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)

1. Management of HIV/AIDS
(and the curious case of
the ‘BERLIN PATIENT’)
Submitted by-
Gagandeep S. Gauba
B.D.S 3rd Proff
BJS Dental College, Ludhiana(Punjab)

2. 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)

3. 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.

4. •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

5. History

6. •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

7. Classes of drugs

8. 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 inhibitors
5. Protease inhibitors

9. •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.

10. Diagrams by- Tejnoor Kaur

11. 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

13. 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

14. Diagrams by- Tejnoor Kaur

15. 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.

16. Diagrams by- Tejnoor Kaur

17. 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.

18. Diagrams by- Tejnoor Kaur

19. Combination therapy

20. •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.

21. Treatment guidelines

22. •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.

23. Current guidelines

24. 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

25. Adverse effects

26. 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 andlipoatrophy.
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
withlipodystrophy, 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.

27. "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.

28. THANK YOU
SUBMITTED BY- GAGANDEEP S GAUBA