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
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 andPregnancy” 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 PAEDIATRICIAN MEMBERS OF THE PANEL MEMBERS OF THE PANEL (in alphabetical order) (in alphabetical order) CARERS TABLE OF CONTENTS MEMBER OF THE PANEL (1998) Chairman’s Message 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
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 INTRODUCTION 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 CD4 Count Viral Load Recommendation Symptomatic
– Pravastatin and fibrates can be used instead
• AIDS defining illness
• Psychotropic – Midazolam, Triazolam
• Severe Symptoms *
non-nucleosides reverse transcriptase inhibitors:
• Rifampicin –Not recommended with Nevirapine
Efavirenz can be used but at an increased dose of 800mg/day
• 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 monthThe 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
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 COLUMN B
‘quantifying’ the patient’s health. n Efavirenz 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 Nelfinavir 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 Nevirapine n Didanosine + Lamivudine CD4+ / CD8+ cell count n Ritonavir 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 specialinstructionsCHANGING ANTIRETROVIRAL THERAPY – WHAT TO CHANGE TO? 4 CHANGING ANTIRETROVIRAL THERAPY – WHEN TO CHANGE? 4 General Principles 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
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 Prior Regimen New regimen 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 occasions
• 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 aspretreatment HIV RNA level and regimen potency
‡ Attempts should be made to manage toxicity, but if unsuccessful, substitution of equally potent drug is appropriate. (Donot 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) butstill not reaching target viral load, intensification may be an option. Before using an intensification strategy, adherencemust be carefully assessed.GOALS OF ANTIRETROVIRAL THERAPY INTRODUCTION
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
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) Drug Category Comments
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. Clinical
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) Virologic Response
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
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
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
: 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, andinformation 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 withadherence should be fully assessed and discussed with the HIV-infected infant’s caregivers before thedecision to initiate therapy is made.
‚ Efavirenz plus Nelfinavir and 1 NRTI. Alternative Regimen 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. Not Recommended
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:
• 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 ISSUES
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 INTRODUCTION PATIENT FACTORS
Multiple studies have demonstrated that approximately 50% of all patients, across a widerange of diseases, therapies and individual characteristics, are non-compliant with
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 Determinants Strategies Determinants Strategies
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 Determinants Strategies
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
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”. INTRODUCTION 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
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 Regimen Category Application Drug Regimen
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 consideredOccupational 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, or3 Exposures to OPIM must be evaluated on a case-by-case basis. In general, these bodysubstances 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 theexposure 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 laboratoryresult 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 Suggested Regimen Medium risk High risk 2 NRTI + PI Unknown source or status Monotherapy or 2 NRTI (Risk for exposure high) APPENDICES APPENDIX A14,15,16 TOXICITIES INTERACTIONS INSTRUCTIONS Antiretroviral Drugs Fact Sheet Stavudine I. Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTI) TOXICITIES INTERACTIONS INSTRUCTIONS Didanosine Zalcitabine Zidovudine
2 hours apart from ddI. is 50 mg, administer
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 TOXICITIES INTERACTIONS INSTRUCTIONS TOXICITIES INTERACTIONS INSTRUCTIONS Nevirapine Indinavir
metabolism. Potential for or 2 hours after a meal.
hyperglycemia and Indinavir increases the
increases serumconcentration of bothdrugs. Efavirenz TOXICITIES INTERACTIONS INSTRUCTIONS TOXICITIES INTERACTIONS INSTRUCTIONS Nelfinavir Ritonavir
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 &
Cisapride, ErgotAlkaloids, Trizolam,Midazolam, Rifampin.
Drugs that increasesaquinavir levels:Ritonavir, Ketoconazole,Nelfinavir, Delavirdine. APPENDIX B APPENDIX C 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 Immune category Category 1 No suppression Category 2 Moderate suppression Category 3 Severe suppression *MAC – Mycobacterium avium-intracellulare complexAPPENDIX 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 ) Normal Ranges Calculation
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 / mle.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 peopleGeneric Form Branched-chain DNA (bDNA) They are also significantly influenced by
: other intercurrent infections,: alcohol intakeManufacturer 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; converselyLower limit of detection some with relatively high counts (over 400) are quite ill.(next generation test) Comparison of results Specimen volume (ml) Specimen collection Specimen preparation*
Separate plasma in < 6 hours of
Separate plasma in < 4 hours of Shipping Available in Remember
*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. APPENDIX E APPENDIX F 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 pregnancy Animal teratogen studies
demonstrates residual viral replication when plasma HIV-1 RNA is above 50 copies / ml has underscored
carcinogenicity studies category
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)
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 APPENDIX H Karnofsky Performance Status Scale HIV Websites and Support Groups I. Websites Description
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
Requires considerable assistance and frequent medical care
Disabled, requires special care and assistance
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 Rumah Pengasih 3201 -A Jalan Syers Off Langgak Tunku Bukit Tunku, 50480 Kuala Lumpur Hotline: 03-62013179 Fax: 03-62013013 E-mail:email@example.com Pink Triangle Foundation 7C-1, 1st Floor Jalan lpoh Kecil Off Jalan Raja Laut 50350 Kuala Lumpur or P.O.Box 11859 50760 Kuala Lumpur Tel: 03-4044 4611 Fax : 03 -4044 4622 E-mail: firstname.lastname@example.org Positive Living e-mail : email@example.com BIBLIOGRAPHY Pertubuhan Wanita Dan Kesihatan Kuala Lumpur Tingkat 7 Adults
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The Buddies Of Ipoh
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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
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