What it is:HIV-1 is a retrovirus that specifically targets CD4+ T-helper cells, the cells that coordinate the rest of the immune response. Untreated, it grinds that population down over years until the immune system can no longer hold off infections it would normally shrug off. That endpoint is AIDS.
The core problem:Every day of unchecked replication is a day the virus is destroying CD4 cells, seeding reservoirs, and rolling the dice on new resistance mutations. There's no "watchful waiting" phase anymore. The moment someone tests positive, the clock on immune damage is already running.
What you do about it:Test and treat immediately, at any CD4 count, with a three-drug combination the patient hasn't been exposed to before. Push HIV RNA to undetectable and keep it there for life.
The whole drug list makes sense if you memorize one sentence: every modern regimen is a two-drug NRTI "backbone" plus one "anchor" drugfrom a more potent class (an integrase inhibitor, a non-nucleoside, or a boosted protease inhibitor). Learn what the backbone does, learn what the anchor does, and you can reconstruct almost every regimen in this chapter instead of memorizing them as strings of syllables.
HIV infection moves through three phases, and CD4 count is what tells you where a patient sits on that continuum.
| Phase | What's happening |
|---|---|
| Acute | First 2–4 weeks. Explosive viral replication (often >10⁶ copies/mL) with a precipitous CD4 drop. Most of the damage to the gut-associated mucosal CD4/CCR5+ T-cell pool happens right here, and this is also the window of peak infectiousness. |
| Chronic | Can last years. Viral replication continues at a lower, partially contained level while CD4 count slowly erodes. Often clinically silent, which is exactly why routine testing (not symptom-triggered testing) is how most people get diagnosed. |
| AIDS (terminal) | CD4 <200 cells/mm³ or the appearance of an AIDS-defining opportunistic infection or malignancy, whichever comes first. |
| Stage | CD4 count | CD4 % |
|---|---|---|
| 1 | ≥500 cells/μL | ≥26% |
| 2 | 200–499 cells/μL | 14–25% |
| 3 (AIDS) | <200 cells/μL | <14% |
An AIDS diagnosis is also made at anyCD4 count if the patient develops a qualifying AIDS-indicator condition: things like Pneumocystis jiroveciipneumonia, esophageal candidiasis, disseminated MAC or histoplasmosis, CMV retinitis, Kaposi sarcoma, invasive cervical cancer, HIV-related encephalopathy, or wasting syndrome. The staging cutoffs and the indicator-condition list are two independent doors into the same diagnosis.
"Living with HIV" vs "AIDS diagnosis"is not a synonym pair. Someone can be HIV-positive for decades on suppressive ART and never meet AIDS criteria. AIDS is a specific immunologic or clinical threshold, not just another word for HIV infection.
| Route | Approximate risk |
|---|---|
| Receptive anorectal intercourse (highest sexual risk) | ~1.4 per 100 acts |
| Sexual transmission generally, condom used | ~80% risk reduction vs no condom |
| Sharing injection drug equipment | ~0.67 per 100 episodes |
| Percutaneous needlestick (healthcare worker) | ~0.3% |
| Mucocutaneous exposure (splash to eye/mouth/nose) | ~0.09% |
| Mother-to-child (no ART) | ~25% |
Risk climbs a lot when the source partner is in acute or late-stage disease (both are high-viral-load states) or when either partner has genital ulcers or another STI, since that breaks down the mucosal barrier that would otherwise block entry.
This is the section that turns memorization into logic. HIV has to complete a fixed sequence of steps to make a new virus, and every antiretroviral class blocks exactly one step.
| Step | What happens | Class that blocks it |
|---|---|---|
| 1. Entry | gp120 binds CD4, then a coreceptor (CCR5 or CXCR4), then the virus fuses with the cell membrane | Entry inhibitors (fusion inhibitors, CD4 post-attachment inhibitors, gp120 attachment inhibitors, chemokine receptor antagonists) |
| 2. Reverse transcription | Viral RNA is copied into DNA by reverse transcriptase | NRTIs (chain terminators) and NNRTIs (non-competitive enzyme blockers) |
| 3. Integration | The new viral DNA is spliced into the host cell's own genome | Integrase strand transfer inhibitors (InSTIs) |
| 4. Assembly / maturation | The long gag-pol polyprotein is cleaved into functional structural pieces to build an infectious virion | HIV protease inhibitors (PIs) |
Read that table top to bottom and you've just derived the standard regimen: 2 NRTIs(they hit step 2, and using two makes resistance much harder to develop) plus one drug from step 2 (NNRTI), step 3 (InSTI), or step 4 (boosted PI). Modern first-line therapy is almost always NRTI backbone + InSTI, because integrase inhibitors suppress fastest with the fewest side effects. NNRTI- and PI-based regimens still exist for people who can't use an InSTI-based combo.
