1. June 2004 HITCH Training Slide Set #3 Special Considerations in Antiretroviral Therapy

2. Objectives This lecture will provide information on the following subjects:  Tuberculosis (TB) and antiretroviral (ARV) drug therapy  Immune reconstitution syndrome  Adherence  Clinical and laboratory monitoring for patients in South Africa on antiretroviral treatment (ART) regimens

3. Concomitant Tuberculosis

4. Evaluate patients for TB before starting ART  Suspect TB if 2 or more of the following are present:  Observed weight loss of ≥1.5 kg over the past 4 weeks  Cough >2 weeks  Night sweats >2 weeks  Fever >2 weeks  If patient has symptoms suggestive of TB, collect 2 sputum specimens for 2 smears and a TB culture

5. Patient Presents with TB before Commencing ART  If no history of WHO Stage IV illness, and CD4 count >200 cells/µL, ART is not yet needed.  Start TB treatment and reassess need for ART after completion of TB treatment.  If history of WHO Stage IV illness and/or CD4 count <200 cells/µL:  Complete 2 months of TB therapy before commencing ART.

6. Patient Presents with TB before Commencing ART (cont.)  If CD4 count is <50 cells/µL or other serious HIV- related illness is present, make sure that the patient is tolerating TB treatment before initiating ART.  Complete at least 2 weeks of TB treatment before initiating ART.  Start patient on first-line therapy consisting of stavudine (d4T), lamivudine (3TC), and efavirenz (EFV).

7. Patient Develops TB while on ART  ART should be continued throughout TB treatment, with:  monitoring of clinical status  changes to drug regimens as needed to compensate for drug-drug interactions

8. Patient Taking TB Medication and ARVs Concurrently  Avoid nevirapine (NVP) in ARV drug regimen.  ARV drug concentrations may decrease as a result of TB medication.  There will be an increased risk for hepatotoxicity.  Patients on TB medication and ARVs are taking a large number of tablets: do proactive counseling to improve adherence.

9. If TB Patient Is on ARV Regimen 1b  Change NVP to EFV whenever possible.  If not possible (eg, EFV intolerance or significant risk of pregnancy), NVP may be continued in selected cases, with monthly liver enzyme monitoring.  Discuss these cases with an ARV expert.

10. If TB Patient Is on ARV Regimen 2  Change lopinavir/ritonavir dosage to 400/400 mg (3 extra caps of ritonavir) every 12 hours.  Continue until 2 weeks after completion of TB treatment, when the extra ritonavir can be stopped.

11. Immune Reconstitution Syndrome

12.  As immune system is strengthened by ART, it may begin to aggressively fight coexisting opportunistic infections (OIs).  If immune system response is too vigorous, it causes inflammation of tissues involved in the infection.  This response makes coexisting OIs worse.  This is called immune reconstitution syndrome or immune reconstitution disease.

13. Immune Reconstitution Syndrome (cont.)  Can occur with TB, cryptococcosis, and cytomegalovirus (CMV), among other infections.  Symptoms: fever, sweats, weight loss, cough, decreased visual sharpness (in CMV), enlarged lymph nodes (in TB).  Often seen in patients with advanced HIV disease: low CD4 T-cell count (<50 cells/µL).  Develops in the initial weeks of ART.

14. Immune Reconstitution Syndrome (cont.)  Immune reconstitution syndrome is not a sign of treatment failure.  Not a reason to switch therapy but should be evaluated thoroughly to exclude treatment failure or infections.  In severe cases, patients should be referred to an expert.  There are no clear guidelines for the management of immune reconstitution syndrome.  Approaches include stopping ARVs or using systemic corticosteroid treatment in severe cases.

15. Prophylaxis of Opportunistic Infections

16.  Cotrimoxazole to prevent Pneumocystis jiroveci pneumonia (PCP) and toxoplasmosis must be continued in all patients on ART until CD4 count remains >200 cells/µL.  Also recommended if CD4 count drops to <200 cells/µL, as in cases of treatment failure.  Fluconazole for patients who have had cryptococcal meningitis should continue until CD4 count remains >200 cells/µL.  Patients on isoniazid TB prophylaxis who start ARVs should complete isoniazid treatment.

17. Adherence

18. Adherence Overview  Treatment success depends on tablet-taking behavior.  Ideal adherence means patient takes >95% of doses.  Should miss <3 doses/month  If patient is taking <95% of doses:  Increased risk of developing viral resistance  Decreased viral suppression  Increased risk of long-term treatment failure

19. Adherence Overview (cont.)  Difficult to predict which patients will be adherent.  Important to provide all patients with a comprehensive plan that utilizes multiple strategies to support adherence.  Involve members of the health care team, family, and community in developing plan.

20. Strategies to Promote Adherence  Spend time with patients and have several meetings to explain goals of therapy.  Negotiate treatment plans that patients can understand.  Provide tools such as calendar of medications and pillboxes.  Ask patients about other medications they may be taking.  Develop links with community-based organizations to support adherence.  eg, home-based care organizations

21. Pretreatment: Promoting Adherence before Starting ART  Give patients pretreatment information and education per visit schedule.  Introduce patients to therapeutic counselor and patient advocate.  Do cotrimoxazole pill count for 1 month prior to commencing ART.  This reinforces daily medication-taking behavior and helps identify potential problems before starting ART.

