Guidelines to Antiretroviral Drug Therapy in Kenya

Table of Contents
Guidelines to Antiretroviral Drug Therapy in Kenya......................................................................................1 FOREWORD..........................................................................................................................................1 ACKNOWLEDGMENT ............................................................................................................................2 CHAPTER ONE: INITIATING ANTIRETROVIRAL THERAPY...............................................................3 1.1 Introduction................................................................................................................................3 1.2 Guidelines to making a diagnosis of HIV infection.....................................................................5 1.3 Laboratory Diagnosis of HIV infection........................................................................................6 1.4 Goals of therapy.........................................................................................................................6 1.5 When to start therapy.................................................................................................................6 1.6 Risks and benefits of delayed initiation of therapy and of early therapy in the Asymptomatic HIVInfected Patient ................................................................................................................8 . 1.7 Antiretroviral profile....................................................................................................................8 1.8 What drug combination to start with?.......................................................................................10 CHAPTER TWO: MONITORING AND CHANGING THERAPY...........................................................12 2.1 Surrogate markers...................................................................................................................12 2.2 Resistance testing....................................................................................................................13 2.3 How often should CD4 Cell Count and Viral Load be performed (Frequency)........................13 . 2.4 Treatment failure......................................................................................................................13 2.5 Reasons for nonadherence ....................................................................................................14 2.6 Considerations for changing a failing regimen.........................................................................14 2.7 Guidelines for changing an antiretroviral regimen for suspected drug failure..........................15 2.8 Potential options for changing therapy*...................................................................................15 CHAPTER THREE: PHARMACOTHERAPEUTICS OF ARVS............................................................17 3.1 Characteristics of available antiretroviral drugs.......................................................................17 3.2 Pharmacokinetic properties of Antiretrovirals ...........................................................................20 CHAPTER FOUR: GUIDELINES FOR THE USE OF ANTIRETROVIRAL DRUGS IN PAEDIATRIC HIV INFECTION ............................................................................................................21 4.1 Overview..................................................................................................................................22 4.2 Diagnosis of HIV infection in children .......................................................................................22 4.3 When to initiate treatment........................................................................................................22 4.4 Initiation of treatment ...............................................................................................................23 . 4.5 Agents to choose for initial treatment.......................................................................................23 4.6 Dosages for paediatric formulations .........................................................................................23 4.8 Monitoring................................................................................................................................25 4.9 When to change therapy..........................................................................................................25 CHAPTER FIVE: MANAGEMENT OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTED PREGNANT WOMEN AND PREVENTION OF MOTHER TO CHILD TRANSMISSION (MTCT) OF HIV .................................................................................................................................................26 5.1 Overview..................................................................................................................................26 5.2 Factors affecting mother to child transmission.........................................................................26 5.3 Outline antenatal, intrapartum postpartum and postnatal care................................................27 5.4 Antiretroviral Therapy to prevent MTCT...................................................................................28 CHAPTER SIX: SPECIAL CONSIDERATIONS...................................................................................28 6.1 Acute retroviral syndrome (ARVS)...........................................................................................28 6.2 ARV drugs and the treatment of Tuberculosis.........................................................................29 6.3 Immune recovery syndrome .....................................................................................................29 CHAPTER SEVEN: WHEN TO STOP TREATMENT (INTERRUPTIONS)..........................................30 7.1 Structured treatment interruptions (STI's)................................................................................30 7.2 Non structured treatment interruption......................................................................................31 CHAPTER EIGHT: GUIDELINES FOR POST EXPOSURE PROPHYLAXIS......................................31 8.1 Treatment of exposure sites .....................................................................................................31 8.2 Timing of post HIV exposure prophylaxis initiation...............................................................31 8.3 Assessment of exposure risk...................................................................................................31 8.4 Post HIV exposure prophylaxis.............................................................................................32 8.5 Recommended HIV serology after exposure...........................................................................32 8.6 Management of health care workers with accidental exposure to HIV infection......................32 8.7 Management of hospital staff with sharp injury or exposure to blood and body fluids.............34 8.8 Management of non occupational exposure to HIV infection...................................................34 8.9 Management of nonsexual and non occupational Exposures to HIV .....................................35 CHAPTER NINE: ACCESS TO DRUGS IN KENYA............................................................................36

Table of Contents
Guidelines to Antiretroviral Drug Therapy in Kenya APPENDICES .......................................................................................................................................36 I. Drug to drug interactions.............................................................................................................36 II. Drug to drug interactions (continued).........................................................................................37 III. Drug Interactions Between Antiretrovirals and Other Drugs.....................................................38 IV. Nucleoside Reverse Transcriptase Inhibitors (NRTIS).............................................................39 V. Drug Interactions: Protease Inhibitors.......................................................................................40 VI. Drug Interactions: Protease Inhibitors and NonNucleoside Reverse Transcriptase Inhibitors Cont.....................................................................................................................40 VII. Drug That Should Not be Used With Antiretrovirals................................................................41 VIII. Drugs that should not be used with Protease Inhibitors Antiretrovirals..................................42 IX. HIVrelated drugs with overlapping toxicities...........................................................................43 X. Antiretroviral therapy for preventing MTCT ..............................................................................43 BACK COVER......................................................................................................................................44

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Guidelines to Antiretroviral Drug Therapy in Kenya

Enquiries regarding these Clinical Guidelines should be addressed to: Director National Aids and STD Control Programme (NASCOP) Ministry of Health P.O. Box 19361 Nairobi, Kenya Telephone: +254 2 719502/729549 Email: headnascop@iconnect.co.ke NOTES ON DRUG DOSAGES Every effort has been made to ensure that drug dosages and treatment schedules are correct and in accordance with current accepted medical practice. However, no responsibility can be taken for errors or omissions. When using an unfamiliar drug, clinicians are urged to confirm dosages before prescribing or administering the drug. Ist edition February 2001 Copyright ' 2001, Ministry of Health, Government of Kenya EDITORS Dr. Chebet K.L. Prof. Lule G.N. NASCOP University of Nairobi

OTHER EDITORIAL TEAM MEMBERS Dr. Aluoch. A Dr. Hardika. S Dr. Mbori Ngacha Dr. Mohammed. I. M Dr. Muia Ndavi Nairobi Hospital Nairobi Hospital University of Nairobi NASCOP University of Nairobi

Correct Citation National Aids and STD Control Programme. 2001 Clinical Guidelines on antiretroviral Therapy. NASCOP, Nairobi.

FOREWORD
Acquired Immune Deficiency Syndrome (AIDS) is a rapidly growing public health problem in Kenya. In less than a decade, AIDS has evolved from a fulminant, rapidly fatal illness into a chronic disease. Already more than 2 million are estimated to have been infected in Kenya as from 1985 when the first case of AIDS was recognized. The Guidelines are meant for the use of trained clinicians who have primary responsibility for treatment of HIV/AIDS patients. The mainstay of managing HIV/AIDS epidemic is prevention and advocacy for behaviour change. However, Kenya hospitals continue to offer care to many patients who occupy beds for long with recurrent complications. Currently drugs for opportunistic infections are provided in public hospitals including antiTB drugs. With advancing technology new powerful antiretroviral drugs regimens have become available and now form part of total continuum care of HIV/AIDS patients.

Proper use of these drugs, and monitoring will require capacity building of staff hence need for standard treatment protocols for providing the highest quality and most costeffective health care. With the publication of these Guidelines to antiretroviral drug therapy, the Ministry is establishing standard regimens for antiviral drug use and monitoring of patients. The manual is the result of considerable collective effort of senior clinicians and pharmacists from the Ministry of Health, the University of Nairobi and private hospitals. It is hoped that these stakeholders will participate in training of doctors and nurses in rural hospitals where many AIDS patients are hospitalized. Availability of retroviral drugs to Kenyans who need them is the subject of debate but no doubt the government will soon put in place legal framework to increase access to these drugs. These drugs will be used alongside priority advocacy for behaviour change at all levels in Kenya. The approach adopted by Kenya in the fight of Aids revolves around the sessional paper No. 4 of 1997 and the National Aids Control Strategy. Like most publications, the initial edition requires regular revisions and updates in terms of content and context.

DR. RICHARD O. MUGA, OGW, DSM, DIRECTOR OF MEDICAL SERVICES FEBRUARY, 2002

ACKNOWLEDGMENT
These guidelines are a result of the collaborative effort of many people, whose dedication and hard work is gratefully acknowledged. The alphabetical list of the main contributors are given below. Dr. Aluoch A. Dr. Anzala O. Prof. Bhatt K.M. Dr. Chebet K.L. Dr. Hardika Shah Dr. Ilako, F Dr. Karanja Joseph Dr. Kevin DeCock Prof. Kokwaro, Gilbert Dr. Koskei K. Prof. Lule G.N. Dr. Lwanga Charles Prof. Mati J.K.G Kenya Association of Physicians University of Nairobi University of Nairobi NASCOP Ministry of Health Nairobi Hospital Kenya Association of Physicians University of Nairobi CDC Director (Kenya) Wellcome Trust Chief Pharmacist Ministry of Health University of Nairobi Nairobi Hospital KOGS

Dr. D. Mbori Ngacha Dr. Mohammed I.M. Dr. Mugo Nelly Dr. Muita Jane Dr. Mulindi Sobbie Prof. Musoke Rachel Dr. Mutungi Alice Dr. Mwangi Margaret Dr. Nduati Ruth Dr. Ochiel Stephen Prof. Ojwang S.B.O. Dr. Ombuya Godfrey Dr. Omondi Ogutu Prof. Otieno L.S. Dr. Owili D. Dr. P. Muia Ndavi Dr. Patel S.T. Dr. Qureshi Zahinda Dr. Shah Sital Dr. Tesfaldet G. Dr. Wairagu S.E. Dr. Were Edwin

University of Nairobi NASCOP Ministry of Health Kenyatta National Hospital UNICEF University of Nairobi University of Nairobi University of Nairobi Kenyatta University Hospital University of Nairobi KOGS University of Nairobi Kenyatta National Hospital Kenyatta National Hospital University of Nairobi Aga Khan Hospital KOGS MP Shah University of Nairobi Aga Khan Hospital Aga Khan Hospital Kenyatta National Hospital Moi University

The Director of Medical Services, Dr. Richard Muga, and Director NASCOP Dr. Kenneth Chebet facilitated the harmonization of the various guidelines into one. Further appreciation goes to Dr. M.S. Abdallah, Chairman, and Dr. M. Gachara, Director, National AIDS Control Council for their support to this project. The Ministry of Health gratefully acknowledges the financial assistance from joint United Nations Programme on HIV/AIDS (UNAIDS) and WHO which facilitated the writing, editing, printing and implementation of the guidelines. A special appreciation is extended to Dr. Warren Naamara (UNAIDS), Dr. Marinus Gotink (UNICEF) Dr. Peter Eriki (WHO) and Mr. Andrew Stenton (Nairobi Hospital) for their invaluable contribution.

CHAPTER ONE: INITIATING ANTIRETROVIRAL THERAPY

1.1 Introduction The Human immunodeficiency virus (HIV) is an RNA retro virus existing in two forms: HIV 1 which is the commonest cause of infections, while HIV 2 is confined to certain parts of West Africa. HIV infection is transmitted through:

 Sexual contact Inoculation with infected blood/blood products Use of contaminated needles Vertical transmission from mother to child.

Infection with HIV 1 results in a progressive destruction of the CD4 lymphocytes, and the rate of CD4 T cell decline, determines the rate of immunodeficiency and subsequent development of HIV related opportunistic infections. The destruction of T cell is due mainly to active viral replication. Using the average time taken for development of acquired immunodeficiency syndrome (AIDS) following HIV infection, people can be broadly categorized as follows: "Average developer" who develop AIDS within approximately 10 years. The "rapid developers" (approximately 20% of all cases) who develop AIDS within 5 years following infection. The "slow developers" (approximately 5% of all cases) who remain asymptomatic for over 10 years without a significant decline in CD4 T cell count.

