GUIDELINES FOR USE OF ANTIRETROVIRAL DRUGS ETHIOPIA

Transcription

1 GUIDELINES FOR USE OF ANTIRETROVIRAL DRUGS IN ETHIOPIA Ministry of Health Disease Prevention and Control Department In collaboration with HIV/ AIDS Prevention and Control office (HAPCO) and Drug Administration and Control Authority (DACA) Addis Ababa Feb. 2003

2 Contents Abbreviations 5 Introduction 5-7 Objectives and users (targets) of the guidelines 7 Antiretroviral Therapy in adults and adolescents 8 Indications of ART in adults and adolescents 8-9 Recommended first line drugs Drug adherence and monitoring of ART 13 Drug adherence and drug counseling Relevant issues on adherence Counseling for ART in adults and adolescents Monitoring of ART Clinical monitoring Laboratory monitoring Reasons for changing ART and choice 2 nd line ARV regimens 24 Treatment failure Toxicity 27 Drug resistance Antiretroviral Therapy in women of child bearing age and MTCT prevention 28 Women of childbearing potential and who are pregnant Prevention of MTCT Antiretroviral Therapy for Children Tuberculosis and other co-infections Post exposure prophylaxis Pharmacotherapeutics Annex I-XII References

3 ABBREVATIONS 3TC ABC AFB AIDS ARV ART AUC CAD CBC CD4 cells CNS D4T ddc ddi DNA DOTS FBS EFZ ELIA GoE HAART HAPCO HBV HCV HIV IDV LFT LPV MTCT NFV NNRTI NsRTI NVP OI PCP PCR PEP PI PLHA PMTCT RNA RTV, r RTV-PI RFT RT SQV STD/STI TLC UNGASS UNAIDS UNICEF VL WHO Lamivudine Abacavir Acid fast bacilli Acquired immune deficiency syndrome Antiretroviral Antiretroviral Therapy Area under the curve Coronary Artery Disease Complete blood count T-lymphocytes of with CD4 marker Central nervous system Stavudine Zalcitabine Didanosine Deoxyribonucleic acid Directly observable therapy short course Fasting blood sugar Efavirenz, also abbreviated as EFV Enzyme linked immunosorbent assay Government of Ethiopia Highly active antiretroviral therapy HIV/AIDS Prevention and Control Office Hepatitis B virus Hepatitis C virus Human immunodeficiency virus Indinavir Liver function test Lopinavir Mother to child transmission Nelfinavir Non-nucleoside reverse transferase inhibators Nucleoside analog reverse transcriptase inhibitor Nevirapine HIV related opportunistic infection Pneumocystis carinii pneumonia Ploymerase chain reaction Post-exposure prophylaxis Protease Inhibitor People living with HIV/AIDS Prevention of mother to child transmission Ribonucleic acid Ritonavir Ritonavir boosted Protease Inhibitor Renal function test Reverse transcriptase Squinavir Sexually transmitted disease/sexually transmitted infection Total lymphocyte count United Nations General Assembly Special Session on HIV/AIDS United Nations Joint Co-sponsored Programmed on HIV/AIDS United Nations Children s Education Fund Viral load World Health Organization 5

4 I. INTRODUCTION Worldwide HIV/AIDS has created an enormous challenge on the survival of mankind. Since its recognition, the virus has infected close to 65 million individuals and over 25 million have already died due to AIDS (1). Currently, over 42 million people are living with the virus and of these more than 70 /o arc in sub- Saharan Africa. AIDS has now become the leading cause of death in sub-saharan Africa (2) In Ethiopia, the first cases of AIDS were detected in 1986 (2). As of end of 2001, over 2.2 million people in the country are living with the virus, and nearly 110,000 patients are reported to have developed AIDS defining illnesses (4) The adult prevalence of HIV is estimated at 6.6% in 2002 and the projections of people infected with the virus are expected to increase to over 4 million by the year 2014 (4). Consequently, the number of PLHA and death from AIDS will remarkably increase, with enormously increasing demand for care and support. Cognizant of the negative socio-economic impacts of the pandemic in Ethiopia, the GoE has taken several steps to reduce transmission of the virus and mitigate its impacts. NAC, which is led by the President of the country, is established in order to give dedicated leadership for the all round social mobilization against the epidemic, and HAPCO is formed under NAC to ensure coordination of the multisectoral response against the epidemic. A National Policy and Strategic Framework on the prevention and control of HIV/AIDS are in place. They facilitate the national response to the epidemic. Moreover, a Policy on the supply and use of antiretroviral drugs is developed and has been approved by the Government. The faith-based organizations, the local arid international NGOs, multilateral and bilateral donors and UN agencies are more and more engaged now in prevention and control of HIV/AIDS in the country. Access to ARV drugs will improve the survival and quality of life of PLHA. This has been proved in developed countries and very few middle-income countries where these drugs are available at affordable prices. Today, an estimated 250,000 people in the developing world receive ART. Only 30,000 persons are estimated to be on ART in Africa, where nearly 30 million are infected with HIV and an estimated 5 million suffer from AIDS. The WHO has set a goal for 2005 of having 3 million persons in the developing world on ART--a 12-fold increase in less than 3 years (1). At the moment world opinion has shifted significantly in favor of providing access to ART in developing countries. Currently, the price of ARVs, in particular generic drugs, has remarkably decreased and good number of people in the developing countries may afford these drugs with some assistance. Moreover, guidelines issued by WHO have simplified the monitoring of ARVs. The United Nations General Assembly Special Session on HIV/AIDS (UNGASS) in 2001, advocated for the complementarity of HIV care and prevention and urged governments to provide the highest attainable standard of care, including antiretroviral treatment to people living with HIV/AIDS (5). Nevertheless, the safe and effective use of ARV drugs in any settings, but especially in resource -limited settings, requires treatment planning. It is important to have clinical guidelines that are regularly updated taking into account the rapid 6

