Download Guidelines on Antiretroviral therapy

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Guidelines on Antiretroviral therapy
in Pakistan
Version 17 November 2004
Version 28 October 2004
Table of contents
1.
2.
3.
4.
5.
Introduction ....................................................................................................... 3
Objectives .......................................................................................................... 4
Methods .............................................................................................................. 4
Introduction to Antiretroviral therapy .............................................................. 5
Starting Antiretroviral therapy ......................................................................... 8
5.1. Entry points .................................................................................................. 8
5.2. Criteria to start ART...................................................................................... 8
5.3. First line ART regimen ................................................................................ 10
5.4. Initial evaluation.......................................................................................... 13
5.4.1. Medical examination ........................................................................... 13
5.4.2. Counselling on treatment and adherence ........................................... 14
5.4.3. Integrated medical care ....................................................................... 14
6. Monitoring therapy .......................................................................................... 16
6.1. Follow-up visits ........................................................................................... 16
6.2. Adherence counselling ............................................................................... 17
6.3. Substituting one ARV drug ......................................................................... 18
6.4. Switching ART for failure ............................................................................ 21
6.5. Stopping ART ............................................................................................. 22
7. Second line ART regimen in case of treatment failure ................................. 23
8. Considerations for specific categories of patients ...................................... 25
8.1. Women with reference to pregnancy .......................................................... 25
8.2. Tuberculosis ............................................................................................... 25
8.3. Hepatitis ..................................................................................................... 26
8.4. Children ...................................................................................................... 26
9. Ethical consideration ...................................................................................... 30
10. Recommendations for implementation ......................................................... 30
11. Annexes ........................................................................................................... 32
11.1. Supporting documents ............................................................................... 32
11.2. Agenda of the national workshop on ARV guidelines ................................. 33
11.3. List of participants during the national workshop ........................................ 34
11.4. Antiretroviral drugs ..................................................................................... 35
11.5. WHO clinical staging in adolescents 13 y.o and adults ........................... 37
11.6. 1994 revised classification in children < 13 years old ................................. 39
11.7. Adverse events grading toxicity .................................................................. 41
These guidelines were developed during a national consultation workshop, organised
by the National AIDS Control Program with the technical and financial support of the
World Health Organization.
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1. Introduction
In the past 2 decades, the HIV/AIDS epidemic has spread throughout the world
affecting now up to 42 million people and killing over 20 million people since the
beginning. Not a single country is now free of HIV.
Over 5 million people in South Asia are living with HIV/AIDS. Once, alien to Pakistan,
AIDS has now arisen as the most deadliest disease of today. Rightly known as a
merciless killer, silently consuming peoples of all ages. Still the most frightening fact
is the common man’s ability to get the proper cure. In Pakistan, it is estimated that
70,000 - 80,000 persons (0.1% of the adult population) are infected with the HIV
virus. The number of People Living with HIV/AIDs (PLWHAs) in Pakistan is estimated
at 74,000 persons (UNAIDS 2003 estimates) with 2,700 in need of treatment (NACP
estimates). Up to December 2003, a total of 2197 HIV+ cases, including 246 AIDS
cases, was reported to the NACP. These are serious risk factors that expose
Pakistan to a widespread epidemic if combating strategies are not adopted.
Pakistan has showed an increase in HIV transmission among high-risk populations
and the recent trends are alarming. The country is now facing a concentrated
epidemic in high-risk populations, in particular among injecting drug users. The facts
and figures of year 2004 showed that in certain injecting drug user groups, 1 person
out of 4 is already contaminated. This situation is far from the stage of introduction of
the virus in the country. There is a lack of awareness and knowledge regarding the
HIV epidemic situation, including in the health sector. Most people still believe
Pakistan to be protected by the prevailing socio-cultural norms, which has only
slowed the dynamic of the HIV epidemic. This is also due to limited access to care
and poor visibility of consequences of the epidemic.
The potent antiretroviral therapy (ART), combining 3 antiretroviral drugs, was
introduced in 1996 in Western countries, and showed a dramatic reduction in the
mortality and morbidity related to HIV-infection and improvement in the quality of life
of People Living with HIV/AIDS (PLWHAs). Although ART is not a cure and needs to
be taken life-long with challenges related to adherence, side-effects and drugresistance, HIV infection is now treatable and a dramatic expansion of ART coverage
has become more feasible. The drugs have become more affordable, funding for
AIDS has increased and ART has been shown to be possible in resource-poor
settings.
The Government of Pakistan has committed to the “3 by 5” initiative launched by the
World Health Organization. This initiative aims to treat 3 million persons by 2005,
which is half of the persons in need of treatment today. To reach this objective, WHO
recommends using a simplified approach and has developed simplified guidelines for
the prescription and monitoring of ART.
Poor Wrong practices of prescription, like interruptions in treatment or changes in
regimen can lead to:
 Risks to the patient: exposure to side effects and to development of virus
resistance, compromising his (her) future treatment options,
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
A public health risk:, by emergence and transmission of drug-resistant viruses,
requiring more sophisticated protocols difficult to afford in resource limited
settings.
For these reasons, standardized, simplified and sustainable protocols, based on
scientific evidence, are necessary for implementing ART and for expanding access.
Objectives
The main objective of this document is to provide a standard and simplified
approach, based on scientific evidence, for the use of antiretroviral therapy in
Pakistan. This document contains recommendations for adults and adolescents > 13
years old, while one chapter is dedicated to children less than 13 years old.
This document will serve as a reference manual in the public and the private sector
for the medical teams in charge of prescribing and monitoring PLWHAs under ART.
These guidelines are intended for the physicians, nurses, psychologists, counsellors
and other health care providers involved in an integrated medical care approach.
The guidelines consider when ART should begin, which ARV regimen should be
introduced, the reasons for changing ART and the regimens that should be continued
if treatment has to be changed. They also address how treatment should be
monitored, with specific reference to side-effects of ART and drug adherence, and
make specific recommendations for certain subgroups of patients.
3. Methods
These guidelines were developed during a national consultation workshop, from
October 12th to 14th 2004, conducted by the National AIDS Control Program with the
support of the World Health Organization.
A panel of participants including representatives from the National and Provincial
AIDS Control Programs, private infectious disease specialists, public sector
physicians identified for the HIV/AIDS treatment centers, NGOs, representatives of
People Living With HIV/AIDS and UN agencies from federal and provincial levels,
were invited to discuss and develop a rational consensus for the prescription and
follow-up of ART in Pakistan.
The participants were selected according to their experience and involvement in the
field of HIV and medical care. The size of the workshop was limited to 20 persons.
During the workshop, international guidelines developed by WHO as well as
guidelines developed in India were reviewed and served as reference documents for
the development of these guidelines. The draft was peer-reviewed by the NACP, a
panel of ID specialists, representatives of PLWHAs, WHO and UNAIDS.
The list of participants and the agenda of the workshop are presented in annexes 1
and 2.
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These guidelines will require updating at regular intervals according to experience
and new significant scientific progresses.
Introduction to Antiretroviral therapy
A continuous high level of replication of HIV takes place from the early stages of
infection. Despite this high level of replication, most patients remain apparently
healthy for many years and do not need ART as the infection is partially controlled by
their immune system. This is the clinically latent period of HIV infection.
With time, the ongoing HIV replication leads to progressive immune system damage,
in particular the destruction of CD4 lymphocytes, resulting in susceptibility to
opportunistic infections (OI), malignancies, HIV-related neurological diseases,
wasting and ultimately death. All these syndromes define the AIDS stage of HIV
infection.
Cohort studies have shown that 50% of the persons infected with HIV develop AIDS
within 10 years of the date of infection in the absence of ART.
Antiretroviral drugs aim to stop the HIV replication by blocking some of the viral
enzymes necessary for this. Five classes of drugs are currently available acting on 3
distinct enzymes (table 1 and figure 1). Details on formulation, doses, side effects for
each of the drugs are presented in the annexes.
Potent antiretroviral therapy consists of combining 3 drugs from 2 classes:
 2 Nucleoside Reverse Transcriptase Inhibitors (NRTI) + 1 Non Nucleoside
Reverse Transcriptase Inhibitor (NNRTI), or
 2 Nucleoside Reverse Transcriptase Inhibitors (NRTI) + 1 Protease Inhibitor (PI).
Table 1: List of antiretroviral drugs available and recommended
Target
Reverse Transcriptase
Viral protease
Drug class
Nucleoside Reverse
Transcriptase Inhibitor
(NRTI)
Non Nucleoside Reverse
Transcriptase Inhibitor
(NNRTI)
Protease Inhibitor
Drugs name
Zidovudine (ZDV or AZT)
Nevirapine (NVP)
Indinavir (IND)
Stavudine (D4T)
Efavirenz (EFV)
Nelfinavir (NFV)
(PI)
Lamivudine (3TC)
Saquinavir (SQV)
Didanosine (ddI)
Ritonavir (r) *
Abacavir (ABC)
Lopinavir/ritonavir (LPV/r)
Emtricitabine (FTC)
Atazanavir
Amprenavir
* Ritonavir is no longer used for its antiretroviral effect, but at low dose is used as a booster for other
PIs
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Two classes are more recent with a limited choice of drugs:
 Nucleotide Reverse Transcriptase Inhibitor: Tenofovir (TDF),
 Fusion inhibitor: Enfuvitride (T-20).
Figure 1: Current Targets of AntiRetroviral Drugs
Not all drugs can be combined together, due to potential interactions, antagonism or
increased rate and severity in side effects. The contraindicated combinations are:
 ZDV + D4T
 ddC + 3TC
 ddC + ddI
 ddC + d4T
 monotherapy (except pMTCT) or dual therapy.
NB: ddc (zalcitabine) was an NRTI which was previously used. It is not recommended for use any
more.
Fixed drug combinations (FDC), combining 2 to 3
drugs in the same pill, reduces the pill-burden,
simplifies the administration and favours adherence.
FDCs exist for NRTI and nevirapine, in adult dosages:
 D4T30 mg /3TC 150 mg /Nevirapine 200 mg,
 D4T40 mg /3TC 150 mg /Nevirapine 200 mg,
 ZDV 300 mg /3TC 150 mg /Nevirapine 200 mg,
 ZDV 300 mg /3TC 150 mg,
 D4T30 mg /3TC 150 mg
 D4T40 mg /3TC 150 mg
Adult Tablet
Children Tablets
and in paediatric dosages:
 Baby (3-10 kg) D4T6 mg /3TC 60 mg /Nevirapine 100 mg
 Junior (10-30 kg) D4T12 mg /3TC30 mg /Nevirapine50 mg
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No FDCs are available for Efavirenz or Protease Inhibitor drugs, except for the
lopinavir/ritonavir (LPV/r) combination. Most of the protease inhibitor combining
regimens require a high pill burden (10 to 15 pills a day).
Important Points to Remember about ART
 ART is not a cure. Ittreats HIV infection and prolongs life.
 Maximal viral suppression is the goal of therapy.
 Unlike any other infection, ART is recommended only to patients at a certain
stage of the disease. The prescription of ART requires a careful medical
evaluation to assess the medical criteria to start ART.
 Simultaneous initiation of three drugs is vital. No treatment should include only 1
or 2 drugs.
 Treatment is lifelong. Once established the treatment must not be interrupted or
discontinued unless due to standard medical criteria. Inappropriate interruption or
change, even if the patient is healthier, might expose the patient to virusresistance compromising his/her future chance for treatment.
 Treatment is expensive.
 A high level of adherence is critical. More than 95% of pills should be taken as
prescribed (doses and schedule), otherwise there is a high risk of the
development of virus-resistance compromising future chances of treatment.
 Drug-drug and food-drug interactions are common.
 For all these reasons, the patient has a key role to play in his(her) treatment and
should be informed and supported in that. Confidence building measures
consisting of counselling etc. are vital for maintaining adherence and compliance.
 Safer sexual practices are critical even among patients with clinical improvement.
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5. Starting Antiretroviral therapy
5.1.
Entry points
A critical set of entry points for identifying people in need of treatment are Voluntary
Counselling and Testing (VCT) services, which are limited in Pakistan for the
moment. VCT services within the community need to be strengthened and expanded
for:







