CONSOLIDATED GUIDELINES ON

THE USE OF ANTIRETROVIRAL

DRUGS FOR TREATING AND
PREVENTING HIV INFECTION

SUMMARY OF KEY FEATURES AND RECOMMENDATIONS

JUNE 2013
 Overview
• The 2013 consolidated guidelines compile new , existing
recommendations and other guidance across the continuum
of HIV care.

• Includes guidance on HIV diagnosis, general HIV care and the

strategic use of ARV drugs.

• Developed in accordance with procedures outlined by the

WHO Guidelines Review Committee and are based on the
GRADE (Grading of Recommendations, Assessment,
Development and Evaluation) system.
 KEY FEATURES OF THE
2013 CONSOLIDATED GUIDELINES

• New and easy-to-use HIV testing technologies

• Simpler, safer, once-daily, single-pill treatments

• Programs for preventing mother-to-child transmission of

HIV (PMTCT) - earlier and simpler treatments

• ART to prevent the sexual transmission of HIV.

• Trend towards starting treatment.

 HIV Testing & counselling
Topic Old Guidelines New Guidelines

Community-based HIV
testing and counselling with
Provider-
linkage to prevention, care
HIV Testing initiated testing
and treatment services is
and counselling
recommended, in addition to
old guidelines.

Couples Voluntary HIV testing and counselling

 Who to test When to test

Pregnant women At first antenatal care visit

and Re-test in third trimester or peripartum
male partners Offer partner testing

At 4–6 weeks for all whose mothers are HIV Positive

Infants and children or status uncertain;
<18 months old Final status after 18 months and/or when
breastfeeding ends

Establish HIV status for all health contacts

Children
Tell their HIV status & parents or caregiver’s status

Integrate into all health care encounters.

Adolescents
Annually if sexually active; with new sexual partners
 HIV prevention based on ARV drugs
Oral pre-exposure prophylaxis
Serodiscordant couples daily oral PrEP (either TDF or TDF + FTC)
Men and transgender daily oral PrEP (Specifically TDF + FTC)
women

ART for prevention PLHIV in serodiscordant couples who

among serodiscordant start ART for their own health, ART is also
couples recommended to reduce HIV transmission
to the uninfected partner.

HIV-positive partners with a CD4 count

≥350 cells/mm3.
 Post-exposure prophylaxis for occupational
and non-occupational exposure to HIV

•Recommended duration of PoEP is

Post-exposure 28 days,
prophylaxis
for women •First dose as soon as possible
within within 72 hours
72 hours of
a sexual assault •The choice based on first-line ART
regimen.
 NEW CLINICAL RECOMMENDATIONS

• A new, preferred first-line ART regimen harmonized to all

different eligible groups.

• Accelerate the phasing out of stavudine (d4T).

• HIV testing of adolescents to diagnose people with HIV earlier

and link them to care and treatment.
 GUIDELINES TO START ART
• Start ART in all individuals with a CD4 < 500

• Priority to severe or advanced HIV disease and CD4 < 350 .

• ART at any CD4 count in PLHIV

 Active TB disease ,
 HBV co-infection with severe chronic liver disease,
 HIV-positive partners in sero-discordant couples,
 Pregnant and breastfeeding women and
 Children younger than five years of age
 When to start ART in people living with HIV

Adults and Initiate ART if CD4 cell count ≤500 cells/mm3 NEW
adolescents • As a priority, NEW
(≥10 years)  Severe/advanced HIV (WHO clinical stage 3 or 4)
or
 CD4 count ≤350 cells/mm3

Regardless of WHO clinical stage and CD4

• Active TB disease
NEW • HBV coinfection with severe chronic liver disease

NEW • Pregnant and breastfeeding women with HIV

• HIV-positive individual in a serodiscordant
partnership (to reduce HIV transmission risk)
Infants <1 In all , Regardless of WHO clinical stage and CD4 cell
year old count.
Children ART in all regardless of WHO clinical stage and CD4
1–5 yrs old
• As a priority,
 All HIV-infected children 1–2 yrs old or
 WHO clinical stage 3 or 4 or
NEW  CD4 count ≤750 or <25%, whichever is lower

Any child < 18 months with presumptive clinical

diagnosis of HIV infection.

Children CD4 ≤500 cells/mm3

≥5 yrs to <10 • As a priority,
yrs old  All WHO clinical stage 3 or 4 or
 CD4 count ≤350
NEW
Initiate ART regardless of CD4 cell count
• WHO clinical stage 3 or 4
• Active TB disease
 Populations for which no specific new
recommendation is made

• Individuals with HIV > 50 years of age .

