HIV/AIDS and Opportunistic Infections: Comprehensive Clinical Diagnosis and Management

Clinical Medicine Year 3 • a future-doctor chapter for HIV care in Uganda

Learning outcomes

• Define HIV infection, AIDS, immune failure, opportunistic infection and immune reconstitution inflammatory syndrome.
• Explain HIV structure, CD4-cell infection, viral replication, immune activation and progressive immune dysfunction.
• Describe transmission, prevention, testing, counselling, disclosure, stigma and the principle of undetectable = untransmittable.
• Stage disease using symptoms, WHO clinical staging, CD4 count, viral load and OI patterns.
• Take a complete HIV/OI history and perform a system-based examination.
• Order and interpret HIV tests, viral load, CD4, resistance testing, cultures, imaging, CSF, ophthalmology and tissue studies.
• Recognise the clinical presentation and emergency management of major fungal, bacterial, protozoal and viral OIs.
• Plan ART initiation, drug interactions, adherence, monitoring, prophylaxis, pregnancy/paediatric care and IRIS management.
• Prevent OIs through cotrimoxazole and other appropriate prophylaxis, TB preventive treatment, vaccination, safe water, food safety and screening.

1. Definitions

Human immunodeficiency virus (HIV) is an enveloped RNA retrovirus that targets cells expressing CD4, especially CD4 T lymphocytes, macrophages and dendritic cells. HIV-1 causes most global disease; HIV-2 is less common and has different geographic and resistance considerations.

AIDS describes advanced HIV infection with severe immune suppression, an AIDS-defining condition or both. A patient can have advanced disease despite a single apparently acceptable CD4 result, and a person with a high CD4 can still develop an OI if another immune or structural problem exists.

Opportunistic infections are infections that occur more often, are more severe or behave atypically when host immunity is weakened. The organisms and body sites vary with CD4 level, ART exposure, prophylaxis, geography and local prevalence. The supplied SlideShare sources group OIs into bacterial, fungal, protozoal and viral categories and emphasise that falling CD4 increases OI risk. See the organ-based OI overview.

2. HIV microbiology and replication

1. Attachment and entry: viral gp120 binds CD4 and a co-receptor (usually CCR5 early or CXCR4 later), while gp41 mediates fusion.
2. Reverse transcription: viral RNA is converted into DNA by reverse transcriptase; errors create genetic diversity and drug resistance.
3. Integration: integrase inserts viral DNA into the host genome, creating a long-lived reservoir.
4. Transcription and translation: infected cells produce viral RNA and proteins.
5. Assembly and budding: immature virions bud from the cell membrane.
6. Maturation: protease cleaves polyproteins into functional components; the new virion becomes infectious.

ART targets these stages using nucleoside/nucleotide reverse-transcriptase inhibitors (NRTIs), non-nucleoside reverse-transcriptase inhibitors (NNRTIs), integrase inhibitors, protease inhibitors, entry/fusion inhibitors and pharmacokinetic boosters. Combination therapy prevents one drug from selecting resistant variants.

3. Natural history and pathogenesis

3.1 Acute retroviral syndrome

Two to four weeks after infection, viraemia can cause fever, rash, sore throat, lymphadenopathy, myalgia, headache, diarrhoea, oral/genital ulcers, aseptic meningitis or hepatitis. Symptoms are non-specific and may resemble malaria, EBV, influenza or COVID-like illness. Antibody tests can be negative during the window period; laboratory testing must follow the current algorithm.

3.2 Clinical latency is not viral latency

After acute infection, viral replication continues in lymphoid tissues even when the patient is asymptomatic. CD4 cells are progressively lost through direct infection, apoptosis, immune-mediated killing, exhaustion and damage to gut-associated lymphoid tissue. Without ART, viral load, immune activation and opportunistic disease risk eventually rise.

3.3 Advanced disease

When cellular immunity fails, latent organisms reactivate and new pathogens cause invasive disease. Mucosal barriers, neutrophil function, antibody responses and macrophage activation are also impaired. ART can restore immune function, but rapid immune recovery against a hidden pathogen can trigger inflammatory disease—IRIS.

4. Transmission, prevention and counselling

4.1 Routes of transmission

• Sexual exposure to infected genital/rectal/pharyngeal secretions.
• Blood exposure through shared needles, unsafe injections, unscreened blood or unsterile procedures.
• Vertical transmission during pregnancy, delivery or breastfeeding.
• Occupational exposure to infected blood; casual contact, hugging, sharing food, mosquitoes and intact skin do not transmit HIV.