STI patients,
High risk populations (sex workers, injecting drug users, sexual minorities, long
distance truckers),
Migrant workers who have been deported from overseas,
Blood donors,
NGOs working with high risk groups or PLWHAs
TB patients with symptoms or risk factors
VCT for the general population
VCT services should include counselling regarding the availability of ART, in order to
help client acceptance of a positive result and to orient positive persons on how to
access the available medical care services.
All clients testing HIV positive in Voluntary Counselling and Testing (VCT) services
need to be referred to a ART treatment center for medical examination. Two positive
tests, using different methods (e.g. 2 different rapid tests, 1 rapid test+1 ELISA), are
necessary to confirm HIV+ status.
An integrated family approach needs to be promoted for access to VCT and ART, to
address the vulnerability of women and children in accessing services. During VCT or
HIV related care for men, it is part of the responsibility of health care professionals to
repeatedly request the participation of the wife and children and to promote VCT and
HIV care for the whole nuclear family.
Very few people, including those in the health services, are aware of VCT services. A
communication strategy needs to be evolved and implemented to raise awareness
regarding existing VCT services and future ART services among the general
population and health care providers.
5.2.
Criteria to start ART
The eligibility of an individual to start ART will be assessed using standardised
criteria at the treatment center providing ART, after referral of all HIV+ persons
identified by the VCT services. These criteria to start ART should be purely clinical,
without any consideration of socio-economical, cultural or behavioral factors, so as to
ensure equitable access to ART to all PLWHAs who need it.
Without CD4 Count:
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If CD4 count is not available, treatment should be initiated in all adults/adolescents
presenting with clinical symptomatic disease (WHO Clinical Stages III and IV).
If Total Lymphocyte Count (TLC) is available, Stage II asymptomatic disease with
TLC values below 1,200/mm3 should also start ART. The WHO clinical staging is
presented in the annexes.
When to Start ARV in Adults/Adolescents
• If CD4 assay not available:
– WHO stage IV disease, regardless of TLC*
– WHO stage III disease, regardless of TLC
– WHO stage II disease with TLC <1200
*TLC=total lymphocyte count; only useful in symptomatic patients; in
absence of CD4, would not treat stage I asymptomatic adult
• If CD4 assay available:
– WHO stage IV disease, regardless of CD4
– WHO stage III disease, consider * using CD4 <350
to assist decision-making
– WHO stage I or II if CD4 <200
* In this situation, the decision to start or defer ARV treatment should take
in consideration not only the CD4 cell count and its evolution, but also
concomitant clinical conditions
With CD4 Counts Available
If CD4 testing is available, treatment should be initiated in all patients with CD4
count less than 200/mm3 (independently of symptoms)1.
The treatment of patients should not be dependant on the possibility of a CD4 cell
count determination. However, this test can be helpful in categorizing patients with
stage III conditions with respect to their need for immediate therapy. For example,
pulmonary tuberculosis can occur at any CD4 count level, and if the CD4 cell count is
well maintained (>350/mm3), it is reasonable to defer ART and continue to monitor
the patient. CD4 might also be helpful in identifying asymptomatic patients (stage I
and II) with severe immunodeficiency (<200/mm3) who should start ART.
CD4 testing is also helpful for treatment monitoring and as much as possible an
implementation plan to make CD4 testing available should be developed in parallel to
the implementation of ART. Public-private partnerships could be established for CD4
testing being performed in private facilities where available, free of charge for the
patients.
1
ARV can also be considered if CD4 count is between 200 and 350/mm3 (independently of
symptoms).
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5.3.
First line ART regimen
The recommended preferential 1st line regimen in Pakistan is D4T/3TC/NVP in a
fixed drug combination (FDC).
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Nevirapine should be prescribed at half dose (200 mg once daily) for 14 days to
avoid side effects and then increases to the full dose of 200 mg twice daily,
D4T should be prescribed according to the patient’s weight:
o < 60 kg: 30 mg twice daily
o > 60 kg: 40 mg twice daily
3TC: 150 mg twice daily.
First line regimen in Adults/Adolescents
• Preferential: D4T/3TC/Nevirapine
• In men and women,
• fixed drug combination, with or without food
• If patients < 60 kg
– 14 first days: (D4T30 mg/3TC150 mg) twice daily +
NVP200mg once daily =3 pills/day
– Then: (D4T30 mg/3TC150 mg /NVP200mg ) twice daily
=2pills/day
• If patients > 60 kg
– 14 first days: (D4T40 mg/3TC150 mg) twice daily +
NVP200mg once daily
– Then: (D4T40 mg/3TC150 mg /NVP200mg ) twice daily
• If TB ttt with Rifampicin: substitute Nevirapine for Efavirenz
With regards to food, these 1st line regimens do not have any restrictions. However,
ifgastro-intestinal intolerance develops, ingesting with food can improve the
symptoms, particularly with ZDV.
D4T/3TC/Nevirapine regimen is also the first line regimen in children at
paediatric dosage and for pregnant women.
The following Fixed Drug Combinations should be available:
 (D4T30 mg /3TC 150 mg /Nevirapine 200 mg),
 (D4T40 mg /3TC 150 mg /Nevirapine 200mg).
Other formulations should also be available in order to permit the NVP lead-in dose
schedule in the first 2 weeks of treatment:
 (D4T30 mg /3TC 150 mg) in FDC
 (D4T40 mg /3TC 150 mg) in FDC
 and Nevirapine200mg
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Both 30 and 40 mg D4T-based formulations should be available for patients weighing
less than 60 kg and patients weighing more than 60 kg, respectively.
Alternative drugs that should be available to compose 1st line regimens in case of
toxicity or contraindication are Zidovudine (ZDV) ,as a fixed dose combination with
3TC, and Efavirenz (table 2), resulting in a total of 4 regimens recommended for the
first line:

