The management of HIV/AIDS normally includes the use of multiple
antiretroviral drugs
The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multipl ...
as a strategy to control
HIV infection
Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ma ...
. There are several classes of antiretroviral agents that act on different stages of the
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
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
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
, and prevents
opportunistic infections
An opportunistic infection is an infection caused by pathogens (bacteria, fungi, parasites or viruses) that take advantage of an opportunity not normally available. These opportunities can stem from a variety of sources, such as a weakened immune ...
that often lead to death.
HAART also prevents the transmission of HIV between
serodiscordant
A serodiscordant relationship, also known as mixed-status, is one where one partner is infected by HIV and the other is not. This contrasts with seroconcordant relationships, in which both partners are of the same HIV status. Serodiscordancy contri ...
same sex and opposite sex partners so long as the HIV-positive partner maintains an undetectable viral load.
Treatment has been so successful that in many parts of the world, HIV has become a chronic condition in which progression to
AIDS
Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual m ...
is increasingly rare.
Anthony Fauci
Anthony Stephen Fauci (; born December 24, 1940) is an American physician-scientist and immunologist serving as the director of the National Institute of Allergy and Infectious Diseases (NIAID) and the chief medical advisor to the president. ...
, head of the United States
National Institute of Allergy and Infectious Diseases
The National Institute of Allergy and Infectious Diseases (NIAID, ) is one of the 27 institutes and centers that make up the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services (HHS). NIAID's ...
, has written, "With collective and resolute action now and a steadfast commitment for years to come, an AIDS-free generation is indeed within reach." In the same paper, he noted that an estimated 700,000 lives were saved in 2010 alone by antiretroviral therapy. As another commentary in ''
The Lancet
''The Lancet'' is a weekly peer-reviewed general medical journal and one of the oldest of its kind. It is also the world's highest-impact academic journal. It was founded in England in 1823.
The journal publishes original research articles, ...
'' noted, "Rather than dealing with acute and potentially life-threatening complications, clinicians are now confronted with managing a chronic disease that in the absence of a cure will persist for many decades."
The United States
Department of Health and Human Services
The United States Department of Health and Human Services (HHS) is a cabinet-level executive branch department of the U.S. federal government created to protect the health of all Americans and providing essential human services. Its motto is " ...
and the
World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
(WHO) recommend offering antiretroviral treatment to all patients with
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
.
Because of the complexity of selecting and following a regimen, the potential for side effects, and the importance of taking medications regularly to prevent
viral resistance, such organizations emphasize the importance of involving patients in therapy choices and recommend analyzing the risks and the potential benefits.
The WHO has defined health as more than the absence of disease. For this reason, many researchers have dedicated their work to better understanding the effects of HIV-related stigma, the barriers it creates for treatment interventions, and the ways in which those barriers can be circumvented.
Classes of medication
![HIV-drug-classes](https://upload.wikimedia.org/wikipedia/commons/d/d5/HIV-drug-classes.svg)
There are six classes of drugs, which are usually used in combination, to treat HIV infection. Antiretroviral (ARV) drugs are broadly classified by the phase of the
retrovirus
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...
life-cycle that the drug inhibits. Typical combinations include two nucleoside reverse-transcriptase inhibitors (NRTI) as a "backbone" along with one non-nucleoside reverse-transcriptase inhibitor (NNRTI), protease inhibitor (PI) or integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) as a "base."
Entry inhibitors
Entry inhibitors
Entry inhibitors, also known as fusion inhibitors, are a class of antiviral drugs that prevent a virus from entering a cell, for example, by blocking a receptor. Entry inhibitors are used to treat conditions such as HIV and hepatitis D.
HIV entry
...
(or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets.
Maraviroc
Maraviroc, sold under the brand names Selzentry (US) and Celsentri (EU), is an antiretroviral medication used to treat HIV infection. It is taken by mouth. It is in the CCR5 receptor antagonist class.
It was approved for medical use in the Unit ...
and
enfuvirtide
Enfuvirtide (INN) is an HIV fusion inhibitor, the first of a class of antiretroviral drugs used in combination therapy for the treatment of HIV-1 infection. It is marketed under the trade name Fuzeon (Roche).
Structural formula
Enfuvirtide is ...
are the two available agents in this class. Maraviroc works by targeting
CCR5
C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines.
In humans, the ''CCR5'' gene that encodes the CCR5 pro ...
, 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
A tropism is a biological phenomenon, indicating growth or turning movement of a biological organism, usually a plant, in response to an environmental stimulus. In tropisms, this response is dependent on the direction of the stimulus (as oppose ...
which allows HIV to target an alternative co-receptor such as
CXCR4
C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the ''CXCR4'' gene. The protein is a CXC chemokine receptor.
Function
CXCR-4 is an alpha-chemokin ...
.
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. To prevent fusion of the virus with the host membrane, enfuvirtide can be used. Enfuvirtide 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.
Nucleoside/nucleotide reverse-transcriptase inhibitors
Nucleoside reverse-transcriptase inhibitors (NRTI) and nucleotide reverse-transcriptase inhibitors (NtRTI) are
nucleoside
Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotide ...
and
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
analogues which inhibit reverse transcription. HIV is an RNA virus, so it can not be integrated into the DNA in the nucleus of the human cell unless it is first "reverse" transcribed into DNA. Since the conversion of RNA to DNA is not naturally done in the mammalian cell, it is performed by a viral protein,
reverse transcriptase
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
, which makes it a selective target for inhibition. NRTIs are chain terminators. Once NRTIs are incorporated into the DNA chain, their lack of a 3' OH group prevents the subsequent incorporation of other nucleosides. Both NRTIs and NtRTIs act as
competitive substrate inhibitors. Examples of NRTIs include
zidovudine
Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child ...
,
abacavir
Abacavir, sold under the brand name Ziagen among others, is a medication used to treat HIV/AIDS. Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recom ...
,
lamivudine
Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically ...
,
emtricitabine
Emtricitabine (commonly called FTC, systematic name 2',3'-dideoxy-5-fluoro-3'-thiacytidine), with trade name Emtriva (formerly Coviracil), is a nucleoside reverse-transcriptase inhibitor (NRTI) for the prevention and treatment of HIV infection in ...
, and of NtRTIs –
tenofovir
Tenofovir disoproxil, sold under the trade name Viread among others, is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for preven ...
and
adefovir
Adefovir is a prescription medicine used to treat (chronic) infections with hepatitis B virus. A prodrug form of adefovir was previously called bis-POM PMEA, with trade names Preveon and Hepsera. It is an orally administered nucleotide analog reve ...
.
Non-nucleoside reverse-transcriptase inhibitors
Non-nucleoside reverse-transcriptase inhibitors (NNRTI) inhibit reverse transcriptase by binding to an
allosteric site
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
The site to which the effector binds is termed the ''allosteric site ...
of the enzyme; NNRTIs act as
non-competitive inhibitors of
reverse transcriptase
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
. NNRTIs affect the handling of substrate (nucleotides) by reverse transcriptase by binding near the active site. NNRTIs can be further classified into 1st generation and 2nd generation NNRTIs. 1st generation NNRTIs include
nevirapine
Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mothe ...
and
efavirenz
Efavirenz (EFV), sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlest ...
. 2nd generation NNRTIs are
etravirine
Etravirine (ETR, brand name Intelence, formerly known as TMC125) is a drug used for the treatment of HIV. Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI). Unlike the currently available agents in the class, resistance to o ...
and
rilpivirine
Rilpivirine, sold under the brand names Edurant and Rekambys, is a medication, developed by Tibotec, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer ...
.
HIV-2
The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabey, ...
is naturally resistant to NNRTIs.
Integrase inhibitors
Integrase inhibitor Integrase inhibitors (INIs) are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, block ...
s (also known as integrase nuclear strand transfer inhibitors or INSTIs) inhibit the viral enzyme
integrase
Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage int ...
