HIV Infection: Treatment

HIV is a chronic retroviral infection that, left untreated, progressively damages the immune system and eventually causes death from opportunistic infections or AIDS-defining cancers. Since the mid-1990s, combination antiretroviral therapy (ART) has transformed that trajectory: sustained viral suppression on ART allows near-normal immune function and life expectancy.^[1] The standard of care today is "test and treat" — offering ART to every person with a confirmed HIV diagnosis as soon as possible, ideally the same day the diagnosis is confirmed, regardless of CD4 count or symptoms — because earlier initiation improves survival and because a person with a durably suppressed viral load essentially cannot transmit HIV sexually.^[2][3] This chapter covers treatment of adults with an already-confirmed HIV-1 diagnosis; screening and pre-/post-exposure prophylaxis for HIV-negative individuals are covered in the separate HIV Infection: Prevention chapter.

The clinical spectrum of established HIV infection

Many people are asymptomatic at diagnosis and for years afterward; others present with constitutional symptoms (fatigue, weight loss, lymphadenopathy) or an overt opportunistic infection or AIDS-defining illness. CD4 count is the key marker of where a patient sits on this spectrum and which complications become relevant.

Recognizing immune reconstitution inflammatory syndrome (IRIS)

As the immune system recovers after starting ART, it can mount an exaggerated inflammatory response to a pre-existing infection — either "unmasking" a previously subclinical opportunistic infection or causing a "paradoxical" worsening of one already being treated. IRIS typically appears within days to a few weeks of starting or restarting ART, and is most common in patients who start with a very low CD4 count (roughly under 50-100 cells/mcL) and a rapid subsequent CD4 rise or viral load drop. It presents as new or worsening fever, lymphadenopathy, or localizing symptoms referable to the specific unmasked or paradoxically-worsening infection (for example, worsening respiratory symptoms and new lymphadenopathy in tuberculosis-associated IRIS, or new visual symptoms in cytomegalovirus-associated IRIS) — it is easy to mistake for treatment failure or a new infection if this pattern is not specifically considered.^[5]

Recognizing virologic failure

Unlike an acute opportunistic infection, virologic failure is usually silent — it is detected through routine viral load monitoring rather than through symptoms, which is why the monitoring schedule in this chapter matters as much as the initial regimen choice.

• Low baseline CD4 count or high baseline viral load at the time ART is started.
• Delayed ART initiation after diagnosis.
• Nonadherence — the single most important modifiable driver of virologic failure and drug resistance.
• Active substance use, untreated mental illness, or unstable housing, food, or financial insecurity — all strongly affect adherence and retention in care.
• Hepatitis B or C coinfection.
• Active, untreated tuberculosis or latent tuberculosis infection.
• Transmitted (pretreatment) drug-resistant virus.
• Pregnancy — ART selection and urgency both change (see Special Populations).
• Adolescents and young adults transitioning between pediatric and adult care, who are at particular risk of gaps in follow-up.
• Significant drug-drug interactions with a patient's other medications that reduce antiretroviral levels below the threshold needed for suppression.

History

At-risk behaviours and estimated duration of infection where it can be established; general indicators (anorexia, weight loss, fatigue, lymphadenopathy) and symptoms suggesting an opportunistic infection (fever, night sweats, cough, dyspnea, diarrhea, headache, skin rashes); sexual history and the HIV status of regular partners; mental health, substance use, and social history (housing stability, drug coverage, social support, disclosure concerns); past medical history including other sexually transmitted infections, prior opportunistic infections or AIDS-defining conditions, tuberculosis exposure/testing history, hepatitis A/B/C, varicella, comorbidities that affect regimen choice (renal, hepatic, cardiovascular disease, diabetes, osteoporosis, peripheral neuropathy, mental health disorders, substance use), allergies, immunization history, complete medication history (prescription, nonprescription, complementary/alternative, and any prior antiretroviral exposure including PrEP), and reproductive history/pregnancy plans.

Physical examination

Height, weight, BMI, blood pressure, waist circumference; focused assessment of mental health and cognitive status; skin, oral cavity, lymph nodes, abdomen, and genital/rectal examination (including cervical cytology where applicable).

