MANAGEMENT OF HIV

INFECTION
CONTENTS
1. DIAGNOSIS
2. PRE ART ASSESSMENT
3. WHEN TO START ART?
4. MANAGING OPPORTUNISTIC INFECTIONS
5. LAB MONITORING PRIOR TO ART
6. COMMON ART REGIMENS USED BY NACO
7. VIRADAY
8. HIV TB CO INFECTION
9. HIV PCP COINFECTION
10. SAFETY PROFILE OF DRUGS
11. IRIS
12. TREATMENT FAILURE




Diagnosis of HIV Infection in
Adults and Adolescents
Symptomatic --- 2 samples reactive
Asymptomatic --- 3 samples reactive
Diagnosis of HIV Infection in
Adults and Adolescents
SYMPTOMATIC PATIENTS
SAMPLE 1 reactive SAMPLE 2
SAMPLE 1 & 2 both reactive report
POSITIVE
If, SAMPLE 2 non reactive SAMPLE 3
SAMPLE 1&3 reactive report POSITIVE
Diagnosis of HIV Infection in
Adults and Adolescents
ASYMPTOMATIC PATIENTS
3 SAMPLES to be tested , even if first 2
are positive
Reported reactive only if all 3 positive
2/3 positive reported as EQUIVOCAL
DNA PCR , Western blot done
PRE ART ASSESSMENT

CLINICAL ASSESSMENT
clinical stage of HIV infection
history of past illnesses (especially those related
to HIV)
current HIV-related illnesses that require
treatment
need for ART and OI prophylaxis
coexisting medical conditions and treatments
that may influence the choice of therapy

WHO clinical staging of HIV/AIDS for adults &
adolescents 2010

CLINICAL STAGE 1

Asymptomatic
Persistent generalized lymphadenopathy


WHO clinical staging of HIV/AIDS for adults
& adolescents 2010
CLINICAL STAGE 2

Unexplained moderate weight loss (<10% of
presumed or measured body weight)
Recurrent respiratory tract infections
Herpes zoster
Angular Cheilitis ,Recurrent oral ulceration
Papular pruritic eruptions
Seborrhoeic dermatitis
Fungal nail infections
WHO clinical staging of HIV/AIDS for adults
& adolescents 2010
CLINICAL STAGE 3

Unexplained severe weight loss (>10% of
presumed or measured body weight)
Unexplained chronic diarrhoea > 1month
Unexplained persistent fever (above 37.5C
intermittent or constant for > one month)
Persistent oral candidiais
Oral hairy leukoplakia
Pulmonary tuberculosis

WHO clinical staging of HIV/AIDS for adults
& adolescents 2010
CLINICAL STAGE 3

Severe bacterial infections (e.g. pneumonia, empyema,
pyomyositis, bone or joint infection, meningitis,
bacteraemia)
Acute necrotizing ulcerative stomatitis, gingivitis or
periodontitis
Unexplained anaemia (<8 g/dl)
neutropenia (<0.5 x 109/litre)
chronic thrombocytopenia (<50 x 109/litre3)

WHO clinical staging of HIV/AIDS for adults
& adolescents 2010
CLINICAL STAGE 4

HIV wasting syndrome
Pneumocystis pneumonia
Recurrent severe bacterial pneumonia
Chronic herpes simplex infection
Oesophageal candidiasis
Extrapulmonary tuberculosis
Kaposi sarcoma
Cytomegalovirus infection
WHO clinical staging of HIV/AIDS for adults
& adolescents 2010
CLINICAL STAGE 4

Central nervous system toxoplasmosis
HIV encephalopathy
Extrapulmonary cryptococcosis including menigitis
Disseminated mycosis (extrapulmonary histoplasmosis,
coccidiomycosis)
Recurrent septicaemia (including non-typhoidal
salmonella)
Lymphoma (cerebral or B cell non Hodgkin

WHO clinical staging of HIV/AIDS for adults
& adolescents 2010
CLINICAL STAGE 4

Invasive cervical carcinoma
Atypical disseminated leishmaniasis
Symptomatic HIV-associated nephropathy
or symptomatic HIV associated
cardiomyopathy

TO SIMPLIFY
STAGE 1 : GENERALIZED LAP /
ASYMPTOMATIC
STAGE 2 : FOCAL INFECTIONS ,
MODERATE WEIGHT LOSS
STAGE 3: >10% WEIGHT LOSS, SEVERE
PERSISTANT INFECTIONS, PULMONARY
KOCHS
STAGE 4: DISSEMINATED DISEASE
WHEN TO START ART ???
WHEN TO START ART?
HIV INFECTED ADULTS (INCLUDING
PREGNANT WOMEN)
CLINICAL STAGE 1&2
Start ART if CD4 count < 350

CLINICAL STAGE 3&4
Start ART irrespective of CD4 count
WHEN TO START ART?

