Antiretroviral therapy in 2013 : what a general practitioner must know

Dr Ameet DravidM.D Medicine

Ruby Hall Clinic, Pune

Introduction

• Eradication of HIV infection cannot be achieved with available antiretroviral regimens.

• This is chiefly because the pool of latently infected CD4 T-cells is established during the earliest stages of acute HIV infection and persists with long half-life even with prolonged suppression of plasma viremia.

Antiretroviral therapy : when to start?

Antiretrovirals approved for useNRTI NNRTI PI Newer drugs

Zidovudine(AZT) Nevirapine (NVP)

Nelfinavir CCR5 inhibitors :Maraviroc

Stavudine(d4T) Efavirenz (EFV)

Indinavir Integrase inhibitors : Raltegravir, Elvitegravir/Cobicistat,

Dolutegravir

Lamivudine(3TC) Etravirine Saquinavir Fusion inhibitors : enfuvirtide

Didanosine(ddI) Rilpivirine Ritonavir

Abacavir(ABC) Atazanavir

Tenofovir(TDF) Lopinavir

Emtricitabine(FTC) Darunavir

Tipranavir

Fosamprenavir

DHHS guidelines 2013

WHO guidelines 2013 : what’s new

• ART should be initiated in all individuals with CD4 count < 500 cells/mm3 irrespective of WHO stage

• ART should be initiated irrespective of CD4 count and WHO stage :

• HIV and active TB• HIV/HBV co-infection with severe chronic liver disease• Partners with HIV in sero-discordant couples

HIVMAI Guidelines 2012

NACO GUIDELINES 2012Classification ofHIV-associated clinical disease

WHO STAGE CD4 NOT AVAILABLE

CD4 AVAILABLE

Asymptomatic 1 Do not treatTreat if CD4 <350

Mild symptoms 2 Do not treat

Advanced symptoms

3 Treat Consider treatment if CD4 <350

and initiate ART before CD4

drops below 200

Severe/advanced symptoms

4 Treat Treat irrespective of CD4 count

Why are we moving towards earlier antiretroviral therapy ?

• Current options for initial therapy are highly effective, durable, convenient, and well tolerated and show less evidence of long-term toxicity

Antiretroviral Efficacy Rates Are Improving in Clinical Practice

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Why are we moving towards earlier antiretroviral therapy ?

• Greater risk of developing non-AIDS–defining conditions, including cardiovascular disease, liver disease, and non-AIDS–defining malignancies

Immunosuppression Increases Risk of HIV- and Non-HIV–Related Mortality

• Cohort study of > 23,000 patients in Europe, Australia, and US– 76,577 patient-years of

follow-up

• 1248 (5.3%) deaths from 2000-2004

• Both HIV- and non-HIV–related mortality associated with CD4+ cell count depletion

< 50 50-99 100-199

200-349

350-499

CD4+ Cell Count (cells/mm3)

500

OverallHIVMalignancyHeart

Why are we moving towards earlier antiretroviral therapy ?

• Greater likelihood of CD4 normalization

Likelihood of Achieving Normal CD4+ Cell Count Depends on BL Level

ATHENA National CohortJohns Hopkins HIV Clinical Cohort

Years on HAART

1000

0 48 96 144 192 240 288Weeks From Starting HAART

200

400

600

800

0

1000

> 500351-500

201-35051-200< 50

200

400

600

800

00

1 2 3 4 5

>> 350

350< 200201-350

6

Incomplete Peripheral CD4+ Cell Count Restorationin HIV-Infected Patients Receiving Long-Term

Antiretroviral Treatment (Steve Deeks CID 2009)

Mortality rate in HIV infected adults on ART (French Aquitane Cohort )

HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples

Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm3

(n = 886 couples)

Delayed ARTInitiate ART at CD4+ cell count ≤ 250 cells/mm3*

(n = 877 couples)

HIV-infected, sexually active serodiscordant

couples; CD4+ cell count of the infected partner:

350-550 cells/mm3

(N = 1763 couples)

*Based on 2 consecutive values ≤ 250 cells/mm3.

