Consolidated guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection Summary of key features and recommendations JUNE 2013

1. CONSOLIDATED GUIDELINES ON
THE USE OF ANTIRETROVIRAL
DRUGS FOR TREATING AND
PREVENTING HIV INFECTION
SUMMARY OF KEY FEATURES AND RECOMMENDATIONS
JUNE 2013

2. 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.

3. Topic Old Guidelines New Guidelines
HIV Testing
Provider-
initiated testing
and counselling
“Opt out”
Community-based HIV
testing and counselling with
linkage to prevention, care
and treatment services is
recommended, in addition to
old guidelines.
Couples Voluntary HIV testing and counselling
HIV Testing & counselling

4. Diagnosis
 Recommend HIV serologic testing (ELISA and confirmatory Western
blot) to all prenatal patients as part of standard prenatal care, using
the opt-out model. Consider repeat testing in the third trimester if
from a high prevalence area or engaged in risky behaviors.
• Women with a positive ELISA and negative Western blot do not
have HIV infection.
• Women with an indeterminate Western blot may be in the process
of HIV seroconversion. Repeat the Western blot and obtain a
quantitative HIV RNA PCR.
 Offer a rapid HIV serologic test for women who present intrapartum
with no documented prenatal HIV testing. These tests have high
sensitivity but must be confirmed by standard serologic testing.
Treatment to prevent transmission can begin prior to the
confirmatory test.

5. Oral pre-exposure prophylaxis
Serodiscordant couples daily oral PrEP (either TDF or TDF + FTC)
Men and transgender
women
daily oral PrEP (Specifically TDF + FTC)
ART for prevention
among serodiscordant
couples
PLHIV in serodiscordant couples who
start ART for their own health, ART is also
recommended to reduce HIV transmission
to the uninfected partner.
HIV-positive partners with a CD4 count
≥350 cells/mm3.
HIV prevention based on ARV drugs

6. Post-exposure prophylaxis for occupational
and non-occupational exposure to HIV
Post-exposure
prophylaxis
for women
within
72 hours of
a sexual assault
•Recommended duration of PoEP is
28 days,
•First dose as soon as possible
within 72 hours
•The choice based on first-line ART
regimen.

7. • 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.
NEW CLINICAL RECOMMENDATIONS

8. When to start ART in people living with HIV
Adults and
adolescents
(≥10 years)
Initiate ART if CD4 cell count ≤500 cells/mm3
• As a priority,
 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
• HBV coinfection with severe chronic liver disease
• Pregnant and breastfeeding women with HIV
• HIV-positive individual in a serodiscordant
partnership (to reduce HIV transmission risk)
Infants <1
year old
In all , Regardless of WHO clinical stage and CD4 cell
count.
NEW
NEW
NEW
NEW

9. 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

10. 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.

11. 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

12. • 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.

13. 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.

14. National PMTCT
program option
Pregnant and breastfeeding
women with HIV
HIV-exposed infant
Use lifelong ART
for all pregnant
and breastfeeding
women
(“Option B+”)
Regardless of WHO clinical
stage or CD4
Breastfeeding
Replacement
feeding
Initiate ART and maintain
after delivery & cessation
of breastfeeding
6 weeks of
infant
prophylaxis
with
once-daily NVP
4–6 weeks of infant
prophylaxis with
once-daily NVP (or
twice-daily AZT)
Use lifelong ART
only for pregnant
and breastfeeding
women eligible
for treatment
(“Option B”)
Eligible for
treatment
Not eligible
for
treatment
Initiate ART
and maintain
after delivery
and cessation
of
breastfeeding
Initiate ART
and stop after
delivery
and cessation
of
Breastfeeding

15. • 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.

16. New guidelines
• 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.
NEW

17. 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.