4.2 Prevention package

• Condoms, lubricants, HIV testing and treatment of STIs.
• PrEP for eligible HIV-negative people and PEP after significant exposure, started urgently according to national policy.
• Safe blood, sterile instruments, injection safety and harm-reduction services.
• Universal ART and support for viral suppression: sustained undetectable viral load prevents sexual transmission (U=U), but does not prevent other STIs.
• Prevention of mother-to-child transmission through antenatal testing, maternal ART, safe delivery, infant prophylaxis/diagnosis and breastfeeding guidance under Uganda’s programme.

4.3 Counselling essentials

Obtain consent, protect privacy, use non-judgemental language, assess safety and disclosure risk, involve a chosen treatment supporter, discuss partner testing and screen for depression, violence, substance use, food insecurity and stigma. “Disclosure” is a supported clinical process, not an instruction to tell everyone immediately.

5. HIV diagnosis and staging

5.1 Testing algorithm

Use the national serial or parallel testing algorithm with validated assays. A reactive screening test is not the same as a confirmed diagnosis. Resolve discordant or indeterminate results through the reference algorithm, repeat testing at the correct interval and assess recent exposure.

• Window period: recent exposure may precede detectable antibodies; antigen/antibody or nucleic-acid testing may detect infection earlier.
• Confirmatory testing: never diagnose or label a patient from one unconfirmed reactive test.
• Infants under 18 months: maternal antibody makes antibody testing unreliable; use virological early-infant diagnosis according to national policy.

5.2 Baseline assessment after confirmation

• Complete history and examination, WHO clinical stage, weight/BMI and nutrition status.
• CD4 count where available for advanced-disease risk and prophylaxis decisions; ART should not be delayed solely while awaiting CD4.
• HIV viral load for baseline and treatment monitoring.
• FBC, creatinine/eGFR, ALT/AST/bilirubin, glucose, urinalysis, hepatitis B/C testing where indicated, pregnancy test and STI screening.
• TB symptom screen, TB molecular testing/imaging if indicated, cryptococcal antigen screening in advanced HIV, and symptom-directed OI tests.
• Review medicines, traditional remedies, contraception, renal/bone disease, mental health and immunisation.

5.3 CD4 as a risk map

CD4 thresholds are useful teaching guides, not rigid exclusion rules. OIs can occur at higher counts, and ART can change the expected pattern.

6. Clinical examination of the patient with HIV

Begin with airway, breathing, circulation, mental state, oxygen saturation, temperature, blood pressure and glucose. Then examine deliberately rather than waiting for one “AIDS sign.”

• General: wasting, fever, pallor, jaundice, dehydration, oedema, lymphadenopathy, skin pigmentation and performance status.
• Skin: seborrhoeic dermatitis, pruritic papular eruption, molluscum, zoster, HSV ulcers, fungal lesions, Kaposi plaques/nodules, drug rash and bacterial infections.
• Mouth/throat: oral or oesophageal candidiasis, hairy leukoplakia, ulcers, periodontal disease, Kaposi lesions and dental sepsis.
• Chest: pneumonia, PJP, TB, effusion, bronchiectasis, hypoxia and pulmonary hypertension.
• Neurology: headache, meningism, cognition, focal deficit, seizures, cranial nerves, ataxia and peripheral neuropathy.
• Eyes: visual acuity, fields, floaters, pain, red eye and fundal examination/referral when CD4 is low or symptoms occur.
• Abdomen: hepatosplenomegaly, ascites, tenderness, lymphadenopathy and signs of chronic liver disease.
• Genital/anal: ulcers, discharge, warts, cervical lesions, pelvic tenderness and rectal disease with consent.

7. Approach to a patient with fever or suspected OI

1. Stabilise airway, oxygenation, circulation, glucose and temperature.
2. Ask which organ system is dominant: lung, CNS, eye, skin, mouth, gut, liver, genital tract or bloodstream.
3. Review CD4, viral load, ART adherence, prophylaxis and previous OIs.
4. Search for more than one infection: TB plus bacterial pneumonia, meningitis plus cryptococcus, or diarrhoea plus malnutrition.
5. Collect specimens before antibiotics when safe, but never delay emergency treatment.
6. Consider drug toxicity, IRIS, malignancy and non-infectious mimics.

8. Major opportunistic infections

8.1 Pneumocystis jirovecii pneumonia (PJP/PCP)

Presentation: subacute fever, dry cough, progressive exertional dyspnoea, fatigue, weight loss and inability to take a deep breath. Hypoxia and exercise desaturation may be disproportionate to chest findings. Severe disease causes tachypnoea, cyanosis and respiratory failure.