• Primary efficacy endpoint: virologically linked HIV transmission

• Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death

• Couples received intensive counseling on risk reduction and use of condoms

HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples

Single transmission in patient in immediate ART arm believed to have occurred close to time therapy began and prior to HIV-1 RNA suppression

Total HIV-1 Transmission Events: 39(4 in immediate arm and

35 in delayed arm; P < .0001)

Linked Transmissions: 28

Unlinked or TBD Transmissions: 11

P < .001

Immediate Arm: 1

Delayed Arm: 27

Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

HPTN 052: Primary Clinical Events During Follow-up

• 41% reduction in HIV-related clinical events in HIV-infected patients randomized to immediate vs delayed therapy– Excess events in delayed arm driven mainly by TB (33 vs 17 cases), particularly

extrapulmonary TB (17 vs 3 cases)

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HR: 0.6 (95% CI: 0.4-0.9; P = .01)Delayed (n = 65)

Immediate (n = 40)

877886

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Number at risk

Grinsztejn B, et al. IAS 2011. Abstract MOAX0105. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

• Period of declining new HIV diagnoses in BC coincident with increased HIV testing rates, increased uptake of antiretroviral therapy, and decrease in community viral load (1996-2008)

– Decline in new HIV diagnoses despite increases in syphilis, gonorrhea, chlamydia

Montaner J, et al. CROI 2010. Abstract 88LB.1996

20092008

20072006

20052004

20032002

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Reduction in New HIV Diagnoses in BC: Testing, HAART, and Community VL

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6000

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iagnoses

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1000

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Efficacy of HIV Prevention Strategies From Randomized Clinical Trials

Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print].

1000 20 40 60 80Efficacy (%)

Study Effect Size, % (95% CI)

ART for prevention; HPTN 052, Africa, Asia, AmericasPrEP for discordant couples;Partners PrEP, Uganda, KenyaPrEP for heterosexual men and women; TDF2, BotswanaMedical male circumcision; Orange Farm, Rakai, KisumuPrEP for MSMs; iPrEX, Americas, Thailand, South AfricaSexually transmitted diseases treatment; Mwanza, TanzaniaMicrobicide;CAPRISA 004, South AfricaHIV vaccine;RV144, Thailand

96 (73-99)

73 (49-85)

63 (21-84)

54 (38-66)

44 (15-63)

42 (21-58)

39 (6-60)

31 (1-51)

When should we start ART in the event of acute opportunistic infection?

• ART is only effective treatment :• Progressive multifocal leucoencephalopathy

(PML)• Cryptosporidiosis• Microsporidiosis• Dementia• HIV associated nephropathy• START AS SOON AS POSSIBLE

When should we start ART in the event of acute opportunistic infection?

Systemic and CNS lymphoma Chemotherapy and ART to be started

together

PCPBacterial infectionsToxoplasmosisMycobacterium avium complex Immediate therapy (within 14 days of starting

treatment of OI )

Timing of ART initiation in patients with tuberculosis

CD4 count Time to initiate antiretroviral therapy

< 50 cells /mm3 within 2 weeks

50 – 200 cells/mm3 2 weeks to within 2 months

200 – 500 cells/mm3 Within 2 months

> 500 cells/mm3 Within 2 months

Tubercular meningitis irrespective of CD4 count

2 months

ART initiation in cryptococcal meningitis (COAT study)

• Cryptococcal Optimum ART timing trial :• ART initiation at 2 weeks of starting Amphotericin(early ART)

vs after 4 weeks of starting Amphotericin (delayed ART)• Data safety monitoring board recommended stopping study

enrolment due to substantially higher mortality in early ART group

• 6 month survival : 55% vs 70% with early vs deferred ART group

• Major deaths in early therapy arm were driven by cryptococcosis and not IRIS.