5 evolution in knowledge and experiences gained in different health care settings. It is equally necessary of paramount importance to have a laboratory capacity in order to diagnose and monitor the successes and failures of ART. Sustainable supply of affordable AR\T drugs, as well as basic essential drugs to treat opportunistic infections must as well be available to run a program of ART sustainably. Training of health professionals in proper use of these drugs is indispensable. Finally, these drugs require high level of compliance by the patient; therefore, adherence counseling is imperative for successful outcome of use of these drugs. To make all these real, this guideline is developed to assist trained physicians and other health workers of the team attending to PLHA. The guideline can serve as a resource material for training, developing national drug list and procuring ARVs. II. OBJECTIVES AND USERS (TARGETS) OF THESE GUIDELINES The objectives of this document are: 1. To provide simplified and standardized approaches for the use of AR I as part of comprehensive HIV/AIDS care in Ethiopian setting; 2. Serve as a training material in the care of PLHA; 3. To be a source of reference for physicians and other health care workers providing care for patients with HIV/AIDS, as well as AIDS program managers and health planners involved in national HIV care and treatment program in order to make competent decision on issues pertaining to ARV drugs, and 4. To be source of reference for people living with Hi V/AIDS for advocacy purposes. This document contains recommendations for safe and effective use of ARVs for adults and adolescents, children and patients that require special considerations such as women of child hearing potential and patients co-infected with HIV and TB. Moreover, rational use of ARVs in prevention of mother to child transmission and post-exposure prophylaxis has also been included. The targets or users of this document are: 1. Physicians and other health providers; 2. HIV AIDS program managers, health planners, experts working on drug selection and procurement, To use this guideline adequate training is mandatory. Since new data pertaining HIV/ AIDS are emerging very fast, the guidelines will require regular updating at appropriate intervals. 7

6 III. ANTIRETROVIRAL THERAPY IN ADULTS AND ADOLESCENTS The goals of antiretroviral therapy include maximal and durable suppression of viral multiplication, restoration and/or preservation of immunologic function, improvement of quality of life, and reduction of HIV-related mortality and morbidity (6). The achievement of complete viral suppression depends on the baseline viral load and CD4 cell count at the beginning of therapy, the potency of the regimen used, patient adherence, and previous exposure to ARVs. Although opportunistic infections are uncommon with partial viral suppression (VL <5000 copies/ml RT-PCR), emergence of drug resistant virus occurs if suppression is not maximal (undetectable viral load, or VL <50 copies/mi). ART has epidemiological goal of reducing HIV transmission (7,8) apart from PMTCT. a. Indications of ART in adults and adolescents: a. Clinical AIDS is a clear indication for the use of ARV drugs. Persons with symptomatic disease (AIDS, WHO adult stage IV and advanced stage III disease) should receive ART irrespective of the CD4 cell or total lymphocyte count. b. Earlier symptomatic patients (WHO adult stage II and III) or assymptomatic persons (WHO adult stage I) may be started on ART when the CD4 cell count falls below 200/mm 3 or when the CD4 percentage is below 15%(table 1). This recommendation assists to initiate treatment in setting of established infection without symptoms. c. When CD4 count is unavailable, treatment is recommended for early symptomatic persons (WHO adult stages II and III) with total lymphocyte counts (TLCs) below 1200/ mm 3. When only TLCs are available, assymptomatic persons with low CD4 count who may benefit from treatment cannot be accurately identified and only become eligible for treatment after progression of HTV disease. Therefore, there is strong recommendation for the use of simple low-cost CD4 methodologies in resource-limited setting 8

7 Table 1. Recommendations for initiating ART in adults and adolescents with documented HIV infection (1) If CD4 testing is available WHO [1] stage IV irrespective of CD4 cell count (a) WHO stage I, II, or III (a) with CD4 cell counts less than 200/mm 3 (b) If CD4 testing is not available WHO stage IV irrespective of TLC WHO stage II or III (c) with TLC less than 1200/mm 3 (c) (a) Treatment is also recommended for patients with advanced WHO stage III disease, this includes recurrent or persistent oral candidiasis and recurrent invasive bacterial infections, irrespective of the CD4 cell count or TLC. (b) The precise CD4 level above 200/mm 3 at which to start treatment has not been established but the presence of symptoms and the rate of CD4 cell decline (if measurement is available) should be factored into decision-making. This cut-off (below 200 cells/mm 3 ) may be appropriate in our setting since studies thus far have shown lower baseline CD4 counts among the general population. (c) A total lymphocyte count below 1200/mm 3 can be substituted for the CD4 cell count when the latter is unavailable and HIV-related symptoms exist. It is less useful in asymptomatic persons. Thus, in the absence of CD4 cell testing, asymptomatic HIV infected patients (WHO stage I) cannot be treated because there is currently no other reliable marker available in severely resource-limited settings. [i] See annex 10. p. 75, about the WHO adult staging 9