Most people notice something during acute infection, even if they don't recognize it as HIV. It looks like a bad case of mono: fever, sore throat, headache, fatigue, lymphadenopathy, plus GI upset (diarrhea, nausea, vomiting), weight loss, myalgia, and a morbilliform/maculopapular rash that tends to hit the trunk. Symptoms usually run about 2 weeks. Less common but worth recognizing: aseptic meningitis, oral ulcers, leukopenia.
A "viral syndrome" this nonspecific gets written off as flu or strep constantly, right when the patient has the highest viral load of their entire disease courseand is maximally infectious. Anyone with a plausible exposure and a mono-like illness needs HIV on the differential, not just an antibody test (which may still be in the window period - see Diagnosis).
Can be entirely asymptomatic for years while CD4 count quietly declines. This is the phase where routine screening, not symptoms, is what catches the diagnosis.
Most children born with HIV look asymptomatic at first. Watch for lymphadenopathy, hepatomegaly, splenomegaly, failure to thrive, unexplained weight loss or low birth weight, and fever of unknown origin, alongside labs showing anemia, hypergammaglobulinemia, and altered T-cell subsets. Normal CD4 ranges are age-dependent in children and don't map onto adult cutoffs.
| Marker | What it tells you | Normal / target |
|---|---|---|
| HIV RNA (viral load) | How much active replication is happening, via RT-PCR or similar amplification assays | Goal on therapy: undetectable, generally <20–50 copies/mL |
| CD4 count | How much immune capacity is left; the surrogate for disease progression risk | Normal adult range 500–1600 cells/mm³ (40–70% of total lymphocytes) |
Viral load tells you if the drugs are working. CD4 count tells you how much damage has already been doneand how vulnerable the patient is to opportunistic infection right now. A patient can be undetectable on viral load while their CD4 count is still recovering; that's expected, not treatment failure.
| Goal | What it means in practice |
|---|---|
| Maximal, durable suppression | HIV RNA below the limit of quantitation, usually <20 or <50 copies/mL |
| Decrease morbidity and mortality | Fewer opportunistic infections, longer life expectancy |
| Restore and preserve immune function | CD4 recovery over time |
| Prevent transmission | Undetectable viral load essentially eliminates sexual transmission risk (U=U, see Prevention) |
Suppressing replication below detectable limits isn't just about symptom control. It's what prevents the selection of drug-resistant variantsin the first place. Resistance emerges when the virus keeps replicating in the presence of drug; if replication is fully shut down, there's nothing left to select for resistance. That's the real reason "undetectable" is the target instead of "pretty low."
These are coformulated, once-daily combination pills unless noted. "Selected limitations" are the things that knock a regimen out of first-line contention for a specific patient.
