Management of HIV/AIDS(and the curious case of

the ‘BERLIN PATIENT’)

Submitted by-Gagandeep S. Gauba

B.D.S 3rd ProffBJS Dental College, Ludhiana(Punjab)

MANAGEMENT OF HIV FALLS UNDER THREE MAJOR CATEGORIES

1. POST EXPOSURE PROPHYLAXIS(P.E.P)

2. TREATMENT/MANAGEMENT OF HIV-AIDS

3. TREATMENT OF ADJOINING CONDITIONS

eg- Fungal Infections

-Bacterial infections

-Viral infections

-NEOPLASIAS

-misc.( recurrent apthos ulcers, xerostomia, salivary G.

enlargement)

POST EXPOSURE PROPHYLAXIS(THE EMERGENCY PILL)

• If an individual believes they have been exposed to the virus within the last 72 hours (three days), anti-HIV medication, called PEP (post-exposure prophylaxis) may stop infection. The treatment should be taken as soon as possible after contact with the virus.

• PEP is a very demanding treatment lasting four weeks. It is also associated with unpleasant side effects (diarrhea, malaise, nausea, weakness and fatigue).

• After a positive HIV diagnosis, regular blood tests are necessary to monitor the progress of the virus before starting treatment. The therapy is designed to reduce the level of HIV in the blood.

•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.•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."• 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."

MANAGEMENT OF HIV-AIDS

History

•The first effective therapy against HIV was the nucleoside reverse transcriptase inhibitor (NRTI), zidovudine (AZT).• It was approved by the US FDA in 1987. 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 anti-retroviral therapy (ART), the term highly active anti-retroviral therapy (HAART) was introduced. •In 1996 by sequential publications in The New England Journal of Medicine by Hammer and colleagues and Gulick and coinvestigators illustrating the substantial benefit of combining 2 NRTIs with a new class of anti-retrovirals, protease inhibitors, namely indinavir.• This concept of 3-drug therapy was quickly incorporated into clinical practice and rapidly showed impressive benefit with a 60% to 80% decline in rates of AIDS, death, and hospitalization

Classes of drugs

There are five classes of drugs, which are usually used in combination, to treat HIV infection. Use of these drugs in combination can be termed anti-retroviral therapy (ART), combination anti-retroviral therapy (cART) or highly active anti-retroviral therapy (HAART). Anti-retroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits.

1. Entry inhibitors (or fusion inhibitors)2. Nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide reverse

transcriptase inhibitors (NtRTI)3. Non-Nucleoside reverse transcriptase inhibitors (NNRTI)4. Integrase inhibitors5. Protease 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. •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.

Diagrams by- Tejnoor Kaur

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 (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

Diagrams by- Tejnoor Kaur

Integrase inhibitors 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.

Diagrams by- Tejnoor Kaur

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 inhibitor 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.

•Resistance to some protease inhibitors is high.•Second generation drugs have been developed that are effective against otherwise resistant HIV variants.

Diagrams by- Tejnoor Kaur

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.

Treatment guidelines

•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•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-ACCORDstudy 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.

• 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.

Current guidelines

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

Adverse effects

Each class and individual antiretroviral carries unique risks of adverse side effects.

NRTIsThe NRTIs can interfere with mitochondrial DNA synthesis and lead to high levels of lactate and lactic acidosis, liver steatosis, peripheral neuropathy, myopathy andlipoatrophy.Current first line NRTIs such as lamivudine/emtrictabine, tenofovir, and abacavir are less likely to cause mitochondrial dysfunction.

NNRTIsNNRTIs 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 inhibitorsProtease inhibitors (PIs) are often given with ritonavir, a strong inhibitor of cytochrome P450 enzymes, leading to numerous drug-drug interactions. They are also associated withlipodystrophy, elevated triglycerides and elevated risk of heart attack.

Integrase inhibitorsIntegrase 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.

"Berlin patient“

So far only one adult (the so-called "Berlin patient") has been potentially cured 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 zinc-finger nuclease 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 extra patients (who suffered from both HIV and cancer) had no traceable HIV virus after successful stem cell transplantations, as announced on 17 July 2016 by virologist Annemarie Wensing of the University Medical Center Utrecht, during a speech entitled "Allogeneic Stem Cell Transplantation in HIV-1 Infected Individuals; the EpiStem Consortium", presented during the 2016 Towards an HIV Cure Symposium in Durban, South Africa. However these two patients reported by the EpiStem Consortium 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 from HIV-infection. The cure could be confirmed if the therapy would be stopped and no viral rebound would occur.

THANK YOU

SUBMITTED BY- GAGANDEEP S GAUBA