Evaluation of World Health Organization (WHO) Recommendations on Test and Treat Strategy, Managing Advanced HIV Disease and Rapid Initiation of ART Among People Living With HIV in Nepal: A Cluster Randomized Trial.
Phase: PHASE4
Conditions: HIV
Sponsor: National Centre for AIDs and STD Control, Nepal

 1 
PRAN Study  
Protocol 
Official Title: Evaluation of World Health Organization (WHO) 
Recommendations on Test and Treat Strategy, Managing Ad-
vanced HIV Disease and Rapid Initiation of ART Among People 
Living With HIV in Nepal: A Cluster Randomized Trial.   
Dec 2017  

 2 
• 
Age > 15 years 
• 
Diagnosed with HIV-infection 
• 
ART naive or ART started during study enrollment period 
• 
Consent for study participation  
INCLUSION CRITERIA 
This protocol is a short text compiling essential information for 
the package of care. It has been edited in collaboration be-
tween the National Centre for AIDS and STD Control and Ex-
pertise France. 
For additional and extended information for clinical manage-
ment you can refer to “National HIV Testing and Treatment 
Guidelines 2017” published by the National Centre for AIDS 
and STD Control. 
 29 
NOTES 

 28 
16. Advanced Adherence Support (mHealth and  
community care support 
A. Clinically well PLHIV (WHO Clinical Stage 1 or 2 OR CD4 
cell count >200 cells/mm3 )  
• 
Home-based care service (Make monthly/bimonthly 
visit plan).  
• 
ART follow up: At least after 3 months but make sure to 
analyze current ART adherence level.   
• 
Link with Community care center for transitional shelter 
during initiation of ART.  
• 
mHealth Intervention: Push text messages in mobile 
for appointment reminders and general awareness 
through DHIS-2 tracker system. Seek patient consent to 
push text messages.   
B. PLHIV with Advanced HIV Disease (Presence of symptoms 
of WHO stage 3 or 4 OR  CD4 count ≤ 200 cells/mm3) 
• 
Community Home based care service (Make weekly/
biweekly visit plan).  
• 
ART follow up: Monthly  
• 
Link with Community Care Center for transitional shel-
ter while management of OIs and while observational 
period during initiation of ART.  
• 
mHealth Intervention (Push text messages for appoint-
ment reminders, general awareness through DHIS-2 
tracker system).  
 3 
The present study will implement package of care in 10 different 
sites that are equiped with HIV Care and ART Tracking System 
(DHIS2 tracker, mHealth and Biometric System): 
• 
Teku hospital, Katmandu; Sukraraj Tropical & Infectious 
Disease Hospital, Kathmandu  
• 
Bir Hospital, Katmandu 
• 
TU-Teaching Hospital, Katmandu 
• 
Western Regional Hospital, Pokhara 
• 
Rapti Sub-Regional Hospital, Surkhet 
• 
Bharatpur Hospital, Bharatpur 
• 
Seti Zonal Hospital, Dhangadhi  
• 
B.P. Koirala Institute of Health Sciences,  Sunsari 
• 
Tikapur Hospital, Kailali and Mahakali Zonal hospital , 
Kanchanpur 
 
The inclusion criteria in the study are the following: 
• 
Age > 15 years 
• 
Diagnosis of HIV-infection 
• 
Naive of ART or started ART during study enrollment pe-
riod 
• 
Consent for study participation 
The study follow-up of the patients is summarized on the next 
page. 