There is now sufficient evidence that triple combination antiretroviral therapy reduce viral load plasma level to undetectable levels. HIV related symptoms may disappear, the incidence of opportunistic infections is reduced and quality of life improves as illustrated in the following two graphs:

NATURAL HISTORY OF UNTREATED HIV 1 INFECTION

Mortality in patients with CD4<100 and use of antiretroviral (ARV) therapy including a protease inhibitor among those patients, USA 19941997 Source: Palella et al., New England Journal of Medicene 1998 Mar 26; 33860

The majority of people infected with HIV in the developing world have no access to the antiretroviral treatment. Access to antiretroviral treatment must be seen from a more comprehensive outlook of total continuation of care of HIV/AIDS patients. The Kenyan Health worker has an obligation to provide care, which should be continuous starting from hospital to the community. There should be active participation of doctors, volunteers, nurses, patients and their relatives. Educational programmes for physicians and general practitioners committed to HIV/AIDS care aim at avoiding unnecessary or inadequate therapeutic prescriptions. The guidelines provide information on antiretroviral therapy including when to start treatment, what drugs to initiate, when to change therapy and therapeutic options to consider when changing therapy. Laboratory monitoring including HIV, RNA, CID4T cell counts and clinical assessment on early diagnosis, choice of combination for antiretroviral management of acute HIV/AIDS, HIV/AIDS infected pregnant women and children, post exposure prophylaxis and structured interrupted treatments are indicated. It is meant to serve as a guide to antiretroviral treatment and we anticipate that these guidelines will trigger development of innovative approaches to better management of patients with HIV/ AIDS in Kenya.

1.2 Guidelines to making a diagnosis of HIV infection 1.2.1 Pretest and Post Test Counselling HIV infection in asymptomatic individuals is often made as a result of a test solicited for routine medical examination required by employers, insurance schemes, or for travel purposes. In symptomatic patients an HIV diagnosis may be made as part of the medical workup for the patient. All patients undergoing an HIV test should do so after adequate pretest counseling where they are informed of the nature of the test and the meaning and consequences of a positive test. Posttest counseling should form an integral part of the process of giving back HIV test results. 1.2.2 Clinical Staging All clients/patients identified to be HIV seropositive should be given the opportunity for ongoing counseling and support. For purposes of clinical management, all individuals diagnosed, as HIV+ should classified according to disease stage as follows:

 Acute seroconversion syndrome Asymptomatic HIV infection Symptomatic HIV disease

1.3 Laboratory Diagnosis of HIV infection Laboratory testing for the diagnosis of HIV infection can be divided into four main categories: Antibody detection Antigen detection Testing for viral nucleic acid (RNA or PRO DNA) Culturing for the virus

Elisa antibody detection is the serological screening test used often to detect HIV Infection. Third generation ELISA's, which use recombinant antigens, are highly specific and highly sensitive. It is therefore recommended that for laboratory diagnosis of HIV infection, two ELISA'S for antibody detection should be done, one for screening and the other for confirmation. The two have to be positive for one to make a laboratory diagnosis of HIV 1 infection. In the event that one ELISA is positive and another negative, testing for viral nucleic acid (polymorase chain reaction PCR) can be used for confirmation of the serostatus or Western blot assays.

1.4 Goals of therapy The primary goals of antiretroviral therapy are maximal and durable suppression of plasma viral load, preservation and/or restoration of immunologic function, improvement of quality of life and reduction of HIV related morbidity and mortality. Clinical benefit has been demonstrated in controlled trials only for patients with CD4+T cells <200/mm3. However, most experts would offer therapy at a CD4+T cell threshold <350/mm. All decisions to initiate therapy should be based on prognosis for diseasefree survival in the absence of treatment, as determined by the CD4+ cell count and level of plasma HIV RNA shown in Table 5, the potential benefits and risks of therapy shown in Table 4, and the willingness of the patient to accept therapy.

Goals of HIV Therapy and Tools to achieve them Goals of therapy Maximal and durable suppression of Viral load. Restoration and/or preservation of immunologic function. Improvement of quality of life. Reduction of HIV related morbidity and mortality.

Tools to Achieve Goals of Therapy Maximum adherence to the antiretroviral regimen Rational sequencing of drugs Preserving future treatment options. Use of resistance testing in selected Clinical settings where possible.

1.5 When to start therapy The decision to start therapy should be made after considering the patient's acceptance or readiness and the probability of adherence. The strength of the recommendation is dependant on the prognosis as determined

by clinical state, CD4 cell count and viral burden. Table showing when to start therapy. Indication for the initiation of Antiretroviral Therapy in the Chronically HIV1 infected patient Clinical Category Symptomatic (AIDS, Severe symptoms) Asymptomatic AIDS, Asymptomatic CD4+ Cell Count Any Value CD4+ cells<200/mm3 CD4+ cells>200/mm3 but < 350/mm3 CD4+T cells >350/mm3 Plasma HIV RNA Any Value Any Value Any Value Recommendation Treat Treat Treatment should generally be offered, though controversy exists Some experts would recommend initiating therapy, recognizing that the 3 year risk of developing AIDS in untreated patients is >30%. In the absence of very high levels of plasma HIV RNA, some would defer therapy and monitor the CD4 + cell count and level of plasma HIV RNA more frequently. Clinical outcomes data after initiating therapy are lacking.

Asymptomatic

>30,000(bDNA) or >55,000(RTPCR)

In resource poor setting, initation for symptomatic patients can be started even when CD4 or viral load assessment tools are absent. The two assessments tests are, however, useful for monitoring therapy. Initiating Therapy in established HIV infection Before initiating therapy in any individual the following basic evaluation should be performed Complete history and physical examination Total blood count, Urea and electrolytes and liver function tests. CD4 (Tlymphocyte count) Viral load (Plasma HIV RNA)

Additional investigations should be targeted towards establishing factors leading to symptomatology including common opportunistic infections such as Tuberculosis, Cryptococcal Meningitis and Atypical pneumonia's. It may also be advantageous to follow lipid profiles in most patients on antiretroviral therapy. Initiating Therapy in Patients with Asymptomatic HIV infection This is still controversial. A few facts however are well known: If the CD4 count falls below 200 then one is bound to suffer increasing incidences of opportunistic infections Although there is theoretical benefit to antiretroviral therapy for patients with CD4T cell counts greater than 200 cells/m3, no studies have been conducted to compare immediate against delayed potent therapy. The optimal time to initiate antiretroviral therapy is not known.

One should therefore weigh the risks and benefits of delayed and early therapy and discuss them fully with the patient before initiating therapy. These risks and benefits are as outlined in the table.

1.6 Risks and benefits of delayed initiation of therapy and of early therapy in the Asymptomatic HIVInfected Patient Risks and benefits of early therapy Benefits of early therapy Control of viral replication easier to achieve and maintain Delay or prevention of immune system compromise. Lower risk of resistance with complete viral suppression. Possible decreased risk of HIV transmission

Risks of early therapy Greater cumulative drugrelated adverse affects. Earlier development of drug resistance, if viral suppression is suboptimal. Limitation of future antiretroviral treatment options.

Risks and benefits of delayed therapy Benefits of delayed therapy Avoid negative effects on quality of life (i.e., inconvenience) Avoid drugrelated adverse effects. Delay in development of drug resistance Preserve maximum number of available and future drug options when HIV disease risk is highest.

Risks of delayed therapy Possible risk of irreversible immune system depletion Possible greater difficulty in suppressing viral replication Possible increased risk of HIV transmission It is important to note that the risk of viral transmission still exists, and antiretroviral therapy cannot substitute for primary HIV prevention measures (e.g. Abstinace, faithfulness, condoms and safer sex practices).

1.7 Antiretroviral profile The gold standard of antiretroviral therapy is HAART. What is HAART? Highly Active Antiretroviral Therapy is a combination of three or more antiretroviral drugs in the treatment of HIV infection. These antiretroviral drugs fall in three different classes and work at different sites on the HIV virus. Nucleoside analogue Reverse Transcriptase Inhibitors (NRTIs) The first effective class of antiretroviral, drugs was the nucleoside analogues. They act by incorporating themselves into the DNA of the virus thereby stopping the building process. The resulting DNA is incomplete.

Name and class of drug Nucleoside analogue Reverse Transcriptase Inhibitors (NRTIs) Zidovudine (AZT)** Didanosine (ddl)** Lamivudine (3TC)** Stavudine (d4T)**

Strength of preparation Adult Dosing

Capsules, 100mg Tablets, 100mg, 25mg Tablets, 150mg Capsules, 40mg Capsules, 30mg

250300mg BID 100200mg BD 150mg BID 40mg BID 30mg BID 0.75mg TO 300mg BD

Zalcitabine (ddC) Abacavir (ABC) NonNucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Tablets, 0.75mg Capsules, 300mg

The second class of antiretroviral drugs are the NonNucleoside Reverse Transcriptase Inhibitors (NNRTIs) which stop HIV production by binding directly onto reverse transcriptase preventing the conversion of RNA to DNA. These drugs are called nonnucleoside inhibitors because even though they work at the same stage as nucleoside analogues, they act in a completely different way. NonNucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz (EFZ) Nevirapine (NVP) Delavirdine (DLV) Protease Inhibitors The last class of antiretroviral drugs are the Protease Inhibitors which work at the last stage of the virus reproduction cycle. They prevent HIV virus from being successfully assembled and released the infected cell. Protease Inhibitors Saquinavir hard gel (SQV) Saquinavir soft gel (SQV) Ritonavir** (RTV) Indinavir (IDV) Nelfinavir** (NFV) Amprenavir^ (AMV) Lopinavir + Ritonavir^ Capsules, 200mg Capsules, 200mg Capsules, 100mg Capsules, 200mg Tablets, 250mg Tablets, 300mg Capsules (13.3mg Lopinavir + 33.3mg Ritonavir). 600Jmg TID 1200mg TID 600mg BD 800mg TID 1250mg BD or 750mg TDS 1200mg BD 400mg Lopinavir + 100mg Ritovavir BD Capsules, 200mg Tablets, 200mg Capsules, 100mg 600mg OD 200mg BD 600mg BD

Drugs marked ^ are not currently available in Kenya and drugs marked ** are available in pediatrics formulations.

1.8 What drug combination to start with? Initiation of Therapy Leading Regimens to consider 2 Nucleoside RTI's + Protease Inhibitor NNRTI sparing

2 Nucleoside RTI's + NonNucleoside RTI PI sparing

3 Nucleoside RTI's (including abacavir) PI and NNRTI sparing

Advantages and disadvantages of class sparing regimens Regimen PI based HAART regimen (NNRTIsparing) Possible Advantages clinical, virologic, and mmunologic efficacy welldocumented. Continued benefits sometimes seen despite viral breakthrough. Resistance requires multiple mutations Targets HIV at two steps of viral replication (RT and PI) Sparing of PIrelated side effects Generally easier to use and adhere to compared with Pis Possible Disadvantages May be difficult to use and adhere to Longterm side effects may include lipodystrophy,* hyperlipidemia, and insulin resistance Drug Interaction Complications Mild to severe inhibition of cytochrome P450 pathway; Ritonavir is most potent inhibitor, but this effect can exploited to boost levels of other Pis Impact on future Options Preserves NNRTI for use in treatment failure Resistance primes for crossresistance with other Pis

NNRTIsbased HAART regimen (PIsparing)

Comparability to PIcontaining regimens with regard to clinical endpoints unknown Resistance Conferred by single or few mutations Compatibility to PIcontaining regimens with regard to clinical endpoints unknown Longterm virologic efficacy with high baseline plasma vital load (i.e.,> 100 000 copies/ml may be suboptimal

Fewer drugdrug interactions Pis

Preserves Pis for later use Resistance usually leads to cross resistance across entire NNRTI class Preserves both PI and NNRTI classes for later use Limited crossresistance within the NRTI class

Triple NRTI Regimen (NNRTI and PIsparing)

Generally easier to Use and adhere to compared with PIs Sparing of PI and NNRTI side effects Resistance to 1 NRTI does not confer crossresistance to entire class