8 b. Recommended First Line Antiretroviral Regimen In general WHO recommends countries to use a public health approach to facilitate the scale-up of ARV use in resource-limited settings. (1) This means that ART programs should be developed and ARV treatment be standardized. In particular, it is suggested that countries select a single first and limited number of second line regimens for large scale use, recognizing that individuals who cannot tolerate or fail the first and second line regimens would be referred for individualized care to a center with specialized facilities. Considerations of selection of ARV treatment at both the program level and at the level of an individual patient should include potency, side effect profile, the potential for maintenance of future treatment options, the anticipated adherence of the patient population with a regimen, coexistent conditions (i.e., co-infections, metabolic abnormalities), the potential for primary acquisition of a resistant viral strain, and cost and access. Additional considerations relevant to the de\ eloping world may include access to only a limited number of ARV drugs, limited health service infrastructure, the need to deliver drugs to rural areas, a high incidence of TB and HB and/or HC viruses, and the presence of varied HIV groups and subtypes. Currently there are three classes of ARV drugs available for clinical use although the number and category of drugs are increasing from time to time. The drugs suppress the multiplication of the virus through interfering with the life cycle of the virus. The virus has enzymes that facilitate multiplication within the host cell. One of the vital enzymes for viral multiplication is reverse transcriptase, which copies the viral genome (RNA) to a complimentary provirus (DNA) using the DNA and cellular machineries and raw materials of the host cell. One big category of ARV drugs, called RT1 (reverse transcriptase inhibitors), blocks this enzyme. These drugs are further divided into two: NRTI (nucleoside reverse transcriptase inhibitors) and NNRTI (non-nucleoside reverse transcriptase inhibitors). The virus has another essential enzyme called protease that is responsible for post-translational processing of viral proteins; this is blocked by a category of ARV drugs called protease inhibitors (PI). There are various combinations and formulations of these drugs. These drugs are given in different regimens; the most effective combination currently is HAART (highly active antiretroviral therapy), which includes at least three drugs from one or all the three categories. Table 2. Names and Categories of ARV Drugs used in this guidelines NRTI NNRTI PI Zidovudine (ZDV) Nevirapine (NVP) Saquinavir (SQV) Didanosine (ddi) Efavirenz (EFZ) Ritonavir (RTV) Zalcitabine (ddc) lndinavir (IDV) Lamivudine (3TC) Nelfinavir (NFV) Stavudine (d4t) Lopinavir (LPV) Abacavir (ABC) LPV/r ZDV+3TC SQV/r ZDV+3TC+ABC IDV/r 10

9 Table 3. Recommended first-line antiretroviral regimens in adults and adolescents with documented HIV infection Pregnancy considerations Major toxicities Regimen (a) ZDV/ 3TC/EFZ or ZDV/3TC/ NVP Substitute NVP for EFZ in pregnant women for whom effective contraception cannot be assured. ZDV-related anemia EFZ-associated CNS symptoms Possible teratogenicity of EEZ NVP-associated hepatotoxicity and severe rash NsRTI-related side-effects ZDV/ 3TC/ABC (a) ABC safety data limited ZDV-related anemia ABC hypersensitivity NsRTI-related metabolic side effects ZDV/3TC/RTV-PI (b) or ZDV/3TC/NFV LPV/r safety data limited NVF most supportive safety data ZDV-related anemia NFV-associated diarrhea ID V-related nephrolithiasis PI-and NsRTI-related metabolic side effects. (a) ZDV/ 3TC is listed as initial recommendation for dual NsRTI component based on efficacy, toxicity, clinical and availability of fixed dose formulation. Other dual NsRTI components can be substituted, including d4t/3tc, d4t/ddi and ZDV/ddI. ZDV and d4t should never be used together because of proven antagonism. Fixed dose formulations are preferred whenever possible as they promote enhanced drug adherence. (b) RTV-PI includes IDV/r, LPV/r or SQV/r As indicated above, the recommendation for ART programs in resource-limited settings is to choose one potent first-line ART regimen with which to start treatment in the majority of patients. Clinical trials of different triple-drug regimens in HAART have in general showed comparable antiviral efficacy. The choice among these regimens in general relies on other considerations, including side-effect profiles, potential drug interactions, comorbidities (e.g., TB, hepatitis), and the maintenance of alternative options in the setting of treatment failure, and drug availability and cost. The recommended regimens (table 3) each contain a dual nucleoside component (backbone) to be combined with an NNRTI, the potent NsRTI, abacavir (ABC) or a PI. The following dual NsRT1 can be considered: ZDV3TC, d4t/3tc, ddi/zdv, ddi/3tc and ZDV/ddC. Of these the first two have emerged as leading candidates for use in initial regimens because of their efficacy, toxicity profiles and years of clinical experience. Although d4t/ddi remains important component of dual regimens, cautions have been raised about its potential to cause lactic acidosis, particularly in pregnant women, 11

