Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Antiretroviral therapy what a general practitioner must know

1,720 views

Published on

Educational resource on AIDS

Published in: Health & Medicine
  • Be the first to comment

Antiretroviral therapy what a general practitioner must know

  1. 1. Antiretroviral therapy in 2013 : what a general practitioner must know Dr Ameet Dravid M.D Medicine Ruby Hall Clinic, Pune
  2. 2. Introduction • Eradication of HIV infection cannot be achieved with available antiretroviral regimens. • This is chiefly because the pool of latently infected CD4 T-cells is established during the earliest stages of acute HIV infection and persists with long half-life even with prolonged suppression of plasma viremia.
  3. 3. Antiretroviral therapy : when to start?
  4. 4. Antiretrovirals approved for use NRTI NNRTI PI Newer drugs Zidovudine(AZT) Nevirapine (NVP) Nelfinavir CCR5 inhibitors :Maraviroc Stavudine(d4T) Efavirenz (EFV) Indinavir Integrase inhibitors : Raltegravir, Elvitegravir/Cobicistat, Dolutegravir Lamivudine(3TC) Etravirine Saquinavir Fusion inhibitors : enfuvirtide Didanosine(ddI) Rilpivirine Ritonavir Abacavir(ABC) Atazanavir Tenofovir(TDF) Lopinavir Emtricitabine(FTC) Darunavir Tipranavir Fosamprenavir
  5. 5. DHHS guidelines 2013
  6. 6. WHO guidelines 2013 : what’s new • ART should be initiated in all individuals with CD4 count < 500 cells/mm3 irrespective of WHO stage • ART should be initiated irrespective of CD4 count and WHO stage : • HIV and active TB • HIV/HBV co-infection with severe chronic liver disease • Partners with HIV in sero-discordant couples
  7. 7. HIVMAI Guidelines 2012
  8. 8. NACO GUIDELINES 2012 Classification of HIV-associated clinical disease WHO STAGE CD4 NOT AVAILABLE Asymptomatic 1 CD4 AVAILABLE Do not treat Treat if CD4 <350 Mild symptoms 2 Do not treat Advanced symptoms 3 Treat Consider treatment if CD4 <350 and initiate ART before CD4 drops below 200 Severe/advanced symptoms 4 Treat Treat irrespective of CD4 count
  9. 9. Why are we moving towards earlier antiretroviral therapy ? • Current options for initial therapy are highly effective, durable, convenient, and well tolerated and show less evidence of long-term toxicity
  10. 10. Antiretroviral Efficacy Rates Are Improving in Clinical Practice Patients With HIV-1 RNA > 500 copies/mL (%) 50 40 40 42 39 34 31 30 30 25 20 10 0 1996 1997 1998 1999 2000 2001 2002
  11. 11. Why are we moving towards earlier antiretroviral therapy ? • Greater risk of developing non-AIDS–defining conditions, including cardiovascular disease, liver disease, and non-AIDS–defining malignancies
  12. 12. Immunosuppression Increases Risk of HIVand Non-HIV–Related Mortality • Cohort study of > 23,000 patients in Europe, Australia, and US Overall HIV Malignancy Heart – 76,577 patient-years of follow-up • • 1248 (5.3%) deaths from 2000-2004 Both HIV- and non-HIV–related mortality associated with CD4+ cell count depletion < 50 50-99 100199 200349 350- ≥ 500 499 CD4+ Cell Count (cells/mm3)
  13. 13. Why are we moving towards earlier antiretroviral therapy ? • Greater likelihood of CD4 normalization
  14. 14. Likelihood of Achieving Normal CD4+ Cell Count Depends on BL Level Johns Hopkins HIV Clinical Cohort ATHENA National Cohort >> 350 201-350 350 < 200 1000 800 1000 800 600 600 400 400 200 200 0 0 0 1 2 3 4 Years on HAART 5 6 201-350 51-200 < 50 0 > 500 351-500 48 96 144 192 240 288 Weeks From Starting HAART
  15. 15. Incomplete Peripheral CD4+ Cell Count Restoration in HIV-Infected Patients Receiving Long-Term Antiretroviral Treatment (Steve Deeks CID 2009)
  16. 16. Mortality rate in HIV infected adults on ART (French Aquitane Cohort )