• Individuals with HIV-2

• Individuals coinfected with HIV and HCV

 Why to Initiate early ART ?

• Reduces risk of progression to AIDS and/or death, TB, non-AIDS-defining

illness & increased the likelihood of immune recovery.

• Reduces sexual transmission in HIV-serodiscordant couples,

• More convenient and less toxic regimens widely available,

• Costs and epidemiological benefits

• The increased cost of earlier ART would be partly offset by subsequent

reduced costs (such as decreased hospitalization and increased
productivity) and preventing new HIV infections.
 HIV and HBV coinfection with evidence of
severe chronic liver disease

• HIV coinfection affects natural history of HBV

infection.
o higher rates of chronicity;
o less spontaneous HBV clearance;
o accelerated liver fibrosis progression
o increased risk of cirrhosis and hepatocellular carcinoma;
o higher liver-related mortality and decreased ARV response

• Liver disease a leading cause of death in people

coinfected with HIV and HBV
• 2010 guidelines- ART for all HIV + HBV with
chronic active hepatitis, regardless of CD4 or
WHO clinical stage.

• 2013 guidelines - ART to all HIV + HBV

regardless of CD4 count in people with
evidence of severe chronic liver disease.
 ARV drugs for pregnant and breastfeeding women.

• The 2010 WHO PMTCT guidelines recommended

– lifelong ART for women eligible for treatment (based on CD4 ≤350 or
presence of WHO clinical stage 3 or 4 disease)
– ARV prophylaxis for PMTCT for those not eligible for treatment.

• If not eligible for treatment,

• “Option A” - AZT for the mother during pregnancy,
single-dose NVP + AZT and 3TC for mother
at delivery &continued for a week postpartum;

• “Option B”- triple ARV drugs for the mother

during pregnancy & throughout breastfeeding.
 National PMTCT Pregnant and breastfeeding
HIV-exposed infant
program option women with HIV

Regardless of WHO clinical Replacement

Breastfeeding
Use lifelong ART stage or CD4 feeding
for all pregnant
6 weeks of
and breastfeeding 4–6 weeks of infant
Initiate ART and maintain infant
women prophylaxis with
after delivery & cessation prophylaxis
(“Option B+”) once-daily NVP (or
of breastfeeding with
twice-daily AZT)
once-daily NVP

Not eligible
Eligible for
for
treatment
Use lifelong ART treatment
only for pregnant
and breastfeeding Initiate ART Initiate ART
women eligible and maintain and stop after
for treatment after delivery delivery
(“Option B”) and cessation and cessation
of of
breastfeeding Breastfeeding
• Option A and B regimens have similar efficacy .

• Option A is impediment to scaling up PMTCT in many countries.

• Different treatment and prophylaxis regimens

• CD4 measurement to determine eligibility and type of regimen;

• changing antepartum-intrapartum postpartum regimens;

• The need for an additional postpartum ARV “tail” in mothers; and

• Extended NVP prophylaxis in infants.

 New guidelines NEW

• To accelerate the rapid global scaling up, ensure

equitable access , recommendations need to be
further simplified, standardized & harmonized.

• 2013 guidelines recommend ART (one simplified

triple regimen) for all PLHIV women during the
period of risk of mother-to-child HIV
transmission and continuing lifelong ART either
for all women.
 Benefits
• Ease of implementation & Harmonized regimens.

• Increased coverage of ART & acceptability.

• Vertical transmission benefit

• Maternal health benefit

• avoid stopping and starting drugs with repeat pregnancies,

• Early protection against MTCT in future pregnancies,

• Reduce the risk of HIV transmission to HIV-serodiscordant partner.

 ARVs & Duration of breastfeeding

National or sub national health authorities should decide

whether support breastfeed & receive ARV or avoid all.

When breastfeeding and ARV interventions is supported...

Exclusive breastfeeding for the first 6 months,
Introducing appropriate complementary foods thereafter,
and continue breastfeeding for the first 12 months of life.

Breastfeeding should then only stop once a nutritionally

adequate and safe diet without breast-milk can be provided
 HIV in children
• In young children high risk of poor outcomes
from HIV .

• 52% die before 2 yrs age if no intervention

• Most children who are eligible for ART are still

not being treated,

• ART coverage among children lags significantly

behind that among adults (28% versus 57%)

• Unique challenges because of their dependence

on a caregiver.
The 2013 WHO guidelines…
• Simplify and expand treatment in children.

• Eliminates the need for CD4 in <5 yrs for treatment & avoids
delaying ART in settings without access to CD4 testing.

• Targeting these children for HIV care may facilitate treatment

of other preventable causes of under-five mortality.