, which is responsible for
integration
Integration may refer to:
Biology
*Multisensory integration
*Path integration
* Pre-integration complex, viral genetic material used to insert a viral genome into a host genome
*DNA integration, by means of site-specific recombinase technology, ...
of viral DNA into the DNA of the infected cell. There are several integrase inhibitors under clinical trial, and
raltegravir
Raltegravir, sold under the brand name Isentress, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential ex ...
became the first to receive FDA approval in October 2007. Raltegravir has two metal binding groups that compete for substrate with two Mg
2+ ions at the metal binding site of integrase. As of early 2022, four other clinically approved integrase inhibitors are
elvitegravir
Elvitegravir (EVG) is an integrase inhibitor used to treat HIV infection. It was developed by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008. The drug gained approval by the U.S. Food and Drug Adm ...
,
dolutegravir
Dolutegravir (DTG), sold under the brand name Tivicay, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potentia ...
,
bictegravir
Bictegravir (INN; BIC, formerly known as GS-9883) is a second-generation integrase inhibitor (INSTI) class that was structurally derived from an earlier compound dolutegravir by scientists at Gilead Sciences; ''in vitro'' and clinical results were ...
, and
cabotegravir
Cabotegravir, sold under the brand name Vocabria among others, is a antiretroviral medication used for the treatment of HIV/AIDS. It is available in the form of tablets and as an intramuscular injection, as well as in an injectable combination ...
.
Protease inhibitors
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.
Virus particles produced in the presence of protease inhibitors are defective and mostly non-infectious. Examples of HIV protease inhibitors are
lopinavir
Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir (lopinavir/ritonavir).
It was patented in 1995 and approved for medical ...
,
indinavir
Indinavir (IDV; trade name Crixivan, made by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. ...
,
nelfinavir
Nelfinavir, sold under the brand name Viracept, is an antiretroviral medication used in the treatment of HIV/AIDS. Nelfinavir belongs to the class of drugs known as protease inhibitors (PIs) and like other PIs is almost always used in combination ...
,
amprenavir
Amprenavir (original brand name Agenerase, GlaxoSmithKline) is a protease inhibitor (pharmacology), protease inhibitor used to treat HIV infection. It was approved by the Food and Drug Administration on April 15, 1999, for twice-a-day dosing in ...
and
ritonavir
Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor a ...
.
Darunavir
Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir or ...
and
atazanavir
Atazanavir, sold under the brand name Reyataz among others, is an antiretroviral medication used to treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other ...
are recommended as first line therapy choices.
Maturation inhibitor The maturation inhibitors are a class of antiviral drugs for the treatment of infection with HIV. They act by interfering with the maturation of the virus. Specifically, drugs in this class disrupt the final step in the processing of the HIV-1 ''g ...
s have a similar effect by binding to gag, but development of two experimental drugs in this class,
bevirimat
Bevirimat (research code MPC-4326) is an anti-HIV drug derived from a betulinic acid-like compound, first isolated from ''Syzygium claviflorum,'' a Chinese herb. It is believed to inhibit HIV by a novel mechanism, so-called maturation inhibition ...
and
vivecon The maturation inhibitors are a class of antiviral drugs for the treatment of infection with HIV. They act by interfering with the maturation of the virus. Specifically, drugs in this class disrupt the final step in the processing of the HIV-1 grou ...
, was halted in 2010. Resistance to some protease inhibitors is high. Second generation drugs have been developed that are effective against otherwise resistant HIV variants.
Combination therapy
The
life cycle of HIV can be as short as about 1.5 days from viral entry into a cell, through replication, assembly, and release of additional viruses, to infection of other cells. HIV lacks
proofreading
Proofreading is the reading of a galley proof or an electronic copy of a publication to find and correct reproduction errors of text or art. Proofreading is the final step in the editorial cycle before publication.
Professional
Traditional ...
enzymes
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
to correct errors made when it converts its
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
into
DNA via
reverse transcription
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
. Its short life-cycle and high error rate cause the virus to mutate very rapidly, resulting in a high genetic variability. Most of the
mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
either are inferior to the parent
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
(often lacking the ability to reproduce at all) or convey no advantage, but some of them have a
natural selection
Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Charle ...
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, 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 inhibitor
Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs Enzyme inhibition, inhibit activity of reverse transcriptase, a viral DNA polymerase that is requi ...
s
zidovudine
Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child ...
,
didanosine
Didanosine (ddI, DDI), sold under the brand name Videx, is a medication used to treat HIV/AIDS. It is used in combination with other medications as part of highly active antiretroviral therapy (HAART). It is of the reverse-transcriptase inhibitor ...
,
zalcitabine
Zalcitabine (2′-3′-di deoxycytidine, ddC), also called dideoxycytidine, is a nucleoside analog reverse-transcriptase inhibitor (NRTI) sold under the trade name Hivid. Zalcitabine was the third antiretroviral to be approved by the Food and Drug ...
,
stavudine
Stavudine (d4T), sold under the brand name Zerit among others, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick ...
, and
lamivudine
Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically ...
were used serially or in combination leading to the development of multi-drug resistant mutations.
In contrast, antiretroviral combination therapy defends against resistance by creating multiple obstacles to HIV replication. This keeps the number of viral copies low and reduces the possibility of a superior mutation.
If a mutation that conveys resistance to one of the drugs 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
In tort law, the standard of care is the only degree of prudence and caution required of an individual who is under a duty of care.
The requirements of the standard are closely dependent on circumstances. Whether the standard of care has been b ...
is to use combinations of antiretroviral drugs.
Combinations usually consist of three drugs from at least two different classes.
This three drug combination is commonly known as a triple cocktail. Combinations of antiretrovirals are subject to positive and negative
synergies
Synergy is an interaction or cooperation giving rise to a whole that is greater than the simple sum of its parts. The term ''synergy'' comes from the Attic Greek word συνεργία ' from ', , meaning "working together".
History
In Christian ...
, which limits the number of useful combinations.
Because of HIV's tendency to mutate, when patients who have started an antiretrovial regimen fail to take it regularly, resistance can develop.
On the other hand, patients who take their medications regularly 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.
![Antiretroviral Therapy for HIV Infection (27423001115)](https://upload.wikimedia.org/wikipedia/commons/b/b7/Antiretroviral_Therapy_for_HIV_Infection_%2827423001115%29.png)
In recent years, drug companies have worked together to combine these complex regimens into single-pill
fixed-dose combinations
A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for a FDC prod ...
.
More than 20 antiretroviral fixed-dose combinations have been developed. This greatly increases the ease with which they can be taken, which in turn increases the consistency with which medication is taken (
adherence), and thus their effectiveness over the long-term.
Adjunct treatment
Although antiretroviral therapy has helped to improve the quality of life of people living with HIV, there is still a need to explore other ways to further address the disease burden. One such potential strategy that was investigated was to add
interleukin 2
Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for ...
as an adjunct to antiretroviral therapy for adults with HIV. A Cochrane review included 25
randomized controlled trials
A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...
that were conducted across six countries. The researchers found that interleukin 2 increases the
CD4 immune cells, but does not make a difference in terms of death and incidence of other infections. Furthermore, there is probably an increase in side-effects with interleukin 2. The findings of this review do not support the use of interleukin 2 as an add-on treatment to antiretroviral therapy for adults with HIV.
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 opportunistic 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.
In April 1995, Merck and the National Institute of Allergy and Infectious Diseases began recruiting patients for a trial examining the effects of a three drug combination of the protease inhibitor indinavir and two nucleoside analogs.
illustrating the substantial benefit of combining 2 NRTIs with a new class of antiretrovirals,
protease inhibitors
Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS and hepatitis C. These protease inhibitors prevent viral replicat ...
, namely
indinavir
Indinavir (IDV; trade name Crixivan, made by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. ...
. Later that year
David Ho became an advocate of this "hit hard, hit early" approach with aggressive treatment with multiple antiretrovirals early in the course of the infection.
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 immunosuppression (CD4 counts less than 350/μL).
Treatment with antiretrovirals was expensive at the time, ranging from $10,000 to $15,000 a year.
The timing of when to start therapy has continued to be a core controversy within the medical community, though recent studies have led to more clarity. 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.
