Human Immunodeficiency Virus Infection (HIV)

Introduction

Human Immunodeficiency Virus (HIV) is a retrovirus, which infects primarily CD4 T cells (T helper cells)
Infection leads to a progressive destruction of the immune system with a consequent myriad of opportunistic infections and the development of certain malignancies
Acquired Immuno Deficiency Syndrome (AIDS) is defined as the presence of an AIDS-defining illness (see table 1) with a positive antibody test for HIV

HIV transmission

Sexual transmission through vaginal and anal sex is the commonest route globally and in Nigeria, accounting for about 80%
Transfusion of infected blood and blood products
Use of contaminated instruments; sharing needles, tattooing and occupational exposures
Mother-to-child transmission of HIV: from an infected mother to her baby during pregnancy, at delivery and, after birth through breast-feeding

Clinical Course of HIV Disease:

Acute (Primary) HIV infection: This occurs 1-4 weeks after infection during which infected people experience transient flu-like symptoms, which may include:

Mild fever
Muscle aches and pains
Fatigue
Enlargement of lymph nodes
Sore throat
Fever
Skin rash

This stage is difficult it is difficult to diagnose by standard laboratory assays.

Seroconversion: Usually occurs within 4 weeks.

Patients develop antibody response, which is detectable by a positive HIV Ab test.

Asymptomatic Infection:

The individual feels well despite on-going viral replication.
Usually last a variable amount of time and is marked by a gradual decline in CD4 cell counts.

Early Symptomatic Infection:

Generalized lymphadenopathy
Weight loss
Night sweats
Pruritic skin rash
Unexplained fever
Chronic diarrhea
Oral candidiasis
Oral hairy leukoplakia
Herpes zoster
Pneumococcal infections
Pulmonary tuberculosis

Late Disease/AIDS defining Illness:

This period is marked by the appearance of opportunistic infections and neoplasms

Opportunistic infections:

Pulmonary/extrapulmonary tuberculosis and Disseminated TB
Pneumocytis jiroveci (carinii) pneumonia.
Cryptococcal meningitis
Recurrent bacterial pneumonia
Candida oesophagitis
CNS toxoplasmosis
Kaposi sarcoma
Non-Hodkin’s lymphoma
Disseminated/extrapulmonary coccidiomycosis, crytococcosis or histoplasmosis
Chronic (> 1month) intestinal cryptosporidiosis or isosporiasis
Disseminated extrapulmonary mycobacteria (non-tuberculous)
Progressive multifocal leukoencephalopathy (PML)
Recurrent salmonella septicaemia
HIV wasting syndrome

Staging of HIV/AIDS

WHO Staging System for HIV Infection and Disease in Adults and Adolescents

Clinical Stage I:

Asymptomatic

Generalised lymphadenopathy
Performance scale 1: asymptomatic, normal activity

Clinical Stage II:

Weight loss < 10% of body weight
Minor mucocutaneous manifestations (seborrhoeic dermatitis, prurigo, fungal nail infections, recurrent oral ulcerations, angular cheilitis)
Herpes zoster within the last five years
Recurrent upper respiratory tract infections (i.e. bacterial sinusitis)
And/or performance scale 2: symptomatic, normal activity

Clinical Stage III:

Weight loss > 10% of body weight
Unexplained chronic diarrhoea, > 1 month
Unexplained prolonged fever (intermittent or constant)
>1month Oral candidiasis (thrush)
Oral hairy leucoplakia
Pulmonary tuberculosis within the past year
Severe bacterial infections (i.e. pneumonia, pyomyositis)
And/or performance scale 3: bedridden < 50% of the day during last month

Clinical Stage IV:

HIV wasting syndrome
Pneumocystic carinii pneumonia
Toxoplasmosis of the brain
Cryptosporidiosis with diarrhoea > 1 month
Cryptococcosis, extrapulmonary Cytomegalovirus disease of an organ other than liver, spleen or lymph node (e.g. retinitis)
Herpes simplex virus infection, mucocutaneous (>1month) or visceral
Progressive multifocal leucoencephalopathy
Any disseminated endemic mycosis
Candidiasis of oesophagus, trachea, bronchi
Atypical mycobacteriosis, disseminated or lungs
Non-typhoid salmonella septicaemia
Extrapulmonary tuberculosis
Lymphoma
Kaposi sarcoma 2
HIV encephalopathy
And/or performance scale 4: bedridden > 50% of the day during last month
1: Weight loss of > 10% plus either unexplained chronic diarrhoea > 1 month, or chronic weakness and unexplained prolonged fever > 1 month.
2: Clinical findings of disabling cognitive and/or motor dysfunction interfering with activities of daily living, progression over weeks or months in absence of concurrent illness or condition other than HIV infection that could explain the finding

Differential diagnoses:

Tuberculosis
Malignancies
Diabetes mellitus
Other wasting syndromes

Complications:

Table 1: Complications of HIV disease at different CD4 cells cut-offs.