  17. 17. HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: 350-550 cells/mm3 (N = 1763 couples) Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm3 (n = 886 couples) Delayed ART Initiate ART at CD4+ cell count ≤ 250 cells/mm3* (n = 877 couples) *Based on 2 consecutive values ≤ 250 cells/mm3. • Primary efficacy endpoint: virologically linked HIV transmission • Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death • Couples received intensive counseling on risk reduction and use of condoms Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].
  18. 18. HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples Total HIV-1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P < .0001) Linked Transmissions: 28 Delayed Arm: 27 Immediate Arm: 1 P < .001 Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print]. Unlinked or TBD Transmissions: 11 Single transmission in patient in immediate ART arm believed to have occurred close to time therapy began and prior to HIV-1 RNA suppression
  19. 19. HPTN 052: Primary Clinical Events During Follow-up • 41% reduction in HIV-related clinical events in HIV-infected patients randomized to immediate vs delayed therapy – Excess events in delayed arm driven mainly by TB (33 vs 17 cases), particularly extrapulmonary TB (17 vs 3 cases) HR: 0.6 (95% CI: 0.4-0.9; P = .01) Delayed (n = 65) Failure Probability 0.25 0.20 0.15 Immediate (n = 40) 0.10 0.05 0 877 886 701 700 0 1 317 333 86 85 32 36 2 3 4 Yrs Since Randomization Grinsztejn B, et al. IAS 2011. Abstract MOAX0105. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print]. 25 Number at risk 29 5
  20. 20. Reduction in New HIV Diagnoses in BC: Testing, HAART, and Community VL • Period of declining new HIV diagnoses in BC coincident with increased HIV testing rates, increased uptake of antiretroviral therapy, and decrease in community viral load (1996-2008) – Decline in new HIV diagnoses despite increases in syphilis, gonorrhea, chlamydia Patients (n) 10,000 8000 6000 Censored at the time of death or move New HIV+ Diagnoses (All) 4000 2000 0 96 97 98 99 00 01 02 03 04 05 06 07 08 09 19 19 19 19 20 20 20 20 20 20 20 20 20 20 Montaner J, et al. CROI 2010. Abstract 88LB. 1400 1200 1000 800 600 400 200 0 Number of New HIV+ Diagnoses 12,000 HIV-1 RNA, copies/mL < 500 500-3499 3500-9999 10,000-49,999 ≥ 50,000
  21. 21. Efficacy of HIV Prevention Strategies From Randomized Clinical Trials Study Effect Size, % (95% CI) ART for prevention; HPTN 052, Africa, Asia, Americas PrEP for discordant couples; Partners PrEP, Uganda, Kenya PrEP for heterosexual men and women; TDF2, Botswana Medical male circumcision; Orange Farm, Rakai, Kisumu PrEP for MSMs; iPrEX, Americas, Thailand, South Africa Sexually transmitted diseases treatment; Mwanza, Tanzania Microbicide; CAPRISA 004, South Africa HIV vaccine; RV144, Thailand 0 96 (73-99) 73 (49-85) 63 (21-84) 54 (38-66) 44 (15-63) 42 (21-58) 39 (6-60) 31 (1-51) 20 40 60 Efficacy (%) Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print]. 80 100
  22. 22. When should we start ART in the event of acute opportunistic infection? • ART is only effective treatment : • Progressive multifocal leucoencephalopathy (PML) • Cryptosporidiosis • Microsporidiosis • Dementia • HIV associated nephropathy • START AS SOON AS POSSIBLE
  23. 23. When should we start ART in the event of acute opportunistic infection? Systemic and CNS lymphoma Chemotherapy and ART to be started together PCP Bacterial infections Toxoplasmosis Mycobacterium avium complex Immediate therapy (within 14 days of starting treatment of OI )
  24. 24. Timing of ART initiation in patients with tuberculosis CD4 count Time to initiate antiretroviral therapy < 50 cells /mm3 within 2 weeks 50 – 200 cells/mm3 2 weeks to within 2 months 200 – 500 cells/mm3 Within 2 months > 500 cells/mm3 Within 2 months Tubercular meningitis irrespective of CD4 count 2 months