Diagnosis: pulse oximetry at rest and after exertion, chest radiograph (often bilateral diffuse interstitial/ground-glass changes), high-resolution CT where available, induced sputum or bronchoalveolar lavage for microscopy/PCR, and serum beta-D-glucan where available. A normal early radiograph does not exclude PJP.

Treatment: high-dose cotrimoxazole for 21 days is first-line; severe disease requires IV therapy and close renal/electrolyte monitoring. Alternatives include clindamycin–primaquine, dapsone–trimethoprim, atovaquone or pentamidine depending on availability and G6PD status. Add corticosteroids when significant hypoxaemia meets current criteria, ideally within the first 72 hours.

Prevention: cotrimoxazole preventive therapy for eligible people with advanced HIV according to national criteria; start/optimise ART and stop prophylaxis only when immune recovery meets guideline criteria.

8.2 Oropharyngeal and oesophageal candidiasis

Clinical features: removable white plaques, erythematous burning mouth, angular cheilitis, altered taste, dysphagia or odynophagia. Oesophageal disease may occur without visible oral plaques and can cause retrosternal pain or inability to eat.

Diagnosis: clinical in typical oral disease; endoscopy and culture/biopsy for refractory, recurrent, severe or atypical disease. Consider CMV/HSV oesophagitis, reflux and malignancy when pain persists.

Management: systemic fluconazole is preferred for significant oral or oesophageal disease; use an alternative azole or echinocandin when resistance, interactions or intolerance occurs. Correct diabetes, recent antibiotics, dentures and ART failure; investigate odynophagia that does not improve.

8.3 Cryptococcosis and cryptococcal meningitis

Presentation: subacute headache, fever, photophobia, nausea, vomiting, confusion, personality change, cranial-nerve palsy, blurred vision or seizures. Neck stiffness may be absent. Pulmonary, skin and disseminated disease can occur.

Diagnosis: serum or plasma cryptococcal antigen (CrAg) screening in advanced HIV; lumbar puncture with opening pressure, CSF CrAg, microscopy and culture when safe. Measure opening pressure every time where possible—raised intracranial pressure is a central cause of death. Brain imaging precedes LP when focal deficit, papilloedema, seizure, reduced consciousness or mass-effect risk is present.

Treatment: induction with amphotericin B plus flucytosine is preferred where available, followed by high-dose fluconazole consolidation and then maintenance. Resource-adapted regimens may use liposomal amphotericin single-dose plus flucytosine/fluconazole or amphotericin plus fluconazole according to current WHO/national guidance. Monitor renal function, potassium, magnesium, haemoglobin and infusion reactions.

Raised intracranial pressure: therapeutic lumbar punctures remove CSF until symptoms and pressure improve; repeat or use a drain/shunt with specialist care. Steroids, mannitol and routine acetazolamide are not substitutes for therapeutic CSF drainage.

ART timing: do not start ART immediately in cryptococcal meningitis; defer according to current guidance to reduce fatal CNS IRIS, coordinate with HIV/neurology teams and ensure fluconazole interaction review.

8.4 Toxoplasma encephalitis

Presentation: headache, fever, confusion, seizures, focal weakness, speech disturbance, visual symptoms or altered consciousness. Reactivation of tissue cysts is typical in advanced HIV.

Diagnosis: contrast-enhanced MRI/CT often shows multiple ring-enhancing lesions, frequently in basal ganglia with oedema. Toxoplasma IgG supports prior exposure but is not proof of active CNS disease; IgG negativity makes reactivation less likely. CSF PCR, ophthalmic examination, biopsy or alternative infection testing may be required. Consider primary CNS lymphoma, TB, cryptococcus, bacterial abscess and PML.

Treatment: pyrimethamine plus sulfadiazine plus folinic acid is a classic regimen; cotrimoxazole is an important alternative where appropriate. Treat for at least six weeks and continue until clinical/radiological improvement, then secondary prophylaxis until immune recovery. Give corticosteroid only for substantial mass effect/oedema and anticonvulsants after seizures, not routinely.

Prevention: cotrimoxazole may prevent both toxoplasmosis and PJP. Advise safe meat cooking, hand hygiene, avoiding cat-litter exposure where possible and washing soil-contaminated produce.

8.5 Tuberculosis in HIV

TB may be pulmonary, disseminated, lymph-node, CNS, abdominal, pleural or pericardial. Advanced HIV often produces atypical radiology, smear-negative disease and extrapulmonary infection. Use molecular testing, site-specific specimens, LF-LAM in eligible seriously ill patients and the current Uganda TB/HIV regimen. Start TB treatment promptly, manage rifampicin interactions and begin ART according to current guidance; TB meningitis requires special timing and specialist care. Refer to the site’s detailed TB chapter for the full diagnostic and treatment pathway.

