The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Item
- Title
-
The Use of Antiretroviral Therapy:
A Simplified Approach for
Resource-Constrained Countries
- extracted text
-
SEA-AIDS-133
Distribution: General
The Use of Antiretroviral Therapy:
A Simplified Approach for
Resource-Constrained Countries
WHO Project: ICR HIV 001
World Health Organization
Regional Office for South-East Asia
New Delhi
July 2002
Community Health Library and
Information Centre (CLIC),
SOCHARA
359,1st Main, 1st Block, Koramangala,
BENGALURU - 560 034.
Phone: 080 2553 1518
email: clic@sochara.org
website: www.sochara.org
©World Health Organization (2002)
This document is not a formal publication of the World Health Organization
(WHO), and all rights are reserved by the Organization. The document may,
however, be freely reviewed, abstracted, reproduced or translated, in part or in
whole, but not for sale or for use in conjunction with commercial purposes.
The views expressed in documents by named authors are solely the
responsibility of those authors.
■poj-
The following persons prepared this document:
1.
Dr Taimor Nawaz - Professor of Medicine, Bangladesh Medical College, Dhaka,
Bangladesh- Editor-in-Chief
2.
Dr Jai P. Narain - WHO SEARO, New Delhi, India - Coordinator
3.
Dr Emanuele Pontali - WHO SEARO, New Delhi, India
4.
Dr Basil Vareldzis - WHO Headquarters*, Geneva, Switzerland
5.
Dr Anupong Chitwarakorn - Department of Communicable Disease Control,
Ministry of Public Health - Bangkok, Thailand
6.
Dr Chris Duncombe - HIV-NAT, Thai Red Cross AIDS Research Centre Bangkok, Thailand
7.
Professor Subhash Hira - AIDS Research and Control Centre (ARGON), Sir J.J.
Hospital - Mumbai, India
8.
Dr Htin Aung Saw - Specialist Hospital, Waibargi, Yangon, Myanmar
9.
Dr D. Sengupta - National AIDS Control Organization (NACO) - New Delhi, India
10. Professor S.K. Sharma - Department of Medicine, All India Institute of Medical
Sciences (AllMS), New Delhi, India
11. Dr Broto Wasisto - Ministry of Health, Jakarta, Indonesia
12. Dr N. Kumara Rai - WHO-SEARO, New Delhi, India
13. Dr Ying-Ru Lo - WHO Country Office , Bangkok, Thailand
14. Dr Nani Nair - WHO-SEARO, New Delhi, India
15. Dr D.C.S. Reddy - WHO Country Office, New Delhi, India
16. Dr K. Weerasuriya - WHO-SEARO, New Delhi, India
ACKNOWLEDGEMENTS
While preparing this document, WHO headquarters' documents on Scaling
up antiretroviral therapy in resource-limited settings: Guidelines for a public
health approach" (WHO/HIV/2002.01 and WHO/HIV/2002.02) were
consulted.
We acknowledge Steven Fine, MD, PhD, Division of Infectious Diseases,
University of Rochester Medical Center, NY, USA, for reviewing the draft text
and providing helpful comments and suggestions.
Sincere thanks are expressed to the following persons and institutions in
Thailand and Brazil who provided useful information for the development of
these guidelines:
Thailand
Dr Pimjai Satasit, Division of AIDS, MOPH, Bangkok; Dr. Pikul Moolasaart,
Bamrasnaradura Hospital, Ministry of Public Health, Bangkok; Paul
Cawthorne, MSF Belgium; Dr Chris Duncombe, HIV-NAT, Thai Red Cross
AIDS Research Centre, Bangkok; Dr Tasana Leusaree, The Office of CDC
Region 10, Chiang Mai; Dr Nopporn Pattanapornpun, Ms Anchalee Puttajak,
representative of NCO/PHA group, Mae On Hospital; Waewdao
Bauprasertying, Pawida Somsuwan, representative of NCO/PHA group, Doi
Sa Ret Hospital; Dr Surasing Visarutaratna, Chonlisa Jariyalertsak, Chiang Mai
Provincial Health Office; Laksami Suebseang, WHO Thailand, Bangkok; Dr.
Ying-Ru Lo, WHO Thailand, Bangkok.
Brazil
Dr Mercedes Vaz, Secretaria LEP, Coordenagao Prevengao e Controle de
Doengas, OPAS/OMS, Brasil; Dr. Jacob Finkelman, World Health
Organization, Brazil.
CONTENTS
Page
ix
FOREWORD .
ABBREVIATIONS...
1
1.
INTRODUCTION.
2.
DOCUMENT OBJECTIVES
3.
PRINCIPLES OF HIV THERAPY
4.
STARTING ANTIRETROVIRAL THERAPY
5
4.1
4.2
Prerequisites
Clinical Evaluation
4.3
Indications
*
ANTIRETROVIRAL DRUGS RECOMMENDED FOR USE
5.1
Drugs and Doses......................................................
5.2
Side Effects
6.
CHOICE OF REGIMEN
7.
MONITORING THERAPY
8.
CHANGING THERAPY
8.1
Change Due to Adverse Effects/lntolerance
8.2
9.
Change due to Treatment Failure
ANTIRETROVIRAL THERAPY IN SPECIAL SITUATIONS
9.1
Adolescents
9.2
Women, with Specific Reference to Pregnancy................
9.3
Tuberculosis
Other Opportunistic Infections and Hepatitis....................
9.4
9.5
9.6
Immune Reconstitution Syndrome.....................................
Prophylaxis for Opportunistic Infections and Tuberculosis
4
6
7
9
....12
... 12
... 13
18
21
26
26
26
29
29
29
33
35
35
36
Page vii
Guidelines for the Use of Antiretroviral Treatment in Adults and Adolescents with H1V/AIDS in SEAR
10. IMPLEMENTING ARV TREATMENT PROGRAMMES
36
10.1 Situation Assessment..........................................
36
10.2 Programme Planning..........................................
37
10.3 Steps for Implementation..................................
38
References
.
40
Annexes
1.
Interim Proposal for a WHO Staging System for HIV Infection and
Disease in Adults and Adolescents......................................................
45
1993 Revised GDC Classification System for HIV Infection and Expanded
Surveillance Case Definition for AIDS Among Adolescents and Adults.....
47
3.
Patient Visit Record..............................................................
50
4.
Karnofsky Score...........
52
5.
Plasma HIV RNA Assay
53
6.
Useful Internet Links....
54
2.
Page viii
FOREWORD
Highly active antiretroviral treatment (ART) has decreased morbidity and
mortality of people living with HIV/AIDS in Australia, Europe and Northern
America. However the vast majority of the 40 million people living with
HIV/AIDS in developing countries do not have access to comprehensive
HIV/AIDS care and to antiretroviral treatment in particular. WHO
conservatively estimates that in 2002, some 6 million people in developing
countries are in need of ART. However, only 230,000 have access to ART,
and half of these live in Brazil.
Health care providers in the public and private sector and policy makers
face an increasing demand for ART of people affected. Antiretroviral
medicines are available in the private sector. However treatment guidelines
and services to administer ART are lacking and health care providers have
often not received adequate training in comprehensive HIV/AIDS care
including the administration of ART in many countries of the region.
To respond to this situation, the WHO South-East Asia Regional Office
has developed guidelines for The Use of Antiretroviral Therapy: A Simplified
Approach for Resource-Constrained Countries and Fact Sheets on
Antiretroviral Drugs. There are wide variations among member countries in
the availability of resources and health infrastructures. It is hoped that these
guidelines will provide a model to assist countries in the region to formulate
national antiretroviral treatment guidelines according to their own needs and
resources.
€
Dr. Uton Muchtar Rafei
Regional Director
WHO South-East Asia Region
Page ix
ABBREVIATIONS
3TC
ABC
AIDS
ALT
ARV
Antiretroviral
ART
Antiretroviral therapy
AST
AZT
Aspartate transamfnase
Azidothymidine (Zidovudine)
BHIVA
CBC
CD4
d4T
ddl
British HIV Association
Complete blood count
Lamivudine
Abacavir
Acquired immune deficiency syndrome
Alanine transaminase
CD4+ T Lymphocyte
Stavudine
Didanosine
DHHS
DOT
Department of Health and Human Services of USA
Directly observed therapy
DOTS
EFZ
HIV
IDV
LPV
LPV/r
MTCT
NFV
Directly observed therapy, short-course
Efavirenz
Human immunodeficiency virus
Indinavir
Lopinavir
Lopinavir/ritonavir
Mother-to-child transmission of HIV
Nelfinavir
NNRTI
NsRTI
NtRTI
NVP
Nucleoside analog reverse transcriptase inhibitor
Nucleotide analog reverse transcriptase inhibitor
Nevirapine
Ol
Opportunistic infection
PCP
PI
Pneumocystis carinii pneumonia
Protease inhibitor
People living with HIV/AIDS
PLHA
PMTCT
Non-nucleoside reverse transcriptase inhibitor
Prevention of Mother-to-Child Transmission of HIV
Page xi
Guidelines for the Use of Antiretroviral Treatment in Adults and Adolescents with HIV/AIDS in SEAR
RTV
Ritonavir
r
Low dose ritonavir boost
Saquinavir
SQV
STI
TB
TDF
TLC
VCT
WHO
ZDV
Sexually transmitted infection
Tuberculosis
Tenofovir disoproxil fumarate
Total lymphocyte count
HIV voluntary counseling and testing
World Health Organization
Zidovudine
i
Page xii
1.
INTRODUCTION
The Acquired Immunodeficiency Syndrome (AIDS) was first reported in the
Morbidity and Mortality Weekly Report as "Pfiemnocystis pneumonia - Los
Angeles/'1 in 1981. Since then, AIDS has become the most devastating
disease that mankind has ever faced.
Since the epidemic began, more than 60 million people have been
infected with the human immunodeficiency virus (HIV). By the end of 2001
an estimated 40 million people globally were living with HIV with about onethird aged between 15-24 years. Ninety-five percent of new infections are
occurring in developing countries and almost 50% are women. 2
HIV/AIDS was late in coming to Asia. Until the late 1980s, no country in
the region had experienced a major epidemic and, in 1999, only Cambodia,
Myanmar and Thailand had documented significant nationwide epidemics.
This situation is now rapidly changing. In 2001, 1.07 million adults and
children were newly infected with HIV in Asia and the Pacific bringing to a
total of 7.1 million people living with I IIV/AIDS in this region. Of particular
concern are the marked increases registered in some of the world's most
heavily populated countries. At the end of 2001, the national adult HIV
prevalence rate in India was under 1%, with an estimated 3.97 million Indians
living with HIV/AIDS. India ranks second alter South Alricvi in the number of
people living with HIV/AIDS. In Indonesia and Nepal there are concentrated
epidemics in high-risk groups such as injecting drug users (IDU). In
Bangladesh, Bhutan, Maldives and Sri Lanka infection rates are low, though
risk behaviour is common.3 TB is the leading opportunistic infection in HIV
positive persons. HIV fuels the TB epidemic and is a particular threat to Asia
and the Pacific, which bears more than 60?^ of the World's TB burden.
Early, large-scale and focused prevention programmes can reduce
infection rates in high-risk groups and the risk of spread of HIV among the
wider population. An excellent example is Thailand, where prevention efforts
have probably averted millions of HIV infections.4 Cambodia is another
Page 7
I he Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
example where preventive measures have been effective. Strategies to
prevent HIV transmission should remain a priority in combating HIV/AIDS.
Antiretroviral treatment for HIV infected patients was first introduced in
1986. Zidovudine (ZDV), a nucleoside reverse transcriptase inhibitor (NsRTI)z
was the first drug that was used and was shown to reduce deaths and
accompanying opportunistic infections in patients with advanced HIV
infection.5 Over the next few years other NsRTIs like didanosine (ddl),
lamivudine (3TC), and stavudine (d4T) were introduced. However, the
benefits of single drug therapy were short-lived due to the emergence of
resistance. Subsequently, it was shown that combining 2 or 3 antiretroviral
(ARV) drugs produced more sustained benefit. New classes of drugs, the
protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors
(NNRTI) permitted the use of more potent antiretroviral regimens. These
regimens, consisting of three or more drugs, have resulted in dramatic
reduction in HIV levels in blood and markedly improved immune function. In
developed countries treatment of HIV infection using regimens of 3 or more
antiretroviral drugs has been recommended.6,7
In Europe and North America, AIDS mortality has dropped significantly
in large part due to access to regimens of 3 or more antiretroviral drugs.8’10
Patients receiving these regimens are less likely to develop opportunistic
infections including TB and require less admissions to hospital than patients
with untreated disease.11,12 Combination antiretroviral therapy (ART) leads to
reduction in plasma HIV RNA level (viral load) and rise in CD4 counts with at
least partial restoration of immune function.13'15 Combination therapy also
significantly slows the progression of HIV-1 disease.13 Furthermore, studies
indicate that low viral load is associated with lower risk of heterosexual and
perinatal transmission.16,17 Although combination of three antiretroviral drugs
is expensive, studies indicate that it is a cost effective use of resources in the
developed world.18,19 Since the advent of combination antiretroviral therapy,
the disease has been transformed into a treatable and chronic condition for a
significant proportion of those with access to this treatment. Appropriate
treatment can prevent not only infected individuals from succumbing to life
threatening illness from AIDS, but may play a major role in prevention by
reducing viral load of those under treatment and by encouraging greater
participation in prevention programmes.
