HIV and AIDS — Written Clinical Reasoning

SAQ 1 — ART initiation in a complex patient with TB, hepatitis B and renal impairment (25 marks, 30 minutes)

Prompt: Outline your integrated assessment, the investigations you would order, your ART selection with justification, the drug-interaction and ART-TB timing considerations, opportunistic infection prophylaxis, the monitoring plan, and the shared decision-making framework. Justify each decision with evidence. [1]

Model Answer

Problem list (4 marks): [1]

1. Newly diagnosed HIV with advanced immunodeficiency — CD4 140 cells per microlitre (below 200 threshold for PCP prophylaxis) and viral load 180,000 copies per millilitre. He requires immediate ART under the Treat All policy, with careful sequencing given his active TB.
2. Active pulmonary tuberculosis on rifampicin-based therapy — the dominant timing dilemma, because rifampicin is a potent CYP3A4 inducer that interacts with multiple antiretrovirals, and because early ART in TB carries an IRIS risk that must be weighed against the mortality benefit of prompt immune recovery.
3. Chronic hepatitis B co-infection — HBeAg-negative chronic hepatitis B with high HBV DNA (2 million IU/mL). His ART regimen must include two agents active against both HIV and HBV (tenofovir plus lamivudine or emtricitabine), because stopping single-agent anti-HBV coverage in the context of HIV drives HBV resistance and flares.
4. Renal impairment — creatinine 190 micromol per litre, eGFR 35 mL/min, attributed to HIV-associated nephropathy. Tenofovir disoproxil fumarate (TDF) requires dose adjustment or substitution with tenofovir alafenamide (TAF) at this GFR, and nephrotoxic co-administration must be avoided.
5. Injection drug use and depression — adherence barriers and drug interactions that affect regimen choice, monitoring frequency, and psychosocial support needs.
6. Risk of opportunistic infections by CD4 threshold — at CD4 140 he is at risk for Pneumocystis jirovecii pneumonia and toxoplasma encephalitis (if seropositive); he is approaching the CD4 50 threshold for CMV and MAC risk. [1]

Step 1 — Immediate assessment and confirmatory workup (3 marks): [1]

I would confirm the diagnosis with a 4th-generation HIV combination antigen/antibody test (already reactive) and a supplementary differentiation assay to confirm HIV-1 (versus HIV-2, which alters the dolutegravir and non-nucleoside choices). I would obtain baseline bloods: full blood count, liver function tests, creatinine and eGFR, fasting lipid panel, glucose, CD4 count (repeat to confirm), HIV RNA viral load, and a genotypic resistance test (never start ART in a complex patient without knowing the baseline resistance pattern). Hepatitis serology is known (HBsAg positive); I would add anti-HCV, hepatitis A serology, and a syphilis serology. I would check a toxoplasma IgG (to determine prophylaxis strategy), a CMV IgG, and a Quantiferon (though he already has active TB). I would arrange a baseline ECG, a chest X-ray (to track the TB response), and a DEXA scan if he will receive tenofovir long-term. I would perform a baseline urinalysis (proteinuria from HIVAN) and consider a renal ultrasound. I would assess his mental state (PHQ-9 for depression), his substance use pattern, and his readiness to start therapy. [1]

Step 2 — ART regimen selection with justification (6 marks): [1]

The regimen must simultaneously address HIV, hepatitis B, and the renal impairment, while being compatible with rifampicin. My approach: [1]

The backbone must include tenofovir plus lamivudine (or emtricitabine) because these agents are active against both HIV and hepatitis B [1]. Given his eGFR of 35 mL/min, I would use tenofovir alafenamide (TAF) rather than TDF — TAF achieves equivalent antiviral efficacy at approximately one-tenth of the plasma tenofovir exposure, with significantly less bone and renal toxicity, and does not require dose adjustment until eGFR falls below 30 mL/min. I would use lamivudine 300 mg daily as the second NRTI. This addresses both the HIV and the HBV.

