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ARV Drug Use in Management of HIV/AIDS in a Resource Poor Setting Henry Njuguna, MBChB IV Contents 1 Introduction 3 2 3 4 4 5 6 6 7 7 8 9 5 6 7 ARV drugs currently available for use Life cycle of HIV and sites of drug action Treatment of HIV in adolescents and adults Diagnostic tests When to start treatment W.H.O. staging of HIV/AIDS disease When to start treatment Recommended drug regimen Long term adverse effects of HAART Monitoring Adherence 11 13 13 INTRODUCTION. HIV/AIDS has caused and is still causing immense losses both socially and economically. Over 700 lives are being lost daily in Kenya to AIDS and millions of children being left as orphans. Patients suffering from AIDS related opportunistic infections occupy more than 60% of our hospitals’ bed capacity. It is not only expensive to treat this infections but treatment is often ineffective as most patients have low immunity. The developed countries have managed to control this pandemic with the use of anti-retroviral (ARV) drugs, in a treatment protocol now referred to as the highly active anti-retroviral therapy (HAART). They have less patients succumbing to AIDS and are able to prolong and give quality life to HIV/AIDS patients. Some developing countries too have been able to successfully manage HIV/AIDS using ARV drugs; in Guatemala, Thailand, Malawi and other developing countries, hundreds of people who would have died are instead living normal productive lives. Credit goes to the wide use of these ARV drugs. With the availability of cheaper generic drugs and pressure to drug companies to lower costs of these drugs, it is expected that these drugs will soon be available to the average citizen. We should therefore not lose hope but arm ourselves with the necessary skills that will enable us use these drugs effectively. Despite the fact that ARV drugs have the benefit of prolonging life, their use is associated with numerous side effects and threat of emerging resistance. Health care personnel will play a pivotal role in deciding who to treat, when to treat and the most suitable regimen of drugs to use. It is therefore necessary that health care personnel concerned with management of HIV/AIDS understand the ARV drugs available, the recommended regimens and their side effects and ensure that patients know the importance of adherence to treatment. This will help reduce resistant strains to the available drugs. ARV DRUGS CURRENTLY AVAILABLE FOR USE. These are grouped into four categories based on their mechanisms of action: 1. 2. 3. 4. NRTIs Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Protease Inhibitors (PIs) Fusion Inhibitors (FIs) They compete with the hosts’ nucleotides to be incorporated into the viral DNA. Once incorporated, they cause termination of the viral DNA chain. To be activated, they are first phosphorylated by cellular kinases into the active triphosphate form. They include: Common names Other names Abacavir Ziagen Didanosine Videx, ddI Emtricibine Emtriva, Lamivudine Epivir, 3TC Stavudine Zerit, d4T Tenofovir* Zalcitabine HIVID, ddC Zidovudine Retrovir, AZT, ZDV *Nucleotide reverse transcriptase inhibitor Combined drugs: Trizivir: Abacavir+Zidovudine+Lamivudine Combivir: Lamivudine+Zidovudine NNRTIs They do not require phosphorylation to be activated. They directly block the reverse transcriptase enzyme and are not incorporated into the viral DNA. They include: Common names Other names Delavirdine Rescriptor Efavirenz Sustiva Nevirapine Viramune PIs They interfere with viral maturation process by blocking viral enzyme protease. They include: Common names Other names Amprenavir Agenerase Atazanavir Reyataz Indinavir Crixivan Nelfinavir Viracept Ritonavir Norvir Saquinavir Fortovase, Invirase FIs They work by preventing HIV from entering healthy T cells, proteins on outer surface of HIV i.e. Gp140 and gp 41 must interact with cellular proteins and receptors on T cells i.e. CD4, CCR5, CXCR4. Fusion inhibitors target these proteins and receptors to prevent the virus from infecting new cells. Only one drug is available for clinical use: - Fuzeon (T20). LIFECYCLE OF HIV AND SITES OF DRUG ACTION The diagram shown below illustrates the lifecycle of HIV and the sites of drug action. See explanation below 1: Fusion stage The viral envelope proteins; gp120 and gp41 bind to host T cells containing CD4 receptors, CCR5 andCXCR4 co receptors. Fusion takes place and the virus is able to penetrate into the cell. FIs attack this stage of the HIV lifecycle. 