Highly active antiretroviral therapy

Small presentation of current scenario on HAART

1. Dr Abhishek k GUPTA H ighly A ctive A ntiretroviral T herapy (HAART)

2. Introduction 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

3. History The first effective therapy against HIV was the nucleoside reverse transcriptase inhibitor (NRTI)  zidovudine  (AZT ) To distinguish from this early anti-retroviral therapy (ART), the term highly active anti-retroviral therapy (HAART) was introduced Hammer and colleagues  and Gulick and co-investigators  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.

4. Goals of Antiretroviral Therapy The currently available ARV drugs cannot eradicate the HIV infection from the human body Clinical goals : Prolongation of life and improvement in quality of life Virological goals : Greatest possible reduction in viral load for as long as possible Immunological goals : Immune reconstitution that is both quantitative and qualitative Reduction of HIV transmission in individuals : Reduction of HIV transmission by suppression of viral load

5. Therapeutic goals : Rational sequencing of drugs in a fashion that achieves clinical, virological and immunological goals while maintaining treatment options, limiting drug toxicity and facilitating adherence

6. Clinical Staging of HIV

7. Current guidelines: when to start ART 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 . AIDS-defining condition Pregnancy Symptomatic from HIV including any of the following: HIV-associated neurocognitive disorder ( HAND)

8. Severe thrombocytopenia HIV-associated nephropathy HIV-related malignancies Chronic hepatitis B or C infection and, Age 50 or older Patients with seronegative partners should be counselled Decisions to initiate ART should be individualized, particularly for long-term nonprogressors or and for patients with potential barriers to adherence

9. Current World Health Organization guidelines ( dated June 30, 2013) Initiate ART if CD4 cell count ≤500 cells/ml • As a priority, initiate ART in all individuals with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD4 count ≤ 350 cells/mm Initiate ART regardless of WHO clinical stage or CD4 cell count in • Active TB disease • HBV  co-infection with severe chronic liver disease • Pregnant and breastfeeding women with HIV • HIV-positive individual in a  serodiscordant  partnership (to reduce HIV transmission risk)

10. When to start ART in Adults and Adolescents WHO Clinical Stage WHO Clinical Stage HIV infected Adults & Adolescents (Including pregnant women) Clinical Stage I and II Start ART if CD4 < 350 cells/mm3 Clinical Stage III and IV Start ART irrespective of CD4 count For HIV and TB co-infected patients Patients with HIV and TB co-infection (Pulmonary/ Extra-Pulmonary) Start ART irrespective of CD4 count and type of tuberculosis (Start ATT first, initiate ART as early as possible between 2 weeks to 2 months when TB treatment is tolerated) For HIV and Hepatitis B and C co-infected patients -Without any evidence of chronic active Hepatitis Start ART if CD4 < 350 cells/mm3 -With documented evidence of chronic active Hepatitis Start ART irrespective of CD4 count

11. Counseling and Education Before Initiating ART RECOMMENDATIONS : Counselling and education should include the following : Basic education about HIV, CD4 cells, viral load, and resistance Available treatment options and potential risks and benefits of therapy The need for strict adherence to avoid the development of viral drug resistance Use of safer-sex practices and avoidance of needle-sharing activity, regardless of viral load, to prevent HIV transmission or super-infection

12. BENEFITS AND RISKS OF EARLY ART IN ASYMPTOMATIC HIV-INFECTED PATIENTS Early therapy = initiation at CD4 counts >500 cells/mm3 ) Benefits of early therapy Earlier treatment reduces both HIV-related and non-HIV-related morbidity and mortality Delay or prevention of immune system compromise Possible lower risk of antiretroviral resistance Decreased risk of sexual transmission of HIV

13. Disadvantages of early therapy Potential drug-related reduction in quality of life in otherwise asymptomatic individuals Possibility of greater cumulative side effects from ART Possibility for earlier development of drug resistance and limitation in future antiretroviral options if adherence and viral suppression are suboptimal Possibility for earlier onset of treatment fatigue Higher prescription drug costs for the individual

14. Potential barriers to adherence include: Communication difficulties that arise when the patient’s attitude about disease and therapy is different from that of the provider’s. Without open and nonjudgmental communication from the healthcare team, patients may not trust or may misunderstand the prescribed regimen Language or literacy barriers Unstable living situations (including limited or absent social support) Discomfort with disclosure of HIV status, which may become known when medications are taken

15. Inability to set long-term goals Inadequate knowledge about disease and effectiveness of medications or healthy living, including a patient’s lack of belief in his/her ability to take medications regularly Difficulty accessing adequate healthcare Housing, food, lack of childcare, or other immediate life needs, which are viewed as more pressing than taking the medications regularly