Generally manageable drug interaction problems

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 Some side effects being attributed to protease inhibitor therapy, such as lipodystrophy, have not been proven to be strictly associated with use of protease inhibitorcontaining regimens. Lipodystrophy has also been discerened uncommonly in patients on NRTIs alone and patients on other antiretroviral therapy. Possible first line Regimen for Adults (with substitutions) Zidovudine/Lamivudine/Nelfinavir (or LPV or Indinavir) Stavudine for Zidovudine (in case of toxicity)

Zidovudine/Lamivudine/Efavirenz (or Nevirapine) Stavudine for Zidovudine (in case of toxicity)

Zidovudine/Lamivudine/Abacavir Stavudine for Zidovudine (in case of toxicity)

Stavudine, Didanosine, Efavirenz Stavudine, Lamivudine, Nelfinavir Stavudine, Didanosine, Nevirapine The choice of regimen should take consideration of patient's affordability, drug potency and other factors detailed in this book. There is an interim WHO ARV Treatment Working Group drafting guidelines for Resource Poor Settings. Kenya is a member of the steering team and the recommended 1st line drugs will be indicated in the 2nd Edition of this booklet. The following table of recommendations is based on IAS and DHHS guidelines for antiretroviral therapy. Antiretroviral drug regimens are comprised of one choice each from column A and B. Drugs are listed in alphabetical and not in priority order. Strongly recommended Column A Efavirenz Indinavir Nelfinavir Ritonavir + Indinavir Ritonavir + Lopinavir Ritonavir + Saquinavir Recommended as alternatives Column A Abacavir Column B Column B Stavudine + Didanosine Stavudine + Lamivudine Zidovudine + Didanosine

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Didanosine + Lamivudine Amprenavir Delarvidine Nelfinavir + Saquinavir Ritonavir Saquinavir No recommendation/ insufficient data Hyroxyurea in combination with antiretroviral drugs Ritonavir + Amprenavir. Ritonavir + Nelfinavir Not recommended/should not be offered All monotherapies whether from column A or B including Hydroxyurea Column A Saquinavir (Invirase) except with Ritonavir Column B Stavudine + Zidovudine Zalcitabine + Didanosine Zalcitabine + Lamivudine Zalcitabine + Stavudine Zidovudine + Zalcitabine

CHAPTER TWO: MONITORING AND CHANGING THERAPY

2.1 Surrogate markers CD4 + Lymphocytes CD4 cells, also known as Helper Tcells, are a type of lymphocytes which play an important role in immune system. They control both arms of the immune system (humoral and cellular).HIVI infection targets these CD4 cells resulting in killing of those infected as well as those not yet infected. The CD4 cell count is a laboratory marker of the strength of one's immune system. Normal CD4 counts in adults range from 5001800 cells per cubic millimeter of volume. In HIV1 infection, CD4 cell count is used to determine the progress of HIV disease i.e. (staging) and predicts the risk of developing complications. Viral Load: Viral burden in peripheral blood can be determined by using quantitative HIV RNA assays. During the period of primary infection in adults, HIV RNA copies initially rise to high levels. Coincident with the body's humoral and cellmediated immune response, RNA levels decline. Several studies conducted among adults have indicated that infected persons with lower HIV copy number have slower progression and improved survival compared with those with high HIV RNA copy numbers. On the basis of such data, recommendations for the use of HIV RNA copy number in deciding to initiate and change antiretroviral therapy in infected adults have been developed.

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2.2 Resistance testing In the majority of patients who have never received antiretroviral therapy, the wild type, or nonmutant virus predominates. During therapy the disappearance or suppression of wildtype virus creates the environment in which the mutant virus can become the dominant species. The degree of suppression provided by a treatment regime is therefore, a critical factor in the emergence of HIV drug resistance. Resistance assays may assist clinicians in individualizing initial as well as subsequent antiretroviral treatment regimens for their patients. Resistance testing is recommended for persons on antiretroviral treatment whose viral is increasing and CD4 cell count is declining. Many studies in patients on treatment have shown strong associations between the presence of drug resistance and failure of the antiretroviral therapy. There are mainly 2 types of resistance testing which unfortunately are not yet readily available in Kenya. Genotypic Assays These detect drug resistance mutations that are present in the relevant viral genes. They may involve sequencing of the entire RI and Protease genes while others go for selected mutations that are known to confer drug resistance. Phenotyping Assays These assays measure the ability of viruses to grow in various concentrations of antiretroviral drugs. Although available they are more expensive and time consuming to perform. In general resistance testing may be useful in the setting of virologic failure of antiretroviral therapy or in acute HIV infection.

2.3 How often should CD4 Cell Count and Viral Load be performed (Frequency) A CD4 cell count and viral load titer are obtained as part of a baseline laboratory data when initial diagnosis of HIV infection is made or prior to the initiation of antiretroviral drugs. Both tests should be repeated about four weeks after starting antiretroviral therapy. If the regimen is maintained, the tests for CD4 count and viral load titer should be performed every three moths thereafter along with other laboratory studies (Full Haemogram, U/E, and LFTs)

2.4 Treatment failure Virologic Failure Failure to reduce the viral load to an undetectable level or Failure to reduce the viral load by at least 2 to 2.5 log 10 or A persistent increase in viral load following a period of adequate suppression. Immunologic Failure Failure to restore the CD4 count to more than 200 cells/mm3 or Failure to significantly increase CD4cell count or A persistent decline in CD4cell counts after a period of immune reconstruction. Clinical Failure Development of new opportunistic infections, wasting, or dementia or Failure to resolve pretreatment opportunistic infections, wasting, or dementia. ARV Failure: Causes

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i) Patient Factors Adherence failure

ii) Clinical Factors Patient selection

iii) Viral Factors Resistance

2.5 Reasons for nonadherence just forgetting Regimen complexity Side effects Substance abuse Fear of medications Denial of need for treatment

2.6 Considerations for changing a failing regimen As with the initiation of antiretroviral therapy, 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 CD4T lymphocyte count and changes in these counts. Other factors that influence decisions include remaining treatment options in terms of potency, potential resistance patterns from prior antiretroviral therapies and potential for compliance/tolerance; assessment of adherence to medications; and preparation of the patient for the implications of the new regimen. Failure of a regimen may occur for many reasons, including initial viral resistance to one or more agents, altered absorption or metabolism of the drug, multidrug pharmacokinetics that adversely affects therapeutic drug levels, and poor patient adherence to a regimen due to either poor compliance or inadequate patient education about the therapeutic agents. In this regard, it is important to carefully assess patient compliance prior to changing antiretroviral therapy. It is important to distinguish between the need to change therapy due to drug failure versus drug toxicity. In the latter case, it is appropriate to substitute one or more alternative drugs of the same potency and from the same class of agents as the agent suspected to be causing the toxicity. In the case of drug failure where more than one drug had been used, A detailed history of current and past antiretroviral medications, as well as other HIV related medications, should be obtained. Optimally and when possible, the regimen should be changed entirely to drugs that have not been taken previously. With triple combinations of drugs, at least two and preferably three new drugs should be selected that are not subject to anticipated crossresistance to drugs given previously; this is based on the current understanding of strategies to prevent drug resistance. Viral resistance to antiretroviral drugs is an important, but not the only, reason for treatment failure. Genetically distinct viral variants emerge in each HIVrelated individual over time after initial infection. Viruses with single drug resistance mutations exist even prior to therapy. VIROLOGIC CONSIDERATION FOR CHANGING THERAPY Ideally, antiretroviral therapy should maximally suppress viral replication to below levels capable of being detected with HIV RNA assays.

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Consensus recommendations have been developed using plasma HIV RNA measurements to guide changes in antiretroviral therapy for HIV infected adults. Consider changing therapy if: a) HIV RNA levels drop less than tenfold (I log) after 8 weeks of therapy. b) HIV RNA has not decreased to undetectable levels after 46 months of therapy.

IMMUNOLOGIC CONSIDERATION FOR CHANGING THERAPY CD4 + lymphocyte count and percentage are independent predictors of disease progression. Normal CD4 counts in adults in Kenya range from 5001800 cells per millimeter of volume. Consider changing antiretroviral therapy if there is a rapid and substantial decrease in absolute CD4 + lymphocyte count (a> 30% decline in < 6 months).

2.7 Guidelines for changing an antiretroviral regimen for suspected drug failure Criteria for changing therapy include a suboptimal reduction in plasma viremia after initiation of therapy, reappearance of viremia after suppression to undetectable, significant increases in plasma viremia from the nadir of suppression, and declining CD4+T cell numbers. When the decision to change therapy is based on viral load determination, it is, preferable to confirm with a second viral load test. Distinguish between the need to change regimen due to drug intolerance or inability to comply with the regimen versus failure to achieve the goal of sustained viral suppression; single agents can be changed or dose reduced in the event of drug intolerance. In general, do not change a single drug or add a single drug to a failing regimen; it is important to use at least two new drugs and preferably to use an entirely new regimen with at lease three new drugs. Many patients have limited options for new regimens of desired potency; in some of these cases it is rational to continue the prior regimen if partial viral suppression was achieved. In some cases, regimens identified as suboptimal for initial therapy are rational due to limitations imposed by toxicity, intolerance or noadherence. This especially applies in late stage disease. For patients with no rational alternative options who have virologic failure with return of viral load baseline (pretreatment levels) and declining CD4+T cell count, there should be consideration for discontinuation of antiretroviral therapy. Experience is limited with regimens using combinations of two protease inhibitors or combinations of protease inhibitors with Nevirapine and Delavirdine; for patient with limited options.

2.8 Potential options for changing therapy* Reasons for change Toxicity or intolerance HIV RNA suppressed below target HIV RNA suppressed but still above target And fewer than 816 weeks with therapy. HIV RNA above target, more than 816 weeks Difficulty with adherence HIV RNA suppressed below target, but adherence problems present HIV RNA above target, more than 816 weeks with therapy. HIV RNA above target, more than 816 weeks with therapy or prior successes. Change Change the offending drug (if discernible) Change offending drug if discernible Change entire regimen Change to simplified regimen with equal potency; substitute single drug if known Change to simplified regimen with equal potency substitute single drug if known. Change entire regimen

15

Virologic failure adherence, Failure to reach target viral load within adherence 816, weeks of therapy

Continue current regimen, assess consider intensification.

Failure to reach target viral load within 2436 weeks Change entire regime of therapy Prior success but now confirmed drug faiture. Change entire regime

Possible Regimens for patients who have failed initial Antiretroviral Therapy: Possible Second line Regimens for Treatment Failure Following AZT/3TC/NFV d4T/ddl/EFZ or d4T/ddl/LPV or d4T/ddl/IDV

Following AZT/3TC/EFZ(or NVP) d4T/ddl/NFV or d4T/ddl/LPV,

Following AZT/3TC/NFV d4T/ddl/EFZ or d4T/ddl/LPV or d4T/ddl/IDV

Prior Regimen 2 NRTIs + Nelfinavir Ritonavir Indinavir

New Regimen (Not listed in priority order) 2 new NRTIs RTV; IDV; or SQV + RTV; or NNRTI + RTV; or NNRTI ID** SQV + RTV**; NFV + NNRTI; or NFV + SQV SQV + RTV; NFV + SQV

Saquinavir RTV + SQV; OR NNRTI + IDV RTV + IDV 2 NRTIs + NNRTI 2 NRTIs 2 new NRTIs + a protease inhibitor 2 new NRTIs + a protease inhibitor 2 new NRTIs + RTV + SQV 1 new NRTI + 1 NNRTI + a protease inhibitor 2 protease inhibitors + NNRTI 1 NRTI 2 new NRTIs + a protease inhibitor 2 new NRTIs + NNRTI 1 new NRTI + 1 NNRTI + a protease inhibitor These alternative combinations are still being studied in clinical trials and will be amended as more information is published.

