Current Indian Guidelines for Antiretriviral Therapy 2012


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ART Guidelines 2012

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Current Indian Guidelines for Antiretriviral Therapy 2012

  2. 2. Antiretroviral Therapy (ART)  AIDS ( Acquired immuno-deficiency syndrome) is a fatal disease, caused by human immuno-deficiency virus (HIV), which breaks down the body’s immune system, leaving the patient vulnerable to a host of life-threatening opportunistic infections, neurological disorders or malignancies.  If a person infected once, he will remain infected for life.  AIDS is called Modern Pandemic, as it affecting both developed and developing countries.
  3. 3.  At present there is no vaccine or cure for HIV infection/AIDS. So, HIV can be control by either prevention i.e. by education and prevention of blood-borne viral transmission or by antiretroviral treatment (ART).  Antiretroviral therapy (ART) are the combination of drugs which suppress the HIV infection, but not cure it, and proved to be useful in prolonging the life of severely ill AIDS patients and it also improves the quality of life of HIV infected patients.  But adequate suppression requires strict adherence to antiretroviral therapy.
  4. 4. Goals of Antiretroviral Therapy 1) To achieve maximal and durable virological suppression (ideally a viral load < 50 copies/ml). 2) To reconstitute and preserve immunologic function. 3) To reduce morbidity and mortality, associated with both HIV infection and use of antiretroviral drugs (ARVs). 4) To improve quality of life. 5) To prevent sexual transmission of HIV.
  5. 5. When to Initiate ART ?
  6. 6. Why Initiate ART Early ?  Better survival.  Potent, durable and convenient regimens are readily available.  Decrease risk of non-AIDS defining complications.  Prevent neurocognitive decline.  Reduce immune activation, inflammation.  Greater likelihood of CD4 normalization.  Lesser risk of development of IRIS.  Lesser likelihood of developing ARV resistance.  Lesser risk of development of toxicities.  Prevention of transmission.  Cost-effective.
  7. 7. When should ART be Initiated in the setting of an Acute Opportunistic Infections (OI) ?  Most Opportunistic Infections: as soon as possible.  Cryptococcal meningitis: 4-6 weeks after initiation of anti- fungal treatment.  Tuberculosis (TB) CD4<50/mm3: Around 2 weeks of initiation of anti-TB treatment. CD4>50/mm3: Around 8 weeks of initiation of anti-TB treatment.  CNS Opportunistic Infections May be delayed until clinical stabilization. Careful monitoring for Immune Reconstitution Inflammatory Syndrome (IRIS).
  8. 8. Assessing Patient Readiness Prior to Initiating ART Before starting the ART to a patients, the following issues should be discussed :  Availability of treatment in the free ART program,  Affordability (referral to free ART program if long term affordability suspect),  Conceptual understanding of treatment and it’s benefits,  The importance of high level lifelong adherence to drugs and the consequences of sub-optimal adherence (more expensive second-line regimens, progression of clinical disease) and  The need to address alcohol abuse Treatment should be initiated only after ensuring that patient has understood the consequences of initiating and being on lifelong treatment.
  9. 9. Baseline Evaluation  History and physical examination  The patient’s comorbid conditions (e.g., cardiovascular disease          [CVD], chemical dependency, liver or renal disease, psychiatric illnesses, or tuberculosis [TB]) Routine chemistry and hematology HIV antibody testing (if prior documentation is not available or if HIV RNA is below the assay’s limit of detection) Liver function test Lipid profile and blood glucose CD4+ T-lymphocyte count Plasma HIV RNA level (viral load) HIV resistant testing HLA-B5701 screening RPR or VDRL testing
  10. 10.  Anti-toxoplasma antibody titer  PPD skin testing  Serology for hepatitis A, hepatitis B and hepatitis C  Immunization with pneumococcal polysaccharide; influenza as indicated.  Immunization with hepatitis A and hepatitis B if seronegative.  Counseling regarding natural history and transmission.  Help contacting others who might be infected.