For HIV and TB co-infected patients

Start ART irrespective of CD4 count and type of
tuberculosis

Start ATT first initiate ART between 2 weeks
to 2 months when TB treatment is tolerated

WHEN TO START ART?

HIV and HBV / HCV co-infection
without any evidence of chronic
active Hepatitis
Start ART if CD4 < 350

WHEN TO START ART?

HIV and HBV / HCV co-infection
With documented evidence of chronic
active Hepatitis
Start ART irrespective of CD4 counts.

WHEN TO START ART?
As per NACO 2013 guidelines
CD4 < 350
Clinical stage 3&4
HIV + TB
HIV + CHRONIC ACTIVE HEPATITIS
CD4 MONITORING & FOLLOW UP
SCHEDULE
WHEN TO START ART ?
WHO guidelines
ART initiation irrespective of CD4 counts
HIV viral load --- preferred for treatment
monitoring
Viral load should be tested at 6 months and then
at least every 12 months.
Treatment failure viral load >1000 copies/ml
2 consecutive samples within a three month
interval.
WHAT TO TREAT FIRST ??
OIs or HIV
Manage OIs before Starting
ART
Any undiagnosed active infection
with fever
Diagnose and treat first; start ART when
stable
TB
Treat TB first; start ART within 2 weeks to
2 months

Manage OIs before Starting
ART
PCP/ BACTERIAL PNEUMONIA/
MALARIA
Treat first
Start ART when treatment completed
Manage OIs before Starting
ART
INVASIVE FUNGAL DISEASES
Treat first
Start ART as soon as patient is stable /
treatment completed
OESOPHAGEAL CANDIDIASIS
As soon as patient is able to swallow
Manage OIs before Starting
ART
DRUG REACTION : Do not start ART

Acute diarrhoea which may reduce
absorption of ART : Treat diarrhoea first

Skin conditions such as PPE and
seborrhoeic dermatitis, psoriasis, HIV-
related exfoliative dermatitis : Start ART



Manage OIs before Starting
ART
Suspected MAC, cryptosporidiosis and
microsporidiosis : Start ART

Cytomegalovirus infection : Treat if drugs
available; if not, start ART

Toxoplasmosis: Treat; start ART after 6 weeks
of treatment and when patient is stabilized




Co trimoxazole Preventive
Therapy
NACO May 2013 GUIDELINES
WHO REQUIRES CPT?
Any WHO clinical stage and CD4 <250
cells/mm3 or
Any WHO clinical stage, CD4 <350
cells/mm3 and if patient is symptomatic or
WHO stage 3 or 4 irrespective of CD4
count

WHEN TO START
Start co-trimoxazole prophylaxis first.

Start ART about two weeks later if the
patient can tolerate co-trimoxazole and
has no symptoms of allergy (rash,
hepatotoxicity)

DOSAGE
One double-strength tablet or two single-
strength tablets once daily total daily
dose of 960 mg (800 mg SMZ + 160 mg
TMP)
Allergy to sulpha drugs : Dapsone 100 mg
OD
No specific lab monitoring required

CPT KEY POINTS

Start co-trimoxazole when CD4 <250 or WHO
Clinical Stage 3 or 4. (HIV-TB co infection)

Discontinue 2 consecutive CD4 counts >
respective levels, patient on ART >6 months

Reintroduce prophylaxis if CD4 count falls below
250 again

Secondary prophylaxis is indicated to prevent
recurrence
COTRIMOXAZOLE
DESENSITIZATION
SECONDARY PROPHYLAXIS FOR
OIs
LAB MONITORING PRIOR TO
ART
LAB MONITORING PRIOR TO ART

CBC,
Urine for routine and microscopic examination,
fasting blood sugar,
blood urea,
ALT (SGPT),
VDRL,
Serum creatinine (when considering TDF)
CD4 count,
X-ray Chest PA view.
Pregnancy test (if required)
Symptoms and signs directed investigations for ruling out Ols.


