GUIDELINES ON ANTIRETROVIRAL THERAPY (ART) AMONG ADULTS AND ADOLESCENTS WITH HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION

The World Health Organization projects that 45 million people will
get infected with Human Immunodeficiency Virus (HIV) between 2002 and
2010. Of this, 40% will come from Asia and Pacific if current prevention
efforts are not continued. Prevention efforts however, should be
complemented with making treatment available to as many HIV positive and
AIDS cases as possible.

In the Philippines, although the HIV and AIDS national prevalence is
less than 0.1% of the population, the number of people affected by HIV
and AIDS continues to grow.

The National Epidemiology Center (NEC) AIDS registry reported that as
of December 2008, 3,589 cases of HIV antibody seropositive individuals
had been identified in the Philippines, and on the same month, there
were 565 PLHIV on antiretroviral therapy (ART).

In line with the global initiative on Universal Access, the health
sector has to facilitate access to antiretroviral drugs (ARVs) by People
Living with HIV (PLHIV) in need of treatment. A major step of this
endeavor is the provision of guidelines to health care providers on the
proper use of ARVs in the management of PLHIV. According to WHO,
evidence from many parts of the world indicates that introducing
treatment in affected communities can reduce the fear, stigma, and
discrimination that surround HIV/AIDS, increase uptake of HIV testing
and counseling, and reinforce prevention efforts.

Significant decrease in morbidity and mortality due to AIDS has been
observed in countries where ARVs are widely used. To ensure safe and
effective use of ARVs, there must be standardized treatment guidelines,
continuous access to medicines and laboratory facilities for monitoring
treatment response and toxicity associated with use of the ARVs, and
availability of counseling services for patients to reinforce adherence
to ART.

This guideline adapted the current recommendations of WHO for HIV
Infection in Adults and Adolescents (2006) in its approach to the
delivery of a comprehensive HIV treatment and care, in harmony with
current local practices and experiences in treating PLHIV for 3 years in
Philippines.

II. OBJECTIVE

To provide standards for the use of ARVs among adults and adolescent living with HIV in the Philippines.

III. SCOPE AND LIMITATION

This guideline is intended for physicians from government and private
health facilities managing PLHIVs with established referral networks to
Department of Health (DOH) – designated treatment hubs. Management of
HIV infections among pregnant women and children will be discussed in a
separate guideline.

IV. DEFINITION OF TERMS

1. Adherence counseling – Includes provision of
information on HIV, manifestations of the disease, and benefits and
side-effects of ARVs; discussion on how the medications should be taken
stressing on the importance of not missing any doses as well as risks
associated to poor adherence, assessment of adherence to include
identifying obstacles to adherence, and treatment planning to enhance
adherence.

2. Antiretrovirals (ARVs) – Drugs that are given to people living with HIV infection to improve or maintain their immune function.

3. HIV and AIDS Core Team (HACT) – A
multi-disciplinary team composed of doctors, nurses, pharmacists, social
workers, and other health care providers that implements prevention,
treatment and care services for HIV and AIDS in the hospital setting.
Its specific functions are described in the Administrative Order Number
18 s. 1995 (Revised Guidelines in the Management of HIV/AIDS Patients in
the Hospital).

4. HIV Counseling and Testing – A confidential
process that enables individuals to examine their knowledge and behavior
in relation to their personal risks of acquiring or transmitting HIV. Counseling helps an individual decide on whether or not to undergo
HIV testing and provides support to an individual receiving his or her
test results.

5. Immune reconstitution inflammatory syndrome (IRIS) –
A spectrum of clinical signs and symptoms resulting from the restored
ability of an individual’s immune system to mount an inflammatory
response and this is associated with immune recovery during ART. Also
defined as paradoxical clinical worsening due to a sub-clinical and
unrecognized opportunistic pathogen or previously known treated
opportunistic pathogen in a setting of adequate response to ART.

6. Opportunistic infections – Illnesses caused by
various organisms, some of which usually do not cause disease in persons
with healthy immune systems. Persons living with advanced HIV infection
may suffer opportunistic infections of the lungs, brain, eyes and
other organs.

7. People Living with HIV (PLHIV) – Refers to people
living with HIV infection. With proper management and provision of ART,
these individuals can continue to live well and be productive for many
years.

