34  HIV

34.1 Definition

Human immunodeficiency virus (HIV) is an infection that attacks the body’s immune system, specifically the white blood cells called CD4 cells. HIV destroys these CD4 cells, weakening a person’s immunity against opportunistic infections, such as tuberculosis, fungal infections, severe bacterial infections, and some cancers.(World Health Organization (WHO) 2023)

34.2 Incidence/prevalence

Globally, 39 million people were living with HIV in 2022 out of which 1.5 million were children below 15 years. In Ghana, out of 354,927 people living with HIV in 2022, 7% (24,845) were children below 15 years. There were 16,574 new HIV infections in 2022 out of which 17% (2,818) were children. Mother-to-child transmission of HIV at 6 weeks in 2022 was 9.12% while the final MTCT rate at 18 months was 17.75%. In 2022, there were 21,439 adolescents (10-19 years) living with HIV out of which 1,791 were newly infected.(Ghana Health Service 2023)

34.3 Aetiology

HIV is a retrovirus with two main subtypes namely HIV 1 and HIV 2. HIV-1 is the most common type of HIV and accounts for 99% of all infections in Ghana, whereas HIV-2 is relatively uncommon (0.08%) and less infectious. Ghanaians co-infected with HIV 1 and HIV 2 form 0.02% of total infections. HIV-2 is mainly concentrated in West Africa and the surrounding countries. HIV-2 is less fatal and progresses more slowly than HIV-1. Modes of HIV transmission are sexual (80% in Ghana) mainly heterosexual but also same-sex; parenteral transmission (5%) examples include blood transmission, shared needles, and needle stick accidents, and mother-to-child transmission (15%) of which in-utero, intrapartum and postpartum accounts for 10-25%, 60-75%, and 10-20% respectively.

34.4 Pathogenesis

HIV entry, the first phase of the viral replication cycle, begins with the adhesion of the virus to the host cell and ends with the fusion of the cell and viral membranes with subsequent delivery of the viral core into the cytoplasm. The intricate series of protein-protein interactions that ultimately result in virus infection can be divided into several phases, some of which are essential and others that may modulate the efficiency of the process.(Wilen, Tilton, and Doms 2012)

Infection with HIV starts without symptoms or ill-feeling and is accompanied by slight changes in the immune system. This stage spans up to three months after infection until seroconversion where HIV-specific antibodies can be detected in individuals following recent exposure. The outcome of infection and duration of disease progression with clinical symptoms may vary greatly between individuals, but often it progresses fairly slowly. It takes several years from primary infection to the development of symptoms of advanced HIV diseases and immunosuppression.(Cunningham et al. 2000) Although individuals may look healthy during primary infection, the virus replicates in infected individuals’ lymph nodes and bloodstream. As a result, the immune system may get slowly damaged by the burst of viral load in their bodies.(Moir, Chun, and Fauci 2011)

34.5 Signs and symptoms

Signs and symptoms develop when the immune system’s ability to fight the disease is compromised due to viral replication and reduced CD4 cells.

34.5.1 Early/ acute HIV

Acute HIV infection, also known as primary HIV infection, can cause a range of symptoms that can begin a few days after exposure to the virus and last for a few days to several months

34.5.2 Late chronic HIV

The late stage of HIV infection is AIDS (acquired immunodeficiency syndrome), which occurs when the virus weakens the immune system.

