The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs in an attempt to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death.
HAART also prevents the transmission of HIV between serodiscordant 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 is increasingly rare. Anthony Fauci, head of the United States National Institute of Allergy and Infectious Diseases,
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
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 and the World Health Organization recommend offering antiretroviral treatment to all patients with HIV. 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 World Health Organization 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.
The United States Department of Health and Human Services and the World Health Organization recommend offering antiretroviral treatment to all patients with HIV. 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 World Health Organization 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
Schematic description of the mechanism of the four classes of currently available antiretroviral drugs against HIV
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
life-cycle that the drug inhibits. Typical combinations include 2
Nucleoside reverse-transcriptase inhibitors (NRTI) as a "backbone" along
with 1 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 (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. Maraviroc and enfuvirtide are the two currently available agents in this class. Maraviroc works by targeting CCR5,
a co-receptor located on human helper T-cells. Caution should be used
when administering this drug, however, due to a possible shift in tropism which allows HIV to target an alternative co-receptor such as CXCR4.
In rare cases, individuals may have a mutation in the CCR5 delta
gene which results in a nonfunctional CCR5 co-receptor and in turn, a
means of resistance or slow progression of the disease. However, as
mentioned previously, this can be overcome if an HIV variant that
targets CXCR4 becomes dominant.
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 and nucleotide analogues
which inhibit reverse transcription. HIV is an RNA virus and hence
unable to become integrated into the DNA in the nucleus of the human
cell; it must be "reverse" transcribed into DNA. Since the conversion of
RNA to DNA is not done in the mammalian cell it is performed by a viral
protein which makes it a selective target for inhibition. NRTIs are
chain terminators such that once incorporated, work by preventing other
nucleosides from also being incorporated into the DNA chain because of
the absence of a 3' OH group. Both act as competitive substrate inhibitors. Examples of currently used NRTIs include zidovudine, abacavir, lamivudine, emtricitabine, and tenofovir.
Non-nucleoside reverse-transcriptase inhibitors
Non-nucleoside reverse-transcriptase inhibitors (NNRTI) inhibit reverse transcriptase by binding to an allosteric site of the enzyme; NNRTIs act as non-competitive inhibitors of reverse transcriptase.
NNRTIs affect the handling of substrate (nucleotides) by reverse
transcriptase by binding near the active site. NNRTIs can be further
classified into 1st generation and 2nd generation NNRTIs. 1st generation
NNRTIs include nevirapine and efavirenz. 2nd generation NNRTIs are etravirine and rilpivirine. HIV-2 is naturally resistant to NNRTIs.
Integrase inhibitors
Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) inhibit the viral enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. There are several integrase inhibitors currently under clinical trial, and raltegravir
became the first to receive FDA approval in October 2007. Raltegravir
has two metal binding groups that compete for substrate with two Mg2+ ions at the metal binding site of integrase. As of early 2014, two other clinically approved integrase inhibitors are elvitegravir and dolutegravir.
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, indinavir, nelfinavir, amprenavir and ritonavir. Darunavir and atazanavir are currently recommended as first line therapy choices. Maturation inhibitors have a similar effect by binding to gag, but development of two experimental drugs in this class, bevirimat and vivecon, was halted in 2010.[15]
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 enzymes to correct errors made when it converts its RNA into DNA via reverse transcription.
Its short life-cycle and high error rate cause the virus to mutate very
rapidly, resulting in a high genetic variability of HIV. Most of the mutations either are inferior to the parent virus (often lacking the ability to reproduce at all) or convey no advantage, but some of them have a natural selection
superiority to their parent and can enable them to slip past defenses
such as the human immune system and antiretroviral drugs. The more
active copies of the virus, the greater the possibility that one
resistant to antiretroviral drugs will be made.
When antiretroviral drugs are used improperly, multi-drug
resistant strains can become the dominant genotypes very rapidly. In the
era before multiple drug classes were available (pre-1997), the reverse-transcriptase inhibitors zidovudine, didanosine, zalcitabine, stavudine, and lamivudine were used serially or in combination leading to the development of multi-drug resistant mutations.