 4 
 
Baseline Day-15 M-3/6 M-12 M-24 
Inclusion  criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Clinical characteristics 
X 
 
 
 
 
HIV infection details 
X 
 
 
 
 
Biological testing 
• 
Standard 
• 
Specialized 
 
X 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Radiology testing 
X 
X 
 
 
 
Treatment  
(prophylaxis, ART) 
X 
 
X 
X 
X 
Outcomes 
(AIDS, Death, LTFU) 
 
 
X 
X 
X 
STUDY FOLLOW-UP 
 27 
 
15. Corticosteroids and Strongyloides stercoralis 
The corticosteroids have a particular and specific association 
with the development of hyperinfection syndrome and dissemi-
nation due to Strongyloides stercoralis in PLHIV and in IRIS.  
Hyperinfection syndrome has been described regardless of 
dose, duration, or route of administration of corticosteroids. 
Even short courses (6–17 days) of steroids in immunocompe-
tent patients without underlying immunosuppressive conditions 
have even been associated with hyperinfection syndrome and 
death. 
Therefore a preventive treatment of Strongyloides stercoralis is 
recommended in case of corticosteroid use, as follow:  
Albendazole 
400mg, orally, BD, for 3 days 
 
 

 26 
14.  Immune Reconstitution Inflammatory Syn-
drome (IRIS)  
This is a condition that can occur shortly after a person starts 
HIV therapy for the first time. It occurs in 10–30% of patients ini-
tiating ART, usually within first 4–8 weeks but can occur up to 
six months.  
The possible risk factors for IRIS are as shown below:  
• 
People with CD4 counts below 100 before starting therapy;  
• 
People with greater drops in HIV viral load due to therapy; 
• 
People with diagnosis of another infection before 
starting 
therapy, the closer the appearance or diagnosis is to start-
ing therapy, the higher the risk; 
• 
Severity of TB disease, especially high pathogen burden, 
and less than 30-day interval between initiation of TB and 
HIV treatment.  
 
IRIS is generally self-limiting and interruption of ART is rarely 
indicated, but people may need to be reassured in the face of 
protracted symptoms to prevent discontinuation of, or poor ad-
herence to, ART. 
Decrease immune response by:  
Corticosteroids  
1 to 2 mg/kg usually for 1 to 2 weeks, decreased by 50% 
over the next 2 weeks (sometimes up to 12 weeks). 
1 
Continue HAART and OI therapy + steroids 
2 
Treatment of OI for standard period or longer 
3 
 5 
1. 
Baseline tests, essential for all patient registe-
ring in HIV care  
Some tests must be performed for every patient at the time of 
HIV-infection diagnosis. The purpose is to rule out concomitant 
infections, Opportunistic Infections (OIs) and determine baseline 
safety parameters. 
STANDARD BIOLOGY 
TC, DC, ESR, Hb, Platelets 
ALT/SGPT, if needed, LFT (Liver function test) 
Blood urea, Serum creatinine and if needed, kidney function test 
(Electrolytes  - sodium, potassium) 
Urine analysis to assess for proteinuria 
Urine pregnancy test as indicated in female 
Blood sugar level 
ADVANCED BIOLOGY 
Hepatitis B serology (HbS Antigen) 
Hepatits C serology (IgG) 
VDRL titer 
Toxoplasmosis IgG, CMV IgG if CD4<350/mm3 
CD4 cell/count  
Sputum GeneXpert if TB symptoms. If GeneXpert not available, 
Sputum AFB for TB 
RADIOLOGY 
Chest-X-Ray 
Some additional tests might be done as per physician’s decision 
depending on clinical presentation, to rule out OIs (eg. USG ab-
domen, lumbar puncture, etc). 

 6 
2. 
Screen for TB 
Screening for TB is essential since it is a very common OI that 
can be revealed by HIV-infection, or be unmasked by ART     
initiation. 
TB screening has to be done at baseline, within 3 days after the 
first visit and every month until stabilized HIV-infection. It relies 
on asking systematic questions to the patient:  
• 
Cough? 
• 
Night sweats? 
• 
Weight loss? 
• 
Fever? 
 
3. 
When to start ART ? 
ART should be initiated in all adults living with HIV, regardless 
of WHO clinical stage and CD4 count. 
The actual « test and treat » strategy implies that every patient 
newly diagnosed with an HIV-infection should be rapidly initiated 
on ART after serology result disclosure except in case of sus-
pected or active OIs. 
Two situations may be encountered:  
1– patient without suspicion or active OI: initiate ART within 7 
days after HIV serology disclosure 
2– patient with suspicion or active OI: differ initiation of ART by 
15 days after OI treatment starting date (4 to 6 weeks in crypto-
coccal meningitis) 
This situations are summarized in the table on the next page. 
  