• Increase the CD4 count threshold for ART initiation to ≤500 in

children > 5 Yrs, aligning with the new threshold in adults.

• ? Risk of resistance if treatment is initiated early in young

children when adherence is poor/ suboptimal drug supplies.
 Ideal first-line ART ?

• Simplified,
• less toxic
• more convenient regimens
• fixed-dose combinations.
 What ART to start ?
Once-daily regimens comprising a non- thymidine NRTI backbone
(TDF + FTC or TDF + 3TC) and one NNRTI (EFV) as the preferred
choices in adults, adolescents and children >3 yrs.

First-line ART First-line ART = two (NRTIs) + (NNRTI).

regimens for adults • TDF + 3TC (or FTC) + EFV (fixed-dose combination)

If TDF + 3TC (or FTC) + EFV is contraindicated/not

available, options are…
NEW
• AZT + 3TC + EFV
• AZT + 3TC + NVP
• TDF + 3TC (or FTC) + NVP

Countries should discontinue d4T use in first-line

regimens because of its well-recognized metabolic
toxicities.
• For pregnant and breastfeeding women…
• The 2010 guidelines - choice of 4 different ART regimens :
AZT + 3TC or TDF + 3TC (or FTC) plus either NVP or EFV.

• Because of risk of toxicity of NVP among pregnant women,

for PMTCT,

– Preferred NNRTI regimens were AZT + 3TC + EFV or TDF +

3TC (or FTC) + EFV

– Alternative regimens were AZT + 3TC + LPV/r (or ABC)

• Although TDF & EFV were recommended, there were limited

safety data on their use during pregnancy and breastfeeding.
 First-line ART for pregnant and
breastfeeding women

TDF + 3TC (or FTC) + EFV as first-line ART including pregnant

women in the first trimester and women of childbearing age as
well as breastfeeding women with HIV.

The recommendation applies both to lifelong treatment

and to ART initiated for PMTCT and then stopped

First-line ART
Adults
(including pregnant and
breastfeeding women and
adults with TB and HBV
coinfection)
Adolescents
(10 to 19 years) ≥35 kg
Children 3 - 10 years and
adolescents <35 kg
Children <3 years
New guidelines promote further simplification of ART delivery by reducing the number
of preferred first-line regimens.
Preferred Alternative
first-line regimens first-line Regimens
AZT + 3TC + EFV
AZT + 3TC + NVP
NEW
TDF + 3TC (or FTC) + NVP
TDF + 3TC (or FTC) + EFV
AZT + 3TC + EFV
AZT + 3TC + NVP
TDF + 3TC (or FTC) + NVP
ABC + 3TC + EFV (or NVP)
ABC + 3TC + NVP
AZT + 3TC + EFV
ABC + 3TC + EFV AZT + 3TC + NVP
TDF + 3TC (or FTC) + EFV
TDF + 3TC (or FTC) + NVP
ABC or ABC + 3TC + NVP
AZT + 3TC + LPV/r AZT + 3TC + NVP
• People receiving NVP discontinue because of adverse events

• With EFV no increased risk of birth defects compared with

other ARV drugs during the first trimester of pregnancy

• TDF/FTC or TDF/3TC are the preferred NRTI backbone for

HIV + HBV
HIV with TB and
pregnant women.

• EFV is the preferred NNRTI for

HIV & TB (pharmacological compatibility with TB drugs)
HIV +HBV coinfection (less risk of hepatic toxicity) and
Pregnant women, including first trimester.
 Stopping NNRTI-based ART (use of a “tail”)

• Because of longer ½ -life of EFV (and NVP), suddenly stopping

NNRTI-based regimen risks developing NNRTI resistance.

• For women who stop EFV-based ART due to toxicity or other

conditions, more data are needed to determine whether an
NRTI “tail” coverage is needed to reduce this risk.

• Guidelines suggests that, if the NRTI backbone included TDF,

such a tail may not be needed,

• But if the NRTI backbone included AZT, a two-week tail is

advisable (EFV has a longer half-life than NVP)
 TDF toxicity
• TDF has a low rate of renal toxicity in the short to medium term,
especially with pre-existing, or risk factors for, renal disease.

• Reduction in renal function reflected by decrease in the eGFR.

• Reduction in bone mineral density

• High-risk populations, like hypertension , diabetes or those using

boosted PIs.

• Usually tubular, hence glomerular function tests do not provide a direct

measure, and no other simple test can detect renal tubular toxicity.