34.5.3 Staging of HIV

Table 34.1: HIV Staging

Stage 1 Asymptomatic Generalised lymphadenopathy
Stage 2 Unexplained persistent hepato-splenomegaly Recurrent or chronic upper respiratory tract infections (otitis media, otorrhoea, sinusitis, tonsillitis) Herpes zoster Linear gingival erythema Recurrent oral ulceration Papular pruritic eruption Fungal nail infections Extensive wart virus infection Extensive Molluscum contangiosum Unexplained persistent parotid enlargement
Stage 3 Unexplained moderate malnutrition and not adequately responding to standard therapy Unexplained persistent diarrhoea (14 days or more) Unexplained persistent fever (above 37.5°C, intermittent or constant, for longer than one 1 month) Persistent oral candidiasis (after first 6 weeks of life) Oral hairy leukoplakia Lymph node tuberculosis	Stage 3 Pulmonary tuberculosis Severe recurrent bacterial pneumonia Acute necrotising ulcerative gingivitis or periodontitis Unexplained anaemia (<8g/dl), neutropenia (<0.5x 109/l) and chronic thrombocytopenia (<50 x 109/l).  Symptomatic lymphoid interstitial pneumonitis Chronic HIV-associated lung disease, including bronchiectasis
Stage 4 Unexplained severe wasting, stunting or severe malnutrition not responding to standard therapy Pneumocystis (jiroveci) pneumonia Recurrent severe bacterial infections (such as empyema, pyomyositis, bone or joint infection, and meningitis, but excluding pneumonia) Chronic herpes simplex infection (orolabial or cutaneous of more than 1 month’s duration or visceral at any site) Oesophageal candidiasis (or candidiasis of the trachea, bronchi or lungs) Extrapulmonary tuberculosis Kaposi sarcoma Cytomegalovirus infection (retinitis or infection of other organs with onset at age more than 1 month) Central nervous system toxoplasmosis (after the neonatal period)	Stage 4 HIV encephalopathy Cytomegalovirus infection (retinitis or infection of other organs with onset at age more than 1 month) Extrapulmonary Cryptococcosis, including meningitis Disseminated non-tuberculous mycobacterial infection Progressive multifocal leukoencephalopathy Chronic cryptosporidiosis (with diarrhoea) Chronic Isosporiasis Disseminated endemic mycosis (Extrapulmonary histoplasmosis, coccidioidomycosis, penicilliosis) Cerebral or B-cell non-Hodgkin lymphoma HIV-associated nephropathy or cardiomyopathy

34.6 Investigations

Depending on signs and symptoms, a patient could be suspected of HIV infection and AIDS. Children are then tested for HIV depending on their age.

34.6.1 Newborn to <18 months

Younger children (< 18 months) who are exposed to HIV or are suspected of HIV should be tested at any time they have symptoms of HIV disease. The preferred test is the DNA PCR which is done using dried blood spots (DBS) taken from pricking the heel of a child onto filter paper. If the test is positive, the child should be started on treatment, but a second confirmatory test must be done. Infants born to HIV-positive mothers without symptoms are routinely tested within 6 weeks of birth, at 9 months of age using DNA PCR. At 18 months such children are tested with antibody tests using a “triple algorithm” as detailed below.

34.6.2 18 months and above

Should be tested using the “triple algorithm” when a patient is sequentially tested using first response, Oraquick, and SD biofilm test. ALL three tests must be positive before a child is confirmed HIV positive. Figure 34.1 below gives further information

flowchart TD
    A(Screen with First response)-->B(Reactive First Response);
    A-->C(First Response non-reactive <br> Report HIV Negative);
    B-->D(Test with Oraquick <br> HIV 1&2);
    D-->E(If reactive to <br> both First Response <br> & Oraquick);
    D-->F(If First Response <br> was reactive but <br> not Reactive to Oraquick);
    E-->G(Confirm with SD Bioline);
    F-->H(Repeat both First <br> Response & Oraquick <br> sequentially);
    H-->I(Reactive to First <br> Response & Oraquick: <br> Confirm with SD Bioline);
    H-->J(If Non-reactive <br> to first response report <br> HIV Negative);
    G-->K(Reactive to First <br> Response, Oraquick <br> and SD Bioline <br> Report HIV-positive);
    G-->L(Reactive to First <br> Response & Oraquick <br> but non-reactive to <br> SD Bioline Report HIV <br> inconclusive. Retest in 14 days);
    H-->M(If reactive to First <br> Response but non-reactive <br> to Oraquick report <br> HIV Negative);
    I-->G

Figure 34.1: HIV testing algorithm for non-pregnant women and general population

Baseline investigations are needed before initiating antiretroviral treatment/ monitoring of the disease. These are listed in Table 34.2

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Table 34.2: Baseline investigations for HIV

Test	Types
Haematological	Full blood count
Biochemistry	Blood Urea Electrolytes and Creatinine
	Liver Function tests
	Fasting Blood Sugar
	Cholesterol and lipid profile
Routine	Urinalysis (Urine R/E)
	Stool R/E
Respiratory	TB screening
	GeneXpert
	Chest X-ray
Serological	Hepatitis B Surface antigen
Immunological	CD4
Optional (Patient dependent)	Histology on skin and lymph node biopsy
	Kidney biopsy
	Screening for STIs
	Pap smear, HPV DNA
	Abdominal Ultrasound