16. Monitoring

17. VIROLOGIC AND IMMUNOLOGIC MONITORING FOR NON-PREGNANT PATIENTS HIV RNA Levels (copies/mL) CD4 Lymphocyte Count (cells/mm3 ) Baseline All patients Yes Yes Treatment Monitoring Following: (1) initiation of ART or (2) a change in ART regimen after virological failure with new resistance to prior ART Within 4 weeks of initiation of ART or change in regimen. At least every 8 weeks until complete suppression is documented Repeat at 12 weeks and then every 4 months until CD4 >200 cells/mm3 on two measurements obtained at least 4 months apart, then monitor as below once suppressed Following a change in ART to simplify treatment regimen or reduce toxicity for patients with suppressed virus Within 4 weeks after change in regimen Monitor as below for suppressed

18. Patients on ART who achieve complete suppression At least every 4 months after complete suppression . May extend intervals to every 6 months in selected stable patients with CD4 counts >200 cells/mm3 after 1 year of complete suppression If CD4 300 to 500 cells/mm3 :At least every 6 months . If CD4 >300 to 500 cell/mm3:At least every 12 months. If CD4 >500 cells/mm3 :further monitoring is optional Patients Not on ART: all HIV-infected patients should be offered ART regardless of CD4 count If CD4 ≤500 cells/mm 3 : At least every 4 months If CD4 >500 cells/mm 3 : At least every 6 months  If CD4 ≤500 cells/mm 3 : At least every 4 month. If CD4 >500 cells/mm 3 : At least every 6 month

19. HIV Resistance Assays Clinicians should perform resistance testing under the following circumstances: At baseline, regardless of whether ART is being initiated (genotypic testing) In patients experiencing treatment failure or incomplete viral suppression while receiving ART (genotypic and/or phenotypic testing ) Genotypic assays detect mutations in the genes of the reverse transcriptase and protease enzymes, as well as the gp41 domain for the currently available fusion inhibitors

20. Phenotypic assays directly measure susceptibility of the patient’s HIV strain to specific individual drugs compared to sensitive HIV

21. Classes of drugs There are five classes of drugs, which are usually used in combination, to treat HIV infection 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.

22. 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 includes Z idovudin , Abacavir , Lamivudine, Emtricitabine and tenofavir . Non-Nucleoside reverse transcriptase inhibitors ( NNRTI)- I nhibit reverse transcriptase by binding to an allosteric site of the enzyme; NNRTIs act as  non-competitive inhibitors  of reverse transcriptase

23.  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. 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

24. Examples of HIV protease inhibitors are Lopinavir , Indianavir , Nelfinavir , Amprenavir and Ritonavir. Darunavir and   A t azanavir  are currently recommended as first line therapy choices. Resistance to some protease inhibitors is high . Integrase inhibitors  (also known as integrase nuclear strand transfer inhibitors or INSTIs )-   R a ltegravir became the first to receive FDA approval in October 2007. As of early 2014, two other clinically approved integrase inhibitors are  elvitegravir  and  dolutegravir .

25. Entry inhibitors-   (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell.   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.

26. 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

27. 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 ) The WHO preferred initial regimen for adults and adolescents as of June 30, 2013 is : tenofovir + lamivudine (or emtricitabine ) + efavirenz

28. For Children The WHO & DHHS recommends for children less than 3 years : abacavir (or zidovudine ) + lamivudine + lopinivir / ritonivir For children 3 years to less than 10 years and adolescents <35 kilograms: abacavir  + lamivudine + efavirenz

29. In India- by NACO Zidovudin + lamivudine + Nevirapine / efavirenz . Tenofovir + lamivudine + Nevirapine / efavirenz . Zidovudin + lamivudine + Atazanavir /Ritonavir Zidovudin + lamivudine + Lopinavir /Ritonavir

30. Adverse events

31. How to manage adverse events

32. Do not start ART in the presence of an active OI. In general, OIs should be treated or stabilized before commencing ART. Mycobacterium avium complex (MAC) and progressive multifocal leukoencephalopathy (PML) are exceptions, in which commencing ART may be the preferred treatment. Manage OIs before Starting ART

33. ART in Pregnant women

34. HIV and Hepatitis Co-infection HIV modified the natural history of HBV infection, higher rate of progression to advance liver disease among co infection. Choice of ART- ARV with anti HBV activity such as 3TC and TDF First line regime- TDF + 3TC +EFV Alternative – AZT+ 3TC+EEV No ARV drugs are active against HCV infection , but they decline the progression

35. ART Treatment Failure and when to switch

36. Second line regime A second-line regimen should be recommended only by CoE / ART plus Centre. When failure has been identified clinically or immunologically, many patients can be expected to have significant NRTI resistance at the time of switching Cross resistance exists between d4T and AZT; thus NRTI-component in the second-line regimens should be either ddI /ABC or TDF/ABC. High level AZT/3TC resistance reduces susceptibility to ABC.

37. NNRTI (such as EFV and NVP): usually there is complete cross-resistance

38. Management algorithm

39. Final words HIV care requires, as always, partnerships and open communication. The provider can make recommendations most likely to lead to positive outcomes only if the patient's own point of view and social context are well known. Guidelines are only a starting point for medical decision making. They can identify some of the boundaries of high-quality care but cannot substitute for sound judgment.

40. Thank you