For the third agent, the dolutegravir question is central. Dolutegravir is the WHO-preferred first-line INSTI worldwide and has a high genetic barrier to resistance [6]. However, when co-administered with rifampicin, dolutegravir levels are reduced by approximately 50 per cent because rifampicin is a potent inducer of UGT1A1 and CYP3A4. The standard compensatory strategy is to double the dolutegravir dose to 50 mg twice daily for the duration of rifampicin therapy, then revert to 50 mg once daily after rifampicin is completed. This approach is endorsed by WHO and DHHS. An alternative is efavirenz 600 mg nightly, which is rifampicin-compatible without dose adjustment, but efavirenz has a lower barrier to resistance, neuropsychiatric side effects (relevant given his depression), and is inferior to dolutegravir in the SINGLE trial (81 per cent versus 88 per cent viral suppression at week 48) [6].

My regimen would therefore be: tenofovir alafenamide 25 mg plus lamivudine 300 mg plus dolutegravir 50 mg twice daily (the extra dose for rifampicin), reverting to once-daily dolutegravir after the rifampicin course is completed. This is a single regimen that controls HIV, controls hepatitis B, is safe in moderate renal impairment, and is compatible with rifampicin. [1]

Step 3 — The ART-TB timing question (3 marks): [1]

The timing of ART initiation in the setting of active TB is governed by two competing risks: delaying ART risks further opportunistic infections and death from uncontrolled HIV, while early ART risks TB-associated IRIS. The evidence base is the CAMELIA and SAPiT trials, which showed that early ART (within 2 weeks of TB therapy initiation) reduced mortality in patients with CD4 below 50. For patients with CD4 50 to 220 (this patient has CD4 140), the SAPiT trial showed that ART within 4 weeks reduced the composite of AIDS and death compared with delaying to after TB treatment completion, though the IRIS rate was higher. [1]

My approach: start ART within 2 weeks of TB therapy initiation, because his CD4 is below 200 and he is at significant risk of further opportunistic infections. I would counsel him explicitly about TB-IRIS — paradoxical fever, worsening lymphadenopathy, worsening infiltrates or effusions within the first 4 to 8 weeks of ART — and explain that this is an inflammatory response to recovering immunity, not treatment failure, and that ART is continued through it. Severe IRIS (respiratory compromise, significant effusions) is managed with corticosteroids (prednisolone 1.5 mg/kg/day for 2 weeks, tapering over 4 weeks, based on the prednisolone for TB-IRIS trial). [1]

Step 4 — Hepatitis B co-infection management (3 marks): [1]

The critical principle is that his ART regimen must never be stopped or the anti-HBV component removed without an alternative anti-HBV agent in place, because sudden withdrawal of anti-HBV therapy can precipitate a severe hepatitis B flare, hepatic decompensation, and death. Tenofovir (TAF here) and lamivudine are both active against HBV; together they provide dual anti-HBV coverage that suppresses HBV DNA and prevents resistance. I would monitor his HBV DNA, liver function tests and HBV serology every 3 to 6 months. If his HBV DNA does not suppress, I would involve hepatology. I would ensure he is screened for hepatocellular carcinoma (liver ultrasound and AFP every 6 months, given the HBV co-infection). I would vaccinate against hepatitis A if seronegative. [1]

Step 5 — Opportunistic infection prophylaxis (3 marks): [1]

At CD4 140, he is below the threshold for PCP prophylaxis (CD4 below 200). I would start co-trimoxazole 960 mg daily (or 480 mg daily if tolerated), which covers Pneumocystis jirovecii, Toxoplasma gondii (if he is toxoplasma IgG positive), and common bacterial respiratory and enteric pathogens. If his toxoplasma IgG is positive, co-trimoxazole is the preferred prophylaxis because it covers both PCP and toxoplasma. If toxoplasma IgG is negative, co-trimoxazole still covers PCP. [1]

When his CD4 falls below 50 (if it does before ART takes effect — though the expectation is that ART will drive CD4 recovery, the baseline is 140 so this is unlikely), I would add azithromycin 1200 mg once weekly for MAC prophylaxis and arrange baseline ophthalmology screening for CMV retinitis. [1]