8.6 Bacterial pneumonia and recurrent bacterial infection

HIV increases severe pneumococcal, staphylococcal, gram-negative and atypical pneumonia. Fever, productive cough, pleuritic pain, hypoxia and sepsis may be rapid. Obtain chest imaging, blood/sputum cultures where indicated, oxygenation and severity assessment. Treat according to local pneumonia/sepsis guidelines, review vaccination and investigate recurrent episodes for bronchiectasis, aspiration, smoking, TB, PJP and poor viral suppression.

8.7 Disseminated Mycobacterium avium complex (MAC)

Consider in very advanced untreated HIV with prolonged fever, night sweats, weight loss, diarrhoea, anaemia, lymphadenopathy or hepatosplenomegaly. Diagnosis requires culture/PCR from blood or sterile sites; disseminated TB, lymphoma and histoplasmosis are differentials. Treat with a macrolide plus ethambutol and specialist-guided additional therapy, while optimising ART. Primary prophylaxis is generally unnecessary when effective ART is started promptly, but follow current national criteria.

8.8 Cytomegalovirus (CMV)

CMV disease usually occurs at very low CD4 counts. Retinitis presents with floaters, blurred vision, scotomas, photopsias or visual-field loss and can become bilateral blindness. Colitis causes abdominal pain, fever, diarrhoea or bleeding; oesophagitis, pneumonitis and encephalitis are less common.

Diagnosis: urgent dilated retinal examination by an experienced clinician is central. Blood CMV PCR or antibodies alone does not prove retinitis; tissue histology/PCR supports tissue disease. The supplied OI deck emphasises that blood biomarkers cannot establish CMV retinitis by themselves.

Treatment: induction with IV ganciclovir or oral valganciclovir according to severity, absorption, renal function and eye involvement; intravitreal therapy may be needed for sight-threatening lesions. Maintenance continues until immune recovery and ophthalmology confirms healing. Check FBC and renal function and manage IRIS carefully.

8.9 Herpes simplex virus (HSV)

Chronic painful oral, genital or perianal ulcers lasting more than a month, severe oesophagitis, pneumonitis, hepatitis or encephalitis can occur. Diagnose clinically with PCR/swab when atypical or severe. Treat with acyclovir/valacyclovir; IV acyclovir is required for encephalitis or disseminated disease. Resistance in persistent lesions needs specialist testing and foscarnet consideration.

8.10 Varicella-zoster virus

Disseminated, recurrent, ophthalmic or multidermatomal zoster is more severe in HIV. Examine the eye and ear, assess for pneumonia/encephalitis, treat promptly with an antiviral and use current isolation precautions. Vaccination and ART reduce recurrence; avoid live vaccines in severe immunosuppression unless the national guideline specifically permits them.

8.11 Chronic protozoal diarrhoea

Cryptosporidiosis, cystoisosporiasis, cyclosporiasis and microsporidiosis cause watery diarrhoea, cramps, weight loss, dehydration and malabsorption. Send repeated stool specimens with special stains/antigen/PCR, evaluate for bacterial and CMV disease, rehydrate aggressively and optimise ART—the most important intervention. Use organism-specific therapy where effective and available, safe water, food hygiene and nutritional support.

8.12 Histoplasmosis and other disseminated fungi

Disseminated histoplasmosis can cause fever, weight loss, cough, lymphadenopathy, hepatosplenomegaly, mucocutaneous lesions, cytopenias and adrenal/CNS disease. Consider it in advanced HIV with travel/residence in endemic regions. Diagnosis uses antigen, culture, microscopy or tissue histology. Severe disease requires liposomal amphotericin induction followed by itraconazole maintenance under specialist guidance. Aspergillosis and other mould infections usually occur with profound immune compromise, neutropenia or structural lung disease.

8.13 Human papillomavirus and HIV-related malignancy

Persistent HPV causes anogenital warts, cervical intraepithelial neoplasia, anal disease and cervical cancer. HIV care must include cervical cancer screening, treatment of precancer, HPV prevention according to national policy and examination of anal/genital lesions. Kaposi sarcoma presents as violaceous skin, oral, lymphatic or visceral lesions; pulmonary or GI involvement can be life-threatening and requires oncology/HIV collaboration. Non-Hodgkin lymphoma and primary CNS lymphoma are important differentials for mass lesions, weight loss and neurological disease.