In 2015 the START and TEMPRANO studies both showed that patients lived longer if they started antiretrovirals at the time of their diagnosis, rather than waiting for their CD4 counts to drop to a specified level.
Other arguments for starting therapy earlier are that people who start therapy later have been shown to have less recovery of their immune systems, and higher CD4 counts are associated with less cancer.
The
European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
(EMA) has recommended the granting of marketing authorizations for two new antiretroviral (ARV) medicines,
rilpivirine
Rilpivirine, sold under the brand names Edurant and Rekambys, is a medication, developed by Tibotec, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer ...
(Rekambys) and
cabotegravir
Cabotegravir, sold under the brand name Vocabria among others, is a antiretroviral medication used for the treatment of HIV/AIDS. It is available in the form of tablets and as an intramuscular injection, as well as in an injectable combination ...
(Vocabria), to be used together for the treatment of people with human immunodeficiency virus type 1 (HIV-1) infection.
[ Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.] The two medicines are the first ARVs that come in a long-acting injectable formulation.
This means that instead of daily pills, people receive intramuscular injections monthly or every two months.
The combination of Rekambys and Vocabria injection is intended for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/ml) with their current ARV treatment, and when the virus has not developed resistance to certain class of anti-HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (INIs).
Treatment as prevention
A separate argument for starting 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. This has been shown to lead to dramatically reduced transmission of HIV when one partner with a suppressed
viral load
Viral load, also known as viral burden, is a numerical expression of the quantity of virus in a given volume of fluid, including biological and environmental specimens. It is not to be confused with viral titre or viral titer, which depends on the ...
(<50 copies/ml) has sex with a partner who is HIV negative. In
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
HPTN 052 HPTN 052 is the name of a clinical trial conducted in nine countries which examined whether starting people living with HIV on antiretroviral therapy (ART) can reduce the chance that they will pass HIV on to their sexual partners who do not have HIV ...
, 1763
serodiscordant
A serodiscordant relationship, also known as mixed-status, is one where one partner is infected by HIV and the other is not. This contrasts with seroconcordant relationships, in which both partners are of the same HIV status. Serodiscordancy contri ...
heterosexual couples in 9 countries were planned to be followed for at least 10 years, with both groups receiving education on preventing HIV transmission and condoms, but only one group getting ART. The study was stopped early (after 1.7 years) 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
In the design of experiments, hypotheses are applied to experimental units in a treatment group.
In comparative experiments, members of a control group receive a standard treatment, a placebo, or no treatment at all. There may be more than one tr ...
consistent with a 96% reduction in risk of transmission while on ART. The single transmission in the experimental group occurred early after starting ART before viral load was likely to be suppressed.
Pre-exposure prophylaxis
Pre-exposure prophylaxis (PrEP) is the use of medications to prevent the spread of disease in people who have not yet been exposed to a disease-causing agent, usually a virus. The term typically refers to the use of antiviral drugs as a strate ...
(PrEP) provides HIV-negative individuals with medication—in conjunction with safer-sex education and regular HIV/STI screenings—in order to reduce the risk of acquiring HIV. In 2011, the journal ''
Science
Science is a systematic endeavor that builds and organizes knowledge in the form of testable explanations and predictions about the universe.
Science may be as old as the human species, and some of the earliest archeological evidence for ...
'' gave the
Breakthrough of the Year
The Breakthrough of the Year is an annual award for the most significant development in scientific research made by the AAAS journal ''Science,'' an academic journal covering all branches of science. Originating in 1989 as the ''Molecule of the Ye ...
award to treatment as prevention.
In July 2016 a consensus document was created by the Prevention Access Campaign which has been endorsed by over 400 organisations in 58 countries. The consensus document states that the risk of HIV transmission from a person living with HIV who has been undetectable for a minimum of six months is negligible to non-existent, with negligible being defined as "so small or unimportant to be not worth considering". The Chair of the British HIV Association (BHIVA),
Chloe Orkin
Chloe Meave Orkin is a British physician and Professor of HIV/AIDS medicine at Queen Mary University of London. She works as a consultant at the Royal London Hospital, Barts Health NHS Trust. She is an internationally renowned expert in HIV ther ...
, stated in July 2017 that 'there should be no doubt about the clear and simple message that a person with sustained, undetectable levels of HIV virus in their blood cannot transmit HIV to their sexual partners.'
Furthermore, the PARTNER study,
which ran from 2010 to 2014, enrolled 1166 serodiscordant couples (where one partner is HIV positive and the other is negative) in a study that found that the estimated rate of transmission through any condomless sex with the HIV-positive partner taking ART with an HIV load less than 200 copies/ml was zero.
In summary, as the WHO HIV treatment guidelines state, "The ARV regimens now available, even in the poorest countries, are safer, simpler, more effective and more affordable than ever before."
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.
One trial showed higher rates of opportunistic infections, cancers, heart attacks and death in patients who periodically interrupted their ART.
Guideline sources
There are several 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). In the United States there are both the International AIDS Society-USA (IAS-USA) (a 501(c)(3) not-for-profit organization in the US) as well as the US government's
Department of Health and Human Services
The United States Department of Health and Human Services (HHS) is a cabinet-level executive branch department of the U.S. federal government created to protect the health of all Americans and providing essential human services. Its motto is " ...
guidelines.
In Europe there are the European AIDS Clinical Society guidelines.
For resource limited countries, most national guidelines closely follow the
World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
(WHO) guidelines.
Guidelines
The 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 US DHHS guidelines (published April 8, 2015) state:
* Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression.
* ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.
* Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks of therapy 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.
The newest WHO guidelines (dated September 30, 2015) now agree and state:
* Antiretroviral therapy (ART) should be initiated in everyone living with HIV at any CD4 cell count
Baseline resistance
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.
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
Stavudine (d4T), sold under the brand name Zerit among others, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick ...
+ lamivudine +
nevirapine
Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mothe ...
. 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. 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. With baseline resistance testing, a combination of antiretrovirals that are likely to be effective can be customized for each patient.
Regimens
Most HAART regimens consist of three drugs: 2
NRTI
Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replicatio ...
s ("backbone")+ a
PI/
NNRTI
Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replicat ...
/
INSTI ("base"). Initial regimens use "first-line" drugs with a high efficacy and low side-effect profile.
The US
DHHS preferred initial regimens for adults and adolescents in the United States, as of April 2015, are:
* tenofovir/emtricitabine and
raltegravir
Raltegravir, sold under the brand name Isentress, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential ex ...
(an
integrase inhibitor Integrase inhibitors (INIs) are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, block ...
)
* tenofovir/emtricitabine and
dolutegravir
Dolutegravir (DTG), sold under the brand name Tivicay, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potentia ...
(an integrase inhibitor)
*
abacavir
Abacavir, sold under the brand name Ziagen among others, is a medication used to treat HIV/AIDS. Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recom ...
/
lamivudine
Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically ...
(two NRTIs) and dolutegravir for patients who have been tested negative for the
HLA-B*5701 gene
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
* tenofovir/emtricitabine,
elvitegravir
Elvitegravir (EVG) is an integrase inhibitor used to treat HIV infection. It was developed by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008. The drug gained approval by the U.S. Food and Drug Adm ...
(an integrase inhibitor) and
cobicistat
Cobicistat, sold under the brand name Tybost, is a medication for use in the treatment of human immunodeficiency virus infection (HIV/AIDS). Its major mechanism of action is through the inhibition of human CYP3A proteins.
Like ritonavir (Norvir) ...
(inhibiting metabolism of the former) in patients with good kidney function (
gfr GFR may refer to:
* Gas-cooled fast reactor
* Gefreiter
* General fertility rate
* Glomerular filtration rate
* Government Flight Representative
* Grand Forks Railway, a Canadian railway
* Grand Funk Railroad, an American rock band
* Grup Ferovi ...
> 70)
* tenofovir/emtricitabine,
ritonavir
Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor a ...
, and
darunavir
Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir or ...
(both latter are
protease inhibitors)
Both efavirenz and nevirapine showed similar benefits when combined with NRTI respectively.
