HIV in Children

DR HARDIK SHAH ST. STEPHEN’S HOSPITAL,DELHI

ETIOLOGY

HIV 1 and HIV 2 belong to Genus – Lentivirus Family – Retroviridae HIV 1 contains 2 copies of SS-RNA At both ends of the genome there are

identical regions called long terminal repeats It contains regulation and expression genes

for HIV The remainder of the genome includes 3

major sections 1. GAG region : encodes viral core proteins

I(p24,p17,p9,&p6)

2. POL region :encodes viral enzymes ( reverse transcriptase(p51), protease (p10),integrase (p32))

3. ENV region : encodes the viral envelope proteins (gp120, gp41)

Gp120 glycoprotein carries binding site for CD4 molecule which is the most common host cell surface receptor of T lymphoctes

STRUCTURE OF HIV

LIFE CYCLE

HIV 2 has a similar life cycle to HIV 1 It is known to cause infection in

several monkey species HIV 2 differs from HIV 1 in accesory

genes

TRANSMISSION

Primary route of infection in the pediatric population is vertical transmission accounting for almost all new cases

Vertical transmission can occur Intrauterine Intrapartum Through breast fedding • 30-40% of the infected newborns are infected in utero • Intrauterine infection has been suggested by

identification of HIV by culture or PCR in fetal tissue as early as 10 weeks

• Children infected in the intrauterine period have positive viral culture or PCR in the 1 st wk of life

60-70% acquire infection in the intrapartum period

The mechanism of transmission is exposure to infected cervicovaginal secretions and blood in the birth canal

Breast feeding is responsible for 40% of perinatal transmission in resource limited countries

The risk of transmission through breast feeding in chronically infected women is appx 9to 16% but 29-53% in women who acquire HIV postnatally

Several risk factors influence the rate of vertical transmission

Preterm delivery (<34 weeks gestation )

A low maternal antenatal CD4 count Use of recreational drugs during

pregnancy > 4 hr duration of Ruptured

membranes Birthweight < 2500gm doubles the transmission rate

Elective ceaserean section decreases the transmission rate by 87% if used in conjunction with zidovudine in infant and mother

In USA it is recommended to consider Cesearean section if the viral load is > 1,000 copies / ml

Transfusion of infected blood or blood products has been accounted for 3-6 % of all pediatric AIDS cases

Sexual contact is a major route of transmission in adolescent population accountig for most of the cases

CLINICAL MANIFESTATIONS

HIV classification is used to categorise the stage of pediatric disease by 2 parameters : clinical classification and immunological parameters

IMMUNOLOGICAL CLASSIFICATION

Normal CD4 count/% in children are:A. <12 months: >1500 cells/mm3

( >= 25%)B.1-5 years: >1000 cells/mm3 (>=

25%)C. > 6 years: >500 cells/mm3

DIAGNOSIS IN CHILDREN < 18 MONTHS

Maternal antibody persists for as long as 18 months

Breast feeding poses an ongoing risk for infection

HIV infection can only be excluded after breast-feeding is stopped for > 6 weeks.

In India, antibody tests and ELISA can be used for infants > 18 months as per adults; and for infants < 18 months, DNA PCR will be done using dried blood spots (DBS).

There are two ways to exclude HIV infection in infants and children:

1. A child has negative virologic test result and > 6 weeks after complete cessation of breastfeeding.

HIV- DNA PCR can be done ideally at age 6–8 weeks to exclude HIV infection acquired during delivery. The infection can only be ruled out by DNA PCR test done at more than 6 weeks after stopping breast-feeding.

2. A child has negative HIV antibody test resultat ≥ 18 months of age if not breast-feeding and more than 6 weeks after complete cessation ofbreast-feeding.

A child who has negative HIV antibody test result at the age of ≥ 9 months and at least 6 weeks after complete cessation of breastfeeding is HIV-uninfected. Confirm by repeat HIV antibody testing at 18 months.

A report of “HIV Positive” is given when 2 PCR tests are positive; and a report of “HIV negative” is given when 2 PCR tests are negative.

DIAGNOSIS IN CHILDREN > 18 MONTHS

For symptomatic children: the sample should be reactive with two different kits.

For asymptomatic children : the sample should be reactive with three different kits

The blood sample collected at one time is tested with the 1st kit, and if reactive, retested sequentially with the 2nd and 3rd kits depending on the clinical status of the child.