• Treat CM first, verify CSF culture sterility and then start ART after 4 weeks is the way to go.

Antiretroviral therapy : what to start?

NACO GUIDELINES 2012Preferred regimen (2NRTI’s + 1 NNRTI)AZT + 3TC + NVP (Zidovudine + Lamivudine +

Nevirapine )

Alternative regimen (2NRTI’s + 1 NNRTI)AZT + 3TC + EFV (Zidovudine + Lamivudine +

Efavirenz)TDF + 3TC + NVP/EFV (Tenofovir + Lamivudine +

Nevirapine/Efavirenz )

Other optionsStavudine (d4T) + 3TC/FTC + NVP/EFVPi’s not recommended for first line therapy

HIVMAI guidelines 2012

Why are we moving away from zidovudine and stavudine?

Zidovudine

Short term • Gastritis• Anemia• Bone marrow suppression• Myopathy, myalgia Long term• Dyslipidemia• Lipodystrophy syndrome

Stavudine

Long term• Peripheral neuropathy• Pancreatitis• Lactic acidemia/acidosis• Lipodystrophy syndrome• Dyslipidemia• Avascular necrosis• Cardiovascular risk

Antiretroviral therapy related lipodystrophy syndrome

Why Tenofovir/Emtricitabine (TDF/FTC) ?

GS 934 trial : TDF/FTC/EFV demonstrated superior efficacy and less toxicity (anemia) as compared to AZT/3TC/EFV over 144 weeks

GS 903 trial : less toxicity (neuropathy, lipoatrophy, and hyperlipidemia) as compared to d4T/3TC/EFV

Available as one tablet once a day FDCPreferred regimen for HIV/HBV and HIV/HCV

co-infectionToxicity : renal insufficiency and osteomalacia

Monitoring patients on antiretroviral therapy

Antiretroviral therapy in special situations

ART in pregnancy In absence of treatment, rate of mother to child

transmission of HIV is 30 %.With 3 drug c ART, the rate decreases to < 2 %.3 drug cART should be used for prevention of mother

to child transmission irrespective of CD4 count Single dose Nevirapine must be discouraged Tenofovir and Efavirenz are now recommended to be

used in pregnancy as a single pill fixed dose combination.

Adverse potential for the pregnant mother (combination stavudine [d4T]/didanosine [ddI]).

Viral load monitoring close to delivery Elective Lower segment caesarean section must if viral

load monitoring not possibleAvoid breast feeding

ART in pregnancy NACO GUIDELINES 2007 NVP based HAART if CD4 <

250 cells/mm3

Single dose NVP if CD4 > 250 cells/mm3

Preferred PI : Nelfinavir Ritonavir boosted

Saquinavir No clear cut

recommendation for Breast feeding and C-Section

API ART GUIDELINES 2008 NVP based HAART if CD4 <

250 cells/mm3

PI based HAART if CD4 > 250 cells/mm3

Preferred PI Ritonavir boosted Lopinavir Nelfinavir Breast feeding Elective C-Section

mandatory if viral load testing not available

WHO PMTCT guidelines 2013

• All pregnant and breast feeding women should initiate triple ARV’s

• ART should be given as lifelong treatment• In special situations, women who are not

eligible for ART for their own health, consideration can be given to stop ART regimen after the period of mother to child transmission risk has ceased

WHO guidelines 2013 : what to start ?