Prophylaxis can be discontinued once his CD4 count rises above 200 for at least 3 consecutive months on ART, demonstrating sustained immune reconstitution. I would also ensure he is up to date on vaccinations (pneumococcal, influenza, hepatitis A and B, COVID-19, and HPV if eligible), given before ART takes full effect to maximise immunogenicity. [1]

Step 6 — Renal management and comorbidities (2 marks): [1]

His renal impairment (eGFR 35) is attributed to HIV-associated nephropathy, which typically improves with effective ART. I would monitor creatinine and eGFR every 2 to 4 weeks for the first 3 months (watching for TAF-related tubular dysfunction, though much less than TDF, and for ART-driven immune recovery improving the HIVAN). I would avoid all nephrotoxins, check his blood pressure, and involve nephrology if the renal function does not improve or worsens. I would address cardiovascular risk (the D:A:D study showed abacavir and didanosine increased MI risk — I am not using either, but I would note the signal [7]) with a lipid panel, smoking cessation counselling, and a statin if indicated.

Step 7 — Adherence, psychosocial support, and shared decision-making (2 marks): [1]

His intermittent methamphetamine use and depression are significant adherence barriers. The START trial established that ART benefits all patients regardless of CD4 [1], but benefit requires sustained adherence. I would take a non-judgemental approach, offer mental health support (psychology, addiction medicine), simplify his regimen as much as possible (a single-tablet regimen once rifampicin is completed), arrange a peer support worker, and ensure he has a named contact. I would explain U equals U — that once his viral load is undetectable, he cannot transmit HIV sexually [2][3] — which is a powerful adherence motivator. For his female partner, I would offer HIV testing, and if she is HIV-negative and at ongoing risk, discuss PrEP (tenofovir plus emtricitabine daily). I would frame HIV as a chronic, manageable condition with near-normal life expectancy on ART, and document the shared plan.

SAQ 2 — Opportunistic infection management in advanced HIV (15 marks, 20 minutes)

Prompt: A 45-year-old woman with HIV (not yet on ART) presents with a two-week history of subacute dyspnoea, dry cough and fever. Her CD4 count (taken one month ago) was 60 cells per microlitre. On examination, oxygen saturation is 92 per cent on room air at rest, dropping to 86 per cent on walking. Chest X-ray shows bilateral perihilar interstitial infiltrates. Serum LDH is 720 U per litre. Arterial blood gas on room air shows PaO2 64 mmHg. Three days into her admission she develops new visual floaters in the right eye. Outline your diagnosis, investigations, immediate management, and the management of each complication, with evidence. [1]

Model Answer

Step 1 — Establish the diagnosis of Pneumocystis jirovecii pneumonia (3 marks): [1]

This is Pneumocystis jirovecii pneumonia (PCP) until proven otherwise. The clinical tetrad — subacute dyspnoea and dry cough over two weeks, fever, bilateral interstitial infiltrates on chest X-ray, and exertional desaturation — is the classic presentation in a patient with CD4 below 200. The elevated LDH (720 U per litre) is a supportive but non-specific marker. The exertional desaturation (92 per cent resting dropping to 86 per cent on walking) is a hallmark of PCP and reflects the diffuse alveolar involvement. The PaO2 of 64 mmHg on room air places her in the moderate-to-severe category (PaO2 below 70 mmHg on room air), which is the threshold for adding corticosteroids. [1]

Diagnosis is by demonstration of the organism in induced sputum or bronchoalveolar lavage (with immunofluorescence or PCR). I would arrange induced sputum first (less invasive), proceeding to bronchoalveolar lavage if negative or if the diagnosis remains uncertain. A beta-D-glucan may be elevated (supportive). I would send atypical pneumonia serology and respiratory viral PCR to exclude alternative or concurrent diagnoses. A HRCT chest would show the characteristic ground-glass infiltrates if the chest X-ray is equivocal, but the X-ray here is already diagnostic. [1]

Step 2 — Immediate PCP treatment with corticosteroids (4 marks): [1]