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

D4T + 3TC + nevirapine (preferential)
D4T + 3TC + efavirenz
ZDV + 3TC + nevirapine
ZDV + 3TC + efavirenz.
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Table 2: Description of ARV first line drugs
1st line
drugs
D4T
(preferential)
3TC *
dose
use with
TB ttt
Yes
Neuropathy
Pancreatitis
None
With or
without food
150 mg bd
With or
without food
Yes
Yes
With or
without food
Yes
With or
without food
Yes
Caution in
RMP
based
regimen
Yes
Nevirapine 14 first days:
(preferential)
200mg od
then:
200mg bd
ZDV
300 mg bd
(substitution)
(substitution)
use in
pregnant
women
Yes
< 60kg:
30 mg bd
> 60 kg:
40 mg bd
(preferential)
Efavirenz
Special
consideration
600 mg od
Bed time to
No (1st
avoid CNS
trimester)
symptoms
With or without
food
Contraceptive
method
Yes
Contraindications
Clinical hepatitis
Drug interaction
with rifampicin **
Severe anemia
<8 g/dl
Neutropenia
<750/mm3
1st trimester of
pregnancy
Adverse effects
1st line
substitution
Pancreatitis
Peripheral neuropathy
Lipoatrophy
Lactic acidosis with hepatic steatosis
(rare)
The risk of intolerance is higher in
association with ddI
Well tolerated
Lactic acidosis with hepatic steatosis
(rare)
Skin rash, Lyell, Stevens Johnson
syndrome,
Hepatic toxicity, elevated
transaminase levels, life-threatening
hepatitis
Anaemia, neutropenia, gastrointestinal
intolerance
headache, insomnia, myopathy
Lactic acidosis with hepatic steatosis
(rare)
ZDV
CNS symptoms: dizziness,
somnolence, insomia, confusion,
hallucinations, agitation
Elevated transaminase levels
Skin rash
Nevirapine
Efavirenz
D4T
* 3TC is also active on hepatitis B
** During TB treatment with rifampicin, Nevirapine can be used as an alternative drug, if EFV is contraindicated or not available, but with caution and close
clinical monitoring of hepatitis symptoms.
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5.4.
Initial evaluation
5.4.1. Medical examination
Prior to starting therapy, patients should have a confirmed HIV positive test (by 2
tests using different methods) and a complete history and physical examination. A
detailed clinical evaluation is essential to:
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assess the clinical stage of HIV infection (based on current and past HIV-related
illnesses),
identify current illnesses that would require treatment,
identify co-existing medical conditions (TB, pregnancy, major psychiatric illness)
that may influence the choice of therapy,
detail of concomitant medications including traditional therapy,
document the weight of the patient,
assess patients’ readiness for therapy.
With the d4T/3TC/NVP preferential 1st line regimen, no laboratory test is essential to
initiate the treatment. If ZDV is used, hemoglobinemia should always be evaluated
as a baseline.
If EFV is recommended and a contraceptive is not used, a pregnancy test is
mandatory before starting therapy and effective contraception must be achieved.
No other laboratory tests are essential for starting ART. However the list of
examinations desirable before starting ART is presented in Table 3. Those tests
should be performed if available and if it is not a financial obstacle for the patients in
accessing ART. If this is an issue, the tests should be free of charge.
Table 3: List of laboratory and other investigations before starting ART
Essential
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Confirmed HIV+ test (2 tests)
If ZDV: hemoglobinaemia
If EFV: pregnancy test
Desirable
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CD4-count
HIV viral load
Total lymphocyte count
Complete blood count
Chest X ray
Sputum smear for TB
Syphilis serology
Hepatitis serology
Liver function test
Blood chemistry profile
Urine examination
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5.4.2. Counselling on Treatment and Adherence
A patient starting ART should receive adequate treatment counselling before starting
therapy and should be committed to the continuation of the treatment. The following
points should be particularly stressed in the counselling sessions:
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ART it is not a cure, but a life long treatment,
How and when the medications should be taken,
the potential side effects which are more frequent during the first weeks of
treatment, and what to do in case these develop,
the potential interactions with other drugs, including traditional medicines, and
whether it is necessary to stop taking these when starting ART,
the need to strictly follow the doses and schedule as prescribed, due to the risk of
drug resistance that will compromise the chance for future treatment,
the need to monitor all family members of HIV positive patients and in need of
treatment.
In all cases, the patient should voluntarily consent to start ART and for its life
long continuation. ARV treatment is not considered as an emergency and its use
should be initiated only after checking the patient’s readiness and clinical criteria. A
patient’s readiness refers to the information he(she) was given by the
practitioner/counsellor and his (her) commitment to adhere to ARV prescription,
without any consideration of socio, cultural, economical, behavioural criteria.
One of the main aims of counselling is to help patients to identify methods to maintain
adherence and compliance to the treatment regimens as they are prescribed. If
possible, a family member should be identified and deputed by the patients as a
support or someone to remind them to take the drugs.
Counselling should be flexible and ART may be started at the first visit, if necessary.
However, it might be necessary to perform 1 or 2 adherence counselling sessions
prior to it.
5.4.3. Integrated medical care
An ART treatment centre should offer integrated medical care and support, which
should not be limited to simply ART. Other essential activities to be integrated are:
 Prophylaxis for opportunistic infections
 Psychological support,
 Nutrition support,
 Behaviour change communication, promotion of safe sexual practices and
condom promotion.
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All adults starting ART should be prescribed cotrimoxazole as primary prophylaxis
against bacterial infections like pneumocystosis and toxoplasmosis, unless their CD4
count is >200/mm3:
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Cotrimoxazole 480mg, once daily
Cotrimoxazole 960 mg, three times a week.
Or Dapsone 100 mg once daily in case of cotrimoxazole contraindication,
NB: For cotrimoxazole, both dosing regimens have been proved to be effective. The choice will
depend on the patient total pill burden and the most adequate dosing to support adherence (not
missing a dose).
Prophylaxis for tuberculosis is recommended for PPD-positive HIV-infected
individuals who do not have active tuberculosis. Prophylaxis for tuberculosis should
be prescribed only if it is possible to exclude active TB (chest X ray and sputum
examination), due to the risk of development of resistance.

Isoniazid 5mg/kg or 300 mg once daily during 6 months, is the recommended
regimen.
The use of chemoprophylaxis for major OI (pneumocystosis, toxoplasmosis and TB)
should be started as soon as possible if indicated, even before initiating ART.
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6. Monitoring therapy
6.1.
Follow-up visits
Once ART is started, a reasonable minimum schedule for clinical monitoring
includes:
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
a first follow-up visit at 2 weeks to increase the prescription of nevirapine to full
dose,
and a minimum of every three to four months thereafter.
Monthly visits are encouraged, in particular in the first months of treatment to
reinforce adherence, screen for side effects and immune reconstitution syndromes
(see below) which are more frequent at the beginning. The frequency of visits should
be adapted to the patient’s convenience (for example for those living far from the
treatment centre).
Follow-up visits should be scheduled a few days before the patient’s current stock of
ARV drugs is due to finish.
At each visit, a clinical examination should be conducted to:
 Assess signs and symptoms of potential drug toxicity (table 5),
 Assess the response to therapy (table 6),
o Body weight,
o Occurrence of symptoms related to OI,
 Assess and support of adherence.
For 1st line regimens, the use of any laboratory monitoring test is generally
recommended only on a symptom-directed basis. Routine monitoring of
transaminases, Hb or pancreatic enzymes in patients without clinical complaints is
not necessary.
Table 4: list of laboratory and other investigations to monitor first line ART
Essential

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None
Only on a symptom-directed basis
Desirable
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CD4-count (q 6 to 12 months)
HIV viral load (q 6 to 12 months)
Hb, Full blood count
Chest X ray
Sputum smear for TB
Syphilis serology
Hepatitis B & C serology
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6.2.
Adherence counselling
For treatment success and optimal results, up to 95% of pills should be taken as
prescribed with respect to the dose and schedule. Poor adherence exposes the
patient to the risks of treatment failure, development of resistance and compromises
future treatment options. Poor adherence is also a public health threat to the
emergence and transmission of drug-resistant HIV.
Adherence is difficult for patients everywhere and is a dynamic process different for
each individual. Studies have shown that health providers are unable to predict which
of their patients will be adherent to their medications and which are not. Adherence
can be reinforced as and when needed.
During each follow-up visit, specific attention should be paid to reinforce adherence
by adherence counselling. As a pre-requisite, specific materials have to be developed
in local languages and adapted to the local context. Usually adherence counselling
sessions last for up to 30 minutes and are conducted by a nurse, psychologist or
counsellor. It is highly recommended that PLWHAs are also linked to a as ‘peer
counsellor’.
Adherence counselling functions not only as an assessment of actual adherence, but
also as a facility to help the patient identify the reasons for missing pills and the
solutions to reinforce adherence. Adherence implies an engaged and accurate
participation of a patient in a plan of care with mutual understanding, consent
and partnership. Adherence counselling should be comprehensive, always taking
into account that adherence is difficult and that poor adherence can happen to
everyone.
Among the reasons for poor adherence, the most frequent are:
 Stock-out of drugs: This might be related to poor programme management
which can have tremendous consequences on the continuity of the treatment. It
leads to inappropriate interruption and change in regimens with rapid emergence
of resistance. It might also be related to patients who were not able to attend the
scheduled appointment on time and thus run out of drugs. For patients living far
away or who might have problems attending appointments on time, a security
stock of ARVs could be given for a few days.
 Cost for the patient: The direct and indirect costs for the patient are a major
cause of poor adherence. Even if ART is free, the cost of laboratory monitoring
and even the cost of transportation if the patient lives far from the treatment
centre, might be an obstacle to accessing follow-up visits for prescription renewal.
 Inadequate understanding of the regimen (when and how to take what drugs).
For this reason, it is highly recommended to simplify drug administration by using
FDCs.
 Misconception about the disease and the treatment: ART is not a cure and
has to be taken lifelong even if the person is healthier.
 Drug interactions: ARVs have interaction with other medicines including
traditional medicines and the patients should be reminded to never take drugs
without informing their doctor.
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