10 hepatotoxicity and neurotoxicity (both peripheral neuropathy and a condition resembling Guillain-Barre syndrome). Although ABC can also be used as NsRTI backbone in initial regimens but it is recommended that its use be restricted to the cornerstone of triple NsRTI regimens. Monotherapy should never be given and dual NsRTI therapy alone is not recommended as initial therapy because the regimen potencies are suboptimal and the emergence of drug resistance is predictable. In order to establish a potent ARV regimen a third drug must be added to the dual nucleoside backbone. One of the following three can be added to the backbone: 1) NNRTT; 2) abacavir; 3) a PI (+/- low-dose ritonavir for pharmacoenhancenient). These are PI-sparing, dual-class-sparing and NNRTI-sparing respectively. This is important with respect to the maintenance of alternative treatment options following therapeutic failure. When available, fixed-dose combinations are advantageous with respect to the simplification of regimens and consequent improved adherence. These fixed-dose combinations available now include: ZDV/3TC, ZDV/3TC/ABC, LPV/r, d4t/3tc/nvp and ZDV/3TC/NVP. The 3 major regimens for initiating ART in adults and adolescents: 1. NNRTI-based regimens NNRT1s are very potent anti-hiv-l agents but are inactive against the group O HIV-1 subtype and HIV-2. The two drugs recommended in this category are EFZ and NVP. Each drug should be administered with dual NsRTIs. Comparable to PI-based regimens in efficacy. There are no standard studies showing the superior potency of EFZ to NVP. EFZ is contraindicated in women on ART who are pregnant or desire to become pregnant. NVP should be replaced. Potential side effects of NVP are rash and hepatotoxicity. 2. Triple NRTI-based regimens NsRTI-based regimens are considered to be those containing ABC. Usual combination is ZDV/3TC/ABC, but the other dual NsRTI combination may be used flexibly. Low pill burden (1 tab bid) No interaction with rifampicin therefore can be given with TB medication at any phase. However, the regimen has uncertain efficacy in patients with advanced disease or high viral load, and there is a risk of ABC hypersensitivity that may affect 5% of patients starting on the medication, and there are only limited data on the use of ABC in pregnancy. 3. PI-based regimens There are 6 PIs but only four are recommended as first-line agents for reasons of tolerance, clinical trial experience and expert consensus on their applicability in resource-limited settings. These are: NFV, IDV combined with low dose RTV, LPV/r. and SQV combined with low-dose RTV. 12

11 Each of these PIs, in combination with 2 NsRTs, offers sufficient potency to be recommended as starting ART regimen, but each has drawbacks. Low pill burden, (but NFV has moderate pill burden.) PIs combined with low-dose RTV may need refrigeration, therefore, a problem in resource-limited settings, but can be used where refrigeration facilities are available. PIs, except SQV/r, interact with Rifampicin, therefore, cannot be administered in patients co-infected with TB and receiving anti-tb medication. Taking all these factors into account, the first line regimen for treatment-naïve patients in Ethiopia among adults and adolescents is NNRTI based regimen. That is Efavirenz with Zidovudine/Lamivudine backbone. In female patients with childbearing potential or with pregnancy Nevirapine replaces EFZ. If patients cannot tolerate this regimen say for severe anemia of ZDV, disabling CNS manifestation of EFZ, or hepatotoxicity of lifethreatening dermatological complication of NVP, then appropriate modification of the first line regimen is made or triple NsRTI regimen (ZDV/ 3TC/ RVT-PI or ZDV/ 3TC/ NFV can be used as first line regimen. In all patients thorough clinical examination, serological test for HIV-I infection and Hemoglobin (or hematocrit) and total white cell count and differential must be done before starting on ART. This has been very well described in the Monitoring section of this guideline. At the level of zonal hospitals (public, private or NGO) one first line regimen (EFZ/ZDV/3TC, replacing NVP for EFZ in women of childbearing potential or pregnant women) will be used as first line regimen among adults and adolescents. If patients cannot tolerate this regimen due to anemia of ZDV, d4t can be substituted. If the intolerance demands to use other first line regimen instead of the NNRTI-based regimen, patients should be referred to referral hospitals where better ART care facilities are available. At the level of referral hospitals with facilities of CD4 count with or without viral load and toxicity monitoring laboratory facilities and other laboratory and imaging facilities, as well as specialist physicians with sufficient knowledge and experience of ART, all the three first line regimens will be made available. By making such standard of drug availability the concern of misuse of drugs and early emergence of resistance can be diminished. Zonal and equivalent hospitals are expected to have ART- trained health care workers that make a team of ART. These include a physician (GP or specialist), a counselor, a pharmacist or other pharmacy personnel and laboratory technician. In addition to the team the minimum laboratory facilities include serology test for HIV-1, hemoglobin or hematocrit and complete WBC count with differential count. Sometimes a district hospital may be in a better situation in terms of manpower and facilities. If that is the case the responsible government office will give the authorization of providing the ART. As long as a public, NGO or private hospital can fulfill the basic requirement of providing ART, authorization will be given irrespective of the geo-political location of a given hospital. 13

12 IV. DRUG ADHERANCE AND MONITORING OF ANTIRETROVIRAL THERAPY 1. DRUG ADHERENCE AND DRUG COUNSELING a. Relevant issues on adherence Innovative and culturally sound strategies for enhancing adherence to ART is highly recommended because of the life long nature of the therapy. Success of ART depends on strict drug adherence in the range of more than 95% compliance. Poor adherence has been shown to increase the likelihood of virologic failure, evolution of drug resistance and subsequent immunological and clinical failure, thus increased morbidity and mortality. Therefore, the ability of a patient to adhere to the regimen is vital for the success of the treatment. Imperfect adherence is common even in settings where there is considerable assistance to comply with treatment. Table 4. Virologic failure and adherence (9) Adherence with HAART Number with viral load (# prescribed pills taken) <500 copies/ml >95% 82% 90-95% 45% 80-90% 33% 70-80% 29% >70% 18% Surveys have shown that one-third of patients missed doses within 3 days of the survey. The reasons for missed doses included forgetting, being depressed, having adverse side effects, being too busy, and being too ill. Poor clinician-patient relationship, active drug and alcohol use, active mental illness, in particular depression, lack of patient education and lack of access to primary medical care or medication are among the many predictors of poor adherence. In resource-limited settings affordability in the case of out of pocket funding makes patients discontinue or take drugs irregularly. There are predictors of good adherence as well, such as availability of emotional and practical life supports; the ability of patients to fit the medications into their daily routine: the understanding that poor adherence leads to resistance; etc. There are different approaches to increase the patient drug adherence, the most important of which is developing adequate drug counseling with ART program. All members of the medical team (clinicians, nurses, counselors, dispensers. and lab. Technicians) that are involved in the administration of ART in a hospital, have important role in order to ensure ARV drug adherence. Enlisting the support of the family, friends and the community is also indispensable. Drug regimens with low pill burden and less adverse effects, preferably with fixed drug combinations, are better complied. Drug timetable and pill counting may also assist monitoring adherence. In some settings, sites may wish to try to introduce DOT with carers or family members assistance. In particular, sites with TB treatment programs may wish to 14