  25. 25. ART initiation in cryptococcal meningitis (COAT study) • Cryptococcal Optimum ART timing trial : • ART initiation at 2 weeks of starting Amphotericin(early ART) vs after 4 weeks of starting Amphotericin (delayed ART) • Data safety monitoring board recommended stopping study enrolment due to substantially higher mortality in early ART group • 6 month survival : 55% vs 70% with early vs deferred ART group • Major deaths in early therapy arm were driven by cryptococcosis and not IRIS. • Treat CM first, verify CSF culture sterility and then start ART after 4 weeks is the way to go.
  26. 26. Antiretroviral therapy : what to start?
  27. 27. NACO GUIDELINES 2012  Preferred regimen (2NRTI’s + 1 NNRTI)  AZT + 3TC + NVP (Zidovudine + Lamivudine + Nevirapine )  Alternative regimen (2NRTI’s + 1 NNRTI)  AZT + 3TC + EFV (Zidovudine + Lamivudine + Efavirenz)  TDF + 3TC + NVP/EFV (Tenofovir + Lamivudine + Nevirapine/Efavirenz )  Other options  Stavudine (d4T) + 3TC/FTC + NVP/EFV  Pi’s not recommended for first line therapy
  28. 28. HIVMAI guidelines 2012
  29. 29. Why are we moving away from zidovudine and stavudine? Zidovudine • • • • • • Short term Gastritis Anemia Bone marrow suppression Myopathy, myalgia Long term Dyslipidemia Lipodystrophy syndrome Stavudine • • • • • • • Long term Peripheral neuropathy Pancreatitis Lactic acidemia/acidosis Lipodystrophy syndrome Dyslipidemia Avascular necrosis Cardiovascular risk
  30. 30. Antiretroviral therapy related lipodystrophy syndrome
  31. 31. Why Tenofovir/Emtricitabine (TDF/FTC) ? GS 934 trial : TDF/FTC/EFV demonstrated superior efficacy and less toxicity (anemia) as compared to AZT/3TC/EFV over 144 weeks GS 903 trial : less toxicity (neuropathy, lipoatrophy, and hyperlipidemia) as compared to d4T/3TC/EFV Available as one tablet once a day FDC Preferred regimen for HIV/HBV and HIV/HCV co-infection Toxicity : renal insufficiency and osteomalacia
  32. 32. Monitoring patients on antiretroviral therapy
  33. 33. Antiretroviral therapy in special situations
  34. 34. ART in pregnancy  In absence of treatment, rate of mother to child transmission of HIV is 30 %.  With 3 drug c ART, the rate decreases to < 2 %.  3 drug cART should be used for prevention of mother to child transmission irrespective of CD4 count  Single dose Nevirapine must be discouraged  Tenofovir and Efavirenz are now recommended to be used in pregnancy as a single pill fixed dose combination.  Adverse potential for the pregnant mother (combination stavudine [d4T]/didanosine [ddI]).  Viral load monitoring close to delivery  Elective Lower segment caesarean section must if viral load monitoring not possible  Avoid breast feeding
  35. 35. ART in pregnancy  NACO GUIDELINES 2007  NVP based HAART if CD4 < 250 cells/mm3  Single dose NVP if CD4 > 250 cells/mm3  Preferred PI :  Nelfinavir  Ritonavir boosted Saquinavir  No clear cut recommendation for Breast feeding and CSection  API ART GUIDELINES 2008  NVP based HAART if CD4 < 250 cells/mm3  PI based HAART if CD4 > 250 cells/mm3  Preferred PI  Ritonavir boosted Lopinavir  Nelfinavir  Breast feeding  Elective C-Section mandatory if viral load testing not available
  36. 36. WHO PMTCT guidelines 2013 • All pregnant and breast feeding women should initiate triple ARV’s • ART should be given as lifelong treatment • In special situations, women who are not eligible for ART for their own health, consideration can be given to stop ART regimen after the period of mother to child transmission risk has ceased
  37. 37. WHO guidelines 2013 : what to start ? First line ART ADULTS (including pregnant and breastfeeding women and HIV/TB co-infection Preferred first line Alternative first line AZT + 3TC + EFV TDF + 3TC(OR FTC) + EFV AZT + 3TC + NVP TDF + 3TC + NVP Adolescents (10-19 yrs of age) and >= 35 kg AZT + 3TC + EFV Children 3 – 10 yrs of age and adolescents < 35 kg ABC + 3TC + EFV AZT + 3TC + NVP ABC + 3TC + NVP TDF + 3TC + NVP TDF + 3TC + EFV Children < 3 yrs of age ABC or AZT + 3TC + LPV/r ABC or AZT + 3TC + NVP
  38. 38. POST EXPOSURE PROPYLAXIS (PEP)