Antiretroviral combination therapy defends against
resistance by suppressing HIV replication as much as possible, thus
reducing the potential pool of spontaneous resistance mutations.
Combinations of antiretrovirals create multiple obstacles to HIV
replication to keep the number of offspring low and reduce the
possibility of a superior mutation. If a mutation that conveys
resistance to one of the drugs being taken arises, the other drugs
continue to suppress reproduction of that mutation. With rare
exceptions, no individual antiretroviral drug has been demonstrated to
suppress an HIV infection for long; these agents must be taken in
combinations in order to have a lasting effect. As a result, the
standard of care is to use combinations of antiretroviral drugs. Combinations usually 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, which limits the number of useful combinations.
In recent years, drug companies have worked together to combine these complex regimens into simpler formulas, termed fixed-dose combinations. For instance, there are now several options that combine 3 or 4 drugs into one pill taken once daily.
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. Not taking
anti-retrovirals regularly is a cause of resistance development in
people who have started taking them previously. Patients who take 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.
Fixed-dose combinations
Fixed-dose combinations of antiretrovirals are multiple antiretroviral drugs combined into a single pill, which helps reduce pill burden. They may combine different classes of antiretrovirals (e.g., Atripla) or contain only a single class (e.g., Epzicom).
Licensed fixed-dose combinations are shown in the table below. Some are
complete single-tablet regimens for the management of HIV/AIDS (the
drug is one pill taken once daily); the others must be combined with one
or more additional pills to complete a regimen.
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 as an adjunct to antiretroviral therapy for adults with HIV. A Cochrane review included 25 randomized controlled trials 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 anti-retrovirals, protease inhibitors, namely indinavir. 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.
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 (<50 a="" copies="" has="" hiv="" href="https://en.wikipedia.org/wiki/Clinical_trial" in="" is="" ml="" negative.="" partner="" sex="" title="Clinical trial" who="" with="">clinical trial
HPTN 052, 1763 serodiscordant
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
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 (PrEP) provides HIV- 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 gave the Breakthrough of the Year 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 6 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, 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 2010–2014, 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 efficacious 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 where ART therapy was periodically stopped had higher rates
of opportunistic infections, cancers, heart attacks and death in
patients who 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 USA) as well as the US government's Department of Health and Human Services guidelines. In Europe there are the European AIDS Clinical Society guidelines.
For resource limited countries, most national guidelines closely follow the World Health Organization guidelines.
Current guidelines
The
current guidelines use new criteria to consider starting HAART, as
described below. However, there remain a range of views on this subject
and the decision of whether to commence treatment ultimately rests with
the patient and his or her doctor.
Current 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 World Health Organization 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 + lamivudine + nevirapine. 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 current HAART regimens consist of three drugs: 2 NRTIs ("backbone")+ a PI/NNRTI/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 (an integrase inhibitor)
- tenofovir/emtricitabine and dolutegravir (an integrase inhibitor)
- abacavir/lamivudine (two NRTIs) and dolutegravir for patients who have been tested negative for the HLA-B*5701 gene allele
- tenofovir/emtricitabine, elvitegravir (an integrase inhibitor) and cobicistat (inhibiting metabolism of the former) in patients with good kidney function (gfr > 70)
- tenofovir/emtricitabine, ritonavir, and darunavir (both latter are protease inhibitors)
In the case of the protease inhibitor based regimens, ritonavir is used at low doses to inhibit cytochrome p450
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 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 (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.
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
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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 (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:="" p="">
- abacavir + lamivudine + efavirenz
US DHHS guidelines are similar but include PI based options for children > 3 years old.
A systematic review
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 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.