If yes to any question for TB: CXR + Sputum GeneXpert 
 25 
 
Cryptococcal therapy 
Step 1: Induction phase 
2 weeks until CSF sterile, followed by consolidation phase 
Repeated Lumbar Puncture 
(decrease intra-cranial pressure) 
Preferred therapy 
 
• 
Amphotericin B, IV  
0.7 to 1mg/kg/day 
• 
Flucytosine, PO  
25mg/kg/ 6 hours 
Alternative therapy - 1 
• 
Amphotericin B, IV  
0.7 to 1mg/kg/day 
• 
Fluconazole  
800mg/day, IV or PO 
Alternative therapy - 2 
• 
Flucytosine, PO  
25mg/kg/ 6 hours 
• 
Fluconazole , IV or PO 
800mg/day 
Alternative therapy - 3 
• 
Fluconazole , IV or PO 
1200mg/day 
Creatinine clearance should be monitored 
Step 2: Consolidation phase 
8 weeks, followed by maintenance phase 
Preferred therapy 
Alternative therapy 
Fluconazole 400mg/day if pre-
ferred therapy during induc-
tion phase 
Fluconazole 800mg/day if any 
alternative therapy during induc-
tion phase 
Step 3: Maintenance phase 
At least one year 
Fluconazole 200mg/day 

 24 
CM treatment is detailed on the next page.  
It is important to notice that corticosteroids and mannitol are 
ineffective to decrease intracranial pressure; therefore they are 
not recommended for the management of CM. The principal in-
tervention in patients with symptomatic raised Intra-Cranial 
Pressure (ICP) is repeated Lumbar Puncture (LP):, as follow:  
ART should be started  
• 
After the patient stabilizes to avoid severe IRIS,  
Usually after 4 weeks of induction and consolidated treatment 
with amphotericin B–containing regimens combined with flucy-
tosine or fluconazole.  
Focal sign 
LP contra-indicated 
CT scan first 
No Focal sign 
Perform a first LP 
CSF Pressure 
 
<20 mmHg or  
<25 mmHg without Headaches No depletion 
20—24 mmHg + Headaches 
Depletion 30 mL 
25—34 mmHg 
Depletion 30 mL 
Control LP after 48H 
≥ 35 mmHg 
Depletion 30 mL 
Control LP after 24H 
Repeat LP to confirm clearance of infection is not necessary in 
patients with clinical improvement by 2 weeks of treatment.  
A repeated LP may be necessary if new symptoms develop in 
patients after 2 weeks of treatment; ICP should be assessed 
and India ink stain repeated on the CSF. Patients failing fluco-
nazole therapy should be treated with amphotericin. Repeated 
CSF CrAg is not indicated (positive for months). 
 7 
Opportunistic infection 
 
Not suspected 
Suspected  
OR  
Active 
ART  
Rapid ART Initia-
tion (same day/ 
within a week 
time) 
Delay  
Initiation 
15 days to 6 weeks  
according to type of OI 
Investigation for OI 
According to  
CD4 count 
Yes, systematic 
Prophylaxis 
Immediate  
initiation, as follow 
Initiation  
as follow while  
screening for OI  
CPT  
CD4<350/mm3  
CD4<350/mm3 
High dose of  
Cotrimoxazole if suspicion of 
PCP / Toxoplasmosis 
IPT  
All patients 
All patients 
ATT if suspicion of TB 
Fluconazole  
CD4<100/mm3 
AND 
Positive blood  
Cryptococcal Ag  
CD4<100/mm3 
AND 
Positive blood  
Cryptococcal Ag 
Amphotericin B + Flucytosine 
if suspicion of Cryptococcal 
meningitis 

