AIDS antiretroviral drugs

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

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).

Since viral load is the single greatest risk factor for all modes of HIV transmission, use of ART decreases the risk of HIV transmission from one person to another.

Classes of antiretroviral drugs

Antiretroviral drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits. There are thus six broad classifications of antiretroviral drugs in development:

  • 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.
  • Entry inhibitors include fusion inhibitors and CCR5-inhibitors. CCR5-inhibitors block HIV-1 from the host cell by binding CCR5, a molecule on the host membrane termed a co-receptor that HIV-1 normally uses for entry into the cell together with a primary receptor. Fusion inhibitors block HIV from fusing with a cell's membrane to enter and infect it. There is currently only one FDA-approved drug in this class, enfuvirtide, marketed as Fuzeon.
  • Maturation inhibitors inhibit the last step in gag processing in which the viral capsid polyprotein is cleaved, thereby blocking the conversion of the polyprotein into the mature capsid protein (p24). Because these viral particles have a defective core, the virions released consist mainly of non-infectious particles. Alpha interferon is a currently available agent in this class.[1] Two additional inhibitors under investigation are bevirimat [2] and Vivecon.

Current Scenario: Presently known drugs

Organizations such as the United States National Institutes of Health recommend offering antiretroviral treatment to all patients with AIDS. 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.[3]

Nucleoside reverse transcriptase inhibitors (NRTI) Protease Inhibitors Non-Nucleoside reverse transcriptase inhibitors (NNRTI) Integrase inhibitor Entry inhibitors
Abacavir (ABC) Atazanavir Delavirdine Raltegravir (2007)[4] Chemokine Receptor Antagonists (Maraviroc - 2007)
Didanosine (ddI) (1991) Darunavir Efavirenz Elvitegravir (Phase III trial terminated) [[2]] Fusion Inhibitors (Enfuvirtide - 2003)
Emtricitabine (FTC) Fosamprenavir Nevirapine (1996)
Lamivudine (3TC) Indinavir Etravirine
Stavudine (d4T) Lopinavir/ritonavir Rilpivirine (2011) [3]
Tenofovir (TDF) Nelfinavir
Zalcitabine (ddC;no longer available in the United States) Saquinavir
Zidovudine (ZDV, Retrovir; formerly azidothymidine [AZT] (1987) Tipranavir

Investigational approaches

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.[5]

Recent developments

IMOD (short for "Immuno-Modulator Drug") is the name of a new herbal drug developed by scientists in Iran, which has been reported to rein the AIDS virus and boost the body’s immune system. Its efficiency and safety have not yet been confirmed by the mainstream scientific community.

Synergistic enhancers

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 that drug (often by altering the metabolism of the other antiretroviral). This group include ritonavir.

Example: Ritonavir is an antiretroviral drug which 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 1:5. 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.

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 → release of additional viruses → infection of other cells.

Rationale for combination therapy: Advantages

  • Human Immunodeficiency Virus 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 usually comprise two nucleoside-analogue RTIs and one non-nucleoside-analogue RTI or protease inhibitor.[6] This three drug combination is commonly known as a triple cocktail. [7]

Disadvantages

  • 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.[8]
  • Combinations of antiretrovirals are subject to positive and negative synergies, which limits the number of useful combinations.
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 Scenario

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 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.

Fixed dose combinations

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

Brand Name Drug Names (INN) Date of FDA Approval
Combivir zidovudine + lamivudine September 26, 1997
Trizivir abacavir + zidovudine + lamivudine November 15, 2000
Kaletra lopinavir + ritonavir September 15, 2000
Epzicom (in USA)
Kivexa (in Europe)
abacavir + lamivudine August 2, 2004
Truvada tenofovir/emtricitabine August 2, 2004
Atripla efavirenz + tenofovir/emtricitabine July 12, 2006

Portmanteau Inhibitor

A portmanteau inhibitor is a combination of two drug molecules, each of which itself is a type of inhibitor. The term was coined in 2007 by University of Minnesota researchers who designed and synthesized a combination HIV reverse transcriptase inhibitor and an integrase inhibitor,[9][10][11] and in 2011 by a team of researchers combining an integrase inhibitor with a CCR5 entry inhibitor.[12]

Treatment Guidelines

Initiation of antiretroviral therapy

Antiretroviral drug treatment guidelines have changed over time. Prior to 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.[13]

In 1995, David Ho promoted a "hit hard, hit early" approach with aggressive treatment with multiple antiretrovirals early in the course of the infection.[14] Later reviews noted that this approach significantly increased the risks, side effects and development of multidrug resistance, and this approach was largely abandoned.[15] 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.

