BACKGROUND

To understand HIV medication, one must first understand the 6 crucial steps that HIV needs to complete in order to replicate and spread. In order, they are:

  1. Binding and fusion: HIV binds to either or both of two cell receptors known as CCR5 (typically in initial stages of infection) and CXCR4 (often in later stages) in order to enter the cell. HIV is surrounded by a lipid envelope that allows it to fuse with the target cell’s membrane, releasing the virus’s core contents into the cytoplasm.
  2. Reverse transcription: HIV’s genetic code is RNA-based, so its reverse transcriptase enzyme generates a DNA template.
  3. Integration: The DNA template is then integrated into the host cell’s genome.
  4. Transcription: The host cell’s protein machinery transcribes and translates mRNA based on the integrated DNA template.
  5. Protease cleavage: HIV proteins are initially made in large chains known as poli-proteins, which are cleaved into their functional pieces by proteases.
  6. Assembly and release: New virions assemble at the cell membrane and bud from the cell surface.

DRUG CLASS 1: ENTRY INHIBITORS

CCR5 antagonists prevent the first binding step, stopping the virus from entering any cells. The problem is that this is only effective for patients whose variant of HIV solely relies on the CCR5 receptor for virility, so if a tropism test reveals a CXCR4-dependent virus, this option is not used.

  • Maraviroc is the only FDA-approved drug in this class.
  • Common side effect (CSE): hepatotoxicity (liver problems)

Fusion inhibitors allow the virus to bind initial receptors, but prevent the next step of fusion between the viral and cellular membranes.

  • Enfuvirtide is the only FDA-approved drug in this class, and is given through subcutaneous injections.
  • CSE: Injection site inflammation/redness in 90% of patients, usually mild.

DRUG CLASS 2: REVERSE TRANSCRIPTASE INHIBITORS

Nucleoside analogue reverse transcriptase inhibitors (NRTIs) compete with natural nucleotides, leading to premature DNA chain termination.

  • Drugs: Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir, Zidovudine
  • CSE: Mitochondrial toxicity from inhibition of the enzyme responsible for mitochondrial DNA synthesis.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind to the reverse transcriptase enzyme, inhibiting its function.

  • Drugs: Delavirdine, Efavirenz, Etravirine, Nevirapine
  • CSE: Rash, hepatitis

DRUG CLASS 3: INTEGRASE INHIBITORS

These inhibit incorporation of viral DNA into the host’s genome.

  • Raltegravir is the only FDA-approved drug in this class.
  • CSE: muscle damage/problems

DRUG CLASS 4: PROTEASE INHIBITORS (PIs)

PIs inhibit viral proteases from cleaving viral poli-proteins into their functional bits, preventing assembly of the virus.

  • Drugs: Atazanavir, Fosamprenavir, Darunavir, Indinavir, Lopinavir, Nelfinavir, Saquinavir, Tipranavir
  • Ritonavir is a PI that is frequently used in low doses for its interesting effect of preventing metabolism of other PIs–increasing their efficacy.
  • CSE: Many possible–nausea, vomiting, diarrhea, hepatitis, etc.

TREATMENT REGIMENS

Treatment regimens vary widely based on the patient, the progression of the disease, the strain of HIV, etc. Broadly speaking, initiation of therapy in treatment-naive patients often begins with one of the following 3-drug combos:

  • 2 NRTIs + 1 PI (usually boosted with ritonavir)
  • 2 NRTIs + 1 NNRTI
  • 2 NRTIs + 1 integrase inhibitor

The idea is to prevent further spread of the virus in the patient with a cocktail to prevent easy resistance mutations. Some of the many things to consider to individualize the treatment for each patient:

  • patient preference
  • toxicity profile
  • child-bearing potential (women)
  • strain’s baseline resistance(s)
  • does the patient have other conditions that require treatment? (drug interactions)

Key to the regimen are regular check-ups which evaluate adherence to treatment, potential psychological concerns, side effects/complications, resistances, etc. Patients are counseled on prevention of HIV transmission and opportunistic infections, as well as other health changes that might be appropriate.

Nota bene: HIV/AIDS research is a very active field, and the above information could change at any time!