Acquired immunodeficiency (HIV, drugs, post-transplant)

At a glance

• Secondary immunodeficiency is far commoner than primary. Most immunocompromised adults have it because of drugs, cancer, transplant, HIV, or protein loss.
• The component lost predicts the infection: T cells (HIV, steroids, calcineurin inhibitors), antibody (CLL, myeloma, anti-CD20), neutrophils (chemotherapy), spleen, or complement. The infection-by-defect table and drug toxicities are in Complications of immunosuppression.
• HIV: CD4 count sets the opportunistic infection risk and prophylaxis. Start ART for everyone, as soon as possible, except early in cryptococcal and TB meningitis.
• Secondary hypogammaglobulinaemia with infections is treated with immunoglobulin under the NBA Criteria.
• Opportunistic infection with no known cause needs an HIV test first.

Causes

Group	Examples	Main defect
Infection	HIV, measles (immune amnesia), EBV, CMV, sepsis	CD4 T cells (HIV); transient T-cell suppression
Drugs	Glucocorticoids, calcineurin inhibitors, antimetabolites, alkylators, biologics, JAK inhibitors, anticonvulsants	Varies by drug
Haematological malignancy	CLL, myeloma, lymphoma, after HSCT	Hypogammaglobulinaemia, neutropenia, T-cell dysfunction
Transplantation	Solid organ and stem cell	T cells, plus antibody and neutrophils
Loss of immunoglobulin	Nephrotic syndrome, protein-losing enteropathy, lymphangiectasia, burns, chylothorax	Low IgG with low albumin
Anatomical	Splenectomy, sickle cell disease	Encapsulated bacteria
Metabolic and systemic	Diabetes, CKD and dialysis, cirrhosis, malnutrition, older age	Neutrophil and T-cell dysfunction, poor vaccine responses
Thymoma	Good syndrome	Absent B cells, hypogammaglobulinaemia, T-cell defects

HIV as an immunodeficiency

Diagnosis and notification

• Fourth-generation antigen/antibody immunoassay, confirmed by supplementary testing and viral load. Most infections are detectable by 3 to 4 weeks and reference labs quote a 6-week window; HIV RNA turns positive first.
• HIV is notifiable in every Australian state and territory. Partner notification is part of care.
• Test anyone with an opportunistic infection, TB, an STI, hepatitis B or C, unexplained lymphopenia, thrombocytopenia, zoster under 50, lymphoma, or a mononucleosis-like illness. Offer testing routinely in pregnancy.

CD4 count and opportunistic infection

CD4 (cells/µL)	Typical infections and tumours
Any level	TB, bacterial pneumonia, zoster, Kaposi sarcoma, lymphoma
Under 200	PJP, oesophageal candidiasis, Cryptosporidium, PML; AIDS by definition
Under 100	Toxoplasma encephalitis, cryptococcal meningitis
Under 50	CMV retinitis, disseminated MAC, primary CNS lymphoma

Prophylaxis (HHS OI guidelines, used by ASHM)

Infection	Start	Drug	Stop
PJP	CD4 under 200, CD4 under 14%, or oral candidiasis	Co-trimoxazole 160/800 mg daily or three times a week	CD4 200 or more for over 3 months on ART; consider at CD4 100 to 200 with viral load suppressed for 3 to 6 months
Toxoplasma	IgG positive and CD4 under 100	Co-trimoxazole 160/800 mg daily	CD4 over 200 for over 3 months
MAC	Not needed if ART starts straight away	Azithromycin only if ART is delayed	When virally suppressed
Cryptococcus	Serum cryptococcal antigen screen if CD4 under 100	Pre-emptive fluconazole if positive and no meningitis (after LP)
TB	Latent TB on IGRA or TST	Isoniazid or rifamycin-based regimen