13 consider this, although the open-ended nature of ART, as opposed to the limited course of treatment of TB, raises questions about the sustainability of such an approach (10) b. Counseling for Antiretroviral Therapy (ART) [11,12,13,14,15] Treating AIDS patient with ART requires a team approach among treating physicians, pharmacists, nurses, counselors and laboratory technicians. The physician will take the responsibility of leading the team. All the ART team members along with their routine responsibility of giving clinical care to PLHA, will provide adequate information on ART, this includes over emphasizing the vital importance of adherence to treatment outcome. Furthermore, the teams are expected to maintain high level of confidentiality and wisely involve the family and other relevant care provider such as friends, and neighbors through developing excellent rapport. ART is a lifelong undertaking; a relationship of confidence needs to be established from the outsets between the patient and the care team. In order to further reduce stigma and discrimination of patient coming for ART, such measures as staff orientation on confidentiality and destigmatization, as well as promoting patient-friendly service and regular monitoring of progress are essential. As one method of ensuring the quality of the service regularly assessing client satisfaction using different approaches (questionnaires, suggestion boxes, etc.) is strongly recommendable. It is important that adequate time is set aside for counseling, so that appropriate and informed decision on therapy and its implication given to the patients. The information given should be as accurate and as complete as possible. Several counseling sessions may be needed initially in order to enable the patients cope with positive serostatus in addition to understanding the implications of the use and monitoring of ARV treatment. Counselors should have: 1. Basic counseling knowledge and skill and 2. Knowledge on ART Preferably ART counselor should be a provider with health background. i.e., nurses or physicians, Invariably, all patients that are going to be started on ART after a thorough medical and lab evaluation, should be given adequate counseling before they start swallowing the pills. The objectives of ART counseling include: 1. Help patients to make decision on ART 2. Assist patients to cope with the therapy and provide appropriate information 3. Assist patients to protect others and maintain their protective sexual behavioral changes. i. Counseling patients before taking the ART The counselor after the introduction, should explain to the patient about confidentiality related with the issues they are going to discuss, and establish a trustworthy environment. Counselor should make sure whether the patient has received pre and post-test counseling services during the time of diagnosis. If that is the case the positive messages and future plans initiated during the pre and post-test counseling should be re-enforced during counseling for ART. Moreover, the 15

14 counselor should try to get information as to how the patient is coping with his/her serostatus, and to whom they have disclosed their status. In the process of drug counseling in addition to ensuring confidentiality the ART team and other health providers should always observe privacy, dignity and informed consent in rendering care to PLHA. Patients who have decided to start treatment will need information, support and encouragement on a regular basis in order to maintain adherence. The issues that must be addressed during drug counseling include, financial considerations, emotional support, issues of disclosure, adherence and drug information. Financial consideration It is important to discuss how the drugs are going to be paid for before embarking on treatment since financial constraints are common reasons for default from treatment. Identify patient s family members or friends that may help the patient deal with HIV therapy and provide with emotional support. Explore available financial resource to cover the cost of drugs and complementary expenses for the whole course of therapy. The importance of adherence to therapy, and the consequences of irregular therapy, cessation of therapy or of taking sub-optimal doses to minimize drug costs, should be candidly discussed with all concerned. Discussion on financial support and commitment include; 1. Cost of treatment 2. Discuss about duration of therapy and possible expenditure 3. Available money or support 4. Cost for laboratory for monitoring ART. Where ARVs are not available or are very expensive, knowledge of these treatments may create additional stresses, for both the client and the counsellor. In such situations, counsellors will be helping clients cope with the anguish of knowing that a treatment exists which is not accessible to them, and explain the existence of other options to live longer, such as prevention and treatment of opportunistic infection, diet, exercise, good hygiene and avoiding beverages such as alcohol or other recreational drugs. Where ARVs are provided routinely, counselling will focus on encouraging correct use, coping with a return (albeit temporary) to a more healthy and productive life, and overall emotional well-being. In settings where the client and his/her family will be investing large sums of money in the drugs, problems relating to this use of scarce resources will have to be discussed. Emotional support and difficult decision Many PLHA commencing ART experience feeling of guilt, fear and anxiety because this therapy is expensive. Many may have partners and/or children who also require treatment and who cannot access it for financial reasons and vital family resources may be diverted to buy the medication. Time taken to work through these feelings and doubts will significantly enhance commitment to therapy. Adherence to Antiretroviral Therapy In order to maximize the benefits of treatment immense personal discipline and commitment are required of the patient. Possible barriers to adherence should be discussed with the patient before the patients start on the treatment. It is good also to take previous drug administration history of the patients. 16

