THE NATURAL HISTORY OF HIV INFECTION

A. Primary HIV infection

Primary infection usually refers to the first six months after infection. During this period, HIV and the immune system
are engaged in a very active battle.
For the first 10 days or so, everything appears quiet. Even though HIV infection has occurred, there are rarely
symptoms. The first virus – and usually it is just one virus – is picked up by an immune cell and taken to the closest
lymph nodes. For most infections, the story would end here because the immune cells in the lymph nodes destroy most
infections.
With HIV something very different happens. HIV uses CD4 cells inside the lymph nodes to reproduce many times. This
activity causes these lymph nodes to swell and enlarge with new cells and virus. After two weeks the infected lymph
nodes are so full that they burst. HIV then travels throughout the body.

1. Acute Retroviral Syndrome

Approximately half of patients that acquire HIV develop a mononucleosis-like syndrome within 3-6 weeks during
which the viral titers are very elevated. This causes a rapid drop in CD4 T-Cell count as these cells are the primary host
for viral replication. During the next few weeks, viral load increases to very high levels. This is often higher than 10
million copies/mL. HIV reaches every part of the body – brain, lungs, kidneys, liver etc. HIV wipes out 80–90% of the
total CD4 cells in the body in just a few weeks. Symptoms are variable in those who have them, these include:
 Fever (96%)
 Enlarged lymph nodes (74%)
 Sore throat/Pharyngitis (70%)
  Rash (70%)
 Muscle or joint aches (54%)
 Low blood counts, platelets, and white cells (45%, 38%)
 Diarrhea (32%)
 Headache (32%)
 Nausea/Vomiting (27%)
 Hair loss (alopecia)
 Mood changes (depression, irritability)

2. Clinical Latency (Asymptomatic Infection)

 Within several weeks patients mount a strong immune response to the virus that causes a drop in the viral titers.
Immune system develops antibodies to suppress the virus and the viral load stabilizes (viral set point). This
process of making antibodies to HIV is called seroconversion.
 However, this response is not adequate to completely suppress viral replication. Although viremia may become
undetectable, replication persists in the lymphoid organs. Over time, there is typically a gradual decline in CD4+
lymphocytes (on average 50-75 cells per year)
 Median time from infection to development of AIDS is approximately 8-10 years
 Some may develop AIDS in <5 years (approximately 20%)
 Few will remain asymptomatic without evidence of immunosuppression for more than 10 years (<5%)
 B. Chronic HIV infection (Clinically Apparent Disease (AIDS)

Over the next few months, even without ART, viral load drops to lower levels. The CD4 count recovers, though
not as high as before infection. The first six months are therefore a very active, dynamic and busy time.
 After six months, HIV enters the chronic phase. Compared to the activity during primary infection, this phase
usually progresses slowly. Even without ART, many people can go for years without complications from HIV.
However, over time, the CD4 count will steadily drop and viral load will steadily increase. As the CD4 count
drops the risk of a serious infection increases.
The lower the CD4 count in chronic infection, the higher the risk from HIV-related infections.
Clinically apparent disease is classically diagnosed following an AIDS-defining illness i.e. an opportunistic
infection or neoplasm that demonstrates a significant compromise of the immune system. Another diagnostic sign,
although not strictly clinical, is the decline of CD4 T-cell count below 200 cells/mm 3. Without treatment, individuals
diagnosed with AIDS may survive approximately 1-3 years

Characteristics of HIV
It is a retrovirus
Retroviruses are RNA-containing viruses that use the enzyme reverse transcriptase to copy their RNA into the DNA of a
host cell.
HIV LIFE CYCLE
• Once HIV enters the host (CD4) cell, it converts its RNA(ribonucleic acid) to DNA(deoxyribonucleic acid)
via its enzyme reverse transcriptase.
• HIV is completely dependent upon CD4 cells for replication and survival.
• Replication and survival of HIV occurs through a number of steps:
• HIV gains entry into the CD4 cell by binding onto receptors on the outside of the CD4 cell and fusing with
the lipid outer layer of the cell.
• Once inside the cell, HIV removes its outer coating, exposing its RNA, and releases reverse transcriptase
enzyme to convert the HIV RNA to DNA.
• HIV DNA then enters the nucleus of the CD4 cell and is integrated into the host (CD4) DNA by intergrase
enzyme
• Replication and survival of HIV then continues
• Once the cellular DNA has been altered in this way, it is known as pro viral DNA (part virus/part cell) and
begins the process to produce more viruses.
• The CD4 cell is now programmed to be an ‘HIV factory.’
• Long viral protein chains are produced which are then cut into the necessary pieces to produce more HIV.
This process is activated by the viral protease enzyme.
Classes of Antiretrovirals
Each step in this process is a target for antiretroviral therapy