16

CHAPTER THREE: PHARMACOTHERAPEUTICS OF ARVS

3.1 Characteristics of available antiretroviral drugs Currently, there are three classes of drugs used in the management of HIV infected patients. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) include Abacavir, Didanosine, Lamivudine, Stavudine, Zalcitabine and Zidovudine. The NonNucleoside Reverse Transcriptase Inhibitors (NNRTIs) include Efavirenz, Nevirapine, and Delarvidine. Protease Inhibitors including Saquinavir, Ritonavir, Indinavir, Amprenavir, Nelfinavir, and a combination of Lopinavir and Ritonavir. Patients who have been offered antiretroviral treatment should be managed with a maximally suppressive regimen (e.g. two NNRTIs and a PI). Clinical issues such as drug toxicity, ability to adhere to treatment regimens, drug interactions and laboratory abnormalities should be considered when initiating therapy and during treatment. As most patients will be multiple drug therapy, the clinician should be alert to the potential for multiple drug interactions. Thus, the choice of which antiretroviral agent to use must be made with consideration given to potential drug interactions and overlapping drug toxicities. Other issues to be considered are factors such as wasting and anorexia which may prevent patients from adhering to dietary requirements for efficient absorption of certain protease inhibitors. Bone marrow suppression associated with AZT and the neuropathic effects of ddC, d4T, and ddl may combine with the direct effects of HIV to render the drugs intolerable. Hepatotoxicity associated with certain Pis may limit the use of these drugs, especially in patients who have underlying liver dysfunction. The absorption and halflife of certain drugs may be altered by anti retrovirals, particularly the Pis and NNRTIs whose metabolism involves the hepatic cytochrome P 450 (CYP450) enzyme pathway. Some of these Pis and NNRTIs (i.e. Ritonavir, Indinavir, Nelfinavir, and Delarvidine) inhibit the CYP450 pathway; others (e.g. Nevirapine) induce the CYP450 metabolism. CYP450 inhibitors have the potential to increase blood levels of drugs metabolized by this pathway. Adding a CYP40 inhibitor can sometimes improve the pharmacokinetic profile of selected agents (e.g. adding Ritonavir therapy to the hardgel formulation of Saquinavir) as well as contribute an additive antiviral effect; however, these interactions can also result in lifethreatening drug toxicities. As a result, healthcare providers should inform their patients of the need to discuss any new drugs, including overthe counter agents and alternative mediations, that they may consider taking, and careful attention should be given to the relative risk versus benefits of specific combinations of agents. I. Characteristics Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Nucleoside analogues Combivir (Lamivudine 150mg, Zidovudine 300mg) tablets (A) Stavudine, d4T, Zerit 30mg & 40mg Dose 1 tablet Frequency BD Dietary restrictions Major side effects Same as Lamivudine and Zidovudine Lab monitoring Liver function tests.

40mg for patients over 60kg; 30mg for

BD

Take without Pancreatitis. Peripheral regard to meals neuropathy. Lactic acidosis with hepatic

Liver function tests. Renal function tests

17

capsules (A)

patients under 60kg.

steatosis is a rare but potentially lifethreatening toxicity with use of NRTIs. TDS Do not take magnesium/ aluminum containing snack. Take without regard to meals. Peripheral neuropath. Stomatitis. Lactic acidosis with hepatic steatosis is a rare but potentially lifethreatening toxicity with NRTIs.

Complete blood count.

Zalcitabine, ddC, Hivid 0.75mg tablets (A) 0.375mg (NA)

0.75mg

Liver function tests. Complete blood count. Serum amylase levels for individuals at risk for pancreatitis. Liver function tests. Complete blood count with differentials. (RBC indices and Patelet count.

Zidovudine, ZDV, AZT, Retrovir 100mg capsules (A) 300mg (NA)

200mg

TDS

BD

Take without Bone marrow regard to meals suppression: Anemia and/or Neutropenia. Subjective complaints: GI intolerance, headache, insomnia, asthenia. Lactic acidosis with hepatic steatosis is a rare but potentially life threatening toxicity with the use of NRTIs Take without regard to meals. Alcohol increases ABC levels to 41 % Hypersensitivity reaction (can be fatal); Fever, rash, nausea, vomiting, malaise of fatigue and loss of appetite. Respiratory symptoms may also be component (sore throat, cough, SOB) Lactic acidosis with hepatic steatosisrare. Pancreatitis. Peripheral neuropathy. Nausea. Diarrhea Lactic acidosis with hepatic steatosis is a rare but potentially life threatening toxicity with the use of NRTIs. Pancreatitis Liver disease/hepatitis, severe hepatomegally, steatosis, lactic acidosis. Rash.

Abacavir, ABC, 300mg Ziagen 300mg tablets (A)

BD

Liver function tests. Complete blood count. Routine serum chemistry.

Didanosine, >60mg200mg ddl, Videx 25 & 100mg tablets <60mg 125mg (A) 50, 150 and 200mg tablets Lamivudine, 3TC, Epivir 150mg tablets (A) 150mg

BD BD

Take 30 min before or 2 hours after food.

Liver function tests. Complete blood count. Serum amylase. Liver function tests. Renal function tests Complete blood count.

BD

Take without regard to meals. Should not be prescribed to patients requiring dose adjustment

2) Protease Inhibitors (PIs) Protease Inhibitor Dose Frequency TDS Lab Monitoring Dietary restrictions Major side effects

18

Nelfinavir, Viracept 250mg tablets (A)

750mg or 1250mg

BD

Routine clinical chemistry including HB, neutropil and lymphocyte counts as well as ALT, AST and CK monitoring Liver function tests. Renal function tests. Complete blood count with differentials and routine blood chemistry every 24 weeks. or low fat meal.

Take with meal or snack

Diarrhea. Hyperglycemia Fat redistribution and lipid abnormalities. Possible increased bleeding episodes in patients with hemophilia Nephrolithiasis. GI intolerance, nausea. Misc.: headache, asthenia, blurred vision, Dizziness, rash, metallic taste, thrombocytopenia, alopecia. Hyperglycemia Fat, redistribution and lipid abnormalities Possible

Indinavir Crixivan 400mg capsules (A) 200mg capsules (NA)

800mg

TDS

To be taken on an empty stomach 1 hour before of 2 hours after meal. Plenty of fluids to be taken approx. 1.5 L per day. May take with skim milk increased bleeding episodes in patients with hemophilia. Should be refrigerated. Take with meals. This may improve tolerability

Ritonavir Norvir 100mg capsules (A)

600mg

BD NB. Dose escalation required for Ritonavir to improve tolerability Day 12: 300mg BD; Day 35: 400mg BD; Day 613 500mg BD; Day 14: 600mg BD.

Complete blood count Routine blood chemistry. Liver function tests and serum lipid/lipoprotein profile every 24 weeks.

GI intolerance, nausea, vomiting, diarrhea. Parenthesis circumpolar and extremities. Hepatitis Pancreatitis Asthenia Taste perversion Hyperglycemia Fat redistribution and lipid abnormalities Possible increased bleeding episodes in patients with hemophilia. GI intolerance, nausea and diarrhea. Headache. Hyperglycemia Fat redistribution and lipid abnormalities Possible increase bleeding episodes with hemophilia. GI intolerance, nausea, diarrhea, abdominal pain and dyspepsia. Headache, Hyperglycemia Fat redistribution and

Saquinavir (hard gel) formulation Invirase 200mg capsules (A)

600mg

TDS

Complete blood count and routine blood chemistry periodically.

Take within 2 hours of a meal. Oral bioavailability is erratic.

Saquinavir (soft gel) formulation Fortovase 200mg capsules

1200mg

TDS

Complete blood count and routine blood chemistry periodically.

Take with large meal. This increase levels 6fold

19

lipid abnormalities. Possible increased bleeding episodes in patient with hemophilia. Amprenavir Agenerase 50, 100mg capsules 15mg.ml oral solution. NB. Capsules and solution not interchangeable on mg per mg basis. (NA) >50kg: 1200mg BID capsules 1400mg BID oral solution <50kg: 20mg/kg BD capsules Maximum 2400mg/day >50kg: 1.5ml/kg BID oral solution maximum 2800mg/day 400mg Lopinavir + 100mg Ritonavir. BID Hepatic renal/function. Routine blood chemistry. With or without meals but not with a high fat meal since this decreased bioavailability. GI intolerance, nausea vomiting, diarrhea Rash parenthesis Fat redistribution and lipid abnormalities Hyperglycemia Possible increased bleeding episodes in patients with hemophilia.

Lopinavir + Ritonavir Kaletra133.3mg Lopinavir 433.3 mg Ritonavir (capsules). (NA)

BID

As for Ritonavir

To be taken with food: moderate fat meal increased bioavailability.

3) NonNucleoside Reverse Transcriptase Inhibitors (NNRTIs) Drug (NNRTI) Efavirenz Stocrin 200mg capsules (A) 50, 100mg capsules (NA) Nevirapine Viramune 200mg capsules (A) 600mg Dose Frequency OD Lab Monitoring Routine blood chemistry. Liver function tests. Cholesterol levels. Liver function tests Renal function tests Routine blood chemistry and complete blood count periodically during therapy. Liver function tests Renal function tests. Routine blood chemistry and complete blood count periodically during therapy. Dietary restrictions Major side effects

High fat meals Rash. should be avoided Central nervous system symptoms Take without regard to meals Rash Hepatitis

200mg. Dose escalation required to improve tolerability: 200mg OD for 14 days: then 200mg BD from day 15 onwards 400mg

BD

Delarvidine Rescriptor 100, 200mg tablets (NA)

TDS

Take without regard to meals: separate dosing with ddl or antacids by 1 hour.

Rash (usually mild) Headache Nausea Vomiting

3.2 Pharmacokinetic properties of Antiretrovirals Drug Oral Bioavailability Serum Halflife Intracellular Halflife Elimination

20

Zidovudine (AZT, ZDV) Retrovir Didanosine (ddl) Videx Zalcitabine (ddc) Hivid. Stavudine (d4T) Zerit Lamivudine (3TC) Epivir Abacavir (ABC) Ziagen Nevirapine Viramune

60%

1.1 hours

3 hours

Metabolized to AZT glucoronide (GAZT) Renal excretion of GAZT Renal excretion 50% Renal excretion 70% Renal excretion 50% Renal excretion unchanged Metabolized by alcohol dehydrogenate and glucoronyl transferase. Renal excretion of metabolites 82% Metabolized by cytochrome P450 (3A inducer); 80% excreted in urine (glucoronidated metabolites, <5% unchanged), 10% in faeces. Metabolized by cytochrome P450 (3A mixed inducer/ inhibitor); 1434% excreted in urine (glucoronidated metabolites, <1% unchanged), 1661 % in faeces. Serum Halflife 1.52 hours Metabolism Cytochrome P450 3A4 inhibitor (less than Ritonavir) Cytochrome P45U Potent 3A4 inhibitor Cytochrome P450 3A4 inhibitor (less than Ritonavir) Cytochrome P450 3A4 inhibitor (less than Ritonavir) Cytochrome P450 3A4 inhibitor (less than Ritonavir)

3040% 85% 86% 86% 83%

1.6 hours 1.2 hours 1.0 hours 36 hours 1.5 hours

2540 hours 3 hours 3.5 hours 12 hours 3.3 hours

>90%

2530 hours

Data not available

Efavirenz Stocrin,

Data not available

4055 hours

Data not available

Drug Indinavir (Crixivan)

Oral Bioavailability 65%

Ritonavir (Norvir) Nelfinavir (Viracept)

Not determined 2080%

35 hours 3.55 hours

Saquinavir, hard gel formulation (Invirase) Saquinavir, soft gel formulation (Fortovase) Amprenavir (Agenerase) Lopinavir + Ritonavir (Kelatra)

4% but is erratic

12 hours

Not determined

12 hours

Not determined Not determined

7.110.6 hours Cytochrome P450 3A4 inhibitor 56 hours Cytochrome P450 3A4 inhibitor

CHAPTER FOUR: GUIDELINES FOR THE USE OF ANTIRETROVIRAL DRUGS IN PAEDIATRIC HIV INFECTION

21

4.1 Overview HIV infection in children is predominantly acquired perinatally and differs from disease in adults in its clinical presentation and disease progression. There are marked age dependent differences in the profile of T lymphocyte subsets in children. In infancy, CD4 cell counts are generally higher than adult levels and attain adult levels by the age of 6 years. Unlike the absolute CD4 cell counts where the levels specifying immune suppression changes with age, the CD4 percentage specifying immune suppression does not change with age and is therefore a more useful marker for identifying disease progression in children. Infants with CD4 percentage of 1525% are considered moderately immune suppressed and those with percentage CD4 levels < 15% are considered severely immune suppressed. Regarding the use of viral load to guide therapy it is worth noting that perinatally infected infants have high plasma viral loads within the first 2 months of life. This is followed by a slow decline in the first few years of live. The level of HIV RNA considered indicative of increased risk for disease progression is not well defined for young children and will have to be reviewed as more data becomes available. Treatment guidelines for children will therefore have to take these differences into account although they follow the same principles as in adults.