15 Examples of possible barriers to adherence: 1. Unable to continue the drugs because of shortage of money and etc. 2. Lack of patient education 3. Number and timing of doses 4. Food restriction and undesirable side effect 5. Poor patient clinician relationship Combination therapy is very expensive; poor adherence means a waste of valuable resources. As indicated above, factors associated with good adherence include emotional and other support, ability of patients to fit medication into their daily routine, understanding that it is essential to take medications regularly and keep medical appointments. Information about therapy Many people with HIV/A1DS know about antiretroviral drugs and may at times have unrealistic expectations about the availability and effects of ART. Counselors should be knowledgeable to answer question related to ART and the requirements for clinical monitoring. The counselors inform to PLHA that ART is not a cure but improve the condition of the sick person and prolong their lives. Elimination of HIV from the body has not yet been achieved using the most potent antiretroviral combination therapies available and even when HIV viral RNA is not detectable in the plasma (blood); there is still ongoing viral replication. The drugs will therefore need to be taken for an indefinite period of time. Discuss also adverse effect of the drugs and interaction with other drugs such as anti TB drug (Rifampicin). Interruption of ART drug because of adverse effect also incurs cost to the patients. ii. Initiating and follow- up of Antiretroviral therapy For optimal efficacy; antiretroviral drugs usually from different classes, must be used in combination. The success of ART is determined more by the patient s compliance with and adherence to the prescribed regimen than by the specific drug combination used. Decision about when to start therapy and what regimen to use is the task of physicians. Physicians and patients together need to weigh the advantage and disadvantage of starting antiretroviral therapy and make individualized informed decision. Decision on option for antiretroviral therapy should also consider individual s financial capacity. iii. Specific ART drug Information Once ART drugs are prescribed to the patient specific information about the drugs have to be provided. The information should include; Numbers of tablets/capsules that the patient should take: Drug administration timetable; Meal and drug taking timetable; Adverse reactions of the drugs. All HIV medicines have side effects. Some of the adverse reactions may be very severe; however, most can be controlled or may go away in a few weeks. Instruct the patient to report immediately to the treating physician in case patients develop one or more of the adverse effects. Patients should not stop taking the drugs before talking with their doctors. However, no time should be wasted to report to the physician. 17

16 Drug interaction. ARV drugs frequently interact with other drugs (e.g. counselor should always ask if patient is taking rifampicin-containing SCC). Sometimes this reaction can be very dangerous. Not only with other drugs ARV drugs have interaction with food and recreational beverages, therefore, all should be informed to the patient. Importance and frequency of ART monitoring (clinical and available laboratory tests including CD4 cell counts and VL) If the patient is pregnant she should talk to the doctor about this, since this has significance in decision of drug regimens. If patients miss a dose sometime, they should take the pills that they missed as soon as possible. If they don t remember until the next dose is due. don't take twice the normal number of pills. Instead, just get back on schedule with next dose. A drug timetable is useful and helps patients with drugs taking schedule. Format ART drug taking schedule for patients use Time ART drug Dose Special instruction Example with drug regimen containing Zidovudine, Lamivudine and Indinavir combination Time ART drug/meal Dose Special instruction 7.00 Indinavir 2 capsules (400mg x2) One hour before meal 8.00 Meal (Breakfast) Zidovudine and Lamivudine (combivir) 1 tab ( mg) TMP/SMX one tab combivir 2 tabs For prophylaxis Meal (lunch) Indinavir 2 capsules (400mgx2) Two hours after meal Meal (supper) Zidovudine + (combivir) 1 tab Indinavir 2 capsules (400mgx2) Two hours after meal 18

17 iv. Drug adherence The patient should have regular follow up with the physician and counselor, to discuss regularity of drug taking habit and any barriers interfering with drug intake. Adherence should be ensured throughout the follow-up period. A caring and trusting relationship between the patient and care provider is critical. Regular appointments and follow up visits assist to maintain adherence of acceptable levels for ARV drugs. Provider s supportive and non-judgmental attitudes encourage the patient to be honest about their adherence. v. Patients coping with the response to ART With the patient s general conditions getting better, quality of life also changes. The individual will return back to his/her normal life, if the treatment fails to bring improvement it will create disappointment, depression and other emotional disturbance. This should also be addressed in the process drug counseling. Patients need support of counselors when they encounter disappointment and depression in time of treatment failure. This time counselors assist the patients to balance between optimism and realistic situations. Depression and despair are common when CD4 counts do not rise and weight is not gained as expected. This is aggravated when the patient s financial resources are draining into the treatment that is not resulting in any favorable outcome. There will also be times when counselor and patient will have to discuss cessation of therapy, if the disadvantages of taking the drugs outweigh the benefits vi. Sexual behavior Although the epidemiological goal of administering ART for a given population is reducing transmission, when it comes to the individual patient, counselors should always overemphasize use of safe sex among patients taking treatment since they are always infectious regardless of the clinical status, CD4 count or viral load levels. There are observations that with improvement in the health and quality of life of patients on ART, there is a tendency of increased risk taking behavior in the individual and the population where the ART is widely available as in the West, therefore intensive preventive counseling is mandatory among patients on ART. 2. MONITORING OF ANTIRETROVIRAL THERAPY All drugs are poison unless properly used and monitored. It is, in particular, so with ARV drugs. The baseline evaluation and continuing monitoring of ART are important for assessing the efficacy of the ART and ensuring safety. In resource-limited settings, decisions about the minimal standard necessary have to be made. For all patients aged 18 months and older it is assumed that HIV infection is documented on the basis of a positive HIV antibody test. It is desirable to have at least minimal services and facilities to initiate ART due to the complexity of the treatment, the need for monitoring and the cost of therapy. These services include: Access to VCT and on-going counseling services. Medical services to identify and treat common HIV-related diseases including opportunistic infections. 19

