Opportunistic Infection Prophylaxis in HIV: The Evidence Behind the Pathway

A 34-year-old man has just been told he has HIV. He came because of a sore mouth and weight loss over three months. His CD4 count is 82 cells/µL, and he is in WHO clinical stage 3. He has not started ART yet. He has no known drug allergy, and he has never had cryptococcal disease. This is an illustrative case, not a real patient.

By the end of this article you will know the three things he needs before he leaves the clinic. You will know why each one starts when it does, and when each one can stop.

1. Three Questions for Every Prophylaxis

An opportunistic infection (OI) is one that a healthy immune system keeps away, and that takes its chance when the CD4 count falls. Prophylaxis means giving a medicine, or doing a test, before that infection shows itself. For each one, ask three questions. When do I start it? What do I give? When can I stop it?

The tool answers all three in one quick reference table. In the tool it is now shown as two narrower tables; here it is as one:

Read the first and last columns together. Each start has its own stop, and most of the stops are set by the CD4 count on ART, not by the calendar. The two TB preventive regimens are the exception: they are courses, and they stop when the course is complete.

2. Cotrimoxazole: Easy to Start, Careful to Stop

Cotrimoxazole (trimethoprim-sulfamethoxazole, TMP-SMX) prevents Pneumocystis jirovecii pneumonia (PCP) and toxoplasmosis. The tool starts it at a CD4 below 350 cells/µL, or at WHO stage 3 or 4 whatever the count. It also gives it to every person with pulmonary or extra-pulmonary tuberculosis, whatever the CD4 and whatever the stage. The dose is one double-strength tablet, 960 mg, once daily.

“His count will rise on ART. Can I stop the cotrimoxazole when it crosses 350?” Not on one reading. The tool stops it only once the CD4 has been above 350 on two readings 6 months apart, with a suppressed viral load, on ART. A single count is not enough. And it is never stopped during a pregnancy.

Three cautions come with it. A sulfonamide rash occurs in 3 to 5%. It is usually mild and settles. But if the reaction is severe, Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), the drug is stopped at once and never given again. In a sulfonamide allergy, dapsone 100 mg once daily takes its place. Screen for G6PD deficiency first, because dapsone can cause a severe haemolytic anaemia. And remember that it covers PCP only, not toxoplasmosis. In pregnancy, cotrimoxazole continues, and the tool adds folic acid 5 mg daily, because trimethoprim is a folate antagonist.

3. TB Preventive Treatment: Exclude Active TB First

TB preventive treatment (TPT) is given at any CD4 count, once active TB has been excluded. NACO’s guidance of 20 May 2024 prefers 1HP: isoniazid 300 mg with rifapentine 600 mg daily for 28 days, for everyone aged 13 and above. 6H, isoniazid 300 mg daily for 6 months, is for three groups: pregnant or breastfeeding women, children below 13, and anyone on a protease inhibitor. Rifapentine is not given with a protease inhibitor. Dolutegravir needs no dose change with 1HP. Pyridoxine 25 mg daily goes with both.

You may read that WHO now prefers a different regimen. It does: its update of 7 January 2026 prefers 3HP, weekly isoniazid with rifapentine for three months, for adults and adolescents living with HIV. NACO’s guidance names 1HP, and NACO is the operative source for Indian practice, so the tool prints 1HP. Check the current NACO edition before you change a TPT regimen.

“Why can’t I just start the isoniazid today?” Because he may already have TB. Before TPT, ask about the four symptoms: cough for more than 2 weeks, fever, weight loss and night sweats. If any one is positive, do a GeneXpert first. Otherwise you are giving isoniazid alone against an undiagnosed active TB, and resistance follows quickly. Our patient has lost weight, so his screen is positive, and he needs a GeneXpert before any TPT.

Two harms of isoniazid are watched for. The first is the liver. The risk rises with age above 35, with alcohol use and with pre-existing liver disease. The tool asks for the ALT at baseline, then monthly for the first 3 months. It stops the drug if the ALT is above 3 times the upper limit of normal (ULN) with symptoms, or above 5 times without. The second is the nerves. Isoniazid depletes pyridoxine (vitamin B6), so pyridoxine 25 mg daily is prescribed from the first day of the course, not once the tingling begins.