18. 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
ARVs & Duration of breastfeeding

19. Drug Abbreviation
• 3TC lamivudine
• TDF tenofovir disoproxil
fumarate
• EFV efavirenz
• FTC emtricitabine
• ABC abacavir
• ATV atazanavir
• AZT zidovudine
• d4T stavudine
• DRV darunavir
• DTG dolutegravir
• ETR etravirine
• LPV/r lopinavir/ritonavir
• NVP nevirapine
• ddI didanosine
• RAL raltegravir
• RPV rilpivirine
• RTV ritonavir
• TAF tenofovir alafenamide
fumarate
• TNA threose nucleic acid
• XTC 3TC or FTC

20. Ideal first-line ART ?
• Simplified,
• less toxic
• more convenient regimens
• fixed-dose combinations.

21. What ART to start ?
First-line ART
regimens for adults
First-line ART = two (NRTIs) + (NNRTI).
• TDF + 3TC (or FTC) + EFV (fixed-dose combination)
If TDF + 3TC (or FTC) + EFV is contraindicated/not
available, options are…
• 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.
NEW
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.

22. • 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.

23. 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

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

25. • 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.

26. • 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)
Stopping NNRTI-based ART (use of a “tail”)

27. 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.

28. 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 .

29. 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.

30. Simplified Infant Prophylaxis doses
Drug Infant age Daily dosing
NVP
Birth to 6 weeks
• Birthweight 2000−2499 g
• Birthweight ≥2500 g
10 mg once daily
15 mg once daily
> 6 weeks to 6 months 20 mg once daily
> 6 months to 9 months
30 mg once daily
> 9 months until breastfeeding ends
40 mg once daily
AZT
Birth to 6 weeks
• Birthweight 2000−2499 g
• Birthweight ≥2500 g
10 mg twice daily
15 mg twice daily
If toxicity from NVP requires discontinuation or if NVP is not available,
infant 3TC can be substituted.

31. 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.

32. • 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 .

33. WHO definitions of clinical,
immunological and virological failure
Failure Definition Comments
Clinical
failure
Adults and adolescents
New or recurrent clinical event
indicating severe immunodeficiency
(WHO clinical stage 4 condition) after
6 months of effective treatment
--------------------------------------------------
Children
New or recurrent clinical event
indicating advanced or severe
immunodeficiency (WHO clinical
stage 3 and 4 clinical condition with
exception of TB) after 6 months of
effective treatment
differentiate from IRIS
For adults, certain
WHO clinical stage 3
conditions (PTB and
severe bacterial
infections) also
indicate treatment
failure

34. Immunological
failure
Adults and adolescents
CD4 count falls to baseline (or
below) or Persistent CD4 <100
------------------------------------------
Children < 5 years
Persistent CD4 <200 or <10%
>5 years
Persistent CD4 <100
Without
concomitant or
recent infection to
cause a transient
fall in CD4
Virological
failure
Plasma viral load >1000 based
on two consecutive viral load
measurements after 3 months,
with
adherence support
Must be on ART
for at least 6
months before
declaring failure

35. 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

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

37. Receiving ART CD4
(every 6 months)
HIV viral load
(at 6months after
initiating ART and
every 12 months )
Urine dipstick for glycosuria and
Serum creatinine for TDF
Treatment
failure
CD4
HIV viral load
HBV (HBsAg) serology
(before switching ART regimen if
not done or negative at baseline)
Lab monitoring during ART
Phase of HIV
management
Recommended Desirable (if feasible)

38. Preferred second-line ART regimens
for adults and adolescents
Target
population
Preferred second-line regimen
Adults and
adolescents
(≥10 years)
If d4T or AZT was used in first-
line ART
TDF + 3TC (or FTC) + ATV/r or LPV/r
If TDF was used in first line
ART
AZT + 3TC + ATV/r or LPV/r
Pregnant
women
Same regimens recommended for adults and adolescents
HIV and TB
Coinfection
If rifabutin is available Standard PI-containing regimens
If rifabutin is not available
Same NRTI plus double-dose LPV/r
(ie, LPV/r 800 mg/200 mg ) or
standard LPV dose with an adjusted
dose of RTV
(i.e, LPV/r 400 mg/400 mg )
HIV +HBV
coinfection
AZT + TDF + 3TC (or FTC) + (ATV/r or LPV/r)
NEW

39. 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
considerations
for children
Strategies that balance the benefits and risks for children need to be
explored when second-line treatment fails.
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.

40. 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 .

41. 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

42. 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.

43. 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 .

44. 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.