8. Treatment Hub – A hospital
facility with an established HIV/AIDS Core Team (HACT) providing
prevention, treatment, care and support services to People Living with
HIV (PLHIV) including but not limited to HIV Counseling and Testing,
clinical management, patient monitoring and other care and support
services. ARVs can only be accessed through these facilities. Refer to
annex^[*] for the complete list treatment hubs in the country.

V. IMPLEMENTING GUIDELINES

A. Determine if Anti-Retroviral (ARV) is indicated

The decision to start a patient on ARV will be based on the
clinical findings and/or CD4 level determination as shown in table 1.
The benefits, toxicity, adherence issues and costs of the treatment must
be a component of counseling.

Table 1. Criteria for Initiating Anti-retroviral Therapy (Adopted from WHO ART for HIV Infection in Adults and Adolescents 2006).

Criteria for Initiation of ARVs
WHO Clinical Staging	CD4 Testing Not Available	CD4 Testing Available
I – Asymptomatic	Do not treat	Treat if CD4 cells is below 200 cells/mm3
II – Mild	Do not treat
III – Advanced	Treat	Consider treatment if CD4 is below 350 cells/mm3 and initiate treatment before CD4 falls below 200 cells/mm3
IV – Severe	Treat	Treat irrespective of CD4 count

B. Perform Adherence Counseling

HIV can develop resistance to ARVs. The success of ARV therapy
largely depends on patient’s adherence to treatment. A 95% adherence
rate is required to prevent the development of drug resistance.
Adherence counseling should always be done prior to and while on
treatment.

References and training on adherence counseling for anti-retroviral
treatment (ART) will be provided by the DOH to participating physicians

C. Get Laboratory Tests prior to indicating ARV treatment

1. Complete Blood Count (CBC)
2. Chest x-ray, sputum Acid Fast Bacilli (AFB) and sputum culture to rule out active tuberculosis

3. Pregnancy test for females of reproductive age
4. Baseline urinalysis, fasting blood sugar, liver function test, creatinine, and lipid profile when indicated

D. Choose initial ARV Regimen

Recommended regimen (see annex^[*] for dosages)

a. First line regimen: NN RTI-based (2 N RTI + 1NN RTI)

i. First line N RTIs: Zidovudine (AZT) + Lamivudine (3TC)

Alternative first line N RTI:

a. Tenofovir (TDF) + Lamivudine (3TC)
b. Stavudine (d4T) + Lamivudine (3TC) – When TDF and AZT are contraindicated

ii. First line NNRTI:
Nevirapine (NVP)

Alternative first line NNRTI:

Efavirenz (EFV) – for patients with hypersensitivity to
nevirapine and/or taking rifampicin. EFV is constraindicated in pregnant
patients

b. Second line regimen: 2 NRTIs + Lopinavir/ritonavir (LPV/r)

– AZT + 3TC + LPV/r if previously on TDF
– TDF + 3TC + LPV/r if previously on AZT or d4T

E. Monitor for ARV toxicity

1. For AZT +3TC + EFV/NVP

a. CBC – every month for the first three months and every 4-6 months thereafter
b. SGPT, SGOT, alkaline phosphatase, amylase – after 1 month, after 6 months and every 12 months thereafter

2. For TDF + 3TC + EFV/NVP

a. annual creatinine and urinaysis
b. SGPT, SGOT, alkaline phosphatase, amylase – after 1 month, after 6 months and every 12 months thereafter

3. For d4T + 3TC + EFV/NVP

a. annual CBC
b. SGPT, SGOT, alkaline phosphatase, amylase – after 1 month, after 6 months and every 12 months thereafter
c. Total cholesterol, triglyceride, LDL – after 6 months and every 12 months thereafter

4. For PI—containing regimen (AZT/TDF + 3TC + (PI/r)

4.1 For TDF + 3TC + (LPV/r)

a. annual creatinine and urinalysis
b. Total cholesterol, triglyceride, LDL-after 6 months and every 12 months thereafter
c. FBS – after 6 months and every 12 months thereafter