• Overall improvement in renal function resulting from ART can offset the
risk of TDF toxicity in people not having secondary renal disease.
 EFV USE Concerns
• Birth defects, including anencephaly, microphthalmia and cleft palate
among primates with EFV exposure in utero.

• The United States Food and Drug Administration & European Medicines
Agency advise against using EFV unless the benefits outweigh the risks.
• But, the British HIV Association recently allowed EFV in the 1st trimester .

• Risk of neural tube defects (NTDs) is limited to the first 5-6 weeks of
pregnancy, and pregnancy is rarely recognized this early,

• NTDs are relatively rare & available data sufficiently rule out a risk

• Guidelines Development Group felt confident that this low risk should be
balanced against the programmatic advantages & clinical benefit of EFV .
 HIV-2 infection
• HIV-2 is naturally resistant to NNRTIs

• Treatment-naive people coinfected with HIV-1 and HIV-2

should be treated with three NRTIs TDF + 3TC / FTC + AZT or
AZT + 3TC + ABC or a ritonavir-boosted PI plus two NRTIs.

• In PI-based regimen, the preferred option is LPV/r

• SQV/r and DRV/r are alternative boosted-PI options, but

they are not available as heat-stable fixed-dose
combinations.
 Simplified Infant Prophylaxis doses
Drug Infant age Daily dosing
Birth to 6 weeks 10 mg once daily
• Birthweight 2000−2499 g 15 mg once daily
• Birthweight ≥2500 g

> 6 weeks to 6 months 20 mg once daily

NVP
30 mg once daily
> 6 months to 9 months

40 mg once daily
> 9 months until breastfeeding ends

Birth to 6 weeks
10 mg twice daily
AZT • Birthweight 2000−2499 g
15 mg twice daily
• Birthweight ≥2500 g

If toxicity from NVP requires discontinuation or if NVP is not available,

infant 3TC can be substituted.
 Monitoring ART response and
diagnosis of treatment failure
• Before 2010, clinical outcomes and CD4 count were used for
monitoring the response to ARV drugs.

• However, viral load is a more sensitive and early indicator of

treatment failure & gold standard for monitoring response to ARV.

• In 2010 WHO recommended phasing in viral load testing to monitor

response to ART and viral load threshold > 5000 copies/ml in an
adherent person with no other reasons for an elevated viral load
(such as drug interactions, poor absorption and inter current
illness)

• 2013 guidelines strongly recommend viral load as monitoring tool.

• Also reduced viral load threshold for treatment failure from 5000
to 1000 copies/ml.
• Treatment failure
is defined by a persistently detectable viral load exceeding
1000 copies/ml (i.e. two consecutive viral load measurements within
a 3 month interval, with adherence support between measurements)
after at least 6 months of ARV.

• Viral load testing is usually performed in plasma; tests using whole

blood as a sample type, are unreliable at this lower threshold

• Viral load testing is done after initiating ART (at 6 months) and then
every 12 months .

• When not available, CD4 and clinical monitoring is used .

 WHO definitions of clinical,
immunological and virological failure
Failure Definition Comments

Adults and adolescents

New or recurrent clinical event
indicating severe immunodeficiency
differentiate from IRIS
(WHO clinical stage 4 condition) after
6 months of effective treatment
--------------------------------------------------
Clinical For adults, certain
Children
failure WHO clinical stage 3
New or recurrent clinical event
conditions (PTB and
indicating advanced or severe
severe bacterial
immunodeficiency (WHO clinical
infections) also
stage 3 and 4 clinical condition with
indicate treatment
exception of TB) after 6 months of
failure
effective treatment
 Adults and adolescents
CD4 count falls to baseline (or
Without
below) or Persistent CD4 <100
concomitant or
Immunological ------------------------------------------
recent infection to
failure Children < 5 years
cause a transient
Persistent CD4 <200 or <10%
fall in CD4
>5 years
Persistent CD4 <100

Plasma viral load >1000 based

Must be on ART
on two consecutive viral load
Virological for at least 6
measurements after 3 months,
failure months before
with
declaring failure
adherence support
 Test viral load

Viral load >1000 copies/ml

Evaluate for adherence concerns

Repeat viral load testing after 3–6 months

Viral load ≤1000 Viral load >1000

Maintain first-line therapy Switch to second-line therapy

 Lab monitoring before starting ART
Phase of HIV
Recommended Desirable (if feasible)
management
HBV (HBsAg) serology
HCV serology
HIV serology, Cryptococcus antigen if CD4 ≤100
HIV diagnosis CD4 Screening for STIs
TB screening Assessment for major
noncommunicable chronic diseases
and comorbidities
F/U before ART CD4 cell count (every 6–12 mths)
Hemoglobin for AZT
Pregnancy test
Blood pressure
ART initiation CD4 cell count
Urine dipsticks for glycosuria and
(eGFR) and serum creatinine for TDF
ALT for NVP
 Lab monitoring during ART