 Fusion inhibitor
 CCR5 antagonist
 Reverse Transcriptase
inhibitors
 Non-nucleosides (NNRTIs)
 Nucleoside/tide (NRTIs)
 Integrase inhibitor
 Protease inhibitors
Classes of Antiretroviral Drugs
• Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by
blocking one of several targets. Maraviroc and enfuvirtide are the two currently available agents in this class.

• CCR5 receptor antagonists are the first antiretroviral drugs which do not target the virus directly. Instead,
they bind to the CCR5 receptor on the surface of the T-Cell and block viral attachment to the cell. Most
strains of HIV attach to T-Cells using the CCR5 receptor. If HIV cannot attach to the cell, it cannot gain
entry to replicate.

• Nucleoside and nucleotide reverse transcriptase inhibitors (NRTI) inhibit reverse transcription by being
incorporated into the newly synthesized viral DNA strand as a faulty nucleotide. This causes a chemical
reaction resulting in DNA chain termination.eg AZT (Zidovudine) ,TDF (Tenofovir)

• Non-nucleoside reverse transcriptase inhibitors (NNRTI) inhibit reverse transcriptase directly by binding
to the enzyme and interfering with its function. E.g Viramune (Nevirapine)

• Protease inhibitors (PIs) target viral assembly by inhibiting the activity of protease, an enzyme used by HIV
to cleave and assemble proteins for the final assembly of new virions. e.g Norvir (Ritonavir)

• Integrase inhibitors inhibit the enzyme integrase, which is responsible for integration of viral DNA into the
DNA of the infected cell. There are several integrase inhibitors currently under clinical trial, and raltegravir
became the first to receive FDA approval in October 2007.

March 2012 www.aidsetc.org

NRTI
 Abacavir (ABC)
 Didanosine (ddI)
 Emtricitabine (FTC)
 Lamivudine (3TC)
 Stavudine (d4T)
 Tenofovir (TDF)
 Zidovudine (AZT, ZDV)
NNRTI
 Delavirdine (DLV)
 Efavirenz (EFV)
 Etravirine (ETR)
Initial Treatment: Choosing Regimens
 Nevirapine (NVP)
 Rilpivirine (RPV)
PI Integrase Inhibitor
 Atazanavir (ATV) Integrase inhibitors (II)
 Darunavir (DRV)  Raltegravir (RAL)
 Fosamprenavir (FPV)
 Indinavir (IDV) Fusion Inhibitor
 Lopinavir (LPV) Enfuvirtide (ENF, T-20)
 Nelfinavir (NFV)
 Ritonavir (RTV) CCR5 Antagonist  Saquinavir (SQV) 
Maraviroc (MVC)
March 2012 www.aidsetc.org
 3 main categories:
 1 NNRTI + 2 NRTIs
 1 PI + 2 NRTIs
 1 II + 2 NRTIs
 Combination of NNRTI, PI, or II + 2 NRTIs preferred for most patients
 Fusion inhibitor, CCR5 antagonist not recommended in initial ART
 Few clinical end points to guide choices
 Advantages and disadvantages to each type of regimen
 Individualize regimen choice

March 2012 www.aidsetc.org

 INITIAL REGIMENS: PREFERRED

NNRTI based EFV/TDF/FTC1,2

PI based ATV/r + TDF/FTC²

DRV/r (QD) + TDF/FTC²

Pregnant women LPV/r (BID) + ZDV/3TC²

1. EFV should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective
and consistent contraception.
2. 3TC can be used in place of FTC and vice versa. TDF should be used with caution in patients with renal insufficiency.

March 2012 www.aidsetc.org

 Initial Regimens: Alternative

NNRTI EFV¹ + ABC/3TC2,3 based RPV + (TDF/FTC or ABC/3TC)2,3

EFV should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective
and consistent contraception. 3TC can be used in place of FTC and vice versa. TDF should be used with caution in
patients with renal insufficiency. ABC should not be used in patients who test positive for HLA-B*5701; caution if
HIV RNA >100,000 copies/mL, or if high risk of cardiovascular disease. RPV: Use with caution if pretreatment HIV
RNA >100,000 copies/mL.