4.2 Diagnosis of HIV infection in children Inmost settings in Kenya viral diagnostic assays are not available. Diagnosis of HIV infection is therefore dependent on the use of antibody based tests. In children due to the presence of maternal antibodies a definitive diagnosis of HIV infection can only be made at or after the age of 1 8 months. The' current Ministry of Health guidelines for HIV diagnosis is a concordant positive result using 2 different ELISA kits. (In the event that viral diagnostics become widely available then a definitive diagnosis can. be made within 48 hours of birth in 38% of infants. By the end of the 2nd week of life a definitive diagnosis can be made in 93% of infected children. In this context HIV infection is diagnosed by 2 positive HIV virologic tests performed on separate blood samples.)

4.3 When to initiate treatment Antiretroviral therapy is indicated for any child with definitive diagnosis of HIV infection who has evidence of significant immune suppression and/or who has HIV associated clinical symptoms regardless of the age or viral load. Specific guidelines for initiating therapy are: Symptomatic HIV disease Development of clinical symptoms Moderate and Severe immune suppression High HIV RNA levels (> 10,000 copies/ml) Asymptomatic disease in a 30 month old infact with HIV RNA copy number of > 10,000 copies/ml Increasing HIV RNA copy number as follows: A fivefold increase for children aged < 2 years and a > 3 fold increase for children aged > 2 years.

22

 All children diagnosed as HIV infected within the first year of life regardless of clinical, immunologic or virologic status.

4.4 Initiation of treatment Age Asymptomatic Symptomatic CD4 percentage <25% Treat Treat Treat HIV RNA levels >10,000c/ml Treat Treat Treat HIV RNA levels > 100,000c/ml Treat Treat Treat

<12 months ? 30 months 012 years

Treat

Treat Treat Treat

4.5 Agents to choose for initial treatment As in adults use Paediatric formulations where available.

4.6 Dosages for paediatric formulations Paediatric formulations and dosages Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Drug Zidovudine, ZDV, AZT Retrovir pediatric suspension, 50mg/5ml (A) Stavudine, d4T Zerit pediatric 1 mg/ml (A) Dose Dose for prophylaxis (full term new born): 2mg/kg orally every six hours starting within 12 hours of birth and continuing for 6 weeks. Treatment 180Mg/M2 every six hours (total 720mg.m2/day). Maximum dose should not exceed 600mg/day 1 mg/kg every 12 hours for patients less than 30kg: 30mg twice daily for patients between 3059kg: 40mg twice daily for patients over 60kg. 120mg/m2 every 12 hours Special precautions Strawberry flavoured syrup. Store at 15250c.

Oral solution (made from powder) should be refrigerated (280c) after reconstitution. shake well before use. Discard 30 days after reconstitution. This is an oral solution made from Shake well before use and keep refrigerated (2080c). The solution is stable for 30 days. Take > 30 minutes before or 2 hours after eating. The oral solution can be stored between The oral solution can be stored between 230c. Can be taken with or without food.

ddl, pediatric Videx powder. 10mg/ml(NA)

Lamivudine, 3TC Epivir solution

4mg/kg twice daily for children aged 3 months to 16 years.

10mg/ml(A)

Daily maximum dose is 300mg/day.

23

Abacavir, Ziagen 20mg/ml (NA)

8mg/kg twice a day for children aged > months to 16 years. Maximum dose is 600mg/day.

Store at 20250c. Can be taken with or without food.

NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIS) Efavirenz, Stocrin 50, 100, 200mg capsules. (A) 20mg once a day (10 to < 15kg) 250mg once a day (15 to <20kg) 300mg once a day (20 to <25kg) 350mg once a day (25 to 32.5kg) 400mg once a day (32.5 to >40kg) 600mg once a day (>40kg) Nevirapine, Viramune pediatric 10mg/ml. 4mg/kg once a day for 14 days. Thereafter, maintenance dose: Children > 2 months to <8 years: 7mg/kg twice a day. Children > 8 years: 4mg/kg twice a day. Maximum recommended dose: 400mg/day. Protease Inhibitors (Pis) Drug Nelfinavir, Pediatric Viracept powder, 50mg per 19 scoop. (A) Dose 3030mg/kg three times daily for children aged 213 years. Special Precautions The oral solution is made from the powder is Stable for upto 6 hours after reconstitution. The powder may be reconstituted with water, milk formula, soy formula, soy milk or dietary supplements. It has a bitter taste I reconstituted with acidic food/juice. It can be taken with a meal or light snack and should be taken 1 hour after or more than 2 hours before ddl. The oral solution Oral solution should be stored between 2 and 30c. Can be taken with or without food. Indicated for children aged 3 years and above, weighing > 10kg and who can swallow hard capsules.

Ritonavir, Pediatric Norvir

Initial dose 250Mg/M2 every 1 2 hours, increased by

24

syrup 80mg/ml

50mg/m2 at 23 day intervals to 400mg/m2 twice daily (recommended dose). If 400mg/m2 is not tolerated, the highest tolerated dose should be used. Maximum dose: 600mg twice daily. Efficacy and safety of Amprenavir have not been established in patients younger than 4 years of age. Oral capsules: for patients between 412 years of age or for patients 13 to 16 years of age who weigh less than 50kg, the recommended dose is 20mg/kg twice daily or 15mg/kg three times daily. The maximum daily dose is 2400mg. For adolescents 1316 years of age who weigh 50kg or more the recommended dose is 1200mg twice daily. Oral solution: for patients between 412 years of age or for patients 13 to 16 years of age who weigh less than 50kg, the recommended dose or oral solution is 22mg/kg twice daily or 17mg three times daily. The maximum daily dose of Amprenavir oral solution is 2800mg.

should not be refrigerated but stored at 2025C. Shake well before use. Amprenavir may be taken with or without food, but should not be taken with a high fat meal. Amprenavir oral solution and capsules should be stored at room temperature and neither solution nor the capsules should be refrigerated. Amprenavir capsules and oral solution are NOT bioequivalent, and thus are not interchangeable on a milligram per milligram basis.

Amprenavir, Agenerase, 50, 100mg capsules Oral solution: 15mg/ml. NB: Capsules and oral solution are not interchangeable on a milligram per milligram basis. (NA)

4.8 Monitoring Virologic response should be assessed 4 weeks after initiating therapy. Once maximal suppression of HIV RNA levels is achieved then levels should be measured every 3 months to evaluate continued response to therapy.

4.9 When to change therapy Virologic considerations i) Inadequate virologic response after 812 weeks of therapy Le.< 10 fold reduction from baseline levels in children receiving "NRTIs and PI or <5 fold reduction from baseline in children receiving "NRTIs. ii) Repeated detection of HIV RNA in children who were initially undetectable. iii) A greater than 3 fold increase in viral copy number in infants <2 years. iv) A greater than 3 fold increase in viral copy number in infants>2 years.

Immunologic considerations i) Change in immune classification (e.g. from moderate to severe immune suppression) ii) For patients with severe immune suppression (CD4 levels <15%), a persistent decline of 5 percentiles or more. iii) A rapid and substantial decrease in CD4 counts i.e. >30% decline in <6 months.

Clinical considerations i) Progressive neurodevelopment deterioration.

25

ii) Growth failure.

CHAPTER FIVE: MANAGEMENT OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTED PREGNANT WOMEN AND PREVENTION OF MOTHER TO CHILD TRANSMISSION (MTCT) OF HIV

5.1 Overview The seroprevalence rate of HIV among pregnant women in Africa exceeds 20% in many areas. In Kenya HIV prevalence in urban sentinel sites in 1998 among pregnant women was reported to range between 4 10% in low seroprevalence sites to 20 35% in high seroprevalence sites. With the observed trends, the percentage of pregnant women who are HIV infected is increasing at an alarming rate. Upto 90% of HIV infection in pregnant women is due to heterosexual contact. In 1 999, 1 0% of reported AIDS cases in children were under 5 years of age, out of which 90% of the HIV infection was due to MTCT With our population estimated at 28.2 million, a birth rate of 1.2 million per annum, a seroprevalence rate of 20% in mothers, and an MTCT rate of 40%, the expected number of HIV infected infants per annum in Kenya will be approximately 100,000. This is a big number that the country will find difficult to cope with. Transmission of HIV from infected mothers to their babies can occur during the antenatal period (10 20%), labour and delivery (35 50%), and breastfeeding (40 50%). In order to reduce MTCT these areas must be targeted. There are measures which can be put in place in the management of expectant mothers so as to reduce the rate of transmission of HIV from an infected mother to the baby. These measures include voluntary counseling and testing (VCT), antiretroviral therapy and modification of obstetric practices and replacement feeding for the baby. With reduction of MTCT, the following benefits will be derived: Increase in child health and survival; Decrease in the number of HIV infected orphans; Opportunity to improve, expand health services and strengthen health infrastructure. In order to achieve these set goals collaboration between health care providers and other significant stake holders must be put in place.

5.2 Factors affecting mother to child transmission a) According to the current state of knowledge, table 5.1 summaries factors affecting mother to child transmission of HIV infection. TABLE 5.1 FACTORS AFFECTING MTCT Category VIRAL Strong evidence High viral load Viral genotype and Phenotype Advanced disease (immune deficiency) HIV infection acquired during pregnancy or breastfeeding period. Limited evidence Viral resistance (theoretical possibility) Vitamin A deficiency, anemia Sexually Transmitted Diseases/ Chorioamnionities, Frequent unprotected Sexual intercourse, Multiple sexual partners, Smoking, Injection drug abuse.

MATERNAL

26

OBSTETRICAL

Vaginal delivery (compared to elective Caesarian section). Rupture of the membranes for more than 4 hours. Prematurity

Invasive procedure: instrumental deliveries, amniocentesis, episiotomy. Intrapartum hemorrhage, external cephalic version (ECV). Genetic, lesions or the skin/or mucous membranes (e.g. oral thrush)

FOETAL/INFANT

BREASTFEEDING

Duration, mixed feeding, breast disease (mastitis/ cracked nipple).

b) Factors known to reduce MTCT Elective caesarian section: Nonbreastfeeding: Antiretroviral therapy Knowledge of the above should form the basis for providing care to mothers and their babies.