Baseline investigations

• Confirm HIV status with an antibody/antigen test if a prior positive result is not already documented.
• Plasma HIV RNA (viral load) and CD4 count/percentage — the key prognostic markers and the baseline against which treatment response is measured.
• Genotypic resistance testing at baseline, as soon as possible after diagnosis — do not wait to start ART for this result to return; start a regimen expected to remain active against most resistance patterns and adjust once results are available. Repeat resistance testing with any confirmed virologic failure (viral load rebound above 200 copies/mL on therapy).^[2]
• Screen every patient for the HLA-B*5701 allele before starting abacavir. A positive result is recorded in the chart as a lifelong abacavir allergy/contraindication — do not use abacavir in a patient who tests positive, even though most HLA-B*5701-positive patients would never actually develop a reaction; the test is used because a true reaction can be severe or fatal.^[6]
• A tropism assay (to determine CCR5, CXCR4, or dual/mixed tropism) is needed only if maraviroc is being considered — this is not a routine baseline test.
• CBC with differential and platelets; liver panel (ALT, AST, bilirubin, albumin, INR) and renal panel (creatinine, eGFR, phosphorus, urinalysis, urine albumin- or protein-to-creatinine ratio); fasting glucose and/or HbA1c and a lipid panel; pregnancy test where relevant.
• Hepatitis A, B, C, syphilis, and Toxoplasma serologies (abdominal ultrasound if hepatitis B or C is positive); gonorrhea/chlamydia testing by site of exposure; tuberculosis screening (TST and/or IGRA), with a chest x-ray and sputum studies if indicated; a serum cryptococcal antigen if the CD4 count is under 100 cells/mcL.

• Achieve and maintain viral suppression below the detection limit of the assay used (commonly under 20-40 copies/mL) — virologic failure is defined as an inability to sustain a viral load under 200 copies/mL.
• Restore and preserve CD4 count and overall immune function.
• Prevent opportunistic infections and AIDS-defining illness.
• Prevent onward sexual transmission of HIV — a durably suppressed viral load (confirmed for at least 6 months, with good adherence) reduces sexual transmission risk to a negligible level.
• Delay or prevent the emergence of drug-resistant HIV.
• Slow disease progression, prolong survival, and improve quality of life.

• Adherence counselling and support at every visit — pillboxes, reminder apps, pharmacist-led follow-up, and addressing drug coverage or access barriers — since adherence is the single most important determinant of durable viral suppression.^[7]
• General counselling at every visit, regardless of CD4 count: risk of onward transmission and how to reduce it, the legal implications of not disclosing HIV status to sexual partners (which vary by jurisdiction — direct patients to local legal resources when this is a concern), proper nutrition, physical activity, and the importance of ongoing follow-up.
• Tuberculosis screening (TST and/or IGRA) with treatment of latent tuberculosis infection when indicated.
• Vaccination: pneumococcal vaccine; hepatitis A and B vaccines if nonimmune on serology; updated diphtheria/tetanus/pertussis; annual influenza; MMR and varicella if the CD4 count is over 200 cells/mcL and the patient is not pregnant; meningococcal vaccine periodically; HPV, herpes zoster, and COVID-19 vaccines per current local guidelines; mpox vaccine where available and appropriate.
• Cervical cytology (Pap testing) and anal cytology screening where indicated, per local screening guidance.
• Screen for and address comorbid mental health and substance use concerns, and unstable housing, food, or financial insecurity — these strongly affect both adherence and retention in care.
• Harm-reduction services (sterile injection equipment, opioid agonist therapy) for people who inject drugs.
• Contraception and pregnancy-planning counselling, since ART regimen choice differs meaningfully around a planned or confirmed pregnancy (see Special Populations).
• Antiretroviral drug-interaction counselling — this is one of the highest-yield things a pharmacist does for a person on ART. Integrase inhibitors that are not boosted (dolutegravir, bictegravir, raltegravir) have GI absorption impaired by polyvalent cations — separate dolutegravir- or bictegravir-containing regimens from calcium, iron, magnesium, or aluminum-containing antacids, laxatives, sucralfate, or mineral supplements by roughly 2 hours before or 6 hours after (raltegravir has its own specific spacing requirements — check the product monograph, since the high-dose once-daily tablet and the standard twice-daily tablet differ). A cobicistat- or ritonavir-boosted regimen (darunavir/cobicistat, darunavir/ritonavir, atazanavir/ritonavir, elvitegravir/cobicistat combinations) is a potent CYP3A inhibitor with a broad interaction footprint — review every new prescription and over-the-counter/natural health product against a validated, currently maintained HIV drug-interaction resource (for example, the University of Liverpool HIV Drug Interactions checker) before dispensing, since boosted regimens can substantially raise levels of statins (avoid simvastatin and lovastatin outright; reduce the dose of others), hormonal contraceptives (efficacy can be reduced — recommend a backup method), inhaled or intranasal corticosteroids (risk of Cushing syndrome and adrenal suppression, most documented with fluticasone), and PDE5 inhibitors (reduce the dose).

