Management of HIV/AIDS

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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[edit]

The first effective therapy against HIV was the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine. It was approved by the US FDA in 1987.[2] Subsequently several more NRTIs were developed but even in combination were unable to supress the virus for long periods of time and patients still inevitably died.[3] To distinguish from this early anti-retroviral therapy (ART), the term highly-active anti-retroviral therapy (HAART) was introduced. 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, of the Aaron Diamond AIDS Research Center, New York, NY, and George Shaw, 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 more potent treatment was necessary to completely suppress viral replication.[4] The conference was followed by sequential publications in The New England Journal of Medicine by Hammer and colleagues[5] and Gulick and coinvestigators[6] illustrating the substantial benefit of combining 2 NRTIs with a new class of anti-retrovirals, protease inhibitors, namely indinavir. 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.[7]

Classes of drugs[edit]

Schematic description of the mechanism of the four classes of currently available antiretroviral drugs against HIV

There are several classes of drugs, which are usually used in combination, to treat HIV infection. Use of these drugs in combination can be termed anti-retroviral therapy (ART) or highly active anti-retroviral therapy (HAART). Anti-retroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits. Typical combinations include 2 NRTIs as a "backbone" along with 1 NNRTI, PI or INSTI as a "base."[8]

Combination therapy[edit]

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.[15] 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.[16]

When antiretroviral drugs are used improperly, these multi-drug resistant strains can become the dominant genotypes very rapidly. In the era before multiple drug classes were available (pre-1997), the reverse transcriptase inhibitors zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were used serially or in combination leading to the development of multi-drug resistant mutations.[17]

Antiretroviral combination therapy defends against resistance by suppressing HIV replication as much as possible, thus reducing the potential pool of spontaneous resistance mutations.[16]

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.[8] Combinations usually comprise two nucleoside-analogue RTIs and one drug from another class such as PIs, NNRTIs, or INSTIs.[8] This three drug combination is commonly known as a triple cocktail.[18] Combinations of antiretrovirals are subject to positive and negative synergies, which limits the number of useful combinations.

In recent years, drug companies have worked together to combine these complex regimens into simpler formulas, termed fixed-dose combinations.[19] For instance, there are now several options that combine 3 drugs into one pill taken once daily.[20][21][22] This greatly increases the ease with which they can be taken, which in turn increases the consistency with which medication is taken (adherence)[23], and thus their effectiveness over the long-term. Not taking anti-retrovirals regularly is a cause of resistance development in people who have started taking them previously.[24] Patients who take medications regularly can stay on one regimen without developing resistance.[24] This greatly increases life expectancy and leaves more drugs available to the individual should the need arise.

Fixed-dose combinations[edit]

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

Brand NameDrug Names (INN)Date of FDA ApprovalCompany
Combivirzidovudine + lamivudineSeptember 26, 1997GlaxoSmithKline
Trizivirabacavir + zidovudine + lamivudineNovember 15, 2000GlaxoSmithKline
Kaletralopinavir + ritonavirSeptember 15, 2000Abbott Laboratories
Epzicom (in USA)
Kivexa (in Europe)
abacavir + lamivudineAugust 2, 2004GlaxoSmithKline
Truvadatenofovir/emtricitabineAugust 2, 2004Gilead Sciences
Atriplaefavirenz + tenofovir/emtricitabineJuly 12, 2006Gilead Sciences and
Bristol-Myers Squibb
Complerarilpivirine + tenofovir/emtricitabineAugust 10, 2011Gilead Sciences and
Tibotec (Johnson & Johnson)
Stribildelvitegravir + cobicistat + tenofovir/emtricitabineAugust 27, 2012Gilead Sciences

The preferred initial regimens in the United States, as of February 2013, are:[8]

Treatment guidelines[edit]

Initiation of antiretroviral therapy[edit]

Antiretroviral drug treatment guidelines have changed over time. Before 1987, no antiretroviral drugs were available and treatment consisted of treating complications from oportunistic infections and malignancies. 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.[25]

In 1995, David Ho promoted a "hit hard, hit early" approach with aggressive treatment with multiple antiretrovirals early in the course of the infection.[26] Later reviews in the late 90s and early 2000s 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. The only consensus was on treating patients with advanced immunosuppresion (CD4 counts less than 350/ml).[27] Treatment with antiretrovirals was expensive at the time, ranging from $10,000 to $15,000 a year.[28]