2: Reverse transcription stage Reverse transcriptase a viral enzyme, translates the viral genetic material, RNA into DNA. NRTIs and NNRTIs attack this stage by inhibiting the viral enzyme. 3: Integration The translated viral DNA is incorporated into the host cell DNA by the viral enzyme integrase. This programs the host cell to produce more HIV. Integrase inhibitors are currently being developed. 4: Transcription The two strands of DNA separate, a molecule known as messenger RNA (mRNA) is formed. This is a step in the synthesis of new viruses. Antisense nucleotides are being developed to attack this stage. 5: Translation Protein building blocks are assembled according to the information contained by the mRNA to form new viral particles 6: Viral assembly Protein building blocks are cut into smaller pieces by viral enzyme protease. These pieces form the structure of the new HIV particle including enzymes and proteins needed to repeat the reproductive process. Once this has occurred, the new virus particle buds off the human cell and may infect new cells. Protease inhibitors attack this stage. TREATMENT OF HIV/AIDS IN ADOLESCENTS AND ADULTS DIAGNOSTIC TESTS Tests for diagnosis and monitoring HIV infection can broadly be divided into two: 1. Those that detect immunoglobulin antibodies (IgG) specific for HIV. (Antibody detection tests). 2. Those that identify viral material. 1. Antibody detection tests. These tests identify virus specific antibodies in serum. It takes about three months from the point of infection for the antibodies to be produced in sufficient quantities for the tests to detect them. This is known as the window period and it is important to keep it in mind when testing patients. IgGs are able to pass through the placenta into the fetus and therefore infants of HIV positive mothers may test positive when antibody detection tests are used. These maternal IgGs are cleared from the fetal circulation after a period of about eighteen months and the infant may test negative after this period has elapsed. Some of the antigen detection tests available include: Antibody sensitive enzyme linked immunosorbent assay (ELISA). It requires expensive equipment and skilled manpower and therefore is not widely used. Western blot. It is usually used to confirm positive results where two ELISA or rapid tests are discordant. It is expensive and requires skilled personnel. Rapid antibody detection tests which include brands like: Determine, Unigold, Capillus, Immunocomb etc that are locally available. They are cheap and simple to use and interpret. They are widely used in voluntary counseling and testing (VCT) centers. 2. Tests that identify viral material. Most of these tests require expensive equipment and skilled manpower and therefore are used in special circumstances. They include: Polymerase Chain Reaction tests (PCR). This tests is used to determine the viral load in HIV positive individuals in order to determine whether to initiate treatment or to note how effective the treatment is. P24 antigen test. Viral culture WHEN TO START TREATMENT, This is based on: Patient’s clinical as well as laboratory staging of the disease Patients acceptance as well as willingness to adhere to treatment WHO STAGING OF HIV/AIDS There are several classifications of HIV/AIDS staging. In this article W.H.O. classification, which is recommended for resource poor settings, is shown below: WHO classification is based on clinical manifestations of HIV/AIDS and is categorized into the following stages: Stage 1 1. Asymptomatic infection 2. Persistent generalized lymphadenopathy 3. Acute retroviral infection Patient’s performance: Asymptomatic with normal activity. Stage 2 1. Unintentional weight loss < 10% body weight 2. Minor mucocutaneous manifestations e.g. Dermatitis, fungal nail infection, angular cheilitis 3. Herpes zoster within previous 5 years 4. Recurrent upper respiratory tract infections Patient’s performance: Symptoms but nearly fully ambulatory. Stage 3 1. Unintentional weight loss > 10% body weight 2. Chronic diarrhea > 1 month 3. Prolonged fever:>1 month 4. Oral candidiasis 5. Oral hairy leukoplakia 6. Pulmonary TB 7. Severe bacterial infections 8. Vulvovaginal candidiasis Patient’s performance: in bed more than normal but <50% of normal day time during the previous month Stage 4 1. HIV wasting syndrome 2. Pneumocystis jiroveci pneumonia (pcp) 3. Toxoplasmosis of the brain 4. Cryptosporidiosis with diarrhea > 1 month 5. Isosporiasis with diarrhea > 1 month 6. CMV disease in any organ other than liver spleen or lymph nodes 7. Herpes simplex virus infection , mucocutanious 8. Disseminated mycosis 9. Candidiasis