Breastfeeding

A person on ART with a sustained, suppressed viral load has a low, but not zero, risk of transmitting HIV to an infant through breastfeeding; replacement feeding with infant formula eliminates that risk. Provide evidence-based, non-judgmental counselling on infant feeding options to support shared decision-making, rather than defaulting to a single recommendation for every patient.

Renal impairment

Tenofovir disoproxil fumarate requires dose-interval adjustment as creatinine clearance falls, and caution is warranted with pre-existing or high risk of osteoporosis given its bone mineral density effect; tenofovir alafenamide has a smaller effect on renal function and bone density and is often preferred at lower creatinine clearance, though most tenofovir alafenamide combination products are also not recommended below a specific creatinine clearance threshold (commonly 30 mL/min) — check the specific product. Elvitegravir/cobicistat combinations have their own, higher renal cutoffs. Darunavir, dolutegravir, bictegravir (as part of its combination product, subject to the same renal floor as its backbone), raltegravir, and lenacapavir do not require dose adjustment for renal impairment.

Hepatic impairment

Most antiretrovirals require no adjustment in mild-to-moderate hepatic impairment; boosted protease inhibitors carry the most hepatotoxicity risk and need closer monitoring. Consult product-specific guidance for severe (Child-Pugh C) impairment.

Hepatitis B coinfection

Use a backbone with 2 agents active against both HIV and hepatitis B — emtricitabine or lamivudine plus tenofovir (disoproxil fumarate or alafenamide). Never discontinue or switch off these agents without ensuring continued hepatitis B coverage — stopping them abruptly can precipitate a severe hepatitis B flare.

Hepatitis C coinfection

Screen for significant interactions between the antiretroviral regimen and direct-acting antiviral hepatitis C therapy before starting either — several antiretrovirals and DAAs share metabolic pathways.

Older adults

No specific dose adjustment is generally required based on age alone, but screen more closely for polypharmacy-related interactions, renal function decline, and cardiovascular/bone comorbidities that affect regimen choice.

Pediatrics and adolescents

This chapter's dosing is for adults. Pediatric and adolescent antiretroviral dosing is weight- and age-based, differs substantially from adult dosing, and must be directed by a pediatrician or pediatric HIV specialist using pediatric-specific guidance — do not extrapolate adult doses downward.

Mental health and substance use comorbidity

Avoid efavirenz in patients with a history of anxiety, depression, or psychosis given its CNS toxicity profile. Integrase inhibitors, particularly dolutegravir, have also been associated with insomnia and other neuropsychiatric effects in some patients — monitor for this after starting or switching to any integrase-inhibitor-based regimen.

Routine monitoring, once on ART

Plasma viral load every 3-4 months; this can be extended to every 6 months once the patient has an undetectable viral load and good adherence on a stable regimen for over 1 year, and should be increased again if the patient becomes symptomatic or is diagnosed with an AIDS-defining illness. CD4 count every 3-4 months; CD4 monitoring becomes optional once the viral load is undetectable and the CD4 count has been 300 cells/mcL or higher for 1-2 years, and should resume if the patient becomes symptomatic or is diagnosed with AIDS. Genotypic resistance testing at baseline and again with any confirmed viral load rebound above 200 copies/mL.^[2]

Renal function (creatinine/eGFR, urinalysis) and hepatic function at baseline and periodically thereafter — more frequently with a tenofovir- or boosted-PI-containing regimen. Fasting lipids and glucose/HbA1c periodically, since several antiretroviral classes affect metabolic risk. Consider bone density assessment in patients with additional osteoporosis risk factors on a tenofovir disoproxil fumarate-containing regimen. History and physical examination at least annually, including reinforcement of adherence, vaccination status, and cancer screening appropriate to age and risk (including cervical and anal cytology where indicated).

After starting or changing ART

Watch specifically for signs of immune reconstitution inflammatory syndrome in the weeks after starting or restarting ART, particularly in a patient who started with a very low CD4 count.^[5] Reassess tolerability within the first weeks, since most antiretroviral adverse effects that prompt a regimen change occur early.

Update the complete medication history — prescription, nonprescription, and complementary/alternative products, including short-term and non-oral medications such as seasonal allergy treatments and inhalers — at every visit, and screen for interactions whenever anything changes.