When children are on treatment viral load tests are done regularly. This is done to detect early virological failure. When highly active antiretroviral therapy (HAART) is started, the first viral load test is done at 6 and 12 months. If there is virological suppression, then monitoring is done yearly. The table below outlines what to do with various viral load cut-offs and actions to take

flowchart TD
    A(Routine viral load monitoring for <br> early detection of treatment failure: <br> Obtain and review results by <br> 6 months after ART initiation., 12 <br> months after ART initiation and <br> yearly thereafter)-->B(Undetectable  <=50 copies /ml);
    A-->C(Viral load <br>  >50 to <= 1000 copies /ml);
    A-->D(Viral load <br> >1000 copies /ml);
    B-->F(Maintain ARV drug regimen);
    C-->G(Provide enhanced adherence <br> counselling: Repeat viral load <br> testing after 3 months);
    D-->G;
    D-->E(if NNRTI regimen switch to <br> the appropriate regimen);
    G-->H(Undetectable  <=50 copies /ml);
    G-->I(Viral load  >50 to <= 1000 copies /ml);
    G-->J(Viral load >1000 copies /ml);
    H-->K(Maintain ARV drug regimen);
    I-->L(Maintain ARV drug <br> regiment but continue<br> enhanced adherence counselling <br> and repeat viral load <br> testing after 3 months);
    J-->M(Switch to the <br> appropriate regimen)

Figure 34.2: Treatment Monitoring Algorithm

34.7 Treatment

Before commencing HAART for any child or adolescent, counsel the caregiver and the child if old enough to appreciate the counselling

34.7.1 Infants born to HIV-positive mothers (post-exposure prophylaxis)

All newborns of HIV-positive mothers are called HIV-exposed babies. These babies should be given antiretroviral prophylaxis namely nevirapine and zidovudine daily starting from birth (within 24 hours) for 3 months. At week 6, infants should be started on cotrimoxazole daily till HIV infection is ruled out at 18 months. At any point in time when a child tests positive for HIV, treatment with cotrimoxazole should be continued for a longer duration till the child’s immune system is fully re-constituted and appropriate for age. The best marker is appropriate CD4 for age. In the absence of CD4 testing, the child should be virologically suppressed with no evidence of clinical disease.@borges-lujan2022

34.7.2 Treatment of HIV infection

Counselling caregivers and children is a must before initiating HAART. Emphasise should be on HAART being a lifelong treatment. Adherence counselling should be integrated into clinical care. The HAART consist of 2 Nucleos(t)ide Reverse Transcriptase Inhibitor (N(t)RTI plus Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) or Integrase Strand Transfer Inhibitor (INSTI) or Protease Inhibitor (PI). HAART regimen should have a minimum of three ARVs. The table below shows the types of ARVs available in Ghana

Table 34.3: Antiretroviral Groups

Group 1	Group 2	Group 3
N(t)RTI	NRTI	NNRTI	INSTI	PI
Abacavir (ABC)	Lamivudine (3TC)	Efavirenz (EFV) Weight > 10 kg	Dolutegravir (DTG) Weight >3 kg	Ritonavir boosted Lopinavir (LPV/r)
Zidovudine (AZT) (Hb> 8 g/dl)	Emtricitabine (FTC)	Nevirapine (NVP)	Raltegravir (RAL)	Ritonavir boosted Atazanavir (ATV/r)
Tenofovir (TDF) (Renal disease) Weight=>30 kg	Read around the main side effects/contraindications of each ARV			Ritonavir boosted Darunavir (DRV/r)

HAART combination can be made easy by choosing one ARV from each group.

Table 34.4: Preferred and alternative first-line ART regimens for adolescents, children and neonates

Populations	Preferred first-line regimen	Alternative first-line regimen	Special circumstances
Adolescents	TDF + 3TC (or FTC) + DTG	TDF + 3TC + EFV 400mg	TDF + 3TC (or FTC) + EFV600mg AZT + 3TC + EFV 600 mg TDF + 3TC (or FTC) + PI/r TDF + 3TC (or FTC) + RAL ABC + 3TC + DTG TDF + 3TC (or FTC) + PI/r
Children	ABC + 3TC + DTG	ABC + 3TC + LPV/r TDF+ 3TC (or FTC) + DTG	ABC + 3TC + EFV  ABC + 3TC + RAL AZT + 3TC + EFV  AZT + 3TC + LPV/r (or RAL)
Neonates	AZT (or ABC) + 3TC + RAL(or DTG)	AZT + 3TC + NVP	AZT + 3TC + LPV/r

34.7.3 Side effects of main ARVS

Depending on the type of HAART, children may experience different side effects. Regular clinical and laboratory monitoring will be needed to identify side effects early. There are alternative ARVs in each group to substitute if a child on HAART experiences a major side effect.

