Antiretroviral Therapy in HIV-infected Adults: Therapeutic Review: Background

On February 4, 2002, guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents, developed by the Panel on Clinical Practices for Treatment of HIV Infection of the Department of Health and Human Services (DHHS), were revised. A panel subcommittee reviews and updates these guidelines each month (see the AIDS Web site).

Experts believe that the patient’s clinical condition, readiness for therapy, CD4 count, and plasma viral load are essential parameters to be used in decisions to initiate or change ther-apies. The goal of therapy, according to the DHHS panel, is to suppress plasma HIV RNA below the limits of detection, defined as fewer than 50 copies/ml. Clinical trials have indicated that lowering plasma HIV RNA to below this amount leads to more durable viral suppression than lowering it to between 50 and 500 copies/ml. canadian cialis online

Variability in viral load reporting has increased the difficulty of interpreting trial results and drawing comparisons, the clinical significance of which is unclear. Further, intermittent episodes of low-level viremia, or “blips,” are common and are not associated with progression to virological failure. The study’s results need to be confirmed, but it is thought that changing regimens in patients with low-level or intermittent viremia might not be necessary to maintain long-term viral suppression. Even in the setting of reduced drug susceptibility, HAART can provide immunological and virological benefits by reducing viral replicative capacity.

Table 2   Therapy for Human Immunodeficiency Virus (HIV) Infection

Goals of Therapy Tools to Achieve Goals
• Maximal and lasting suppression of • Maximizing adherence to the anti-
viral load retroviral regimen
• Restoration or preservation of immune • Rational sequencing of drugs
function • Preserving future treatment options
• Improvement of quality of life • Using resistance testing in selected
• Reduction of HIV-related morbidity clinical settings
and mortality

The latest DHHS guidelines include clearly defined goals for HIV therapy and recommendations on when treatment should begin (Table 2). The February 2002 version of the HIV practice guidelines reflected a shift toward delaying the start of therapy until later in disease progression than previously rec-ommended. The optimal time to initiate therapy in asymptomatic patients is unclear, but there are several compelling reasons to delay the initiation of therapy in these patients:

1.  Eradication is not considered achievable with today’s antiretroviral regimens. Barriers include the very long half-life of infected resting memory CD4+ lymphocytes (between six and 44 months) and the possibility that replication might occur even with a viral load of fewer than 50 copies/ml. The CD4 count appears to be the strongest predictor of mortality, and no benefit has been established from initiating HAART in patients with more than 350 cells/mm3.
2.  HAART can cause undesirable, life-threatening adverse side effects, and without strict adherence, viral resistance to therapy develops rapidly. Initiating a regimen before patients are fully committed could be a disservice to them in the long term. Sufficient time must be spent with patients to assess their motivation to commit to therapy and to determine strategies to individualize the therapeutic care plan.

Clinicians have several options when considering a treatment regimen (Table 3). Potential regimens are grouped according to the strength of their recommendation. Initially, it is anticipated that tenofovir (Viread®, Gilead) will be used primarily in previously treated patients; as further experience is gained, it may be increasingly used as an alternative to NRTIs as a first-line agent.

Table 3 Recommended Antiretroviral Agents for the Treatment of Established HIV Infection

Strongly recommended Regimen should consist of one choice from Column A plus one choice from Column B.
Drugs are not listed in order of priority.
Alternative Column A Column B
EFV (Sustiva canadian®) d4T + ddIf (Zerit + Videx®)
IDV (Crixivan®) d4T + 3TC (Zerit canadian + Epivir®)
NFV (Viracept®) ZDV + ddI (Retrovir® + Videx®)
RTV + IDV (Norvir®) ZDV +3TC (Retrovir® + Epivir®)
RTV + LPV (Kaletra®) ddI + 3TC (Videx®)
RTV + SQV* (Norvir + Fortovase®)
ABC ZDV + ddC (HIVID®)
AMP (Agenerase®)
DLV (Rescriptor®)
NFV + SQV-SGC
(Fortovase®)
NVP (Viramune®)
RTV (Norvir®)
SQV-SGC (Fortovase®)
Not recommended; Hydroxyurea (in combination with other antiretroviral agents)
insufficient data RTV + AMP (Norvir® + Agenerase®) RTV + NFV (Viracept®) Tenofovir (Viread®)^
Not recommended; should not be offered (evidence against use, virologically undesirable, or overlapping toxicities) All monotherapies, whether from Column A or Column B below.§
SQV-HGC (Invirase®)** d4T + ZDV (Zerit® + Retrovir®) ddC + 3TC (HIVID® + Epivir canadian) ddC + d4T (HIVID® + Zerit®) ddC + ddI (HIVID® + Videx®)

A systematic review of HAART clinical trials, in which therapy consisted of two NRTIs plus a PI, an NNRTI, or a third NRTI, showed that these three types of regimens were similar in their ability to suppress viral load and to increase CD4 cell counts. In a multivariable regression analysis, the pill count was the most significant predictor of the antiretroviral response.

Several factors influence the choice of an initial regimen in patients who are new to antiretroviral therapy, because each possible combination has both advantages and disadvantages. Initiating therapy with NNRTIs—for example, efavirenz (EFV) (Sustiva®, Bristol-Myers Squibb) plus two nucleosides—might mean a lower pill burden, fewer drug-drug interactions, simplified dosing regimens, and fewer side effects than a regimen containing PIs. A major disadvantage, however, is that resistance can be conferred to the NNRTIs by as little as one mutation or a few; resistance to one NNRTI might also translate to resistance to the entire class of NNRTIs. pharmacy uk

PI-containing regimens are also favored as initial therapies, and there is much clinical, virological, and immunological evidence for the use of these plans. Resistance often requires multiple mutations, and a typical PI-containing regimen has two targets in HIV viral replication, compared with only the reverse transcriptase enzyme in an NNRTI/NRTI regimen.

PI regimens have potential disadvantages as well:

  • They can be difficult for patients to follow.
  • They frequently have a higher pill burden.
  • They may be associated with long-term metabolic side effects.

Therefore, no single plan appears to be an optimal regimen for initiating HIV therapy. Clinical judgment must consider issues specific to each patient.

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