In the case of the protease inhibitor based regimens, ritonavir is used at low doses to inhibit
cytochrome p450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
enzymes and "boost" the levels of other protease inhibitors, rather than for its direct antiviral effect. This boosting effect allows them to be taken less frequently throughout the day.
Cobicistat
Cobicistat, sold under the brand name Tybost, is a medication for use in the treatment of human immunodeficiency virus infection (HIV/AIDS). Its major mechanism of action is through the inhibition of human CYP3A proteins.
Like ritonavir (Norvir) ...
is used with elvitegravir for a similar effect but does not have any direct antiviral effect itself.
The WHO preferred initial regimen for adults and adolescents as of June 30, 2013 is:
* tenofovir +
lamivudine
Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically ...
(or emtricitabine) + efavirenz
Special populations
Acute infection
In the first six months after infection HIV viral loads tend to be elevated and people are more often symptomatic than in later latent phases of HIV disease. There may be special benefits to starting antiretroviral therapy early during this acute phase, including lowering the viral "set-point" or baseline viral load, reduce the mutation rate of the virus, and reduce the size of the viral reservoir (See section below on
viral reservoirs).
The SPARTAC trial compared 48 weeks of ART vs 12 weeks vs no treatment in acute HIV infection and found that 48 weeks of treatment delayed the time to decline in CD4 count below 350 cells per ml by 65 weeks and kept viral loads significantly lower even after treatment was stopped.
Since viral loads are usually very high during acute infection, this period carries an estimated 26 times higher risk of transmission. By treating acutely infected patients, it is presumed that it could have a significant impact on decreasing overall HIV transmission rates since lower viral loads are associated with lower risk of transmission (See section on
treatment as prevention
Treatment as prevention (TasP) is a concept in public health that promotes treatment as a way to prevent and reduce the likelihood of HIV illness, death and transmission from an infected individual to others. Expanding access to earlier HIV diagn ...
). However an overall benefit has not been proven and has to be balanced with the risks of HIV treatment. Therapy during acute infection carries a grade BII recommendation from the US DHHS.
Children
HIV can be especially harmful to infants and children, with one study in Africa showing that 52% of untreated children born with HIV had died by age 2. By five years old, the risk of disease and death from HIV starts to approach that of young adults. The WHO recommends treating all children less than 5 years old, and starting all children older than 5 with stage 3 or 4 disease or CD4 <500 cells/ml.
DHHS guidelines are more complicated but recommend starting all children less than 12 months old and children of any age who have symptoms.
As for which antiretrovirals to use, this is complicated by the fact that many children who are born to mothers with HIV are given a single dose of
nevirapine
Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mothe ...
(an NNRTI) at the time of birth to prevent transmission. If this fails it can lead to NNRTI resistance. Also, a large study in Africa and India found that a PI based regimen was superior to an NNRTI based regimen in children less than 3 years who had never been exposed to NNRTIs in the past. Thus the WHO recommends PI based regimens for children less than 3.
The WHO recommends for children less than 3 years:
* abacavir (or zidovudine) + lamivudine + lopinivir + ritonivir
and for children 3 years to less than 10 years and adolescents <35 kilograms:
*
abacavir
Abacavir, sold under the brand name Ziagen among others, is a medication used to treat HIV/AIDS. Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recom ...
+ lamivudine + efavirenz
US DHHS guidelines are similar but include PI based options for children > 3 years old.
A
systematic review
A systematic review is a Literature review, scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from publ ...
assessed the effects and safety of abacavir-containing regimens as first-line therapy for children between 1 month and 18 years of age when compared to regimens with other NRTIs. This review included two trials and two observational studies with almost eleven thousand HIV infected children and adolescents. They measured virologic suppression, death and adverse events. The authors found that there is no meaningful difference between abacavir-containing regimens and other NRTI-containing regimens. The evidence is of low to moderate quality and therefore it is likely that future research may change these findings.
Pregnant women
The goals of treatment for pregnant women include the same benefits to the mother as in other infected adults as well as prevention of transmission to her child. The risk of transmission from mother to child is proportional to the plasma viral load of the mother. Untreated mothers with a viral load >100,000 copies/ml have a transmission risk of over 50%. The risk when viral loads are < 1000 copies/ml are less than 1%.
ART for mothers both before and during delivery and to mothers and infants after delivery are recommended to substantially reduce the risk of transmission.
The mode of delivery is also important, with a planned
Caesarian section
Caesarean section, also known as C-section or caesarean delivery, is the surgical procedure by which one or more babies are delivered through an incision in the mother's abdomen, often performed because vaginal delivery would put the baby or mo ...
having a lower risk than vaginal delivery or emergency Caesarian section.
HIV can also be detected in breast milk of infected mothers and transmitted through breast feeding. The WHO balances the low risk of transmission through breast feeding from women who are on ART with the benefits of breastfeeding against diarrhea, pneumonia and malnutrition. It also strongly recommends that breastfeeding infants receive prophylactic ART.
In the US, the DHHS recommends against women with HIV breastfeeding.
Older adults
With improvements in HIV therapy, several studies now estimate that patients on treatment in high-income countries can expect a normal life expectancy. This means that a higher proportion of people living with HIV are now older and research is ongoing into the unique aspects of HIV infection in the older adult. There is data that older people with HIV have a blunted CD4 response to therapy but are more likely to achieve undetectable viral levels. However, not all studies have seen a difference in response to therapy. The guidelines do not have separate treatment recommendations for older adults, but it is important to take into account that older patients are more likely to be on multiple non-HIV medications and consider drug interactions with any potential HIV medications.
There are also increased rates of HIV associated non-AIDS conditions (HANA) such as
heart disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...
,
liver disease
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the sig ...
and
dementia
Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...
that are multifactorial complications from HIV, associated behaviors, coinfections like
hepatitis B
Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.
Many people have no symptoms during an initial infection. Fo ...
,
hepatitis C
Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, a ...
, and
human papilloma virus
Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and res ...
(HPV) as well as HIV treatment.
Adults with depression
Many factors may contribute to
depression in adults living with HIV, such as the effects of the virus on the brain, other infections or tumours, antiretroviral drugs and other medical treatment.
Rates of major depression are higher in people living with HIV compared to the general population, and this may negatively influence antiretroviral treatment. In a
systematic review
A systematic review is a Literature review, scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from publ ...
,
Cochrane researchers assessed whether giving antidepressants to adults living with both HIV and depression may improve depression.
Ten trials, of which eight were done in high-income countries, with 709 participants were included. Results indicated that antidepressants may be better in improving depression compared to placebo, but the quality of the evidence is low and future research is likely to impact on the findings.
Concerns
There are several concerns about antiretroviral regimens that should be addressed before initiating:
* Intolerance: The drugs can have serious side-effects which can lead to harm as well as keep patients from taking their medications regularly.
* Resistance: Not taking medication consistently can lead to low blood levels that foster drug resistance.
* Cost: The WHO maintains a database of world ART costs which have dropped dramatically in recent years as more first line drugs have gone off-patent. A one pill, once a day combination therapy has been introduced in South Africa for as little as $10 per patient per month. One 2013 study estimated an overall cost savings to ART therapy in South Africa given reduced transmission. In the United States, new on-patent regimens can cost up to $28,500 per patient, per year.
* Public health: Individuals who fail to use antiretrovirals as directed can develop multi-drug resistant strains which can be passed onto others.
Response to therapy
Virologic response
Suppressing the viral load to undetectable levels (<50 copies per ml) is the primary goal of ART.
This should happen by 24 weeks after starting combination therapy.
Viral load monitoring is the most important predictor of response to treatment with ART. Lack of viral load suppression on ART is termed virologic failure. Levels higher than 200 copies per ml is considered virologic failure, and should prompt further testing for potential viral resistance.
Research has shown that people with an undetectable viral load are unable to transmit the virus through condomless sex with a partner of either gender. The 'Swiss Statement' of 2008 described the chance of transmission as 'very low' or 'negligible,' but multiple studies have since shown that this mode of sexual transmission is impossible where the HIV-positive person has a consistently undetectable viral load. This discovery has led to the formation of the
Prevention Access Campaign are their 'U=U' or 'Undetectable=Untransmittable' public information strategy, an approach that has gained widespread support amongst HIV/AIDS-related medical, charitable, and research organisations.