Table 34.5: Common ARV toxicities

Haematological toxicity	Drug-induced bone marrow suppression is most commonly seen with AZT (anaemia, neutropenia).
Mitochondrial Dysfunction	Primarily seen with the NRTI drugs, including lactic acidosis, hepatic toxicity, pancreatitis, peripheral neuropathy, lipoatrophy, myopathy
Renal Toxicity	Renal tubular dysfunction is associated with Tenofovir (TDF). ATV/r can also cause nephrolithiasis.
Other Metabolic Abnormalities	More common with PIs and INSTIs. Include hyperlipidaemia, fat accumulation, insulin resistance, diabetes and osteopenia. Lipodystrophy is also associated with Zidovudine. The risk of cardiovascular events with Abacavir (ABC) is still debatable.
Allergic Reactions	Skin rashes and hypersensitivity reactions, are more common with the NNRTI drugs but also seen with certain NRTI drugs, such as ABC and some PIs.
Hepatic Toxicity	Liver enzyme elevation with DTG especially in patients with HBV or HCV co-infection. DRV/r also causes liver enzyme elevation
Muscular Toxicity	Muscle weakness and sometimes rhabdomyolysis are seen with RAL

34.8 Complications

The main complication of HIV infection is the progression to AIDS when HAART is not initiated. Those children on treatment with non-adherence or poor adherence to HAART can ultimately develop AIDS. This will be the consequence of reduced CD4 cell count and increased viral load

34.9 Prognosis

Patients who start treatment early before immune dysgenesis and are virologically controlled have a life expectancy like an HIV-negative individual

34.10 Differential diagnosis

Acute HIV infection may be asymptomatic or may cause a mononucleosis-like syndrome. It should be differentiated from similar diseases that cause fever, fatigue, sore throat, myalgia, and lymphadenopathy such as acute toxoplasmosis, acute CMV/EBV infections, and acute viral hepatitis

34.11 Further reading

Consolidated Guidelines for HIV care in Ghana

34.12 Sample case scenarios

1. A 10-year-old boy presented to your facility with skin rashes, weight loss, fever, and cough of 3 months duration. On examination, he was semi-conscious. Chest X-ray was suggestive of pulmonary tuberculosis. CSF from Lumber puncture was positive on GeneXpert
   1. How would you confirm HIV in this child?
   2. What is the appropriate WHO clinical staging
2. A 5-year-old boy has recently been diagnosed with HIV. You intend to start antiretrovirals. He weighs 25 kg with Hemoglobin of 6 gm/dl.  His renal and liver function is normal. Which option will be your best HAART?
   1. ABC/3TC/EFV
   2. ABC/3TC/DTG
   3. AZT/3TC/LPV/r
   4. TDF/3TC/EFV
3. A 15-year-old male drug addict, newly diagnosed with HIV. He weighs 35 kg. The renal and liver functions are normal. Based on the history, what additional questions will you ask? What additional test would you do?
   1. Propose ARVs
4. A 6-month-old was admitted to your facility with a fever, poor weight gain and oral thrush. HIV antibody test came up positive in both mother and infant
   1. Does this HIV antibody test confirm HIV in the child?
   2. What other tests are required in this child?
5. A 2-month-old newly diagnosed with HIV. Weight 5kg, Hb=12 g/dl normal renal and kidney function.     
   1. Suggest ARVs for treatment

34.13 Answers to sample questions

1. It is important to know the duration of the other symptoms if they are beyond 3 months. Ask about interventions, facilities visited and what was done for the patient. The top three possibilities are HIV/AIDS, Malignancy and tuberculosis. Malignancy should be ruled out (REFER TO ONCOLOGY LECTURES). Tuberculosis is confirmed in this child. Since HIV is a risk factor for developing TB, it is right to think of HIV in this child. Remember HIV is a family disease. Parents and other siblings MUST also be screened if they exist.

   To diagnose HIV test, this child must have positive tests on all tests using the “triple algorithm” namely first response, Oraquick, and SD bioline.