Presumptive diagnosis where no testing is available

If the child is < 18 months and has symptoms and signs that are suggestive of HIV infection and there is no virologic testing available, it is possible to make a presumptive diagnosis by addressing the following issues:

Is there evidence of HIV exposure mother or baby’s serology is HIV positive?

Is there evidence of immuno-suppression (low CD4 count/%) and symptoms or illness

consistent with HIV infection? Does the child meet the clinical criteria for

presumptive diagnosis of severe HIV infection?

When to start antiretroviral therapy in infants and children

Infants1. I nitiate ART for all HIV-infected infants diagnosed in the firsst

year of life, irrespective of CD4 count or WHO clinical stage.Children

1. Initiate ART for all HIV-infected children between 12 and 24 months of age irrespective of CD4 count or WHO clinical stage

2. Initiate ART for all HIV-infected children between 24 and 59 months of age with CD4 count of ≤750 cells/mm3 or %CD4+ ≤25, whichever is lower, irrespective of WHO clinical stage.

3. Initiate ART for all HIV-infected children more than 5 years of age with a CD4 count of ≤350 cells/mm3 (as in adults), irrespective of WHO clinical stage.

4. Initiate ART for all HIV-infected children with WHO clinical stages 3 and 4, irrespective of CD4 count.

5. Initiate ART for any child less than 18 months of age who has been given a presumptive clinical diagnosis of HIV infection.

Classification of ART

NRTI: Zidovudine (ZDV, AZT) Didanosine (ddI) Zalcitabine (ddC)Stavudine (d4T)Lamivudine (3TC) Abacavir (ABC)Emtricitabine 

NNRTI: Nevirapine (NVP)Delavirdine (DLV)Efavirenz (EFZ): PI: RitonavirIndinavirNelfinavirSaquinavir Atazanavir (ATV)Fos-amprenavir (FPV)Darunavir (DRV)Lopinavir

RATIONALE OF COMBINATION THERAPY

To prevent drug resistance To act at different points of the life

cycle and to achieve maximal suppression of the viral replication

NRTI: inhibit viral DNA synthesis Thymidine analogs (Stavudine and

Zidovudine ): inhibit atively proliferating virus

Non Thymidine (Didanosine , lamivudine)Act on resting virus NNRTI attach to the reverse transcriptase:

inhibit its activity PI : prevent viral proteins to form an

assembely Thus the combination therapy includes aa thymidine analog + a non thymidine

analog to inhibit active and resting cells and a PI or NNRTI to produce prolong viral suppresion

What to start

The use of three ARV medications is the current standard treatment for HIV infection, in order to achieve the best possible suppression of viral replication and to arrest the progression of HIV disease

Standard regimen for 1 st line Art therapy is 2 NRTI + 1NNRTI

What to start

Infants1. For infants not exposed to ARVs, start

ART with nevirapine (NVP) + 2 nucleoside reverse transcriptase inhibitors (NRTIs).

2. For infants exposed to maternal or infant NVP or other NNRTIs used for maternal treatment or PMTCT, start ART with lopinavir/ritonavir (LPV/r) + 2 NRTIs.

3. For infants whose exposure to ARVs is unknown, start ART with NVP + 2 NRTIs.

Children1. For children between 12 and 24 months of age exposed

to maternal or infant NVP or other NNRTIs used for maternal treatment or PMTCT, start ART with lopinavir/ritonavir (LPV/r) + 2 NRTIs.

2. For children between 12 and 24 months of age not exposed to NNRTIs, start ART with NVP + 2 NRTIs.

3. For children more than 24 months and less than 3 years of age start ART with NVP + 2 NRTIs.

4. For children 3 years of age and older, start ART with NVP or efavirenz (EFV)-containing regimen + 2 NRTIs.

5. For infants and children, the nucleoside backbone for an ART regimen should be one of the following, in preferential order:

Lamivudine (3TC) + zidovudine (AZT) or 3TC + abacavir (ABC) or 3TC + stavudine (d4T)

Infants and children with special conditions1. For children more than 3 years of age with

tuberculosis (TB), the preferred regimen is EFV + 2 NRTIs.

2. For infants and children less than 3 years of age with TB, the preferred regimens are NVP + 2 NRTIs or a triple nucleoside regimen.