  11. 11. What ART Drugs To Be Initiated ?
  12. 12. Choice of First Line Regimen Preferred : Efavirenz/Tenofovir /Emtricitabine or Nevirapine (EFV/TDF/FTC or NVP) Tenofovir/Lamivudine/Efavirenz (TDF/3TC/EFV) Acceptable : Zidovudine/Lamivudine/Efavirenz or Nevirapine (AZT/3TC/EFV or NVP) Consider (only in special situations) : Abacavir/Lamivudine/Efavirenz (ABC/3TC/EFV) Didanosine/Lamivudine/Efavirenz (ddl/3TC/EFV)
  13. 13. Doses of commonly used ARVs DRUG DOSE Zidovudine (AZT) 300 mg bd Lamivudine (3TC) 150 mg bd OR 300 mg od Didanosine (ddl) 200 mg bd (BW>60 kg), 125 mg bd (BW<60 kg) Abacavir (ABC) 300 mg bd OR 600 mg od Emtricitabine (FTC) 200 mg od Efavirenz (EFV) 600 mg od Nevirapine (NVP) 200 mg od, increase later to 200 mg bd Tenofovir (TDF) 300 mg od Ritonavir (r) 600 mg bd; as boosted dose 100 mg
  14. 14.  Efavirenz is preferred over NVP when concomitant use of rifampicin is indicated, patients preference for once daily (lower pill burden) regimen and if pre-therapy CD4 count is >250/mm3 and >400/mm3 in women and men respectively.  Nevirapine is preferred over EFV in women planning pregnancy and those with underlying severe psychiatric illness.
  15. 15.  TDF/FTC is the preferred backbone because it has similar virological response as compared to AZT/3TC but has been associated with lower toxicity particularly in women, low pill burden (one pill once a day when combined with EFV), better sequencing options after failure of first-line regimen, concomitant treatment of underlying undiagnosed HBV infection and has been proven to be cost effective in an analysis in India.  AZT/3TC is a powerful backbone and preferred in women who plan pregnancy/or are pregnant but has been associated with higher short term hematological and long term morphologic and metabolic toxicities.  Stavudine should be avoided because of long term toxicity concerns that are often irreversible.
  16. 16. Clinical situations for use of Protease Inhibitors in first-line regimens :  HIV-2 or HIV-1/HIV-2 infection.  Pregnancy with CD4>250/mm3.  Sub-optimal NRTI use in the past (e.g. 2NRTIs)  Exposure to NVP in pregnancy (especially within 1 year of receipt).  Dual toxicity to NVP and EFV.
  17. 17. ARVs combinations not recommended for use
  18. 18. Monitoring Patients on ART
  19. 19.  The utility of virological monitoring has been debated. Few recent studies have documented better outcomes amongst programs offering routine viral load monitoring versus not offering the same.
  20. 20. Complications in the use of ART 1. Immune Reconstitution Inflammatory Syndrome (IRIS) :  It is a paradoxical worsening of pre-existing, untreated or partially treated opportunistic infections or exacerbations of pre-existing or development of new autoimmune conditions, after initiation of ART.  It occurs due to inflammatory response to pre-existing clinical or sub-clinical pathogens or nonpathogenic antigens.  It occurs in 10 – 30% of patients, especially in when CD4+ T cell count is <50 cells/µl and initiating ART closer to starting of OI treatment.
  21. 21.  It is of two types : First, paradoxical IRIS is the worsening of well controlled underlying infection; Second, unmasking IRIS is the occurrence of new manifestations in a patient apparently well prior to initiation of ART  Signs and symptoms appears within 2 weeks to 2 years after initiation of ART, which includes localised lymphadenitis, prolonged fever, pulmonary infiltrates, increased intracranial pressure, uveitis, sarcoidosis and grave’s disease.  No clear strategies exist for management of IRIS, however 4 weeks of steroids (1.5 mg/kg/day for 2 weeks followed by 0.75 mg/kg/day for 2 weeks) has been found to be effective, while specific antimicrobial therapy is more effective.