4. A Low CD4 Count Means a Cryptococcal Antigen Test

At a CD4 below 100, the tool asks for a serum cryptococcal antigen (CrAg) test by lateral flow assay. This is a screening test: it looks for the cryptococcus in a patient who has not yet been diagnosed with cryptococcal disease.

“And if it is positive?” Then do a lumbar puncture (LP) before anything else. The tool’s reason is that a positive antigen may come with a meningitis that has not yet shown itself, a subclinical meningitis, and that needs far more than prophylaxis. If the LP is negative, the tool gives pre-emptive fluconazole: 800 mg daily for 2 weeks, then 400 mg daily for 8 weeks, then 200 mg daily. If the LP shows meningitis, that needs full induction treatment with amphotericin B, and the tool asks for ART to be delayed by 4 to 6 weeks.

A patient who has already been treated for cryptococcal disease does not need the screening test. He needs secondary prophylaxis: fluconazole 200 mg once daily. It continues until the CD4 has been above 200 for at least 6 months on suppressive ART, and at least a year of fluconazole has been completed.

Back to Our Patient

His CD4 of 82 is below 350, and he is in stage 3, so he starts cotrimoxazole 960 mg once daily today. It continues until his CD4 has been above 350 on two readings 6 months apart, with a suppressed viral load. His weight loss makes the TB symptom screen positive, so he has a GeneXpert. If it is negative, he starts 1HP with pyridoxine 25 mg, with an ALT at baseline and then monthly. His CD4 is below 100, so a serum CrAg is sent before he starts ART. If it comes back positive, an LP comes next.

The Common Mistake

The common mistake is to stop cotrimoxazole on the first good CD4 count. It is easy to see why: the patient is well, the number has crossed the line, and one tablet fewer is welcome. But the tool’s rule asks for two readings above 350, 6 months apart, with a suppressed viral load. One reading tells you where the count is today. Two readings, with a suppressed viral load, tell you that it is staying there.

Try This

A 41-year-old man has been on a protease inhibitor regimen for two years. He has taken cotrimoxazole all along. His last two CD4 counts, 6 months apart, are 410 and 460, and his viral load is suppressed. He has never had TPT, and his symptom screen is negative. What changes? Illustrative case.

Answer. Two counts above 350, 6 months apart, with a suppressed viral load on ART: the cotrimoxazole can stop. For TPT, he is on a protease inhibitor, so rifapentine is not given and 1HP is not an option. He gets 6H: isoniazid 300 mg with pyridoxine 25 mg once daily for 6 months, with an ALT at baseline and monthly for 3 months.

Take-Home Points

• Ask three questions of every prophylaxis: when to start, what to give, when to stop.
• Cotrimoxazole starts at a CD4 below 350 or at WHO stage 3 or 4, and stops only after two counts above 350, 6 months apart, with a suppressed viral load.
• Screen for active TB before TPT: any one of cough, fever, weight loss or night sweats means a GeneXpert first.
• 1HP is NACO’s preferred TPT from 13 years; 6H is for pregnancy, breastfeeding, children below 13 and anyone on a protease inhibitor.
• A CD4 below 100 means a serum CrAg; a positive CrAg means an LP before pre-emptive fluconazole.

How the regimen itself is monitored once ART starts is in Monitoring Antiretroviral Therapy: The Evidence Behind the Guide.

Declaration: the author built and maintains the tool. It is free to use. The figures in this article are those the tool carried on 5 November 2026, in its Evidence tab and in the plan it prints, each from the NACO, NTEP and WHO guidance the tool names. The illustrative cases follow the tool’s rules; check the tool’s result for a real patient.

References

1. NACO. National Guidelines for HIV Care and Treatment. MoHFW, GoI; 2021.
2. NACO. Guidance on TB Preventive Treatment (TPT) for People Living with HIV. MoHFW, GoI; 20 May 2024.
3. WHO. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. Geneva: WHO; 2021.
4. WHO. WHO consolidated guidelines on tuberculosis. Module 1: prevention. Tuberculosis preventive treatment. Geneva: WHO; 2020, with the 2024 update.
5. Gupta A, Montepiedra G, Aaron L, et al. Isoniazid preventive therapy in HIV-infected pregnant and postpartum women. N Engl J Med. 2019;381(14):1333-1346.
6. World Health Organization. WHO updated recommendations on HIV clinical management: recommendations for a public health approach. Geneva: WHO; 7 January 2026.