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.

World Health Organization

In 2010, WHO has made the following recommendations[4]:

When to start?
  • All adolescents and adults including pregnant women with HIV infection and CD4 counts of ≤350 cells/mm3, should start ART, regardless of the presence or absence of clinical symptoms.
  • Those with severe or advanced clinical disease (WHO clinical stage 3 or 4) should start ART irrespective of their CD4 cell count.
What to use in first line therapy?
  • First-line therapy should consist of an NNRTI + two NRTIs, one of which should be zidovudine (AZT) or tenofovir (TDF).
  • Countries should take steps to progressively reduce the use of stavudine (d4T) in first-line regimens because of its well-recognized toxicities.
What to use in second-line therapy?
  • Second-line ART should consist of a ritonavir-boosted protease inhibitor (PI) plus two NRTIs, one of which should be AZT or TDF, based on what was used in first-line therapy.
  • Ritonavir-boosted atazanavir (ATV/r) or lopinavir/ritonavir (LPV/r) are the preferred PI's.
Laboratory monitoring
  • All patients should have access to CD4 cell–count testing to optimize pre-ART care and ART management.
  • Viral-load testing is recommended to confirm suspected treatment failure.
  • Drug toxicity monitoring should be symptom-directed.
HIV/TB coinfection
  • Irrespective of CD4 cell counts, patients coinfected with HIV and TB should be started on ART as soon as possible after starting TB treatment.
HIV/HBV coinfection
  • Irrespective of CD4 cell counts or WHO clinical stage, patients who require treatment for HBV infection should start ART.
  • First-line and second-line regimens for these individuals should contain TDF and either emtricitabine (FTC) or lamivudine (3TC).

Department of Health and Human Services

The treatment guidelines in the USA are set by the United States Department of Health and Human Services (DHHS). Following recommendations were made in 2005 guidelines for adults and adolescents [16]:

  • 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.

In 2011, following changes were made to the existing guideline: [[5]]

Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)-Based Regimens
  • Rilpivirine added as an alternative NNRTI option for initial therapy in treatment-naive patients.
  • All nevirapine-based regimens reclassified as acceptable options for treatment-naive patients (females with pretreatment CD4 count <250 cells/mm3 or males with pretreatment CD4 count <400 cells/mm3).
Protease Inhibitor (PI)-Based Regimens
  • “Ritonavir-boosted darunavir + abacavir/lamivudine” reclassified as an alternative regimen (BIII); previously the regimen was recommended as a regimen that may be acceptable but more definitive data are needed (CIII).
Raltegravir-Based Regimens
  • “Raltegravir + abacavir/lamivudine” reclassified as an alternative regimen (BIII); previously, the regimen was classified as a regimen that may be acceptable but more definitive data are needed (CIII)
Dual-Nucleoside Reverse Transcriptase Inhibitor (NRTI) Options
  • “Zidovudine + lamivudine” reclassified from an alternative dual-NRTI option to an acceptable option because the combination has greater toxicities compared with tenofovir/emtricitabine and abacavir/lamivudine and requires twice daily dosing. However, zidovudine + lamivudine remains as the preferred dual-NRTI for pregnant women receiving antiretroviral therapy (ART) for prevention of perinatal transmission of HIV.

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.

Regimens

The preferred initial regimens are[17]:

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 zidovudine + lamivudine + efavirenz, and 6.4% medium to high level resistance to stavudine + lamivudine + nevirapine.[18]

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 [19].

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])[20]. 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.