The studies demonstrating that U=U is an effective strategy for preventing HIV transmission in serodiscordant couples so long as "the partner living with HIV
asa durably suppressed viral load" include:
Opposites Attract,
PARTNER 1,
PARTNER 2,
(for male-male couples)
and HPTN052
(for heterosexual couples).
In these studies, couples where one partner was HIV-positive and one partner was HIV-negative were enrolled and regular HIV testing completed. In total from the four studies, 4097 couples were enrolled over four continents and 151,880 acts of condomless sex were reported, there were zero phylogenetically linked transmissions of HIV where the positive partner had an undetectable viral load. Following this the U=U consensus statement advocating the use of 'zero risk' was signed by hundreds of individuals and organisations including the US
CDC
The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
,
British HIV Association
The British HIV Association (BHIVA) is an organisation of healthcare professionals interested in the treatment and care of people with HIV.
The current BHIVA Chair is Dr Laura Waters.
The aims of BHIVA are, to advance:
* Promotion of good prac ...
and ''
The Lancet
''The Lancet'' is a weekly peer-reviewed general medical journal and one of the oldest of its kind. It is also the world's highest-impact academic journal. It was founded in England in 1823.
The journal publishes original research articles, ...
'' medical journal.
[ Note: When the statement and list of endorsements was retrieved, it had last been updated on 23 August 2018 and included "over 850 organizations from nearly 100 countries."] The importance of the final results of the PARTNER 2 study were described by the medical director of the
Terrence Higgins Trust
Terrence Higgins Trust is a British charity that campaigns about and provides services relating to HIV and sexual health. In particular, the charity aims to end the transmission of HIV in the UK; to support and empower people living with HIV, to ...
as "impossible to overstate," while lead author Alison Rodger declared that the message that "undetectable viral load makes HIV untransmittable ... can help end the HIV pandemic by preventing HIV transmission." The authors summarised their findings in ''The Lancet'' as follows:
This result is consistent with the conclusion presented by
Anthony S. Fauci, the Director of the
National Institute of Allergy and Infectious Diseases
The National Institute of Allergy and Infectious Diseases (NIAID, ) is one of the 27 institutes and centers that make up the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services (HHS). NIAID's ...
for the U.S.
National Institutes of Health
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
, and his team in a viewpoint published in the ''
Journal of the American Medical Association
''The Journal of the American Medical Association'' (''JAMA'') is a peer-reviewed medical journal published 48 times a year by the American Medical Association. It publishes original research, reviews, and editorials covering all aspects of bio ...
'', that U=U is an effective HIV prevention method when an undetectable viral load is maintained.
Immunologic response
CD4 cell counts are another key measure of immune status and ART effectiveness.
CD4 counts should rise 50 to 100 cells per ml in the first year of therapy.
There can be substantial fluctuation in CD4 counts of up to 25% based on the time of day or concomitant infections. In one long-term study, the majority of increase in CD4 cell counts was in the first two years after starting ART with little increase afterwards. This study also found that patients who began ART at lower CD4 counts continued to have lower CD4 counts than those who started at higher CD4 counts. When viral suppression on ART is achieved but without a corresponding increase in CD4 counts it can be termed immunologic nonresponse or immunologic failure. While this is predictive of worse outcomes, there is no consensus on how to adjust therapy to immunologic failure and whether switching therapy is beneficial. DHHS guidelines do not recommend switching an otherwise suppressive regimen.
Innate lymphoid cell
Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling mo ...
s (ILC) are another class of immune cell that is depleted during HIV infection. However, if ART is initiated before this depletion at around 7 days post infection, ILC levels can be maintained. While CD4 cell counts typically replenish after effective ART, ILCs depletion is irreversible with ART initiated after the depletion despite suppression of viremia. Since one of the roles of ILCs is to regulate the immune response to commensal bacteria and to maintain an effective gut barrier, it has been hypothesized that the irreversible depletion of ILCs plays a role in the weakened gut barrier of HIV patients, even after successful ART.
Salvage therapy
In patients who have persistently detectable viral loads while taking ART, tests can be done to investigate whether there is drug resistance. Most commonly a
genotype
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
is sequenced which can be compared with databases of other HIV viral genotypes and resistance profiles to predict response to therapy. Resistance testing may improve virological outcomes in those who have treatment failures. However, there is lack of evidence of effectiveness of such testing in those who have not done any treatment before.
If there is extensive resistance a
phenotypic
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
test of a patient's virus against a range of drug concentrations can be performed, but is expensive and can take several weeks, so genotypes are generally preferred.
Using information from a genotype or phenotype, a regimen of 3 drugs from at least 2 classes is constructed that will have the highest probability of suppressing the virus. If a regimen cannot be constructed from recommended first line agents it is termed
salvage therapy
Salvage therapy, also known as rescue therapy, is a form of therapy given after an ailment does not respond to standard therapy. The most common diseases that require salvage therapy are HIV and various cancers. The term is not clearly defined; it ...
, and when 6 or more drugs are needed it is termed mega-HAART.
Structured treatment interruptions
Drug holidays (or "structured treatment interruptions") are intentional discontinuations of antiretroviral drug treatment. As mentioned above, randomized controlled studies of structured treatment interruptions have shown higher rates of opportunistic infections, cancers, heart attacks and death in patients who took drug holidays.
With the exception of
post-exposure prophylaxis
Post-exposure prophylaxis, also known as post-exposure prevention (PEP), is any preventive medical treatment started after exposure to a pathogen in order to prevent the infection from occurring.
COVID-19
In 2021, the FDA has approved bamlanivi ...
(PEP), treatment guidelines do not call for the interruption of drug therapy once it has been initiated.
Adverse effects
Each class and individual antiretroviral carries unique risks of adverse side effects.
NRTIs
The
NRTI
Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replicatio ...
s can interfere with
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
l DNA synthesis and lead to high levels of lactate and
lactic acidosis
Lactic acidosis is a medical condition characterized by a build-up of lactate (especially -lactate) in the body, with formation of an excessively low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive acid accumulates ...
, liver
steatosis
Steatosis, also called fatty change, is abnormal retention of fat (lipids) within a cell or organ. Steatosis most often affects the liver – the primary organ of lipid metabolism – where the condition is commonly referred to as fatty liver disea ...
,
peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
,
myopathy
In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease (Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meani ...
and
lipoatrophy
Lipoatrophy is the term describing the localized loss of fat tissue. This may occur as a result of subcutaneous injections of insulin in the treatment of diabetes, from the use of human growth hormone or from subcutaneous injections of copaxone use ...
.
First-line NRTIs such as lamivudine/emtrictabine, tenofovir, and abacavir are less likely to cause mitochondrial dysfunction.
Mitochondrial Haplogroups(mtDNA), non pathologic mutations inherited from the maternal line, have been linked to the efficacy of CD4+ count following ART. Idiosyncratic toxicity with mtDNA haplogroup is also well studied.(Boeisteril et al., 2007).
NNRTIs
NNRTIs are generally safe and well tolerated. The main reason for discontinuation of
efavirenz
Efavirenz (EFV), sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlest ...
is neuro-psychiatric effects including suicidal ideation.
Nevirapine
Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mothe ...
can cause severe hepatotoxicity, especially in women with high CD4 counts.
Protease inhibitors
Protease inhibitors
Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS and hepatitis C. These protease inhibitors prevent viral replicat ...
(PIs) are often given with
ritonavir
Ritonavir, sold under the brand name Norvir, is an antiretroviral drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor a ...
, a strong inhibitor of cytochrome P450 enzymes, leading to numerous drug-drug interactions. They are also associated with
lipodystrophy
Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissue. ...
, elevated
triglycerides
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other vertebrates, as we ...
and elevated risk of
heart attack
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tr ...
.
Integrase inhibitors
Integrase inhibitors (INSTIs) are among the best tolerated of the antiretrovirals with excellent short and medium term outcomes. Given their relatively new development there is less long term safety data. They are associated with an increase in creatinine kinase levels and rarely myopathy.