CD4 count (cells/ mms)	Infectious complications	Non-infectious complications
> 500	Acute HIV, candidal vaginitis	PGL, Guillain-Barre syndrome, myopathy, aseptic meningitis
200 - 500	Pneumococcal and other bacterial pneumonias, pulmonary TB, Herpes zoster, oropharyngeal candidiasis, oral hairy leukoplakia, Kaposi sarcoma	Cervical cancer, anaemia, lymphomas
< 200	Milliary/extrapulmonary TB, pneumocystis carinii pneumonia (PCP), disseminated histoplasmosis anc coccidiomycosis, progressive multifoca leukoencephalopathy (PML)	Wasting, peripheral neuropathy, progressive polyradiculopathy, HIV-associated dementia, cardiomyopathy
< 100	Disseminated herpes simplex, toxoplasmosis, crytococcosis, cryptosporidium, chronic microsporidiosis, and oesophageal candidiasis
< 50	Disseminated cytomegalovirus (CMV), disseminated Mycobacterium avium complex (MAC)	Central nervous system lymphomas

Investigations

Full Blood Count and differentials
VDRL (or RPR)
Tuberculin test (PPD)
Sputum smears for TB Electrolytes,
Urea and Creatinine
Blood glucose
Liver function tests
Lipid studies (fasting trigycerides, LDL, HDL)
HBV, HCV serology
Cervical (PAP) smears
CD4 T cell counts
HIV RNA level (viral load)
HIV DNA (paediatric diagnosis <18 months of age)
Genotype and phenotype assays for resistance testing
Pregnancy assessment, family planning and counselling services, where required

Treatment goals

Clinical: prevent disease progression
Immunological: restore immunity
Virological: control or suppress viral replication
Public health: reduce infectivity

Criteria for initiating ART based on Nigerian ART guidelines

The current national guidelines recommend initiation of ART in all persons testing positive for HIV including children, adolescents, adults, pregnant and breastfeeding women, regardless of clinical and immunological stages of the diseaseDrug treatment

Recommended first-line ART regimens for adults, adolescents, pregnant and breastfeeding women and children.¹

Recommended first-line ARV regimen for ART naïve adults and adolescents

First-line ART

Preferred first-line regimens

Alternative first-line regimen

Adults

TDF + 3TC + DTG

TDF+ 3TC(or FTC)+ EFV

AZT + 3TC + EFV

TDF+3TC(or FTC) +EFV (400mg)

AZT+3TC+NVP

TDF+3TC(or FTC) +NVP

ABC+3TC+DTG

Adolescents (10-19 years)

TDF + 3TC(or FTC) + EFV

TDF+3TC(or FTC) +EFV (400mg)

AZT+3TC+NVPor EFV

ABC+3TC (or FTC) +DTG

ABC+3TC (or FTC) +EFV (400mg)

TDF+3TC(or FTC) +NVP

ABC+3TC (of FTC) +NVP

3 to 10 years

ABC⁺+3TC+DTG,

ABC+3TC+EFV** or

TDF+3TC+DTG(for childrenweighing >30kg)

ABC+3TC+NVP

AZT+3TC+NVP

TDF+3TC(or FTC) +EFV

TDF+3TC(or FTC) +NVP

Children (< 3 years)

ABC + 3TC + LPV/ror

AZT + 3TC + LPV/r

ABC+ 3TC + NVP

AZT + 3TC + NVP

ABC + 3TC + RAL

AZT + 3TC + RAL

Pregnant and breastfeeding women

TDF + 3TC(or FTC)+ EFV

TDF + 3TC + DTG^#

AZT + 3TC + EFV(or NVP)

TDF+ 3TC(or FTC) + NVP

3TC: lamivudine; ABC: abacavir; AZT: zidovudine; DTG: dolutegravir; EFV: efavirenz; LPV/r: lopinavir/ritonavir; NRTI: nucleoside reverse-transcriptase inhibitor; NVP: nevirapine; TDF: tenofovir disoproxil fumarate; RAL: raltegravir.

ABC + 3TC + EFV- may be considered in cases of impaired renal function and osteoporosis (TDF induced or post- menopausal).