Occurrence of side effects: Simple side effects, like gastro-intestinal symptoms,
might lead the patient to stop ART. It is very important when starting the regimen
to explain the potential side effects and what to do in case of occurrence of side
effects.
Depression. People who are depressed have more difficulty taking their
medicines. Psychological support to assess and treat depression is necessary.
Stigma and secrecy. People may have difficulties taking their pills during meals
because they do not want the others to notice. This is a problem of stigma and
confidentiality within the socio-familial context.
Assessment of adherence should be done at each visit by:
 Pill count (number of pills remaining since the last visit/ total of pills that should
have been taken since the last visit)
 Patient self-report (number of pills taken in the last 7 days/ number of pills that
should have been taken in the last 7 days).
 To support adherence and confidence in medical services, it is pivotal to develop
the concept of a medical team (patient, doctor, nurse, counsellor, psychologist) all
of whom are critical to respecting patient confidentiality, where the patient has to
be considered as a key actor for his (her) well-being.
 More frequent visits in the first weeks of treatment and prompt information about
the occurrence of specific side effects and their management during the initial
weeks are highly recommended to improve treatment adherence.
 All drug prescription and other related medical information should be given using
appropriate language and considering the patient’s emotional status and cultural
context.
 Use of simplified regimens with low pill burden and with minimal interference in
food and social habits, engagement of family members or close friends in the
patient's treatment process and use of patient support groups are recommended
as general strategies to improve ART adherence.
 Psychological and nutrition support have to be integrated into treatment follow-up
for the patient’s well-being as these factors are related to adherence.
6.3.
Substituting one ARV drug
Specific drug substitutions should be performed in case of suspected intolerance,
toxicity or specific contraindication to one or more components of the 1 st line regimen
used. Only the suspected drug should be changed.


In case of intolerance, toxicity or contraindication to d4T, it should be replaced by
ZDV. The major adverse effects associated with d4T are neuropathy and
lipodystrophy (generally after long term use). ZDV can cause GI side effects (self
limited) and anaemia (sometimes severe).
In case of intolerance, toxicity or contraindication to NVP, it should be replaced by
EFV. The major adverse effect associated with NVP are hepatitis and rash
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

(sometimes life threatening). EFV can also cause CNS effects (generally self
limited) and is contraindicated during the 1st trimester of pregnancy because of its
teratogenic risk.
NVP can interact with rifampicin with a high risk of hepatitis and should be
substituted by EFV during the period of the rifampicin-containing regimen for TB.
If EFV is contraindicated or not available, NVP can be prescribed with rifampicin
with close monitoring of clinical hepatitis.
3TC in general is well tolerated and rarely needs to be replaced.
Substituting 1 drug in preferential 1st line regimen
D4T/3TC/Nevirapine
• D4T - neuropathy or pancreatitis
 D4T for ZDV
• D4T related lipoatrophy
 D4T for ABC, ZDV or TDF (2nd line
drug)
• NVP related hepatotoxicity
 NVP for EFV
• NVP severe rash (but not life threatening)
 NVP for EFV
• NVP related life threatening rash
 NVP for NFV or SQV/r (2nd line drugs)
• TB ttt with rifampicin
 NVP for EFV
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Table 5: Major toxicities and other indications for drug substitution
Regimen
Toxicity or indications
Symptoms
directed lab
assessment (if
available)
D4T/3TC/NVP  D4T related neuropathy or
(preferential)
pancreatitis#
 Substitute D4T for ZDV
 D4T related lipoatrophy
 NVP related hepatotoxicity
Drug substitution
ALT
 Substitute D4T for ABC,
ZDV or TDF (2nd line drug)*
 Substitute NVP for EFV
 NVP severe rash (but not life
threatening)
 Substitute NVP for EFV
 NVP related life threatening rash
CXR, sputum
Hb, FBC
 Substitute NVP for NFV
or SQV/r (2nd line drugs)
 Substitute NVP for EFV**
 Substitute ZDV for D4T
ALT
 Substitute NVP for EFV
 rifampicin treatment for TB
ZDV/3TC/NVP  ZDV related persistent gastro
intestinal intolerance or
haematological toxicity
 NVP related hepatotoxicity
 NVP severe rash (but not life
threatening)
 Substitute NVP for EFV
 NVP related life threatening rash
 Substitute NVP for NFV
or SQV/r (2nd line drugs)
 Substitute NVP for EFV**
 Substitute D4T for ZDV
 rifampicin treatment for TB
D4T/3TC/EFV  D4T related neuropathy or
pancreatitis#
CXR, sputum
 D4T related lipoatrophy
 Substitute D4T for ABC,
ZDV or TDF (2nd line drug)*
 Substitute EFV for NVP
 EFV related persistent CNS toxicity
 Pregnancy***
ZDV/3TC/EFV  ZDV related persistent gastro
intestinal intolerance or
haematological toxicity
 EFV related persistent CNS toxicity
Pregnancy test
Hb, FBC
 Substitute EFV for NVP
 Substitute ZDV for D4T
 Substitute EFV for NVP
 Pregnancy***
Pregnancy test
 Substitute EFV for NVP
The measurement of blood amylase levels is not useful in many cases. A presumptive diagnosis of
pancreatitis should be made in the case of unexplained severe abdominal pain of more than 12 hours
of duration and the patient should be referred for adequate evaluation.
* if available, D4T may also be substituted by Abacavir, the only ARV drug which hase demonstrated
partial benefit in lipodystrophy. Substituting D4T will depend on patient reaction. Substituting D4T
typically does not reverse lipoatrophy but may slow its progression. Tenofovir (TDF, recommended as
2nd line in Pakistan) can be considered as an alternative. In the absence of this drug, ddI (2nd line
regimen in Pakistan) and ZDV are alternatives to consider.
** During TB treatment with rifampicin, nevirapine can be used as an alternative drug, if EFV is
contraindicated or not available, but with caution and close clinical monitoring of hepatitis symptoms.
*** Pregnancy should not happen as an EFV-containing regimen should be prescribed only with an
accurate contraceptive method due to its teratogenicity
#
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6.4.
Switching ART due to Treatment Failure
Treatment failure can be defined clinically by assessing by disease
progression, immunologically using measurement of CD4 counts and/or
virologically by measuring HIV viral load (table 6).
The failure criteria recommended to be adopted in Pakistan are clinical. Adequate
adherence to 1st line regimen should be evaluated before switching ART.
Clinical disease should be differentiated from the immune reconstitution syndrome
that can be seen early after ARV is introduced, generally during the first 3 months.
This syndrome is characterized by the appearance of signs and symptoms of an
opportunistic disease after the start of ART in the setting of advanced
immunodeficiency, as an inflammatory response to previously subclinical
opportunistic infection. It is also possible that this immunological reconstitution may
lead to the development of atypical presentations of some opportunistic infections.
Due to the immune reconstitution syndrome, physicians should not consider clinical
progression as a failure during the first months. OIs should be treated as usual and
the ART regimen should not be changed.
In the case of treatment failure, ALL drugs of the initial regimen should be
replaced by the 2nd line regimen, after assessment of the level of adherence to
the first line regimen.
Table 6: Clinical and immunological definition of treatment failure in adults and
adolescents
Clinical signs of treatment failure
(preferential in Pakistan)


Occurrence of new opportunistic infection or 
malignancy signifying disease progression,
after at least 3 months on treatment. (This
must be differentiated form the immune
reconstitution syndrome which can occur in
the first 3 months of ART) see text

Recurrence of previous opportunistic infection
(except TB as reinfection may occur and
clinical evaluation is necessary to define
failure in case of TB recurrence)
CD4 cell criteria for treatment failure
(whenever CD4 monitoring is possible)
Return of CD4 cell count to pretherapy
baseline or below without other concomitant
infection to explain transient CD4 cell
decrease*
> 50% fall from therapy CD4 peak level
without other concomitant infection to explain
transient CD4 cell decrease*