5.3 Outline antenatal, intrapartum postpartum and postnatal care The care of HIV infected women during antenatal period, labor and delivery and the postpartum period includes intensive counseling and voluntary testing (both pre and post), screening/obstetric interventions, laboratory investigations, treatment and prophylaxis. a) The antenatal care of a women identified to be HIV positive is summarized in table 5.2 Category HIV seropositive HIV infected with opportunistic infections Immune suppression Diseases Well and Asymptomatic e.g. Pneumonia Treatment Usual ANC care, VCT, MTCMAZT, Nutritional support, Treatment of STI Usual ANC, VCT, MTCTAZT, Treatment o STI, Specific treatment of opportunistic infections. Usual ANC, VCT MTCTAZT, Treatment of specific infections, Multivitamin.

e.g. Kaposis sarcoma, CNS manifestations, Military TB.

b) Intrapartum care Due to the HIV/AIDS Pandemic, modification of routine care during the Intrapartum period is necessary. As shown in table 5.1, some practices may increase the risk of HIV transmission to the baby having little or no proven obstetric value. Some of these practices include avoiding early rupture of membranes during labor, selective use of episiotomy and sucking of the oral pharynx of the baby while vaginal cleaning with hibitane (chlorhexidine 0.25%) solutions may reduce the risk of puerperal and neonatal sepsis. Elective caesarian section reduces the risk of MTCT of HIV infection as shown in table 5.1. However, its use in our setup is debatable. At the same time, proper management of labor using the partogram consistently will reduce the risk of prolonged labor in all women while avoiding invasive procedures. c) Postpartum and postnatal care Practices toward reduction of MTCT during the postpartum and postnatal period involve appropriate maternal care and breast care to avoid cracked nipples and mastitis. Ideally, adequate and timely counseling regarding contraception and breast feeding should have been part of the care all through pregnancy and continued during the postpartum and postnatal periods. Overall half of the breast milk transmission takes place by 6 weeks, and three quarters by 6 months after delivery.

27

5.4 Antiretroviral Therapy to prevent MTCT The safety of most antiretroviral agents to the foetus and infant has not been established thus narrowing the choice of ARV drug therapy to prevent MTCT during pregnancy, labor, delivery and the postpartum/postnatal/ Infant periods. There are, however various regimes of ARV therapy currently favored and available for prevention of mother to child transmission of HIV infection as shown in table 5.3. According to the 'American FDA Pregnancy Categories", Zidovudine (ZDC) and Nevirapine (NVP), are in class "C" in which safety in human pregnancy has not been determined, animal studies are either positive for foetal risk, or have not been conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the foetus". TABLE 5.3 ANTIRETROVIRAL THERAPY FOR REDUCTION/PREVENTION OF MCT Breast Feeding Status Non breast feeding Non breast feeding Breast feeding Drug ANC Labour Baby % Reduction of MTCT 68% (infection) status at 18 months) 50% (infection status at 6 months age) 47% (infection status at 6 weeks age)

ZIDOVUDINE 100mg p.o. 5 times daily from 1434 wk gest. ZIDOVUDINE 300mg p.o o.d, from 3640 from gest. NEVIRAPINE No

1.V 2.0mg/kg st, then 1 mg/kg/hr 300mg p.o, 3hrly

2mg/kg p.o. 6hrly x 6 wks No

200mg single dose at the onset of labour

2mg/kg single dose in the first 72 hours

In our Kenyan set up, if one is to use The Thai Regime, it is advisable to start treatment at 34 weeks gestation since most of our patients deliver before 40 weeks gestation and they would not have had optimum therapy, if the therapy is started at 36 weeks. Details of further regimes recommended in preventing MTCT are provided in Appendix XT 11.

CHAPTER SIX: SPECIAL CONSIDERATIONS

6.1 Acute retroviral syndrome (ARVS) At least 60% of patients acutely infected with HIV will experience at least some symptoms of the acute retroviral syndrome. Acute HIV infection is often not recognized in the primary care setting because of the similarity of the symptoms with those of other common diseases or flu. Physicians should maintain a high level of suspicion especially where there are known or established recent high risk factors. It is still controversial whether there are any benefits of antiretroviral therapy at this early stage, but most clinicians would offer treatment during this acute attack. Symptoms one could look for include: Fever (96%) Lymphadenopathy (74%) Pharyngitis (70%) Rash (70%)

28

Erythematous maculopapular rash with lesions on face and trunk and sometimes extremities including palm and soles. Mucocutaneous ulceration involving mouth, oesophagus or genitals. Myalgia or arthralgia (54%) Diarrhea (32%) Headache (32%) Nausea and vomiting (27%) hepatosplenornegaly (14%) Weight loss (13%) Thrush (12%) Neurologic symptoms (12%) Meningoencephalitis or aseptic meningitis Peripheral neuropathy or radiculopathy Facial palsy GuillainBarre syndrome Brachial neuritis Cognitive impairment or psychosis

6.2 ARV drugs and the treatment of Tuberculosis Several antituberculosis regimes can be administered with effective antiretroviral therapy in HIV infected person. The use of Rifampicin to treat active TB is specifically contraindicated for patients taking any of the Pis or NNRTIS, and drugs regimens that include Rifabutin were suggested as preferable alternatives. New data indicate that Rifampicin can be used for the treatment of active TB in situations where the patient is taking NNRTI (Efavirenz) and two NRTI, or PI (Ritonavir) and one or more NNRTIS or a combination of two PI (Ritonavir and Saquanavir). Rifabutin originally recommended for use is too expensive and toxic.

6.3 Immune recovery syndrome Initiation of potent antiretroviral therapy is associated with recovery of immune function. In this period, patients with advanced disease could present with skin rash, lymphademopathy, mucocutaneous, ulceration and immunological response to subclinical opportunistic infection e.g. Kaposi Sarcoma, and tuberculosis. This is not drug failure and the treatment should be continued. Steroids could be administered in some of these cases and careful use of antihistamines.

29

CHAPTER SEVEN: WHEN TO STOP TREATMENT (INTERRUPTIONS)

7.1 Structured treatment interruptions (STI's) With the growing number of drawbacks and uncertainties with long term antiretroviral therapy, it should come as no surprise that both clinicians and patients are finding optimism in structured treatment and interruptions (STIs). Various rationales for stopping treatment in HIV infected patients for short periods of time have been hypothesized. Adherence Poor adherence had been identified as a leading cause of drug failure in patients receiving antiretroviral therapy. Stopping therapy in these patients, until at least these adherence issues are dealt with may prove to be a shortterm preventive solution to a longterm dilemma of multiple drug resistance. Side Effects Initiation of STI to control or prevent some longterm toxicities associated with HAART therapy might be useful. There is not enough data to support the fact that the temporary cessation of therapy has any significant impact on side effects such as elevated liver function or peripheral neuropathy or nutritional disorders. Pregnancy Although antiretroviral therapy has shown considerable benefits in reducing perinatal HIV transmission rates, scant data are available to indicate that antiretrovirals are safe for a developing foetus during the first trimester of pregnancy when teratogenicity is most common. In such cases, stopping treatment will be a feasible option for HIV infected women receiving HAART prior to pregnancy, carried through to the second trimester when such side effects are less common. Boosting HIV specific cellular responses Hypothesis that STIs might induce HIV specific immune responses synonymous with robust HIV specific CD4+ and CD8 cells responses believed to control veremia in seropositive longterm nonprogressors. Successful HAART appears to be associated with decreased HIV specific cellular immunity to the virus as a result of limited antigen stimulation just enough to challenge the immune system without overdoing it ultimately leading to the HIV specific CD4+ and CID8 cells. Before initiating Structured Treatment Interruptions, a patient should have immune reconstitution within acceptance limits, i.e. viral load below 50/mml for at least a period of one year. On commencing STI, the viral load and CD4+ and CD8+ values should be monitored on every three monthly intervals. Restart therapy if there is viral rebound of 0.8 + I load and a significant decrease in CD4 + count. On the commencement of therapy, the patient should be monitored by clinical, laboratory and surrogate markers as it was done prior to STI. STI is a new concept and new data is needed to be available before it is advocated universally. However, STI although a new concept holds a great promise in the future management of HIV/AIDS. Patients with multipledrug resistance and experiencing treatment failure In patients who have multiple drug resistance, STIs have been suggested as an option. STIs in treatment failure will halt the evolution of additional mutations, which conferdrug resistance and in many cases allow for a shift to drugsensitive wildtype virus.

30

7.2 Non structured treatment interruption All patients on antiRetroviral Therapy need to be fully committed to the regimes prescribed. Many individuals stop treatment on their own due to various factors which include financial reasons, drug toxicities, psychological problems and other issues. Most drug therapy discontinuation have been associated with a rapid rise in viral load and a fall in CD4 cell count. Thus for the majority of individuals continuation of therapy is associated with better prognosis than discontinuation. Results from structured treatment interruptions trials are still awaited. When initiating therapy, the following should be considered at least: 1 ) The motivation of an individual to begin and continue therapy. 2) The impact of therapy on an individual s lifestyle and psychology, including the need to establish and maintain a pilltaking routine, perhaps using memory aids. 3) The potential risks and benefits of therapy in the short and long term. 4) The provision of written information to provide support outside the clinic setting.

CHAPTER EIGHT: GUIDELINES FOR POST EXPOSURE PROPHYLAXIS

The following actions should be taken immediately following possible exposure to HIV

8.1 Treatment of exposure sites Wounds and skin sites should be washed with soap and water. Mucous membranes should be flushed thoroughly with water.

8.2 Timing of post HIV exposure prophylaxis initiation Therapy should be initiated within 1 2 hour of exposure.

8.3 Assessment of exposure risk Low risk exposure is Exposure to a small volume of blood or blood contaminated with fluids from asymptomatic HIV positive patients with low viral titre. Following an injury with a solid needle. Any superficial injury or mucocutaneous exposure.

High risk exposure Exposure to a large volume of blood or potentially infectious fluids. Exposure to blood or blood contaminated fluids from a patient with a high viral titre like in clinical AIDS phase or early seroconversion phase of HIV. Injury with a hollow needle.

31

 Deep and extensive injuries. Confirmed drug resistance in source patient.

8.4 Post HIV exposure prophylaxis Risk category Low risk High risk ARV prophylaxis Retrovir 200 mg tds (300 mg bd) Epivir 150 mg be or combivir 1 bd. Retrovir 200 mg tds (300 mg bd) + Epivir 150 mg bd + Indinavir 800 mg tds Or. Combivir 1 bd + Indinavir 80 Otds. Duration 28 days 28 days

8.5 Recommended HIV serology after exposure Time period from exposure Baseline Two weeks Six weeks Three weeks Six months Recommended tests Full blood count Liver and renal function tests HIV Serology Full blood counts Liver and renal function tests HIV Serology HIV Serology HIV Serology

* Please note that nonprotective casual sex is considered to be a HIGH RISK EXPOSURE

8.6 Management of health care workers with accidental exposure to HIV infection 1) Introduction A Health Care Worker (HCW) becomes exposed to HIV infection When he/she comes in contact with blood or body fluids (amniotic fluid, CSF, peritoneal fluid, secretions from the genital tract) from HIV infected person through any of the following ways: Pricks by contaminated solid and hollow needles. Pricks and cuts by contaminated sharps Contact of such contaminated blood and body fluids with non intact skin, or with intact skin for duration's in excess of 3 minutes and over extensive body surface area. Splashing of such contaminated blood and body fluids to muco cutaneous membranes (eyes, mouth and nose).

32

The term source person is use in rerence to the person whose blood or body fluids the HCW becomes exposed. 2) HIV spot test should be performed on the source person. If the result is positive, a start dose of combivir should be given to the HCW. Should the result be negative, no antiretroviral chemoprophylaxis needs to be recommended. If the spot test is not available, a start dose of combivir should be given then the rest of the management of the HCW continued after the emergency care referred to above. 3) After receiving the immediate care, the affected HCW should present herself/himself to a Medical Officer who should ensure the following: The necessary documentation including names of HCW, source person, address, time of incident, size of exposure etc. is done. 4) Pretest Counselling The following pertinent points should be part of the contents of the pretest counselling of the affected HCW. That the testing has significance beyond a mere offering of epidemiological data. That the testing is done under confidential status. That the possible chances of infection from the accidental exposure (percutaneous inoculation from HIV positive source person) is approximately 0.3% and mucocutaneous exposure to blood is approximately 0.03% (CDC statistics), That antiretroviral chemoprohylaxis is beneficial. That failure to take the HIV test by the affected HCW will negatively affect any future proceedings which require proper documentation.

Incase the source person is unwilling to be HIV tested, the attending Medical officer should contact the consultant in charge or any other senior Administrator who should have overriding powers to authorise HIV testing in such cases. These powers could be exercised where: The source person objects to being HIV tested. The source person is confused or in coma. The case of a minor where a guardian or parent is not available.