Initiation of DTG in pregnancy in ARV naïve pregnant women should be started after the first trimester. Effective contraception should be offered to adult women and adolescent girls of childbearing age or potential. DTG can be prescribed for adult women and adolescent girls of childbearing age or potential who wish to become pregnant or who are not otherwise using or accessing consistent and effective contraception if they have been fully informed of the potential increase in the risk of neural tube defects (at conception and until the end of the first trimester.

*For adolescents with weight > 30 kg, DTG in fixed dose TLD can be used.

**EFV is only indicated for use in children >3 years of age and >10 kg.

+ In case of ABC hypersensitivity reactions, do not ever re-use in-patient.

Dosing schedule for DTG by weight band for children up to 6yrs weighing

<30 kg.

15 - 19 kg (20 mg once daily)
20 - 29 kg (25 mg once daily)

Recommendations for ART in HIV + children with active TB

Considerations	Time of initiation of ART^a	Preferred ART regimen
Active TB diagnosed, not yet on HAART	Start anti-TB treatment* Start ART 2 to 8 weeks after commencing anti-TB treatment	Children <3 years and PMTCT exposure to NNRTI Use Triple NRTI (AZT + 3TC + ABC) Children < 3 years and no PMTCT exposure to NNRTI Initiate NVP-based regimen and increase NVP dose to 200 mg/m² per day, OR Triple NRTI (AZT + 3TC + ABC) Children >3 years: Standard 1^st line AZT + 3TC + EFV^e is preferred. Consider 1st line alternatives if preferred regimen not applicable.
Active TB diagnosed, already on HAART	If <3 years and on NVP-based regimen	Continue regimen but increase NVP to maximum dose (200mg/m²/day)
	If >3 years and on NVP-based regimen	Substitute: Replace NVP with EFV
	If on LPV/r based regimen	Increase dose of Ritonavir to make 1:1 ratio with LPV

^aAdministration of CPT is important in children with TB/HIV co-infection.

* Regimen assumed to contain Rifampin

^cCareful clinical monitoring with lab support, is recommended where NVP is used with rifampicin. This combination should only be used if there are no other options

^eEFV is not currently recommended for children <3 years of age.

Monitoring Response to ART and diagnosis of Treatment Failure

Clinical and laboratory monitoring of patient on ART is critical to achieving the treatment objectives. Through this, treatment response and possible toxicity of ARVs are monitored and patients that are eligible for drug switch are easily detected.

Recommended and desirable laboratory tests during monitoring of ART

Laboratory Tests after the initial baseline investigations and during follow-up on ART

Phase of HIV management

Recommended

Desirable (if feasible)

Receiving ART

CD4 cell count (every 6 months)

HIV viral load (at 6 months after initiating ART and every 12 months thereafter)

Urine dipstick for glycosuria and serum creatinine for TDF^d

Treatment failure

CD4 cell count

HIV viral load

HBV (HBsAg) serology^f (before switching ART regimen if this testing was not done or if the result was negative at baseline)

WHO definitions of clinical, immunological and virological failure for the decision to switch ART regimens

Definition of clinical, immunological and virological failure

Failure

Definition

Comments

Clinical Failure

Adults and adolescents

New or recurrent clinical event indicating severe immunodeficiency (WHO clinical stage 4 condition) after 6 months of effective treatment.

Children

New or recurrent clinical event indicating advanced or severe immunodeficiency

(WHO clinical stage 3 and 4 clinical

condition with exception of TB) after 6 months of effective treatment

The condition must be differentiated from Immune Reconstitution Inflammatory Syndrome occurring after initiating ART

For adults, certain WHO clinical

stage 3 conditions (pulmonary TB

and severe bacterial infections)

may also indicate treatment failure

Immunological failure

Adults and adolescents

CD4 count falls to the baseline (or below)

Or Persistent CD4 levels below 100 cells/ mm3

50% decline from on-therapy CD4 cell peak level

Without concomitant or recent infection to cause a transient decline in the CD4 cell count

A systematic review found that current WHO clinical and immunological criteria have low sensitivity and positive predictive value for identifying individuals with virological failure. The predictive value /would be expected to be even lower with earlier ART initiation and treatment failure at higher CD4 cell counts.

Children Younger than 5 years

Persistent CD4 levels below 200 cells/mm3 or <10%

Older than 5 years

Persistent CD4 levels below 100 cells/mm3

Virological

Failure

Plasma viral load above 1000 copies/ ml based on two consecutive viral load measurements after 3 months, with adherence support

The optimal threshold for defining virological failure and the need for switching ART regimen has not been determined. An individual must be taking ART for at least 6 months before it can be determined that a regimen has failed

Assessment of viral load using DBS and point-of-care technologies should use a higher threshold*

Blips are a transient increase in viral load between 50 and 1,000 copies/ml and can occur during periods of inter-current infections.