Page 2
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Millions of people in developing countries infected with HIV face
disease and early death unless they receive appropriate life-extending medical
care. WHO conservatively estimates that in 2002, some 6 million in
developing countries ar^ in need of antiretroviral therapy. However, only
270,000 have access to them, and half of these live in Brazil. The United
Nations General Assembly Special Session on HIV/AIDS (UNGASS) in 2001
advocated for the complementarity of HIV care and prevention and urged
governments to provide the highest attainable standard of care, including
antiretroviral treatment to people living with HIV/AIDS.
a
The main obstacles to the use of antiretroviral drugs in developing
countries have been the high cost and the lack of health infrastructure
necessary to use them. Also, there are concerns that difficulties with
adherence to complicated medication regimens would promote and spread
drug resistance.2" However, it is time to look more seriously at antiretroviral
treatment as a part of comprehensive care for people living with HIV/AIDS.
The delivery of effective care and antiretroviral treatment for people living
with HIV/AIDS in poorest countries is an urgent priority and should
complement programmes to prevent HIV transmission. The reasons for
combining AIDS prevention and care include a humanitarian rationale, to
save children and the fabric of society, for continuing economic development
and to optimize preventive efforts. When testing is linked to care, people
have an incentive to be tested providing a rational response: primary
prevention for HIV negative persons and comprehensive care for HIV-positive
patients.21
Brazil and Thailand have demonstrated that it is possible to deliver ART
in a mid-income developing country. Data from Brazil show that HIV
associated morbidity and mortality, in particular TB incidence and
hospitalization time were markedly reduced through the introduction of ART
(Vitoria M, Ministry of Health Brazil, Second Global TB/HIV Working Group
Meeting, Durban, South Africa, 14-16 June 2002). In a study in Haiti, directly
observed therapy (DOT) was used for the administration of ART with
considerable success.22
Some of the pharmaceutical companies in developing countries produce
generic drugs at a fraction of the cost in developed countries, making it
possible for these drugs to be made available for therapy in resource poor
settings.23 These guidelines on the appropriate and rationale use of ART are
relevant because these drugs are now available in developing countries,
Page 3
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
although mostly in the private sector and patients are using them. There is a
growing international consensus and pressure that treatment of people living
with HIV/AIDS with combination antiretroviral therapy in developing
countries is possible. On the basis of clinical data, both, from developed and
developing countries, there is evidence that AIDS treatment results in
significant gains in extending duration and quality of life.
The guidelines are primarily intended for:
(1)
Physicians and other health care providers
(2)
National AIDS programme managers and other health planners
involved in national HIV care and treatment programmes as a
reference for national treatment guidelines.
The guidelines will require
significant data emerge.
2.
updating at regular intervals as new
DOCUMENT OBJECTIVES
The objectives of WHO guidelines are:
(D
to provide a standard approach for the use of antiretroviral treatment
(ART) as part of comprehensive HIV/AIDS care;
(2)
to be a source of reference for physicians and other healthcare providers
caring for patients with HIV/AIDS as well as AIDS programme managers
and health planners involved in national HIV care and treatment
programmes, and
(3)
to be a source of reference for people living with HIV/AIDS.
This document contains recommendations for the use of antiretroviral
drugs for the treatment of adults and adolescents > 13 years of age
particularly in countries of the WHO South-East Asia Region.
3.
PRINCIPLES OF HIV THERAPY
The goals of antiretroviral therapy are:
>
Page 4
reduction of HIV related morbidity and mortality
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
>
improvement of quality of life
>
restoration and/or preservation of immunological function
>
maximal and durable suppression of viral replication.
The following general principles apply for the clinical use of ART:
(1)
A continuous high level of replication of HIV takes place from the
early stages of infection. Al least IO11’ particles are produced and
destroyed each day.24 Despite this high level of viral replication,
most patients remain well for many years without any antiretroviral
therapy.
(2)
Ongoing HIV replication leads to progressive immune system
damage resulting in susceptibility to opportunistic infections (Ol),
malignancies, neurological diseases, wasting and, ultimately, death.
(3)
Plasma HIV RNA levels indicate the magnitude of HIV replication
and the associated rate of CD4+ T cell destruction, whereas CD4 +
T cell counts indicate the extent of HIV induced immune damage.
(4)
Measured concentration of viral load is predictive of the subsequent
risk of disease progression and death. Regular measurements of
CD4+T cell and plasma HIV RNA levels (if possible to perform) are
necessary to determine the risk of disease progression in HIV infected
patients and to determine when to initiate or modify ART regimens.
(5)
Rates of disease progression differ among HIV infected persons.
Treatment decisions should be individualized by CD4+ T cell
counts and by plasma HIV RNA levels (where it is possible to
perform)
(6)
Combination antiretroviral therapy to suppress HIV replication to
below the levels of detection of sensitive plasma HIV RNA assays
limits the potential for selection of antiretroviral resistant HIV
variants and delay disease progression. Therefore, maximum
achievable suppression of HIV should be a goal of therapy.
(7)
The most effective means to establish durable suppression of HIV
replication is the simultaneous initiation of a combination of
effective anti-HIV drugs with which the patient has not been
Page 5
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
previously treated and that are not cross-resista nt with ARV drugs
with which the patient has been previously treated.
(8)
Antiretroviral drugs used in combination therapy regimens should
be used according to optimum schedules and dosages. ARV drugs
are limited in number and mechanism of action, and cross
resistance between specific drugs has been documented. Change in
ART increases future therapeutic constraints.
(9)
Women should receive optimal antiretroviral therapy regardless of
pregnancy status.
(10) The same principles of ART apply to HIV infected children,
adolescents and adults, although the treatment of HIV infected
children involves special considerations.
(11) HIV infected persons, even those whose viral loads are below
detectable limits, should be considered infectious. Therefore, they
should be counselled to avoid sexual and drug use behaviours that
are associated with either transmission or acquisition of HIV and
other infectious pathogens.25
4.
STARTING ANTIRETROVIRAL THERAPY
4.1
Prerequisites
It is most desirable to have specific services and facilities before starting ART
due to the complexity of the therapy, the need for monitoring and the cost of
therapy.
These services include:
Page 6
(1)
Access to HIV voluntary counseling and testing (VCT) and institution
of follow up counseling services to identify those who could benefit
from the programme to ensure continued psychosocial support and
to enhance adherence to treatment. VCT is useful to identify HIV
infected people.
(2)
Medical services capable of identifying and treating common HIVrelated illnesses and opportunistic infections.
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
(3)
Reliable laboratory services capable of doing routine laboratory
investigations Such as complete blood count and chemistry. Access
to a referral laboratory capable of doing CD4 + T lymphocyte count
is desirable to monitor therapy.
(4)
4.2
Reliable and affordable access to quality antiretroviral drugs, and
drugs to treat opportunistic infections and other related illness.
Clinical Evaluation
Prior to starting therapy patients should have the following evaluation
performed:
>
Complete history and physical examination
>
Routine laboratory investigations
>
CD4 + T lymphocyte count/ total lymphocyte count (TLC)
A detailed clinical ^valuation is essential prior to initiating antiretroviral
therapy and should aim toy
>
Assess the clinical stage of HIV infection
>
Identify past HIV-related illnesses
>
Identify current HIV-related illnesses that would require treatment
>
Identify co-existing medical conditions and treatments that may
influence the choice of therapy
History and Physical Examination
A medical history should include questions on the following:
>
when and where was the diagnosis of HIV made
>
what is this person's possible source of HIV infection
>
what are the current symptoms and concerns of the patient
>
past medical history of symptoms, known diagnoses and treatments
given
Page 7
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
>
history of symptoms of or previous treatment for tuberculosis
>
history of possible contact with tuberculosis
>
history of possible sexually transmitted infections
>
history of pregnancy
>
history of previous antiretroviral therapy
>
history of medication and oral contraceptive use in women
>
social habits and sexual history
The physical examination should include the following points:
>
patient's weight
>
skin: herpes zoster, Kaposi's sarcoma, HIV dermatitis
>
lymphadenopathy
>
oropharyngeal
leucoplakia
>
examination of heart and lungs
>
examination
enlargement
>
examination of neurological and musculoskeletal system: mental
state, motor and sensory deficit
>
examination of optic fundus: retinitis and papilloedema
>
examination of the genital tract/gynaecological examination
mucosa:
of
candidiasis,
abdomen
Kaposi's sarcoma,
hairy
and
spleen
particularly
for
liver
Laboratory Investigations
Essential
Page 8
>
HIV serology
>
CD4+T lymphocyte counts (if available) or total lymphocyte count
(TLC)
>
Complete blood count and chemistry profile
>
Pregnancy test
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Supplementary tests indicated by history and physical examination
>
Chest x-ray
>
Urine for routine and microscopic examination
>
Hepatitis C virus (HCV) and hepatitis B virus (HBV) serology
(depending on test availability and resources)
It is most important to confirm the diagnosis of HIV infection by tests
performed by a trained technician, preferably in a diagnostic laboratory. The
test results should include the type of test performed to establish the diagnosis
based on WHO guidelines. In case there is any doubt, the tests should be
repeated in a standard/referral laboratory.
The blood chemistry profile should, if possible, include serum creatinine
and/or blood urea to assess baseline renal function, serum glucose, and serum
alanine or aspartate aminotransferase to assess the possibility of hepatitis and
to monitor drug toxicity. Other tests that may be performed include serum
bilirubin, serum lipids and serum amylase.
4.3
Indications
With currently available antiretroviral agents, eradication of HIV infection is
not likely. This is largely due to the establishment of a pool of latently infected
CD4 + T lymphocytes during the very early stage of acute HIV infection that
persists with an extremely long half-life, even with prolonged suppression of
plasma viraemia to <50 copies/ml.26'28 The decay half-life of resting memory
CD4 lymphocytes with latent HIV provirus is calculated to be at least 6
months and as long a$ 44 months. Thus, HIV eradication with ART alone
would take a decade or more and is not a realistic goal.28'29
The aim of treatment is thus to prolong and improve the quality of life
by maintaining maximal suppression of virus replication for as long as
possible. Reductions in plasma viraemia achieved with antiretroviral therapy
account for much of the clinical benefits associated with ART50.
9
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Table 7. Recommendations for initiating antiretroviral therapy
in adults and adolescents with documented HIV infection31,32
If CD4 testing available:
WHO Stage IV disease irrespective of CD4 cell count(a)
WHO Stage I, II or III,a) with CD4 cell counts
200/mm3 (b)
If CD4 testing unavailable:
-
WHO Stage IV disease irrespective of total lymphocyte count
-
WHO Stage II or III disease with a total lymphocyte count 1200/mm3 (c)
(a) Treatment is also recommended for patients with advanced WHO Stage III disease including
recurrent or persistent oral thrush and recurrent invasive bacterial infections irrespective of CD4
cell or total lymphocyte count.
(b) A CD4 level of 200/mm3 corresponds to a CD4 percentage of approximately 15%. The precise
CD4 level above 200/mm3 at which to start ARV treatment has not been established but the
presence of symptoms and the rate of CD4 cell decline (if measurement possible) should be
factored into the decision making.
(d A total lymphocyte count of 1200/mm3 can be substituted for the CD4 count when the latter is
unavailable and HIV-related symptoms exist. It is less useful in the asymptomatic patient. Thus, in
the absence of CD4 cell testing, asymptomatic HIV infected patients (WHO Stage I) should not be
treated because there is currently no other reliable marker available in severely resourceconstrained settings.
For WHO staging system for HIV infection32 and CDC classification
system for HIV infection,33 please see annexes I and II.
Antiretroviral drugs may also be used for post-exposure prophylaxis
(PEP) following accidental occupational and possible sexual or other nonoccupational exposure to HIV.34,35
Antiretroviral drugs are used for prevention of mother to child
transmission of HIV, which is beyond the scope of this document.
Important considerations for starting therapy also include medium/long
term availability and affordability of drugs by the patient or the programme.
Page W
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Asymptomatic HIV Infection
l ■.
Therapy is recommended for asymptomatic patients (WHO Adult Stage I
disease) when CD4 count nears or falls below 200 cells/mm'.6 7,31,32
Randomised clinical trials provide strong evidence for treating patients with
<200 cells/mm3 CD4 count.13,,‘’36
CD4 count of 200/mm! corresponds to CD4 percentage of 15%. The
CD4 percentage may be used as an alternate to the CD4 count/mm3.