Onset or recurrence of WHO stage III
conditions (including but not restricted to loss
of weight, chronic diarrhoea of unknown
etiology, prolonged fever of unknown etiology,
recurrent invasive bacterial infections or
recurrent/persistent mucosal candidiasis)
* if patient is asymptomatic and treatment failure is being defined by CD4 cell criteria alone,
consideration should be given to performing a confirmatory CD4 cell count if resources permit.
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6.5.
Stopping ART
ARV treatment should be stopped if adequate treatment adherence cannot be
achieved or temporarily in situations of life-threatening ARV-related adverse
effects or when the exact causative drug cannot be easily identified.
The occurrence of intercurrent opportunistic disease is not a general indication to
interrupt treatment, but if necessary, ART should be reintroduced only after the
patient’s clinical stabilization.
If permanent or temporary interruption of ART is indicated, all drugs should be
stopped simultaneously.
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7. Second line ART regimen in case of treatment failure
In the case of treatment failure, all drugs of the initial regimen should be replaced by
the 2nd line regimen, after assessment of the level of adherence to the first line
regimen. Switching ART due to treatment failure and starting the 2nd line regimen
may require referral to an infectious disease specialist.
The recommended preferential 2nd line regimen in Pakistan is tenofovir (TDF) +
ddI (in enteric coated formulation) + Saquinavir boosted ritonavir (SQV/r).
Nelfinavir (NFV) is recommended as the most suitable alternative PI drug in case of
SQV/r intolerance or in settings without safe cold chain facilities. Then two second
line regimens for failure should be available:
 TDF+ddI+SQV/r
(preferential)
 TDF+ddI+NFV
Both regimens have a high pill burden with 12 to 14 pills to take every day. No FDC
exists.
The conventional ddI dose should be reduced to 250 mg (> 60 kg) or 125 mg (< 60
mg) because of drug interactions with TDF.
TDF can cause renal toxicity and ddI can be associated with neuropathy and
pancreatitis. SQV/r can promote GI intolerance and dyslipidemia. NFV can cause
diarrhoea. Both PI options currently require high pill burden.
During 2nd line treatment, fasting glucose and lipids levels should be evaluated at
baseline and subsequently periodically due to PI use. Basal and periodic BUN (blood
urea nitrogen) or creatinine measurement is also recommended if TDF is used. Other
laboratory tests for toxicity monitoring are mandatory only if specific related
symptoms are observed.
In 2nd line, the selected drugs should preferentially taken with food, with the
exception of ddI that should be ingested on an empty stomach.
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Table 7: Description of ARV second line drugs
1st line
drugs
dose
Tenofovir
(TDF)
300 mg od
With food
(fat meal)
ddI (enteric
< 60kg:
125mg od*
> 60 kg:
250mg od*
Empty
stomach
coated EC
formulation)
Saquinavir
boosted by
ritonavir
SQR/r**
1000mg/100mg
bd or
Nelfinavir
(NFV)
1250 mg bd
1600mg/200mg
od
Special
consideration
use in
pregnant
women
Use with
caution***
use with
TB ttt
Yes
Gastrointestinal intolerance
Renal toxicity
Yes
Yes
Yes
Yes
Yes
Yes
Pancreatitis
Peripheral neuropathy
Nausea, diarrhoea
Lactic acidosis with hepatic
steatosis (rare)
Gastrointestinal intolerance,
nausea, vomiting, headache,
elevated transaminases
enzymes, hyperglycaemia, fat
redistribution and lipid
abnormalities
Diarrhoea, hyperglycaemia, fat
redistribution and lipid
abnormalities
(1/2 h before or 2 h
after meals)
Cold chain#
With food
With food
Adverse effects
Essential lab monitoring
(otherwise symptoms directed)
BUN (blood urea nitrogen) or
creatininaemia
Fasting glycaemia and lipids
Fasting glycaemia and lipids
* Conventional ddI doses reduced by half because of drug interaction with TDF
** Both hard gel and soft gel capsule formulations can be used when SQV is combined with RTV
*** TDF not fully evaluated during pregnancy
# The cold chain specificities for storage of RTV and SQV soft gel capsules in pharmacies is between 2 to 8 °C. For patient use or in situations where the
refrigeration is not possible, the temperature should be maintained below 25 °C and it is safe for until 3 months. SQV in hard gel capsules does not need cold
chain.
24
8. Considerations for specific categories of patients
8.1.
Women with specific reference to pregnancy
For women, both pregnant and non-pregnant, the decision to start potent
antiretroviral therapy should be based on their clinical eligibility to ART as stated in
section 5.2.
In a pregnant woman, d4T/3TC/NVP is the preferential 1st line ART regimen.
EFV is contraindicated only during the 1st trimester and women prescribed a EFVcontaining regimen should receive and utilise an adequate contraceptive method
after a pregnancy test.
Symptomatic NVP-associated hepatic or serious rash toxicity, although uncommon,
is more frequent in women than in men and is more likely to be seen in women with
comparatively elevated CD4 cell counts (> 250/mm3). It is not know if pregnancy
further predisposes women to such toxicities but cases have been reported in
pregnant women.
For a second line regimen, SQV/r and ddI are considered safe drugs during
pregnancy. TDF has not been fully evaluated in pregnant women and should be
used with caution.
8.2.
Tuberculosis
Due to the frequency of HIV/TB coinfection, many patients who are candidates for
ART will have active TB. In addition, patients already receiving ART may develop
clinical TB. Effective treatment and control of TB is a central priority when developing
treatment strategies for co-infected patients.
The management of HIV and TB co-infection is complicated because of the high pill
burden and adherence, rifampicin interaction with NVP and PIs and drug toxicity.
In all cases, tuberculosis treatment following the DOTS strategy should be initiated
promptly in diagnosed cases of TB. The two major issues in the clinical management
of patients with HIV and TB are when to start ART and which regimen to use.
The optimal time in patients with TB is not known.
 ART is recommended for all patients with TB at high risk of HIV disease
progression and mortality (CD4 count <200 cells/mm3) and should be considered
in patients with CD4 < 350 cells/mm3.
 In the absence of CD4 cell-count, ART is recommended for all patients with TB.
 ART should be started as soon the patient has stabilized on this therapy (2 weeks
to 2 months after beginning of TB treatment).
Version 28 October 2004
In TB/HIV co-infection , the preferential 1st line regimen is d4T/3TC/EFV. EFV
should be used in its conventional dose. NVP can be used as an alternative drug if
EFV is not available or contra-indicated, but with caution and with a close clinical
monitoring of hepatitis symptoms. After completing the rifampicin-based TB
treatment, NVP can replace EFV using the full dose without any need of the usual
lead-in schedule.
In 2nd line regimens, SQV/r can be used with antituberculosis regimens
containing rifampin.
8.3.
Hepatitis
In HIV-Hepatitis B or Hepatitis C co-infected patients, the decision about NNRTI use
in the 1st line regimen should be made taking in consideration the patient’s clinical
status and the presence of clinical or laboratory evidence of active hepatic disease.
The simple presence of seropositivity to HBV or HCV is not a contraindication to
NVP, but close clinical monitoring is generally recommended.
All ARVs should be used with caution in patients with evidence of hepatic dysfunction
and ARVs with major hepatotoxic risk (NVP in the first 6-8 weeks of treatment and
RTV in full dose) should be avoided.
As 3TC and TDF have anti-HBV activity, the 1st line regimen must include 3TC,
and 2nd line regimen must include TDF, for patients with hepatitis B infection to
avoid flares.
8.4.
Children
These guidelines are mainly dedicated to ART in adolescents and adults. Reference
can be made to specific international guidelines (including “3x5 guidelines: treatment
guidelines for a public health approach) for more information on ART for children.
The laboratory diagnosis of HIV infection in infants of less than 18 months is difficult
because of the persistence of maternal antibodies. It requires an HIV viral load to
confirm the infection. Therefore the recommendations to initiate ART in children are
dependent on the age of the child and of the availability of virological tests (table 9).
Formulations for children are not available for all drugs. Solid formulations present
problems with swallowing in young children. Dosages must be adjusted as a child
grows. Splitting of adult dose tablets orcapsules may be the only way to provide
therapy to children, with the inherent risks of under or overdosing.
In HIV+ children, the preferential 1st line regimen is the same as in adults
(d4T/3TC/NVP). FDC combinations have being recently developed for this regimen
with 2 doses:

Baby (3-10 kg) D4T6 mg /3TC 30 mg /Nevirapine 50 mg
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Version 28 October 2004

Junior (10-30 kg) D4T12 mg /3TC 60 mg /Nevirapine 100 mg
ZDV can be used safely in children. EFV is approved for use in children of more than
3 years-old.
For the 2nd line regimen, SQV/r should be used only in children with a body
weight higher than 25 kg. TDF is not approved for paediatric use and should be
substituted by Abacavir.
ART regimen for children
First line regimen
 D4T/3TC/NVP in fixed drug combination (preferential)
 ZDV/3TC/NVP
 D4T/3TC/EFV (if > 3 years old)
 ZDV/3TC/EFV (if > 3 years old)
Second line regimen
 ABC/ddI/NFV
 ABC/ddI/SQV/r (if weight > 25 kg)
The laboratory assessments recommended for children on ART are the same as
those recommended for adults.
In addition to the clinical assessments recommended for adults, the clinical
monitoring of ART in children should cover:




Nutrition and nutritional status,
Weight and height increases,
Developmental milestones,
Neurological symptoms.
27
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Table 8: Paediatric drug doses
Drug
D4T
3TC
ZDV
ddI
Abacavir
Nevirapine
Dose