1. Confirm virologic failure — an inability to maintain a viral load under 200 copies/mL, confirmed on repeat testing rather than acted on from a single result.
2. Assess adherence first, along with drug-drug and drug-food interactions and any absorption issue (for example, a missed spacing interval between an integrase inhibitor and a polyvalent-cation product) — these are more common causes of an isolated rebound than true resistance.
3. If confirmed rebound persists, obtain genotypic resistance testing while the patient remains on the current (failing) regimen, or within about 4 weeks of stopping it — resistant mutations can become undetectable once drug pressure is removed, so testing off therapy for longer than this risks a falsely reassuring result.^[2]
4. Select a new regimen with at least 2, and preferably 3, fully active agents based on the resistance results and the patient's complete antiretroviral history — involve an HIV specialist for anything beyond a straightforward first failure.
5. Never reduce to, or continue on, only 1 or 2 drugs of a failing regimen while deciding on a new one — if a regimen must be stopped for toxicity, stop all agents simultaneously and start the replacement regimen together, since partial continuation promotes further resistance.
6. Before concluding a patient has failed treatment, rule out immune reconstitution inflammatory syndrome as an alternative explanation for new or worsening symptoms, particularly soon after starting or changing therapy.
7. Once resuppressed, address any modifiable barrier that was identified (psychosocial support, cost/coverage, pill burden) — switching to a lower-burden single-tablet or long-acting option is often appropriate once the patient is stable and virologically suppressed.

• Starting abacavir without a documented negative HLA-B*5701 result.
• Rechallenging with abacavir after any hypersensitivity reaction, even in a patient who previously tested HLA-B*5701-negative.
• Stopping only 1 or 2 drugs of a multidrug regimen instead of the entire regimen simultaneously when a change is needed — this promotes resistance.
• Planned treatment interruptions ("drug holidays") — shown to increase the risk of opportunistic infection and death compared with continuous ART; treatment interruptions are not recommended.^[10]
• Taking an unboosted integrase inhibitor (dolutegravir, bictegravir, raltegravir) at the same time as a calcium, iron, magnesium, or aluminum-containing product without the required spacing interval.
• Missing hepatitis B coinfection before stopping or switching a patient off tenofovir- or emtricitabine/lamivudine-containing therapy — this can precipitate a hepatitis B flare.
• Starting a rilpivirine-containing regimen at a viral load above 100,000 copies/mL or a CD4 count of 200 cells/mcL or under.
• Using cobicistat as a pharmacokinetic booster in the second or third trimester of pregnancy.
• Assuming new or worsening symptoms shortly after starting ART automatically mean treatment failure, without considering immune reconstitution inflammatory syndrome.
• Missing a clinically significant interaction — rifampin with most integrase inhibitors, NNRTIs, and boosted protease inhibitors; dolutegravir/bictegravir significantly raising metformin levels; proton pump inhibitors, which are contraindicated with rilpivirine and with atazanavir.
• Delaying ART initiation while waiting on baseline results that are not actually needed before starting (the only true exception is HLA-B*5701 when abacavir specifically is planned).
• Forgetting to repeat genotypic resistance testing with a confirmed virologic rebound, or waiting too long after stopping a failing regimen to send it.

How to use this table: Doses shown are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Pediatric and adolescent antiretroviral dosing is weight-based and differs substantially from adult dosing -- it is not included here; see Special Populations. Select any drug name to open its complete Pharmasist Drug Database page.

Integrase strand transfer inhibitors (INSTIs)

Fewer drug interactions than boosted regimens, but GI absorption is reduced by polyvalent cations.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

All carry numerous potential drug interactions -- consult a validated interaction resource before adding or removing any medication.

Nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs)

The antiretroviral backbone of most regimens; generally fewer CYP-mediated interactions than boosted or NNRTI regimens.

Protease inhibitors (boosted)

Extensive CYP3A-mediated interaction potential -- review the complete medication list before starting any of these.

CCR5 antagonist, attachment inhibitor, and capsid inhibitor (treatment-experienced, multidrug-resistant HIV)

Reserved for patients with limited remaining options because of resistance, contraindication, or intolerance to first-line classes.

Evidence note: Lenacapavir efficacy and safety data in heavily treatment-experienced patients with multidrug-resistant HIV-1 are from the CAPELLA trial.^[11]

Complete single-tablet and combination regimens

Combining agents into 1 tablet improves adherence; interaction and adverse-effect profiles follow each component drug above.

Opportunistic infection prophylaxis

Thresholds and regimens for the 2 CD4-driven prophylaxis decisions most relevant to community and specialist pharmacists -- see the algorithm above for the decision structure.