The optimal time to start ART for asymptomatic patients with CD4 + T cell
counts >200/mm3 is not known.37,38 Recommendation for therapy in this
group should be based on patient's wishes for therapy, the CD4 count, and
the rate of decline of CD4 count.
In asymptomatic patients with CD4+ T cell count
should be deferred.6,7
350/mm3, therapy
Symptomatic HIV Infection
Antiretroviral therapy is recommended for patients with symptomatic disease
(AIDS, WHO Adult Stage IV and advanced Stage III) irrespective of the CD4
cell count or total lymphocyte count. Therapy is also recommended for WHO
Adult Stages II and III patients when CD4 count is less than 200 cells/mm’or a
CD4 percentage of <15%. If CD4 cell count monitoring is unavailable,
treatment is recommended for symptomatic patients (WHO Adult Stage II and
III disease) with total lymphocyte counts below 1200/mm3. In symptomatic
patients, the total lymphocyte count in combination with clinical staging is a
useful marker of prognosis and survival. However, in asymptomatic HIV
infected individuals, total lymphocyte count is less useful.
Treatment of tuberculosis and other serious opportunistic infections may
be more important than antiretroviral therapy. In the event of possible drug
interactions, it may be necessary to postpone antiretroviral therapy until the
opportunistic infection is adequately controlled.
Plasma HIV RNA level strongly predicts the rate of decrease in CD4 +
lymphocyte count and progression to AIDS and death, but the prognosis of
HIV-infected persons is more accurately defined by combined measurement
of plasma HIV-1 RNA and CD4+ lymphocytes.39The HIV viral load is a strong
predictor of clinical outcome in the mid- and long-term period but the
Page 7 7
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
immediate risk of opportunistic complications of HIV-1 disease is better
dictated by the CD4 cell count. However, in resource-limited settings, an
assessment of viral load (using HIV-1 RNA levels) is not considered
essential to start therapy.
5.
ANTIRETROVIRAL DRUGS RECOMMENDED FOR USE
5.1
Drugs and Doses
Twelve antiretroviral drugs have been included in the WHO Model List of
Essential Medicines in April 2002 and are as follows:
Table 2. Antiretroviral drugs
Nucleoside reverse transcriptase inhibitors (NsRTI)
Abacavir (ABC)
tablet 300 mg, oral solution 100 mg/5 ml
Didanosine (ddl)
tablet 25 mg, 100 mg, 150 mg, 200 mg
Lamivudine (BTC)
tablet 150 mg, oral solution 50 mg/5 ml
Stavudine (d4T)
capsule 15 mg, 20 mg, 30 mg, 40 mg, oral solution 5 mg/ml
Zidovudine (ZDV or
AZT)
capsule 100 mg, 250 mg, 300 mg; injection 10 mg/ml in
20 ml vial; oral solution 50 mg/5 ml___________________
Non nucleoside reverse transcriptase inhibitors (NNRTI)
Efavirenz (EFV or EFZ)
capsule 50 mg, 100 mg, 200 mg
Nevirapine (NVP)
tablet 200 mg, oral suspension 50 mg/5 ml
Protease inhibitors
Indinavir (IDV)
capsule 100 mg, 200 mg, 333 mg, 400 mg
Ritonavir (RTV, r) a
capsule 100 mg, oral solution 400 mg/5 ml
Lopinavir -T ritonavir
(LPV/r)
capsule 133.3 mg + 33 mg, oral solution 400 mg/5 ml +
100 mg/5 ml
Nelfinavir (NFV)
tablet 250 mg, powder 50 mg/g
Saquinavir (SQV)
capsule gel filled 200 mg
a Ritonavir is recommended for use in combination with indinavir, lopinavir and saquinavir as a
booster and not as a drug in its own right.
Doses and common side effects are listed in tables 3-7.
Page 12
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
5.2
Side Effects
NsRTIs
Drugs belonging to the class of NsRTIs are associated with hepatic steatosis
and lactic acidosis due to cellular mitochondrial toxicity. Lactic acidosis may
initially present with nonspecific gastrointestinal symptoms of nausea,
vomiting, abdominal pain and distension, generalised weakness. This may
progress to tachypnoea and dyspnoea and eventually respiratory failure.
Serum lactate levels may be elevated. NsRTI should be stopped if lactic
acidosis is suspected. Approximately 3-5% of adults and children receiving
abacavir develop a potentially fatal hypersensitivity reaction 40 Symptoms
include fever, gastrointestinal complaints (nausea, vomiting, diarrhoea, or
abdominal pain), fatigue and/or respiratory symptoms (pharyngitis, cough, or
dyspnoea). Physical findings may include lymphadenopathy, ulceration of
mucous membranes and skin rash. Laboratory abnormalities may include
elevated
liver enzymes,
creatinine
phosphokinase, creatinine and
thrombocytopenia.
Abacavir
should
be
stopped
immediately
if
hypersensitivity reaction is suspected and should never be restarted since
deaths have occurred within hours of rechallenge.
NNRTIs
Drugs belonging to the class of NNRTIs are associated with skin rash that may be
mild or progress to Stevens-Johnson syndrome. NNRTI may also cause serum
alanine/aspartate aminotransferase elevation and rare fatal cases of hepatitis.
Among the NNRTIs, nevirapine most frequently causes clinical hepatitis.
Approximately two thirds of nevirapine associated clinical hepatitis occur within
the first 12 weeks; it may rapidly progress to fulminant hepatic failure.
Nevirapine must be given 200 mg once daily for 2 weeks and then increased
to 200 mg twice daily to reduce the incidence of hepatotoxicity. Close
monitoring of clinical symptoms and serum transaminases are recommended
after starting nevirapine therapy, initially every 2 weeks for the first month, then
monthly for 12 weeks and every one to three months thereafter. Patients who
develop hepatic toxicity while treated with nevirapine should not be restarted on
that drug. Efavirenz is considered to be teratogenic and should be avoided in
pregnancy. Efavirenz has also adverse effects on central nervous system.
Pls
The class specific side effects of protease inhibitors include insulin resistance,
diabetes mellitus, hyperlipidemia, lipodystrophy, hepatitis, bone disorders,
and increased bleeding in haemophiliacs.
Page 13
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
When patients are receiving ART, it is appropriate to routinely monitor
complete blood count, serum alanine or aspartate aminotransferase, serum
glucose and serum creatinine and/or blood urea, if possible, every 3-6
months. Other tests such as serum amylase and serum lipid may be
performed, if indicated. Such testing will help to detect adverse drug effects so
that therapy may be modified, if necessary.
Table 3. Nucleoside Reverse Transcriptase Inhibitors (NsRTI)32,41,42
Generic name
Abacavir
(ABC)
Pose_________
300 mg twice daily or
with ZDV and 3TC
(Trizivir®) 1 tablet twice
daily
Trizivir® contains 300
mg ZDV, 150 mg 3TC,
and 300 mg ABC
Didanosine
(ddl) '
>60 kg: 200 mg twice
daily or 400 mg once
daily *
<60 kg: 125 mg twice
daily or 250 mg once
daily
Page 74
Adverse effects
_
Hypersensitivity reaction (can be
fatal)
Fever, rash, fatigue
Nausea, vomiting, anorexia
Respiratory symptoms (sore throat,
cough)
Lactic acidosis with hepatic steatosis
(rare)
Pancreatitis
Peripheral neuropathy
Nausea, diarrhoea
Lactic acidosis with hepatic steatosis
(rare)
Lamivudine
(3TC)
150 mg twice daily
<50 kg: 2 mg/kg bid
Minimal toxicity
Lactic acidosis with hepatic steatosis
(rare)
Stavudine
(d4T)
>60 kg: 40 mg twice
daily
<60 kg: 30 mg twice
daily
Pancreatitis
Peripheral neuropathy
Lactic acidosis with hepatic steatosis
(rare)
Lipoatrophy
Zidovudine
(ZDV, AZT)
300 mg twice daily
250 mg twice daily
(alternative dose)
ZDV/3TC combination
300 mg/150 mg twice
daily
Anaemia, neutropenia,
Gastrointestinal intolerance,
Headache, insomnia, myopathy
Lactic acidosis with hepatic steatosis
(rare)
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Table 4. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)3--4142
\
Generic
name
Dose
Adverse effects
\
Nevirapine
(NVP)
_______________
200 mg once daily for 14 days
followed by 200 mg twice daily
Skin rash, Stevens-Johnson
syndrome
Elevated serum aminotransferase
levels
Hepatitis, life-threatening
hepatic toxicity
Efavirenz
(EEV)
600 mg once daily
(bed time administration is
suggested to decrease CNS side
effects)
CNS symptoms: dizziness,
somnolence, insomnia,
confusion, hallucinations,
agitation
Elevated transaminase levels
Skin rash
Table 5. Protease Inhibitors (PI)32
Generic name^
Dose
Nelfinavir (NEV)
1 250 mg twice daily
Indinavir/ritonavir (IDV/r)
800 mg/100 mg twice daily a’c
Lopinavir/ritonavir (LPV/r)
400 mg/100 mg twice daily
(533 mg/133 mg twice daily when
combined with EFZ or NVP)
Saquinavir/ ritonavir (SQV/r)
1000/100 mg twice daily b'c
a This dosage regimen is not approved but supportive data exist and the regimen is in
common clinical use.
bThis dosage regimen is not approved but supportive data exist for its use. Both the hard-gel
Both the hard-gel
and soft-gel capsule formulations can be used when SQV is combined with RTV.
( Dosage adjustment when combined with an NNRTI is indicated but a formal
recommendation cannot be made at this time. One consideration is to increase the RTV
component to 200 mg bid^when EFZ or NVP is used concomitantly. More drug interaction
data are needed.
Page 15
rhe Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Table 6. Protease Inhibitors 41,4-2
Generic name
Adverse effects
Indinavir
(IDV)
Nephrolithiasis, gastrointestinal intolerance, hyperglycaemia,
fat redistribution and lipid abnormalities, headache,
dizziness, rash, thrombocytopenia, alopecia, bleeding in
haemophilia patients
Ritonavir
(RTV)
Gastrointestinal intolerance, hausea, vomiting, paresthesia,
hepatitis and pancreatitis, hyperglycaemia, fat redistribution
and lipid abnormalities
Lopinavir +
ritonavir
(LPV/r)
Gl intolerance, nausea, vomiting, elevated transaminase
enzymes, hyperglycaemia, fat redistribution and lipid
abnormalities
Nelfinavir
(NFV)
Diarrhoea, hyperglycaemia, fat redistribution and lipid
abnormalities
Saquinavir
Gastrointestinal intolerance, nausea, vomiting, headache,
elevated transaminase enzymes, hyperglycaemia, fat
redistribution and lipid abnormalities
(SQV)
The doses listed are those for individuals with normal renal and hepatic
function.
Product specific
information
should
be
referred
to
for
dose
adjustments that may be indicated with renal or hepatic dysfunction or for
potential drug interactions with other HIV and non-HIV medications.
Table 7. Clinical signs, symptoms, monitoring and management of
symptoms of serious adverse effects of antiretroviral drugs
that require drug discontinuation32
Adverse
Effect
Acute
hepatitis
Page 76
Possible offending drug/s
Clinical signs / symptoms
Nevirapine (NVP); EFV less Jaundice, liver
common; more uncommon enlargement,
with zidovudine (ZDV),
gastrointestinal symptoms,
didanosine (ddl), stavudine fatigue, anorexia; NVP(d4T) (<1%); and protease associated hepatitis may
inhibitors (PI), most
have hypersensitivity
frequently with ritonavir
component (drug rash,
(RTV)
systemic symptoms,
eosinophilia)
Management
_____________________
If possible, monitor serum
transaminases, bilirubin. All
ARV should be stopped
until symptoms resolve.
NVP should be
permanently discontinued.
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
*’
Adverse’'
Hfect
Acute
pancreatitis
\
Possible offending dfug/s Clinical signs / symptoms
——- ' ~
ddl, d4T; lamivudin^ (3TC) Nausea, vomiting, and
(infrequent)
abdominal pain
Management
If possible, monitor serum
pancreatic amylase, lipase.
All ART should be stopped
until symptoms resolve.
Restart ART with change to
different NRTI, preferably
one without pancreatic
toxicity (e.g,, ZDV, ABC),
Lactic
acidosis
All nucleoside analogue
reverse transcriptase
inhibitors (NsRTIs)
Hyper
sensitivity
reaction
Abacavir (ABC) Nevirapine ABC: Constellation of acute Discontinue all ARVs until
(NVP)
onset of symptoms
symptoms resolve. The
including: fever, fatigue,
reaction progressively
myalgia, nausea/vomiting, worsens with drug
diarrhoea, abdominal pain, administration and can be
pharyngitis, cough, dyspnea fatal. Administer supportive
(with or without rash).
therapy. Do not
While these symptoms
rechallenge with ABC (or
overlap those of common
NVP), as anaphylactic
infectious illness, the
reactions and death have
combination of acute onset been reported. Once
of both respiratory and
symptoms resolve, restart
gastrointestinal symptoms
ARVs with change to
after starting ABC is more
different NRTI if ABCtypical of a hypersensitivity associated or to PI- or
reaction.