Guidelines for initiation of ART

Year AIDS/Symptoms CD4 <200 CD4 200-350 CD4 350-500 CD4 >500
DHHS [6] 2011 Yes Yes Yes Yes Yes (optional)
IAS-USA[21] 2010 Yes Yes Yes Yes consider
UK 2008 Yes Yes Yes clinical trial clinical trial
EACS[22] 2011 Yes Yes Yes consider defer
WHO [[7]] 2010 Yes Yes Yes No No

Concerns

There are several concerns about antiretroviral regimens:

  • Intolerance: The drugs can have serious side-effects,[23] particularly in advanced disease.[24]
  • Resistance: If patients miss doses, drug resistance can develop.
  • Cost: Providing anti-retroviral treatment is costly and resource-intensive,Template: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.[25]

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.

Responses to treatment in older adults

As people age, their bodies aren't 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 doesn't 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.

Limitations of antiretroviral drug therapy

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 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.

Intermittent therapy

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.

With the exception of post-exposure prophylaxis, current treatment guidelines do not call for the interruption of drug therapy once it has been initiated.[[8]]

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: [26]

Causative Drug Side-effect
Nucleoside reverse transcriptase inhibitors
Abacavir Hypersensitivity reaction, Diarrhea
Didanosine Peripheral neuropathy, pancreatitis, nausea, lactic acidosis
Emtricitabine Hyperpigmentation, Insomnia
Lamivudine Severe acute exacerbation of hepatitis may occur with HBV

-coinfection upon discontinuation, Headache

Stavudine Peripheral neuropathy, pancreatitis, nausea, lactic acidosis

Lipoatrophy, hyperlipidemia

Tenofovir Diarrhea, nausea, flatulence, vomiting, renal failure [27]
Zalcitabine Peripheral neuropathy, pancreatitis, nausea, lactic acidosis,

stomatitis

Zidovudine Nausea, vomiting, headache, asthenia, anemia, neutropenia
Non-Nucleoside Reverse Transcriptase inhibitors (NNRTI's)
Delavirdine Rash, headache
Efavirenz Rash, hyperlipidemia , CNS (somnolence, confusion, visual hallucination), teratogenic
Etravirine Rash, nausea
Nevirapine Rash, hepatitis
Rilpivirine Rash, headache , Depressive disorder, insomnia
Protease Inhibitors (PI's)
Atazanavir Hyperbilirubinemia, prolonged PR interval, hyperglycemia, skin rash (20%)

hyperlipidemia

Darunavir Rash, nausea, hyperlipidemia , diarrhea
Fosamprenavir Rash, nausea, hyperlipidemia , diarrhea, hyperlipidemia
Indinavir Nephrolithiasis, Hyperbilirubinemia, hyperlipidemia], hyperglycemia
Lopinavir/ritonavir Nausea, vomiting, diarrhea, asthenia, hyperglycemia, hyperlipidemia
Saquinavir Diarrhea, nausea, hyperlipidemia , hyperglycemia,prolonged PR interval & QT interval
Tipranavir Hepatotoxicity, Intracranial hemorrhage (rare cases), hyperlipidemia], hyperglycemia
Integrase Inhibitor
Raltegravir Diarrhea, nausea, headache , CK elevation, myopathy/rhabdomyolysis (rare)
Chemokine Receptor Antagonists (CCR5 Antagonist)
Maraviroc Dizziness, Constipation, rash
Fusion inhibitor (FI)
Enfuvirtide Injection-site reactions (pain, erythema, induration, nodules)

Latest Updates

According to World Health Organization (WHO)[9]:

13 July 2011 UNAIDS and WHO hail new results showing that a once-daily pill for HIV-negative people can prevent them from acquiring HIV
3 June 2011 HIV treatment reaching 6.6 million people, but majority still in need
April 2011 Short-term priorities for antiretroviral drug optimization

Post-exposure prophylaxis

To read more about post-exposure prophylaxis, click here

Pre-exposure prophylaxis

To read more about pre-exposure prophylaxis, click here

External links

Related Chapters

References

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