18 Reliable laboratory services capable of performing routine laboratory tests such as CBC and, if possible, blood chemistries. Access to the referral laboratory capable of doing CD4 count and viral load. Dependable and affordable access to quality ARV drugs, and drugs to treat opportunistic infections. A. Clinical monitoring 1. Baseline assessment: Prior to initiating ART patients should undergo the following evaluation: a. Complete history and physical examination b. Routine laboratory investigations (HIV-1 antibody test. CBC according to absolute minimum, and basic (standard) in case of referral centers. c. CD4 count if available. d. If viral load can be determined we have to use this facility wisely in order to minimize cost, specific indications such as: Treatment failure Difficult clinical conditions such as patient sick vet the CD4 count above 200 cells/mm 3 If we plan to put patients on triple NRTI regimen (such as Trizivir). A detailed clinical evaluation is essential to start ART and should include: Assessing the clinical stage of HIV infection (based on WHO staging. cf. annex 10) Identifying past HIV-related illnesses Identifying current HIV-related illnesses that will require treatment, such as active TB. Identifying co-existing medical conditions and treatments that may influence the choice of therapy. e.g.. liver disease, diabetes mellitus, etc. History and physical examination History should include: When and where the diagnosis of HIV made Current symptoms and concerns of patient Past medical history of symptoms, known diagnosis and treatment given History of TB, or past treatment of TB History of possible contact with TB History of STIs History of pregnancy History of previous ART History of medication and oral contraceptive use in women Personal, social and family history 20

19 The physical examination should include the following: Weight of the patient Skin: herpes zoster, HIV dermatitis, seborrheic dermatitis, Kaposi s Sarcoma, Lymph node enlargement Oropharyngeal mucosa: candida, hairy leucoplakia, Kaposi s sarcoma Systematic and adequate examination of the chest, cardiovascular system, the abdomen, the genitourinary system, the musculoskeletal system and nervous system (including the fundus). The patient should be adequately prepared for ART through sufficient drug counseling. This ensures adherence to therapy. Once ART has been commenced a reasonable schedule for clinical monitoring includes a first follow-up visit one month after initiation (which may also be useful to evaluate and re-enforce drug adherence) and at least one visit every three to four months. However, this has to be individualized depending on the clinical conditions and reliability of compliance to therapy and the nature of the combination treatment. 2. Clinical monitoring for toxicities and effectiveness of ART: Inform patient about symptoms of ARV drug toxicities Patient should be aware of the need to seek care and/or to stop therapy in the interim if necessary. Whether CD4 count is available or not, the clinical evaluation of the effectiveness of ART is important and helpful. The clinical parameters include patients feeling of well being, weight increase over the course of therapy; changes in the frequency and/or severity of HIV-associated symptoms (e.g. fever, pruritus, diarrhea) and physical findings (e.g. oropharyngeal candidiasis); and signs of immune reconstitution syndromes. Table 5. During history taking, a few questions should be asked regarding: History taking Three months Six months Nine months Every 3 months HIV related diseases incl. TB Yes Yes Yes Yes Cough >2 weeks Yes Yes Yes Yes Fever Yes Yes Yes Yes Weight loss Yes Yes Yes Yes Diarrhea Yes Yes Yes Yes Other symptoms: GI, CNS, Yes Yes Yes Yes neurology, skin rash Other medication Yes Yes Yes Yes 21

20 Table 6. A complete physical examination should be performed during the same visit and should include at least: Physical examination Three Six Nine Every 3 months months months months Body weight Yes Yes Yes Yes ENT Yes Yes Yes Yes Skin Yes Yes Yes Yes Lymph nodes Yes Yes Yes Yes Respiratory system Yes Yes Yes Yes CVS Yes Yes Yes Yes Abdomen Yes Yes Yes Yes GU Yes Yes Yes Yes Neurology Yes Yes Yes Yes B. Laboratory Monitoring B.1. Initial laboratory evaluation in adults According to guidelines in North America and Europe standard tests such as CBC, CD4 count, VL, VDRL/RPR, chemistry profile (electrolytes, blood sugar. cholesterol, RFT, LFT, serum amylase), HIV resistance assay, serology for hepatitis A, B, and C, toxoplasma IgG, and Pap smear are performed (6). However, this is unlikely in resourcelimited countries. In Uganda, for example, a CD4 count can cost more than one-month HAART, the cost of VL test equates to HAART for two months, and the cost for resistance testing equates to HAART for one year (16) Not only cost, these tests are not widely available in resource-limited countries. Moreover, there are also concerns about the technology and machinery. For example, Coulter counters and FAC machines may fail due to interrupted electricity, or power surges, and maintenance requirements are lacking in most regions. Therefore, the issue concerns the definition of those tests that are essential (Annex- 12) In Ethiopian setting, to start ART it is recommended that the absolute minimum laboratory tests are HIV antibody testing and complete blood count, including WBC count and differential, and hemoglobin or hematocrit (Table 7). The reason to include WBC is to determine TLC, which helps to broaden the number of patients that will receive treatment at the lowest level. Just like the hemoglobin the WBC count also helps to monitor hematological toxicity. Therefore, Zonal hospital levels (the lowest setting where ART will be started) will invariably have these tests to be eligible to start ART. The referral levels are expected to have even the desirable tests since they will handle more complicated cases. Therefore, at the zonal and equivalents WHO s absolute minimum plus WBC count must be available, where as at the referral hospital level the desirable with or without viral load, optional laboratory facilities are expected to avail. 22