 8 
4. 
What to start  - 1st Line of treatment? 
Except for some special conditions, the first line of treatment re-
commended is the same for adults, pregnant or breastfeeding 
women, and adolescents. 
FIXED DOSE COMBINATION IN A SINGLE PILL  
TENOFOVIR 
(TDF) 
LAMIVUDINE (3TC) 
OR 
EMTRICITABINE (FTC) 
EFAVIRENZ 
(EFV) 
 
5. 
TDF + 3TC/FTC + EFV toxicities? 
3TC and FTC are less at risk of toxicities.  
Efavirenz—EFV  
Central nervous system toxicity (dizziness, insomnia, 
abnormal dreams) or Mental symptoms (anxiety, de-
pression, mental confusion) 
Convulsions 
Hepatotoxicity 
Hypersensitivity reaction, Stevens—Johnson 
Drug interaction with Daclatasvir (HepC treatment) 
Tenofovir—TDF 
Chronic kidney disease 
Acute kidney injury 
Fanconi syndrome 
Dicrease in bone mineral density 
Lactic acidosis or severe hepatomegaly with steatosis 
 23 
MENINGITIS 
STEP 1: Take history and examination 
Meningitis  
symptoms present 
Meningitis  
symptoms absent 
Lumbar puncture 
CD4 <100 
Blood CrAg 
— 
Headache / Confusion / Neck stiffness and  
Photophobia / Impaired consciousness, Coma? 
STEP 2: Screen for Meningitis 
CSF Microscopy 
CSF CrAg 
CSF GeneXpert 
+ 
CSF CrAg 
Positive 
CSF CrAg 
Negative 
CSF Xpert 
Positive 
Blood Toxo  
IgG Positive 
START 
Crypto Treatment 
START 
Crypto  
Pre-emptive 
Treatment 
START 
ATT 
+ 
Steroids 
Head CT 
+/-
Cotrimoxazole 
Full-dose 
 
 
 
 

 22 
13. Cryptococcal Meningitis (CM) 
Cryptococcal disease in HIV infected patients is caused by 
Cryptococcus neoformans, a yeast-like fungus.  
The incidence of cryptococcal meningitis increases in patient 
with CD4 <100 cells/mm3, and most cases occurs when CD4 
<50 cells/mm3.  
Cryptococcal disease presentation in PLHIV, is: 
• 
Sub-acute meningitis or meningo-encephalitis with  
• 
Fever,  
• 
Malaise,  
• 
Headache,  
• 
Neck stiffness and photophobia, 
• 
Altered mental status/confusion,  
• 
Personality changes, memory loss, 
• 
Impaired consciousness and coma,  
• 
Focal signs, including cranial nerve palsies. 
 
Diagnosis relies on two components: 
1- Blood cryptococcal antigen (Cr Ag): it has to be carried out in 
patient with CD4 <100 cells/mm3 and no symptoms of CM. 
2- CSF analysis after performing a lumbar puncture: 
• 
CSF opening pressure (usually >200 mm H2O) 
• 
CSF CrAg (more sensitive than indian ink) 
• 
Indian ink needs to be performed if CSF CrAg is not avai-
lable 
• 
Fungal culture if available 
 
The screening algorithm for meningitis including cryptococcal 
meningitis is detailed on the next page. 
 9 
6. 
Viral load and CD4 monitoring  
CD4 count has to be carried out at baseline, at 6th month, at 12th 
month and every 6 months thereafter until virologicaly suppres-
sed. 
Viral load monitoring can be carried out at 6th month, at 12th 
month and every 12 months thereafter if the patient is undetec-
table. 
 