First line ART Preferred first line Alternative first line

ADULTS (including pregnant and

breastfeeding women and HIV/TB co-infection TDF + 3TC(OR FTC) + EFV

AZT + 3TC + EFV

AZT + 3TC + NVP

TDF + 3TC + NVPAdolescents (10-19 yrs of age) and >= 35 kg

Children 3 – 10 yrs of age and adolescents < 35 kg

ABC + 3TC + EFV

AZT + 3TC + EFV

AZT + 3TC + NVP

ABC + 3TC + NVP

TDF + 3TC + NVP

TDF + 3TC + EFV

Children < 3 yrs of age ABC or AZT + 3TC + LPV/r ABC or AZT + 3TC + NVP

POST EXPOSURE PROPYLAXIS (PEP)

Classification of body fluidsInfectious fluids Fluids potentially

infectiousNon infectious fluids

Blood CSF Feces

Visibly bloody body fluids Pleural fluid Nasal secretions

Semen Peritoneal fluid Saliva

Vaginal fluid Amniotic fluid Sputum

Pericardial fluid Sweat

Synovial fluid Tears

Urine

Vomitus

Risk factors for occupational exposure of HIV

• HIV transmission after per-cutaneous exposure to HIV infected blood 0.3 %

• Mucous membrane exposure 0.09 %• Transmission through non intact skin : present

but lower than mucous membrane exposure• Exposure to body fluids other than blood :

lower than blood exposure

Risk factors for occupational exposure of HIV

• Needle visibly contaminated with patients blood

• Needle directly placed in artery or vein• Deep injury• Terminal illness in source patient

PEP : General guidelines• Occupational exposure to HIV should be treated as urgent medical concern.• 2 drug HIV PEP regimens are no longer used• PEP should include 3 (or more) antiretrovirals consonant with current treatment

guidelines• PEP should begin within “hours” and certainly not later than 72 hours• Appropriate initial source patient and exposed service provider laboratory testing

should be done immediately.• Total duration should be 4 weeks• Adherence to PEP should be emphasized• If a patient is known to harbour drug resistant HIV, expert consultation for PEP

should be done• If PEP offered and then source patient found negative, PEP should be stopped

immediately• HIV testing to be done at baseline, 6 weeks and 4 months post exposure if 4th

generation p24 antigen - HIV antibody ELISA used• If HIV NAT is used, 2 HIV DNA PCR tests should be performed after 14 days post

exposure.

Can we end the AIDS epidemic ?

• Measures if used judiciously can reduce AIDS related deaths and new HIV infections (International AIDS conference, Washington 2012)

• These include:• The use of HIV treatment as prevention.• The rolling out of male circumcision programmes.• The use of triple-drug HIV therapy during pregnancy and

breastfeeding.• Pre-exposure prophylaxis (PrEP).• Intensified case finding for TB in patients with HIV, and HIV in

patients with TB.• Earlier HIV therapy.

HIV cure ??• “The Berlin patient”• This person was cured of HIV after undergoing a gruelling

course of chemotherapy, immunosuppressive treatment, and a bone marrow transplant from a donor with a rare genetic mutation making him naturally resistant to infection with HIV.

• This isn’t an attractive or realistic therapy• Cure would be a therapy that either eradicated HIV from the

body or a treatment that allowed the body’s natural defences to keep HIV in check, even after any antiretroviral therapy was stopped.

• The Mississippi baby : administration of antiviral therapy within 30 hours of birth leads to “functional cure”

CONCLUSIONS• Opt out HIV testing should be practiced in India as well• Time has come to start ART irrespective of CD4 count provided patient

understands importance of lifelong adherence to ART• Tenofovir based ART as preferred regimen for all patients should be rigorously

followed• HIV has changed from a acute life threatening illness to a chronic manageable

condition• Our patients can live up to their 70’s and 80’s with good adherence to current

antiretroviral drugs.• Identifying HIV early and putting all patients on Antiretroviral therapy can help

slowing or even ending the AIDS epidemic• In such a scenario management of co-morbidities like Diabetes, Hypertension,

Lipids, Bone, liver, neurocognitive and kidney ailments becomes extremely important.

• Drug-drug interactions and drug toxicities come into play with polypharmacy and should be scrupulously looked into.

• Next 10 years will most probably be the era of HIV cure research

THANK YOU