NRTI-based regimen if
NVP-associated.
NVP; Systemic symptoms
of fever, myalgia, arthralgia,
hepatitis, eosinophilia with
or without rash.
Initial symptoms are
Discontinue all ARV;
variable: a clinical
symptoms may continue or
prodromal syndrome may worsen after
include generalized fatigue discontinuation of ART.
and weakness,
Supportive therapy.
gastrointestinal symptoms
Regimens that can be
(nausea, vomiting,
considered for restarting
diarrhoea, abdominal pain, ART include a PI combined
hepatomegaly, anorexia,
with an NNRTI and possibly
and/or sudden unexplained either ABC or TDF.
weight loss), respiratory
symptoms (tachypnea and
dyspnea) or neurologic
symptoms (including motor
weakness).
Page 7 7
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Adverse
Effect
Possible offending drug/s Clinical signs / symptoms
Management
Severe rash/ Non nucleoside reverse
Stevenstranscriptase inhibitors
Johnson
(NNRTIs): nevirapine
syndrome
(NVP), efavirenz (EFV)
Rash usually occurs during
the first 2-4 weeks of
treatment. The rash is
usually erythematous,
maculopapular, confluent,
most prominent on the
body and arms, may be
pruritic and can occur with
or without fever. Life
threatening StevensJohnson Syndrome or toxic
epidermal necrolysis
(SJS/TEN) has been
reported in —0.3% of
infected individuals
receiving NVP
Severe
ddl, d4T, 3TC
peripheral
neuro-pathy
Pain, tingling, numbness of Stop suspect NsRTI and
hands or feet; distal sensory switch to different NsRTI
loss, mild muscle weakness, that does not have
and areflexia can occur.
neurotoxicity (e.g., ZDV,
ABC). Symptoms usually
resolve in 2-3 weeks.
6.
Discontinue all ARVs until
symptoms resolve.
Permanently discontinue
NVP for rash with systemic
symptoms such as fever,
severe rash with mucosal
lesions or urticaria, or
SJS/TEN; once resolves,
switch ART regimen to
different ARV class (e.g., 3
NsRTIs or 2 NsRTIs and PI).
If rash moderate but not
severe and without
mucosal or systemic
symptoms, change in
NNRTI (e.g., NVP to EFV)
could be considered after
rash resolves.
CHOICE OF REGIMEN
The choice of regimen depends on a number of factors. These include
amongst others, cost of therapy, availability and medium/long term
affordability, convenience and likelihood of adherence, regimen potency,
tolerability and adverse effect profile, possible drug interactions, and potential
for alternate treatment options in the event that the initial drug regimen fails.
Antiretroviral therapy with single or dual drug regimen is not
recommended due to the rapid emergence of drug resistance. Monotherapy
with zidovudine is recommended for the prevention of mother-to-child
transmission of HIV.43,44 Monotherapy with nevirapine has also shown to
reduce mother to child transmission of HIV infection.45
Page 18
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Persons doing well on dual NsRTI regimens can be switched to one of
the more potent regimens. If this is not feasible or advisable, then treatment
should be continued for Those persons who are deemed to be benefiting.
This, however, is not an endorsement of continued initial use of these
regimens and effort should be made to provide standard care regimens to all
patients newly initiating therapy.32
The use of a protease inhibitor with two NsRTI has shown potent and
durable suppression of viral replication.13'14,46'47 Combination of an NNRTI
with 2 NsRTIs also produces viral suppression and immunological
improvements which are at least comparable to those seen in combinations
that include protease inhibitors.15,48 Dual protease inhibitor combinations such
as ritonavir with saquinavir or other protease inhibitors have also
demonstrated potent and durable viral suppression.49 Ritonavir combined with
other protease inhibitors results in increased plasma concentration of these
drugs. These combinations have been used with some success although the
risks and toxicities are not fully known. Abacavir plus 2 NsRTIs (namely ZDV
4- 3TC), a triple NsRTI regimen, has been used, but seems to have reduced
potency in patients with baseline viral load > 100,000 copies/mL.
Currently, several regimens with acceptable antiviral potency are
available. These regimens are composed of three or four drugs. Two NsRTIs
generally form the backbone of most combinations.
Possible NsRTI combinations include:
zidovudine 4- lamivudine
stavudine + lamivudine
zidovudine 4- didanosine
didanosine 4- lamivudine
stavudine 4- didanosine
Zidovudine and stavudine are not used together due to their antagonistic
effects.
Zidovudine 4- lamivudine 4- abacavir may be combined as 3 NsRTI regimen
The dual combination of stavudine 4- didanosine should only be used
during pregnancy when no other alternatives exist, due to the potential
increased risk of lactic acidosis with this combination in pregnant women.
Page 79
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Table 8. Choice of regimen 6'7'32'50
Recommended first line Antiretroviral Regimens in adults and adolescents
Regimen*
ZDV/3TC plus
EFZ or NVP
Recommendation
Recommended
Advantages
Spares PI
Equivalent to Pl
based regimens
Low pill burden
Disadvantages
Limited long-term
data
NVP may cause
severe hepatitis.
EFZ is
contraindicated in
pregnancy
ZDV/3TC/
ABC
Consider for
patients with low
viral loads (if
possible to
determine) and
adherence concerns
Spares PI and
NNRTI
Fewer drug
interactions
Low pill burden
May be less
effective in patients
with high viral load
Limited long-term
data
Abacavir may cause
hypersensitivity
reactions
ZDV/3TC plus
RTV-enhanced
PI (IDV/r,
LPV/r, SQV/r)
or NFV
Consider
Better
pharmacokinetics
Long-term toxicities
unknown with
with RTV-enhanced
PI
RTV-enhanced PI
Convenient dosing
High pill burden
High potency
Drug interactions
with some
regimens
’ZDV/3TC is listed as initial recommendation for dual NsRTI component based on efficacy,
toxicity, clinical experience and availability of fixed dose formulation. Other dual NsRTI
components can be substituted including d4T/3TC (preferred alternative), ZDV/ddl and
d4T/ddl depending upon country-specific preferences. ZDV/d4T should never be used
together because of proven antagonism. Fixed dose formulations are preferred whenever
possible as they promote enhanced drug adherence.
Table 8 is a useful guide to the use of available antiretroviral regimens in
individuals with no prior or limited experience of HIV treatment.
Page 20
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Initial regimen of 2 NsRTI with 1 NNRTI is effective, spares Pls, and with
low pill burden, is often preferred over other regimens. A combination of
d4T/3TC and NVP is available in a single pill in some countries; it is relatively
inexpensive, and may be given twice daily. A regimen containing 3 NsRTIs
(abacavir, zidovudine, lamivudine) has twice daily convenient dosing with
fewer drug interactions but may be less effective in patients with high viral
load. Regimens containing Pls are also effective with long-term data. RTVenhanced PI regimens have convenient twice daily dosing schedule.
However, there is concern about Pl-related toxicities and drug interactions.
For Group O HIV-1 subtype or HIV-2 infections, only the triple NsRTI
and PI based regimens should be used because of inherent resistance of these
viruses to NNRTI compounds.
7.
MONITORING THERAPY
Once ART is started, a reasonable schedule for the clinical monitoring
includes a first follow-up visit one month after initiation (which may be useful
also to evaluate and possibly reinforce adherence to antiretroviral treatment),
and a minimum of every three/four months thereafter. Monthly visits, which
can be combined with drug dispensing, are encouraged, as they are useful
opportunities to reinforce adherence. At each visit, inquiries should be made
regarding any new symptoms that may be related to drug side effects, to HIV
disease progression or to intercurrent processes. (Please see annex III for
proposed patient visit record.)
Adherence
Adherence should be assessed and routinely reinforced.
A high degree of adherence to ARV drugs is necessary for optimal virological
suppression. Studies indicate that 90-95% of the doses should be taken for
optimal suppression and lesser degrees of adherence are more often
associated with virological failure.51 Maintaining this level of adherence is
difficult. Imperfect adherence is common and surveys indicate that one-third
of patients missed doses within 3 days of survey.52
Factors that are associated with poor adherence include poor patient
clinician relationship, high pill burden, forgetfulness, mental depression, lack
Page 21
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
of patient education, inability of patients to identify their medications, drug
toxicity and being too ill.53 Appropriate patient education is essential for a
successful ARV programme. Factors associated with good adherence include
emotional and practical life support, ability of patients to fit medications into
their daily routine, understanding that it is essential to take medications
regularly and keep medical appointments.
Important determinants of adherence to antiretroviral therapy in
resource limited settings include: 54
>
the quality of initial and continuing counseling resulting in well
informed decisions and commitment by the patient to start and
maintain antiretroviral therapy.
>
the availability of accessible,
medical support teams.
>
the assurance of affordable and continued supply of antiretroviral
medications.
>
low pill burden and convenient dosing.
knowledgeable and
committed
Prior to starting therapy, the patient's willingness to take such therapy
should be clearly established. A treatment plan should be made which the
patient understands and can commit to. The importance of taking medicines
on a regular basis and the implications of non-compliance should be
explained to the patients. Written instructions should be given to help patients
understand the use of prescribed drugs. Possible side effects should be
explained in advance. Educating the patient's family and friends may be
helpful. A patient suffering from active substance abuse or mental illness may
benefit more if these problems are taken care of prior to starting antiretroviral
therapy.
A trusting and caring relationship between the patient and health care
provider is essential. Regular appointments and follow up visits help in the
continued care of the patient. Provider attitudes that are supportive and nonjudgmental will encourage patients to be honest about their adherence. The
healthcare team should have updated knowledge on antiretroviral therapy
and adherence, and should undertake training if necessary. New medical
problems may influence adherence. Temporary discontinuation of all
medicines may be more appropriate than uncertain adherence.
Page 22
I
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
The treatment regimen should be simplified by reducing the number of
pills, reducing the frequency of therapy such as twice daily dosing, and
minimizing side effects. Simplified regimens improve adherence.
Adherence may b£ measured by patient self-report, pill count, and the
report of the primary care provider.
Questions to assess adherence should include:
>
number of doses missed in the last 7 days
>
number of doses missed since last visit
>
if dose taken at correct time (if no, ask for delay in hours/days)
>
if correct dose taken
>
specification^ of reasons for interruption or modification/failure to
take prescribed doses.
Monitoring efficacy and toxicity of antiretroviral therapy
The efficacy of antiretroviral drugs is indicated by clinical improvement of the
patient, and by rise in CD4 cell counts. It is important also to exclude the
occurrence of new HIV-related opportunistic disease since this may mean
failure of the current antiretroviral regimen.
Clinical monitoring
Some of the clinical indicators of response to therapy are: 54,55
>
gain in body weight
>
decrease in frequency and severity of opportunistic infections
Karnofsky score may be used to assess the clinical status of the patient
(please see annex 4).
To promptly diagnose a new or a recurrent HIV-related opportunistic
illness as well as drug-related side effects, it is advisable to regularly perform
the history taking process regarding the period from the last clinical
evaluation.
During history taking, a few questions should be asked regarding:
Page 23
I he Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
History taking
Three
months
HIV related diseases incl.
TB
V
Cough
Six
months
Nine
months
V
V
2 weeks
Fever
V
Weight loss
7
Diarrhoea
V
Other symptoms as Cl,
CNS, neurology, skin rash
V
7
V
V
V
Other medications taken
Cl = gastrointestinal tract, CNS
Every three
months
central nervous system
A complete physical examination should be performed during the same
visit and should include at least:
Three
nL
•
l
Physical examination •
'
months
_
-■
Six
months
Nine
months
Every three
months
BW
V
KS
V
ENT
Skin
V
V
Lymph nodes
7
V
Respiratory system
7
V
CVS
Abdomen
V
cu
V
Neurology
V
BW = body weight, KS = Karnofsky score, ENT
system, GU = Genitourinary tract,
Page 24
V
V
V
V
V
V
ear nose throat, CVS= cardiovascular
TheUse of Antiretroviral Therapy: A Simpliried Approach for Resource-Confined Countries
Laboratory investigations
A
Routine laboratory testing is necessary to monitor drug adverse effects, and
appearance of new disease or progression of disease. These may include CBC,
serum ALT or AST, serum creatinine, blood glucose, and serum lipids
depending on the drug regimen and possible drug adverse effects. At the time
of follow up, history and physical examination may indicate other relevant tests.