In the event of the HCW objecting to being HIV tested, the attending Medical Officer should ensure the following: The consultant in charge or a Senior Administrator is informed. The HCW is aware that Hospital may not take responsibilities for any eventuality arising out of that accidental exposure. The source person should still be HIV tested but no antiretroviral chemoprophylaxis recommended for the HCW who instead, should be further counselled. If the source person turns out to be HIV positive, the HCW should be further counselled and if he/she still objects to being HIV tested, then he/she should not be commenced on any antiretroviral chemoprophylaxis.

Evaluation of the risk category (in terms of high or low) of the affected HCW and making a decision to recommend or not to recommend anteretroviral chemoprophylaxis should be done urgently, if antiretroviral

33

chemoprophylaxis is recommended, it should be initiated as soon as possible preferably within an hour post exposure. The chemoprophylaxis should be discontinued once the source person turns out to be HIV NEGATIVE or HCW turns out to be HIV POSITIVE from baseline tests. There are certain factors which increase the risk of transmission of HIV, some of which are as follows: The stage of infection of the source person. Terminal AIDS persons have a higher viral load. The degree of injury: Multiple injuries or deep and extensive injuries carry a higher risk of infection in addition to those listed earlier.

8.7 Management of hospital staff with sharp injury or exposure to blood and body fluids Introduction Members of the health professions and paramedical staff who are in contact with patients and or clinical materials are at a continuous risk of infection with HIV from accidental sharps injury or exposure to body fluids. Recommendations to be taken in case of accidental sharps injury or exposure to blood or body fluids are as follows: 1. Encourage bleeding by squeezing site if a puncture wound. Do not suck out blood. 2. Wash the affected area gently with plenty of soap and water. Note: Do not scrub the area or use a nail brush.

3. Irrigate with water if splashing occurs into eye, mucus membrane or nonintact skin. 4. Apply Betadine, Iodine, Methylated spirit or other verucidal disinfectant (Optional). 5. Cover with waterproof dressing if appropriate. 6. Inform the senior member of staff incharge immediately who will confirm that the above have been followed.

The patient will then be referred for treatment as earlier indicated.

8.8 Management of non occupational exposure to HIV infection I. Definitions Non occupational exposures to HIV can be grouped into two broad categories: Sexual exposures and nonsexual exposures. These two categories exclude perinatal exposure A person becomes sexually exposed to HIV when he/she comes in contact with secretions from an HIV infected sexual partner/assailant through a discrete penetrative sex act (penovaginal, penoanal and penooral). The majority of cases that fall under this category comprise victims of rape or consensual casual sex partners who have suffered burst condoms. Nonsexual nonoccupational exposure to HIV occurs when a victim comes in contact with blood or body fluids from an infected person through any of the following ways:

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Pricks and cuts by needles and sharps through such means as injectingdruguse, RTAs and other mass accidents (e.g. bomb blasts, train and air traffic crashes, mass shootings, multiple assaults with a common weapon and certain practices such as traditional circumcision, shaving and tattooing, where a common needle/sharp is used. Contact of such contaminated blood and body fluids with mucous membranes, nonintact skin or with intact skin for prolonged periods (in excess of 3 minutes) and over extensive body surface. This often happens to participants in rescue mission at traffic and sports accidents and also at obstetric emergencies that occur in public places. 1. Management of sexual exposures to HIV: Identification data of the victim which should include the victim's marital status, the number of children the victim has, record of any contraceptives currently being used and LMP for female victims. The place and time the exposure took place, the identity of the informant and also that of the assailant (if possible) should be recorded. 2. Evaluation of the sexual exposure in terms of the number of assailants involved, whether penetration and ejaculation was achieved and what the victim did immediately after the exposure in order to minimize the risk (e.g. douche). 3. Determination of evidences of the exposure (e.g. semen on the victims underwear, vaginal or anal tears) and determination of factors that could affect the degree of the risk of HIV transmission (e.g. visible angenital ulcers and inflammations). 4. Taking specimens for laboratory analysis for use in verification of exposure and determination of conditions that may modify other consequences of the exposure (e.g. whether victim was already pregnant or already had STD infections at the time of the exposure). Such laboratory specimens include HVS for MCS, urine for MCS, PDT, VDRL and HbsAg. 5. Pretest counselling and obtaining of informed consent for HIV testing. 6. Determination of the risk category, the length of time which has elapsed from the exposure to the moment the victim presented for medical care and making of the decision to recommend or not to recommend antiretroviral chemoprophylaxis. Victims with a low exposure risk and those who come too late after the exposure need not to be recommended for antiretroviral chemoprophylaxis. However, they should be "followed up in the appropriate clinics, although the efficacy of antiretroviral chemoprophylaxis has been proven (mostly in animal studies) to be optimal when it is commenced early within a few hours of exposure, only those who come after two weeks of exposure should be disqualified from receiving antiretroviral chemoprophylaxis on account of lateness. (The risk of HIV transmission per episode for receptive penoanal sexual exposure is estimated at 0. 1 % to 0.2%. Other factors that increase risk of transmission include: victim with STD and nogenital ulcers, multiple assailants and assailants with unknown HIV status lifestyles). Apart from when the assailant is know to be HIV seronegative, all HIV seronegative rape victims should be recommended for antiretroviral chemoprophylaxis.

8.9 Management of nonsexual and non occupational Exposures to HIV Recording of the victims identification data, nature of the exposure, place and time the exposure took place, the identity of the informant and the time the victim presented for medical care. If the exposure is of the injectingdrug use type, the medical officer should determine the number of persons sharing the injection device and the length of time the victim has been on the method. (The risk of HIV transmission per episode of IV needle exposure is estimated at 0.67%). Pretest counselling the victim and obtaining of informed consent for HIV testing. Blood samples or other diseases which could be transmitted through the same exposure (such as syphilis, Hepatitis B, Hepatitis C) should be taken along side that for HIV). There is hardly any benefit in recommending antiretroviral chemophylaxis for those who expose themselves to HIV through injectingdrug use unless they are willing to

35

be rehabilitated through counselling and psychiatric care aimed at weaning them from their dangerous habit. Those who get exposed to HIV through RTAs and other mass accidents where multiple exposure to blood and body fluids of other victims of the same accident can not be ruled out, should be recommended for Antiretroviral chemoprophylaxis. The chemoprophylaxis should be taken for a period of 28 days. The computed risk of HIV transmission (computed for available data on the local HIV prevalence multiplied by the number of RTA victims assisted) should also be disclosed to the patient.

CHAPTER NINE: ACCESS TO DRUGS IN KENYA

The lack of accessibility to ARV drugs by the majority of Kenyans remains a major obstacle to HIV/AIDS patients. Access to ARV therapy is restricted currently to major hospitals and big urban health institutions. The main barriers to providing ARV therapy in Kenya as in many other developing countries is the cost of drugs themselves. The standard care in ARV therapy requires viral load monitoring and CD4 cell counts. Both of these are expensive and available in only limited institutions within the country; factors which hinder access to a bigger portion of the population. A good infrastructure for the provision of ARV therapy, in particular training of physicians involved in monitoring ARV therapy is crucial to ensure quality services. Facilities for ARV therapy currently focused in urban health institutions with better infrastructure will need gradual scaleup to the other parts of the country. The Ministry of Health will take the lead in these scaleup activities and ensure that affordable quality ARV drugs are accessible to all Kenyans. The recent legislative amendments by the Government of Kenya is aimed at enhancing ARV access to the majority of the HIV/AIDS patients The dramatic price reductions witnessed recently offers hope that ARV drugs will soon be available. These guidelines will become useful to prescribers and other Health workers.

APPENDICES

I. Drug to drug interactions Drugs Affected ANTIFUNGALS Ketoconazole ANTIMYCOBACTERIALS Rifabutin Amprenavir (APV) Levels: APV increases 31% 3X Ketor reduces 44% Levels: APV AUC decreases 82%. No change in rifabutin AUC Avoid concomitant use. Levels: APV AUC decreases 15% Rifabutin increases 193% Dose: No Lopinavir (LPV) Levels: LPV AUC decreases 13% Keto increases 3fold. Nelfinavir (NFV) No dose adjustment necessary

Levels: LPV AUC Level: 82% decreases 75% Contraindicated Avoid concomitant use. Levels: Rifabutin AUC increases 3fold. Decrease Rifabutin Levels: NFV 32% Rifabutin increases 2X

Rifabutin

36

change in APV dose Decrease Rifabutin to 150mg qds or 300mg 23x/week

dose to 150mg gds

Dose: Increase Rifabutin to 150mg qd Decrease NFV dose to 1000 mg tid. No data

Clarithromycin

Levels: APV AUC increase No data 18%. No change in clarithromycin AUC No dose adjustment Levels: Potential for metabolic interactions use alternative or additional methods Levels: Ethinylestradiol decreases 42% Use alternative or additional methods.

ORAL CONTRACEPTIVES

Levels: Norethindrone 18% Ethinylestradiol 47% Use alternative or additional method. Levels: Potential for large increase in statin levels. Avoid concomitant use Unknown but may decrease NFV levels substantially Monitor anticonvulsant level.

LIPID LOWERING AGENTS Simvastatin Lovastatin

Levels: Potential for large increase in statin levels. Avoid concomitant use

Levels: Potential for large increase in statin levels. Avoid concomitant use Unknown but may decrease LPV levels substantially Monitor anticonvulsant level.

ANTICONVULSANTS Phenobarbitol Phenytoin Carbamazephine

Unknown but may decrease APV levels substantially Monitor anticonvulsant level.

II. Drug to drug interactions (continued) Drugs Affected ANTIFUNGALS Ketoconazole Indinavir (IDV) Ritonavir (TRV) Levels: Ketoconazole 3X Dose: Use with caution; do not exceed 200mg Ketoconazole daily Levels: 35% Dose: No Data Increased liver toxicity possible Level: SQV 84% Contraindicated, unless using RTV+SQV, then use rifampin 600 mg qd or 23x per week Level: 82% Contraindicated Saquinavir (SQV) Levels: SQV 3x Dose: Standard Nelfinavir (NFV) No dose adjustment necessary

Level: IDV 68% Dose: IDV 600 mg tid

ANTIMYCOBACTERIALS Rifabutin Level: IDV 89% Contraindicated

Rifabutin

Level: IDV 32% Rifabutin 2X

Levels: 4X Dose: Rifabutin to

Level: SQV 40% No dose adjustment unless

Levels: NFV 32% Rifabutin 2X

37

Dose: Rifabutin to 150mg qd, or 300mg 203x /week IDV 1000mg tid Clarithromycin Level: Clari. 53% No dose adjustment ORAL CONTRACEPTIVE Level: Norethindrone 26% Ethinylestradiol 24% No dose adjusted LIPID LOWERING AGENTS Simvastatin Lovastatin Levels: Potential for large increase in statin levels. Avoid concomitant use Carbamazephine markedly decreases IDV AUC. Consider alternative agent. Grapefruit juice decreases IDV levels by 26%

150 mg qds or dose 3x per week RTV: standard

using RTV+SQV, then use Rifabutin 150mg 23x/week

Dose: Rifabutin to 150 mg qd NFV does to 1000 mg tid.

Levels: Clari. 45% Level: Clari. 77% Dose adjusted for renal insufficiency Levels: Ethinylestradiol 40%, Use alternative or additional methods SQV 177% No dose adjustment.

No data

No data

Levels: Norethindrone 18% Ethinylestradiol 47% Use alternative or additional method

Levels: Potential for large increase in statin levels. Avoid concomitant use Unknown Use with caution Monitor anticonvulsant level Theophylline decreases 47% monitor theo levels.

Levels: Potential for large increase in statin levels. Avoid concomitant use Unknown but may decrease SQV level substantially Monitor anticonvulsant level Grapefruit juice increases SQV levels. Dexamethasone decreases SQV levels.

Levels: Potential for large increase in statin levels. Avoid concomitant use Unknown but may decrease NFV Level substantially Monitor anti convulsant level.