Efavirenz
(if > 3 years old)
Nelfinavir







<30 kg: 1mg/kg bd
30-60 kg: 30 mg bd
<30 days: 2 mg/kg bd
>30 days and <60 kg: 4mg/kg bd
<4 weeks: 4mg/kg bd
4 weeks to 13 years: 180 mg/ m 2 bd
<3 months: 50 mg/ m2 bd
3 months to 13 years: 90-120 mg/ m2 bd or 240 mg/ m2 od
<16 years or <37.5 kg: 8 mg/kg bd
15-30 days:
o 5 mg/kg od for 2 weeks
o then 120 mg/ m2 bd for 2 weeks
o then 200 mg/ m2 bd
>30 days to 13 years
o 120 mg/ m2 od for 2 weeks
o then 120-200 mg/ m2 bd
10-<15 kg: 200mg od
15-<20 kg: 250 mg od
20-<25 kg: 300 mg od
25-<33 kg: 350 mg od
33-<40 kg: 400 mg od
<1 year: 50 mg/kg td or 75 mg/kg bd
1 to <3 year: 55-65 mg/kg bd
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Version 28 October 2004
Table 9: WHO recommendations for initiating ART in infants and children
CD4
testing
Age
HIV diagnostic
testing
HIV virological
testing not
available
Treatment recommendation
WHO Paediatric Stages II and III disease with
CD4 <20%
WHO Paediatric Stage III irrespective of CD4 %
Positive HIV
virological test
If CD4
testing is
available
< 18 months
WHO Paediatric Stage II disease with
consideration of using CD4 <20% to assist in
decision-making
WHO Paediatric Stage I with CD4 <20%
WHO Paediatric Stage III disease, irrespective of
CD4 %
18 months
HIV antibody
seropositive
WHO Paediatric Stage II disease, with
consideration of using CD4 <15% to assist in
decision-making
WHO Paediatric Stage I disease with CD4 <15%
HIV virological
testing not
available
Treatment not recommended
WHO Paediatric Stage III, irrespective of total
lymphocyte count
If CD4
testing is not
available
<18 months
 18 months
Positive HIV
virological test
HIV antibody
seropositive
WHO Paediatric Stage II disease, with
consideration of using total lymphocyte count
<2500/mm3 to assist in decision-making
WHO Paediatric Stage III irrespective of total
lymphocyte count
WHO Paediatric Stage II disease, with
consideration of using total lymphocyte count
<1500/mm3 to assist in decision-making
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9. Ethical considerations
Stigma and discrimination toward PLWHAs and highrisk populations remain very high
among health staff in the public and private sector in Pakistan. Stigma and
discrimination can present an obstacle to accessing VCT and care. Codes of conduct
and the responsibility of health professionals need to be enforced among health staff.
ART treatment centres should advocate for solidarity, tolerance, compassion and
equity in access to care.
The concept of shared confidentiality needs to be respected between all members of
the the medical team, including laboratory technicians. Security measures should be
ensured for medical files with restricted access and secure storage. In the case of the
computerisation of patient data, identification numbers should be used and the
names of the patients should not be entered.
The consultation workshop stressed the high vulnerability of women and children in
the patriarchal society of Pakistan. In the socio-cultural context of Pakistan, medical
care of women and children is often dependent on the decision of males (husband,
father, brother). An integrated family approach needs to be promoted in accessing
VCT and care services. During VCT or HIV related care for men, it is part of the
medical responsibility to repeatedly request the participation of the wife and children
and to promote VCT and HIV care for the full nuclear family.
It is highly necessary to strengthen prevention during medical care. Behavior change
communication and condom promotion have to be integrated into ART services.
10. Recommendations for implementation

Core groups should be identified to develop specific policies covering the
following issues:
o Access to ART, including the private sector
o Prevention of Mother to Child Transmission (pMTCT),
o TB/HIV coinfection
o Post exposure prophylaxis (PEP) for professional and non professional
accidental injury, sexual intercourse, sexual violence
o Injecting drug use, hepatitis and ART

A plan of action should be developed for implementation and enlargement of
access to ART. This plan should include a mapping of existing and future services
for VCT and ART delivery in the public and private sector (profit and non profit
organizations). The plan of action should include the public private partnerships,
the role of social services, integration of services within the primary health care
system, the drug/reagent procurement and quality control measures, the
monitoring and evaluation system. Special attention should be paid to the publicprivate agreement for laboratory monitoring (CD4) being performed in the private
sector in the initial step.
30
Version 28 October 2004

A national core technical group on ART should be established with members
designated by the NACP. The group should include a limited number of specialist
ID doctors, specialists in public health, representatives from PLWHAs, UNAIDS
and WHO, with equitable representation of the provinces. The group should be
specifically in charge to answer technical points regarding prescription of ARV,
like the future revision of the guidelines.

Technical questions need to be addressed urgently in particular:
o Materials for adherence counseling in local languages, taking into
consideration the cultural, social and religious context
o A monitoring and evaluation system taking into account the core
international quantitative indicators (indicators to produce, data to collect
and forms for data collection). A qualitative indicator on the client’s
satisfaction should be added.
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Version 28 October 2004
11. Annexes
11.1.
Supporting documents

Scaling up antiretroviral therapy in resource-limited settings: Treatment guidelines
for a public health approach. WHO 2003 revision.

Guidelines on Antiretroviral Therapy in India. NACO, New Delhi, 2003.

Chronic HIV care with ARV therapy. Interim guidelines for 1st level facility health
workers. WHO 2004.

Access to HIV/AIDS drugs and diagnostics of acceptable quality. List of
prequalified products (WHO 8/2004).
http://mednet3.who.int/prequal/hiv/hivdefault.htm

A public health approach for scaling-up ARV treatment. A toolkit for programme
managers. WHO 2003.

Treating 3 million by 2005. Making it happen. WHO 2003.

Technical and Operational Recommendations to achieve 3 by 5. WHO 2004.

Working document on monitoring and evaluating of national ART programmes in
the rapid scale-up to 3 by 5.