  39. 39. Classification of body fluids Infectious fluids Fluids potentially infectious Non infectious fluids Blood CSF Feces Visibly bloody body fluids Pleural fluid Nasal secretions Semen Peritoneal fluid Saliva Vaginal fluid Amniotic fluid Sputum Pericardial fluid Sweat Synovial fluid Tears Urine Vomitus
  40. 40. Risk factors for occupational exposure of HIV • HIV transmission after per-cutaneous exposure to HIV infected blood 0.3 % • Mucous membrane exposure 0.09 % • Transmission through non intact skin : present but lower than mucous membrane exposure • Exposure to body fluids other than blood : lower than blood exposure
  41. 41. Risk factors for occupational exposure of HIV • Needle visibly contaminated with patients blood • Needle directly placed in artery or vein • Deep injury • Terminal illness in source patient
  42. 42. PEP : General guidelines • • • • • • • • • • • Occupational exposure to HIV should be treated as urgent medical concern. 2 drug HIV PEP regimens are no longer used PEP should include 3 (or more) antiretrovirals consonant with current treatment guidelines PEP should begin within “hours” and certainly not later than 72 hours Appropriate initial source patient and exposed service provider laboratory testing should be done immediately. Total duration should be 4 weeks Adherence to PEP should be emphasized If a patient is known to harbour drug resistant HIV, expert consultation for PEP should be done If PEP offered and then source patient found negative, PEP should be stopped immediately HIV testing to be done at baseline, 6 weeks and 4 months post exposure if 4 th generation p24 antigen - HIV antibody ELISA used If HIV NAT is used, 2 HIV DNA PCR tests should be performed after 14 days post exposure.
  43. 43. Can we end the AIDS epidemic ? • Measures if used judiciously can reduce AIDS related deaths and new HIV infections (International AIDS conference, Washington 2012) • These include: • The use of HIV treatment as prevention. • The rolling out of male circumcision programmes. • The use of triple-drug HIV therapy during pregnancy and breastfeeding. • Pre-exposure prophylaxis (PrEP). • Intensified case finding for TB in patients with HIV, and HIV in patients with TB. • Earlier HIV therapy.
  44. 44. HIV cure ?? • “The Berlin patient” • This person was cured of HIV after undergoing a gruelling course of chemotherapy, immunosuppressive treatment, and a bone marrow transplant from a donor with a rare genetic mutation making him naturally resistant to infection with HIV. • This isn’t an attractive or realistic therapy • Cure would be a therapy that either eradicated HIV from the body or a treatment that allowed the body’s natural defences to keep HIV in check, even after any antiretroviral therapy was stopped. • The Mississippi baby : administration of antiviral therapy within 30 hours of birth leads to “functional cure”
  45. 45. CONCLUSIONS • • • • • • • • • Opt out HIV testing should be practiced in India as well Time has come to start ART irrespective of CD4 count provided patient understands importance of lifelong adherence to ART Tenofovir based ART as preferred regimen for all patients should be rigorously followed HIV has changed from a acute life threatening illness to a chronic manageable condition Our patients can live up to their 70’s and 80’s with good adherence to current antiretroviral drugs. Identifying HIV early and putting all patients on Antiretroviral therapy can help slowing or even ending the AIDS epidemic In such a scenario management of co-morbidities like Diabetes, Hypertension, Lipids, Bone, liver, neurocognitive and kidney ailments becomes extremely important. Drug-drug interactions and drug toxicities come into play with polypharmacy and should be scrupulously looked into. Next 10 years will most probably be the era of HIV cure research
  46. 46. THANK YOU

×