ANTICONVULSANTS Phenobarbitol Phenytoin Carbamazephine

Miscellaneous

III. Drug Interactions Between Antiretrovirals and Other Drugs NonNucleoside Reversed Transcriptase Inhibitors (NNRTIs) Drugs Affected ANTIFUNGALS Ketoconazole Levels: Keto.63% NVP 1530% Dose: Not recommended No data Nevirapine (NVP) Delavirdine (DLV) Efavirenz (EFV)

No data

ANTIMYCOBACTERIALS

38

Rifampin Levels: NVP 37% Not recommended Rifabutin Levels: NVP 16% No data for Rifabutin dose Levels: DVL 80% Rifabutin 100% Not recommended Level: DVL 6% Contraindicated Levels: EFV 25% No dose adjustment Levels: EFV unchanged; Rifabutin 35% Dose: Rifabutin dose to 450 mg qd. Clarithromycin Levels: NVP 26%, Levels: Clari. 100%, Levels: Clari. Alternative recommended 39%

Clari. 30%. No dose adjustment. ORAL CONTRACEPTIVES Levels: Ethinylestradiol decreases 20%. Use alternative or additional methods.

DVL 44% Dose adjusted for renal failure No data

Level: Ethinylestradiol 37% No data on other component Use alternative or additional methods.

LIPID LOWERING AGENTS Simvastatin Lovastatin No data Levels: Potential for Large increase in statin levels. Avoid concomitant use. No data

ANTICONVULSANTS Phenobarbital Phenytoin Unknown Use with caution monitor anticonvulsant level. No data Unknown but may decrease DLV levels Substantially Monitor anticonvulsant May increase levels of Dapsone, Warfarin and Quinidine Sildenafil: Potential for increased concentrations and adverse effects. Do not exceed 25mg in a 48 hour period. No data decreases significantly. Titrate dose to effect. Unknown Use with caution monitor anticonvulsant level. Monitor Warfarin when used concomitantly

MISCELLANEOUS

METHADONE

Levels: NVP unchanged, Methadone decreases Significantly. Titrate methadone dose to effect.

Levels: Methadone

IV. Nucleoside Reverse Transcriptase Inhibitors (NRTIS) Drug Interactions Requiring Dose Modifications or Cautions Use

39

Drugs affected Methadone

Zidovudine (ZDV) No data

Stavudine (d4T) Levels: d4T 27% Methadone unchanged No dose adjustment. No data

Didanosine (ddl) Levels: ddl 41%, Methadone unchanged. Consider ddl dose increase. No data

Miscellaneous

Ribavirin inhibits phosphorylations of ZDV; this combination should be avoided if possible.

V. Drug Interactions: Protease Inhibitors Effects of Drug on Levels (AUCs)/Dose Drug Affected Indinavir (IDV) Ritonavir Levels: IDV^ 25X Dose: IDV 400mg bid, or IDV 800mg bid + RTV 100 or 200mg bid Saquinavir* Levels: IDV no effect SQV^ 47x Dose: Insufficient data Nelfinavir Levels: IDV^ 50% NFV^ 80% Dose: Limited data for IDV 1200mg bid + NFV 1250mg bid Levels: RTV no effect NFV^ 1.5x Dose: RTV 400mg bid + NFV 500750 mg bid Levels: SQV^ 35x NFV^ 20%+ Dose: Standard NFC Fortovase 800mg tid or 1 200mg bid Amprenavir Levels: APV AUC^ 33% Dose: No change Dose: IDV Lopinavir/ Ritonavir Levels: IDV AUC And Cmin increased. 600mg bid

Ritonavir

Levels: RTV no effect SQV^ 20X Dose: Invirase or Fortovase 400mg bid + RTV 400mg bid

Levels: APV AUC^ 2.5fold. Dose: Limited data APV 6001200mg bid + RTV 100200mg bid Levels: APV AUC decreases 32% Dose: insufficient data

Lopinavir is Coformulated with Ritonavir as Keletra.

Saquinavir (SQV)

Levels: SQV AUC and Cmin increased Dose: SQV 800mg bid LPV/r standard.

Nelfinavir (NFV)

Levels: APV AUC^ 1.5fold. Dose: insufficient data Levels: APV AUC and Cmin increased Dose: APV600750mg bid, LPV/r Standard.

Amprenavir

VI. Drug Interactions: Protease Inhibitors and NonNucleoside Reverse Transcriptase Inhibitors Cont. Effect of Drug on levels (AUGs)/Dose

40

Drug Affected Indinavir (IDV)

Nevirapine Levels: IDV decreases 28% NVP no effect Dose: IDV 1000mg q8h NVP: standard

Delavirdine Levels: IDV^ >40% DLV no effect Dose: IDV 600mg q8h DLV: standard Levels: RTV^ 70% DLV: no effect Dose: Standard RTV: no data Levels: SQV^ 5x DLV no effect Dose: Fortovase 800mg tid, DLV standard (monitor transaminase levels) Levels: NFV^ 2x DLV decreases 50% Dose: No data (monitor for neutropenic complications)

Efavirenz Levels: IDV 31%

Dose: IDV 1000mg q8h EFV: standard Levels: RTV^ 18% EFV^ 21% Dose: RTV 600mg bid (500mg bid for intolerance) EFV standard Levels: SQV 62% EFV 12% Coadministration not Recommended Levels: NFV increases 20%

Ritonavir

Levels: RTV decreases 11 % NVP no effect Dose: Standard

Saquinavir (SQV)

Levels: SQV decreases 25% NVP no effect Dose: No data

Nelfinavir (NFV)

Levels: NFV^ 10% NVP no effect Dose: Standard

VII. Drug That Should Not be Used With Antiretrovirals Drug Category Ca++ channel blocker Cardiac Lipid Lowering Agents AntiMyco bacterial Antihistamine Gastrointestinal drugs Nevirapine Delavirdine (None) (None) (None) (None) (None) (None) (None) (None) Simvastatin Lovastatin Rifampin Rifabutin Astemizole Terfenadine Cisapride H2 blockers Proton pump inhibitors (None) Midazolam Triazolam Efavirenz (None) (None) (None) (None) Astemizole Terfenadine Cisapride

Neuroleptic Psychotropic

(None) (None)

(None) Midazolam Triazolam

** This is likely a class effect.

Suggested Alternatives

41

Simvastatin, Lovastatin: atorvastatin, pravastatin, fluvastatin, cerivastatin (alternatives should be used with caution) Rifabutin: clarithromycin, azithromycin (MAI prophylactics); clarithromycin ethambutol (MAI treatment) Astemizole, Terfenadine: loratidine, fexofenadine, cetirizine Midazolam, Triazolam: temazepam, lorazepam.

VIII. Drugs that should not be used with Protease Inhibitors Antiretrovirals Drug Category Amprenavir Ca+ Channel bocker Indinavir Lopinavir+ (None) (None) Cardiac (None) Amiodarone Flecainide Flecainide Propafenone Lipid Lowering Agents Simvastatin Simvastatin Lovastatin Lovastatin Antimycobacterial Rifampin Rifampin Antihistamine Astemizole Terfenadine Terfenadine Terfenadine Gastrointestinal Drugs Cisapride Simvastatin Simvastatin Lovastatin Lovastatin (None) Rifampin Astemizole Terfenadine Terfenadine Terfenadine Cisapride Cisapride Neuroleptic (none) (none) Clozapine Pimozide Pimozide Psycotropic Midazolam Midazolam Trizolam Trizolam Ergot Alkaloids Midazolam Midazolam Trizolam Trizolam Midazolam Trizolam Midazolam Midazolam Midazolam Terfenadine Cisapride Cisapride (None) (None) (None) Cisapride Cisapride Lovastatin Rifampin Rifampin Astemizole Astemizole Astemizole Astemizole Lovastatin Rifampin Rifampin Simvastatin Simvastatin Simvastatin (None) (None) Ritonavir* Bepridil Saquinavir (None) Nelfinavir (None) Ritonavir Bepridil

Dihydroergotamine Dihydroergotamine Dihydroergotamine Dihydroergotamine Dihydroergotamine Dihydroergotamine Dihydroergotamine

42

(Vasoconstrictor)

(D.H.E. 45) (D.H.E. 45) Ergotamine** Ergotamine** (Various forms) (Various forms)

(D.H.E. 45) (D.H.E. 45) Ergotamine** Ergotamine** (Various forms) (Various forms)

(D.H.E. 45)

(D.H.E. 45)

Ergotamine**

Ergotamine**

(Various forms)

(Various forms)

Some of the contraindicated drugs listed are based on theoretical considerations. Thus, drugs with low therapeutic indices yet with suspected major metabolic contribution from cytochrome P450 3A, CYP2D6, or unknown pathways are included in this table. Actual interactions may or may not occur in patients.

IX. HIVrelated drugs with overlapping toxicities BONE MARROW SUPPRESSION Cidofovir Cotrimoxazole Cytotoxic Chemotherapy Dapsone Flucytosine Ganciclovir Hydroxyurea Interferonprimaquine Pentamidine Ritonavir Stavudine Pyrimethamine Ribavirin Rifabutin Sulfadiazine PERIPHERAL NEUROPATH Didanosine Isoniazid Stavudine Zalcitabine Didanosine Lamivudine (children) PANCREATITIS NEPHROXICITY Cotrimoxazole Adefovir HEPATOTOXICITY RASH Delavirdine Abacavir

AminoglycoSides Efavirenz Amphotericin B Cidofovir Foscarnet Indinavir Pentamidine Fluconazote Isoniazid Itroconazole Ketoconazole Nevirapine NRTIs Protease inhibitors Rifabutin Rifampin Dapsone Amprenavir

ContrimoXazo

X. Antiretroviral therapy for preventing MTCT STUDY PACTOG 076 Non Breast feeding Thailand Non breast feeding DRUG AZT ANTEPARTUM 100 mg p.o. 5 times daily starting at 1434 week gestation. 300 mg p.o. bd, p.o starting at 36 weeks gestation INTRAPARTUM 1v 2mg/kg loading, then 1 mg/kg/hr POSTPARTUM No INFANT 2mg/kg p.o. 6 hourly for 6 weeks No REDUCTION IN MTCT 68% (infection status at 18 months 50% (infection status at 6 months age)

AZT

300mg p.o 3hrly

No

43

Cote D voire AZT Breast feeding Cote D voire AZT Burkina Faso breast feeding AfricaPetra AZT +3TC Arm A 67% Breast feeding

300 mg p.o. Bd, p.o. starting at 36 weeks gestation 300 mg p.o. bd, starting at 36 weeks gestation

300mg p.o 3hrly

No

No

47% (infection status at 6 weeks age) 38% (infection status at 6 months age) 38% (infection status at 6 months age)

600mg p.o at the 300mg bd for 1 onset of labour week

No

300mg AZT + 150mg +3TC . starting at 36 weeks gestation

300mg AZT+ 150mg 3TC p.o 3 hourly

300mg AZT + 150mg 3TC p.o bd for 1 week

AZT 4mg/kg + 3TC 2mg/ kg p.o bd for 1 week AZT 4mg/kg + 3TC 2mg/ kg p.o bd for 1 week 2mg/kg single dose in the first 72 hours

AfricaPetra Arm B 67% Breast feeding

AZT 300mg +3TC 150mg (combivir)

No

300mg AZT+ 150mg 3TC p.o 3 hourly

300mg AZT + 150mg 3TC p.o bd for 1 week

37% (infection status at 6 weeks age)

VIVNET Breast feeding

No

200mg single dose at the onset of labor

No

47% (infection status at 6 weeks)

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BACK COVER
Preparation and printing of this document was made possible by funding and assistance from the World Health Organization and United Nations Programme on HIV/AIDS (UNAIDS)

Republic of Kenya

World Health Organization

National AIDS and STD Control Programme (NASCOP) PO Box 19361, Nairobi, Kenya tel: 254 2 729502,714972 email: headnascop@iconnect.co.ke

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