Fellow's quick read · Infectious Diseases
HIV Basics — a foundational sweep
DHHS Adult/Adolescent ARV + DHHS OI (rev. 5/27/2026) + IDSA/HIVMA Primary Care 2024 + NEJM review · reviewed 2026-07-07
Personal study digest for the first HIV didactic. Recommendations are drawn from the DHHS Adult & Adolescent ARV and OI guidelines, the IDSA/HIVMA Primary Care Management of HIV 2024, the NEJM review "HIV Infection — Screening, Diagnosis, and Treatment," and the PURPOSE 1 & 2 trials. The "What's changed" callout is reviewer synthesis of newer evidence, each claim cited. Not a substitute for the full guidelines.
In one line
On early, sustained ART a person with HIV has a near-normal lifespan and does not transmit HIV sexually (U=U). The fellow's five moves: diagnose → stage (CD4 + viral load) → start ART fast → prevent OIs by CD4 → prevent new infections (PrEP/PEP/U=U).◆Virology & natural history — only what changes management
- HIV-1 is a retrovirus that enters CD4 T cells via CD4 + a coreceptor (CCR5 or CXCR4). The three enzymes it needs are the three main drug targets: reverse transcriptase, integrase, protease (plus the newer capsid target — lenacapavir).
- Course: acute (≈2–4 wk) = "acute retroviral syndrome," mononucleosis-like, with a very high viral load and p24 antigen/RNA positive before antibody → clinical latency (years, set-point viremia) → advanced/AIDS as CD4 falls.
- Two numbers define the patient: CD4 count = risk of opportunistic infection; HIV RNA (viral load) = transmission risk and the readout of ART success.
◆Screening & diagnosis — the fellow drives the algorithm
- Screen everyone 13–64 at least once (opt-out); repeat ≥ annually with ongoing risk; test in every pregnancy. CDC opt-out screening; IDSA PCM 2024
- The lab algorithm (CDC/APHL):
- 4th-generation HIV-1/2 antigen/antibody combo immunoassay (detects p24 antigen + antibody).
- Reactive → HIV-1/HIV-2 antibody differentiation immunoassay.
- Differentiation negative/indeterminate → HIV-1 RNA (NAT).
- Acute HIV = Ag/Ab or RNA positive with a negative/indeterminate antibody differentiation. If you suspect acute HIV, order an HIV RNA — the earliest window can precede a positive 4th-gen test. design used in PURPOSE 1/2
- Staging (CDC): AIDS = CD4 <200 cells/mm³ (or <14%) or an AIDS-defining condition.
◆When to start & what to start (DHHS "What to Start")
- Start ART immediately (or as soon as possible) after diagnosis, regardless of CD4 (AII). Many clinics do same-day/rapid start to speed suppression and linkage — do not delay for genotype results; start, then adjust.
- Baseline labs: HIV genotype (RT/protease; add integrase if prior CAB-LA PrEP), CD4, HIV RNA, HLA-B*5701 if abacavir considered, HBV & HCV serologies, chemistries/renal, pregnancy test, STI screen. DHHS; IDSA PCM 2024
| First-line for most people (Table 6a) | Regimen | Strength |
|---|---|---|
| Single-tablet INSTI | BIC/TAF/FTC (bictegravir/tenofovir alafenamide/emtricitabine) | AI |
| INSTI + 2 NRTIs | DTG + (TAF or TDF) + (FTC or 3TC) | AI |
| 2-drug | DTG/3TC — except HIV RNA >500,000, HBV coinfection, or starting before genotype/HBV results are back | AI |
| Prior CAB-LA PrEP | Do INSTI genotype first; if starting before results → DRV/c or DRV/r + (TAF/TDF) + (FTC/3TC) | AIII |
- Goal: HIV RNA below assay limit, usually by ~3 months. The three preferred options are all INSTI-based.