Interim patient monitoring guidelines for HIV care and ART (draft 2004).
32
Version 28 October 2004
11.2.
Agenda of the national workshop on ARV guidelines
Tuesday October 12th
8:30-9:00
Registration
9:00-10:00
Opening session
10:00-10:30
Current access and strategic plan for access to ART in Pakistan
10:30-10:45
Tea break
10:45-11:30
International guidelines for ART
11:30-12:00
Integrated approach to TB/HIV coinfection in Pakistan
12:00-12:30
Current limits in access to voluntary confidential testing in high risk population
12:30-13:00
Discussion
13:00-14:00
Lunch
14:00-16:00
Working session: entry points and criteria to start ART
Wednesday October 13th
8:30-11:00
Working session: choice of regimen, treatment monitoring and adherence support
10:15-10:30
Tea break
11:00-13:00
Working session: Role of the community, drug procurement,
13:00-14:00
Lunch
14:00-15:00
“3x5” initiative: presentation and discussion
15:00-15:15
Tea break
15:15-16:00
Monitoring and evaluation of ART programs
Thursday October 14th
8:30:10:45
Working session: models of care in the perspective of universal access to ART
10:45-11:00
Tea break
11:00-13:00
Working session: plan of action for implementation of the ARV guidelines
13:00-14:00
Lunch
14:00-15:30
Writing session: national recommendations for ART
15:30-16:00
Closing remarks
33
Version 28 October 2004
11.3.
List of participants during the national workshop
Gen Karamat (Chairman)
Dr. Khalife Bile Mohamud
Dr. Asma Bokhari
Dr. Aldo Landi
Dr. Fayyaz Khan
Dr. A K Jamali
Mr. Abdul Rasool Zehri
Dr. Rajwal Khan
Dr. Perveen Farooqi
Dr. Faisal Sultan, ID Specialist
Dr. Nargis Hassan Farooqi
Dr. Mehmood Noor
Dr. Rizwan Aziz Kazi
Dr. Amer Raza
Dr. Zafar Toor
Dr. Aslam Khan, ID Specialist
Mr. Nazir Masih
Dr. AK Ghauri
Dr. Muhammad Imran
Dr. Ayesha Rasheed
Dr. Qudsia Uzma
Dr. Wajeeha Ghias
Dr. Mehmood Javaid
Dr. Samia Hashim
Dr. Yasmin Hadi
Dr. Marco Vitoria
Dr. Jean Michel Tassie
ED , National Institute of Health
WHO Representative, WHO Pakistan
National AIDS Control Programme,
Islamabad
Country Coordinator UNAIDS
Provincial AIDS Programme, Punjab
Provincial AIDS Programme, Sindh
Provincial
AIDS
Programme,
Balochistan
Provincial AIDS Programme, NWFP
Provincial AIDS Programme, AJK
Shaukat Khanum Hospital, Lahore
ARV, Treatment Centre, Civil Hospital,
Karachi
ARV, Treatment Centre, Hayatabad
Medical Complex, Peshawar
ARV,
Treatment
Centre,
PIMS,
Islamabad
Catholic Relief Services, Islamabad
National TB Programme, Rawalpindi
Aga Khan Hospital Karachi
New Light AIDS Awareness Group
Marie Stopes Society
National AIDS Control Programme,
Islamabad
National AIDS Control Programme,
Islamabad
National AIDS Control Programme,
Islamabad
GFATM
Shifa International Hospital Islamabad
UNAIDS Pakistan
WHO Pakistan
WHO HQ Geneva, Department of
HIV/AIDS
WHO Consultant EMRO
34
11.4.
Antiretroviral drugs
Drug
Formulation (mg)
adolescents and adults
Dose
adolescents and
adults
Special
Considerations
Adverse effects
Nucleoside Reverse transcriptase inhibitors
Zidovudine(ZDV)
Tablet : 100,250, 300*
Oral Solution: 50mg/5ml
300 mg bd
With or without food
Lamivudine (3TC)
Tablet : 150
Oral Solution: 50mg/5 ml
Tablet: 250, 400
150 mg bd
With or without food
empty stomach (1/2h
Didanosine (ddI)
Stavudine (d4T)
Capsule: 30,40
Oral solution: 5mg/ml
<60 kg:125 mg
bd or 250 mg od
>60 kg: 200 mg
bd or 400 mg od
<60kg:30 mg bd
>60 kg:40 mg bd
Abacavir (ABC)
Tablet: 300
300 mg bd
With or without food
Emtricitabine (FTC)
200
200 mg od
With or without food
prior or 2 h after meals)
doses reduced by
half with TDF
With or without food
Anaemia, neutropaenia, Gastrointestinal intolerance,
Headache, insomnia, myopathy
Lactic acidosis with hepatic steatosis (rare)
Minimal toxicity
Lactic acidosis with hepatic steatosis (rare)
Pancreatitis
Peripheral neuropathy
Nausea, diarrhoea
Lactic acidosis with hepatic steatosis (rare)
Pancreatitis
Peripheral neuropathy
Lactic acidosis with hepatic steatosis(rare)
Lipoatrophy
Hypersensitivity reaction (can be fatal)
Fever, rash, fatigue
Nausea, vomiting, anorexia
Respiratory symptoms(sore throat, cough)
Latic acidosis with hepatic steatosis (rare)
Headache, nausea, skin rash and discoloration
Lactic acidosis with hepatic steatosis(rare)
Non nucleoside reverse transcriptase inhibitors
Efavirenz (EFV)
Capsule 50 mg, 100 mg, 200
mg
600 mg od
Nevirapine (NVP)
Tablet 200 mg, oral
suspension 50mg/ 5ml
200 mg od x 14
days then 200
mg bd
With or without food
Bed time
administration to
avoid CNS
symptoms
With or without food
CNS Symptoms: dizziness, somnolence, insomnia,
confusion, hallucinations, agitation
Elevated transaminase levels
Skin rash
Skin rash, Stevens-Johnson Syndrome
Elevated serum aminotransferase levels
Hepatitis, life-threatening
Hepatic toxicity
Version 28 October 2004
Protease inhibitors
Indinavir (IND)
Capsule: 100, 200, 333, 400
mg
400 mg q8h
Empty stomach
Lot of fluid intake (2
litres per day)
Nelfinavir (NFV)
Tablet: 250 mg
With food
Saquinavir SGF (SQV)
Capsule gel: 200 mg
750 mg tds
1250 mg bd
1200 mg tds
Ritonavir
Capsule: 100 mg
Oral Solution: 400 mg/ 5 ml
600 mg bd
Use only as booster
PI
Lopinavir + ritonavir
(LPV/r)
533 mg/133 mg
bd
when combined
with EFV/NVP
400mg od
With food
Atazanavir
Capsule: 133.3 + 33 mg
400 mg/100 mg bd
Syrup: 400 mg. 5 ml + 600
mg/5 ml
200mg
Amprenavir
150 mg
1200 mg bd
With or without food
300 mg od
With food
With food
With food
Nephrolithiasis, gastrointestinal intolerance,
hyperglycaemia, fat redistribution and lipid
abnormalities, headache, dizziness, rash,
thrombocytopaenia, alopecia, bleeding in haemophilia
patients
Diarrhoea, hyperglycaemia, fat redistribution and lipid
abnormalities
Gastrointestinal intolerance, nausea, vomiting,
headache, elevated transaminase enzymes,
hyperglycaemia, fat redistribution and lipid
abnormalities
Gastrointestinal intolerance, nausea, vomiting,
paraesthesia, hepatitis and pancreatitis,
hyperglycaemia, fat redistribution and lipid
abnormalities
GI intolerance, nausea, vomiting, elevated
transaminase enzymes, hyperglycaemia, fat
redistribution and lipid abnormalities
Insufficient data
Allergy, hyperglycaemia, jaundice, GI intolerance, pain,
cough, depression, lipodystrophy
Well tolerated
abdominal pain, diarrhoea, hyperglycemia, nausea, oral
paresthesia, skin rash, and vomiting
skin rash
hyperglycemia, lipodystrophy
Nucleotide reverse transcriptase inhibitor
Tenofovir(TDF)
300 mg
abdominal pain, anorexia, asthenia, diarrhoea,
dizziness, dyspnoea, flatulence, headache,
hypophosphataemia, lactic acidosis, nausea,
pancreatitis, renal impairment, rash, vomiting
Lactic acidosis with hepatic steatosis (rare)
* ZDV available at this dosage as a co-formulation with 3TC
36
11.5.
WHO clinical staging in adolescents 13 y.o and adults
Clinical Stage I:
1. Asymptomatic
2. Persistent generalized lymphadenopathy (PGL)
Performance scale 1: Asymptomatic, normal activity
Clinical Stage II:
3. Weight loss, < 10% of body weight
4. Minor mucocutaneous manifestations (seborrheic dermatitis,
prurigo, fungal nail infections, recurrent oral ulcerations, angular
cheilitis)
5. Herpes Zoster, within the last 5 years
6. Recurrent upper respiratory tract infections (i.e., bacterial
sinusitis)
And/or Performance scale 2: symptomatic, normal activity
Clinical Stage III:
7. Weight loss, > 10% of body weight
8. Unexplained chronic diarrhoea, > 1 month
9. Unexplained prolonged fever (intermittent or constant), > 1
month
10. Oral candidiasis (thrush)
11. Oral hairy leukoplakia.
12. Pulmonary tuberculosis, within the past year
13. Severe bacterial infections (i.e., pneumonia, pyomyositis)
last
and/or performance scale 3: bed-ridden, < 50% of the day during the
month
Version 28 October 2004
Clinical Stage IV:
14. HIV wasting syndrome, as defined by CDC a
15. Pneumocystis carinii pneumonia
16. Toxoplasmosis of the brain
17. Cryptosporidiosis with diarrhoea, > 1 month
18. Cryptococcosis, extrapulmonary
19. Cytomegalovirus (CMV) disease of an organ other than liver,
spleen or lymph nodes
20. Herpes simplex virus (HSV) infection, mucocutaneous > 1
month, or visceral any duration
21. Progressive multifocal leukoencephalopathy (PML)
22. Any disseminated endemic mycosis (i.e. histoplasmosis,
coccidioidomycosis)
23. Candidiasis of the oesophagus, trachea, bronchi or lungs
24. Atypical mycobacteriosis, disseminated
25. Non-typhoid Salmonella septicaemia
26. Extrapulmonary tuberculosis
27. Lymphoma
28. Kaposi’s sarcoma (KS)
29. HIV encephalopathy, as defined by CDC b
And/or Performance scale 4: bed-ridden, > 50% of the day during the
last month
(Note: both definitive and presumptive diagnoses are acceptable.)
a
HIV wasting syndrome: Weight loss of > 10% of body weight, plus either unexplained
chronic diarrhoea (> 1 month), or chronic weakness and unexplained prolonged fever (> 1
month).
b
HIV encephalopathy: Clinical findings of disabling cognitive and/or motor dysfunction
interfering with activities of daily living, progressing over weeks to months, in the absence
of a concurrent illness or condition other than HIV infection that could explain the findings.
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Version 28 October 2004
11.6.
1994 revised classification in children < 13 years old
Category N: Not Symptomatic
Child with no signs or symptoms considered to be the result of HIV infection or with only 1 of the
conditions listed in category A.
Category A: Mildly Symptomatic
Children with  2 of the following only
- Lymphadenopathy (0.5cm at >2 different sites)
- Hepatomegaly
- Splenomegaly
- Dermatitis
- Parotitis
- Recurrent or persistent upper respiratory infection, sinusitis, or otitis media
Category B: Moderately Symptomatic