| Regimen (class basis) | Selected limitations |
|---|---|
| Preferred for most people with HIV (InSTI-based) | |
| Bictegravir + tenofovir alafenamide + emtricitabine | Avoid if CrCl <30 mL/min; interacts with polyvalent cations (Ca, Mg, Al); can raise SCr by inhibiting its tubular secretion (not true renal injury); CNS/psychiatric effects, mainly in those with preexisting conditions |
| Dolutegravir + abacavir + lamivudine | Only if HLA-B*5701 negative; avoid in chronic hepatitis B; same cation-interaction and SCr-bump caveats as above |
| Dolutegravir + (TDF or TAF) + (emtricitabine or lamivudine) | Same as above, minus the HLA-B*5701 requirement (no abacavir in this combo) |
| Dolutegravir + lamivudine (2-drug regimen) | Avoid if HIV RNA ≥500,000 copies/mL, unknown or active hepatitis B, or no genotype available / resistance to either component |
| Recommended in certain clinical situations | |
| Elvitegravir + cobicistat + TDF + emtricitabine | Avoid initiation if CrCl <70 mL/min; food requirement; heavy CYP3A4 interaction burden; cobicistat also bumps SCr |
| Elvitegravir + cobicistat + TAF + emtricitabine | Avoid if CrCl <30 mL/min; otherwise same as above |
| Raltegravir + (TDF or TAF) + (emtricitabine or lamivudine) | Dosed once or twice daily depending on formulation; cation interactions; watch creatine kinase; renal cutoffs mirror the TDF/TAF component |
| Boosted PI: atazanavir + ritonavir (or cobicistat) + NRTI backbone | GI effects; food requirement; hyperbilirubinemia risk (especially Gilbert's syndrome) that often drives discontinuation |
| Boosted PI: darunavir + ritonavir (or cobicistat) + NRTI backbone | Rash (darunavir carries a sulfonamide moiety); GI effects; food requirement; generally preferred over boosted atazanavir |
| NNRTI-based: doravirine + TDF (or TAF) + emtricitabine/lamivudine | Renal cutoffs by component; CNS side effects, but milder than efavirenz |
| NNRTI-based: efavirenz + TDF + emtricitabine/lamivudine | Significant CNS/psychiatric effects; take on an empty stomach at bedtime; extensive CYP450 interactions |
| NNRTI-based: rilpivirine + (TDF or TAF) + emtricitabine | Avoid if HIV RNA >100,000 copies/mL or CD4 <200; no proton pump inhibitors; food requirement; antacid timing matters |
Monotherapy with any single agentor any NRTI-only regimen: inferior efficacy, high rebound and resistance risk. Unboosted PIs(inadequate bioavailability without ritonavir/cobicistat). Etravirine with an unboosted PI.Nevirapine in a treatment-naive patient with a high starting CD4(>250 in women, >400 in men) because of a high rate of symptomatic hepatotoxicity.
Nucleos(t)ide reverse transcriptase inhibitors get incorporated into the growing viral DNA chain in place of a natural nucleotide, and because they lack the 3'-OH group the next nucleotide needs to attach to, the chain simply stops there. Two NRTIs form the backbone of nearly every regimen.
Non-nucleoside reverse transcriptase inhibitors bind reverse transcriptase at a site away from the active site and lock it into a non-functional shape, so they don't need to be phosphorylated to work the way NRTIs do.
Efavirenz, etravirine, and nevirapine are CYP3A inducers, the opposite of what PIs and their boosters do. Efavirenz's CNS/psychiatric effects (vivid dreams, dizziness, mood changes) are common enough that dosing at bedtime on an empty stomach is standard advice to blunt the daytime impact. Rilpivirineonly works in patients with a lower starting viral load and adequate CD4 (below ~100,000 copies/mL and CD4 ≥200); push it outside that lane and efficacy drops. It also can't be combined with proton pump inhibitors, which matters a lot given how common PPI use is.
Integrase strand transfer inhibitors block the strand-transfer step where viral DNA is spliced into the host genome, which is why they suppress viral load faster than other classes and have become the preferred anchor for first-line therapy (bictegravir, dolutegravir, cabotegravir, elvitegravir, raltegravir).
Bictegravir, dolutegravir, cobicistat, and elvitegravir all inhibit tubular creatinine secretion, producing a small, expected rise in serum creatinine that looks like renal injury on a basic metabolic panel but isn't. Same logic as the SGLT2 inhibitor creatinine bump in heart failure: confirm it isn't from something else (like volume depletion), don't panic and stop the drug.
Class-wide practical points: separate dosing from polyvalent cation products (calcium, magnesium, aluminum antacids, iron, multivitamins) since they chelate and tank absorption; watch for CNS/psychiatric side effects, mainly in patients with preexisting psychiatric conditions; and weight gain has been observed more with this class than others, worth mentioning if a patient brings it up.
PIs block the HIV protease enzyme from cleaving the gag-pol polyprotein into its functional structural pieces, so the virions that get assembled are immature and non-infectious.
Ritonavir is essentially never used as an antiretroviral in its own right anymore.At low dose it's a potent mechanism-based CYP3A inhibitor, and that's exactly the job it does now: boosting the levels of other PIs (or elvitegravir) so they can be dosed less frequently and more reliably. Cobicistat is a newer pharmacoenhancer that does the same CYP3A-inhibition job without any antiviral activity of its own.
