regimens in the United States, as of August 2012, are:[15]

Treatment guidelines

Initiation of antiretroviral therapy

Antiretroviral drug treatment guidelines have changed over time. Before 1987, no antiretroviral drugs were available and treatment consisted of treating complications from the immunodeficiency. After antiretroviral medications were introduced, most clinicians agreed that HIV positive patients with low CD4 counts should be treated, but no consensus formed as to whether to treat patients with high CD4 counts.[16]

In 1995, David Ho promoted a "hit hard, hit early" approach with aggressive treatment with multiple antiretrovirals early in the course of the infection.[17] Later reviews noted that this approach of "hit hard, hit early" ran significant risks of increasing side effects and development of multidrug resistance, and this approach was largely abandoned.[18] Treatment with these types of medicine can range from $10,000 to $15,000 a year.[19]

The timing of when to initiate therapy has continued to be a core controversy within the medical community. The development of a stable consensus is hampered by the lack of randomized controlled studies with many guidelines and consensus statements basing their recommendations on observational studies. More recently, the trend has been in favor of earlier treatment of asymptomatic HIV patients, with more studies analyzing various treatment regimens in progress.[20]

There is a consensus among experts that, once initiated, antiretroviral therapy should never be stopped. This is because the selection pressure of incomplete suppression of viral replication in the presence of drug therapy causes the more drug sensitive strains to be selectively inhibited. This allows the drug resistant strains to become dominant. This in turn makes it harder to treat the infected individual as well as anyone else they infect.[21]

Current guidelines

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 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 December 1, 2009.[21]

Standard antiretroviral therapy (ART) consists of the combination of at least three antiretroviral (ARV) drugs to maximally suppress the HIV virus and stop the progression of HIV disease.

  • Antiretroviral therapy should be initiated in all patients with a history of an AIDS-defining illness or with a CD4 count <350 cells/mm3 (AI).
  • Antiretroviral therapy should also be initiated, regardless of CD4 count, in patients with the following conditions: pregnancy (AI), HIV- associated nephropathy (AII), and hepatitis B virus (HBV) coinfection when treatment of HBV is indicated (AIII).
  • Antiretroviral therapy is recommended for patients with CD4 counts between 350 and 500 cells/mm3. The Panel was divided on the strength of this recommendation: 55% voted for strong recommendation (A) and 45% voted for moderate recommendation (B) (A/B-II).
  • For patients with CD4 counts >500 cells/mm3, the Panel was evenly divided: 50% favor starting antiretroviral therapy at this stage of HIV disease (B); 50% view initiating therapy at this stage as optional (C) (B/C-III).
  • Patients initiating antiretroviral therapy should be willing and able to commit to lifelong treatment and should understand the benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy based on clinical and/or psychosocial factors.

Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion

Baseline resistance

In countries with a high rate of baseline resistance, resistance testing is recommended before 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.[22]

Regimens

Most current HAART regimens consist of three(3) drugs: 2 NRTIs + a PI/NNRTI/II. Initial regimens use "first-line" drugs with a high efficacy and low side-effect profile.

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 provided by the

In the 2008 update, the panel recommended 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, a ritonavir-boosted PI or an integrase inhibitor. 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 [24]

Another set of guidelines (distinct from those of the IAS-USA) are provided by an expert panel convened by the U.S. Department of Health and Human Services. The preferred initial regimens in the United States, as of August 2012, are:[15]

Children

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.[25]

HIV Postexposure Prophylaxis (PEP)

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]).[26] 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.[27] The effectiveness of this intervention has never been precisely ascertained, but postexposure prophylaxis is most effective when administered sooner, and believed to not be effective if given later than 72 hours after exposure.[27]

Prevention of mother-to-child-transmission (PMCT)

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.[28] Complementary measures that may also be used include caesarean 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%.[29]

Treatment as prevention

Antiretroviral treatment of a person with HIV was shown to prevent HIV transmission to their uninfected heterosexual partner in clinical trial HPTN 052. This study of 1763 heterosexual couples in 9 countries was planned to last 10 years, but it was stopped early for ethical reasons when it became clear that antiviral treatment provided significant protection. Of the 28 couples where cross-infection had occurred, all but one had taken place in the control group consistent with a 96% reduction in risk of transmission.[30] In 2011, the journal Science gave the Breakthrough of the Year award to treatment as prevention.[31]

Concerns

There are several concerns about antiretroviral regimens:

  • intolerance: The drugs can have serious side-effects,[32] particularly in advanced disease.[33]
  • resistance: If patients miss doses, drug resistance can develop,[1]
  • cost: Providing anti-retroviral treatment is costly and resource-intensive,[quantify] and the majority of the world's infected individuals cannot access treatment services.
  • public health: Individuals who fail to use antiretrovirals properly can develop multi-drug resistant strains which can be passed onto others.[34]

In older adults

As people age, their bodies cannot 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.

Mega-HAART

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 causes additional side effects.

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, particularly in the developing world.

Structured treatment interruptions

Drug holidays (or "structured treatment interruptions") are intentional discontinuations of antiretroviral drug treatment.

Intermittent therapy was an experimental approach designed to reduce exposure to antiretroviral drugs in an effort to mitigate side-effects. Intermittent therapy differed from treatment interruptions in that it involved 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 skipped treatment on weekends. Intermittent therapy is ineffective and results in drug resistance.

Suppressing HIV is inadequate to restore normal immune function. 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.

With the exception of post exposure prophylaxis, current treatment guidelines do not call for the interruption of drug therapy once it has been initiated.[21]

Adverse effects

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 adverse effects experienced by patients taking some antiretroviral drugs:[35]

Pregnancy planning

Three quarters of people with HIV infection are in their reproductive years and may consider pregnancy planning. In cases where the woman is HIV negative and the man is HIV positive, the primary assisted reproductive method used to prevent HIV transmission is sperm washing followed by intrauterine insemination (IUI) or in vitro fertilization (IVF). There is no described case of seroconversion in women or their offspring after such sperm washing, but it is yet not certain whether the method is completely safe.[40] Also, pre-exposure chemoprophylaxis could be an alternative method.[40]

For cases where the woman is HIV positive and the man is HIV negative, the usual method is artificial insemination.[40] With appropriate treatment the risk of mother-to-child infection can be reduced to about 1%.[41]

Research

Anti-viral hyperactivation limiting therapeutics

AV-HALTs (AntiViral HyperActivation Limiting Therapeutics or 'virostatics') combine immunomodulating and antiviral properties to inhibit a specific antiviral target while also limiting the hyper-elevated state of immune system activation driving disease progression.[42]

See also

References

Further reading

  • Cohen, Mardge H., MD, et al., "Medically Eligible Women Who Do Not Use HAART: The Importance of Abuse, Drug Use, and Race", American Journal of Public Health, Vol 94, No. 7, July 2004, pp. 1147–1151. American Public Health Association
  • Cohen, Mardge H., MD, et al., Medscape CME, 11/17/2004
  • Lewin, Sharon R., MD, et al., International AIDS Society

External links

  • AIDSinfo - Comprehensive resource for HIV/AIDS treatment and clinical trial information from the U. S. Department of Health and Human Services
  • ASHM - Australian Commentary on HHS Guidelines for the use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
  • Origins of antiretroviral combination therapy
  • Viral Load research papers, including effectiveness of HAART on reducing viral load
  • Current status of gene therapy strategies to treat HIV/AIDS
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