Phase of HIV
Recommended Desirable (if feasible)
management

Receiving ART CD4 Urine dipstick for glycosuria and

(every 6 months) Serum creatinine for TDF
HIV viral load
(at 6months after
initiating ART and
every 12 months )

Treatment CD4 HBV (HBsAg) serology

failure HIV viral load (before switching ART regimen if
not done or negative at baseline)
 Preferred second-line ART regimens
for adults and adolescents
Target
population
Preferred second-line regimen
If d4T or AZT was used in first-
Adults and TDF + 3TC (or FTC) + ATV/r or LPV/r
line ART
adolescents
(≥10 years) If TDF was used in first line
AZT + 3TC + ATV/r or LPV/r
ART
Pregnant
Same regimens recommended for adults and adolescents
women
If rifabutin is available Standard PI-containing regimens

HIV and TB Same NRTI plus double-dose LPV/r

Coinfection (ie, LPV/r 800 mg/200 mg ) or
If rifabutin is not available standard LPV dose with an adjusted
NEW dose of RTV
(i.e, LPV/r 400 mg/400 mg )
HIV +HBV
AZT + TDF + 3TC (or FTC) + (ATV/r or LPV/r)
coinfection
 Third-line ART
All populations National programmers should develop policies for third-line ART

New drugs with minimal risk of cross-resistance to previous

regimens, like integrase inhibitors & 2nd-generation NNRTIs & PIs

Failing second-line regimen with no new ARV options should

continue with a tolerated regimen

Special Strategies that balance the benefits and risks for children need to be
considerations explored when second-line treatment fails.
for children
For older children & adolescents having more therapeutic options
available , novel drugs such as ETV, DRV and RAL may be possible.

Second-line regimen that is failing with no new ARV drug options

should continue with a tolerated regimen.

If ART is stopped, opportunistic infections still need to be prevented,

symptoms relieved and pain managed.
 Timing of ART with TB
• ART should be started in all TB patients, including drug-resistant TB,
irrespective of the CD4 count

• AKT should be initiated first, followed by ART as soon as possible

within the first 8 weeks of treatment.

• HIV-positive TB patients with profound immunosuppression (CD4

<50) should receive ART immediately within the first 2 weeks of AKT
.
• ART should be started in any child with active TB disease as soon as
possible and within 8 weeks After the initiation of AKT irrespective
of the CD4 and clinical stage.

• Preferred NNRTI is EFV in patients starting ART while on AKT .

 Timing of ART with Cryptococcal meningitis

• Immediate ART not recommended in cryptococcal

meningitis due to the high risk of IRIS with CNS disease,
which may be life-threatening .

• Among PLHIV with a recent cryptococcal meningitis,

– ART initiation should be deferred until there is evidence
of a sustained clinical response to antifungal therapy and

– after two to four weeks of induction and consolidation

treatment with amphotericin containing regimens
combined with flucytosine or fluconazole; or
 NEW OPERATIONAL GUIDANCE AND RECOMMENDATIONS

This guidance focuses on:

• Strategies to improve retention in HIV care and
adherence to ART.

• Task-shifting to address human resource gaps.

• Decentralizing delivery of ART and…

• Integrating ART services within maternal and child

health clinics, tuberculosis (TB) clinics and drug
dependence treatment services.
 WHAT IS THE EXPECTED IMPACT OF THE GUIDELINES

• Globally, 26 million PLHIV in low- and middle-income

countries will be eligible for ARV drugs compared with the
previous 17 million people as per 2010 guidelines.

• Full implementation of the guidelines could avert as many as

3 million AIDS-related deaths and 3.5 million new HIV
infections between 2013 and 2025 over and above those
averted by implementing the 2010 WHO treatment
guidelines.

• 10% increase in the total annual investment .

 Ongoing Trials
• The Strategic Timing of Antiretroviral Therapy (START) trial
in ARV-naive adults aged 18 years and older is comparing
immediate ART in those with CD4> 500 to ART deferred
until the CD4 count falls below 350 or an AIDS event
develops.

• The TEMPRANO trial (Early Antiretroviral Treatment

and/or Early Isoniazid Prophylaxis against Tuberculosis in
HIV-infected Adults – ANRS 12136) is comparing the
benefits and risks of initiating ART according to the 2010
WHO guidelines (CD4 ≤350 ) to the benefits and risks of
initiating ART immediately among adults with CD4 counts
>350.