- Anemia (<8mg/dl), neutropenia (<1,000/mm3), or thrombocytopenia (<100,000/mm3) for 30 days.
- Bacterial meningitis, pneumonia, or sepsis (single episode)
- Candidiasis, oropharyngeal for > 2 months in children aged > 6 months
- Cardiomyopathy
- Hepatitis
- Cytomegalovirus infection with onset before age 1 month
- Diarrhoea, recurrent or chronic
- Herpes simplex virus (HSV) stomatitis, recurrent (> 2 episodes in 1 year)
- HSV bronchitis, pneumonitis, or esophagitis with onset before age 1 month
- Herpes zoster involving at least 2 distinct episodes or > one dermatome
- Leiomyosarcoma
- Nephropathy
- Nocardiosis
- Fever lasting > 1 month
- Lymphoid Interstitial Pneumonia (LIP)
- Toxoplasmosis with onset before age 1 month
- Varicella, disseminated
- Failure to Thrive: persistent weight loss > 10% of baseline OR downward crossing of two percentile
lines in the weight-for-age chart OR weight below the 5th percentile on the weight-for-age chart on 2
consecutive measurements at least 4 weeks apart.
Category C: Severely Symptomatic or AIDS
- Serious bacterial infections, multiple or recurrent within a 2 year period, of the following types:
septicemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body
cavity (exception of otitis media or mucosal abscess).
- Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs)
- Coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervical or hilar lymph
nodes)
- Cryptococcosis, extrapulmonary
- Cryptosporidiosis or isosporiasis with diarrhoea > 1 month
- Cytomegalovirus disease with onset of symptoms at age of >1 month (at site other than liver, spleen,
or lymph nodes)
- Encephalopathy (at least one of the following progressive findings present for at least 2 months in the
absence of a concurrent illness other than HIV infection that could explain the findings): a) failure to
attain or loss of developmental milestones or loss of intellectual ability, verified by standard
developmental scale or neuropsychological tests;
b) Impaired brain growth or acquired microcephaly demonstrated by head circumference
measurements or brain atrophy demonstrated by computerized tomography or magnetic resonance
imaging (serial imaging is required for children < 2 years of age); c) acquired symmetric motor deficit
manifested by two or more of the following: paresis, pathological reflexes, ataxia, or gait disturbances
39
Version 28 October 2004
- Herpes simplex virus infection causing a mucocutaneous ulcer that persists for > 1 month; or
bronchitis, pneumonitis, or esophagitis for any duration affecting a child > 1 month of age.
- Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph
nodes)
- Kaposi’s sarcoma
- Lymphoma, primary, in brain
- Lymphoma, small, noncleaved cell (Burkitt’s), or immunoblastic or large cell lymphoma of B-cell type
or unknown immunologic phenotype
- Mycobacterium tuberculosis, disseminated or extrapulmonary
- Mycobacterium, other species or unidentified species, disseminated (at a site other than or in
addition to lungs, skin, or cervical or hilar lymph nodes)
- Mycobacterium avium complex or Mycobacterium kansasii, disseminated (at a site other than or in
addition to lungs, skin, or cervical or hilar lymph nodes)
- Pneumocystis carinii pneumonia
- Progressive multifocal leucoencephalopathy
- Salmonella (nontyphoid) septicemia, recurrent
- Toxoplasmosis of brain with onset at >1 month of age
- Wasting syndrome in the absence of a concurrent illness other than HIV infection could explain the
following findings: persistent weight loss > 10% of baseline OR downward crossing of two percentile
lines in the weight-for-age chart OR weight below the 5th percentile on the weight-for-age chart on 2
consecutive measurements at least 4 weeks apart (=Failure to Thrive) PLUS: Chronic Diarrhoea (>30
days) or Documented Fever (intermittent or constant, >30 days).
40
Version 28 October 2004
11.7.
Adverse events grading toxicity
Adapted from Division of AIDS table for Grading Severity of Adult Adverse Experiences, August 1992 Division of AIDS, National Institute for Allergy and infectious Diseases, National Institutes of
Health, USA
General
Diagnosis
Headache
Tested by
Interview
1 mild
Transient or mild
discomfort; no
limitation in activity; no
medical
intervention/therapy
required.
2 moderate
Mild to moderate
limitation in activity;
some assistance may
be needed; no or
minimal medical
intervention/therapy
required
3 severe
Marked limitation in
activity; some
assistance usually
required; hospitalization
possible
Asthenia
(weakness/fatigue)
Interview
Transient or mild
discomfort; no
limitation in activity; no
medical
intervention/therapy
required.
Mild to moderate
limitation in activity;
some assistance may
be needed; no or
minimal medical
intervention/therapy
required
Marked limitation in
activity; some
assistance usually
required; hospitalization
possible
Neuro-psych/mood
Interview
Mild confusion,
abnormal dreams,
impaired
concentration,
agitation. Interferes
with normal activity <
25%
Moderate confusion,
abnormal dreams,
impaired
concentration, or
agitation that interferes
with normal activity 25
– 50% or
Severe confusion,
abnormal thinking,
amnesia,
depersonalization,
hallucinations that
interfere with normal
activity > 50%
4 very severe
Extreme limitation in
activity; significant
assistance required;
significant medical
intervention/therapy
required;
hospitalization
probable
Extreme limitation in
activity; significant
assistance required;
significant medical
intervention/therapy
required;
hospitalization
probable
Very severe confusion,
abnormal thinking,
amnesia,
depersonalization,
hallucinations that
render a person
unable to care for self.
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Version 28 October 2004
Cutaneous
Gastrointestinal
Diagnosis
Rash
Tested by
Interview
For symptoms of
pruritus
1 mild
Mild pruritus or rash
over < 50% of body
2 moderate
Mode
rate pruritus or over
>50% of body
3 severe
Severe pruritus or
painful lesions
4 very severe
Very severe pruritus
or painful lesions
Physical
Exam
Erythema
Diffuse maculopapular
rash or dry
desquamation
Vesiculation or moist
desquamation or
ulceration
Nausea
Interview
Oral intake decreased
<3 days
Minimal oral intake for >
3 days
Vomiting
Interview
Interview
Persistent: 4-5
episodes per day or
lasting > 1 week
Moderate or persistent:
5-7 loose stools per day
or diarrhoea lasting > 1
week
Vomiting of all
food/fluids in 24 hours
Diarrhoea
Transient;
reasonable oral
intake maintained
Transient: 2-3
episodes per day or
lasting < 1 week
Mild or transient: 3-4
loose stools per day
or mild diarrhoea
lasting < 1 week
Any one of the
following: mucous
membrane
involvement,
suspected SJS or
TEN, erythema
multiforme, necrosis
requiring surgery,
exfoliative dermatitis
Unable to tolerate any
oral intake for > 3
days
Vomiting of all
food/fluids for > 1 day
>7 loose stools per day
or bloody diarrhoea
Very severe diarrhoea
resulting in
hypotensive shock
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Version 28 October 2004
Neurologic
Diagnosis
Peripheral
neuropathy
Tested by
Interview for
paresthesia
(burning, tingling)
1 mild
Mild:
intermittent,
does not interfere
with ambulation
2 moderate
Moderate: continuous,
minimal
interference
with ambulation
Physical exam for
Neuro-motor
Mild weakness in
muscles of feet, but
able to walk and/or
mild
increase
or
decrease in reflexes
Physical exam for
Neuro-sensory
Mild
impairment
(decrease sensation
to vibration, pinprick,
temperature in great
toes) in focal area or
symmetrical
distribution
Moderate weakness in
feet, unable to walk on
heels and/or toes, mild
weakness in hands. Still
able to do most hand
tasks and/or loss of
previously present reflex
or
development
of
hyperreflexia
and/or
unable to do deep knee
bends due to weakness
Moderate
impairment
(moderate decrease in
sensations to vibration,
pinprick, temperature to
ankles)
and/or
joint
position
or
mild
impairment that is not
symmetrical
3 severe
Severe:
continuous,
painful,
moderate
interference
with
ambulation
Marked distal weakness
(unable to dorsiflex toes
or foot drop), and
moderate
proximal
weakness (in hands
interfering with ADLs
and/or
requiring
assistance
to
walk
and/or unable to rise
from chair unassisted)
4 very severe
Incapacitating:
very
painful,
substantially
interferes
with
ambulation
Confined to bed or
wheelchair because of
muscle weakness
Severe impairment
(decrease or loss of
sensation to knees or
wrist)
or
loss
of
sensation of at least a
moderate degree in
multiple different body
areas (ex upper and
lower extremities)
Sensory loss involves
limbs and trunk
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Version 28 October 2004
Hematologic
Diagnosis
Anemia
Tested by
Hemoglobin (g/dL)
1 mild
8.0 – 9.0
2 moderate
7.0 – 7.9
3 severe
6.5 – 6.9
4 very severe
< 6.5
Neutropenia
Absolute neutrophil count
(#/mm3)
Absolute leukocyte count
(#/mm3)
1000 – 1500
750 – 999
500 –749
<500
1500 – 2500
1000 – 1499
750 – 999
<750
Platelet count (#/mm 3)
75,000 – 99,000
50,000 – 74,999
20,000 – 49,999
<20,000
Any of:
Amylase
Pancreatic amylase
Lipase
Any of:
AST (SGOT)
ALT (SGPT)
GGT
Alkaline phosphatase
>1.0 – 1.5 ULN
>1.5 – 2.0 ULN
>2.0 – 5.0 ULN
>5.0 ULN
>1.25 – 2.5 ULN
>2.5 – 5.0 ULN
>5.0 – 10.0 ULN
>10.0 ULN
116 – 160
161 – 250
251 – 500
>500
400 – 750
751 – 1200
>1200
240 – 300
300 – 400
> 400
Leukopenia
(if determination of
absolute neutrophil is
not available)
Thrombocytopenia
Organ toxicity
Pancreatic toxicity
Hepatotoxicity
Endocrinologic
Hyperglycemia
Glucose (mg/dL)
[Non-fasting and no prior
diabetes]
Lipid
Hypertriglyceridaemia
Triglycerides (mg/dL)
Hypercholesterolemia
Cholesterol
(mg/dL)
[total cholesterol]
200 – 239
44