Atazanavircauses hyperbilirubinemia (competes for the same glucuronidation pathway as bilirubin), which is cosmetically obvious (jaundice/scleral icterus) even without true hepatotoxicity, and it's a common reason patients ask to switch, especially with underlying Gilbert's syndrome. Darunavircarries a sulfonamide moiety and can cause rash; it's generally preferred over boosted atazanavir in current practice. Both need food for absorption and both carry a heavy CYP3A4 interaction burden through their boosters, plus GI intolerance and dyslipidemia as class effects.
This single axis explains most of the clinically important antiretroviral drug interactions.
A dedicated, regularly updated drug-interaction database is the standard tool here (hiv-druginteractions.org), because this list changes faster than any handbook chapter can track.
Undetectable = Untransmittable.A person with HIV who achieves and maintains a suppressed viral load (<200 copies/mL) does not sexually transmit HIV to partners. This is Treatment as Prevention (TasP), and it's a genuinely liberating message for patients carrying HIV-related stigma, not just a clinical footnote.
Start as soon as possible and within 72 hoursof a potential exposure. After that window, the evidence for benefit falls off.
| Population | Preferred regimen |
|---|---|
| Occupational (healthcare workers) | TDF/emtricitabine once daily + raltegravir 400 mg twice daily |
| Nonoccupational, normal renal function (CrCl ≥60) | TDF/emtricitabine once daily + raltegravir 400 mg BID ordolutegravir 50 mg once daily |
| Nonoccupational, renal dysfunction (CrCl <60) | Dose-adjusted zidovudine/lamivudine + raltegravir BID or dolutegravir daily |
Three FDA-approved options, and they are not interchangeable in who they cover.
| TDF/emtricitabine | TAF/emtricitabine | Cabotegravir | |
|---|---|---|---|
| Route | Oral | Oral | IM injection |
| Who it covers | Sex or injection drug use risk | Sex risk only, excludesreceptive vaginal sex; ≥35 kg | Sex risk |
| Dosing frequency | Once daily | Once daily | Oral lead-in daily, then IM monthly ×2, then every 2 months |
| On-demand ("2-1-1") option | Yes, MSM only | No | No |
| HIV monitoring | Every 3 months | Every 3 months | Month 1, then every 2 months |
| Renal cutoff | CrCl ≥60 | CrCl ≥30 | No restriction |
| Notable side effects | "Start-up syndrome" first month; headache, ab pain, weight loss | "Start-up syndrome"; diarrhea, weight gain; also monitor lipids | Injection site reactions, headache, fever, fatigue, myalgia, rash |
2 pills 2–24 hours before sex, 1 pill 24 hours after the first dose, 1 pill 48 hours after the first dose. If sex happens again within 7 days of the last 2-1-1 dose, just resume 1 pill daily; if it's been ≥7 days, restart the whole 2-1-1 sequence. This on-demand strategy has no supporting data for TAF/FTC or cabotegravir, so don't extrapolate it to those options.
As of January 2026, Oregon-licensed pharmacists can independently prescribe and dispense both PrEP and PEP under PHPFAC statewide protocols, no outside prescriber needed. That means you may be the one doing this counseling and the renal-function screen yourself, not just filling someone else's script. Community pharmacy sites will expect you to know these cutoffs cold.
OI risk tracks CD4 count. The overarching strategy: prevent exposure where possible, vaccinate, use primary chemoprophylaxis at defined CD4 thresholds, treat infections that break through, use secondary prophylaxis to prevent recurrence, and stop prophylaxis once ART has driven sustained immune recovery. Suppressing HIV itself, so CD4 cells can recover, is the real fix; prophylaxis is a bridge until that happens.