  22. 22. 2. ARV toxicities and management : ACUTE
  23. 23. CHRONIC :
  24. 24. 3. ART-Related Drug Interactions :  Anticonvulsants : Avoid prescribing carbamazepine, phenobarbital, and phenytoin for patients receiving nonnucleoside reverse transcriptase inhibitors (NNRTIs) or PIs. Levetiracetam may be considered.  Antifungal Drugs : Avoid or use caution when combining voriconazole with the NNRTIs or unboosted PIs. Fluconazole decrease Nevirapine clearance by 2 folds. Monitor LFT closely when co-administered.  Antimycobacterial Drugs : Not to use rifampin with any PIs. Give rifabutin with proper dose adjustment.
  25. 25.  Antihypertensive drugs : Calcium channel blockers level increases with protease inhibitors, careful monitoring is advised when co-administered.  Lipid-Lowering Agents : Lovastatin and simvastatin are contraindicated with all PIs and delavirdine (DLV). Pravastatin is the safest drug for treating hyperlipidemia during concurrent PI therapy. Atorvastatin can be used cautiously at lower doses (5 to 10 mg) with careful titration. Rosuvastatin can be used at lower doses (5 mg) with careful titration. Fibric acid derivatives can be used in recommended dosage.
  26. 26.  Oral Contraceptives : Use caution when prescribing oral contraceptives for patients receiving ART because of the variations in effect on ethinyl estradiol levels. Women who are taking efavirenz, nevirapine, lopinavir/ritonavir, nelfinavir, ritonavir, tipranavir/ritonavir, darunavir/ritonavir, or saquinavir to use alternate or additional forms of birth control.  Sedative/Hypnotics : Not to prescribe midazolam or triazolam for patients receiving PIs. Lorazepam or oxazepam may be considered.  Herbal Therapy : All herbal products should be used with caution.
  27. 27. When to change ART?  Substitution (Only after confirmed virological suppression) :  Toxicity (e.g. TDF for AZT anemia)  Simplification (e.g. bid to qd regimens)  Cost (e.g. from EFV to NVP)  Drug-Drug interaction (e.g. from NVP to EFV when initiating rifampicin)  Pregnancy (e.g. from EFV to NVP)  Proactive (e.g. from d4T to TDF)  Switching : For ART failure.
  28. 28. ART failure  Virological failure :  Rebounders: Confirmed re-emergence of virus (defined as viral load>1000 copies/ml) after virological suppression.  Non-responders: Inability to achieve virological suppression after initiation of ART (defined as VL<400 copies at 6 months and <50 copies/ml at 12 months).  Immunologic failure (patients not monitored on viral load) :  Confirmed >30% drop in CD4 count from peak value.  Non-improvement in CD4 count>100 cells in the first year of initiating or changing ART.
  29. 29.  Clinical failure (patients not monitored on viral load ): Development of new AIDS defining condition 3 months after initiation or change in ART regimen.  Virological monitoring is critical to identify failure early.  The disadvantage of immunologic/clinical monitoring is late identification of failure causing increased accumulation of drug resistant mutations that can compromise efficacy of future regimens.
  30. 30. Choice of second-line regimens : Genotypic resistance testing has to be performed when the patient is on or within 2 weeks of discontinuation of a failing regimen as its better predictor of resistance than expert opinion alone.
  31. 31. ART in Special Situations 1. HIV and pregnancy :  Goal : Treat the mother’s HIV infection.     Prevent mother-to-child transmission of HIV. Pregnancy is an indication to initiate ART irrespective of mothers CD4/VL status. Nevirapine is contraindicated amongst women with pretherapy CD4 count > 250 mm3. Discontinuation of ART after delivery when the mother does not need ART for her own health may be associated with higher risk of clinical progression and development of resistance. Therapy may be continued after delivery and simplified to NNRTI based first-line regimens if the mother is virologically suppressed.