22. At Each Treatment Visit:  Do ARV tablet count to calculate adherence.  (Ideal, but depends on clinic staff and workload)  Goal: >95% doses taken  Patient with adherence <80% requires additional support  Tablet count may done before patient is seen by doctor  Address missed/late appointments.  Evaluate for possible side effects of treatment and manage appropriately.  Allow time for questions with therapeutic counselor.  Encourage participation in a support group.  Arrange regular community visits by patient advocates.

23. Additional Adherence Support  Additional adherence support is needed when adherence is <80% with or without viral or clinical failure.  Therapeutic counselor/nurse or doctor must reeducate patient.  Emphasize long-term benefits of treatment.  Supply memory aids such as pillboxes or daily dosing diaries.  Insist on participation in a support group.  Check family situation.  Check psychological profile of patient.  Increase home visits by counselors or patient advocates.  Consider directly observed therapy for a specific amount of time.

24. Calculating Monthly Adherence  Monthly adherence = (tablets dispensed - tablets returned) / (tablets prescribed)  30-5/28 = 25/28  25/28 = 0.9  0.9 x 100% = 90%  Adjust for actual number of days in a given month

25. Clinical and Laboratory Monitoring

26. Types of Clinical/Lab Monitoring Monitoring for:  Side effects  Treatment failure (viral load, CD4 count) Common tests for monitoring side effects:  FBC (full blood count): to test for anemia from zidovudine (ZDV)  ALT: to test liver function  Triglycerides, fasting cholesterol, fasting glucose: to test for elevated cholesterol levels from protease inhibitors

27. Routine Monitoring for Regimen 1

28. Routine Monitoring for Regimen 2

29. Clinical and Laboratory Monitoring for Patients on Regimen 1a or 1b  Patients attend monthly to collect medications.  Seen by a professional nurse to monitor drug tolerance, adverse events, and adherence.  If possible, have clinic nurse, doctor, pharmacist, or therapeutic counselor count drugs.  Patients should be seen by doctor at 4, 8, and 12 weeks, and every 3 months thereafter.  CD4 count and viral load measured every 6 months.  If patient is not doing well, see patient more frequently as determined by doctor or nurse.

30. Special Monitoring for Patients on Regimen 1b  Patients need to be seen by nurse at 2 weeks of treatment.  In addition to monthly visits, to check for adverse effects.  Need to check ALT levels at baseline; at 2, 4, and 8 weeks; and every 6 months thereafter.  Adjust dosing as needed.

31. Clinical and Laboratory Monitoring for Patients on Regimen 2  Patients must come in monthly for first 3 months to see doctor.  Thereafter, must see doctor every 6 months or as required.  Drugs should be collected every month.

32. Special Monitoring for Patients on Regimen 2  There is no viral load monitoring for patients in regimen 2.  FBC will be measured monthly for 3 months and every 6 months thereafter.  In addition, monitor for elevated cholesterol. Check:  Fasting cholesterol  Triglycerides  Fasting glucose

33. Viral Load Monitoring If viral load is <400 copies/mL:  Monitor viral load every 6 months  Provide routine adherence support

34. Viral Load Monitoring (cont.) If viral load count is 400 to 5,000 copies/mL:  Repeat viral load check in 6 months.  Begin stepped-up adherence package. Review at next 6- month viral load check.  If <400 copies/mL, return to monitoring at 6-month intervals and resume adherence support.  If still between 400 and 5,000 copies/mL, continue stepped- up adherence package, repeat viral load check at 6 months.  If >5,000 copies/mL despite stepped up adherence support, switch to second-line therapy only if adherence is >80%.

35. Viral Load Monitoring (cont.) If viral load count is >5,000 copies/mL:  Repeat viral load check in 3 months.  Begin stepped-up adherence package. Review at next 6- month viral load check.  If <400 copies/mL, return to monitoring at 6-month intervals and resume adherence support.  If between 400 and 5,000 copies/mL, continue stepped-up adherence package, repeat viral load check at 6 months.  If >5,000 copies/mL despite stepped-up adherence support, switch to second-line therapy only if adherence is >80%.

36. Unscheduled Visits  Assess whether additional safety bloods are required if patient presents with adverse event.  No extra CD4 count or viral load test should be performed.  Only exception is when repeating viral load test after previous count of >5,000 copies/mL.

37. Treatment Failure  Patients who experience virologic failure on regimen 1 despite adherence may be changed to regimen 2.  Prior to changing, patients should undergo readiness and education process again.  Determine whether patients are hiding their nonadherence.  Patients who experience failure on regimen 2 should receive increased adherence support.

38. Treatment Failure with Regimen 2  If failure occurs despite demonstrated adherence, continue ARVs until the patient ceases to derive any clinical benefit from treatment.  If adherence is consistently <80%, the patient requires ongoing education and counseling.  If the patient has a WHO Stage IV illness on regimen 2, consult with an expert about stopping therapy and starting palliative care.