In resource-limited settings monitoring of disease progression and
response to treatment will be by clinical indicators and CD4 cell count. It
nW not be possible to perform viral load due to the cost of the test and lack
of laboratory facilities and trained personnel.56
Laboratory test
Three
months
CD4
no
Hb or Het
Nine
months
Every six
months
no
V
V
WBC with diff
V
ALT
Hb = haemoglobin, Hot
differential
Six
months
V
V
V
V
_____ L
7
haematocrit, WBC with diff
white blood cell count with
CD4 lymphocyte counts
The clinical manifestations of HIV infection are related to CD4 counts. A low
level of CD4 counts, as below 200 cells/mm3 predicts decreased survival and
increased risk of opportunistic infections. CD4 counts are useful to determine
when to start therapy and to stop prophylaxis against certain organisms. In
patients with optimal antiretroviral therapy, CD4 counts increase by > TOO
cells/mm in the first 6-12 months in ARV naive, adherent patient with drug
susceptible virus. Higher elevations can be seen and response often continues
in subsequent years in the individuals who are maximally virologically
suppressed. Immunologic failure is indicated by a fall in CD4 counts higher
than 30% from the peak value or a return to, or below, the pre-therapy
baseline. A reasonable frequency of CD4 counts measurements in patients
on antiretroviral therapy in resource-limited settings is every 6 months.
Page 25
/Tie Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Treatment decisions should take into account the clinical condition of
the patient, information about adherence and availability of the ARV drugs,
results of routine laboratory tests and CD4 counts.
8.
CHANGING THERAPY
The reasons for changing an antiretroviral therapy regimen include drug
adverse effects, inconvenient regimens such as dosing/number of pills that
may compromise adherence, treatment failure, occurrence of active
tuberculosis and pregnancy.
The decision to change regimen should be based on clinical history and
physical examination; routine and relevant laboratory investigations, CD4
counts and changes in count. An assessment of adherence to medications
should be made and remaining treatment options considered. Potential of
initial viral resistance, drug interaction and diet will also need to be
considered.
8.1
Change Due to Adverse Effects/lntolerance
In a patient who experiences adverse effects or is intolerant to an otherwise
successful regimen, substitution of the offending drug is reasonable. An
example would be metabolic adverse effects of a PI that can be replaced by
an NNRTI. For serious adverse effects, such as abacavir hypersensitivity
reactions and nevirapine related hepatic failure, rechallenge should not be
attempted as this may lead to toxicity and death (please see chapter on
serious adverse effects and drug discontinuation for details).
8.2
Change due to Treatment Failure
Treatment failure can be defined as clinical failure, immunologic failure
and/or virologic failure. Clinical failure is defined as clinical disease
progression with development of an opportunistic infection or malignancy
when the drugs have been given sufficient time to induce a protective degree
of immune restoration. This needs to be differentiated from an immune
reconstitution syndrome which can be seen within the first several weeks after
the institution of therapy if a subclinical infection is present at baseline.57 In
immune reconstitution syndromes, changing the antiretroviral regimen is not
Page 26
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
indicated. Immunologic failure can be defined as a fall in CD4 counts higher
than 30% from the peak value or a return to, or below, the pre-therapy
baseline.6 There is no accepted definition of immunologic failure that can be
used if CD4 counts are not available. Virologic failure has no uniformly
accepted definition but repeated, continued detectable viremia is indicative
of incomplete viral suppression. As measuring viral load in not an option in
the majority of resource-constrained settings, it is not recommended for the
routine monitoring of treatment in the present guidelines. The reader is
referred to other existing guidelines for further reading on the use of viral load
to monitor ARV treatment.6
Treatment failure may occur due to a number of reasons. These include
unsatisfactory patient adherence, viral resistance to one or more drugs,
impaired drug absorption, and altered drug pharmacokinetics.
The entire regimen should be changed from a First to a second line
combination regimen in the case of treatment failure. A single drug should
not be added or changed to a failing regimen. The new second-line regimen
will need to use drugs, which retain activity against the patient's virus strain
and ideally include at least three new drugs, in order to increase the
likelihood of treatment success.
Table 9 lists the second-line regimens one could consider in adolescents
and adults for each of the first-line regimens identified in Table 8.
Nucleoside analog cross-resistance is an increasing concern. When
ZDV/3TC is used in the first-line regimen, nucleoside cross-resistance may
compromise the potency of d4T/ddI in the second-line regimen, in particular
in the presence of long-standing virologic treatment failure. In this regard,
ABC/ddl might also be considered as the nucleoside backbone for a secondline regimen if the first line regimen did not include ABC. However, high-level
ZDV/3TC resistance also confers diminished susceptibility to ABC.
*
The near complete cross resistance between EFZ and NVP means that a
switch between these two agents in the setting of treatment failure is not
advisable. In case of Pls, cross resistance among these agents is also common.
A possible exception to this exists when NFV is the first PI employed.
Therefore, in the case of treatment failure on a Pl-based regimen, it is
recommended that the PI be switched to an NNRTI.
Page 27
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Given the diminished potential of almost any second line nucleoside
component, a ritonavir (RTV, r) enhanced PI component [indinavir (IDV)/r,
lopinavir (LPV)/r, saquinavir (SQV)/r)] is preferred to nelfinavir (NFV) in second
line regimens because of its potency. NFV can be considered as an alternative
for the PI component if a RTV-enhanced PI is not available or if there is a
clinical contraindication to its use.
Table 9. Recommended second-line regimens in adults and adolescents 31,32
First line regimens
ZDV/3TC plus EFZ or
NVP
Second-line regimens
for treatment failure
RTV-enhanced PI a +
d4T/ddl b'd
Alternative second-line
regimen for treatment
failure
-RTV-enhanced PI a +
ABC/ddl c'd
-NFV + ABC/ddl c-d or
d4T/ddl b'd
ZDV/3TC/ABC
NNRTI e + LPV/r +/d4T/ddl b'd
RTV-enhanced PI a +
d4T/ddl b'd
ZDV/3TC/RTV- enhanced
PI or NFV
NNRTI e + d4T/ddl b'd
NNRTIe+ ABC/ddl c'd
d RTV-enhanced PI = IDV/r, LPV/r, SQV/r. A RTV-enhanced PI regimen is preferred given
the potency of these regimens. NFV can be considered as an alternative for the PI
component of second-line therapy if RTV-enhanced PI is not available or if there is a
clinical contraindication to its use.
b Nucleoside cross-resistance may compromise potency of d4T/ddl at the time of
switching for treatment failure as it is assumed that virologic failure will have been
prolonged at that point and several nucleoside analog mutations are likely to be present.
However, choices are limited in the setting of treatment failure. See also footnote d.
c High level ZDV/3TC co-resistance confers diminished susceptibility to ABC.
dTenofovir is a once-daily nucleotide NtRTI with activity against some nucleoside resistant
strains. If available, TDF can either be added to d4T/ddl or ABC/ddl or substituted for
either d4T or ABC in these combinations. Its current limited availability in resource
limited settings is recognized.
j
e NNRTI can be either EFZ or NVP.
Page 28
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
9.
ANTIRETROVIRAL THERAPY IN SPECIAL SITUATIONS
9.1
Adolescents
—
- -
Adolescents infected with HIV through sexual route or injecting drug use
during adolescent period, have a clinical course that is similar to adults. Most
of these patients who were HIV infected sexually during the adolescent period
are in the early stage of HIV infection.6
i
Adolescents infected with HIV as young children either perinatally or
through the parenteral route suchi as blood and blood products may have a
different course and may present in advanced stage of the disease.6
Adolescent < 13 years should receive ART dose based on paediatric
guidelines. Adolescents > 13 years should receive ART dose based on adult
guidelines according to weight.32
9.2
Women, with Specific Reference to Pregnancy
ART recommendations for HIV-infected pregnant women are based upon the
principle that therapies of known benefit to women should not be withheld
during pregnancy unless the risk of adverse effects on the mother, foetus or
infant outweighs the expected benefit to the woman.58 Pregnancy, or the
desire to become pregnant, should not preclude the use of optimal
antiretroviral therapy. However, considerations related to pregnancy may
affect decisions regarding the choice of antiretroviral regimen. Additionally,
the potential impact of such therapy on the foetus and infant must also be
considered when treating women of childbearing age, unless they use
effective contraceptives. For pregnant women who do not yet need ART for
their own disease, the use of antiretroviral drugs to reduce the risk of motherto-child HIV transmission is recommended.43'45 However, a discussion of ART
for this indication falls outside the scope of the present guidelines. The reader
is referred to the recent WHO guidelines on prevention of MTCT for further
information.
(A) Choice of antiretroviral drugs in non-pregnant women of
childbearing age
In non-pregnant women, the recommendations for starting antiretroviral
therapy are similar for men and women.6,50
Page 29
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
The choice of ART in women with the potential to become pregnant
must include consideration of the possibility that the ARV drugs may be
received during the early first trimester, prior to recognition of pregnancy and
during the primary period of foetal organ development. Effective and
appropriate contraceptive methods to reduce the likelihood of unintended
pregnancy should be available for women receiving ART. NNRTIs (NVP and
EFZ) and the Pls (NFV and all low dose RTV-boosted Pls) lower blood
concentrations of oral contraceptives and additional or alternative
contraception methods need to be used to avoid pregnancy in women
receiving these drugs. EFZ may be associated with severe birth defects and
should be avoided in women who desire to become pregnant.
(B) Choice of antiretroviral drugs in pregnancy
ARV regimens given for treatment to pregnant women should preferably
include drugs shown to be effective in reducing mother-to-child transmission.
Drugs shown to be effective in reducing transmission include ZDV, ZDV/3TC,
and NVP.43'45'59'61 The most successful experience in terms of efficacy and
maternal and foetal safety is with ZDV; thus, first-line treatment regimens in
pregnant women should include ZDV whenever possible. Combination of
ZDC/3TC should be the first choice for use in pregnancy. Maternal
antiretroviral drugs should be continued during the period of labor.
Pharmacokinetic studies of ZDV, 3TC, d4T, and ddl in pregnant women
indicate that the dose used for these drugs in pregnancy should be the same
as in non-pregnant individuals.62'64 ABC has not been formally evaluated in
pregnant women. The dual NsRTI combination of d4T/ddl should only be
used during pregnancy when no other alternatives exist, due to the potential
increased risk of lactic acidosis with this combination in pregnant women.
NVP is the NNRTI of choice for use in pregnancy. Pregnancy should be
avoided in women receiving EFZ due to concerns related to teratogenicity
and its use should be avoided during the first trimester.
Pls have been associated with the development of glucose intolerance
and even diabetes mellitus in non-pregnant individuals. Pregnancy is also a
risk factor for hyperglycemia; it is not known if the use of protease inhibitors
exacerbates the risk for pregnancy-associated hyperglycemia. Hyperglycemia
in pregnancy can lead to an increased risk of macrosomia, foetal distress, prePage 30
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
eclampsia and stillbirth. Symptoms of hyperglycemia (e.g., increased urination
and thirst, weight loss) should be discussed with pregnant women receiving
protease inhibitors and they should be instructed that should such symptoms
occur, they should see their health care provider.
NFV, followed by SQV, are the most common protease inhibitors used
to treat pregnant HIV-infected women in resource-rich countries.65 NFV has
been well-tolerated by pregnant women; when administered as 1250 mg
twice daily it produces adequate drug levels, and is the first choice PI for use
during pregnancy.66 IDV carries the theoretical risk of exacerbating neonatal
hyperbilirubinemia if used near to or during labor, and therefore is a less
desirable PI choice in pregnancy. LPV/r has not been studied in pregnant
women.
(C) Women first diagnosed with HIV infection during pregnancy
Women who are in the first trimester of pregnancy may wish to consider
delaying initiation of therapy until after 10-12 weeks gestation due to
potential teratogenic effects of ART. Initiation of ART is rarely a medical
emergency. However, for women who are severely ill, the benefit of early
initiation of therapy may outweigh the theoretical risk to the foetus,
particularly if therapy is initiated with drugs in which there is more experience
with use in pregnancy (such as ZDV, 3TC, NVP or NFV).
(D) HIV-infected women receiving antiretroviral drugs
who become pregnant
a
For women who become pregnant while receiving ART, the options are to
temporarily discontinue therapy during early pregnancy (first trimester), to
continue the same therapy, or change to a different drug regimen.
To reduce the potential for emergence of resistance, if it is decided to
temporarily discontinue antiretroviral treatment during the first trimester, all
drugs should be stopped and restarted simultaneously.
A switch in ART during pregnancy should be considered if the drug
being received has teratogenic potential (i.e., EFZ); if there are concerns
regarding risk of severe toxicity to the pregnant woman (e.g., d4T/ddl); or
Rage 3 7
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
there is significant intolerance of the drug that could be compounded by
pregnancy (e.g., gastrointestinal intolerance compounded by morning
sickness) and lead to poor drug adherence.
(E) Breastfeeding
Current WHO/UNAIDS/UNICEF guidelines recommend that women with
HIV infection be fully informed of both the risks and benefits of breastfeeding
and be supported in their decision about feeding practices.