The timing of when to initiate therapy has continued to be a core controversy within the medical community. Most recently, the NA-ACCORD study observed patients who started antiretroviral therapy either at a CD4 count of less than 500 versus less than 350 and showed that patients who started ART at lower CD4 counts had a 69% increase in the risk of death.[29]

Other arguments for starting therapy earlier are that people who start therapy later have been shown to have less recovery of their immune systems,[30] and higher CD4 counts are associated with less cancer.[31]

A separate argument for have people start antiretroviral therapy that has gained more prominence is its effect on HIV transmission. ART reduces the amount of virus in the blood and genital secretions.[32][33] This has been shown to lead to dramatically reduced transmission of HIV when one partner with a suppressed viral load (<50 copies/ml) has sex with a partner who is HIV negative. While the risk is lowered, it is not eliminated.[34] The term "treatment as prevention" has been used for the concept of treating patients with HIV to help prevent the spread of HIV.[35]

In summary, as the WHO HIV treatment guidelines state, "The ARV regimens now available, even in the poorest countries, are safer, simpler, more efficacious and more affordable than ever before."[36]

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.[8] One trial where ART therapy was periodically stopped had higher rates of opportunistic infections, cancers, heart attacks and death in patients who interrupted their ART.[37][38]

Current guidelines[edit]

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 his or her doctor.

The treatment guidelines specifically for the US are set by the United States Department of Health and Human Services (DHHS). The current guidelines for adults and adolescents were last updated on February 12, 2013.[8]

Current US DHHS guidelines state:

and the importance of adherence. Patients may choose to postpone therapy, and providers, on a case-by-case basis,

may elect to defer therapy on the basis of clinical and/or psychosocial factors. Alternatively, current World Health Organization guidelines (dated June 30th, 2013) state:[36]

• As a priority, initiate ART in all individuals with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD4 count ≤ 350 cells/mm

• Active TB disease

• HBV coinfection with severe chronic liver disease

• Pregnant and breastfeeding women with HIV

• HIV-positive individual in a serodiscordant partnership (to reduce HIV transmission risk)

Baseline resistance[edit]

Baseline resistance is the presence of resistance mutations in patients who have never been treated before for HIV. 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.[39] 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.[40] In the US, 10.8% of one cohort of patients who had never been on ART before had at least one resistance mutation in 2005.[41] Various surveys in different parts of the world have shown increasing or stable rates of baseline resistance as the era of effective HIV therapy continues.[42][43][44][45]

Regimens[edit]

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 International AIDS Society-USA (IAS-USA) since 1996.[46] 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 July 2012 in the Journal of the American Medical Association.[47]

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 [48]

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:[49]

Children[edit]

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; guidelines were published November 3, 2005.[50]

HIV Postexposure Prophylaxis (PEP)[edit]

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]).[51] The World Health Organization (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.[52] The effectiveness of this intervention has never been precisely ascertained,[citation needed] but postexposure prophylaxis is most effective when administered sooner, and believed to not be effective if given later than 72 hours after exposure.[52]

Prevention of mother-to-child-transmission (PMCT)[edit]

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.[53] 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%.[54]

Treatment as prevention[edit]

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.[55] In 2011, the journal Science gave the Breakthrough of the Year award to treatment as prevention.[56]

Concerns[edit]

There are several concerns about antiretroviral regimens:

In older adults[edit]

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.[citation needed] 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[edit]

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[edit]

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.[citation needed]

Suppressing HIV is inadequate to restore normal immune function. HIV can damage the ability of the thymus to produce normally diverse T-cells.[citation needed] Also, rapid suppression of HIV and partial restoration of the immune system sometimes produces a dangerous hypersensitivity reaction, immune reconstitution inflammatory syndrome.[citation needed] 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.[61]

Adverse effects[edit]

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:[62]

Pregnancy planning[edit]

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.[67] Also, pre-exposure chemoprophylaxis could be an alternative method.[67]

For cases where the woman is HIV positive and the man is HIV negative, the usual method is artificial insemination.[67] With appropriate treatment the risk of mother-to-child infection can be reduced to about 1%.[68]

Research[edit]

Anti-viral hyperactivation limiting therapeutics[edit]

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.[69]

See also[edit]

References[edit]

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