7. 
Treatment / virological failure 
HIV viral load is the preferred monitoring approach to diagnose 
and confirm treatment failure. 
Treatment failure is defined by a persistently detectable viral 
load exceeding 1000 copies/mL measured on two different 
samples within a 3-months interval and at least 6 months after 
starting a new ART regimen.  
In case of a first positive viral load: viral load as to be re-
peated 3-months after. 
VL-1  
>1000 cp/mL 
VL-2  
>1000 cp/mL 
3 months 
Virological failure 
ART 

 10 
8. 
Second line of treatment 
The second line of treatment is mostly based on protease-
inhibitors (PI) containing regimen. 
Active TB and Anti-Tuberculosis Treatment (ATT) intake can be 
a challenging situation will being on a PI-based regimen.  
In case of ATT without Rifabutin available, Raltegravir-based 
regimen might be used. 
The different options are displayed in the following table. 
ART: second line  
Without ATT 
Switch EFV to: 
 
Atazanavir / ritonavir — ATV / r 
Lopinavir / ritonavir — LPV / r 
With ATT 
Switch EFV to: 
Rifabutin available 
Atazanavir / ritonavir — ATV / r 
Lopinavir / ritonavir — LPV / r 
Rifabutin not available 
Raltegravir — RAL 
LPV / r, double dose  
LPV 800mg/200mg twice daily 
 21 
Pneumocystosis and Toxosplamosis  
Induction therapy 
Cotrimoxazole IV 
TMP 15 to 20 mg/kg/day 
SMX 75 to 100 mg/kgday 
Given q6h or q8h  
Switch to PO after clinical improvement 
Pneumocystosis 
Adjunctive Corticosteroids :(moderate to 
severe PCP) - PREDNISONE 
- Day 1 to 5: 40 mg, PO, BID 
- Day 6 to 10: 40 mg, PO, QD 
- Day 11 to 21: 20mg, PO, QD 
 
Induction duration = 21 days 
Induction duration = at least 6 weeks 
Toxoplasmosis  
Followed by chronic maintenance therapy: 
TMP-SMX (160 TMP/800 SMX) DS  
 1 tablet BID 6 weeks 
 
Until CD4>200 cells/mm3 for more than 6 
months after ART start. Then switch to CPT. 
The treatment of TE and PCP is detailed in the table below. 

 20 
In the absence of treatment, disease progression results in 
seizures, stupor, coma, and death.  
Retinochoroiditis, pneumonia, and evidence of other multifocal 
organ system involvement can occur but are rare in patients 
with AIDS. 
CT scan or MRI of the brain will typically show  
• 
Multiple contrast-enhancing lesions in the grey matter of 
the cortex or basal ganglia,  
• 
Often with associated edema. 
 
TE treatment is detailed on the next page. 
Note that after induction phase, chronic maintenance therapy is 
necessary. It can be stopped in patients that have successfully 
completed initial therapy for TE, remain asymptomatic with re-
gard to signs and symptoms of TE, and have an increase in 
their CD4 counts to >200 cells/mm3 after ART that is sustained 
for more than 6 months.  After stopping chronic maintenance 
therapy, CPT must be introduced. 
 
Induction therapy, 6 weeks 
Cotrimoxazole IV 
TMP 15 to 20 mg/kg/day + SMX 75 to 100 mg/kgday 
Given q6h or q8h  
Switch to PO after clinical improvement 
Chronic maintenance therapy, usually 6 weeks 
TMP-SMX (160 TMP/800 SMX) DS 1 tablet BID 
CPT 
TMP-SMX (160 TMP/800 SMX) DS 1 tablet daily 
 11 
 9. 
Prophylaxis and Pre-emptive therapies 
OIs are the most important cause of morbidity and mortality in 
PLHIV. 
Cotrimoxazole (TMP/SMX) prophylaxis is effective against 
common bacterial infections, diarrhoea (including Isospora bel-
li), Malaria, Toxoplamosis (primary or recurrent), Pneumocystis 
pneumonia (PCP, primary or recurrent). In case of intolerance, 
Dapsone or desensitization to TMP/SMX might be used. 
CD4<350/mm3 
± WHO stage  + 
No suspicion  
Isoniazid Preventive Therapy (IPT) is used in individuals with 
latent TB infection, regardless of CD4 count or ART status. After 
screening and exclusion for active TB, IPT should be proposed 
to all  patients for 6 months. 
Fluconazole is a drug of choice for treatment of candidiasis 
and pre-emptive therapy of cryptococcal meningitis. It should 
be proposed in all patients with CD4 count <100/mm3  with po-
sitive blood cryptococcocal antigen (Cr Ag) after excluding po-
sitivity of Cr Ag in the cerebro spinal fluid (CSF). 
All patients 
+ 
No suspicion  
CD4<100/mm3 
+ 
Blood CrAg 
positive 
+ 
CSF CrAg  
negative 