21 Table 7. Recommended standard evaluation of HIV for potential ART recipients in Ethiopia Evaluation Critical/ Standard/ Desirable Optional Minimum Essential Clinical records History and physical examination CBC HIV serology Chemistry profile VDRL/RPR AFB smear Malaria smear Chest X-ray CD4 Cell count STD tests Hepatitis serology HIV RNA (VL) Resistance assays Yes Yes Yes Critical = essential for HIV care Standard= should be available through some mechanism or assigned a high priority in planning Desirable = a full service unit or subset cohort should have most of these resources Optional = may be prohibitively expensive(consider at referral levels) In our settings at the primary level of ART initiation, i.e., the Zonal hospital level, the critical category of laboratory investigations is expected to be available. That is the minimum as indicated above. The additions are AFB smear and malaria smear, and these are important for the ART program as well as basic patient care. Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes B.2. Biological Monitoring of ART Laboratory parameters to monitor for effectiveness of treatment and toxicity include CBC, CD4, viral load, and chemistry profiles depending on the availability of the tests in the concerned center. CBC should be monitored every month, but every week if initial anemia or ZDV associated toxicity is present. 23

22 Other parameters should be monitored every 3 months, or six months (e.g. viral load). The most important biological measurements are the CD4 counts and viral load. - The virological goal of treatment is in general to achieve viral load levels below the limits of detection (<LDL) within 4 to 6 months of starting treatment and the achievement of a minimum decline from the baseline viral load of log by the end of the first month of treatment. - Currently approved assays have a LDL 400 copies/ml (using the standard assay) 50 copies/ml (using ultrasensitive assay) When optimal response to therapy is achieved, the CD4 cell count rises ( cells) within the first year. The CD4 cell response may lag behind the virological response in timing and at times the two responses may even be discordant. Thus, even if there is no increase of CD4 cells, but a clear reduction of viral load, the treatment should be continued. In general, viral load is a better marker of monitoring ART. however, as indicated above viral load is optional in resource-limited settings such as Ethiopia. 3. Laboratory monitoring for intolerance of ART Complete Blood Count Tests of liver function Tests of kidney function Complete urinalysis Serum amylase Serum triglycerides Blood glucose If no modem biological measurements available WHO recommends clinical criteria for monitoring repose to ART. Moreover, availability of simple low-cost CD4 technologies at central and provincial levels in resource-limited settings is recommended. Clinical monitoring is essential for the provision of safe and effective ARV therapy. Where laboratory monitoring is limited, close clinical monitoring becomes even more crucial. V. REASONS FOR CHANGING ART AND CHOICE OF SECOND LINE ANTIRETROVIRAL REGIMEN 1.Reasons for Changing ART The goal of ART is to reduce viremia as low as possible for as long as possible, preferably using antiretroviral regimen that preserve future options. are relatively free of side effects, and are tailored to individual patient needs for adherence. There are multiple reasons for temporary or permanent interruption of ART. If there is a need to discontinue any antiretroviral medication, care-providers and patients should be aware of the advantage of stopping all antiretroviral agents simultaneously, rather that continuing one or two agents, to minimize the emergence of resistant viral strains. The following are the commonest reasons to discontinue ART: Rx failure Toxicity 24

23 Intolerance leading to poor adherence a. Treatment Failure Definitions: there may be clinical failure, immunologic failure and/or virologic failure: Clinical failure: clinical disease progression with development of an OI or malignancy when the drugs have been given sufficient time to induce a protective degree of immune restoration. This has to be differentiated from immune reconstitution syndrome, which can be seen within the first several weeks after initiating ART, if a subclinical infection is present at baseline. Immunologic failure: a fall in TLC or CD4 counts higher than 30% from the peak value or a return to, or below, the pre-treatment baseline. Virologic failure: repeated, continued detectable viremia is indicative of incomplete viral suppression. Virologically failure of a regimen is considered when there is: - Failure of viral load to become undetectable - Reappearance of detectable virus after a period of undetectability - Return of viral load to baseline levels or higher - Less than a 10-fold decrease (one log) from baseline viral load receiving potent treatment after 8-12 weeks of therapy Since facilities that can determine immunologic and virologic failure are not normally available in resource-limited settings, it is recommended that programs in such settings should primarily use clinical and, where possible, CD4 count criteria to define treatment failure. Failure of a regimen may occur for many reasons, including initial resistance to one or more agents, altered absorption or metabolism of the drug, multi-drug pharrnacokinetics that adversely affect therapeutic drug levels, and poor patient adherence to a regimen. Studies indicate that drug toxicity accounts for 30% to 50% of regimen changes, and virologic failure accounts for most of the rest. The causes for virologic failure are lack of adherence: reduced potency of the regimen; pharmacologic failure due to reduced drug delivery to the site of infection (due to absorption, protein binding, and drug interactions); and resistance. In general most of the failures in the first 24 weeks of treatment using recommended HAART regimens in treatment-naïve patients, is due to lack of adherence or inadequate potency, and most late failures that follow good virologic response are due to resistance. As with initiation of ART, the decision to change regimens should be approached with careful consideration of several complex factors. These factors include: recent clinical history and physical examination; plasma HIV RNA levels measured on two separate occasions; absolute CD4+ T lymphocyte count and changes in these counts; assessment of adherence to medications; remaining treatment options; potential resistance patterns from prior antiretroviral therapies; and preparation of the patient for the implications of the new regimen which include side effects, drug interactions, dietary requirements and possible need to alter concomitant medications. Mental health disorders in HIV patients should also be looked into, since they jeopardize drug compliance. In resource-limited 25