9. Opportunistic-infection prophylaxis

10. ART initiation and monitoring

ART is indicated for every person diagnosed with HIV unless a short, specific delay is required for a life-threatening CNS OI. Modern WHO guidance emphasises rapid initiation and regimens that suppress viral load, preserve immune function and reduce OIs. Uganda commonly uses dolutegravir-based first-line therapy, but the exact combination must follow the current national guideline, pregnancy/renal status and resistance history.

• Explain lifelong adherence, dosing, missed doses, side effects, disclosure, contraception and drug interactions.
• Check for TB, cryptococcal meningitis, severe OIs and pregnancy before rapid initiation.
• Use viral load as the primary measure of treatment success; investigate a raised result with adherence support, repeat testing and resistance evaluation according to policy.
• CD4 remains useful for advanced-disease risk and prophylaxis even when viral load is suppressed.
• Monitor weight, renal/liver function, glucose, lipids, neuropsychiatric symptoms, pregnancy, bone health and drug toxicity.

11. IRIS: immune reconstitution inflammatory syndrome

IRIS is an inflammatory worsening after ART begins because recovering immunity reacts to a known or previously silent infection. It may be unmasking IRIS (new presentation) or paradoxical IRIS (worsening of a treated OI).

• Common contexts: TB, cryptococcosis, CMV, MAC, herpes zoster and fungal infections.
• Features: fever, enlarging nodes, worsening pulmonary infiltrates, new abscesses, ocular inflammation or CNS deterioration after ART.
• Always exclude non-adherence, resistant infection, drug toxicity, a new infection, malignancy and an untreated OI.
• Continue ART in most cases; provide pathogen-specific therapy, analgesia/anti-inflammatory treatment and corticosteroids only for severe, organ-threatening inflammation under specialist advice.
• Cryptococcal CNS IRIS requires careful intracranial-pressure management and should not be treated by simply stopping ART without expert review.

12. HIV in pregnancy, breastfeeding and children

Pregnancy

Provide immediate linkage to ART and antenatal care, screen for TB/syphilis/hepatitis, prevent OIs, review drug interactions and plan delivery/infant prophylaxis according to national PMTCT guidance. Treat active OIs promptly; maternal hypoxia and severe infection threaten both patient and fetus.

Infants and children

Use virological early-infant diagnosis, weight-band paediatric ART, growth/development monitoring and age-appropriate prophylaxis. Watch for recurrent pneumonia, chronic diarrhoea, oral candidiasis, TB contact, lymphadenopathy, skin disease, developmental delay and HIV encephalopathy. Disclosure and adherence support must be age-appropriate.

13. Emergencies in advanced HIV

14. Clinical reasoning examples

15. Prevention, follow-up and survivorship

• Keep viral load suppressed through respectful adherence support and rapid re-engagement after missed visits.
• Screen for TB symptoms and contacts, cervical disease, STIs, hepatitis, mental illness, hypertension, diabetes, renal disease and cancers.
• Provide condoms, PrEP/PEP referral, safe-injection counselling, vaccination, nutrition and smoking/alcohol support.
• Assess long-term neuropathy, lipodystrophy, metabolic disease, bone health, pulmonary damage, vision, fertility and psychosocial wellbeing.
• Use community ART delivery and treatment supporters while protecting confidentiality and autonomy.

16. Examination pearls

• The type of OI depends on immune depth, geography, ART, prophylaxis and exposure—not CD4 alone.
• A normal chest radiograph does not exclude PJP, TB or early disseminated disease.
• Blood CMV PCR/antibody alone does not diagnose CMV retinitis; the retina must be examined.
• Cryptococcal meningitis is an intracranial-pressure emergency; repeated therapeutic lumbar puncture can be lifesaving.
• Before calling OI treatment failure, assess adherence, absorption, resistance, drug interaction, IRIS and a second infection.
• Start ART promptly in most OIs, but use special timing in cryptococcal and CNS TB disease.
• Every OI visit is an opportunity to prevent the next OI through ART, prophylaxis, vaccination and screening.

17. References and further reading

• SlideShare: HIV and Opportunistic Infections in HIV — PJP, candidiasis, toxoplasmosis, TB, CMV and treatment/prophylaxis teaching points.
• SlideShare: Opportunistic Infections in HIV — CD4-linked risk, organ-based OIs, cryptococcal meningitis, TB in HIV, CMV and prevention.
• WHO HIV treatment and technical guidance.
• Uganda Ministry of Health HIV prevention, testing, ART, PMTCT, TB/HIV and advanced HIV disease guidelines.
• Current WHO guidance for cryptococcal disease, advanced HIV disease, PJP, TB/HIV and opportunistic-infection prophylaxis.