of the esophagus, trachea, bronchi or lungs 10. Disseminated atypical mycobacteria 11. Extra pulmonary TB 12. Lymphomas 13. Kaposi’s sarcoma 14. HIV encephalopathy 15. Non typhoid salmonella septicemia WHEN TO START ARV THERAPY If CD4 testing is unavailable: WHO stage IV disease irrespective of total lymphocyte count WHO stage II or III disease with a total lymphocyte count below 1200/mm3 If CD4 testing is available: WHO stage IV disease irrespective of CD4 count WHO stage I,II or III with CD4 counts below 200/mm3 RECOMMENDED DRUG REGIMEN The table below is a guide to treatment regimens for patients who have no previous experience with HIV therapy. Regimens should be individualized based on the advantages and disadvantages of each combination such as pill burden, dosing frequency, toxicities, and drug-drug interactions, and patient variables, such as pregnancy. Preferred regimens are in bold type; these regimens have been selected by experts based on the totality of virologic, immunologic, and toxicity data. NNRTI-Based Regimens perday Preferred Regimens Efavirenz + lamivudine + (zidovudine or tenofovir DF or stavudine) – except for pregnant women or women with pregnancy potential Alternative Regimens Efavirenz + lamivudine + didanosine - except for pregnant women or women with pregnancy potential Nevirapine + lamivudine + (zidovudine or stavudine or didanosine) PI-Based Regimens of pills per day Preferred Regimens Kaletra® (lopinavir+ ritonavir) + lamivudine + (zidovudine or stavudine) Alternative Regimens Amprenavir + ritonavir + lamivudine + (zidovudine or stavudine) Indinavir + lamivudine + (zidovudine or stavudine) Indinavir + ritonavir + lamivudine + (zidovudine or stavudine) Nelfinavir + lamivudine + (zidovudine or stavudine) Saquinavir (sgc or hgc) + ritonavir + lamivudine + (zidovudine or stavudine) Triple NRTI Regimen – As Alternative to PI- or NNRTI-based regimens # of pills per day Alternative Regimens Abacavir + lamivudine + zidovudine Abacavir + lamivudine + stavudine Preliminary 96-week data comparing stavudine + lamivudine vs. tenofovir + lamivudine revealed higher incidence of lipodystrophy and lipid abnormalities in the stavudine group sgc = soft gel capsule; hgc = hard gel capsule LONG-TERM ADVERSE EFFECTS OF HAART Long-term use of ARV drugs has been associated with the following adverse effects; Hyperlipidemia especially due to efavirenz Lipodystrphy and Lactic acidosis both associated with stavudine Immune reconstitution syndrome refers to the flaring up of dormant infection as a result of immune restoration following HAART. Dormant infections such as TB, CMV, hepatitis B&C, herpes etc may start manifesting again or get worse. This occurs in the early days of treatment and is attributed to the ability of the restored immunity to fight the infection. The table below shows Antiretroviral Regimens or Components That Should Not Be Offered Rationale Antiretroviral Regimens Not Recommended Exception Monotherapy Two-agents drug combinations Rapid development of resistance Inferior antiretroviral activity when compared to combination with three or more antiretrovirals Pregnant women with HIV-RNA < 1,000 copies/mL using zidovudine monotherapy for prevention of perinatal HIV transmission Rapid development of resistance Inferior antiretroviral activity when compared to combination with three or more antiretrovirals For patients currently on this treatment, it is reasonable to continue if virologic goals are achieved Antiretroviral Components Not Recommended As Part of Antiretroviral Regimen No exception Saquinavir hard gel capsule (Invirase®) as single protease inhibitor d4T + ddI in pregnancy Reports of serious, even fatal, cases of lactic acidosis with hepatic steatosis with or without pancreatitis in pregnant women When no other antiretroviral options are available and potential benefits outweigh the risks Efavirenz in pregnancy Teratogenic in nonhuman primate When no other antiretroviral options are available and potential benefits outweigh the risks Amprenavir oral solution in: Oral liquid contains large amount of the excipient propylene glycol, which may be toxic in the patients at risk No exception pregnant women; children <4 yr old; patients with renal or hepatic failure; and patients treated Poor oral bioavailability (4%) Inferior antiretroviral activity when compared to other protease inhibitors with metronidazole or disulfiram d4T + ZDV Antagonistic No exception ddC + d4T Additive peripheral neuropathy No exception ddC + ddI Additive peripheral neuropathy No exception Hydroxyurea ↓ CD4 count ↑ ddI-associated side effects – such as pancreatitis & peripheral neuropathy Inconsistent evidence of improved viral suppression Contraindicated in pregnancy No exception MONITORING Patients on HIV treatment should be assessed regularly. Thorough physical examination should be done to check for signs listed in the WHO clinical staging of HIV/AIDS. Laboratory work up where possible can be done. This will help a great deal to determine whether the treatment is effective and assess any adverse drug reactions. Although progress is being made in the search for more affordable testing methods for use in resource-poor regions, it is important that lack of technology does not prevent the introduction of treatment. For instance, most successful tuberculosis programs in resource-poor countries do not monitor liver enzyme levels. As Joep Lange said, "There is actually very little evidence that laboratory monitoring prevents mortality due to drug toxicity, but there is an awful lot of evidence that not treating symptomatic HIV infection is lethal, and usually not in a nice way; why are we always more concerned about doing harm than about not doing good?" ADHERENCE Adherence refers to the patient ability to take the prescribed drugs at the right dosages, at the right time and in the right way without missing any dose. This enables the drugs to work effectively and more so prevents resistance. It is important to counsel patients on the need of adherence. They should also be made aware of expected side effects of the drugs used. References Bertram G. Katzung: Basic and clinical pharmacology 8th edition Ministry of Health: Guidelines to Antiretroviral Drug Therapy in Kenya http://AIDSinfo.nih.gov Harrison’s textbook of medicine New England journal of medicine 2002, 347:1203-4 MY ELECTIVE TERM AT SEATTLE WASHINGTON I must say that I am fortunate to have represented our medical school in an exchange program with the University of Washington during my elective term. It’s practically impossible for me to put down my two and a half month experience in Seattle but I’ll summarize some of my experiences in this article. Brief history of the program This program was organized by the International Health Group (IHG) in collaboration with the International AIDS Research and Training Program (IARTP).Four students from the University of Washington visited our University in the middle of the year 2003. Unfortunately they were hardly noticed by most of our students owing to their busy schedules in various research programs. Two students from our university were chosen to represent our university as part of the exchange program. We are the pioneer students in this newly started exchange program and we hope it is going to continue. Our university paid for our visa fees and promised to give us some stipend. The IHG working together with other donors paid for our traveling expenses, accommodation expenses as well as a small stipend for our upkeep. IARTP led by Dr Carey Farquhar played a pivotal role in coordinating our learning activities during our stay in Washington, Seattle. The flight to Seattle We took off at exactly 1020pm. It was very exiting but a bit scaring being my first flight. I was amazed, mesmerized and tantalized, though quietly in order not to elicit any unnecessary attention. I settled down after saying a short prayer and I was able to appreciate this enormous vessel that was taking us up right into the skies. I could not help imagine the weight it was caring and yet it was able to keep afloat. There were also some funny contraptions that I had to get myself acquainted to, this I successively did after reading the manuals and carefully stealing glances at passengers already using them. The journey was however long and tiring. We took a connecting flight from Amsterdam after going through some rigorous security checks. We finally arrived at SeaTac airport after nineteen hours of flying; we again went through security checks as well as document verification. At the airport we were paged by one of the students and a member of the I HG. She took us to our hosting family who were very welcoming. We were led to our room and shown the necessary facilities we would need to use. After taking a warm refreshing shower which I badly needed, we had dinner and later on went to sleep. Learning continues The following morning, we were taken to the university district and its environs. Everything looked strange; the huge skyscrapers the big roads with gigantic vehicle riding on them. The streets were amazingly quiet and well organized compared to the big city I knew before i.e. Nairobi. At first I thought I was dreaming and I had to pinch myself on several occasions just to confirm. Learning continued on the third day and serious business began though suffering from jet lag. It was amazing how we managed to attend wardrounds, conferences and clinics with so much enthusiasm. It was so exciting, learning new things especially in the wardrounds and conferences. Well, Americans are well endowed in terns of financial facilities as well as technology. Their medical practice is thus based on investigations. They are able to routinely order for what we consider very expensive investigations such as MRIs. Their laboratories are also very efficient and results are timely for proper management of patients. They are also very strict on infection control systems. There are taps and soap in every ward and medical personnel have to wash their hands after attending to each and every patient. In the infectious diseases wards, one has to wear sterile gowns into each room. It is also important to note how much they respect their patients and take their time to address their concerns. They explain each procedure to the patient and request for his/her consent and respect it. Drug therapy and procedures done are usually based on recent research. A doctor will often quote a certain research to justify his choice of management. Students too are introduced to research quite early and have to carry our one during his/her formative years in medical school i.e. end of their first year. This I came to understand was what the four exchange students who had come to Kenya were doing. This probably explains why they are very particular about research findings. Their lectures are well conducted; reading material is first loaded into the departments’ website for student access. Before attending a given lecture, the students ought to have read the material and answered some given questions. This makes the lectures very interactive. The lecturers also prepare slides, which are accompanied with audiovisual aids to explain the concepts better. The libraries are well equipped with numerous computers, audiovisual aids i.e. TVs and Videos, latest journals and textbooks as well as photocopy machines. Videotapes demonstrating clinical examination techniques of different systems are available. Despite all these seemingly good things, I did not like how medicine is practiced due to the fear of being sued. After seeing a patient a doctor spends a considerably long period of time documenting all he/she has done to the patient. Approximately; for every ten minutes spent in seeing one patient, twenty minutes or even more is spent documenting. Due to this the students don’t have much ‘hands on’ experience with their patients. Social experience We had a very interesting and enlightening moments with our host Dr Hunt who is a professor in psychiatry and also the vice dean in the school of medicine. Note, he prefers being addressed to as Doctor rather than Professor despite having a superior title. He used to drop us at the university and return us back home in his gigantic truck. One question he used to ask and was very motivating was, “without thinking much, what did you learn today?” One had to think fast come up with an interesting learning experience. This made me very observant on things I encountered the following day. He also gave us insights on how to tackle life challenges. One interesting teaching was on how to approach and answer questions. Mrs. Hunt, his wife is very motherly; she would cook for us and ensure we were comfortable. She also gave us a chance to experiment on our cooking skills on Saturdays. The last 6 weeks of my 10 week stay at Seattle was spent with another family. Elizabeth a final year medical student and her husband Bill Hutchinson is a very lovely young couple. I was able to appreciate how good love can be for a young couple. I admired how mature they conducted themselves, full of love and respect for each other. In their house, I learned some cooking skills which were fun. By the time I was returning home, I had added on three kilograms. Through them, I made many friends including Mr. & Mrs. George Kerchney who will be visiting Kenya soon. I was fortunate to get an invitation by some family friends who stay at the Eastern Coast of US in Boston. Here I was able to visit great educational institutions including; Harvard University and MIT amongst other landmarks. I can summarise the whole trip as an eye opener. I believe we too can be able to improve our health delivery system and society as a whole despite our limited resources. We