HIV-infected women should preferably avoid breastfeeding to reduce
the risk of mother-to-child transmission where safe alternatives are available,
affordable and acceptable.67,68
However, safe alternatives to breastfeeding may not be available in some
resource-limited settings, and in such situations, exclusive breastfeeding for
the first 6 months of life is recommended.
Women who require ART and who are breastfeeding should continue
their ongoing antiretroviral therapeutic regimen. However, the efficacy of
potent ART of the mother to prevent postnatal transmission of HIV through
breast milk is unknown.
(F) HIV-infected women who have received short-course
antiretroviral prophylaxis to reduce mother-to-child
transmission and require treatment postpartum
Short-course ARV drug regimens that do not fully suppress viral replication
that are used to prevent MTCT of HIV may be associated with the
development of antiretroviral drug resistance. This is most likely to occur with
prophylaxis regimens using antiretroviral drugs for which a single point
mutation can confer drug resistance, such as NVP or 3TC.
However, based on current information, prior administration of short
course ZDV/3TC or single dose NVP for prevention of mother-to-child
transmission should not preclude use of these agents as part of a combination
ARV drug regimen initiated for treatment of HIV disease in women.
Page 32
*
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
(G) Issues related to adherence to therapy in pregnancy and
postpartum
Adherence to treatment may be more difficult in pregnant and immediately
postpartum women than in non-pregnant individuals.69,70 Potential obstacles
to adherence that are unique to pregnancy include morning sickness and
gastrointestinal upset, which can be further compounded by ART associated
nausea, and fears that antiretroviral drugs might harm the foetus. To reduce
the potential for emergence of resistance, if therapy requires temporary
discontinuation for any reason during pregnancy, all drugs should be stopped
and re-started simultaneously.
The physical changes of the postpartum period coupled with the stresses
and demands of caring for a newborn infant may make adherence to
treatment especially difficult after birth. Particular attention to provision of
additional support for maintaining adherence to therapy during the ante- and
post-partum periods is important.
9.3
Tuberculosis
Due to the high prevalence of tuberculosis (TB) among HIV-infected
individuals living in the South-East Asia Region, many patients who are
candidates for ART will have active TB.71 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.72 The management of HIV and TB co-infection is complicated
because some antiretroviral agents produce unacceptable drug interactions
with anti-tubercular agents and/or can increase toxicity of TB treatment.73'75
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. Initiation of ART for TB
patients at very high risk for HIV disease progression and mortality is
recommended, i.e., a CD4 count <200 cells/mm3, or extrapulmonary TB
(Table 10). For patients who develop TB with CD4 counts in the 50-200
cells/mm range or, in the absence of CD4 testing, have total lymphocyte
counts <1200 cells/mm3, ART should be started after the first two months of
Page 33
I
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
TB therapy, because the toxicity of TB treatment is greatest during this period
(Table 10). In the subset of patients with very low CD4 cell counts (<50
cells/mm3) or with other severe HIV disease, ART should be started as soon as
TB therapy is tolerated.7
Table 10. Antiretroviral therapy for individuals with tuberculosis co-infection
Situation
Recommendations
Pulmonary TB and CD4 count
<5O/mm3 or extrapulmonary TB
Start TB therapy. Start one of
these regimens as soon as TB
therapy is tolerated:
• ZDV/3TC/ABC
• ZDV/3TC/EFZ
• ZDV/3TC/SQV/r
• ZDV/3TC/NVP
Pulmonary TB and CD4 50-200/mm3
or total lymphocyte count <12OO/mm3
Start TB therapy. Start one of
these regimens after 2 months of
TB therapy:
• ZDV/3TC/ABC
• ZDV/3TC/EFZ
• ZDV/3TC/SQV/r
• ZDV/3TC/NVP
Pulmonary TB and CD4 >200/mm3 or
total lymphocyte count >12OO/mm3
Treat TB. Monitor CD4 counts if
available. Start ART according to
Table 8.
The first line treatment options include ZDV/3TC or d4T/3TC plus either
an NNRTI or ABC. The fixed dose combination of ZDV/3TC/ABC has no drug
interactions with anti-tubercular therapy and does not require dose
adjustments. However, the hypersensitivity reaction associated with ABC
overlaps clinically with the immune reconstitution syndrome (see below) seen
with tuberculosis. Therefore, ARV treatment could prematurely and
unnecessarily be discontinued in patients with TB who initiate an ARV
regimen containing ABC. If an NNRTI based regimen is used, EFZ is the
preferred drug as its potential to aggravate the hepatotoxicity of TB treatment
appears less than with NVP. The dose of EFZ may need to be increased to
800 mg/day when used in combination with rifampicin. Except for SQV/r, use
Page 34
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
of other Pls (NFV, IDV/r, LPV/r) is contraindicated because rifampicin induces
hepatic enzymes that reduce exposure to the protease inhibitors to subtherapeutic levels.
Patients already receiving ART when they develop TB should adjust the
regimen to be compatible with TB treatment. Following completion of antitubercular therapy, the ART regimen can be continued or changed depending
upon the clinical and immunologic status of the patient.
9.4
Other Opportunistic Infections and Hepatitis
Patients who develop opportunistic infections should be treated with ART.
Prompt initiation of ART should be considered when opportunistic infections
occur for which treatment is not available or in suboptimal, because
improvement of the immune system may enhance recovery.
Patients co-infected with hepatitis B or C can be safely treated with
several ARV regimens.78 Because of the possibility of additive hepatotoxicity,
regimens with ddl/d4T and/or NVP should be avoided in patients known to
have active hepatitis. 3TC and TDF are both active against hepatitis B and
may even protect against new infections.79,80 Patients receiving 3TC or TDF
known to have hepatitis B who experience ARV regimen failure may wish to
continue these medications when the ARV regimen is switched.
9.5
I
Immune Reconstitution Syndrome
For many opportunistic infections including TB, there can be a transient
worsening of the infection 2-3 weeks after ART initiation; this is referred to as
the immune reconstitution syndrome.81,82 For patients with TB, this syndrome
has been reported to occur in as many as 30% of patients in the developed
world.83 The syndrome is characterized by fever, lymphadenopathy,
worsening pulmonary lesions (at X-ray examination) and expanding central
nervous system (CNS) lesions. These reactions are typically self-limiting,
although may require the use of a brief course of corticosteroids to reduce
inflammation for severe respiratory or CNS symptoms. Initiation of ART can
also unmask previously undiagnosed infections by augmenting the
inflammatory response. In general, ART should not be interrupted for immune
reconstitution syndromes.
Page 35
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
9.6
Prophylaxis for Opportunistic Infections and Tuberculosis
ART is the most effective approach to reducing Ol incidence in HIV-infected
patients, but should not replace efforts to provide antimicrobial prophylaxis.10
Co-trimoxazole reduces the risk of bacterial infections, Pneumocystis carinii
pneumonia and toxoplasmosis and is recommended for all patients who meet
indications for ART.11 In areas with a high prevalence of cryptococcal disease,
fluconazole prophylaxis should be considered for patients with less than 100
CD4 cells/mm3. Based on observations in patients in developed countries,
patients responding to ART with a sustained elevation in CD4 cell counts
above 200 cells/mm3 for 3-6 months may discontinue prophylaxis.
Preventive therapy for TB (i.e., treatment of latent TB) reduces the risk
for active TB in HIV infected patients, although the durability of this effect
may be limited by high rates of re-infection with TB.84’87 Preventive therapy for
TB may not be feasible in many resource-limited settings because of the
difficulty in excluding active disease. TB preventive therapy is therefore
recommended in areas where diagnostic testing is available to exclude active
TB and where PPD skin testing is feasible. In this circumstance, isoniazid
therapy (with pyridoxine-supplementation) for 9 months in tuberculin skin test
reactors is recommended after exclusion of active disease.
10.
IMPLEMENTING ARV TREATMENT PROGRAMMES
Several components of the implementation process must be considered from
the beginning and explored step-wise prior to starting implementation. These
include situation assessment, programme planning and implementation steps.
10.1
Situation Assessment
Estimating the burden of any public health problem is an important tool for
programme planning. The situation assessment should include a realistic
estimate of the burden of HIV infection in the country and in the areas
selected for the intervention. An estimate of the total number of people
needing ART should be made for programme planning. The need can be
estimated from the proportion of people with HIV infection out of the total
population of the country or the selected geographical area, the number of
people who are estimated to know their HIV status, who access HIV/AIDS
Page 36
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
care, who need ART according to the guidelines, and who ultimately will take
antiretroviral treatment. An example is given in Figure 1.
Figure 1. How to estimate the number of people living with
HIV/AlDS (PLHA) to receive ART
I ot.il I IIV
People who know
their I IIV status
PL HA who access
care
PLHA who need
ART
■
PLHA who take
ART
(Note: Affordability includes contribution from government, patient payment, co-payment
schemes, health insurance and external resources.)
10.2
Programme Planning
A few steps need to be followed in the planning phase:
i
>
Define clear programme objectives and priorities
>
Form technical and community advisory board
>
Determine a responsible body and form teams in health care settings
>
Plan for sustainability of the programme
>
Involvement of PLHA, NCOs, communities and other relevant groups
>
Plan ongoing capacity building of health care providers (counsellors,
physicians and nurses)
>
Define inclusion and exclusion criteria
Page 37
The Use of Antiretroviral Therapy: A Simplified Approach for ResourceLConstrained Countries
>
Define target groups for ART when funds are limited e.g. patients with
active TB, mothers from the PMTCT programmes, people who can not
pay
>
Select ART regimens and clinical and laboratory tests for treatment
monitoring
>
Ensure access to ART services
Ensure adherence to ART
10.3
>
Ensure referral to other HIV/AIDS care and support services within
health facility and community
>
Design monitoring, supervision and evaluation tools, plan for data flow
and information exchange
>
Plan for programme expansion
Steps for Implementation
Programme level
>
Establish/strengthen community and home-based care
>
Provide PLHA with education on HIV prevention, care and treatment
>
Establish counseling network for ongoing counseling of PLHA and
support of counselors
>
Establish network for laboratory facilities for developing standard
operating procedures (SOP) and quality assurance and quality control
(QA/QC) for laboratory tests
>
Establish drug procurement, storage and distribution system
>
Analysis and feedback of monitoring and evaluation data
Health facility level
Preparation
>
Papp 3 <8
Provide capacity building of health care
physicians, nurses and laboratory technicians)
providers
(counsellors,
I 111 II Illi
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Components for implementation
>
Establish voluntary counseling and testing (VCT) services
>
Provide:
>
•
Pre-trealment screening and enrolment
•
Pre-treatment monitoring for HIV-infected individuals currently not
eligible for ART
•
Care package to prevent and treat common Ols
•
ART counseling
•
Treatment monitoring
Integrate monitoring and evaluation tools
Establish supervision and support for health care providers
The impact of the ART programme depends on the availability and
utilization of VCT, the availability of trained health care workers, laboratory
capacity, ART for 1st and 2nd line regimens and funds to sustain the
programme.
Page 39
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
References
(i)
Centres for Disease Control and Prevention. Pneumocystis pneumonia - Los Angeles. Morb Mortal
Wkly Rep MMWR 1981 ;30:250-2.
(2)
UNAIDS, WHO. AIDS epidemic update: December 2001. Geneva. Joint United Nations
Programme on HIV/AIDS, 2001.
(3)
National AIDS/STD Programme, MOHFW, Government of the People's Republic of Bangladesh.
HIV in Bangladesh: where is it going? November 2001.
(4)
The Thai Working Group on HIV/AIDS Projection. Projections for HIV/AIDS in Thailand: 20002020. March 2001.
(5)
Fischl M, Richmann DD, Grieco MH, et al. The efficacy of azidothymidine (ZDV) in the treatment
of patients with AIDS and AIDS-related complex. A double blind, placebo controlled trial. N Engl J
Med 1987;317:192-7.
(6)
Department of Health and Human Services (DHHS) and the Henry J Kaiser Family Foundation
2002. Guidelines for the use of antiretroviral agents in HIV- infected adults and adolescents.
Available at http://www.hivatis.org/guidelines/adult.
(7)
British HIV Association Writing Committee 2001. British HIV Association (BHIVA) guidelines for the
treatment
of
HIV
infected
adults
with
antiretroviral
therapy.
Available
at:
http://www.aidsmap.com/bhiva/bhivagd1299
(8)
Mocroft A, Vella S, Benfield TL, et al. Changing patterns of mortality across Europe in patients with
human immunodeficiency virus infection. Lancet 1998;352:1 725-30.
(9)
Moore RD, Chaisson RE. Natural history of HIV infection in the era of combination antiretroviral
therapy. AIDS 1999;13:1933-42.
(10) Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with
advanced human immunodeficiency virus infection. N Engl J Med 1998;338;853-60.