 12 
Preventive / Pre-emptive therapies dosages 
Cotrimoxazole (TMP/SMX) 
• 
CD4 <350 cells/mm3 
• 
WHO stage 3 / 4 
One DS tablet 
(160TMP/800SMX) per day 
————————— 
Two SS tablets  
(80TMP/400SMX) per day 
Continue until evidence of stable on ART with evidence of immune recovery 
and viral suppression  
IPT 
• 
Isoniazid 
• 
Vitamin B6 (Pyridoxine) 
For 6 months: 
• 
300mg per day 
• 
25mg per day 
Avoid IPT if liver disease, active alcohol use, jaundice, habitual treatment 
defaulter, prior Isoniazid resistance, peripheral neuropathy. 
Fluconazole  
(cryptococcal pre-emptive) 
Initial: 
800mg per day for 2 weeks, 
400mg per day for 8 weeks, 
Maintenance: 
200mg per day 
Continue for at least one year: 
• 
If no viral load monitoring: until CD4≥200 cell/mm3, two times 6  
          months apart. 
• 
If viral load monitoring: until CD4≥100 cell/mm3, two times 6 months 
apart, AND viral suppressed viral load. 
 Preventive and pre-emptive therapies dosasges are sum-
marized in the following table 
 19 
TMP/SMX is the treatment of choice for PCP. Patients with mo-
derate-to-severe PCP should received corticosteroids as early 
as possible. It is detailed in the table of treatment recommended 
for PCP and Toxoplasmosis.  
ART initiation:  within 2 weeks of PCP diagnosis and 
treatment.  
Secondary PCP prophylaxis with TMP/SMX should be initiated 
immediatly upon successful completion of therapy. 
12. Toxoplasmic encephalitis (TE) 
A low incidence of toxoplasmosis is seen in patients who are 
seronegative for T. gondii. Most Toxoplasmosis cases are reac-
tivation of latent disease in individuals seropositive for T. gondii. 
Clinical disease is rare among patients with CD4 cell counts 
>200 cells/mm3. 
Clinical presentation of T. gondii infection is: 
• 
Focal encephalitis with headache,  
• 
Confusion, or motor weakness 
• 
Fever 
 
Patients may also present with non-focal manifestations, inclu-
ding: 
• 
Non-specific headache  
• 
Psychiatric symptoms.  
 
TE diagnosis is often presumptive and requires 3 conditions: 
Positive  
T. gondii IgG 
+ 
Compatible 
Clinical symptoms 
+ 
Compatible 
Imaging 

 18 
Thorax CT indications 
STEP 2: Chest-X-ray AND CD4 <350/mm3 
No lesion  
OR 
Any atypical lesion 
Typical lesion 
STEP 1: Presence of respiratory symptoms 
STOP 
Thorax CT 
Head CT indications 
STEP 2: Focal signs or seriously ill (WHO 
stage 3 to 4) 
Yes 
No 
STEP 1: Presence of neurological symptoms 
Lumbar Puncture 
Head CT 
Dypnoea, TB symptoms ? 
 13 
10. Active Tuberculosis (TB) 
All patients with active TB should be initiated on ATT immedia-
tly.  
ART should be started regardless of CD4 count, even in pa-
tients with drug-resistant TB.  
ATT should be initiated first, followed by ART as soon as pos-
sible within the first 8 weeks of treatment (2 weeks if CD4<50 
cells). 
IRIS may occur after initiation of ART. Both ART and ATT 
should be continued while managing IRIS (Cf. IRIS part) 
Tuberculosis screening algorithm is available on next page. 
Hepatotoxicity is frequent during ATT and has to be managed 
as follow:  
Transaminases 
x ULN 
No symptoms 
Symptoms  
(nausea, vomiting, ab-
dominal pain, jaundice) 
1.25 to 2.5  
(grade 1) 
No change 
No change 
2.5 to 5  
(grade 2) 
• 
Continue ATT 
• 
Check ALT at 
next visit 
Discontinue ATT 
5 to 10  
(grade 3) 
Discontinue ATT 
Discontinue:  
• 
ATT 
• 
EFV or RAL 
• 
Cotrimoxazole 
> 10 
(grade 4) 
Discontinue all drugs 
Discontinue all drugs 

