Antiretroviral Pharmacology

The HIV life cycle as a drug map

Principle. Each antiretroviral class blocks one step of the HIV life cycle, and combinations attacking two or more steps prevent resistance. Standard initial therapy pairs an integrase inhibitor with two NRTIs.

Entry inhibitors. Maraviroc antagonizes the host CCR5 coreceptor, so it works only on R5-tropic virus; a coreceptor tropism assay must first exclude CXCR4-using or dual/mixed virus. Enfuvirtide binds viral gp41 and prevents membrane fusion; it is injected subcutaneously twice daily and nearly always causes injection-site nodules.

Nucleoside/nucleotide reverse transcriptase inhibitors

Mechanism. NRTIs are analogs that host kinases phosphorylate to active forms. Reverse transcriptase incorporates them into viral DNA, and because they lack a 3′-OH, no further nucleotide can attach. Tenofovir is a nucleotide that already carries a phosphonate group, so it needs one fewer phosphorylation.

Class toxicity. NRTIs also inhibit mitochondrial DNA polymerase-γ. Depleted mitochondrial DNA produces lactic acidosis with hepatic steatosis, lipoatrophy, peripheral neuropathy, myopathy, and pancreatitis. Risk is highest with stavudine, didanosine, and zidovudine and minimal with the drugs used today.

Abacavir. The hypersensitivity reaction is strongly tied to HLA-B*57:01, so testing precedes every prescription and carriers never receive the drug. Rechallenge after a reaction can be fatal. Keep the alleles straight: HLA-B*15:02 flags carbamazepine SJS and HLA-B*58:01 flags allopurinol SJS/TEN.

Zidovudine. Its marrow toxicity adds to that of ganciclovir and other myelosuppressive drugs. A rising MCV is expected and has been used as a marker of adherence rather than a sign of B12 or folate deficiency. It remains the backbone of prophylaxis for newborns of mothers with HIV.

Tenofovir prodrugs. TDF yields high plasma tenofovir that proximal tubular cells take up, causing Fanconi syndrome (glycosuria with normal serum glucose, phosphaturia, proteinuria), AKI, and reduced bone mineral density; creatinine, phosphate, and urine glucose are monitored. TAF concentrates tenofovir inside cells with about 90% lower plasma levels.

Tenofovir, emtricitabine, and lamivudine also inhibit the HBV polymerase. HIV-HBV coinfected patients need tenofovir plus emtricitabine or lamivudine, and stopping these drugs can provoke a severe hepatitis B flare.

Non-nucleoside reverse transcriptase inhibitors

Mechanism. NNRTIs bind a hydrophobic pocket near, not at, the reverse-transcriptase active site and distort it. They need no phosphorylation. A single point mutation (such as K103N for efavirenz and nevirapine) can abolish activity, a low genetic barrier to resistance, and HIV-2 is intrinsically resistant to the whole class.

• Efavirenz: vivid dreams, insomnia, dizziness, depression or psychosis; dosed at bedtime.
• Nevirapine: severe hepatotoxicity (highest in women with CD4 >250/mm³) and SJS/TEN.
• Rilpivirine: absorption requires gastric acid, so PPIs are contraindicated; low levels mean virologic failure and resistance.
• Doravirine: few CNS or lipid effects.

Integrase strand-transfer inhibitors

Mechanism and role. INSTIs (-tegravir) chelate the Mg²⁺ ions in the integrase active site and block strand transfer of viral DNA into host chromosomes. Bictegravir or dolutegravir plus two NRTIs (tenofovir with emtricitabine or lamivudine) is the recommended initial regimen for most patients: potent, well tolerated, and with a high resistance barrier. Antacids, calcium, iron, and magnesium bind INSTIs in the gut, so doses must be separated.

Adverse effects. Weight gain, insomnia, headache, and CK elevation with myopathy (raltegravir). Dolutegravir and bictegravir inhibit the OCT2 transporter and block tubular creatinine secretion, raising serum creatinine about 0.1–0.15 mg/dL early without any true fall in GFR.

A small, stable creatinine rise with a normal urinalysis after starting dolutegravir needs no action; tubular dysfunction points instead to TDF.

Protease inhibitors and boosters

Mechanism. HIV protease, a pol gene product, cleaves the gag and gag-pol polyproteins into matrix, capsid, reverse transcriptase, integrase, and protease during and after budding. The -navir drugs block this step, so released particles remain immature and noninfectious.

Boosting. Low-dose ritonavir or cobicistat strongly inhibits CYP3A4, raising PI levels to allow once-daily dosing. The same inhibition raises other CYP3A4 substrates: simvastatin (myopathy) and inhaled or intranasal fluticasone (iatrogenic Cushing syndrome). Rifampin, a potent CYP3A4 inducer, makes PIs subtherapeutic, so tuberculosis is treated with dose-adjusted rifabutin; rifapentine also lowers PI levels too far, and rifaximin is not absorbed systemically.

Adverse effects. Insulin resistance and hyperglycemia, dyslipidemia, lipodystrophy (central fat, buffalo hump), and GI upset. Atazanavir inhibits UGT1A1, producing a benign, Gilbert-like unconjugated hyperbilirubinemia with scleral icterus, and can form kidney stones and gallstones.

Prevention: PrEP and PEP

Preexposure prophylaxis. Options for HIV-negative people at risk: daily oral TDF/emtricitabine (or TAF/emtricitabine), long-acting cabotegravir injections every 2 months, or lenacapavir, a capsid inhibitor injected twice yearly. A negative HIV test must precede PrEP, because one or two drugs would undertreat an established infection and select resistance.