Notable adverse drug reactions, caution and Contraindications

Dolutegravir (DTG)

CNS symptoms: insomnia, fatigue, headache, depression, abnormal dreams, dizziness, suicidal ideation, suicidal tendencies- CNS symptoms associated with older age, co-administration with ABC and higher plasma drug level.
GI symptoms- Increased serum lipase, diarrhoea, abdominal distress and pain, flatulence, nausea and vomiting.
Hepatic- Increased serum AST, hyperbilirubinaemia, hepatitis
Hypersensitivity reactions
Limit daily dose of metformin to 1000 mg when used with DTG & monitor glycemic control.
Avoid co-administration of DTG with carbamazepine, nevirapine, phenytoin, phenobarbitone, rifampicin, dofetilide

Nevirapine (NVP)

Life-threatening skin rash (Stevens-Johnson syndrome); occurs in < 5% of patients, usually within 8 weeks of treatment
DRESS syndrome (drug rash, eosinophilia and systemic symptoms): manifests as fever, athralgia, etc
Hepatitis and jaundice reported

Efavirenz (EFV)

Morbilliform rash may appear; usually not life-threatening

CNS side effects in about 50% of patients (usually self-limiting)

Hallucinations
Insomnia
Abnormal dreams
Somnolence
Amnesia
Abnormal thinking
Confusion
Euphoria

For these reasons, EFV is contraindicated in patients who already have psychiatric manifestations

Foetal abnormalities observed in animal models; efavirenz should not be used in pregnant women or women who might become pregnant while on therapy

Zidovudine (ZDV)

Bone marrow suppression resulting in:
Anaemia with macrocytosis
Thrombocytopaenia
Leucocytopaenia
Gastro-intestinal intolerance is fairly common: hypersalivation, nausea, abdominal discomfort

Stavudine (d4T)

Peripheral neuropathy presenting with painful sensations in the lower limbs more than the upper limbs
Lactic acidosis with hepatic steatosis
Stop treatment or switch to a drug less toxic to mitochondria (worse when d4T is used in combination with ddI)
Peripheral fat atrophy
Ascending motor weakness resembling Guillain-Barre syndrome

Lamivudine (3TC)

No major side effect but class side effects may occur

Didanosine (ddI)

Dose-related pancreatitis; worse when combined with hydroxycarbamide (hydroxyurea)
Peripheral neuropathy; worse if combined with d4T
Lactic acidosis (a class adverse effect)

Tenofovir (TDF)

Infrequent; not more than what is observed in placebos in controlled trials
Renal insufficiency and bone demineralization

Abacavir (ABC)

Life-threatening hypersensitivity in 3 - 9% of patients
Lactic acidosis with or without hepatic steatosis

Indinavir (IDV)

Class-specific events
Nephrolithiasis with or without haematuria in 10 - 28% of patients; (fluid intake should be increased)
Alopecia

Nelfinavir (NFV)

Diarrhoea: 10 - 30% of patients; (should be managed with agents such as loperamide)
Fat accumulation
Hyperlipidaemia

Lopinavir/ritonavir (LPV/r)

Well tolerated except for occasional class adverse reactions:

Gastrointestinal
Hepatic transaminitis especially in patients with hepatitis B or C
Hyperlipidaemia
Fat accumulation

Saquinavir (SQV)

GIT intolerance in 5 - 30% leading to:

Nausea
Abdominal pain
Diarrhoea

Amprenavir (AMP)

Class adverse effects
GIT intolerance; oral paraesthesia in 28% of patients

Oral solution contains propylene glycol which may precipitate:

Seizures
Stupor
Tachycardia
Hyperosmolality
Lactic acidosis
Renal failure
Haemolysis

Oral solution is contraindicated in children below 4 years; should be changed to capsules as soon as possible

Ritonavir (RTV)

Class side effects
Perversion of taste
Circumoral and peripheral paraesthesia
Hepatotoxicity
Aesthenia

Atazanavir (ATV)

Unconjugated hyperbilirubinemia
Gastrointestinal effects
No effect on lipids

Note: Refer to standard texts for possible drug-drug interactions in all cases

Prevention

Prevention Of Mother-To-Child Transmission (PMTCT)

ART should be initiated in all HIV pregnant and breast-feeding women regardless of WHO clinical stage and at any CD4+ cell count and continued for life. This is also regardless of gestational age.