March 2012 www.aidsetc.org

 Initial Regimens: Alternative (2)

PI based ATV/r + ABC/3TC1,2

DRV/r + ABC/3TC1,2
FPV/r (QD or BID) + (ABC/3TC or TDF/FTC)1,2 LPV/r (QD or BID)3 +
(ABC/3TC or
TDF/FTC)1,2

II based RAL + ABC/3TC1,2

1. 3TC can be used in place of FTC and vice versa. TDF should be used with caution in patients with renal insufficiency.
2. ABC should not be used in patients who test positive for HLA-B*5701; caution if HIV RNA >100,000 copies/mL, or if high
risk of cardiovascular disease.
3. QD LPV/r is not recommended in pregnant women.

March 2012 www.aidsetc.org

Side Effects and Adherence

 Fear of adverse effects of medications can affect patient willingness to initiate or to continue treatment

 Adverse effects of medications can negatively affect adherence

 Some persons will self-discontinue medications

 Some will selectively discontinue some medications
 Some will drop out of care
 Side effects can negatively impact doctor-patient relationship

 Suboptimal adherence is associated with treatment failure, emergence of drug resistance, and disease progression
Side Effects: Interventions
Counsel patients about treatment options and appreciate
aversion to side
effects.
Review possible side effects prior to selecting
treatment
Anticipate and treat side effects; develop a strategy
to
address the side effect (using
-judgmental
non
communication) before starting a new
regimen
Assess adherence and side effects at every
visit

March 2012 www.aidsetc.org

 Adverse Effects: NRTIs (2)

 ABC
 HSR*
 Rash
 Possible increased risk of MI
 ddI
 GI intolerance
 Peripheral neuropathy
 Possible increased risk of MI
 Pancreatitis
 Possible noncirrhotic portal hypertension

* Screen for HLA-B*5701 before treatment with ABC; ABC should not be given to patients who test positive for
HLA-B*5701.

Adverse Effects: NRTIs (3)

 d4T
 Peripheral neuropathy
 Lipoatrophy
 Pancreatitis
 TDF
 Renal impairment

March 2012 www.aidsetc.org

 Decrease in bone mineral density
 Headache
 GI intolerance
 ZDV
 Headache
 GI intolerance
 Lipoatrophy
 Bone marrow suppression

Adverse Effects: NNRTIs

 All NNRTIs:
 Rash, including Stevens-Johnson syndrome
 Hepatotoxicity (especially NVP)
 Drug-drug interactions
Adverse Effects: NNRTIs (2)

 EFV
 Neuropsychiatric
 Teratogenic in nonhuman primates + cases of neural tube defects in human infants after first-trimester
exposure Dyslipidemia
 NVP
 Higher rate of rash
 Hepatotoxicity (may be severe and life-threatening; risk higher in patients with higher CD4 counts at the
time they start NVP, and in women)
 RPV

March 2012 www.aidsetc.org

 Depression
Adverse Effects: PIs

 All PIs: Hyperlipidemia

 Lipodystrophy
 Hepatotoxicity
 GI intolerance
 Possibility of increased bleeding risk for hemophiliacs
 Drug-drug interactions

Adverse Effects: PIs (2)

 ATV
 Hyperbilirubinemia
 PR prolongation
 Nephrolithiasis
 DRV
 Rash
 Liver toxicity
 FPV
 GI intolerance
 Rash
 Possible increased risk of MI

March 2012 www.aidsetc.org

 Adverse Effects: PIs (3)

 IDV
 Nephrolithiasis
 GI intolerance
 Diabetes/insulin resistance
 LPV/r
 GI intolerance
 Diabetes/insulin resistance
 Possible increased risk of MI
 PR and QT prolongation
 NFV
 Diarrhea

Adverse Effects: PIs (4)

 RTV
 GI intolerance
 Hepatitis
 SQV
 GI intolerance
 PR and QT prolongation
 TPV
 GI intolerance
  Rash
 Hyperlipidemia
 Liver toxicity
 Contraindicated if moderate-to-severe hepatic insufficiency
 Cases of intracranial hemorrhage