LAB MONITORING PRIOR TO ART
ADDITIONAL TESTS

For all patients to be started on ART (as per the
physicians decision depending on clinical presentation)
USG abdomen,
sputum for AFB,
CSF analysis

PAP smear & Fundus examination also (ART initiation not
to be delayed for these tests)

LAB MONITORING PRIOR TO ART
SPECIAL SITUATIONS

HBsAg
Mandatorily for those with history of IDU,
multiple blood & blood products
transfusion, ALT > 2 times of ULN, on
strong clinical suspicion.
Ideally , all patients

LAB MONITORING PRIOR TO ART
SPECIAL SITUATIONS
Anti - HCV antibody
History of IDU, multiple blood & blood
products transfusion, ALT >2 times of
ULN, on strong clinical suspicion.

LAB MONITORING PRIOR TO ART
SPECIAL SITUATIONS

Hepatitis B or C co-infection: further tests
may be required to assess for chronic
active hepatitis
Switch to a PI based regimen: Blood
Sugar, LFT and Lipid profile to be done at
baseline

ART PRINCIPLES --- NACO

Principles for selecting the first-line
regimen
Choose 3TC (Lamivudine) in all regimens
Choose one NRTI to combine with 3TC (AZT or
TDF)
Choose one NNRTI (NVP or EFV)
COMMON REGIMENS USED BY
NACO
Hb 9 gm/dl
No ATT
Zidovudine(300mg BD)
+ Lamivudine(300mg
OD) + Nevirapine
ON ATT
Zidovudine +
Lamivudine
Efavirenz (600mg OD)



Hb <9 gm/dl
NO ATT
Tenofovir + Lamivudine
+ Nevirapine

ON ATT
Tenofovir + Lamivudine
+ Efavirenz
Also for
Hep B, C
Pregnancy

COMMON REGIMENS USED BY
NACO
TOXICITY TO BOTH
NVP/EFV
Zidovudine + Lamivudine
+ Atazanavir/ Ritonavir
(300/100)
Atazanavir toxicity
Zidovudine + Lamivudine
+ Lopinavir / Ritonavir
(133/33)

2
ND
LINE for AZT/d4T
containing regimen failure
Tenofovir + Lamivudine+
Atazanavir/ Ritonavir

Toxicity to Atazanavir
Substitute with
lopinavir/Ritonavir

COMMON REGIMENS USED BY
NACO
2
nd
line for those who
are on TDF containing
regimen (Hb < 9
gm/dl )

Stavudine+
Lamivudine+
Atazanavir/ Ritonavir


Atazanavir toxicity


Substitute with
Lopinavir/ Ritonavir
WHO REGIMENS
Special circumstances :
Toxicities
Drug interactions
Procurement issues
DRUGS--- SAFETY PROFILE
ZIDOVUDINE (AZT) :

Initial headache and nausea
Severe anaemia and neutropenia
Haemoglobin monitoring recommended


DRUGS--- SAFETY PROFILE
LAMIVUDINE (3TC) :

Good safety profile
Non -teratogenic
Once daily Effective against hepatitis B
Low genetic barrier to resistance


DRUGS--- SAFETY PROFILE
TENOFOVIR (TDF) :

Renal dysfunction has been reported
Safety in pregnancy not established
Adverse effects on foetal growth and bone
density reported

DRUGS--- SAFETY PROFILE
STAVUDINE (d4T):

Most associated with lactic acidosis,
lipoatrophy and peripheral neuropathy

Good efficacy profile and cheap No or
limited laboratory monitoring


SAFETY PROFILE --- CLASSES OF
DRUGS
HEPATOTOXICITY:
All FDA-approved NRTIs, NNRTIs, and PIs

HYPERGLYCEMIA : PIs
HYPERLIPIDEMIA : PIs
OSTEONECROSIS , OSTEOPENIA : PIs

SAFETY PROFILE : CLASSES OF
DRUGS
LACTIC ACIDOSIS : NRTIs
LIPOATROPHY : PIs + NRTIs
SKIN RASH : NRTIs, NNRTIs, PIs
RENAL CALCULI : INDINAVIR


NEVIRAPINE : THE LEAD IN
PERIOD
Once a day 200 mg dosing for 2 weeks

Full dosing --- BD
Full NVP dosage --- very high serum
concentration--- hepatotoxicity & rash
After 2 weeks --- enzyme auto induction
levels decline
EFAVIRENZ --- WHEN TO PREFER?
1. Concurrent rifampicin-containing anti-TB
regimen (ATT)
2. Hepatic dysfunction, e.g. due to hepatitis B/C
coinfection or other causes
3. Significant NVP side-effects
SWITCHING BACK TO NVP
2 weeks after completion of ATT
Lead in not required
Close monitoring for hepatotoxicity
Considerations for Co-
infection of Tuberculosis and
HIV
Considerations for Co-infection
of Tuberculosis and HIV
ISSUES:
Drug interactions between rifampicin and NNRTIs and
PIs
IRIS
Pill burden
Adherence
Drug toxicity.
Active TB is the commonest OI
Leading cause of death
WHO 2011 GUIDELINES
Start ATT irrespective of CD4 count
Start ART --- 2weeks --- 2 months
EFV containing ART regimens( 600mg/day dose)

In the absence of ART, TB therapy alone does
not significantly increase the CD4 cell count.