Post-exposure prophylaxis (PEP)
When people are exposed to HIV-positive infectious bodily fluids either through skin puncture, contact with
mucous membranes
A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
or contact with damaged skin, they are at risk for acquiring HIV. Pooled estimates give a risk of transmission with puncture exposures of 0.3% and mucous membrane exposures 0.63%. United States guidelines state that "feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious unless they are visibly bloody."
Given the rare nature of these events, rigorous study of the protective abilities of antiretrovirals are limited but do suggest that taking antiretrovirals afterwards can prevent transmission. It is unknown if three medications are better than two. The sooner after exposure that ART is started the better, but after what period they become ineffective is unknown, with the
US Public Health Service
The United States Public Health Service (USPHS or PHS) is a collection of agencies of the Department of Health and Human Services concerned with public health, containing nine out of the department's twelve operating divisions. The Assistant S ...
Guidelines recommending starting prophylaxis up to a week after exposure.
They also recommend treating for a duration of four weeks based on animal studies. Their recommended regimen is emtricitabine + tenofovir +
raltegravir
Raltegravir, sold under the brand name Isentress, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential ex ...
(an INSTI). The rationale for this regimen is that it is "tolerable, potent, and conveniently administered, and it has been associated with minimal drug interactions."
People who are exposed to HIV should have follow up HIV testing at six, 12, and 24 weeks.
Pregnancy planning
Women with HIV have been shown to have decreased fertility which can affect available reproductive options. 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 Sperm washing is the process in which individual sperms are separated from the semen. Washed sperm is used in artificial insemination using the intrauterine insemination (IUI) technique and in in vitro fertilization (IVF). It may also be used to d ...
followed by
intrauterine insemination
Artificial insemination is the deliberate introduction of sperm into a female's cervix or uterine cavity for the purpose of achieving a pregnancy through in vivo fertilization by means other than sexual intercourse. It is a fertility treatment ...
(IUI) or
in vitro fertilization
In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) ...
(IVF). Preferably this is done after the man has achieved an undetectable plasma viral load.
In the past there have been cases of HIV transmission to an HIV-negative partner through processed artificial insemination, but a large modern series in which followed 741 couples where the man had a stable viral load and semen samples were tested for HIV-1, there were no cases of HIV transmission.
For cases where the woman is HIV positive and the man is HIV negative, the usual method is
artificial insemination
Artificial insemination is the deliberate introduction of sperm into a female's cervix or uterine cavity for the purpose of achieving a pregnancy through in vivo fertilization by means other than sexual intercourse. It is a fertility treatme ...
.
With appropriate treatment the risk of
mother-to-child infection can be reduced to below 1%.
History
Several
buyers clubs sprang up since 1986 to combat HIV. The drug
zidovudine
Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child ...
(AZT), a
nucleoside reverse-transcriptase inhibitor (NRTI), was not effective on its own. It was approved by the US
FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
in 1987. The FDA bypassed stages of its review for safety and effectiveness in order to distribute this drug earlier. Subsequently, several more NRTIs were developed but even in combination were unable to suppress the virus for long periods of time and patients still inevitably died. To distinguish from this early antiretroviral therapy (ART), the term highly active antiretroviral therapy (HAART) was introduced. In 1996 two sequential publications in ''
The New England Journal of Medicine
''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one.
His ...
'' by Hammer and colleagues and Gulick and colleagues
illustrated the substantial benefit of combining 2 NRTIs with a new class of antiretrovirals,
protease inhibitors
Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS and hepatitis C. These protease inhibitors prevent viral replicat ...
, namely
indinavir
Indinavir (IDV; trade name Crixivan, made by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. ...
. 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.
As HAART became widespread,
fixed dose combinations were made available to ease the administration. Later, the term combination antiretroviral therapy (cART) gained favor with some physicians as a more accurate name, not conveying to patients any misguided idea of the nature of the therapy.
Today multidrug, highly effective regimens are long since the default in ART, which is why they are increasingly called simply ART instead of HAART or cART.
This
retronym
A retronym is a newer name for an existing thing that helps differentiate the original form/version from a more recent one. It is thus a word or phrase created to avoid confusion between older and newer types, whereas previously (before there were ...
ic process is linguistically comparable to the way that the words ''electronic computer'' and ''digital computer'' at first were needed to make useful distinctions in
computing
Computing is any goal-oriented activity requiring, benefiting from, or creating computing machinery. It includes the study and experimentation of algorithmic processes, and development of both hardware and software. Computing has scientific, e ...
technology, but with the later irrelevance of the distinction, ''computer'' alone now covers their meaning. Thus as "all computers are digital now", so "all ART is combination ART now." However, the names HAART and cART, reinforced by thousands of earlier mentions in
medical literature
Medical literature is the scientific literature of medicine: articles in journals and texts in books devoted to the field of medicine. Many references to the medical literature include the health care literature generally, including that of denti ...
still being
regularly cited, also remain in use.
Research
People living with HIV can expect to live a nearly normal life span if able to achieve durable viral suppression on combination antiretroviral therapy. However this requires lifelong medication and will still have higher rates of cardiovascular, kidney, liver and neurologic disease.
This has prompted further research towards a cure for HIV.
Patients cured of HIV infection
The so-called "
Berlin patient
The Berlin patient is an anonymous person from Berlin, Germany, who was described in 1998 as exhibiting prolonged "post-treatment control" of HIV viral load
Viral load, also known as viral burden, is a numerical expression of the quantity of vir ...
" has been potentially cured of HIV infection and has been off of treatment since 2006 with no detectable virus. This was achieved through two
bone marrow transplant
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...
s that replaced his immune system with a donor's that did not have the
CCR5
C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines.
In humans, the ''CCR5'' gene that encodes the CCR5 pro ...
cell surface receptor, which is needed for some variants of HIV to enter a cell. Bone marrow transplants carry their own significant risks including potential death and was only attempted because it was necessary to treat a blood cancer he had. Attempts to replicate this have not been successful and given the risks, expense and rarity of CCR5 negative donors, bone marrow transplant is not seen as a mainstream option.
It has inspired research into other methods to try to block CCR5 expression through gene therapy. A procedure
zinc-finger nuclease
Zinc-finger nucleases (ZFNs) are artificial restriction enzymes generated by fusing a zinc finger DNA-binding domain to a DNA-cleavage domain. Zinc finger domains can be engineered to target specific desired DNA sequences and this enables zinc ...
-based
gene knockout
A gene knockout (abbreviation: KO) is a genetic technique in which one of an organism's genes is made inoperative ("knocked out" of the organism). However, KO can also refer to the gene that is knocked out or the organism that carries the gene kno ...
has been used in a Phase I trial of 12 humans and led to an increase in CD4 count and decrease in their viral load while off antiretroviral treatment. Attempt to reproduce this failed in 2016. Analysis of the failure showed that gene therapy only successfully treats 11-28% of cells, leaving the majority of CD4+ cells capable of being infected. The analysis found that only patients where less than 40% of cells were infected had reduced viral load. The Gene therapy was not effective if the native CD4+ cells remained. This is the main limitation which must be overcome for this treatment to become effective.
After the "
Berlin patient
The Berlin patient is an anonymous person from Berlin, Germany, who was described in 1998 as exhibiting prolonged "post-treatment control" of HIV viral load
Viral load, also known as viral burden, is a numerical expression of the quantity of vir ...
", two additional patients with both HIV infection and cancer were reported to have no traceable HIV virus after successful stem cell transplants.
Virologist
Virology is the scientific study of biological viruses. It is a subfield of microbiology that focuses on their detection, structure, classification and evolution, their methods of infection and exploitation of host cells for reproduction, their ...
Annemarie Wensing of the University Medical Center Utrecht announced this development during her presentation at the 2016 "Towards an HIV Cure" symposium. However, these two patients are still on
antiretroviral therapy
The management of HIV/AIDS normally includes the use of multiple Antiviral drug, antiretroviral drugs as a strategy to control HIV/AIDS, HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life- ...