Current 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, liver disease and dementia that are multifactorial complications from HIV, associated behaviors, coinfections like hepatitis B, hepatitis C, and human papilloma virus (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, 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 recent 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 (<50 200="" 24="" after="" and="" art.="" art="" by="" combination="" considered="" copies="" failure.="" failure="" for="" further="" goal="" happen="" higher="" important="" is="" lack="" levels="" load="" ml="" monitoring="" most="" of="" on="" p="" per="" potential="" predictor="" primary="" prompt="" resistance.="" response="" should="" starting="" suppression="" termed="" testing="" than="" the="" therapy.="" this="" to="" treatment="" viral="" virologic="" weeks="" with="">
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 [has] a 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, British HIV Association and The Lancet medical journal. The importance of the final results of the PARTNER 2 study were described by the medical director of the Terrence Higgins Trust
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:
Our results provide a similar level of evidence on viral suppression and HIV transmission risk for gay men to that previously generated for heterosexual couples and suggest that the risk of HIV transmission in gay couples through condomless sex when HIV viral load is suppressed is effectively zero. Our findings support the message of the U=U (undetectable equals untransmittable) campaign, and the benefits of early testing and treatment for HIV.
This result is consistent with the conclusion presented by Anthony S. Fauci, the Director of the National Institute of Allergy and Infectious Diseases for the U.S. National Institutes of Health, and his team in a viewpoint published in the Journal of the American Medical Association, 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 cells (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
is sequenced which can be compared with databases of other HIV viral
genotypes and resistance profiles to predict response to therapy. If there is extensive resistance a phenotypic
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, 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, current 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 NRTIs can interfere with mitochondrial DNA synthesis and lead to high levels of lactate and lactic acidosis, liver steatosis, peripheral neuropathy, myopathy and lipoatrophy.
Current first line NRTIs such as lamivudine/emtrictabine, tenofovir,
and abacavir are less likely to cause mitochondrial dysfunction.
NNRTIs
NNRTIs are generally safe and well tolerated. The main reason for discontinuation of efavirenz is neuro-psychiatric effects including suicidal ideation. Nevirapine can cause severe hepatotoxicity, especially in women with high CD4 counts.
Protease inhibitors
Protease inhibitors (PIs) are often given with ritonavir, a strong inhibitor of cytochrome P450 enzymes, leading to numerous drug-drug interactions. They are also associated with lipodystrophy, elevated triglycerides and elevated risk of heart attack.
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.
HIV postexposure prophylaxis (PEP)
When people are exposed to HIV-positive infectious bodily fluids either through blood puncture, contact with mucous membranes
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 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
(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 followed by intrauterine insemination (IUI) or in vitro fertilization (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. 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. AZT nucleoside reverse-transcriptase inhibitor (NRTI), zidovudine (AZT) was not effective on its own. It was approved by the US FDA 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 by
sequential publications in The New England Journal of Medicine by Hammer and colleagues and Gulick and colleagues illustrating the substantial benefit of combining 2 NRTIs with a new class of antiretrovirals, protease inhibitors, namely indinavir.
This concept of 3-drug therapy was quickly incorporated into clinical
practice and rapidly showed impressive benefit with a 60% to 80% decline
in rates of AIDS, death, and hospitalization.
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 name more accurate for the current era, 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 retronymic 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 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 still being regularly cited, also remain in current use.
Research
People
living with HIV can currently 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" 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 transplants that replaced his immune system with a donor's that did not have the CCR5 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-based gene knockout
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.
After the "Berlin patient",
two additional patients with both HIV infection and cancer were
reported to have no traceable HIV virus after successful stem cell
transplants. Virologist
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, 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. 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", 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".
Viral reservoirs
The
main obstacle to conventional antiretroviral therapy eliminating HIV
infection is that HIV is able to integrate itself into the DNA of host
cells and rest in a latent
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. Recent reports of the cure of HIV in two infants
are presumably due to the fact that treatment was initiated within
hours of infection, preventing HIV from establishing a deep reservoir.
Currently 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 (HDAC) which represses transcription and if inhibited can lead to increased cell activation. The HDAC inhibitors valproic acid and vorinostat 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. Current strategies include using cytokines 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. A brief report of their phase I/II clinical trial reported it was safe and well tolerated in 48 HIV-positive patients. Animal models have shown the generation of neutralizing antibodies and lower levels of HIV viremia.
Drug advertisements
Direct-to-consumer and other advertisements for HIV drugs in the past were criticized for their use of healthy, glamorous models
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,
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 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.
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