Or decrease the HIV viral load.

PATIENTS WHO DEVELOP TB WITHIN 6
MONTHS OF STARTING ART
Substitute NVP with EFV
If on 2
nd
line regimen : change rifampicin
to Rifabutin

TB WHILE ON ART---
TREATMENT FAILURE ??
WHO Recommendations
TB WHILE ON ART--- TREATMENT
FAILURE ??
Within 6 months --- not considered ART
failure
> 6 months : CD4 count & viral load
should be used to assess
LN TB / Uncomplicated pleural disease :
NO treatment failure
Extrapulmonary TB : treatment failure
TREATMENT FAILURE ??
Switch to PI containing 2
nd
line ART
regimen
Substitute Rifampicin with Rifabutin 150
mg thrice weekly
HIV PCP CO-INFECTION
CDC/NIH/IDSA 2009 guidelines
HIV PCP CO-INFECTION
TMP- SMX is the treatment of choice
Dose to be adjusted for renal dysfunction
Corticosteroids :
Severe disease
pO2 < 70 mmHg
Arteriolar alveolar oxygen gradient >
35mmHg
HIV PCP CO-INFECTION
Steroids should be started as early as
possible
Certainly within 72 hours of starting
cotrimoxazole.

HIV PCP CO-INFECTION
ALTERNATIVE REGIMENS FOR MILD
MODERATE DISEASE:
Dapsone + TMP
Primaquine + clindamycin
Atovaquone


HIV PCP CO-INFECTION
ALTERNATIVE REGIMENS FOR SEVERE
DISEASE:
Clindamycin + primaquine
i.v. Pentamidine
HIV PCP CO-INFECTION
Treatment : 21 days
Overall prognosis poor
Survival 50%
Secondary prophylaxis : initiated
immediately after completion of therapy
Maintained till CD4 count >200
HIV PCP CO-INFECTION
Management of treatment failure:
Lack of improvement or worsening of
respiratory function --- 4-8 days of
therapy
Switch to another regimen
Exclude other infections ---BAL
HIV PCP CO-INFECTION
Management of treatment failure
If TMP SMX has failed:
i.v. pentamidine or,
Primaquine + clindamycin
WHAT TO EXPECT IN THE
FIRST 6 MONTHS OF ART?
CD4 COUNTS

CD4 cell count rises with the initiation of
ART and immune recovery
Lower the baseline value --- longer time to
recovery
May never exceed 200 in some patients
DRUG TOXICITIES
Immune reconstitution
inflammatory syndrome
Spectrum of clinical signs and symptoms
resulting from the bodys ability to mount
an inflammatory response associated with
immune recovery

Shelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP, White
AC Jr, et al. Incidence and risk factors for immune reconstitution
inflammatory syndrome during highly active antiretroviral therapy. AIDS
2005; 19 : 399-406
Immune reconstitution
inflammatory syndrome
Practical definition of IRIS in India:
occurrence or manifestations of new OIs
or existing OIs within six weeks to six
months after initiating ART; with an
increase in CD4 count.

NACO 2013 GUIDELINES
Immune reconstitution
inflammatory syndrome
DIAGNOSIS :
TEMPORAL ASSOCIATION
Usually 2-12 weeks of initiation of ART
(may present upto 6 months)
Incidence : 10% overall
25 % in patients with CD4 < 50
Immune reconstitution
inflammatory syndrome
UNUSUAL CLINICAL MANIFESTATIONS
LAP , hepatomegaly , splenomegaly
Exaggerated inflammatory reaction, e.g. severe
fever
Painful lesions
Granulomas, suppuration, necrosis
Perivascular lymphocytic inflammatory cell infiltrate
Progression of organ dysfunction or enlargement
of pre existing lesions
Immune reconstitution
inflammatory syndrome
UNUSUAL CLINICAL MANIFESTATIONS
Development or enlargement of cerebral SOLs
after treatment for cerebral cryptococcosis or
toxoplasmosis
Progressive pneumonitis or the development of
organizing pneumonia after treatment for
pulmonary MTB or PCP
Onset or worsening of uveitis/vitritis after the
resolution of CMV retinitis
Fever and cytopenia after treatment for
disseminated MAC
Immune reconstitution
inflammatory syndrome
RISK FACTORS FOR INFECTIOUS IRIS