◆Decoding the alphabet soup — ARV drugs by class
Regimens are written as their parts: BIC/TAF/FTC = one anchor (an INSTI, BIC) + a two-drug NRTI "backbone" (TAF + FTC). A slash = coformulated in one pill; /r = ritonavir-boosted, /c = cobicistat-boosted. Most modern regimens = 1 anchor + 2 NRTIs; a few are 2-drug (DTG/3TC, DTG/RPV).
| Abbrev | Generic name | Note |
|---|---|---|
| NRTIs — nucleoside/nucleotide RT inhibitors · the 2-drug "backbone" | ||
| FTC | emtricitabine | the "F" in most regimens; active vs HBV |
| 3TC | lamivudine | ≈ FTC; active vs HBV |
| TAF | tenofovir alafenamide | newer tenofovir prodrug; less bone/renal toxicity |
| TDF | tenofovir disoproxil fumarate | older tenofovir; lower lipids; TAF & TDF both active vs HBV |
| ABC | abacavir | only if HLA-B*5701 NEGATIVE |
| ZDV (AZT) | zidovudine | historical |
| INSTIs — integrase strand transfer inhibitors · today's anchor class | ||
| BIC | bictegravir | only in BIC/TAF/FTC (Biktarvy) |
| DTG | dolutegravir | Dovato, Triumeq; high resistance barrier |
| CAB | cabotegravir | long-acting (CAB-LA) — PrEP + CAB/RPV maintenance |
| RAL | raltegravir | older, twice-daily |
| EVG | elvitegravir | older; needs COBI boosting |
| NNRTIs — non-nucleoside RT inhibitors | ||
| DOR | doravirine | newest NNRTI |
| RPV | rilpivirine | in long-acting CAB/RPV |
| EFV | efavirenz | historical first-line; CNS effects |
| ETR | etravirine | salvage |
| NVP | nevirapine | historical |
| PIs — protease inhibitors · almost always boosted (/r or /c) | ||
| DRV | darunavir | preferred PI; high resistance barrier (DRV/r, DRV/c) |
| ATV | atazanavir | ATV/r, ATV/c |
| LPV | lopinavir | older; only as LPV/r |
| Boosters (pharmacokinetic enhancers) — NOT antivirals themselves | ||
| RTV (/r) | ritonavir | boosts PIs |
| COBI (/c) | cobicistat | boosts PIs and EVG |
| Entry & other classes · mostly salvage / heavily treatment-experienced | ||
| MVC | maraviroc | CCR5 antagonist (needs tropism test) |
| FTR | fostemsavir | attachment inhibitor |
| IBA | ibalizumab | post-attachment CD4 mAb (IV) |
| ENF (T-20) | enfuvirtide | fusion inhibitor (SC) |
| Capsid inhibitor · newest target | ||
| LEN | lenacapavir | twice-yearly SC — Yeztugo (PrEP) / Sunlenca (MDR treatment) |
Single-tablet regimens & brands you'll hear on rounds: BIC/TAF/FTC = Biktarvy · DTG/3TC = Dovato · DTG/ABC/3TC = Triumeq · TDF/FTC = Truvada · TAF/FTC = Descovy · CAB/RPV LA = Cabenuva · CAB-LA = Apretude (PrEP).
◆Genotype testing & resistance — the mutations that matter
- Test at entry into care to guide the first regimen (genotypic, AII; genotype preferred over phenotype in ARV-naive, AIII). Standard genotype = reverse transcriptase (RT) + protease (PR). Add a separate integrase (INSTI) genotype if transmitted INSTI resistance is a concern — e.g., prior CAB-LA PrEP.
- At virologic failure, send the genotype while still ON the failing drug (or within ~4 weeks of stopping) — resistant virus is archived and can vanish from the assay once selective pressure is off.
- Suppressed patient with RNA too low to amplify → proviral DNA genotype (useful but has limitations).