4.2 For AZT + 3TC + (LPV/r)

a. CBC – After 1 month, after 6 months and every 12 months thereafter
b. Total cholesterol, triglyceride, LDL – after 6 months and every 12 months thereafter
c. FBS – after 6 months and every 12 months thereafter

4.3 For d4T + 3TC + (LPV/r)

a. annual CBC
b. SGPT, SGOT, alkaline phosphatase, amylase – after 1 month, after 6 months and every 12 months thereafter
c. Total cholesterol, triglyceride, LDL – after 6 months and every 12 months thereafter
d. FBS – after 6 months and every 12 months thereafter

F. Monitor response to treatment

1. Clinical Response

Frequency of clinical monitoring will depend on patient’s response
to ART. Patients should be followed-up on the minimum, at 2, 4, 8, 12
and 24 weeks after starting ART and every six months once patient has
been assessed to be stable. Evaluation for treatment failure, which
includes reassessment of clinical stage, and assessment of symptoms of
drug toxicities should be made during every visit.

Exacerbation of previously sub-clinical coexisting infections (e.g.
TB) may occur, resulting in an apparent worsening of disease. This is
not attributable to failure of the therapy but to its success and the
resulting immune reconstitution. This is called Immune Reconstitution
Inflammatory Syndrome (IRIS). In such cases, the switching of ART would
be inappropriate.

Trial of therapy for at least 6 to 12 months should be given
before concluding that an ARV regimen is failing. For patients with good
compliance to ART, clinical response is recommended to be used together
with CD4 count and viral load determination (when-ever feasible) to
detect treatment failure.

2. Immunologic Response

Patients who initiated therapy with very low baseline CD4 T cell
count may have less response to therapy. As a general rule, new and
progressive severe immunodeficiency as demonstrated by declining CD4
cell counts should trigger a switch in therapy. However, any
measurement that may indicate the need to consider switching should be
repeated and the low level confirmed before any change is implemented.
Where resources are available, CD4 T cell may be done every six months
for monitoring.

Reasonable working definitions of immunological failure are:

1. CD4 count below 100 cells/mm³ after six months of therapy
2. a return to, or a fall below, the pre-therapy CD4 baseline after six months of therapy; or
3. a 50% decline from the on-treatment peak CD4 value (if known)

3. Virologic Response

Since plasma viremia is a strong prognostic indicator of HIV
disease progression, maximal suppression of viremia for as long as
possible is a critical goal of antiretroviral therapy. One (1.0) log
reduction is usually observed 4-8 weeks after initiation of therapy and
falls below limit of assay detection after 4-6 months. Where resources
are available, viral load assay may be done every 12 months.

G. Change of treatment regimen

1. Drug toxicity and side effects (see annex^[*] for specific side effects of ARVs)

Antiretroviral drugs are associated with side e f fect s and long
term toxicities. Although life threatening side effects had been
reported, many side effects can be managed symptomatically. The ARV
component causing toxicity should be identified and changed if
necessary. The general principle is that single-drug substitution
because of toxicity should involve drugs belonging to the same ARV class
(eg. TDF or d4T for AZT where anemia occurs, or NVP for EFV for CNS
toxicity or in pregnancy).

It is also important to ask patients of intake of other medicines because ARVs may interact with these medications.

2. Treatment failure

It is very important to regularly assess patients for treatment
failure, determine the reasons for these and institute appropriate
management immediately. If poor compliance is the cause of treatment
failure, counseling for adherence must be intensified and the current
regimen continued. Determination of CD4 count should be performed after
three months to reassess response to treatment.

Patients who are candidates for second-line ARVs must be managed in
close coordination with the Research Institute for Tropical Medicine or
San Lazaro Hospital.

H. Manage HIV and TB Coinfection

Treatment of TB among HIV patients do not differ from treatment of
TB among non- HIV patients. Diagnosis and treatment will follow the
National Tuberculosis Program (NTP) Guidelines.

ARVs for patients with active TB:

Recommended ARV Regimen

First line regimen: 2 NRTIs + EFV

Due to potential hepatotoxic effects of both ARV and anti-TB drugs,
it is recommend when possible, to commence ARV after the intensive
phase of TB treatment. Patients should be monitored closely for signs
and symptoms of hepatotoxicity.