Drug of choice

Preferred first-line regimen: TDF+3TC + EFV.
Alternative first-line Regimens
- AZT + 3TC + EFV(Recommended alternative to TDF for pregnant and breastfeeding women)
- AZT + 3TC + NVP(For pregnant women who cannot tolerate EFV)
- TDF + 3TC + NVP(For pregnant women who cannot tolerate AZT and EFV)

Prophylaxis for HIV-exposed infants

All infants born to HIV mothers are exposed and should receive post- exposure prophylaxis.
Infants delivered to HIV positive mothers who are stable on ART should receive Nevirapine prophylaxis.
Infants born to mothers with HIV who are at high risk of acquiring HIV should receive dual prophylaxis with AZT (twice daily) and NVP (once daily) for the first 6 weeks of life, whether they are breastfed or formula fed.
Breastfed infants who are at high risk of acquiring HIV should continue infant prophylaxis for an additional 6 weeks (total of 12 weeks of infant prophylaxis) using AZT (twice daily) and NVP (once daily).
Cotrimoxazole prophylaxis is recommended for HIV-exposed infants from 6 weeks of age and should be continued until HIV infection has been excluded by an age-appropriate HIV test 12 weeks after complete cessation of breastfeeding

NVP dosing for Infant HIV prophylaxis^**

Infant age	Daily dosing
Birth to 6 weeks: Birth weight <2,500 grammes Birth weight ≥ 2,500 grammes	10 mg (1 ml) once daily 15 mg (1.5 ml) once daily
>6 weeks to 6 months*	20 mg (2 ml) once daily
>6 months to 9 months*	30 mg (3 ml) once daily
>9 months to 12 months*	40 mg (4 ml) once daily

*Dosing beyond 6 weeks of age should be considered in special situations.

** For the duration of therapy, refer to the Integrated National Guideline on HIV

Prevention, Treatment and Care of Nigeria

Post-exposure prophylaxis

Evaluate the risk of exposure and potential eligibility of post-exposure prophylaxis
Offer prophylaxis as soon as possible, within 1 hour and at the latest within 72 hours of the exposure

Recommended drug regimen for post-exposure prophylaxis

It is recommended that a three-drug ARV regimen should be used for PEP. TDF + 3TC (or FTC) is recommended as the preferred backbone regimen for HIV PEP for adults and adolescents.

DTG or EFV are recommended as the preferred third drug for HIV PEP for adults and adolescents. However, where available, LPV/r, RAL, or DRV/r, can be considered as alternative options.
If the source person is known to be on a second-line regimen or has failed first-line regimen, the preferred prophylaxis regimen should be “a second-line regimen”. If the source person on the second-line regimen has a detectable viral load, the prophylaxis should be a third line regimen.
Children above 30kg should receive TDF/3TC/DTG or EFV.
In children <10 years or less than 30kg, AZT + 3TC is recommended as the preferred backbone regimen for HIV PEP.
Alternative backbone regimen for this age category will include ABC + 3TC or TDF + 3TC (or FTC). DTG is recommended as the preferred third drug for HIV PEP for children < 10 years.
An age-appropriate alternative regimen can be identified from LPV/r, ATV/r, RAL, DRV/r.
Regimen must be continued for at least 28 days or until the result of the HIV status of the source person is known to be negative.
Nevirapine should never be used for PEP as the risk of fatal hepatotoxicity outweighs the risk of HIV infection.

Sexual assault

This should be initiated as soon as possible (and up to 72 hours post- assault) to optimize the potential benefit.

Pre-exposure prophylaxis (PrEP)

PrEP is the preemptive use of antiretroviral (ARV) drugs to reduce the probability of HIV negative individuals acquiring HIV infection especially persons who engage in high-risk activity.
PrEP should be offered only to the category of individuals listed below:
- Serodiscordant couples
- Commercial sex workers
- Injecting drug users
- Individuals who engage in anal sex on a prolonged and regular basis
Before initiating PrEP
- Confirm HIV negative
- Screen and treat for chronic hepatitis B
- Client should have normal renal
Recommend drugs for PrEP.
- Preferred daily oral dose regimen is TDF+ FTC (Truvada) given as one tablet daily
- Alternate regimen is a daily dose of
- These drugs are to be taken indefinitely until the individual no longer qualifies as high risk for HIV.

Behavioral interventions

Mechanisms with established merit:

A: Abstinence

B: Be faithful (mutual fidelity to infected partner)

C: Consistent and correct use of male and female condoms

D: Delay onset of sexual activity

E: Examine yourself

F: Find out your status

Screening and treatment of sexually transmitted infections
Encourage Partner Disclosure and Voluntary
Confidential Couple Counselling (VCCCT)

Promote the rights and protection of children and infusion women