The organizing concept: genetic barrier
LOW barrier (one mutation loses the drug): NNRTIs (EFV, NVP, RPV) and first-generation INSTIs (RAL, EVG). HIGH barrier (needs several mutations): boosted PIs (esp. darunavir) and second-generation INSTIs (DTG, BIC) — which is exactly why DTG/BIC and boosted DRV anchor durable regimens.| Mutation | Class | Effect on drugs |
|---|---|---|
| M184V/I | NRTI | High-level 3TC/FTC resistance — but ↑ susceptibility to TDF/TAF & AZT and ↓ viral fitness (often deliberately kept on board for these effects) |
| K65R | NRTI | Resistance to TDF/TAF and ABC; hypersusceptible to AZT (ZDV) |
| TAMs (e.g., M41L, T215Y) | NRTI | Thymidine-analogue mutations selected by AZT/d4T; accumulate → broad NRTI cross-resistance |
| K103N | NNRTI | Resistance to EFV + NVP; spares RPV, ETR, DOR |
| E138K / Y181C | NNRTI | Resistance to RPV and ETR |
| Y143 / N155H / Q148 | INSTI (1st-gen) | Resistance to RAL & EVG; DTG/BIC usually retain activity — except Q148 plus additional mutations (e.g., G140S) |
| R263K | INSTI (2nd-gen) | Emergent DTG/BIC resistance (usually low-level) — the hard-won second-gen pathway |
| Major PI mutations | PI | Must accumulate — single mutations rarely cause failure; darunavir has the highest barrier |
| N74D | Capsid | Resistance to lenacapavir (seen in PURPOSE 2 breakthrough infections) |
◆Opportunistic-infection prophylaxis — match the CD4 (DHHS OI)
| CD4 threshold | Prophylaxis | Stop when… |
|---|---|---|
| <200 (or <14%, thrush, AIDS dx) | PJP: TMP-SMX (1 DS or 1 SS daily) | CD4 >200 for ≥3 mo on ART (or 100–200 with VL suppressed ≥3–6 mo) |
| <100 and Toxo IgG + | Toxoplasma: TMP-SMX (same drug covers both) | CD4 >200 for ≥3 mo on ART |
| <50 | MAC: primary prophylaxis NOT recommended if starting ART (regardless of CD4); reserve only for those not on / failing ART | — |
- Test every patient with CD4 <200 for Toxoplasma IgG. One drug — TMP-SMX — covers both PJP and Toxo.
- Start ART within ~2 weeks even when treating most OIs — the big exceptions are cryptococcal meningitis and TB meningitis, where ART is delayed to avoid IRIS. DHHS OI
◆Prevention — PrEP, PEP, U=U
- U=U: a durably suppressed viral load means no sexual transmission. This is a guideline-level message and a core counseling point. DHHS; IDSA PCM 2024
- PrEP options:
- Daily oral TDF/FTC (all exposures); TAF/FTC (not for receptive-vaginal exposure).
- Long-acting cabotegravir IM every 2 months.
- Twice-yearly lenacapavir SC (Yeztugo) — see callout.
- Before any long-acting PrEP (lenacapavir, CAB-LA): exclude acute HIV — dosing into undiagnosed HIV is functional monotherapy and selects resistance (lenacapavir N74D capsid mutation seen in PURPOSE 2 breakthroughs).
- PEP: start ≤72 h, a 28-day 3-drug INSTI-based course (e.g., TDF/FTC + DTG); baseline + follow-up HIV testing. CDC nPEP guidance
◆Key decisions a fellow owns
- Start ART fast — don't wait for the genotype (transmitted INSTI resistance is rare in the US).
- Exclude acute HIV before long-acting PrEP — resistance risk.
- Match prophylaxis to CD4, but remember starting ART is what actually retires most prophylaxis (especially MAC).
- Delay ART in cryptococcal and TB meningitis (IRIS); otherwise start early.
- Reinforce U=U at every visit.
What's changed / worth knowing
Reviewer synthesis — not the guideline text.