(11) 2001 USPHS/IDSA. Guidelines for the prevention of opportunistic infections in persons infected
with human immunodeficiency virus, http://www.hivatis.org.
(12) Gebo KA, Chaisson RE, Folkemer IG, Bartlett JG, Moore RD. Cost of HIV medical care in the era of
highly active antiretroviral therapy. AIDS 1999;13:963-9.
(13) Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus
indinavir in persons with human immunodeficiency virus infection and CD4 counts of 200 per
cubic millimeter or less. N Engl J Med 1997;337:725-33.
(14) Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in
adults with human immunodeficiency virus infection and prior antiretroviral therapy N Engl J Med
1997;337:734-9.
(15) Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine,
efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1
infection in adults. N Engl J Med 1999;341:1865-73.
(16) Quinn TC, Wawer MJ, Sekankambo N, et al. Viral load and heterosexual transmission of human
immunodeficiency virus type 1. N Engl J Med 2000;342:921-9.
Page 40
The Use of Antiretroviral Therapy: A Simplified Approach for Resou rce -Con s t ra in ed Cou n t ri es
(17) Garcia PM, Kalish LA, Pitt J, et al. Maternal levels of plasma human immunodeficiency virus type 1
RNA and the risk of perinatal transmission. N Engl J Med 1999;341:394-402.
(18) Bozzette SA, Joyce G, McCaffrey DE, et al. Expenditures for the care of HIV infected patients in the
era highly active antiretroviral therapy. N Engl J Med 2001 ;344:817-23.
(19) Freedberg KA, Losina E, Weinstein MC, et al. The cost effectiveness of combination antiretroviral
therapy for HIV disease. N Engl J Med 2001 ;344:824-31.
(20) Farmer P, Lendre F, Mukherjee J, et al. Community based treatment of advanced HIV disease:
introducing DOT-HAART (directly observed therapy with highly active antiretroviral therapy).
Bulletin of World Health Organization 2001;79:1145-51.
(21) Individual members of the Faculty of Harvard University. Consensus statement on antiretroviral
treatment for AIDS in poor countries. Topics in HIV Medicine 2001 ;9:14-26.
(22) Farmer P, Lendre F, Mukherjee J, et al. Community-based approaches to HIV treatment in
resource-poor settings. Lancet 2001 ;358:404-9.
(23) Cipla Pharmaceuticals, Mumbai, India. Personal communication.
(24) Perelson AS, Neumann AU, Markowitz M, et al. HIV-1 dynamics in vivo: virion clearance rate,
infected cell life-span, and viral generation time. Science 1996;271:1582-6.
(25) Centres for Disease Control and Prevention. Report of the NIH Panel to define principles of therapy of
HIV infection. MMWR. Recommendations and Reports 1998;47(RR-5):1-41.
(26) Chun TW, Engel D, Berrey MM, eLal. Early establishment of a pool of latently infected, resting CD4 + T
cells during primary HIV-1 infection. Vjoc Natl Acad Sci 1998;95:8869-73.
(27) Wong JK, Hezareh M, GunthaYd HF, et al. Recovery of replication of competent HIV despite
prolonged suppression of plasma viraemia. Science 1997;278:1291-5.
(28) Finzi D, Blankson J, Siliciano JD, et al. Latent infection of CD4+T cells provides a mechanism for
lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med
1999;5:512-7.
(29) Zhang L, Ramnatnam B, Tenner-Racz K, et al. Quantifying residual HIV-1 replication in patients
receiving combination antiretroviral therapy. N Engl J Med 1999;340:1605-13.
(30) O'Brien WA, Hartigan PM, Martin D, et al. Changes in plasma HIV-1 RNA and CD4+ lymphocytes
counts and the risk of progression to AIDS. N Engl J Med 1996;334:426-31.
(31) World Health Organization. Scaling up antiretroviral therapy in resource-limited settings:
Guidelines for a public health approach. Executive Summary. WHO/HIV/2002.01.
(32) World Health Organization. Scaling up antiretroviral therapy in
Guidelines for a public health approach. WHO/HIV/2002.02.
resource-limited settings:
(33) Centres for Disease Control and Prevention. 1993 revised classification system for HIV infection
and expanded surveillance case definition for AIDS among adolescents and adults. MMWR
1992;41(51):1-19.
(34) Centres for Disease Control and Prevention. Updated US Public Health Service guidelines for the
management of occupational exposures to HBV, HCV, and HIV and recommendations for
postexposure prophylaxis. MMWR 2001 ;50:RR-11.
Page 4 7
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
(35) Centres for Disease Control and Prevention. Management of possible sexual, injecting-drug-use, or
other nonoccupational exposure to HIV, including considerations related to antiretroviral therapy.
MMWR 1998;47:RR-17.
(36) Hogg RS, Yip B, Chan KJ, et al. Rates of disease progression by baseline CD4 cell count and viral
load after initiating triple-drug therapy. JAMA 2001 ;286:2568-77.
(37) Sterling TR, Chaisson RE, Moore RD. HIV-1 RNA, CD4 T-lymphocytes, and clinical response to
highly active antiretroviral therapy. AIDS 2001;15:2251-7.
(38) Cozzi LA, Phillips AN, d'Arminio Monteforte A, et al. When to start highly active antiretroviral
therapy in chronically infected HIV-infected patients: evidence from ICONA study. AIDS
2001;15:983-90.
(39) Mellors JW, Munoz A, Giorgi JV, et al. Plasma viral load and CD4 lymphocytes as prognostic
markers of HIV-1 infection. Ann Intern Med 1997;126:946-54.
(40) Kessler HA, Johnson J, Follansbee S, et al. Abacavir expanded access programme for adult patients
infected with human immunodeficiency virus type 1. Clin Infect Dis 2002; 34:535-42.
(41) Physicians' Desk Reference (56lh ed.). Montvale, NJ, USA: Medical Economics, 2002.
(42) British National Formulary. British Medical Association, London, UK. March 2002.
(43) Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human
immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trial Group
Protocol 076 Study Group. N Engl J Med 1994;331:11 73-80.
(44) Lallemant M, Jourdain G, Coeur SL, et al. A trial of shortened zidovudine regimens to prevent
mother-to-child transmission
2000;343:982-91.
of
human
immunodeficiency
virus
typel.
N
Engl J
Med
(45) Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared
with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda:
HIVNET012 randomised trial. Lancet 1999;354:795-802.
(46) Mitsuyasu RT, Skolnik PR, Cohen SR, et al. Activity of the soft gelatin formulation of saquinavir in
combination therapy in anti retroviral-naive patients. AIDS 1998; 12: Fl 03-9.
(47) Murphy RL, De Gruttola V, Gulick RM, et al. Treatment with amprenavir alone or amprenavir with
zidovudine and lamivudine in adults with human immunodeficiency virus infection. J Infect Dis
1999;179:808-16.
(48) Montaner JS, Reiss P, Cooper D, et al. A randomized, double-blind trial comparing combinations of
nevirapine, didanosine, and zidovudine for the HIV-infected patients. The INCAS Trial. Italy, The
Netherlands, Canada and Australia Study. JAMA 1998;279:930-7.
(49) Rhone SA, Hogg RS, Yip B, et al. The antiviral effect of ritonavir and saquinavir in combination
amongst HIV-infected adults. Results from a community based study. AIDS 1998;12:619-24.
(50)
Carpenter CC, Cooper DA, Fischl MA, et al. Antiretroviral therapy in adults: updated recommendations
of the International AIDS Society-USA Panel. JAMA 2000;283:381-90.
(51) Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in
patients with HIV infection. Ann Intern Med 2000;133:21-30.
(52) Ickovics JR, Meisler AW. Adherence in AIDS clinical trials: a framework for clinical research and
clinical care. J Clin Epidemiol 1997;50:385-91.
(53) Chesney MA. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis 2000;30 Suppl
2:S171-6.
Page 42
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
V
(54) World Health Organization. Initiative on HIV/AIDS and Sexually Transmitted Infections. Safe and
effective use of antiretroviral treatments in adults with particular reference to resource limited
settings. WHO/HSI/2000;4:23-4. \
(55) Ministry of Public Health, Thailand. National guidelines for the clinical management of HIV
infection in children and adults, 6th Ed, 2000.
(56) World Health Organization and UNAIDS. Guidance modules on antiretroviral treatments. Module
5. Laboratory requirements for the safe and effective use of antiretrovirals. WHO/ASD/98.1.
UNAIDS/98.7.
(57) Behrens GM, Meyer D, Stoll M, Schmidt RE. Immune reconstitution syndromes in human immunodeficiency virus infection following effective antiretroviral therapy. Immunobiology 2000; 202:18693.
(58) Taylor GP, Low-Beer N. Antiretroviral therapy in pregnancy: a focus on safety. Drug Saf 2001;
24:683-702.
(59) Shaffer N, Chuachoowong R, Mock PA, el al. Short-course zidovudine for perinatal HIV-1
transmission in Bangkok, Thailand: a randomised controlled trial. Bangkok Collaborative Perinatal
HIV Transmission Study Group. Lancet 1999; 353:773-80.
(60) Wiktor SZ, Ekpini E, Karon JM, et al. Short-course oral zidovudine for prevention of mother-tochild transmission of HIV-1 in Abidjan, Cote d'Ivoire: a randomised trial. Lancet 1999; 353:781-5.
(61) Dabis F, Msellati P, Meda N, et al. 6-month efficacy, tolerance, and acceptability of a short regimen
of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Cote d'Ivoire and
Burkina .Faso: a double-blind placebo-controlled multicentre trial. DITRAME Study Croup.
Diminution de la Transmission Merb-Enfant. Lancet 1999; 353:786-92.
(62) O'Sullivan MJ, Boyer PJ, Scott GB, et^l. The pharmacokinetics and safety of zidovudine in the third
trimester of pregnancy for women infected with human immunodeficiency virus and their infants:
phase I acquired immunodeficiency syndrome clinical trials group study (protocol 082). Zidovudine
Collaborative Working Group. Am J Obstet Gynecol 1993; 168:1 510-6.
(63) Wang Y, Livingston E, Patil S, et al. Pharmacokinetics of didanosine in antepartum and postpartum
human immunodeficiency virus-infected pregnant women and their neonates: an AIDS clinical
trials group study. J Infect Dis 1999; 180:1536-41.
(64) Mood ley J, Moodley D, Pillay K, et al. Pharmacokinetics and antiretroviral activity of lamivudine alone or
when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant
women and their offspring. J Infect Dis 1998; 178:1327-33.
(65) Morris AB, Cu-Uvin S, Harwell JI, et al. Multicentre review of protease inhibitors in 89 pregnancies.
J Acquir Immune Defic Syndr 2000; 25:306-11.
(66) Reiss G, O'Brien M, Kopicko J, Clark RA. Lack of association between pregnancy and selected
gastrointestinal adverse events among women prescribed nelfinavir. J Acquir Immune Defic Syndr
2001;26:513-4.
(67) UNFPA/UNICEF/WHO/UNAIDS Interagency Task Team on MTCT. New data on the prevention of
mother to child transmission of HIV and their Policy Implications. Geneva: WHO, October 2000.
(68) Nicoll A, Newell ML, Peckham CS, Luo C, Savage-King F. Infant feeding and HIV-1 infection. AIDS
2000;14(suppl 3):57-74.
(69) Laine C, Newschaffer CJ, Zhang D, Cosier L, Hauck WW, Turner BJ. Adherence to antiretroviral
therapy by pregnant women infected with human immunodeficiency virus: a pharmacy claimsbased analysis. Obstet Gynecol 2000; 95:167-73.
Page 43
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
(70)
Turner B), Newschaffer CJ, Zhang D, Cosier L, Hauck WW. Antiretroviral use and pharmacy-based
measurement of adherence in postpartum HIV-infected women. Med Care 2000; 38:91 1-2j.
(71) Narain J.P., Pontali E., Tripathy S. Epidemiology and control strategy; in: Symposium on HIV & TB.
Indian Journal of Tuberculosis. 2002; 49: 3-9.
Santoro-Lope^
C, de Pmho AM, Ha'rison LH, Schechter M. Reduced risk of tuberculosis among
(72)
Brazilian patients with advanced human immunodeficiency virus infection treated with highly
(73)
(74)
active antiretroviral therapy. Clin Infect Dis 2002; 34:543-6.
Burman WJ, Jones BE. Treatment of HIV-related tuberculosis in the era of effective antiretroviral
therapy. Am J Respir Crit Care Med 2001; 164:7-12.
Wagner KR, Bishai WR. Issues in the treatment of Mycobacterium tuberculosis in patients with
human immunodeficiency virus infection. AIDS 2001; 15 Suppl 5:S203-12.
virus infection. N
(75) Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency vi
Engl J Med 1999; 340:367-73.
(76) Dean CL, Edwards SG, Ives NJ, et al. Treatment of tuberculosis in HIV-infected persons in the era
of highly active antiretroviral therapy. AIDS 2002; 16:75-83.