An active or sub-clinical infection by opportunistic
pathogens
The antigens of non-viable microorganisms (e.g.
Cryptococus and CMV) are all possible targets for
an immunopathological response.
A CD4 count of below 50/mm3
Starting ART in close proximity to the diagnosis
and initiation of treatment for OI.
TB- IRIS
8 -43%
Paradoxical disease
within the first two months and commonly
in the first 2-3 weeks
Worsening or appearance of new clinical
or radiological features
Indian J Med Res 134, December 2011, pp 866-877
TB-IRIS
Return of symptoms like fever

Lymph node enlargement or suppuration

Fresh infiltrates, mediastinal
lymphadenopathy or enlarging effusion on
CXR
Indian J Med Res 134, December 2011, pp 866-877
TB-IRIS
Visceral or cutaneous abscesses
CNS disease
Pericardial effusion
Acute respiratory distress syndrome
(ARDS)

Indian J Med Res 134, December 2011, pp 866-877
TB -IRIS
CAMELIA trial reported improved survival of
these patients with early initiation (2 wk)
compared to late initiation (8 wk) of ART


Blanc FX, Sok T, Laureillard D. Significant enhancement in survival with early (2
weeks) vs. late (8 weeks) initiation of highly active antiretroviral treatment (HAART)
in severely immunosuppressed HIV-infected adults with newly diagnosed
tuberculosis. In: Proceedings of the 16th International AIDS Society Conference,
Vienna, Austria; 2010
Immune reconstitution
inflammatory syndrome
NON INFECTIOUS IRIS

Guillain-Barre Syndrome
Autoimmune thyroiditis
Lupus like disease
Reiters syndrome
Polymyositis
Indian J Med Res 134, December 2011, pp 866-877
Immune reconstitution
inflammatory syndrome
NON INFECTIOUS IRIS
Sarcoidosis
Lymphoid interstitial pneumonitis
Folliculitis
Kaposis sarcoma
Lymphoma
Connick E, Kane MA, White IE, Ryder J, Campbell TB. Immune
reconstitution inflammatory syndrome associated with Kaposi sarcoma
during potent antiretroviral therapy. Clin Infect Dis 2004; 39 : 1852-5.
Immune reconstitution
inflammatory syndrome
IRIS :D/D
ART FAILURE
ACTIVE OI
DRUG TOXICITY
FAILURE OF ANTIMICROBIAL THERAPY

Immune reconstitution
inflammatory syndrome
TREATMENT :
No standard guidelines
Milder forms resolve with anti microbial
therapy
Continue ART if CD4 <100 or IRIS
months after initiation of HAART
Life threatening conditions --- discontinue
HAART
Immune reconstitution
inflammatory syndrome
TREATMENT:
NSAIDS --- fever & inflammation
Steroids : severe IRIS (1-2 mg/kg body
weight)
TREATMENT FAILURE
Clinical, immunological and virological
definitions of treatment failure for first-line
regimen (WHO, 2010)

CLINICAL FAILURE :
New or recurrent WHO stage 4 condition,
After at least 6 months of ART

IMMUNOLOGICAL FAILURE:
Fall of CD4 count to pre-therapy
50% fall from the on-treatment peak value
Persistent CD4 levels below 100 cells/mm

Clinical, immunological and virological
definitions of treatment failure for first-line
regimen (WHO, 2010)

VIROLOGICAL FAILURE:
Plasma viral load >5,000 copies/ml after at least 6
months of ART

Treatment Failure : MANAGEMENT
BASIC PRINCIPLES:
Cross resistance exists between d4T and AZT;
thus NRTI-component in the second-line regimens
should be either ddI/ABC or TDF/ABC.


High level AZT/3TC resistance reduces
susceptibility to ABC.
Treatment Failure : MANAGEMENT

BASIC PRINCIPLES:

TDF can be compromised by multiple nucleoside
analogue mutations (NAMs) but often retain
activity against nucleoside-resistant viral strains.

NNRTI (such as EFV and NVP): usually there is
complete cross-resistance.

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