- Twice-yearly lenacapavir PrEP (Yeztugo) — first 6-monthly PrEP, FDA-approved June 18, 2025 (adults/adolescents ≥35 kg). PURPOSE 1: 0 infections in cisgender women, 100% lower than background incidence; PURPOSE 2: 96% lower than background and superior to daily F/TDF. NEJMoa2407001; NEJMoa2411858; FDA/Gilead 2025
- Two-drug ART is mainstream — DTG/3TC is a Recommended Initial Regimen (with the exclusions above), and long-acting CAB/RPV is an option for maintenance in suppressed patients. DHHS ARV
- MAC primary prophylaxis is effectively retired when ART is started promptly. DHHS OI
- Rapid / same-day ART start is now standard practice. DHHS ARV (AII)
◆Likely pimp questions
- First-line ART for most people? BIC/TAF/FTC; or DTG + (TAF/TDF) + (FTC/3TC); or DTG/3TC — all INSTI-based.
- When can't you use DTG/3TC? HIV RNA >500,000, HBV coinfection, or starting before genotype/HBV results.
- When do you start ART? Immediately/ASAP after diagnosis, any CD4 — don't wait for the genotype.
- Confirmatory HIV testing sequence? 4th-gen Ag/Ab combo → HIV-1/2 antibody differentiation → HIV-1 RNA if discrepant.
- What test catches acute HIV first? HIV RNA (then p24 antigen) — before antibody turns positive.
- CD4 for PJP prophylaxis, and the drug? <200 (or <14%/thrush) → TMP-SMX.
- CD4 for Toxo prophylaxis? <100 AND Toxoplasma IgG positive → TMP-SMX (same drug).
- Do you still give MAC prophylaxis? No, if you're starting ART — regardless of CD4.
- Which OIs make you DELAY ART? Cryptococcal meningitis and TB meningitis (IRIS).
- What must you exclude before long-acting PrEP? Acute HIV — dosing into it selects resistance (lenacapavir N74D).
- What is U=U? A durably undetectable viral load = untransmittable sexually.
◆Anki cards minted this run
- First-line ART for most people with HIV (Table 6a) → BIC/TAF/FTC; DTG + (TAF/TDF) + (FTC/3TC); DTG/3TC.
- When NOT to use DTG/3TC as initial therapy → HIV RNA >500,000, HBV coinfection, or before genotype/HBV results.
- Two OIs where you DELAY ART (IRIS) → cryptococcal meningitis and TB meningitis.
- Exclude acute HIV before long-acting PrEP (lenacapavir/CAB-LA) → N74D resistance (PURPOSE 2).
Plus, added on request: 26 drug-abbreviation cards (by class) and 8 resistance-mutation cards. Skipped as already in the deck: PJP/Toxo/MAC prophylaxis thresholds, PURPOSE-1 superiority, and the M184V/K65R/K103N mutations.
Sources: DHHS Panel, Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV (Table 6a; "when to start"). · DHHS/NIH/HIVMA/IDSA Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV (rev. 5/27/2026; PJP, Toxoplasma, MAC). · Horberg/Thompson et al., Primary Care Guidance for Persons with HIV — HIVMA/IDSA, Clin Infect Dis 2024. · NEJM, "HIV Infection — Screening, Diagnosis, and Treatment" (DOI 10.1056/NEJMcp1915826). · Bekker et al., PURPOSE 1, N Engl J Med 2024;391:1179-1192 (DOI 10.1056/NEJMoa2407001). · Kelley et al., PURPOSE 2, N Engl J Med 2025;392:1261-1276 (DOI 10.1056/NEJMoa2411858). · FDA/Gilead — lenacapavir (Yeztugo) PrEP approval, June 18, 2025. · CDC/APHL HIV laboratory testing algorithm; CDC nPEP guidance. · Drug-resistance mappings: DHHS ARV "Drug-Resistance Testing," IAS-USA 2025 Drug Resistance Mutations in HIV-1, and Stanford HIV Drug Resistance Database (hivdb.stanford.edu).