3. For a child or adolescent with severe anaemia (<7.5 g/dl) or severe neutropenia (<0.5/mm3), the preferred regimen is NVP + 2 NRTIs (avoid AZT).

4. For adolescents more than 12 years of age with hepatitis B, the preferred regimen is tenofovir (TDF) + emtricitabine (FTC) or 3TC + NNRTI

CHOICE OF 1 st LINE REGIMEN

EFV is not currently recommended for children <3 years of age or < 10kg

Should be avoided in post-pubertal adolescent girls who are either in 1st trimester of pregnancy or are sexually active and not receiving adequate contraception.

EFV is used to substitute NPV when anti-tuberculous treatment has to be provided concomitantly. However, after 2 weeks of completion of ATT, EFV should be switched back to NVP.

Routine Monitoring of children on ART

CD4 Monitoring 1. CD4 should be measured at the time of diagnosis of

HIV infection, and every 6 months thereafter. Monitor with increasing frequency as CD4 count approaches threshold for starting ART.

2. CD4 should be measured prior to initiating ART.3. CD4 should be measured every 6 months after

initiating ART.4. Measure CD4 if new clinical staging events develop,

including growth faltering and neurodevelopmental delay.

5. Where capacity for CD4 measurement is limited, target the use of CD4 monitoring to assess the significance of clinical events.

Viral Load Monitoring

1. VL determination is desirable, but not essential, prior to initiating ART.

2. VL should be assessed to confirm clinical or immunological failure where possible, prior to switching treatment regimen. viral load should be used whenever possible to confirm suspected clinical or immunological failure.

3.Where available, viral load should be assessed at six months

4. Failure to suppress the viral load to below 5 000 copies/ml in an adherent child at this time warrants switching to a PI-based regimen

Routine clinical and laboratory monitoring1. Baseline haemoglobin level (and white cell count, if

available) should be assessed at initiation of ART.2. For infants and children, measure haemoglobin at

week 8 after initiation of AZT-containing regimens, or more frequently if symptoms indicate.

3. Growth, development and nutrition should be monitored monthly.

4. Laboratory monitoring for toxicity should be symptom directed.

The inability to perform laboratory monitoring, notably for CD4 or viral load, should not prevent children from receiving ART.

Once an infant or child is on ART, the frequency of clinical monitoring will depend on their response to ART. At a minimum, after starting ART, follow-up visits should occur:

• for infants, at weeks 2, 4, 8, and then every 4 weeks for the first year

• for children, at weeks 2, 4, 8, 12, and then every 2 to 3 months once the child has stabilized on therapy.

Key signs of an infant’s and child’s response to ART include:

• improvement in growth in infants and children who have been failing to grow

• improvement in neurological symptoms and development in children with encephalopathy or those who have demonstrated delay in the achievement of developmental milestones

• decreased frequency of infections (bacterial infections, oral thrush and/or other OIs).

ARV Toxicity

The most common toxicities include the following: Haematological: drug-induced bone-marrow suppression,

most commonly seen with AZT (anaemia, neutropenia and, more rarely, thrombocytopenia).

Mitochondrial dysfunction: primarily seen with the NRTI drugs and include lactic acidosis, hepatic toxicity, pancreatitis and peripheral neuropathy. The NRTIs differ in their ability to affect mitochon-drial function: d4T and ddI are worse than AZT; 3TC and ABC have the least toxicity of all.

Lipodystrophy and other metabolic abnormalities: primarily seen with d4T and the PI class, and to a lesser degree with other NRTI drugs. Abnormalities include fat maldistribution and body habitus changes, hyperlipidaemia, hyperglycaemia, insulin resistance, diabetes mellitus, osteopaenia, osteo-porosis and osteonecrosis.

Allergic reactions: including skin rashes and hypersensitivity reactions. These are more common with the NNRTI drugs, but also seen with certain NRTI drugs, such as ABC.

Because of the risk of potentially life-threatening hepatotoxicity associated with NVP, hepatic dysfunction of any etiology in a child on NVP requires careful consideration of whether NVP should be discontinued

COTRIMOXAZOLE PROPHYLAXIS

PREGNANCY AND HIV

For HIV-infected pregnant women, the initiation of ART for their own health is recommended for all women who have CD4 cell counts of ≤350 cells/mm3, irrespective of WHO clinical staging, and for all women in WHO clinical stage 3 or 4, irrespective of the CD4 cell count.

