This document summarizes current guidelines for antiretroviral therapy. It begins by stating that eradication of HIV is not currently possible due to reservoirs of latent infection. It then reviews recommendations for starting ART based on CD4 count from various organizations. A list of approved antiretrovirals is provided grouping them by class. The benefits of earlier treatment include reduced transmission risk, lower non-AIDS related mortality, and increased CD4 recovery. Studies supporting these benefits are summarized. Optimal first-line regimens now include tenofovir/emtricitabine due to lower toxicity compared to older drugs. Special considerations for ART in pregnancy and tuberculosis are discussed.

1. Antiretroviral therapy in 2013 : what
a general practitioner must know
Dr Ameet Dravid
M.D Medicine
Ruby Hall Clinic, Pune

2. 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.

3. Antiretroviral therapy : when to start?

4. Antiretrovirals approved for use
NRTI
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

5. DHHS guidelines 2013

6. 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

7. HIVMAI Guidelines 2012

8. NACO GUIDELINES 2012
Classification of
HIV-associated
clinical disease
WHO STAGE
CD4 NOT
AVAILABLE
Asymptomatic
1
CD4 AVAILABLE
Do not treat
Treat 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

9. 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

10. Antiretroviral Efficacy Rates Are
Improving in Clinical Practice
Patients With
HIV-1 RNA > 500 copies/mL (%)
50
40
40
42
39
34
31
30
30
25
20
10
0
1996
1997
1998
1999
2000
2001
2002

11. 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

12. Immunosuppression Increases Risk of HIVand Non-HIV–Related Mortality
•
Cohort study of > 23,000 patients
in Europe, Australia, and US
Overall
HIV
Malignancy
Heart
– 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
100199
200349
350- ≥ 500
499
CD4+ Cell Count (cells/mm3)

13. Why are we moving towards earlier
antiretroviral therapy ?
• Greater likelihood of CD4 normalization

14. Likelihood of Achieving Normal
CD4+ Cell Count Depends on BL Level
Johns Hopkins HIV Clinical Cohort
ATHENA National Cohort
>> 350
201-350
350
< 200
1000
800
1000
800
600
600
400
400
200
200
0
0
0
1
2
3
4
Years on HAART
5
6
201-350
51-200
< 50
0
> 500
351-500
48 96 144 192 240 288
Weeks From Starting HAART

15. Incomplete Peripheral CD4+ Cell Count Restoration
in HIV-Infected Patients Receiving Long-Term
Antiretroviral Treatment (Steve Deeks CID 2009)

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

17. HPTN 052: Immediate vs Delayed ART in
Serodiscordant Couples
HIV-infected, sexually active
serodiscordant
couples; CD4+ cell count
of the infected partner:
350-550 cells/mm3
(N = 1763 couples)
Immediate ART
Initiate ART at CD4+ cell count 350-550 cells/mm3
(n = 886 couples)
Delayed ART
Initiate ART at CD4+ cell count ≤ 250 cells/mm3*
(n = 877 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
Cohen MS, et al. IAS 2011. Abstract MOAX0102.
Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

18. HPTN 052: HIV Transmission Reduced by 96% in
Serodiscordant Couples
Total HIV-1 Transmission Events: 39
(4 in immediate arm and
35 in delayed arm; P < .0001)
Linked Transmissions:
28
Delayed
Arm: 27
Immediate
Arm: 1
P < .001
Cohen MS, et al. IAS 2011. Abstract MOAX0102.
Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].
Unlinked or TBD
Transmissions: 11
Single transmission in patient in
immediate ART arm believed
to have occurred close to time therapy
began and prior to HIV-1 RNA suppression

19. 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)
HR: 0.6 (95% CI: 0.4-0.9; P = .01)
Delayed (n = 65)
Failure Probability
0.25
0.20
0.15
Immediate (n = 40)
0.10
0.05
0
877
886
701
700
0
1
317
333
86
85
32
36
2
3
4
Yrs Since Randomization
Grinsztejn B, et al. IAS 2011. Abstract MOAX0105.
Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].
25 Number at risk
29
5

20. Reduction in New HIV Diagnoses in BC: Testing,
HAART, and Community VL
•
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
Patients (n)
10,000
8000
6000
Censored at the time of death or move
New HIV+
Diagnoses (All)
4000
2000
0
96 97 98 99 00 01 02 03 04 05 06 07 08 09
19 19 19 19 20 20 20 20 20 20 20 20 20 20
Montaner J, et al. CROI 2010. Abstract 88LB.
1400
1200
1000
800
600
400
200
0
Number of New HIV+ Diagnoses
12,000
HIV-1 RNA,
copies/mL
< 500
500-3499
3500-9999
10,000-49,999
≥ 50,000

21. Efficacy of HIV Prevention Strategies From Randomized
Clinical Trials
Study
Effect Size, % (95% CI)
ART for prevention; HPTN 052, Africa,
Asia, Americas
PrEP for discordant couples;
Partners PrEP, Uganda, Kenya
PrEP for heterosexual men and
women; TDF2, Botswana
Medical male circumcision;
Orange Farm, Rakai, Kisumu
PrEP for MSMs; iPrEX, Americas,
Thailand, South Africa
Sexually transmitted diseases
treatment; Mwanza, Tanzania
Microbicide;
CAPRISA 004, South Africa
HIV vaccine;
RV144, Thailand
0
96 (73-99)
73 (49-85)
63 (21-84)
54 (38-66)
44 (15-63)
42 (21-58)
39 (6-60)
31 (1-51)
20
40
60
Efficacy (%)
Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print].
80
100

22. 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

23. When should we start ART in the event of acute
opportunistic infection?
Systemic and CNS lymphoma
Chemotherapy and ART to be started
together
PCP
Bacterial infections
Toxoplasmosis
Mycobacterium avium complex
Immediate therapy (within 14 days of starting
treatment of OI )

24. 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

25. 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.

26. Antiretroviral therapy : what to start?

28. NACO GUIDELINES 2012
 Preferred 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 options
 Stavudine (d4T) + 3TC/FTC + NVP/EFV
 Pi’s not recommended for first line therapy

29. HIVMAI guidelines 2012

30. 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

31. Antiretroviral therapy related lipodystrophy syndrome

32. 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 FDC
Preferred regimen for HIV/HBV and HIV/HCV
co-infection
Toxicity : renal insufficiency and osteomalacia

33. Monitoring patients on antiretroviral therapy

34. Antiretroviral therapy in special situations

35. 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 possible
 Avoid breast feeding

36. 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 CSection
 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

37. 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

38. WHO guidelines 2013 : what to start ?
First line ART
ADULTS (including
pregnant and
breastfeeding women and
HIV/TB co-infection
Preferred first line
Alternative first line
AZT + 3TC + EFV
TDF + 3TC(OR FTC) + EFV
AZT + 3TC + NVP
TDF + 3TC + NVP
Adolescents (10-19 yrs of
age) and >= 35 kg
AZT + 3TC + EFV
Children 3 – 10 yrs of age
and adolescents < 35 kg
ABC + 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

39. POST EXPOSURE PROPYLAXIS (PEP)

40. Classification of body fluids
Infectious fluids
Fluids potentially
infectious
Non 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

41. 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

42. 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

43. 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 4 th
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.

45. 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.

46. 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”

47. 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

48. THANK YOU