(77) Carr A, Marriott D, Field A, Vasak E, Cooper DA. Treatment of HIV-1-associated microsporidiosis
and cryptosporidiosis with combination antiretroviral therapy. Lancet 1998, 351.2o6-61.
(78) Chung RT, Kim AY, Polsky B. HIV/Hepatitis B and C co-infection: pathogenic interactions, natural history
and therapy. Antivir Chem Chemother 2001; 12 Suppl 1:73-91
(79) Ying C, De Clercq E, Neyts J. Lamivudine, adefovir and tenofovir exhibit long-lasting anti-hepatitis
B virus activity in cell culture. J Viral Hepat 2000; 7:79-83.
(80) DienstagJL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the
United States. N Engl J Med 1999; 341:1256-63.
(81) DeSimone JA, Pomerantz RJ, Babinchak TJ. Inflammatory reactions in HIV-1-infected persons after
initiation of highly active antiretroviral therapy. Ann Intern Med 2000; 133:447-54.
(82) Cheng VC, Yuen KY, Chan WM, Wong SS, Ma ES, Chan RM. Immunorestitution disease involving
the innate and adaptive response. Clin Infect Dis 2000; 30:882-92.
(83) Narita M, Ashkin D, Hollendcr ES, Pitchenik AE. Paradoxical worsening of tuberculosis following
antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998; 158:157-61.
(84) Quigley MA, Mwinga A, Hosp M, el al. Long-term effect of preventive therapy for tuberculosis in a
cohort of HIV-infected Zambian adults. AIDS 2001; 15:215-22.
(85) Johnson JL, Okwera A, Hom DL, et al. Duration of efficacy of treatment of latent tuberculosis
infection in HIV-infected adults. AIDS 2001; 15:2137-47.
(86) Bucher HC, Griffith LE, Guyatt GH, et al. Isoniazid prophylaxis for tuberculosis in HIV infection: a
meta-analysis of randomized controlled trials. AIDS 1999; 13:501-7.
(87) Wilkinson D, Squire SB, Garner P. Effect of preventive treatment for tuberculosis iin adults infected
with HIV: systematic review of randomised placebo controlled trials. BMJ 1998; 317:625-9.
Page 44
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Annex 1
INTERIM PROPOSAL FOR A WHO STAGING SYSTEM FOR
HIV INFECTION AND DISEASE IN ADULTS AND ADOLESCENTS
Clinical Stage I:
1.
Asymptomatic
2.
Persistent generalized lymphadenopathy (PCI)
Performance scale 7: 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
sinusitis)
upper
respiratory
tract
infections
(i.e.,
bacterial
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),
month
1
10. Oral candidiasis (thrush)
11. Oral hairy leukoplakia.
12. Pulmonary tuberculosis, within the pastyear
13. Severe bacterial infections (i.e., pneumonia, pyomyositis)
and/or performance scale 3: bed-ridden, < 50% of the day during the last
month
Page 45
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
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.)
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.
Page 46
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Annex 2
1993 REVISED CDC CLASSIFICATION SYSTEM FOR HIV INFECTION
AND EXPANDED SURVEILLANCE CASE DEFINITION FOR AIDS
AMONG ADOLESCENTS AND ADULTS
The revised CDC classification system for HIV-infected adolescents and adults
categorizes persons on the basis of clinical conditions associated with HIV
infection and CD4+ T lymphocyte counts.
CD 4 lymphocytes
Category A
Category B
Category C
> 500 cells/mm3
Al
Bl
Cl
200-499 cells/ mm3
A2
B2
C2
< 200 cells/mm3
A3
B3
C3
Category A
•
Asymptomatic HIV infection
•
Persistent generalized lymphadenopathy
•
Acute (primary) HIV infection with accompanying illness or history of
acute HIV infection
Category B
Consists of symptomatic conditions in an HIV-infected adolescent or adult
that are not included among conditions listed in Category C and that meet at
least one of the following criteria: a) conditions are attributed to HIV infection
or are indicative of a defect in cell mediated immunity; or b) conditions are
considered by physicians to have a clinical course or to require management
that is complicated by HIV infection. Examples include, but are not limited to:
•
Bacillary angiomatosis
•
Candidiasis, oropharyngeal
•
Candidiasis, vulvovaginal
Page 47
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
•
Cervical dysplasia
•
Constitutional symptoms such as fever 38.5 °C, or diarrhoea lasting longer
than 1 month
•
Hairy leukoplakia, oral
•
Herpes zoster
•
Idiopathic thrombocytopenic purpura
•
Listeriosis
•
Pelvic inflammatory disease
•
Peripheral neuropathy
Category C
This category includes the symptomatic conditions found in patients with
AIDS. Examples in this category include:
Page 48
•
Candidiasis of the bronchi, trachea and lungs
•
Candidiasis, esophageal
•
Cervical cancer, invasive
•
Coccidioidomycosis, disseminated or pulmonary
•
Cryptococcosis, extrapulmonary
•
Cytomegalovirus retinitis
•
Encephalopathy, HIV-related
•
Herpes simplex: chronic ulcer(s) (longer than one month duration);
bronchitis, esophagitis or pneumonitis
•
Histoplasmosis, disseminated or extrapulmonary
•
Isosporiasis, chronic intestinal (greater than 1 month's duration)
•
Kaposi's sarcoma
•
Lymphoma, Burkitt's (or equivalent term)
•
Lymphoma, immunoblastic
•
Lymphoma, primary, of brain
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
•
Mycobacterium avium complex or M. kansasii, disseminated or
extrapulmonary
•
Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)
•
Mycobacterium, other species or unidentified species, disseminated or
extrapulmonary
•
Pneumocystis carinii pneumonia
•
Pneumonia, recurrent
•
Progressive multifocal leukoencephalopathy
•
Salmonella septicaemia, recurrent
•
Toxoplasmosis of brain
•
Wasting syndrome due to HIV
Page 49
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Annex 3
PATIENT VISIT RECORD
Patient name or ID
Date of visit
Hospital/clinic number
PATIENT HISTORY:
DRUG ALLERGIES
ANTIRETROVIRALS: Tick if taken by the patient and circle dose
ABACAVIR 300 BID
ZDV 300/250 BID
3TC 150 BID
ddl 125/200 BID
d4T 15/20/30/40 BID
ddl 250/400 OD
EFAVIRENZ 600 OD
NEVIRAPINE 200 BID
Combination d4T 40/30/3TC/NVP BID
SQV1000/RTV 100 BID
IDV 800 BID / RTV 100 BID
OTHER (specify)
TENOFOVIR 300 QD
Is there any change since last visit?
no
yes
TRIZIVIR BID
COMBIVIR BID
NFV 1250 mg BID
if yes, specify
ADHERENCE TO ANTIRETROVIRAL THERAPY:
N° of doses missed in last 7 days:
N° doses missed since last visit:
Dose taken at correct time: yes no Correct dose taken: yes no Dose delay > 1 hour:
Specify reason for interruption or modification / failure to take prescribed doses:
OTHER MEDICATION: new and ongoing (If new, indicate Start Date)
START DATE
MEDICATION
(tick if ongoing from last visit) COMMENTS
cotrimoxazole (960 mg OD)
INH (300 mg OD)
fluconazole (200 mg 2/week)
azithromycin (1250 mg/week)
/.
J.
J.
J.
/.
/
/.
J.
J.
/
J
I__
__ ./. _/
Page 50
yes
no
Ibe..Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Body Weight
kg
bpm
Pulse
BP
°C Resp Rate
Temp
PHYSICAL EXAMINATION: (tick if normal, describe if abnormal)
General
ENT
Skin
Lymph nodes
Heart
Resp
Abdomen
GU
Musculoskeletal
Extremity
Neuro
Other (describe)
HIV-RELATED ILLNESSES: new and ongoing (If new, indicate Start Date)
□ yes if yes, specify
Are there any new HIV-related illnesses at this visit? □ no
START DATE
oral candidiasis
COMMENTS
/ 7__
oral hairy leukoplakia
J__ !_
J I__
pruritic papular eruption
lymphadenopathy (> 1 cm on both sides)
other HIV related illnesses.
BASIC LABORATORY RESULTS
Haemoglobin J J J g/dl
WBC
WBC
J .J. J J io3cells/pl
Platelets
J J J J 109/l
Total lymphocyte count JJ.JJ 103cells/pl
Glucose
—J -J _J _J mg/dl'
ALT/ SGPT
J U/l
CD4+ cells
—J _J _J _J /pl
Creatinine
J .1
HIV-1 fiNA
I _J
I I mg/dl
I _J
L J
| copies/ml
Other lab results (e.g. CXR, AFB, culture, serology)
WHO Stage:
|
CDC classlficatlon:D A
ll
III
b
C Any disease progression
IV
no
D yes
NOTES/PLAN: _
Follow-up Date
This has to be considered an example taken from the Region; it
has already been used in the Region, however it can be adapted to
each local situation and monitoring and reporting system in use.
Page 5 7
-■
rhe Use olAnwaroM Therapy A S.mpltel Approach for Resouree-CoMreinedCa^nes
Annex 4
karnofsky score
Score
Physical Ability
100
Normal
90
Independent with minimal symptoms
80
Independent with more efforts and symptomatic
70
Can do only activity of daily living
60
Partially independent
50
Partially dependent and require more medical treatment
40
Dependent with specific care
Totally dependent, require hospitalization and not impending to die
Moribund, needs hospitalization with full medical treatment
30
20
10
Comatose
0
Death
>
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Annex 5
PLASMA HIV RNA ASSAY
Plasma HIV RNA assay (viral load) is a useful test to monitor antiretroviral
therapy.
I
The viral load can be determined by the following methods:
(1)
Amplicor HIV-1 Monitor test and Amplicor HIV-1 UltraSensitive
Monitor test (Roche)
(2)
Quantiplex HIV-1 RNA 3.0 (bDNA, Chiron)
(3)
NucliSens HIV-1 QT (NASBA, bioMerieux/Organon)
Roche Amplicor HIV-1 Monitor test and Amplicor HIV-1 UltraSensitive
Monitor test are polymerase chain reaction (PCR) based assay for quantitative
measurement of HIV RNA in plasma. The Amplicor HIV-1 Monitor test is
reproducible at 400 HIV RNA copies per ml of plasma and has an upper limit
of 750,000 copies. The UltraSensitive Monitor test has a range of 50
copies/ml up to 75,000 copies.
The branched DNA (bDNA) Quantiplex HIV-1 RNA 3.0 produced by
Chiron Diagnostics is based on signal amplification and utilizes DNA synthetic
probes to measure viral load. The Quantiplex HIV-1 RNA 3.0 assay has a
detection range from 50 copies/ml to 500,000 copies/ml.
NucliSens HIV-1 QT is based on nucleic acid sequence based
amplification (NASBA). The assay amplifies a target area on HIV, or a
sequence. The lower limit of detection is 40 copies/ml and the upper limit is
5,000,000 copies/ml.
I
The viral load usually decreases rapidly after starling therapy and 1.5 to
2.0 log reduction should occur by 4 weeks. Achieving an early response at 8
week is predictive of subsequent viral suppression. Viral load should continue to
decline over the following weeks and in most patients becomes undetectable
by 16-20 weeks. If HIV RNA remains detectable in plasma after 16-20 weeks of
therapy, the plasma HIV RNA test should be repeated to confirm the result.
Failure to reach undetectable level should cause consideration of poor
adherence, inadequate drug absorption or drug resistance.
For further details the reader is referred to published guidelines.6
Page 53
The Use of Antiretroviral Therapy: A Simplified Approach for Resource-Constrained Countries
Annex 6
USEFUL INTERNET LINKS
•
http://www.who.int/HIV-AIDS/first.html
•
http://www.who.int/medicines/organization/qsm/activities/pilotproc/pilotproc.
shtml
•
http://www.who.int/medicines/organization/par/edl/expertcomm.shtml
•
http://www.medscape.com/Home/Topics/AIDS/AIDS.html
•
http://www.amfar.org
•
http://www.hivandhepatitis.com
•
http://www.bnf.org/AboutBNFFrameHowtoUse.htm
•
http://www.cdc.gov/hiv/treatment.htm
•
http://www.ama-assn.org/special/hiv/hivhome.htm
•
http://www.fda.gov/oashi/aids/hiv.html
•
http://www.hivatis.org
•
http://www.hopkins-aids.edu/
•
http://www.aidsmeds.com/
•
http://www.aidsmap.com
•
http://aids.org
•
http://www.thebody.com/
•
http://www.hivnat.org/
•
http://hivinsite.ucsf.edu/lnSite
•
http://www.paho.org/English/HCP/HCA/antiretrovirals_HP.htm
•
Web sites of drug companies manufacturing antiretroviral drugs
Page 54
- Media
17055.pdf
Position: 1788 (5 views)