The most common life-threatening OI in AIDS. About 90% of cases occur at CD4 <200. Presentation is often insidious over weeks: fever, dyspnea, tachypnea, a dry or mildly productive cough, and bilateral interstitial infiltrates on chest film (though imaging can look deceptively normal early on).
| Regimen | |
|---|---|
| Treatment | Trimethoprim-sulfamethoxazole 15–20 mg/kg/day (trimethoprim component), divided 3–4×/day for 21 days. IV to start for moderate-severe disease; oral is fine for mild, reliable outpatients or to finish a course. |
| Primary prophylaxis | Any HIV patient with CD4 <200 (or CD4 % <14%), or a history of oropharyngeal candidiasis |
| Secondary prophylaxis | Anyone who's had a prior episode |
| Prophylaxis dose | TMP-SMX one DS tablet daily (thrice weekly, or single-strength daily with gradual dose escalation, are options to help adherence/tolerability) |
Moderate-to-severe PCP (PaO₂ <70 mmHg) needs adjunctive corticosteroids started within 72 hoursof beginning PCP treatment. Killing the organism releases inflammatory debris that can transiently worsen oxygenation right after treatment starts; steroids blunt that deterioration. Don't wait to see if the patient gets worse first.
Common TMP-SMX adverse reactions in this population (higher rate than in HIV-negative patients): rash including Stevens-Johnson syndrome, fever, leukopenia, elevated transaminases, thrombocytopenia. A mild rash alone isn't an automatic stop, but watch closely for progression.
| Infection | First-line therapy | Watch for |
|---|---|---|
| Cryptococcal meningitis | Liposomal amphotericin B + flucytosine ≥2 weeks, then fluconazole 400 mg/day for 8 weeks or until CSF clears | Nephrotoxicity, hypokalemia, anemia (amphotericin) |
| Toxoplasmic encephalitis | Pyrimethamine + sulfadiazine (weight-based) + leucovorin rescue for 6 weeks | Bone marrow suppression (pyrimethamine); rash/drug fever (sulfadiazine); leucovorin protects marrow, doesn't treat toxo itself |
| Mycobacterium avium complex | Clarithromycin + ethambutol for at least 12 months | GI intolerance, optic neuritis (ethambutol), elevated LFTs |
| Esophageal candidiasis | Fluconazole 100–400 mg orally or IV daily 14–21 days | Hepatotoxicity, elevated LFTs |
Perinatal transmission risk without any ART is roughly 25%. Breastfeeding is itself an additional transmission route, independent of delivery-related exposure, which is why infant feeding counseling is part of this conversation, not an afterthought.
Two triggers should make you reconsider a regimen: significant toxicity, or treatment failure, defined as failing to get HIV RNA below 200 copies/mL by 24 weeks of therapy, or repeated detection above 200 copies/mL after the patient had previously suppressed.
Pre-existing high viral load or drug resistance going in, nonadherence, new resistance developing on therapy, drug intolerance, drug-drug or drug-food interactions, or plain pharmacokinetic/pharmacodynamic variability between patients.
| Step | Detail |
|---|---|
| Resistance testing | Draw it while the patient is still on the failing regimen, or within 4 weeks of stopping it, and only if HIV RNA >500 copies/mL (the reliability threshold for these assays, roughly 500–1000 copies/mL) |
| New regimen | At least 2, preferably 3, fully active drugs chosen from medication history plus resistance test results |
| If suppression still isn't achievable | Stay on the regimen rather than stopping it entirely |
It feels wrong to keep a patient on a regimen that isn't achieving undetectable HIV RNA, but staying on a partially effective regimen beats stopping altogether.Discontinuing therapy in that situation triggers rapid immunologic and clinical decline. Partial control still beats none.
| Parameter | When | Watching for |
|---|---|---|
| HIV RNA + CD4 | Baseline, early-response check at 2–8 weeks, then every 3 months until undetectable | Trajectory toward suppression; early flag for nonadherence or a poorly matched regimen |
| HIV RNA + CD4 (stable patient) | Can extend to every 6 months once consistently suppressed | Sustained control, so visit burden can ease off |
| HLA-B*5701 | Once, before any abacavir-containing regimen | Hypersensitivity risk - a hard stop if positive |
| Serum creatinine | Baseline and periodically, especially with tenofovir- or InSTI/cobicistat-containing regimens | True renal decline vs the expected, benign SCr bump from tubular creatinine-secretion inhibition |
| Lipid panel | Baseline and periodically, especially on PI-based regimens | Dyslipidemia |
| Resistance genotype | At diagnosis, and again at confirmed virologic failure (while on regimen or within 4 weeks of stopping, HIV RNA >500) | Guides regimen selection at both ends |
| Pregnancy status | Ongoing for anyone of childbearing potential | Regimen safety review (cobicistat avoidance, etc.) |