Antiretroviral therapy

• Everyone with HIV, whatever the CD4. The START trial (NEJM 2015) showed immediate ART more than halved serious AIDS and non-AIDS events in people with CD4 over 500.
• Rapid start, ideally within 7 days and often on the day of diagnosis, once baseline bloods (genotype, HBV serology, creatinine) are taken.
• Preferred first-line regimens are integrase-inhibitor based: bictegravir/emtricitabine/tenofovir alafenamide, or dolutegravir with two NRTIs. Dolutegravir/lamivudine is a recommended option, but not with hepatitis B coinfection or before genotype and HBV results are back. HHS used to exclude viral load over 500,000 copies/mL, but its September 2026 update recommends it regardless of baseline viral load, based on trials in advanced disease: DOLCE (CD4 200 or less, 61% with viral load over 100,000; 82% suppressed at 48 weeks) and VOGUE (non-inferior to bictegravir/emtricitabine/tenofovir alafenamide with no viral load or CD4 limit). It still isn't for rapid same-day starts, because HBV and genotype results are needed first.
• Undetectable = untransmittable: a sustained viral load under 200 copies/mL means no sexual transmission.
• Australian access: ART is PBS-listed under the s100 Highly Specialised Drugs Program, dispensed through hospital and community pharmacies. Daily tenofovir/emtricitabine PrEP is PBS-listed. Six-monthly injectable lenacapavir PrEP was TGA-registered in December 2025 but wasn't on the PBS Schedule as of November 2026; check for later listing.

Timing of ART after an OI, and IRIS

• Most OIs, including PJP: start ART within 2 weeks.
• Cryptococcal meningitis: wait 4 to 6 weeks from the start of antifungal treatment (WHO; HHS allows an individualised 2 to 10 weeks). The COAT trial (NEJM 2014) stopped early because ART at 1 to 2 weeks raised 26-week mortality (45% vs 30%). Cryptococcal IRIS rates did not differ significantly, so the excess deaths are not simply explained by IRIS.
• TB: within 2 weeks if CD4 is under 50, otherwise by 8 weeks (US DHHS). WHO 2021 recommends ART within 2 weeks of starting TB treatment whatever the CD4. TB meningitis is the exception: WHO delays ART by 4 to 8 weeks; get specialist advice.
• IRIS is clinical worsening as immunity recovers: paradoxical (a treated OI flares) or unmasking (a hidden OI appears), usually in the first 3 months. Continue ART and the OI treatment; prednisolone for moderate to severe TB-IRIS. Exclude drug resistance, a new infection and drug toxicity first.
• Preventing TB-IRIS: prophylactic prednisolone (40 mg daily for 2 weeks, then 20 mg daily for 2 weeks) for people with CD4 100 or less starting ART within 30 days of TB treatment. PredART excluded rifampicin-resistant, neurological and pericardial TB, Kaposi sarcoma and hepatitis B. In PredART (NEJM 2018) TB-IRIS fell from 47% to 33%.

Pitfall: a falling viral load with new fever and lymphadenitis is often IRIS, not treatment failure. Don't stop ART.

Drug-induced immunodeficiency

• Glucocorticoids: prednisolone 20 mg or more daily for 4 weeks or longer warrants PJP prophylaxis, particularly with another immunosuppressant: co-trimoxazole 160/800 mg three times a week or 80/400 mg daily. They also mask fever and peritonism.
• Anti-CD20 (rituximab, ocrelizumab, obinutuzumab): B-cell depletion for 6 to 12 months, cumulative hypogammaglobulinaemia with repeated courses, late-onset neutropenia, HBV reactivation, PML. Check IgG and HBV serology before starting and IgG before each further course.
• CAR-T and bispecific antibodies (BCMA, CD20, CD19 targets) cause profound, prolonged hypogammaglobulinaemia. Many centres give immunoglobulin when IgG falls below 4 g/L.
• Anticonvulsants (phenytoin, carbamazepine, lamotrigine), sulfasalazine and penicillamine can lower IgG or IgA; usually reversible on stopping.
• Complement inhibitors (eculizumab, ravulizumab): meningococcal disease. TNF inhibitors: TB reactivation. JAK inhibitors: zoster.