First-line therapy is high-dose co-trimoxazole (trimethoprim-sulfamethoxazole at 15 to 20 mg/kg/day of the trimethoprim component, in 4 divided doses) for 21 days. For a 60 kg woman, this is approximately 4 double-strength tablets (960 mg each) four times daily. I would monitor for adverse effects: rash, fever, neutropenia, thrombocytopenia, transaminitis, and hyperkalaemia (common, especially with high doses and in renal impairment). [1]

Corticosteroids are mandatory because her PaO2 is below 70 mmHg on room air. The evidence is clear that adjunctive corticosteroids reduce mortality in moderate-to-severe PCP by attenuating the inflammatory response to dying organisms. The standard regimen is prednisolone 40 mg twice daily for 5 days, then 40 mg daily for 5 days, then 20 mg daily to complete 21 days (or equivalent intravenous hydrocortisone or methylprednisolone if she cannot take oral). Corticosteroids should be started at the same time as, or slightly before, the co-trimoxazole. If she deteriorates despite co-trimoxazole and steroids, second-line agents include primaquine plus clindamycin, intravenous pentamidine, or trimetrexate. [1]

I would provide supplemental oxygen to maintain saturation above 92 per cent, monitor her gas exchange, and have a low threshold for intensive care involvement if she develops type 1 respiratory failure. I would correct any electrolyte disturbances, ensure hydration, and monitor renal function (co-trimoxazole and potential nephrotoxicity). [1]

Step 3 — When to start ART (2 marks): [1]

For PCP, ART should be started within 2 weeks of presentation, because early ART reduces progression to further opportunistic infections and death without significantly increasing PCP-IRIS risk (unlike TB-IRIS and cryptococcal-IRIS, which require ART deferral). I would start ART once she is clinically stabilising and the PCP therapy is underway — typically within 7 to 14 days of admission. I would use a standard first-line regimen (tenofovir plus emtricitabine plus dolutegravir) and explain the U equals U principle and the need for lifelong adherence. [1]

Step 4 — The new visual symptoms — CMV retinitis (4 marks): [1]

New visual floaters in the right eye at CD4 60 is CMV retinitis until proven otherwise. CMV retinitis is the most common sight-threatening opportunistic infection in AIDS, occurring at CD4 below 50. I would arrange urgent ophthalmology review for dilated fundoscopy — the same day. The classic fundoscopic appearance is yellow-white retinal infiltrates with haemorrhage along the vascular arcades (the "pizza pie" or "cottage cheese and ketchup" appearance). Diagnosis is clinical (fundoscopy), confirmed by CMV PCR of blood or aqueous humour if atypical. [1]

Treatment is valganciclovir 900 mg twice daily for 14 to 21 days (induction), then 900 mg once daily (maintenance), with immediate ophthalmology involvement. For sight-threatening disease (zone 1, near the macula or optic disc), intravenous ganciclovir or foscarnet may be required, and intravitreal ganciclovir injections may be used as adjunctive therapy. The induction phase halts progression; maintenance continues until immune reconstitution (CD4 above 100 for at least 3 to 6 months on ART). I would check a CMV PCR viral load and screen for extraocular CMV disease (colitis, oesophagitis, pneumonitis, polyradiculopathy) with a full assessment. CMV immune recovery uveitis can occur after ART initiation and requires topical or periocular corticosteroids. [1]

Step 5 — Prophylaxis and long-term surveillance (2 marks): [1]

She needs co-trimoxazole prophylaxis for PCP and toxoplasmosis (CD4 below 200), continued until CD4 is above 200 for at least 3 months on ART. She does not need routine anti-CMV prophylaxis (not recommended in developed-world guidelines), but she needs ongoing ophthalmology surveillance until her CD4 recovers. Once on ART with viral suppression and immune reconstitution, her risk of all opportunistic infections falls dramatically, and prophylaxis can be sequentially discontinued. [1]

I would sit with her and explain that these are treatable complications of advanced HIV, that ART is the definitive therapy for the underlying immune deficiency, and that with sustained viral suppression she can expect a near-normal life expectancy. I would offer a named contact, peer support, and a follow-up plan that includes CD4 and viral load monitoring every 3 months, with the explicit goal of achieving an undetectable viral load — and with it, the reassurance of U equals U [2][3].