, which is not the case for the Berlin patient. Therefore, it is not known whether or not the two patients are cured of
HIV infection
Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ma ...
. The cure might be confirmed if the therapy were to be stopped and no viral rebound occurred.
In March 2019, a second patient, referred to as the "
London Patient
Adam Castillejo, also known as "The London Patient", is the second person known to have been cured of HIV infection.
His body became resistant to HIV infection after receiving a bone marrow transplant to treat Hodgkin's lymphoma. The donor carri ...
", was confirmed to be in complete remission of HIV. Like the Berlin Patient, the London Patient received a bone marrow transplant from a donor who has the same CCR5 mutation. He has been off antiviral drugs since September 2017, indicating the Berlin Patient was not a "one-off".
Alternative approaches aiming to mimic one’s biological immunity to HIV through the absence or mutation of the CCR5 gene is being conducted in current research efforts. The efforts of which are done through the introduction of induced pluripotent stem cells that have been CCR5 disrupted through the
CRISPR/Cas9
Cas9 (CRISPR associated protein 9, formerly called Cas5, Csn1, or Csx12) is a 160 kilodalton protein which plays a vital role in the immunological defense of certain bacteria against DNA viruses and plasmids, and is heavily utilized in genetic e ...
gene editing system.
Viral reservoirs
The main obstacle to complete elimination of HIV infection by conventional antiretroviral therapy is that HIV is able to integrate itself into the DNA of host cells and rest in a
latent
Latency or latent may refer to:
Science and technology
* Latent heat, energy released or absorbed, by a body or a thermodynamic system, during a constant-temperature process
* Latent variable, a variable that is not directly observed but inferred ...
state, while antiretrovirals only attack actively replicating HIV. The cells in which HIV lies dormant are called the viral reservoir, and one of the main sources is thought to be central memory and transitional
memory CD4+ T cells. In 2014 there were reports of the cure of HIV in two infants, presumably due to the fact that treatment was initiated within hours of infection, preventing HIV from establishing a deep reservoir. There is work being done to try to activate reservoir cells into replication so that the virus is forced out of latency and can be attacked by antiretrovirals and the host immune system. Targets include
histone deacetylase
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
(HDAC) which represses transcription and if inhibited can lead to increased cell activation. The HDAC inhibitors
valproic acid
Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...
and
vorinostat
Vorinostat (rINN) also known as Suberoylanilide hydroxamic acid ( suberoyl+anilide+hydroxamic acid abbreviated as SAHA) is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) ha ...
have been used in human trials with only preliminary results so far.
Immune activation
Even with all latent virus deactivated, it is thought that a vigorous immune response will need to be induced to clear all the remaining infected cells.
Strategies include using
cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
to restore CD4+ cell counts as well as therapeutic vaccines to prime immune responses. One such candidate vaccine is Tat Oyi, developed by Biosantech. This vaccine is based on the HIV protein
tat. Animal models have shown the generation of neutralizing antibodies and lower levels of HIV viremia.
Sequential mRNA Vaccine
HIV vaccine development
An HIV vaccine is a potential vaccine that could be either a preventive vaccine or a therapeutic vaccine, which means it would either protect individuals from being infected with HIV or treat HIV-infected individuals.
It is thought that an HIV v ...
is an active area of research and an important tool for managing the global
AIDS epidemic
The global epidemic of HIV/AIDS (human immunodeficiency virus infection and acquired immunodeficiency syndrome) began in 1981, and is an ongoing worldwide public health issue. According to the World Health Organization (WHO), as of 2021, HIV/AI ...
. Research into a vaccine for HIV has been ongoing for decades with no lasting success for preventing infection. The rapid development, though, of
mRNA vaccine
An mRNA vaccine is a type of vaccine that uses a copy of a molecule called messenger RNA (mRNA) to produce an immune response. The vaccine delivers molecules of antigen-encoding mRNA into immune cells, which use the designed mRNA as a blueprin ...
s to deal with the
COVID-19 pandemic
The COVID-19 pandemic, also known as the coronavirus pandemic, is an ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel virus was first identif ...
may provide a new path forward.
Like
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
, the virus that causes
COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...
,
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
has a
spike protein
In virology, a spike protein or peplomer protein is a protein that forms a large structure known as a spike or peplomer projecting from the surface of an enveloped virus. as cited in The proteins are usually glycoproteins that form dimers or ...
. In
retrovirus
A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...
es like HIV, the spike protein is formed by two proteins expressed by the
Env gene. This
viral envelope
A viral envelope is the outermost layer of many types of viruses. It protects the genetic material in their life cycle when traveling between host cells. Not all viruses have envelopes.
Numerous human pathogenic viruses in circulation are encase ...
binds to the host cell’s receptor and is what gains the virus entry into the cell. With mRNA vaccines,
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
or messenger RNA, contains the instructions for how to make the spike protein. The mRNA is put into lipid-based
nanoparticles for drug delivery. This was a key breakthrough in optimizing the efficiency and efficacy of in vivo delivery. When the vaccine is injected, the mRNA enters cells and joins up with a
ribosome
Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
. The ribosome then translates the mRNA instructions into the spike protein. The immune system detects the presence of the spike protein and
B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s, a type of
white blood cell
White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...
, begin to develop
antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
. Should the actual virus later enter the system, the external spike protein will be recognized by
memory B cell
In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescen ...
s, whose function is to memorize the characteristics of the original
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
. Memory B cells then produce the antibodies, hopefully destroying the virus before it can bind to another cell and repeat the HIV life cycle.
SARS-CoV-2 and HIV-1 have similarities—notably both are RNA viruses—but there are important differences. As a retrovirus, HIV-1 can insert a copy of its RNA genome into the host’s DNA, making total eradication more difficult. The virus is also highly mutable making it a challenge for the
adaptive immune system
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system ...
to develop a response. As a chronic infection, HIV-1 and the adaptive immune system undergo reciprocal selective pressures leading to the
evolutionary arms race
In evolutionary biology, an evolutionary arms race is an ongoing struggle between competing sets of co-evolving genes, phenotypic and behavioral traits that develop escalating adaptations and counter-adaptations against each other, resembling an a ...
of
coevolution
In biology, coevolution occurs when two or more species reciprocally affect each other's evolution through the process of natural selection. The term sometimes is used for two traits in the same species affecting each other's evolution, as well ...
.
Broadly neutralizing HIV-1 antibodies, or bnAbs, have been shown to attach to the Env spike protein envelope regardless of the specific HIV mutations. This bodes well for vaccine development. Complicating matters, though,
naive B cell A naive B cell is a B cell that has not been exposed to an antigen. These are located in the tonsils, spleen, primary lymphoid follicles in lymph nodes
Once exposed to an antigen, the naive B cell either becomes a memory B cell
In immunology, a ...
s—mature B cells not yet exposed to any antigen and are the progenitors of bnAbs—are rare. Further, the mutation events needed to turn these B cells into bnAbs are also rare.
Because of this, there is a growing consensus that an effective HIV vaccine will need to create not only
humoral
Humoral immunity is the aspect of immunity that is mediated by macromolecules - including secreted antibodies, complement proteins, and certain antimicrobial peptides - located in extracellular fluids. Humoral immunity is named so because it invo ...
(antibody-mediated) immunity, but a
T-cell-mediated immunity.
mRNA vaccines have advantages over traditional vaccines which may help deal with some of the challenges presented by the HIV virus. The mRNA in the vaccine only codes for the protein spike, not the whole virus, so the possibility of
reverse transcription
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
, where the virus copies its genetic material into the host’s genome, is not present. Another advantage when compared to traditional vaccines is the speed of development. mRNA vaccines take months not years, which means a multipart sequential vaccine regime is possible.
Attempts to elicit an immune response that triggers broadly neutralizing antibodies (bnAbs) with a single vaccine dose have been unsuccessful. A multipart sequential mRNA vaccine regime, however, might guide the immune response in the right direction. The first shot triggers an immune response for the correct naive B cells. Later vaccinations encourage the development of these cells further, eventually turning them into memory b cells, and later into
plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...
s, which can secrete the broadly neutralizing antibodies:
In essence, the sequential immunization approach represents an attempt to mimic Env evolution that would occur with natural infection…. In contrast to traditional prime/boost strategies, in which the same immunogen is used repeatedly for vaccination, the sequential immunization approach relies on a series of different immunogens with the goal of eventually inducing bnAb(s).