IMMUNISATION

HIV and TB

DIAGNOSIS Suspect TB if the child has:1.Contact with adult who has pulmonary

TB2. Fever and/or cough for more than 3

weeks3.With or without weight loss or

poor/no weight gain. 4. Pneumonia not responding to antibiotics5. Recent glandular enlargement

Clinical features Pulmonary TB: May be non-specific symptoms such as

fever, weight loss, failure to thrive and cough. Features of presentation in HIV infected children are similar to those among non-HIV infection.

Young children present with localized pulmonary infiltrates with hilar adenopathy. 25% of children may have more than 1 lobe involved. Middle lobe collapse and consolidation may result due to endobronchial tuberculosis.

Older children and adolescents may present with cavitatory tuberculosis.

Extrapulmonary TB: Common sites involved are lymph nodes, Disseminated TB, CNS TB, Bone TB and TB of the serosal surfaces.

Investigations Mantoux test / MT (Tuberculin test):- Can be

done from 3 months onwards using 5 TU PPD injected intradermally. Induration more than 5 mm is considered positive in HIV infected children.

Gastric lavage/ sputum examination: Three consecutive morning gastric aspirates have a better yield than a single sample. Better diagnostic yield is seen on culture.

Other fluids and tissues for culture: Bronchoalveolar lavage (BAL), lung biopsy, lymph node biopsy, serosal fluids and CSF. Specimens should be cultured for 2-6 weeks by radiometric culture methods (Bactec) or culture on L-J medium for 8 weeks.

Chest X-ray: Localized pulmonary infiltrates with hilar

adenopathy Middle lobe collapse and consolidation Pleural effusion In older children – cavitatory tuberculosis. PCR assays are not useful as primary diagnostic

tool because a negative PCR does not rule out TB and a positive result does not absolutely confirm M.tuberculosis infection. Also false positive rates are high with sensitivity ranging from 45-83%. Serological tests for TB are not very specific.

Isoniazid preventive therapy. 1. All HIV-infected infants and children exposed to TB

through household contacts, but with no evidence of active disease, should begin isoniazid preventive therapy (IPT).

2.Children living with HIV (>12 months of age and including those previously treated for TB), who are not likely to have active TB and are not known to be exposed to TB, should receive 6 months of IPT as part of a comprehensive package of HIV care.

3. Infants living with HIV, who are unlikely to have active TB and are not known to be exposed, should not receive IPT

4. The recommended dose of isoniazid (INH) for preventive therapy in HIV coinfection is 10 mg/kg daily for 6 months (maximum 300 mg/day).

Infants and children diagnosed with TB and HIV

1. Any child with active TB disease should begin TB treatment immediately, and start ART as soon as tolerated in the first 8 weeks of TB therapy, irrespective of the CD4 count and clinical stage.

2. The preferred first-line ARV regimen for infants and children less than 3 years of age who are taking a rifampicin-containing regimen for TB is 2 NRTIs + NVP or a triple NRTI regimen.

3. The preferred first-line ARV regimen for children more than 3 years of age who are taking a rifampicin-containing regimen for TB is 2 NRTIs + EFV.

4. The preferred first-line ARV regimen for infants and children less than 2 years of age who have been exposed to NVP and are taking a rifampicin-containing regimen for TB is a triple NRTI regimen.

HIV-infected infants and children who develop TB on ART1. For all HIV-infected children, anti-TB therapy should be

started immediately upon the diagnosis of TB; ART should continue.

2. Make adjustments to ART regimens as needed to decrease the potential for toxicities and drug interactions:

• If on a regimen of 2 NRTIs + NVP, substitute EFV for NVP if the child is 3 years or more in age

• If on a regimen of 2 NRTIs + NVP and substitution with EFV is not possible, ensure NVP is dosed at the maximum dose of 200 mg/m2 per dose twice daily

• If on a regimen of LPV/r, consider adding RTV in a 1:1 ratio of LPV: RTV to achieve a full therapeutic dose of LPV.

All HIV-exposed infants and children should benefit from co-trimoxazole preventive therapy

OPPURTUNISTIC INFECTIONS IN HIV