Initiating ART in HIV and TB Coinfection

1. If CD4<200cells/mm³, ART may be initiated after 2 weeks
of TB treatment, and after patient is stabilized on the TB regimen.
2. If CD4 200-350cells/mm³, ART should be started after 8 weeks of TB therapy.
3. If CD4>350cells/mm³, ART may be deferred until after TB therapy is complete.

Management of HIV patient who are taking nevirapine or protease
inhibitors and diagnosed with active TB should be done in consultation
with physicians experienced in the treatment of these two diseases.

I. Manage HIV and Hepatitis B Coinfection

In situations where both HIV and HBV (Hepatitis B virus) require
treatment, it is preferable to use 3TC and TDF together as both drugs
have anti-HIV and anti-HBV activity. The use of TDF or 3TC as the only
anti-HBV drug can result in more rapid development of resistance.

J. Manage HIV and Hepatitis C Coinfection

The initiation of ART in HIV/HCV coinfected patients should follow
the same principles and recommendations as for the initiation of ART
among HIV patients without HCV infection. However, the patients should
be followed up more closely because of the major risk of drug-related
interactions of some ARVs with anti—HCV drugs.

Major drug-drug interactions have been observed for the following combinations anti HCV drugs and ARVs:

1. Ribavirin with didanosine (ddl) – pancreatitis and lactic acidosis; these drugs should not be given concomitantly

2. Ribavirin and zidovudine (AZT) – anemia; avoid combination if possible; needs close monitoring

3. Interferon and efavirenz (EFV) – severe depression; needs close monitoring

VI. ROLES AND RESPONSIBILITIES

1. National Center for Disease Prevention and Control (NCDPC) shall:

a. convene the technical working group for HIV and regularly
review this guideline through wide consultation with clinicians,
representatives from the treatment hubs and the PLHIV;
b. disseminate this guideline to the treatment hubs, private
medical practitioners, professional medical societies thru the Centers
for Health Development (CHD) NASPCP coordinators;
c. forecast centrally ARV needs of PLHIV and ensure timely procurement and distribution of ARV to treatment hubs;
d. develop manual of procedures for treatment of PLHIV,
including monitoring tools, within six months upon approval of this
A.O.;
e. create and support a monitoring team composed of STI
coordinators, treatment hub staffs and PLHIV groups to ensure compliance
to this guideline

2. Center for Health Development (CHD) shall:

a. disseminate this guideline and other related reference
materials to DOH – retained hospitals and private DOH – accredited
tertiary medical centers;
b. establish system of referrals from various health facilities to DOH – designated treatment hubs;
c. participate in the regular monitoring activities organized by NDCPC.

3. Treatment Hubs through its HIV AIDS Core Team (HACT) shall:

a. provide treatment and clinical monitoring of patients under ART;
b. provide technical assistance to other health facilities and
community-based organizations in need of professional trainings on the
clinical management of HIV infection:
c. respond accordingly to referrals from various health facilities
d. submit report to NCDPC for programme utilization.

4. Research Institute of Tropical Medicine shall:

a. act as the designated training center on clinical management
of HIV infection in coordination with NCDPC and Health Human Resource
Development Bureau;
b. provide NCDPC annual accomplishment reports.

5. Civil Society Organizations for Treatment, Care and Support –
shall work in coordination with the members of HACT in treatment hubs
in providing care and support for PLHIV especially those on ART.

VII. FINANCING

1. The Infectious Disease Office shall allot funds for procurement of ARVs annually based on NASPCP – IDO forecasting.
2. The NCDPC along with the PNAC Secretariat and the PLHIV shall
continuously advocate to the Philippine Health Insurance Corporation
(PHIC) for the development of benefit package for PLHIV in need of
treatment and care.

VIII. REPEALING CLAUSE

Provision s from previous issuances that are inconsistent or contrary
to the provisions of this order are hereby rescinded and modified
accordingly.

IX. EFFECTIVITY

This order shall take effect immediately upon approval.

Adopted: 13 Jan. 2009

(SGD). FRANCISCO T. DUQUE III, MD, MSc
Secretary of Health

^[*] Text Available at Office of the National Administrative Register, U.P. Law Complex, Diliman, Quezon City.