  32. 32. Approach to use of ART in pregnancy
  33. 33. 2. HIV and Tuberculosis (TB) :  Antiretroviral therapy is indicated for all TB patients irrespective of       CD4/PVL status. For patients with CD4<50/mm3 ART should be initiated around 2 weeks of starting anti-TB treatment. For patients with CD4>50/mm3, ART may be delayed until 8 weeks of anti-TB treatment. For CNS TB ART initiation may be deferred until 4-8 weeks after starting ATT. A rifampicin (RMP)/rifabutin (RBT) based regimen is necessary throughout the duration of anti-TB treatment as it has better outcomes (failure and relapse) apart from shortening the duration of TB treatment. Ethambutol should be included in the maintenance phase as the prevalence of primary INH resistance is high in India. Daily treatment (rather than intermittent) throughout the course of TB treatment is more effective in preventing treatment failure and relapse rates.
  34. 34. Choice of ARVs with anti-TB drugs :
  35. 35. 3. HIV and Hepatitis Co-infection : HIV with HBV co-infection  Antiretroviral therapy is indicated for all HIV-infected patients who need HBV treatment irrespective of CD4 counts or HBV DNA/ALT levels.  Choice of ARVs First-Line : Tenofovir/Emtricitabine or Tenofovir/lamivudine (Adefovir can be added if needed) Second-line : maintain Tenofovir in the regimen, e.g. Tenofovir/Zidovudine/Protease Inhibitors.
  36. 36.  HIV and HCV co-infection : Chronic HCV infection is an indication to initiate ART irrespective of the CD4/VL status.  Choice of ARV Preferred : Telaprevir or Boceprevir • Avoid : Zidovudine : Additive Bone marrow toxicity (with Interferon and ribavirin). Stavudine : higher incidence of lactic acidosis. Didanosine : interaction with ribavirin and hepatic decompensation. Abacavir : Lower response, probably related to antagonism with ribavirin (both are guanosine analogs). 
  37. 37. Post-exposure Prophylaxis of HIV Comprehensive management given to minimize the risk of infection following potential exposure to blood-borne pathogens e.g. HIV. This includes: 1. First aid 2. Counseling 3. Risk assessment 4. Relevant laboratory investigations based on informed consent of the source and exposed person. 5. Depending on the risk assessment, the provision of short term (4 weeks) of antiretroviral drugs. 6. Follow up and support
  38. 38. HIV transmission risk of different routes :
  39. 39.  Post-exposure prophylaxis (PEP) has its greatest effect if begun within 2 hours of exposure, it is essential to act immediately. There is little benefit if >72 hours later.  The prophylaxis needs to be continued for 4 weeks (28 days).  Preferred PEP regimen : Tenofovir 300 mg PO qd + Emtricitabine 200 mg PO qd + Raltegravir 400 mg PO bid. (Lamivudine 300 mg PO qd may be substituted for Emtricitabine) Alternative regimen : Zidovudine 300mb bd + Lamivudine 150mg bd OR Stavudine 30mg bd + Lamivudine 300mg bd.
  40. 40.  Follow-up of an exposed person : Clinical follow-up : the exposed person must be monitored for the eventual appearance of signs indicating an HIV seroconversion: acute fever, generalized lymphadenopathy, cutaneous eruption, pharyngitis, non-specific flu symptoms and ulcers of the mouth or genital area. These symptoms almost always appears within 3 to 6 weeks after exposure. Laboratory follow-up : after exposure testing at 3 months and 6 months is recommended.
  41. 41. References 1. Antiretroviral Therapy – Evidence based Treatment Options in 2012, HIV Medicine Association of India. ( 2. Guidelines for the Use of Antiretroviral Agents in HIV Infected Adults and Adolescents,2013. (