CONSOLIDATED GUIDELINES ON

THE USE OF ANTIRETROVIRALDRUGS 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.

Topic Old Guidelines New Guidelines

HIV Testing Provider-initiated testing and counselling

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

Who to test When to test

Pregnant women andmale partners

At first antenatal care visitRe-test in third trimester or peripartumOffer partner testing

Infants and children <18 months old

At 4–6 weeks for all whose mothers are HIV Positive or status uncertain; Final status after 18 months and/or when breastfeeding ends

Children Establish HIV status for all health contacts Tell their HIV status & parents or caregiver’s status

Adolescents Integrate into all health care encounters.Annually if sexually active; with new sexual partners

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

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.

• 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

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 andadolescents(≥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 <1year old

In all , Regardless of WHO clinical stage and CD4 cell count.

NEW

NEW

NEW

NEW

Children≥5 yrs to <10 yrs old

CD4 ≤500 cells/mm3• As a priority,

All WHO clinical stage 3 or 4 or CD4 count ≤350

Initiate ART regardless of CD4 cell count• WHO clinical stage 3 or 4• Active TB disease

Children1–5 yrs old

ART in all regardless of WHO clinical stage and CD4

• As a priority, All HIV-infected children 1–2 yrs old or WHO clinical stage 3 or 4 or CD4 count ≤750 or <25%, whichever is lower

Any child < 18 months with presumptive clinical diagnosis of HIV infection.

NEW

NEW

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 PMTCTprogram option

Pregnant and breastfeedingwomen with HIV HIV-exposed infant

Use lifelong ARTfor all pregnantand breastfeedingwomen(“Option B+”)

Regardless of WHO clinical stage or CD4 Breastfeeding Replacement

feeding

Initiate ART and maintain after delivery & cessation of breastfeeding

6 weeks of infantprophylaxis withonce-daily NVP

4–6 weeks of infant prophylaxis with once-daily NVP (or twice-daily AZT)

Use lifelong ARTonly for pregnantand breastfeedingwomen eligiblefor treatment(“Option B”)

Eligible fortreatment

Not eligible fortreatment

Initiate ART and maintainafter deliveryand cessation ofbreastfeeding

Initiate ART and stop after deliveryand cessation ofBreastfeeding

• 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

• 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

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.

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

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 ?

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.

• 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 treatmentand to ART initiated for PMTCT and then stopped

First-line ARTPreferred

first-line regimensAlternative

first-line Regimens

Adults(including pregnant andbreastfeeding women and adults with TB and HBV coinfection) TDF + 3TC (or FTC) + EFV

AZT + 3TC + EFVAZT + 3TC + NVPTDF + 3TC (or FTC) + NVP

Adolescents (10 to 19 years) ≥35 kg

AZT + 3TC + EFVAZT + 3TC + NVPTDF + 3TC (or FTC) + NVPABC + 3TC + EFV (or NVP)

Children 3 - 10 years and adolescents <35 kg ABC + 3TC + EFV

ABC + 3TC + NVPAZT + 3TC + EFVAZT + 3TC + NVPTDF + 3TC (or FTC) + EFVTDF + 3TC (or FTC) + NVP

Children <3 years ABC orAZT + 3TC + LPV/r

ABC + 3TC + NVPAZT + 3TC + NVP

NEW

New guidelines promote further simplification of ART delivery by reducing the number of preferred first-line regimens.

• 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.

• 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”)

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

NVP

Birth to 6 weeks• Birthweight 2000−2499 g• Birthweight ≥2500 g

10 mg once daily15 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

AZTBirth to 6 weeks• Birthweight 2000−2499 g • Birthweight ≥2500 g

10 mg twice daily15 mg twice daily

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

Clinical failure

Adults and adolescentsNew or recurrent clinical event indicating severe immunodeficiency (WHO clinical stage 4 condition) after 6 months of effective treatment--------------------------------------------------ChildrenNew 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

Immunologicalfailure

Adults and adolescentsCD4 count falls to baseline (orbelow) or Persistent CD4 <100 ------------------------------------------Children < 5 yearsPersistent CD4 <200 or <10% >5 yearsPersistent CD4 <100

Without concomitant or recent infection to cause a transient fall in CD4

Virologicalfailure

Plasma viral load >1000 based on two consecutive viral load measurements after 3 months, withadherence support

Must be on ARTfor at least 6 months before declaring failure

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 HIVmanagement Recommended Desirable (if feasible)

HIV diagnosisHIV serology,CD4 TB screening

HBV (HBsAg) serology HCV serologyCryptococcus antigen if CD4 ≤100 Screening for STIsAssessment 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 AZTPregnancy testBlood pressure Urine dipsticks for glycosuria and (eGFR) and serum creatinine for TDFALT for NVP

Receiving ART CD4 (every 6 months)HIV viral load (at 6months after initiating ART andevery 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 HIVmanagement Recommended Desirable (if feasible)

Preferred second-line ART regimens for adults and adolescents

Target population Preferred second-line regimen

Adults andadolescents(≥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 TBCoinfection

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 +HBVcoinfection AZT + TDF + 3TC (or FTC) + (ATV/r or LPV/r)

NEW

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 considerationsfor 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.

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.