Adverse Effects: II

 RAL
 Nausea
 Headache
 Diarrhea
 CPK elevation, myopathy, rhabdomyolysis
 Rash

OPPORTUNISTIC INFECTIONS
• When CD4 count is in normal range (500-1,600 cells/cm or 28-50%), the immune system defends itself against
most antigens.
 • As T-cell count declines with HIV disease progression, the HIV+ patient is at increased risk for infection.
• Such infections include;
• Pneumococcal pneumonia, Pulmonary tuberculosis, Kaposi's sarcoma
• Herpes zoster, Thrush, Cryptosporidium
• Oral hairy leukoplakia, Oro-pharyngeal candida
• Pneumocystis cariini pneumonia, Candida esophagittiis
• Recurrent/disseminatted viral herpes simplex
• Toxoplasmosiis Histoplasmosiis
• Coccidioidomycosis, Progressive multifocial
• Leukoencephalopathy,
• Extrapulmonary tuberculosis
•

DIAGNOSIS OF HIV INFECTION

Criteria for diagnosis of AIDS HIV:
• HIV blood test must be positive
• Clinical Stage criteria
• CD4 count below 500cells

WHO CLINICAL STAGES FOR CHILDREN

WHO Clinical Stage 1
Asymptomatic
• Persistent Generalised lymphadenopathy
WHO Clinical Stage II
 •Unexplained persistent hepatomegaly and splenomegaly
•Papular itchy skin eruptions, Extensive skin warts
•Extensive molluscum contagiosum
•Recurrent oral ulcerations
•Unexplained persistent parotid gland enlargement
•Linear gingival erythema
•Herpes zoster
•Recurrent or chronic respiratory tract infections (sinusitis, otorrhoea, tonsillitis, otitis media) ,Fungal nail
infections
WHO Clinical Stage III
• Moderate unexplained malnutrition not responding to standard therapy
• Unexplained persistent diarrhea for longer than 14 days
• Unexplained persistent fever above 37.5 (intermittent or constant for more than one month)
• Persistent oral candidaisis (outside the first 6-8 weeks of life)
• Oral hairy leukoplakia
• Acute necrotizing ulcerative gingivitis or periodontitis
• TB lymphadenopathy
• Pulmonary tuberculosis
• Severe recurrent presumed bacterial pneumonia (2 or more episodes in a 6mo period)
• Symptomatic lymphoid interstitial pneumonitis (LIP)
• Chronic HIV-associated lung disease, including bronchiectasis
• Unexplained anaemia (<8g/dl), neutropaenia (<500/mm3) or thrombocytopenia (<50,000/mm3
WHO Clinical Stage IV
• Unexplained severe wasting, stunting, or severe malnutrition not responding to treatment
• Pneumocystis carinii (jeroveci) pneumonia
• Recurrent severe presumed bacterial infections (eg. Empyema, pyomyositis, bone or joint infections, meningitis,
sepsis, but excluding pneumonia)
• Toxoplasmosis of the brain
• Cryptosporidiosis with diarrhea>1 month
• Isosporiasis with diarrhea > 1 month
• Cryptococcosis, extrapulmonary
• Cytomegalovirus of an organ other than liver, spleen or lymph node
• Chronic herpes simplex infection (orolabial or cutaneious for > 1 month)
• Progressive multifocal leukoencephalopathy
• Any disseminated endemic mycosis
• Candidiasis of oesophagus, trachea and bronchus
• Atypical mycobacteriosis, disseminated or lungs
• Extrapulmonary tuberculosis excluding TB lymphadenopathy
• Lymphoma (cerebral or B cell non-Hodgkin), Kaposi’s sarcoma
• HIV encephalopathy
• HIV-associated cardiomyopathy or HIV-associated nephropathy
• Bacterial infections like: Tuberculosis (TB) ,Strep pneumonia
• Viral infections: Kaposi Sarcoma, Herpes, Influenza
• Parasitic infections: Pneumocystis carinii
• Fungal infections like: Candida, Cryptococcus
PREVENTION OF HIV/AIDS IN CHILDREN
• Early diagnosis during antenatal and start of ART I.e PMTCT
• Use of Niverapine syrup at birth up to six weeks followed by diagnosis
• Options of feeding like stopping breastfeeding if AFASS
• Treatment and gradual follow up with counselling in big children