A Phase 1 clinical trial by
Scripps Research
Scripps Research, previously known as The Scripps Research Institute (TSRI), is a nonprofit American medical research facility that focuses on research and education in the biomedical sciences. Headquartered in San Diego, California, the institu ...
and the
International AIDS Vaccine Initiative
The International AIDS Vaccine Initiative (IAVI) is a global not-for-profit, public-private partnership working to accelerate the development of vaccines to prevent HIV infection and AIDS. IAVI researches and develops vaccine candidates, conduct ...
of an mRNA vaccine showed that 97 percent of participants had the desired initial “priming” immune response of naive b cells.
This is a positive result for developing the first shot in a vaccine sequence. Moderna is partnering with Scripps and the International AIDS Vaccine Initiative for a follow-up phase 1 clinical trial of an HIV mRNA vaccine (mRNA-1644) starting later in 2021.
Drug advertisements
Direct-to-consumer
Direct-to-consumer (DTC) or business-to-consumer (B2C) is the business model of selling products directly to customers and thereby bypassing any third-party retailers, wholesalers, or any other middlemen. Direct-to-consumer sales are usually tr ...
and other advertisements for HIV drugs in the past were criticized for their use of healthy, glamorous
models
A model is an informative representation of an object, person or system. The term originally denoted the plans of a building in late 16th-century English, and derived via French and Italian ultimately from Latin ''modulus'', a measure.
Models c ...
rather than typical people with HIV/AIDS. Usually, these people will present with debilitating conditions or illnesses as a result of HIV/AIDS. In contrast, by featuring people in unrealistically strenuous activities, such as
mountain climbing
Mountaineering or alpinism, is a set of outdoor activities that involves ascending tall mountains. Mountaineering-related activities include traditional outdoor climbing, skiing, and traversing via ferratas. Indoor climbing, sport climbing, a ...
; this proved to be offensive and insensitive to the suffering of people who are HIV positive. The US FDA reprimanded multiple pharmaceutical manufacturers for publishing such adverts in 2001, as the Misleading advertising, misleading advertisements harmed consumers by implying unproven benefits and failing to disclose important information about the drugs.
Overall, some drug companies chose not to present their drugs in a realistic way, which consequently harmed the general public's ideas, suggesting that HIV would not affect you as much as suggested. This led to people not wanting to get tested, for fear of being HIV positive, because at the time (in the 80s and 90s particularly), having contracted HIV was seen as a death sentence, as there was no known cure.
An example of such a case is Freddie Mercury, who died in 1991, aged 45, of AIDS-related pneumonia.
Beyond medical management
The preamble to the World Health Organization's Constitution defines health as "a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity."
Those living with HIV today are met with other challenges that go beyond the singular goal of lowering their viral load. A 2009 meta-analysis studying the correlates of HIV-stigma found that individuals living with higher stigma burden were more likely to have poorer physical and mental health.
Insufficient social support and delayed diagnosis due to decreased frequency of HIV testing and knowledge of risk reduction were cited as some of the reasons.
People living with HIV (PLHIV) have lower health related quality of life (HRQoL) scores than do the general population.
The stigma of having HIV is often compounded with the stigma of identifying with the LGBTQ community or the stigma of being an injecting drug user (IDU) even though heterosexual sexual transmission accounts for 85% of all HIV-1 infections worldwide.
AIDS has been cited as the most heavily stigmatized medical condition among infectious diseases.
Part of the consequence of this stigma toward PLHIV is the belief that they are seen as responsible for their status and less deserving of treatment.
A 2016 study sharing the WHO's definition of health critiques its 90-90-90 target goal, which is part of a larger strategy that aims to eliminate the AIDS epidemic as a public health threat by 2030, by arguing that it does not go far enough in ensuring the holistic health of PLHIV.
The study suggests that maintenance of HIV and AIDS should go beyond the suppression of viral load and the prevention of opportunistic infection. It proposes adding a 'fourth 90' addressing a new 'quality of life' target that would focus specifically on increasing the quality of life for those that are able to suppress their viral load to undetectable levels along with new metrics to track the progress toward that target.
This study serves as an example of the shifting paradigm in the dynamics of the health care system from being heavily 'disease-oriented' to more 'human-centered'. Though questions remain of what exactly a more 'human-centered' method of treatment looks like in practice, it generally aims to ask what kind of support, other than medical support, PLHIV need to cope with and eliminate HIV-related stigmas.
Campaigns and marketing aimed at educating the general public in order to reduce any misplaced fears of HIV contraction is one example.
Also encouraged is the capacity-building and guided development of PLHIV into more leadership roles with the goal of having a greater representation of this population in decision making positions.
Structural legal intervention has also been proposed, specifically referring to legal interventions to put in place protections against discrimination and improve access to employment opportunities.
On the side of the practitioner, greater competence for the experience of people living with HIV is encouraged alongside the promotion of an environment of nonjudgment and confidentiality.
Psychosocial group interventions such as psychotherapy, relaxation, group support, and education may have some beneficial effects on depression in HIV positive people.
Food insecurity
The successful treatment and management of HIV/AIDS is affected by a plethora of factors which ranges from successfully taking prescribed medications, preventing opportunistic infection, and food access etc. Food insecurity is a condition in which households lack access to adequate food because of limited money or other resources. Food insecurity is a global issue that have affect billions of people yearly including those living in developed countries.
Food insecurity is a major public health disparity in the United States of America, which significantly affects minority groups, people living at or below the poverty line, and those who are living with one or more morbidity. As of December 31, 2017, there were approximately 126,742 people living with HIV/AIDS (PLWHA) in NYC, of whom 87.6% can be described as living with some level of poverty and food insecurity as reported by the NYC Department of Health March 31, 2019. Having access to a consistent food supply that is safe and healthy is an important part in the treatment and management of HIV/AIDS. PLWHA are also greatly affected by food inequities and food deserts which causes them to be food insecure. Food insecurity, which can cause malnutrition, can also negatively impact HIV treatment and recovery from opportunistic infections. Similarly, PLWHA require additional calories and nutritionally support that require foods free from contamination to prevent further immunocompromising. Food insecurity can further exacerbate the progression of HIV/AIDS and can prevent PLWHA from consistently following their prescribed regimen, which will lead to poor outcomes.
It is imperative that these food insecurity among PLWHA are addressed and rectified to reduce this health inequity.
It is important to recognized that socioeconomic status, access to medical care, geographic location, public policy, race and ethnicity all play a pivotal role in the treatment and management of HIV/AIDS. The lack of sufficient and constant income does limit the options for food, treatment, and medications. The same can be inferred for those who are among the oppressed groups in society who are marginalized and may be less inclined or encouraged to seek care and assistance. Endeavors to address food insecurity should be included in HIV treatment programs and may help improve health outcomes if it also focuses on health equity among the diagnosed as much as it focuses on medications. Access to consistently safe and nutritious foods is one of the most important facets in ensuring PLWHA are being provided the best possible care. By altering the narratives for HIV treatment so that more support can be garnered to reduce food insecurity and other health disparities mortality rates will decrease for people living with HIV/AIDS.
See also
* Antiviral drug
* AV-HALT
* Discovery and development of HIV-protease inhibitors
* Discovery and development of non-nucleoside reverse-transcriptase inhibitors
* Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors
* HIV capsid inhibition
References
External links
HIVinfo – Comprehensive resource for HIV/AIDS treatment and clinical trial information from the U. S. Department of Health and Human ServicesASHM – Australian Commentary on HHS Guidelines for the use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescentsresearch papers, including effectiveness of HAART on reducing viral load
Current status of gene therapy strategies to treat HIV/AIDS
{{DEFAULTSORT:Antiretroviral Drug
Antiretroviral drugs,
Hepatotoxins
Prevention of HIV/AIDS