Management of HIV/AIDS

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 replication cycle of HIV. 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. As another commentary 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 (WHO) recommend offering antiretroviral treatment to all patients with HIV.

Classes of medication

thumb|upright=1.75|Schematic description of the mechanism of the four classes of available antiretroviral drugs against HIV

Antiretroviral (ARV) drugs are medications that are used to prevent and treat infection by retroviruses, most commonly HIV.

Antiretroviral drugs are broadly classified by the phase of the replication cycle of HIV inhibited by the drug. There are six classes of antiretroviral drugs, which are usually used in combination. 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".

In Addition, HIV-1 capsid which is finely regulated and plays critical roles throughout the HIV life cycle, recently emerged as a promising target for Anti-viral drugs.

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, enfuvirtide and Ibalizumab are 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. Ibalizumab is effective against both CCR5 and CXCR4 tropic HIV viruses.

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, 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, 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, abacavir, lamivudine, emtricitabine, and of NtRTIs – tenofovir and adefovir.

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.

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 recommended as first line therapy choices. Resistance to some protease inhibitors is high. Second generation drugs have been developed that are effective against otherwise resistant HIV variants. GS-6207 Lenacapavir is a first in class ultra potent and long acting HIV-1 capsid inhibitor that recently gained approval from European Union and US Food and Drug Administration for the treatment of multi drug resistant HIV-1 infection. Lenacapavir is a long acting injectable medication administered subcutaneously every 6 months, and it shows unprecedented efficacy in pre-exposure prophylaxis for HIV treatment.

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. 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.

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. Combinations of antiretrovirals are subject to positive and negative synergies, 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. 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 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, 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. 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 (EMA) has recommended the granting of marketing authorizations for two new antiretroviral (ARV) medicines, rilpivirine (Rekambys) and cabotegravir (Vocabria), to be used together for the treatment of people with human immunodeficiency virus type 1 (HIV-1) infection. The two medicines are the first ARVs that come in a long-acting injectable formulation. This has been shown to lead to dramatically reduced transmission of HIV when one partner with a suppressed viral load (<50 copies/ml) has sex with a partner who is HIV negative. In clinical trial HPTN 052, 1763 serodiscordant heterosexual couples in nine 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-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 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 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, 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.'

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.

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 guidelines.

For resource limited countries, most national guidelines closely follow the World Health Organization (WHO) guidelines. 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 HAART regimens consist of three drugs: Two 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:

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:

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). 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. 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.

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: 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. 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. 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, 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. 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.

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. 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. 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. PARTNER 1, (for male–male couples) (for heterosexual couples). 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: