TRIBUNAL REGISTRAL PRECEDENTES DE OBSERVANCIA OBLIGATORIA X.- Décimo Pleno del Tribunal Registral de la SUNARP realizado el día 3 de Primer Precedente EXHORTO Cuando el mandato judicial para realizar una anotación o inscripción proviene de un Juez cuyo ámbito de competencia territorial no coinciden con el Registro en donde deba ejecutarse, no será exigible el requisito del exhorto
Consensus on antiretroviral treatmentCHAIRMAN’S MESSAGE
It has been 3 years since the release of the 1st National Guidelines on Antiretroviral Therapy.
The feedback from the 1st edition from medical practitioners have been encouraging and theexpert panel valued all comments made. With the many new developments in HIV medicineover the last 3 years, we felt it was time for a review of the guidelines.
The development of the 2nd edition of the Guidelines on Antiretroviral Therapy has beentaken over by the Malaysian Society of Infectious Diseases & Chemotherapy (MSIDC). TheOrganizing Committee had put together 2 experienced expert panels comprising of cliniciansand microbiologists who are actively involved with HIV care in this country. The expert panels;one for adult management and the other for paediatrics, were recognizant of newdevelopments in basic science, clinical research, therapeutics as well as current local realities.
The most important local development was the significant price reductions of antiretroviralsby some pharmaceutical companies in mid 2001.
Consensus On Antiretroviral Treatment
The expert panel has taken pains to be specific where they could be but we must acknowledgethat individualization of care must always be practiced. It is hoped that this document willguide the clinician in making important therapeutic decisions in managing each individual (2nd Edition)
case. Some new sections have been inserted especially as appendices eg. diseasemonitoring ( esp. with regards to viral load measurements ), role of dual nucleoside(suboptimal) therapies and drug interactions. The section on Reducing maternal-fetal HIVtransmission has been omitted while awaiting the more comprehensive document “HIV and Pregnancy” which is expected next year.
As chairman of the Organizing Committee, I would like to express my warmest appreciationfor the committee members: Assoc. Prof. Yasmin Malik, Assoc. Prof. Adeeba Kamarulzaman,Dr. Suresh Kumar, Dr. Norliza Ariffin, Dr. Mardziah Alias and Dr. Kamarul Azahar who workedhard writing up the document, collating base documents and working on the logistics ofproducing a good quality document. I must also express my appreciation to the MISDC andthe Academy of Medicine for supporting and sponsoring the document this time round. Aword of thanks must also go out to the expert panel members for their time and energy putinto the formulation of this document.
Lastly, on behalf of the Organizing Committee, I would like to thank Merck, Sharp and Dohme(M’sia) for the unconditional grant and secretarial support in producing this set of guidelines.
We hope you will find this document useful in providing quality care to HIV-infected patients.
Dr. Christopher KC LeeOrganizing Chairman2nd National Guidelines on Antiretroviral Therapy PHYSICIANS
MEMBERS OF THE PANEL
MEMBERS OF THE PANEL
(in alphabetical order)
(in alphabetical order)
TABLE OF CONTENTS
MEMBER OF THE PANEL (1998)
Guidelines for Adults
Potentially Dangerous or Ineffective Combinations Commencing Therapy – What to Start With Guidelines for Paediatrics
Commencing Therapy – What to Start With Addressing Adherence Issues
Guidelines for Post-exposure Prophylaxis
Selection Factors – Basic vs Expanded PEP Regimen Appendices
Appendix A : Antiretroviral Drugs Fact sheets Appendix B : CDC Classification – Adults Appendix C : CDC Classification – Paediatrics Appendix D : Use of viral load assays and CD4 counts Appendix E : Use of antiretrovirals in pregnancy Appendix F : Role of double nucleosides in the era of HAART . 49Appendix G : Karnofsky Performance Status Scale Appendix H : HIV websites and support groups Bibliography
GUIDELINES FOR ADULTS
SELECTION OF ANTIRETROVIRAL TREATMENT
Recent advances in the knowledge of HIV pathogenesis, the rapid development of potent The guiding principle for selecting antiretroviral therapy is the need for treatment regimens antiretroviral agents coupled with the availability of more sensitive laboratory tools such as that provide maximum potency and a sustained, durable antiviral response. In situations the viral load assays have greatly altered the management of HIV-infected patients.
where optimal therapy aimed at achieving undetectable viral levels is not possible or Guidelines for the use of the increasingly complex armamentarium of antiretroviral agents, feasible, the selection of antiretroviral agents should be based on combinations with the including new classes of drugs, have been published in many parts of the developed world.
‘least penalty’ i.e. combinations that are likely to provide maximum clinical benefit and at the Recognizing that it may not be feasible to adopt these therapeutic approaches outlined in same time preserving options for future combination regimes. However, the panel strongly these international guidelines, a panel of local physicians involved in the care of HIV-infected advocates against the usage of any suboptimal antiretroviral regimens (including
patients in this country convened to provide therapeutic recommendations appropriate to our monotherapies and dual nucleoside regimens) as research data unequivocally
clinical setting. The panel took into account the many different situations faced by HIV- demonstrates the selection of resistant viral strains with these regimens, which in turn, infected patients and their treating doctors with regards to antiretroviral use in this country.
Financial constraints and the relative lack of access to laboratory facilities are some of themajor considerations that may limit the options for optimum antiretroviral therapy. The fact Compliance with therapy is one of the major determinants of ensuring a durable response.
that recent price reductions of some antiretroviral agents made Highly Active Antiretroviral In all situations the patient must be agreeable and committed to taking what may be a Therapy (HAART) more accessible, was also taken into consideration in developing these complex and toxic drug regime before commencing therapy.
Given the number of possible drug combinations, it is not possible to recommend whichparticular regimens are best for treatment of HIV disease. Factors that will influence thatdecision will include: the condition of the patient (stage of the disease as well as any GOALS OF ANTIRETROVIRAL TREATMENT
concomitant illnesses), the potency and adverse effects of the regimen, any concurrenttherapies and finally, the cost of the regimen.
General goals of antiretroviral therapy 3
The panel agreed that the general goals of antiretroviral therapy are to prolong survival and
At present the antiretroviral drugs that are available in Malaysia (as of August 2001) include decrease morbidity in those infected. An important objective would be to improve the patient’s quality of life and reduce the burden that he generates on his family and thecommunity. Maintenance of the family unit would be an important outcome of prolonging the I. Nucleoside reverse transcriptase inhibitors (NRTI)
In encouraging those who are infected with HIV to seek treatment it is hoped that early identification of HIV infection would lead to a reduction in its transmission within the Finally the general goal of antiretroviral therapy is that it should be affordable and accessibleto all those infected.
II. Protease inhibitors (PI)
Specific goals of antiretroviral therapy
Saquinavir – hard gel capsules (Invirase ) The specific objectives of antiretroviral therapy are to suppress HIV replication and to slow Saquinavir – soft gel capsules (Fortovase ) down the cycle of immune activation and CD4+ cell destruction as effectively and for as long as possible. The aim would be to reduce plasma viral load to below undetectable levels fora maximum duration and to improve, maintain and prevent the ongoing decline of CD4+ III. Non-nucleoside reverse transcriptase inhibitors (NNRTI)
Ideally, viral load assays and CD4+ cell counts should be used to monitor potent & expensiveregimens i.e. HAART. Access to HAART would have little effect if these critical laboratory testsare not available.
*Antiretroviral drugs currently listed in Ministry of Health drug formulary (August 2001) short-term risk of disease progression for untreated patients with < 350 CD4+ T cells/mm3 POTENTIALLY DANGEROUS OR INEFFECTIVE COMBINATIONS
at all levels of plasma HIV RNA. In addition, data from observational cohorts suggest thatinitiation of therapy at a CD4+ T cell count < 200 cells/mm3 is associated with shorter survivalcompared with initiation of therapy at higher CD4+ T cell counts 7. The conservative approach I. Antiretroviral Combinations
is based on the recognition that robust immune reconstitution still occurs in most patients A list of the side-effects of the drugs is attached in the appendix A.
who initiate therapy with CD4+ T cell counts in the 200-350 cells/mm3 range, and thattoxicities and adherence challenges may outweigh benefits at CD4+ T cell counts > 350 The following antiretroviral combinations cannot be recommended for reasons of safety or Although the issue of when therapy should be commenced may have taken a more • Didanosine + Zalcitabine Increased risk of peripheral neuropathy/pancreatitis conservative approach, the aim of therapy remains as aggressive ie. maximum viral Increased risk of peripheral neuropathy/pancreatitis suppression to get plasma viral loads to below levels of detection using current ultra- • Zalcitabine + Lamivudine in vitro evidence of competition for phosphorylation in vitro evidence of cross resistance in vitro evidence of competition for phosphorylation Recent studies have also highlighted the importance of good drug adherence in
maintaining viral suppression and reducing development of resistant viral strains. It is
II. Antiretroviral Drug interactions with other drugs4
thus imperative that antiretroviral therapy should only be commenced when the patient is
committed to long-term treatment 6.
Summary of recommendations on when antiretroviral therapy should be started 4
• Rifampicin• Antihistamines – Terfenadine, Astemizole Clinical Category
– Pravastatin and fibrates can be used instead • AIDS defining illness
• Psychotropic – Midazolam, Triazolam • Severe Symptoms *
non-nucleosides reverse transcriptase inhibitors: Asymptomatic
• Rifampicin –Not recommended with Nevirapine Efavirenz can be used but at an increased dose of 800mg/day Asymptomatic
• Antihistamines – Terfenadine, Astemizole – Not recommended with Efavirenz • Psychtopics – Midazolam, Triazolam – Not recommended with Efavirenz Asymptomatic
COMMENCING ANTIRETROVIRAL THERAPY – WHEN TO START 4
* Examples include but not limited to Advances in the knowledge of HIV pathogenesis have led to widespread recommendations • Candidiasis, vulvovaginal: persistent > 1 month, poorly responsive to treatment for early initiation of antiretroviral therapy. Proponents for an aggressive approach to treatment argue that early therapy prevents viral genetic evolution and diminishes the • Herpes Zoster: more than 1 episode, or involving more than 1 dermatome potential for future antiviral drug resistance. A further argument for early treatment is that it will • Cervical dysplasia, severe or Carcinoma in situ prevent or limit irreversible immune system destruction and may also lead to an earlier • Constitutional symptoms e.g., fever (> 38.5 °C) or diarrhoea more than 1 month The above must be attributed to HIV infection or have clinical course or managementcomplicated by HIV However drug toxicities and problems related to incomplete viral suppression (esp. withregards to poor adherence) are some reasons against this aggressive approach.
** WHO recommendation is in mIU/ml – 2 million copies/ml = 800,000mIU/ml Over recent years, increasing recognition of the risks associated with initiation of # Some experts recommend initiating treatment since the 3-year risk of developing AIDS in untreated antiretroviral therapy has shifted expert opinion to a more conservative stance concerning the initiation of therapy compared with earlier guidelines. In general, it is now felt that patientswith < 350 CD4+ T cells/mm3 should be offered therapy. This recommendation is based on Antiretroviral therapy can be deferred until serious opportunistic infections have been
brought under control to reduce risk of drug interactions or adverse drug effects.
COMMENCING ANTIRETROVIRAL THERAPY – WHAT TO START WITH 4
MONITORING ANTIRETROVIRAL THERAPY
When initiating therapy in the patient naive to antiretroviral therapy, one should begin with a In order to determine the appropriate time for changes in antiretroviral therapy, there must be regimen that is expected to achieve sustained suppression of plasma HIV RNA (ie. HAART), effective and close follow-up. Monitoring antiretroviral therapy should entail, at least, the a sustained increase in CD4+ T cell count, and a favorable clinical outcome (i.e., delayed progression to AIDS and death). Additional consideration should be given to the regimen’spill burden, dosing frequency, food requirements, convenience, toxicity, and drug interaction Clinical aspects
profile compared with other regimens.
The clinical well-being of the patient should be monitored. With effective therapy, clinicalsigns and symptoms should gradually improve or disappear. Development of new Antiretroviral therapy comprises of one choice each from Column A and B
opportunistic infections would often mean treatment failure unless they occur during the first Drugs are listed in alphabetical, not priority, order
few weeks of treatment. The Karnofsky score (refer to Appendix G) may also be useful in COLUMN A
‘quantifying’ the patient’s health.
n Stavudine + Didanosine 11
Adverse drug effects should also be actively sought so as to ensure good adherence. A Strongly
n Indinavir 9,11
n Stavudine + Lamivudine 10
check on drug compliance is made regularly and this may include performing pill counts, recommended
n Zidovudine + Didanosine
interviewing family members and parameters like mean corpuscular volume (MCV) if n Ritonavir + Indinavir
n Zidovudine + Lamivudine
n Ritonavir + Saquinavir (SGC/HGC)
n Didanosine + Lamivudine
CD4+ / CD8+ cell count
n Zidovudine + Zalcitabine
CD4+ / CD8+ cell counts should be regularly monitored i.e. 3 – 6 monthly. Specimens for n Saquinavir SGC
CD4+ cell measurements should be taken at the same time of day and preferably when thepatient is not having an acute opportunistic disease. Sending blood specimens for CD4+ n Hydroxyurea in combination with any antiretroviral drugs
cell counts to the same laboratory will reduce inter-laboratory inconsistencies.
n Ritonavir + Nelfinavir
n Stavudine + Zidovudine
Viral Load assays
n Saquinavir- HGC
n Zalcitabine + Didanosine
Viral load (VL) monitoring is necessary in patients who are on optimal antiretroviral therapy.
n Zalcitabine + Lamivudine
The first VL assay should be done at least 2 months after initiation of therapy. The expected n Zalcitabine + Stavudine
VL reduction is at least a 2 log10 reduction (ie. 100 fold reduction) by 2 months of therapy.
n All monotherapies whether from Column A or B
Subsequently VL assays maybe done at 3 monthly intervals if the VL at 2 months achieves n All dual nucleoside analogue regimens
the expected results; if not, it should be repeated earlier.
Examples of some possible combinations (not in any order of preference or efficacy)
Other laboratory investigations
• Stavudine + Didanosine + Efavirenz
The other laboratory investigations are requested for the following reasons: • Stavudine + Didanosine + Indinavir + Ritonavir
Supportive evidence of disease progression • Zidovudine + Lamivudine + Efavirenz 8
• Zidovudine + Lamivudine + Indinavir + Ritonavir
Detection of adverse drug effects and other therapeutic complications The choice of the initial regimen should be carefully chosen as the success of antiretroviral The common investigations requested at regular intervals include; full blood counts, liver treatment is best seen in treatment-naive patients. Decision on the actual regimen will be and renal profile, erythrocyte sedimentation rate, creatine kinase (if on zidovudine) and serum amylase (if using didanosine, zalcitabine).
If patients are on protease inhibitors, 6-monthly serum lipid and 3-monthly blood sugar assays should be performed. Hyperglycemia is treated according to standard diabetic u ability of the individual to tolerate and comply / adhere with certain combinations protocols. Raised serum lipids should be approached with dietary advice and counseling, u adverse effects of the antiretroviral agents failing which lipid-lowering therapy may need to be commenced especially if other risk u the patient’s financial situation (ie. affordability) and the cost of the regimen factors for ischaemic heart disease are present.
Thus treatment will have to be individualized.
Notes : Refer to Appendix A for dosages, major toxicities, drug interactions and other specialinstructions CHANGING ANTIRETROVIRAL THERAPY – WHAT TO CHANGE TO? 4
CHANGING ANTIRETROVIRAL THERAPY – WHEN TO CHANGE? 4
Criteria for changing therapy:
Before any change of therapy is initiated, the indication or reason for change must always be • Failure to suppress plasma HIV RNA to undetectable levels within four to six months of
borne in mind. The indication for change of therapy will determine the type of changes that initiating therapy
In this regard, the degree of initial decrease in plasma HIV RNA and the overall trend indecreasing viremia should be considered. For instance, a patient with 10 6 viral copies/ml It is preferable that antiretroviral agents that have been used before should not be used prior to therapy who stabilizes after six months of therapy at an HIV RNA level that is again. It is preferable that all components of the previous regimen be changed and detectable but < 10,000 copies/ml may not warrant a change in therapy.
antiretroviral agents with the least potential for cross-resistance with the previous agents beused as substitutes. If a complete change is not possible, change at least 2 drugs; one of • Repeated detection of virus in plasma after initial suppression to undetectable levels,
which must include the protease inhibitor.
suggesting the development of resistance
However, the degree of plasma HIV RNA increase should be considered. The physician For adverse effects, intolerance or suboptimal adherence to an otherwise successful may consider short-term further observation in a patient whose plasma HIV RNA regimen (i.e. HIV RNA level below detectable limit), selective substitution of individual increases from undetectable to low-level detectability (e.g. ,50 – 5000 copies/ml) at four identifiable offending component is reasonable. Cross-resistance in this scenario maybe months. In this situation the patient should be followed very closely. It should be noted, however, that most patients who fall into this category will subsequently show progressiveincrease in plasma viremia that will likely require a change in the antiretroviral regimen.
Suggested Empiric Regimens for Patients Who Failed Antiretroviral Therapy
• Any reproducible significant increase, defined as 3-fold or greater, from the lowest point
of plasma HIV RNA not attributable to intercurrent infection, vaccination or test
methodology except as noted above
• Undetectable viremia in the patient receiving double nucleoside therapy
Patients currently receiving 2 NRTIs who have achieved the goal of no detectable virus have the option of continuing this regimen or may have modification to conform toregimens in the strongly recommended category. Prior experience indicates that most of these patients on double nucleoside therapy will eventually have virological failure with a frequency that is substantially greater compared to patients treated with the strongly • Persistently declining CD4+ T cell numbers, as measured on at least two separate
• Clinical deterioration
In this regard, a new AIDS-defining diagnosis that was acquired after the time treatment Note : Never add 1 new drug to a failed regime
was initiated suggests clinical deterioration but may or may not suggest failure ofantiretroviral therapy. If the antiretroviral effect of the therapy was poor (e.g, <10-fold * Suggested dosages for double PI regimens: reduction in viral RNA), then the judgement of therapeutic failure could be made. However, Ritonavir – 400mg bid + Saquinavir – 400mg bid if the antiretroviral effect was good but the patient was already severely Ritonavir – 100 or 200mg bid + Indinavir 800mg bid immunosuppressed, the appearance of a new opportunistic infection may notnecessarily reflect a failure of antiretroviral therapy, but rather a persistence of severeimmunocompromise that did not improve despite adequate suppression of virusreplication. Similarly, an accelerated decline in CD4+ T cell counts suggests progressiveimmune deficiency providing there are sufficient measurements to assure quality controlof CD4+ T cell measurements.
Potential Options For Changing Therapy
(IAS-USA Recommendation, JAMA 2000; 283-381)
Reason for Change
HIV RNA suppressed but still above target, HIV RNA above target, more than 8 – 16wk† GUIDELINES FOR PAEDIATRICS
Failure to reach target VL within 8 – 16wk† Failure to reach target VL within 24 – 36wk Prior success § but now confirmed drug failure § Prior success refers to patients who previously achieved target viral load but now have confirmed viral load above that † Actual time to achieve target viral load level (eg, HIV RNA< 50 copies/ml) varies depending on factors such as pretreatment HIV RNA level and regimen potency ‡ Attempts should be made to manage toxicity, but if unsuccessful, substitution of equally potent drug is appropriate. (Do not attempt this with suspected abacavir toxicity) ¶ For patients treated for 8 – 16wk with substantial reduction and continued decline in viral load (>1.5 log10 decrease) but still not reaching target viral load, intensification may be an option. Before using an intensification strategy, adherencemust be carefully assessed. GOALS OF ANTIRETROVIRAL THERAPY
This would be to decrease viral replication as much as possible for as long as possible In Malaysia, the number of HIV infections in women is rising and this trend appears to be resulting in preservation or reconstitution of the immune system and diminishing viral reflected in the increasing number of perinatal cases. Perinatal transmission now accounts dissemination thereby preventing disease progression and thus leading to improved quality for most of the children acquiring HIV infection.
Much of the advances in HIV are based on studies carried out in adult patients and limiteddata obtained from children. However specific clinical trials are currently being carried out in children and they include studies on highly active antiretroviral therapy, viral load monitoring, immunomodulatory therapies and others. For instance, results from recent paediatric trials involving symptomatic antiretroviral-naive patients have demonstrated the superiority of combination therapy of either zidovudine and lamivudine or zidovudine and didanosine(ACTG 152) over monotherapy in terms of virologic and immunologic benefits. Results from Therapeutic Strategy
the ACTG 338, a study conducted on antiretroviral experienced children, has demonstrated The aim is to decrease the viral load to as low as possible.
that combination therapy that include a protease inhibitor is virologically andimmunologically superior to dual nucleoside combination therapy.
This is achieved by using at least 2 antiretrovirals with no overlapping toxicity plusdemonstrated antiviral synergy so as to maximise the length of the response.
There are however unique considerations in perinatally acquired and paediatric HIVdisease: Effective management of the diverse needs of the HIV infected infant or child and their most are thought to acquire the infection perinatally i.e. around the time of birth, and families requires a multidisciplinary team approach in a family centred clinic that includes therefore raises the possibility of treatment at initial or primary infection physicians, nurses, social workers, psychologists, dieticians, pharmacists and others.
the infection is acquired when the immune system is developing, thus clinicalmanifestations and the course of immunologic and virologic markers differ from adults Knowledge of HIV disease and therapy in children are rapidly evolving. Thus this guideline treatment in the child will occur in the context of prior exposure to AZT and other antiretrovirals will need to be reviewed and updated as more advances in HIV infection in children occurs.
given to the mother as prophylaxis for perinatal transmission and maternal treatment differing pharmacokinetics from adults and that changes occur with growth anddevelopment Category of Drugs
issues of adherence are a special concern in children There are 3 main categories of drugs currently employed in HIV disease. These are thenucleoside reverse transcriptase inhibitors (NRTIs), the non-nucleoside reversetranscriptase inhibitors (NNRTIs) and the protease inhibitors (PIs) (refer to Appendix A forDrug Details).
DIAGNOSIS OF HIV INFECTION
In infants (perinatal infection)
For confirmation of positive status, need at least 2 positive tests (i.e. HIV RNA by PCR, p24 Ministry approved drugs that are available at antigen, &/or viral culture) performed at separate intervals. The use of p24 antigen alone is not sufficient to diagnose infection in infants aged less than 1 month because of high frequency of false positive assays during this time. In Malaysia, diagnosis of HIV infection in infants is based on PCR technique measuring HIV RNA level. Viral culture is not a routine test as it is more complex and expensive to carry out.
In children of more than 18 months of age
Nevirapine is available as in the syrup form Need at least 2 consecutive positive HIV antibody tests Not infected (perinatal exposure)
Infection reasonably excluded :
2 negative virologic tests at less than 6 months of age, done more than 1 month of age (one test to be done between : 2 negative serologic tests, both done at more than 6 months age, at least 1 month apart, plus no clinical evidence of General Guidelines
HIV RNA concentration assays
As in adults, combination therapy is used in the treatment of all HIV children. Monotherapy is Tests for quantification of HIV viraemia are available commercially in Malaysia but are no longer recommended to treat HIV infection except for the first 6 weeks of life as expensive. Although it is recommended that every HIV infected individual be monitored using chemoprophylaxis to prevent perinatal transmission.
viral load assays, this may not be possible for the majority of our patients. The followinghowever, are short notes on the tests available, their uses and interpretation: The treatment should be tailored to individual needs and constraints.
Recent data show that the level of HIV RNA in the plasma accurately reflects the extent of In HIV infected children with suspected central nervous system (CNS) involvement, virus replication. Mellors et al reported on the correlation of plasma HIV RNA level with consideration should be given to include drugs with good CNS penetration such as disease progression and death and also provided conclusive evidence of the zidovudine (AZT), stavudine (d4T) or nevirapine(NVP).
independence of viral load from CD4+ cell counts with regards to prognosis.
The HIV RNA pattern in perinatally infected infants differs from that in infected adults. HighRNA copy numbers persist in infected children for prolonged periods. In one study2 HIVRNA levels were generally low at birth (i.e. < 10,000copies/ml) increasing to high values MONITORING DISEASE PROGRESSION
by 2 months, most having > 100,000 copies/ml (range undetectable to nearly 10 million)and then decreasing slowly. After the first year of life, the load slowly declines over the nextfew years.
Monitoring of disease progression is currently through immunologic (CD4+), virologic (viralload), and clinical means. Laboratory monitoring is done at diagnosis and every 3-4 months, High HIV RNA levels in infants and children as in adults correlate with disease more often if change of therapy is made or progression of disease occurs.
The methods include: RT-PCR and bDNA. Both are comparable with regard to Regular (2 – 3 monthly) follow-up with careful clinical assessment includes evaluating reproducibility and physiologic variability. However these tests cannot be used growth and development and careful examination for signs and symptoms of disease interchangeably and one test should be used consistently for the same patient. Ideally, the test should be sent to the same laboratory.
Immunologic (CD4+ T cell)
In infected children and adults, the CD4+ cell count declines as HIV infection progresses, Changes greater than 5-fold (0.7 log10) in infants < 2 years and greater than 3-fold (0.5 log10) and patients with lower CD4+ cell count have a poorer prognosis than patients with higher in children • 2 years after repeated testing should be considered a significant change. No counts. It is useful to regard the CD4+ values as indicative of the level of alteration in therapy should be made as a result of a change in HIV copy number unless this immunosuppression. Recent data indicate that CD4+ percentage and HIV RNA-copy change is confirmed by a second measurement.
number used together can more accurately define prognosis.
CD4+ counts are age-dependent, being higher in infants and young children than in adults COMMENCING ANTIRETROVIRAL THERAPY – WHEN TO START
and slowly declining to adult values by 6 years. Therefore age-related definitions of immunesuppression are applied (refer to Appendix C). A change in CD4+ percentage, not number,may be a better marker of identifying disease progression in children. Immunologic Prerequisites
evidence of immunosuppression occurs when CD4+ percentage values approach <25%. Of v Intensive education of caregivers and patients about the importance of adherence to the concern also is a rapid and substantial drop in CD4+ percentage e.g. 35 to 25% or >30% in prescribed treatment regimen should be provided before therapy is initiated so that • potential problems and solutions can be identified, and• frequent follow-up can be provided to assess virologic response to therapy, Measurement of CD4+ cell values can be associated with considerable intrapatient variation. For example, intercurrent illness or vaccinations may produce a transientdecrease in CD4+ T-cell values. Thus CD4+ measurements are best made when the child v Parents or caregivers should be ready to comply with the difficult regimens. Non- is clinically stable. Change or modification of therapy should therefore not be based on a adherence to medication allows continued viral replication and encourages the single value but the change in CD4+ value should be substantiated by a second emergence of drug resistance and subsequent treatment failure.
determination with at least 1 week interval between determinations.
Indications for initiation of ARVT in children with HIV infection
Recommended antiretroviral regimens for initial therapy for HIV infection in children
v Clinical symptoms associated with HIV infection, ie. clinical categories A, B or C (refer Preferred Regimen
Evidence of clinical benefit and sustained suppression of HIV RNA in clinical trials in HIV-infected adults; clinical trials in HIV-infected children are ongoing.
v One highly active protease inhibitor (PI) plus two nucleoside reverse transcriptase v Evidence of immune suppression, indicated by CD4+ T-lymphocyte absolute number percentage, ie. immune category 2 or 3 (refer to Appendix C) • Preferred protease inhibitor for infants and children who cannot swallow pills or v Age < 12 months – regardless of clinical, immunologic or virologic status* • Alternative for children who can swallow pills or capsules: indinavir v For asymptomatic children aged • 1 year with normal immune status, two options canbe Preferred approach
: Initiate therapy, regardless of age or symptom status • The most data on use in children are available for the combinations of Alternative approach : Defer treatment in situations in which the risk for clinical
– zidovudine (AZT) and dideoxyinosine (ddI), and for disease progression is low and other factors (e.g. concern for the durability of response, safety and adherence) favour postponing treatment. In such cases, the • More limited data are available for the combinations of health-care provider should regularly monitor virologic, immunologic and clinical status. Factors to be considered in deciding to initiate therapy include the following: • High or increasing HIV RNA copy number; • Rapidly declining CD4+ T-lymphocyte number or percentage to values approaching those indicative of moderate immune suppression, i.e. immune category 2 (refer to Appendix C); * Clinical trial data documenting therapeutic benefit from this approach are not available, and information on drug dosing in neonates is limited. Because resistance to antiretroviral drugs(particularly protease inhibitors) can develop rapidly when drug concentrations fall below therapeutic v Alternatives for children who can swallow capsules: levels (either as a result of inadequate dosage or incomplete adherence), issues associated with adherence should be fully assessed and discussed with the HIV-infected infant’s caregivers before the decision to initiate therapy is made. ‚ Efavirenz plus Nelfinavir and 1 NRTI.
Less likely to produce sustained HIV RNA suppression in infected patients
v Nevirapine plus 2 NRTIs (AZT + ddI*; AZT + 3TC; D4T + 3TC) COMMENCING ANTIRETROVIRAL THERAPY – WHAT TO START WITH
v Abacavir + AZT + 3TC*(the combination of nevirapine, AZT and ddI produced substantial and sustained Combination therapy is recommended for all infants, children and adolescents who are suppression of viral replication in two of six infants first treated at age < 4 months) treated with antiretroviral agents. Combination therapy slows disease progression and improves survival, Offer only in Special Circumstances
results in greater and more sustained virologic response, delays development of virus mutations resistant to the drugs being used.
Monotherapy with the currently available antiretroviral drugs is no longer recommended.
Evidence against use because of overlapping toxicity and/or because use may bevirologically undesirable.
Many factors are involved in choice of regimen ability of care giver to comply with complex regimens, options available for subsequent treatment if initial regimen fails.
CHANGING ANTIRETROVIRAL THERAPY – WHEN TO CHANGE
Possible Treatment Options for ART-Experienced Patients
The following reasons may warrant a need to change antiretroviral therapy: Previous Regimen
• treatment failure due to development of viral resistance• adverse drugs reactions • 2 New NRTIs* and PI ± NNRTI• 2 New NRTIs and dual PI** Adherence problems that may potentially contribute to treatment failure should beaddressed and education regarding adherence to the therapy and training in the administration of the prescribed medications should be offered prior to initiation of the new • 2 New NRTIs and ritonavir + saquinavir** The indications for changing antiretroviral therapy is a failure of the current regimen with evidence of disease progression based on clinical, immunologic and virologic parameters: • 2 New NRTIs and ritonavir + saquinavir**• 2 New NRTIs and amprenavir + nevirapine • Clinical parameters warranting a change in therapy are progressive neurodevelopment
deterioration, growth failure and disease progression i.e. progression from one clinicalcategory to another based on the CDC 1994 paediatric classification according to the • Immunologic parameters that may warrant a change in therapy include change in
immune classification, a persistent decline of five percentile or more in the CD4+ cell percentage in patients with severe immune suppression (as per CDC 1994classification), and a rapid and significant decrease in CD4+ count.
** Pharmacokinetic data on dual protease inhibitor (PI) combinations is not available for children.
Based on adult data, when used with ritonavir, saquinavir SGC might be given 20 – 30 mg/kg q 12h up • Virologic parameters for initiating a new therapy include less than a minimally
to 400mg q 12h. Additional dual PI combinations (nelfinavir + indinavir, nelfinavir + ritonavir, indinavir acceptable virologic response after 8-12 weeks of therapy (< 10-fold decrease in viral load + ritonavir) are being evaluated in adults, but pharmacologic indications should be determined in from baseline in children receiving 2 NRTIs and a protease inhibitor, and < 5-fold children before dosing can be determined. decrease in children receiving two NRTIs), and persistent detectable HIV RNA in childrenwho initially responded with undetectable HIV RNA.
CHANGING ANTIRETROVIRAL THERAPY – WHAT TO CHANGE TO
v Long term adverse effects of new antiretrovirals especially in children may not yet be There are limited paediatric data on alternative antiretroviral drugs currently available.
However, some principles can be followed to make new drug therapy decisions in v Measures should be taken to ensure greater availability of highly active antiretrovirals to antiretroviral experienced HIV-infected children: v The provision of viral load monitoring should also be made more accessible to infected ‚ When therapy is changed because of drug toxicity, drugs with different toxicity and side- ‚ Adherence problems should be fully assessed as a potential cause of treatment failure and emphasis on adherence to the new regimen should be stressed.
‚ If drug resistance is suspected, change at least two drugs to new agents and the new regimen should include at least three drugs, if possible. Change in one drug oraddition of a new drug to a failing regimen is considered suboptimal15.
‚ Possible drug interactions and the patient’s quality of life should also be considered in the new regimen before therapy is changed in those with advanced disease.
ADDRESSING ADHERENCE ISSUES 12,13,16
Multiple studies have demonstrated that approximately 50% of all patients, across a widerange of diseases, therapies and individual characteristics, are non-compliant with Determinants
prescribed treatment regimens. An ACTG study of 76 patients on combination HIV therapyshowed that 36% of them missed at least 1 dose within the two weeks prior to the study. Even more worrying, this study was carried out on patients who were early in the course of therapy, a.) patient education related to the disease, the importance when adherence is expected to be best.
of adherence & resistance to therapy.
Adherence is now recognized as an important issue in antiretroviral therapy. It has been b.) giving pre-written materials with information regarding the highlighted in the International AIDS Society – USA Guidelines, which state that, drugs they will be on, why therapy is of benefit and why itis being prescribed. Allow for notes to be written by “the ability to maintain long term adherence is a major challenge. Less than excellent
patient during his visit (it has been found that much of adherence may result in virus breakthrough & emergence of drug resistant strains.
what is discussed during the visit is quickly forgotten).
Even short term non-adherence can lead to virus repopulating in lymph nodes.”
To take this aspect of the patient seriously by In HIV infection, patients are expected to take extremely complex regimens of therapy for a.) referral to appropriate rehabilitation centers, mental health prolonged periods of time without the guarantee that such therapy will ultimately be effective professionals or social service agencies/ NGOs. In order in preventing disability or death. This makes it even more difficult to ensure adherence.
to maximize antiretroviral treatment benefits, substance abuse has to be kept to a ‘controllable’ level.
This guideline has been prepared to remind doctors of the importance of adherence and theneed to discuss thoroughly with the patient this aspect before actually embarking on b.) providing ongoing counseling by health care providers at treatment. It is hoped that the recommendations will help doctors to make successful adherence an achievable goal. Multiple factors have been identified as associated with non-adherence.
a.) Close follow-up after initiation of therapy, to sort outproblems as they arise and not wait for usual In Malaysia, the scenario is different from that in the USA and other developed countries. Lack of finances is a major problem here. Another major issue is the stigma surrounding the b.) Ensure that patient truly understands the prescribed disease. This makes secrecy an important factor, causing patients to lack support systems and making the availability of a “safe space” in the workplace and elsewhere a problem.
Judgmental attitudes among health care workers are still prevalent.
Therefore, strategies required must target not just the patient, the physician and the treatment regime but also the general community and health care system.
c.) Help patient cue pill taking with other routine activities(e.g.: brushing teeth in the morning).
d.) Help patient develop special routine for pill taking duringchanges in normal schedule, e.g. during weekends & e.) Help patient develop simple cards (e.g. color coded cards)showing appearance, timings & number of pills to take.
f.) Suggest pill timers, e.g. alarms on watches.
g.) Construct regime using minimum number of drugs, whenpossible, e.g. combination pills & once or twice daily dosing agents, based on available therapy.
h.) monitoring of treatment progress by patient, e.g. patient to participate in their healthcare by keeping record oftheir CD4 / viral load counts, weight, nutritional intake, a.) Human support within the healthcare team: a. These issues need special consideration : give positive reinforcement (inform patient if CD4 Disclosure of diagnosis to paediatric patient Disclosure of diagnosis to baby-sitter/ school give assistance in organizing pill-taking routine.
iii) give contact number/ person to approach outside b. Discuss the issues listed below prior to starting therapy in older children as adherence may be lacking if theydo not understand the need for treatment. Also include iv) have member of team available to answer questions regarding pill taking schedules or problems with drugs (e.g. the clinic nurse or receptionist).
children refusing to take medications – how to avoidthis b.) Support within family and work environment: non-palatable drugs – how to disguise the taste help patient break news of diagnosis to family if iii) frequent blood taking to monitor progress – parents have at least one session with the family, to discuss ways of helping the patient & to allay their fears and iv) abandoned children – who is responsible clear misconceptions regarding the disease.
v) coping skills of caregivers – set up parent support iii) discuss with family, methods to help with adherence, e.g. reminding patient about his/her medications.
iv) support within the work environment is more difficultdue to confidentiality. However, if there is asympathetic friend/ colleague/ office nurse, who isaware of patient’s diagnosis, then to include him/her v) provide safe space for rest and privacy in takingmedications a.) Encourage disclosure and discussion between patient & physician so that proper advice can be given onalternative therapies. Many patients spend much of their savings on so-called “cures” & have no money left fortherapy. To facilitate open discussion with patient to helpthem make informed choices & decisions.
b.) Establish humane approach from various religious organizations towards patients, so that emotional & psychological support is available – can be facilitated byeducating religious workers on disease & methods of a.) Explore financial options with the patient such as EPF, SOCSO, insurance policies, social welfare allowance, b.) Assist patient in getting access from available options (e.g. liaising with EPF/ SOCSO officials, social welfare c.) To help patient discuss with family members who canassist financially CAREGIVER FACTORS
SOCIAL / ENVIRONMENTAL FACTORS
a.) More specialized training for staff concerned.
a.) Assist patient in informing family, if desired.
b.) Co-management of patients between various caregivers b.) Counsel family regarding all aspects of disease.
c.) Counsel family on methods of ensuring adherence by c.) Accreditation to centers/ physicians who treat patients giving continuous support, taking active part in patient with complex antiretroviral regime – an issue to be care & providing financial assistance, when needed.
Staff should be trained to be empathetic and non-judgmental by providing adequate education and exposure of health a.) Train staff to carry out approaches, such as: b.) Provide up to date information to patients via these c.) To do counseling and outreach programs via these groups through help- line service and face-to-face iv) helping patient prepare color coded cards, timers, pilldiaries etc, Increase knowledge and awareness of the general public: v) giving continuous counseling on medication & side i) through public awareness campaigns, forums, seminars, vi) giving positive feedback for successful adherence, ii) through media campaigns presented with a local flavor.
vii) identification of non-adherent patients by discussion, iii) with special emphasis on schools & colleges.
viii) carrying out defaulter tracing & reminding patients iv) by ensuring rural population is reached.
about appointments & purchasing medications, v) through sufficient information disseminated in vernacular ix) being accessible to patients via contact numbers, etc.
b.) Providing retreat and support groups for caregivers.
vi) by providing community centers for patients affected by the illness, and halfway homes/ respite care for those in c.) Review existing technical systems e.g. laboratory need. NGO involvement is to be encouraged.
problems, such as missing specimens and results.
HEALTH CARE SYSTEMS
a.) Coordinate various disciplines involved, e.g. physician, paediatrician, obstetrician, physiotherapist, dietitian, socialworker, etc. The approach should be flexible & user friendly to minimize the number of hospital visits & b.) Provide continuity of care from hospital to community, e.g. when a patient is discharged, a community nurse/ NGO worker should be informed for follow-up care.
Liaison workers are required for this.
c.) Ensure that the information provided to the patient isconsistent from one health care worker to another.
a.) evaluation of all educational programs by health careproviders so as to improve the quality of education.
b.) ongoing communication between health care system Guidelines for Post-exposure Prophylaxis 17
providers, policy makers and PWHAs to ensure all To provide care and support to HCWs through supervision, regular meetings, discussion and feedback CONCLUSION
It is hoped that these strategies, once implemented will help patients adhere to their drugregimes. However, no two patients are alike and all patients need to be assessedindividually with regimes tailored to their needs.
The health care provider needs to be committed to helping the patient to be adherent. Thereneeds to be close coordination between patients, caregivers, NGOs and the government, toimplement these strategies. No matter how effective the drugs that are available, we need toremember that, “ drugs don’t work if people don’t take them,” and in the case of antiretroviral therapy, “
take them correctly”.
Recommendations for the management of potentially exposed HCWs
Every health care setting need to establish a system for prompt reporting, evaluation,
Occupational exposure to HIV among health care workers is an increasingly common counseling, treatment and follow-up of occupational exposures that may place HCWs at risk problem as the incidence and prevalence of HIV infection in Malaysia continues to increase.
for acquiring bloodborne infection. Access to clinicians who can provide post exposure care Prevention of occupational exposure is a challenge that must be addressed in virtually every and to the antiretroviral agents for PEP should be readily available.
medical setting. Despite scrupulous attention to infection control practices, health careworkers remain at some risk for exposure. Developing strategies to manage exposed Exposure management
persons is therefore an important priority in every health care setting. Post-exposure caremust encompass two main goals 1) to prevent HIV infection among those sustaining Immediate post exposure care should emphasize the importance of decontaminating the exposure 2) to provide information and support during the follow-up interval until infection is exposed site as soon as possible. Wounds and skin sites that have been in contact with diagnosed or excluded with certainty.
blood or body fluids should be washed with soap and water; and mucous membranesshould be flushed with water. There is no evidence that the use of antiseptics for wound careor expressing fluid by squeezing the wound further reduces the risk for HIV transmission.
Risk for occupational transmission of HIV to HCWs
Prospective studies of HCWs have estimated that the average risk for HIV transmission after
Assessment of Infection Risk
a percutaneous exposure to HIV-infected blood is approximately 0.3% (95% CI=0.2-0.5%) After an occupational exposure, the source-person and the exposed HCW should be and after mucous membrane exposure is 0.09% (95% CI=0.0006-0.5%). The risk is evaluated to determine the need for HIV PEP. Follow-up for hepatitis B and C virus infections dependent upon factors such as the type of body fluid involved, the type of exposure that has occurred, the volume of fluid involved and the disease stage, and therefore the viral load ofthe source patient.
Evaluation of exposure
The exposure should be evaluated for potential to transmit HIV based on the type of body
Efficacy of post exposure prophylaxis
substance involved and the route and severity of the exposure. Exposures to blood, fluid Studies in animals and humans provide direct and indirect evidence of the efficacy of containing visible blood or other potentially infectious fluid (e.g. semen, vaginal secretions, antiretroviral drugs as agents for post exposure prophylaxis (PEP). There is little direct cerebrospinal, synovial, pleural, peritoneal, pericardial and amniotic fluids) or tissue evidence with which to assess the efficacy of PEP in humans. No prospective studies have through percutaneous injury (e.g. needlestick) or through contact with mucous membrane been performed and based on the current indirect evidence of PEP efficacy it is unlikely that are situations that pose a risk for bloodborne transmission. For skin exposures, follow-up is a placebo-control trial will be performed to demonstrate the efficacy of PEP.
indicated if it involves direct contact with body fluid as described above and there is evidenceof compromised skin integrity.
In a retrospective case-control study of HCWs, after controlling for other risk factors for HIVtransmission, the risk for HIV infection among HCWs who used Zidovudine as PEP wasreduced by approximately 81% (95% CI=43-94%). It should be noted that only a small Evaluation and testing of exposure source
number of cases were included in this study and the cases and controls were from different The person whose blood or body fluids are the source of an occupational exposure should cohorts. Failure of zidovudine PEP to prevent HIV infection in HCWs has been reported in at be evaluated for HIV infection. If the source is known to have HIV infection, the person’s stage of infection and the antiretroviral history should be assessed. If the exposure source isunknown, information about where and under what circumstances the exposure occurredshould be assessed epidemiologically for risk for transmission of HIV.
Antiretroviral agents for PEP
At present, zidovudine (AZT) is the only agent shown to prevent HIV transmission in humans.
There are no data to directly support the addition of other antiretroviral drugs to zidovudine to
enhance the effectiveness of the PEP regime. However in HIV infected individuals,
combination regimens have proved superior to monotherapy regimens in reducing HIV viral
load. Therefore theoretically, a combination of drugs with activity at different stages of the viral
replication cycle could offer an additive preventive effect in PEP, particularly for occupational
exposures that pose an increased risk for transmission.
SELECTION FACTORS – BASIC VS EXPANDED PEP REGIMEN
STRATIFICATION OF RISK OF TRANSMISSION
Determining the need for HIV post-exposure prophylaxis (PEP) after an occupational expose 1
Factors in selection of a PEP regimen
(Adapted from Center for Disease Control and Prevention. Public Health Service Guidelines for the Management of Selection of the PEP regimen should be based on the comparative risk represented by the Healthcare Worker Exposure to HIV and Recommendations for Post exposure Prophylaxis. MMWR 1988;47 (No.RR-7) : 1-35) exposure and information about the source. Most exposures will only require a two-drugregimen using 2 NRTIs. The addition of a third drug, usually a PI should be considered Step 1 : Determine the Exposure Code (EC)
where there is a very high risk for transmission or where drug resistance is suspected.
Is the source material bloody fluid, or other potentially infectious material (OPIM2) , or an PEP should be initiated as soon as possible. The interval after which PEP has no benefit has instrument contaminated with one of these substances? not been defined in human. PEP can be considered even up to 7 days in high risk cases.
PEP Recommendation – Basic and Expanded PEP regime
which there is a recognized zidovudine 600 mg/day in divided that poses an increased risk Basic regimenfor transmission (e.g. larger plus *In cases of intolerance to indinavir, efavirenz can be considered Occupational exposure to treatment experienced patients
When the source person’s virus is known or suspected to be resistant to one or more of the drugs considered for the PEP regimen, the selection of drugs to which the source person’s virus is unlikely to be resistant is recommended; expert consultation is advised. If thisinformation is not immediately available, initiation of PEP, if indicated, should not be delayed; changes in the PEP regimen can be made after PEP has been started, as appropriate.
1 This algorithm is intended to guide initial decisions about PEP and should be used in Re-evaluation of the exposed person should be considered within 72 hours post exposure, conjunction with other guidance provided in this report. especially as additional information about exposure or source person becomes available.
2 Semen or vaginal secretions; cerebrospinal, synovial, pleural, peritoneal, pericardial, or 3 Exposures to OPIM must be evaluated on a case-by-case basis. In general, these body substances are considered a low risk for transmission in health-care settings. Any unprotectedcontact to concentrated HIV in a research laboratory or production facility is considered anoccupational exposure that requires clinical evaluation to determine the need for PEP. 4 Skin integrity is considered compromised if there is evidence of chapped skin, dermatitis, 5 Contact with intact skin is not normally considered a risk for HIV transmission. However, if the exposure was to blood, and the circumstance suggests a higher volume exposure, (e.g. anextensive area of skin was exposed or there was prolonged contact with blood), the risk for HIVtransmission should be considered. 6 The combination of these severity factors (e.g. large-bore hollow needle and deep puncture) contribute to an elevated risk for transmission if the source person is HIV-positive. POST-EXPOSURE TESTING
Step 2 : Determine the HIV Status Code (HIV SC)
What is the HIV status of the exposure source? HCWs with occupational exposure to HIV should receive counseling, post exposure testing,and medical evaluation regardless of whether they receive PEP. HIV-antibody testing should be performed for at least 6 months post exposure (e.g. 6 weeks, 12 weeks and 6 months) Monitoring and Management of PEP Toxicity
If PEP is used, drug-toxicity assessment should be performed at baseline and again 2 weeks after starting PEP. Tests should include full blood count, renal liver function tests.
Monitoring for hyperglycemia should be included for HCWs whose PEP regimen includes aPI.
Counseling and Education
Although seroconversion following occupational exposure to HIV rarely occurs, the emotional impact of the exposure is often substantial. Therefore access to persons knowledgeable about occupational HIV transmission and who can deal with the manyconcerns raised is an important element of management.
1 A source is considered negative for HIV infection if there is laboratory documentation of a HCWs should be advised to adopt measures to prevent secondary transmission during the negative HIV antibody, HIV polymerase chain reaction (PCR). Or HIV p24 antigen test result first 6 – 12 week period after exposure. Prevention of sexual transmission, pregnancy and from a specimen collected at or near the time of exposure and there is no clinical evidence ofrecent retroviral-like illness. donation of tissue organs and body fluids should be advised. Discontinuation of breast-feeding should also be considered.
2 A source is considered infected with HIV (HIV positive) if more has been a positive laboratory result for HIV antibody, HIV PCR, or HIV p24 antigen or physician-diagnosed AIDS. Exposed HCWs who choose to take PEP should be advised of the importance of adherence 3 Examples are used as surrogates to estimate the HIV titer in an exposure source for purposes and completion of the prescribed regimen.
of considering PEP regimens and do not reflect all clinical situations that may be observed.
Although a high HIV titer (HIV SC 2) in an exposure source has been associated with anincreased risk for transmission, the possibility of transmission from a source with a low HIVtiter also must be considered. Step 3 : Determine the PEP Recommendation
2 NRTI + PI
Unknown source or status
Monotherapy or 2 NRTI
(Risk for exposure high)
Antiretroviral Drugs Fact Sheet
I. Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTI)
2 hours apart from ddI. is 50 mg, administer Lamivudine
clarithromycin decreases be necessary.
(administer 4 hrs apart) Reduced dosage in For i.v. solution:Refrigerated dilutedsolution stable for24 hrs.
II. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
III. Protease Inhibitors
metabolism. Potential for or 2 hours after a meal.
hyperglycemia and Indinavir increases the increases serumconcentration of bothdrugs.
increased levels of decrease digoxin levels.
metabolism of indinavir & over 5 days as concentrations of these Techniques to increase nelfinavir levels 1.5 fold, can also be crushed & Saquinavir
Cisapride, ErgotAlkaloids, Trizolam,Midazolam, Rifampin.
Drugs that increasesaquinavir levels:Ritonavir, Ketoconazole,Nelfinavir, Delavirdine.
1993 Revised Classification System For HIV Infection And Expanded Surveillance
1994 Revised HIV Paediatric Classification
Case Definition For AIDS Among Adults And Adolescents 2
I. Clinical categories
CD4+ Cell Category Clinical Category A
Clinical Category B
Clinical Category C
Children who have no signs or symptoms considered to be the result of HIV infection or who have only one of theconditions listed in category A.
Category A: Mildly Symptomatic
Childrien with two or more of the following conditions but none of the conditions listed in categories B and C: Lymphadenopathy (- 0.5cm at more than two sites; bilateral=one site) Category A Conditions
Category B Conditions
Category C Conditions
Recurrent or persistent upper respiratory infection, sinusitis or otitis media.
Category B: Moderately Symptomatic
Children who have symptomatic conditions other than those listed for category A or category C that are attributed to HIV infection. Examples of conditions in clinical category B include but are not limited to the following: Anaemia (< 8gm/dL), neutropenia (1,000/mm3), or thrombocytopenia (< 100,000mm3), Bacterial meningitis , pneumonia, or sepsis (single episode) Persistent oropharyngeal candidiasis (i.e thrush) Cytomegalovirus infection with onset before age 1 month Herpes simplex virus (HSV) stomatitis, recurrent (i.e., more than two episodes within 1year) HSV bronchitis, pneumonitis, or esophagitis with onset before age 1 month Herpes zoster (i.e., shingles) involving at least two distinct episodes or more than one dermatome Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia complex Toxoplasmosis with onset before age 1 month Varicella, disseminated (i.e., complicated chickenpox) Category C : Severely Symptomatic
Children who have any condition listed in the 1987 surveillance case definition for acquired immunodeficiency syndrome, with the exception of LIP (which is a category B condition).
II. Immune categories (based on age specific CD4+ T-cell count and percentage)
< 12 months
1 - 5 years
6 - 12 years
*MAC – Mycobacterium avium-intracellulare complex APPENDIX D
II. Use of Viral Loads
Relationship between HIV RNA copies / ml and log10 HIV RNA values
Use of CD4+ counts and viral load assays
Copies / ml
Copies / ml
Copies / ml
I. Use of CD4+ / CD8+ counts (CD=cluster differentiation )
To avoid influence of change in WBC, use %CD4+s : > or equal 29% = CD4+ count > 500/mm3 Note : Fold variation is obtained by dividing the larger HIV RNA level in copies / ml by the
smaller HIV RNA level in copies / ml e.g. If start at 100,000 copies / ml, Remember
The test must be done within 48 hours after blood collection. Do not ship if the blood sample
is expected to reach the laboratory after 48 hours.
The counts are highly variable. They vary
Summary Comparison of 2 quantitative HIV RNA Assays
: even from hour to hour in some HIV-infected people Generic Form
Branched-chain DNA (bDNA)
They are also significantly influenced by : other intercurrent infections,: alcohol intake Manufacturer
Standard Detection range 400 to 750,000
(copies / ml)
Note as well that, in some cases persons with less than 50 or 100 remain healthy; conversely Lower limit of detection
some with relatively high counts (over 400) are quite ill. (next generation test)
Comparison of results
Specimen volume (ml)
Separate plasma in < 6 hours of
Separate plasma in < 4 hours of
*Infected CD4+ cells have an average life span of < 2 days and that of HIV particle is < 1
day. Do not delay specimen preparation and shipping
As the assay kits are continually making improvements, it is sensible to choose one particularassay and use it exclusively.
It’s a technical variation if there’s < 0.3 log10 (2-fold drop) change.
Reflect real change in viral burden if there’s > 0.5 log10 (3-fold drop) change.
Role of double nucleosides in the era of HAART
Safety and Toxicity of Individual Drugs in Pregnancy 4,18
Since the introduction of protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI), the goal of antiretroviral therapy has been to achieve maximal viral suppression. Data that Long term animal
Animal teratogen studies
demonstrates residual viral replication when plasma HIV-1 RNA is above 50 copies / ml has underscored carcinogenicity studies
the risk of developing viral resistance, if maximal viral suppression is not achieved. Dual nucleosideregimens have not been able to achieve adequate viral suppression to ensure sustainable antiviral control. At best, there maybe a 1-1.5 log10 plasma viral load reduction which often rebounds between 6 Since treatment failure is inevitable, dual nucleoside regimens are no longer recom-
mended. The panel is unanimous in recommending that suboptimal therapies like dual nucleoside
regimens should not be used except in very exceptional situations. This may be considered in patients
who have very limited financial resources and are unable to access Highly Active Antiretroviral Therapy (HAART). For these patients, dual nucleoside regimens may be considered as a ‘time-buying’ exercise;especially when their CD4 cell counts are < 100-200 cells. The fact that the therapy will fail with time must be adequately explained to the patients and their significant others. Commencing dual nucleoside regi- mens as starting regimens will also limit future antiretroviral options for HAART if it does become accessible then. Current treatment policy of the Ministry of Health does not support the usage of dual Unanimous recommendation of expert panel:
The preferred treatment strategy in Malaysia in 2001 is :
Highly Active AntiRetroviral Therapy (HAART)
monkey-anencephaly,anophthalmia,microopthalmia Positive (rodent, liver adenomas Negative (but cryptorchidismand carcinomas in male mice) FDA pregnancy categories:
Adequate and well controlled studies of pregnant women fail to demonstrate a risk to the fetusduring the first trimester of pregnancy (and there is no evidence of risk during later trimester) Animal reproduction studies fail to demonstrate a risk to the fetus and adequate and well-controlled studies of pregnant women have not been conducted II Safety in human pregnancy has not been determined. Animal studies are either positive for fetal risk or have not been conducted. Thus the drug should not be used unless the potential benefitsoutweighs the potential risk to the fetus IV Positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, but the potential benefits from the use of the drug in pregnant women maybe acceptable despite its potential risks APPENDIX G
Karnofsky Performance Status Scale
HIV Websites and Support Groups
HIV/AIDS Treatment Information Service website Able to carry on normal activity, minor symptoms or signs or Normal activity with effort, some signs or symptoms of disease Cares for self; unable to carry on normal activity or to do active Requires occasional assistance, but is able to care for most of http://hopkins-aids.edu/publications/book/book_toc.html Requires considerable assistance and frequent medical care Disabled, requires special care and assistance http://hiv.medscape.com/Home/Topics/Aids/AIDS.html Severely disabled, hospitalization is indicted although death is II. HIV Support Groups
Malaysian Aids Council
Hospitalisation is necessary, very sick, active supportive Moribund, fatal processes progressing rapidly Off Jalan Sentul, 51000 Kuala LumpurTel: 03-4045 1033 Karnofsky DA, et al. Cancer 634-656; 1984 on HIV/AIDs: 03-707 7007Counseling: 03-4043 9711 Antiretroviral Treatment:Toll Free Line: 1800-881848Homepage: htp://www.mac.org.my Persatuan Pengasih Malaysia
3201 -A Jalan Syers
Off Langgak Tunku
Bukit Tunku, 50480 Kuala Lumpur
Pink Triangle Foundation
7C-1, 1st Floor Jalan lpoh Kecil
Off Jalan Raja Laut
50350 Kuala Lumpur
50760 Kuala Lumpur
Tel: 03-4044 4611
Fax : 03 -4044 4622
Positive Living e-mail : firstname.lastname@example.org
Pertubuhan Wanita Dan Kesihatan Kuala Lumpur
11. Mellors JW, Munoz A, Giorgi JV, et al., Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann of Intern Med 1997, 126:946-54 12. Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR, 1992.
Community AIDS Service Penang
13. Report of the NIH panel to define principles of therapy of HIV infection. MMWR 1998. 47: p.1-41 14. Guidelines for the use of Antiretroviral agents in HIV-infected Adults and Adolescents. Available at 15. Palella FJ Jr, Delaney KM, Moorman AC, et al., Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J 16. Powderly WG, Saag MS, Chapman S, et al., Predictors of optimal virological response to potent antiretroviral therapy. AIDS, 1999. 13: p. 1873-1880.
17. Montaner JSG, Hogg RS, Yip B, et al., Diminished effectiveness of antiretroviral therapy among patients initiating therapy with CD4+ T cell counts below 200/mm3 . 13th International AIDS Federation of Family Planning Association Malaysia
Conference. Durban, South Africa, 2000. (Abstract LbPeB7050).
18. Staszewski S, Morales-Ramirez J, Tashima KT, et al., Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N Engl J Med, 1999. 341: p. 1865-1873.
19. AVANTI study group. AVANTI-2. A randomized, double-blind trial to evaluate the efficacy and safety of Zidovudine plus Lamivudine versus Zidovudine plus Lamivudine plus Indinavir in HIV-infected antiretroviral naive patients. AIDS 2000, 14:367-74 Malaysian CARE
10. Squires K, Gulik R, Tebas P, et al. A comparison of Stavudine plus Lamivudine versus Zidovudine plus Lamivudine in combination with Indinavir in antiretroviral naïve individuals with HIV infection: selection of thymidine analog regimen therapy (START 1). AIDS 2000, 14: 1591-1600 11. Eron J, Murphy R, Peterson D, et al. A comparison of Stavudine, Didanosine and Indinavir with Zidovudine, Lamivudine and Indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START-II). AIDS 2000, 14:1601-1610 Email:email@example.comHomepage:http://www.mcare.org.my 12. Chesney MA, Factors affecting adherence to antiretroviral therapy. Clin Infect Dis, 2000. 30 Suppl The Buddies Of Ipoh
13. Cheever L, Forum for Collaborative HIV Research. What do we know about adherence levels in (A project of The Family Planning Association, Perak) different populations? Adherence to HIV therapy: Building a bridge to success. Available at http:// (Address of Family Planning Association Perak) www.gwu.edu/~chsrp/. Washington, D.C. 1999: p. 10.
58A-60A Regat Sri CempakaTawan Cempaka, 31400 lpoh, Perak 14. Andrew Carr, David Cooper, Adverse effects of antiretroviral therapy. Lancet, 2000. 356: p.1423 15. Max B, Sherer R, Management of the adverse effects of antiretroviral therapy and medication adherence. Clin Infect Dis, 2000. 30 Suppl 2: p. S96-S116.
16. Carr A, Samaras K, Thorisdottir A, et al., Diagnosis, prediction, and natural course of HIV-1 Kuala Lumpur AIDS Support Services Society
protease-inhibitor associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study.
Lancet, 1999. 353: p. 2093-2099.
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18. Hughes W, McDowell JA, Shenep J, et al., Safety and single-dose pharmacokinetics of abacavir (1592U89) in human immunodeficiency virus type 1-infected children. Antimicrobial Agents 11. Center for Disease Control and Prevention, Guidelines for the use of antiretroviral agents in Chemother, 1999. 43: p. 609-615.
paediatric HIV infection. MMWR, 1998. 47((No. RR-4)): p. 1-38.
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Suite 1250Philadelphia, Pennsylvania 19106-4476(215) 861-8200 NOVARTIS PHARMACEUTICALS CORPORATION TO PAY $422.5 MILLION FOR OFF-LABEL DRUG MARKETING Company reaches plea and civil settlement agreements PHILADELPHIA – A criminal information1 was filed today against NovartisPharmaceuticals Corporation (“NPC”) for the off-label marketing of the anti-epileptic drugTrileptal, anno