Haematological malignancy and secondary hypogammaglobulinaemia

• CLL and myeloma reduce normal immunoglobulin production. Infection is a leading cause of death in CLL.
• Look for bacterial sinopulmonary infection; check IgG excluding the paraprotein, and vaccine responses where they would change treatment.
• NBA Criteria (version 3) for haematological malignancy or after HSCT: IgG under 4 g/L (excluding paraprotein), or IgG above 4 g/L but below the reference range with serious (such as life-threatening) infection in the past 12 months. Check the exact infection wording on the current Criteria site before applying through BloodSTAR.
  • Dose: 0.4 g/kg every 4 weeks, with a loading dose in the first month if IgG is under 4 g/L; aim for a trough at least at the lower limit of normal. Review benefit regularly and trial cessation where infections have settled.
• Hypogammaglobulinaemia after anti-CD20 therapy for autoimmune disease, solid organ transplantation or thymoma is outside this indication. Secondary hypogammaglobulinaemia unrelated to haematological malignancy has its own, stricter NBA indication.
• Prophylactic antibiotics are an alternative where infections are mild.

The workup of a low IgG is in Agammaglobulinaemia and hypogammaglobulinaemia.

After transplantation

• Solid organ: induction (basiliximab or ATG) then tacrolimus, mycophenolate and prednisolone. The infection timeline (surgical in month 1, opportunistic in months 1 to 6, community and late CMV after that) and CMV and BK management are in Fever in renal transplant recipients.
• Allogeneic HSCT: neutropenia until engraftment, then a T-cell deficit for 6 to 12 months or longer, prolonged by GVHD and its treatment (see Graft-versus-host disease). Recipients lose vaccine immunity and need revaccination from scratch, inactivated vaccines from 3 to 6 months and live vaccines only under the "2-1-8" rule: at least 24 months after transplant, at least 1 year off systemic immunosuppression, at least 8 months since the last immunoglobulin dose, and no active GVHD.
• PTLD: EBV-driven, highest in year 1 and in EBV-negative recipients of EBV-positive organs.

Investigations for suspected acquired immunodeficiency

• HIV test first in unexplained or opportunistic infection.
• FBC and film (lymphopenia, neutropenia, Howell-Jolly bodies after splenectomy), UEC, LFTs, albumin, urine protein.
• IgG, IgA, IgM, serum protein electrophoresis and free light chains.
• Lymphocyte subsets (CD4 count) and, where relevant, vaccine responses.
• CT chest and abdomen for thymoma or lymphoma when the cause is unclear.

Vaccination

• Inactivated vaccines are safe; give them ideally 2 weeks before immunosuppression starts (Australian Immunisation Handbook): influenza, COVID-19, pneumococcal, recombinant zoster.
• Live vaccines are contraindicated with significant immunosuppression. In HIV, MMR and varicella vaccines can be given if CD4 is 200 cells/µL or more.
• Responses are poor during anti-CD20 therapy; vaccinate before it or at least 6 months after.

Special populations

• Pregnancy: HIV testing at the first antenatal visit; ART with suppressed viral load makes perinatal transmission under 1%.
• Aboriginal and Torres Strait Islander people: screen for strongyloides, HTLV-1 (central Australia), TB and hepatitis B before immunosuppression.
• Older people: a new low IgG is CLL, myeloma or a drug until proven otherwise; immunosenescence lowers vaccine responses, so give the higher-dose or adjuvanted influenza vaccine.

Pitfalls

• Missing HIV in a patient with PJP, TB, zoster or unexplained cytopenias because they "don't fit the risk profile".
• Starting ART within 2 weeks of cryptococcal meningitis.
• Stopping ART for IRIS.
• Calling hypogammaglobulinaemia primary before excluding CLL, myeloma, rituximab, anticonvulsants and protein loss.
• Measuring total IgG in myeloma without excluding the paraprotein.
• Giving live vaccines to transplant recipients or people on high-dose steroids or biologics.
• Forgetting revaccination after allogeneic HSCT.