   This child has confirmed Pulmonary TB. PTB is airborne and therefore there is the need to screen close contacts. This will help identify the index case and put in necessary screening tests. Those who have the disease are treated while those exposed without the disease will need TB preventive therapy.

   This child’s HIV test was positive. He has both pulmonary TB and TB meningitis. Referring to the notes on WHO clinical staging, PTB is stage 3 while TB Meningitis (TBM) is stage 4. This child therefore has clinical stage 4

   Remember that this child has an opportunist infection (TB). To prevent Immune Reconstitutive Inflammatory Syndrome (IRIS), this child has to start TB treatment before starting HAART, for PTB HAART is started preferably 2 weeks after TB medication. For TBM, HAART should be started 4-6 weeks after initiating TB medications.

   Note: Drug-drug interaction occurs between some ARVs and rifampicin. Dolutegravir, lopinavir/ritonavir, and nevirapine should be doubled when administered simultaneously with rifampicin. When TB treatment ends, extend the duration of the double dose of the ARVs for 2 weeks before reducing the dose to the expected age and weight of the children.

2. In deciding on the best HAART, an ARV should each be selected from groups 1,2 and 3. From group 1, the only feasible option is abacavir because HB is < 8g/dl and weight is < 30 kg(AZT and TCF cannot be used). Under group 2, either 3TC or FTC are possible but 3TC is readily available. Under group 3, DTG will be the best option because EFV has a lower resistance barrier and high community resistance. LPV/r is plausible but twice daily regimen makes compliance more difficult. The best option will be ABC/3TC/DTG (option b is the best choice)

3. Being a drug addict, he may be using intravenous injection which increases his risk of being infected with hepatitis B or hepatitis C. Again, he may be having sexual partners exposing him to STI. He, therefore, has to be investigated for hepatitis B/C, full blood count, and screened for other STIs. The choice of HAART will have to factor in hepatitis B status. TDF can be given because he weighs more than 30 kg and renal function is normal. Based on the previous explanation, TDF/3TC/DTG is the best choice. This option comes as a Fixed dose combination so he will take just 1 tablet daily, improving compliance among adolescents. Should the adolescent be Hepatitis B positive, TDF/3TC are also active against hepatitis B. Adolescents should be referred for appropriate services if there are other co-morbidities. Referral to a clinical psychologist will also be needed because he is addicted to drugs

4. Antibodies are IgG and cross the placental to the baby. Newborns testing positive using antibody tests might be maternally transmitted. Antibody tests do not confirm HIV in children below 18 months. These antibodies are expected to disappear by 18 months. The recommended test for a 6-month-old baby is a DNA PCR test (refer to above). Other tests and timelines if the baby is negative at 6 months, are at 9 months (DNA PCR) and 18 months (antibody test)

5. For a 2-month-old, an Hb of 12 is low; therefore, AZT will not be a good option. The HAART of choice is ABC/3TC/DTG

34.14 Self-assessment questions

1. A 15-year-old takes HAART which he thinks are vitamins for SCD. How would you disclose his true status to him?
2. A 17-year-old adolescent girl is about to start HAART. Explain the content of your counselling.

Cunningham, A L, S Li, J Juarez, G Lynch, M Alali, and H Naif. 2000. “The Level of HIV Infection of Macrophages Is Determined by Interaction of Viral and Host Cell Genotypes.” Journal of Leukocyte Biology 68 (3): 311–17. https://doi.org/10.1189/jlb.68.3.311.

Ghana Health Service. 2023. “Ghana Health Service Holds Annual Joint TB/HIV Performance Review Meeting.” GHS News. https://ghs.gov.gh/2023/01/22/ghana-health-service-holds-annual-joint-tb-hiv-performance-review-meeting/.

Moir, Susan, Tae-Wook Chun, and Anthony S. Fauci. 2011. “Pathogenic Mechanisms of HIV Disease.” Annual Review of Pathology: Mechanisms of Disease 6 (1): 223–48. https://doi.org/10.1146/annurev-pathol-011110-130254.

Wilen, C. B., J. C. Tilton, and R. W. Doms. 2012. “HIV: Cell Binding and Entry.” Cold Spring Harbor Perspectives in Medicine 2 (8): a006866–66. https://doi.org/10.1101/cshperspect.a006866.

World Health Organization (WHO). 2023. “HIV and AIDS.” Fact Sheets. https://www.who.int/news-room/fact-sheets/detail/hiv-aids.