 14 
Cough / Night sweat / Fever / Weight loss?
STEP 2: Screen for TB symptoms 
TB symptoms present 
TB symptoms absent 
START IPT 
STEP 1: Take history and examination 
CD4 <100 
CD4 >100 or unvailable 
Sputum Xpert 
Sputum Xpert 
LF-LAM 
LF-LAM if seriouly ill 
Positive for TB  
Or 
High TB suspicion 
Negative for TB 
START ATT 
START IPT 
TUBERCULOSIS 
 17 
11. Pneumocystis Pneumonia (PCP) 
The most common clinical manifestations of PCP are  
• 
Subacute onset of progressive dyspnea 
• 
Fever, 
• 
Non-productive cough,  
• 
and chest discomfort that worsens within days to weeks.  
 
Hypoxemia, can range from  
Thorax CT-scan 
Very sensitive 
High negative predictive value 
Induced sputum 
50 to 90% 
Bronchoalveolar lavage (BAL) 
90 to 99% 
LDH dosage 
Expected to be >500 UI 
Chest radiograph:  
• 
Diffuse, bilateral, symmetrical “ground-glass” interstitial 
infiltrates emanating from the hila in a butterfly pattern.   
• 
Chest-X-ray may be normal in patients with early di-
sease.  
 
Thin-section computed tomography (CT) is a useful adjunc-
tive test, since CT scan will be abnormal, demonstrating 
“ground-glass” attenuation that may be patchy, while a normal 
CT has a high negative predictive value. 
Additional diagnostic tests are listed below:  
Mild 
Moderate 
Severe 
 
>70 mmHg 
 
<45 mmHg 
PaO2 
SpO2 
>90% 
 
 

 16 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Ethambutol 
15-20mg/kg 15-20mg/kg 
15-20mg/kg 
15-20mg/kg 
15-20mg/kg 
Rifampicin 
10mg/kg 
10mg/kg 
10mg/kg 
10mg/kg 
10mg/kg 
Isoniazide 
 
5mg/kg 
5mg/kg 
5mg/kg 
5mg/kg 
Pyrazinamide 
 
 
(25-35mg/kg)* 
(25-35mg/kg)* 
(25-35mg/kg)* 
TDF-3TC 
Stop after 
Week 1 
 
 
300/300mg 
300/300mg 
EFV or RAL 
 
 
 
600 QD (EFV)  
600 QD (EFV)  
TMP/SMX 
 
 
 
 
Reintroduce 
* Do not reintroduce Pyrazinamide in case of Grade 4 hepatotoxicity. 
 15 
Additional monitoring is required for patients experiencing Hepa-
totoxicity. The following table presents the additional measures 
requested according to the severity of the Hepatotoxicity: 
Grade 1  
Check drug dosage according to patient 
weight  
Grade 2 
Grade 3 
5 to 10  x ULN 
If EFV is discontinued:  
Continue TDF and 3TC for 2 weeks.  
 
Check ALT  weekly. 
 
When ALT <2.5 and symtoms resolves:  
Re-introduce drugs as in the following table. 
Grade 4 
 
> 10 x ULN 
Check ALT twice a week 
For patient experiencing Grade 3+ Hepatotoxicity we recom-
mend to comply with the scheme presented in the following 
page and summarizing how to reintroduce ATT, ARV and CPT.