should also appreciate and respect the freedom we have when attending to our patients and not take advantage of this. Finally the most important thing we need is determination and hard work, with the changes we are experiencing in our country now, the future is bright. Let us support and encourage one another in building our great Nation. Henry Njenga Njuguna MBChB IV The following is a draft copy of what we intend to do in rehabilitating the health center. Wangige Health Center Rehabilitation Project Introduction Wangige Health center opened its doors to serve the public on ---- by the late founding father Mzee Jomo Kenyatta. Then, while still new, it was able to serve the community surrounding it with the much needed vital health services. People were proud of it and benefited very much from it. There was a sense of ownership as the community was deeply involved in its running and management. It was well equipped with the following facilities; A general out patient clinic Maternal and family planning clinic Maternity ward Child welfare clinic A well stocked pharmacy Minor theatre A laboratory An ambulance for referral cases In addition it had staff quotas as well as room for future expansion Today we talk of a different story and a sad story indeed. The facility has been grossly neglected. Most of the facility’s services are not running as they were supposed to. Some of the services e.g. maternity have actually been withdrawn. All this can be attributed to lack of community involvement in running the facility. Most people now seek health services in private clinics which are actually business entities with an aim of making profit. Those who cannot afford remain at home suffering. Problem statement The aim of this proposal is to create awareness amongst the community on the need to have ownership of the facility. This by extension will lead to long term improvement of the facility’s services as the community will scrutinize its running and this will help restore its lost glory. Methodology Friends of Wangige have come up with various activities that will greatly involve the community in rehabilitating the facility. These activities will be carried out during the Easter holidays as scheduled; Friday 9th April Cutting grass and clearing bushes Planting flowers and trees Repairing fences Saturday 10th April Cleaning the rooms; removing cobwebs etc Repainting the health center’s buildings Repairing leaking roofs and damaged ceiling boards. Monday 12th April Health education facilitated by medical students Free medical check up Laying down long term activities e.g. fixing water source, purchase of sterilizers, surgical equipment Target group We are targeting the local community through churches and schools surrounding the facility. We will also target companies and individuals who are in a position to donate items listed below: --liters of oil paint --numbers of paint brushes --rolls of barbed wire --numbers of fencing poles --kg of nails --numbers of ceiling soft boards --blankets and bed sheets for the maternity ward Suction pump Surgical kit Two sterilizers, one for the maternity ward and another for the minor surgery theatre a fridge Justification Wangige health center serves a population of --- people. The out patient clinic serves an average of-- per month. Monthly postnatal as well as child welfare clinic visits averagely total ----while monthly antenatal visits --- unfortunately none of these mothers get to deliver in this facility. Most of them deliver in hospitals far away from their homes while others deliver at home. This is not only inconveniencing but can be a risk to the pregnant mother as well as her child. The facility is not able to provide basic surgical services such as wound dressing. Emergency cases e.g. road traffic accidents, severe dehydration etc that may benefit from basic first aid, may not benefit much from this facility. Background of friends of Wangige Friends of Wangige was established six years ago, it is a group of young people drawn from the neighborhoods of Wangige. It organizes Christmas parties for destitute children at the Nairobi children’s home in Kabete every year for the last six years. During these parties, it mobilizes people to donate foodstuffs, clothing, drugs as well as their services to brighten up the lives of these children. Our humble appeal Finally we appeal to you as an individual or company to kindly assist us with the above items. We would appreciate if you give as physical items instead of cash. Your ideas on how to improve it will also be appreciated. Yours truly, Friends of Wangige