WHO Drug Information Vol. 16, No. 2, 2002
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International AIDS Society recommendations for antiretroviral treatment: adult HIV infection

Because of increased awareness of the activity and toxicity of current drugs, the threshold for initiation of therapy has shifted to a later time in the course of HIV disease. However, the optimal time to initiate therapy remains imprecisely defined. Availability of new drugs has broadened options for therapy initiation and management of treatment failure. The present updated recommendations written by the International AIDS Society, USA panel, are intended to guide practising physicians in the care of HIV infection and AIDS.

Progress in antiretroviral therapy has resulted in achievements as well as new challenges. The partial restoration of CD4 and CD8 T cell number and function during suppression of HIV replication with potent antiretroviral therapy has resulted in dramatic reductions in morbidity, mortality, and health care utilization. However, the toxicity of many current regimens, suboptimal activity and tolerability, and the emergence of drug resistance all point to the need for effective treatment strategies.

The emerging threshold for initiating therapy is the result of recognition of limitations of currently available agents and is not necessarily a reflection of a major change in understanding of disease patho-genesis, nor an indication that more aggressive treatment approaches should not be pursued.

When to initiate antiretroviral therapy

Highly active antiretroviral therapy (HAART) is usually effective in reducing plasma HIV RNA levels (viral load) in antiretroviral-naive patients, accompanied by a gradual increase in CD4 cell counts. Because currently available antiretroviral regimens will not eradicate HIV, the goal of therapy is to durably inhibit viral replication so that the patient can attain and maintain an effective immune response to most potential microbial pathogens.

Recent cohort data have provided support for the CD4 cell count being the major determinant of initiating therapy. It is clear that antiretroviral therapy should not be delayed until the patient is at high risk for serious opportunistic diseases.

The CD4 cell level above 200/mL at which to initiate therapy remains unclear and the following considerations support use of a CD4 cell count threshold higher than 200/mL.

• Some serious illnesses, especially active tuberculosis and bacteraemic pneumonia, may occur when the CD4 cell count is above 200/mL (16).

• The immune reconstitution syndrome and its associated morbidity may be observed in some patients starting antiretroviral therapy at low CD4 cell counts.

• Some laboratory markers show lower rates of favourable responses when antiretroviral therapy is delayed until the 200 cells/mL threshold is reached.

• Finally, the genetic complexity of HIV in persons increases with time, and this may facilitate escape from host immune defences.


In persons with CD4 cell counts above 350/mL, risk of 3-year clinical progression is low. For persons who have already initiated therapy at higher CD4 cell count thresholds and have had durable HIV RNA suppression and no adverse effects over periods of months to years, it is not clear whether it is safe to discontinue therapy.

Physicians and patients must thoroughly weigh risks and benefits of starting antiretroviral therapy for CD4 cell counts in the 200/mL to 350/mL range and above, and make individualized informed decisions. The strength of the recommendation should depend on the immunologic status, as well as the patient’s understanding of and commitment to an often complex regimen.

Therapy continues to be recommended in all patients with symptomatic established HIV infection. Immediate treatment, but not prophylaxis, of a serious opportunistic infection in patients with advanced HIV disease may take precedence over starting antiretroviral therapy. If potential for adverse drug-drug interactions exists, it is wise to choose drugs with minimal or no interactions, or to delay antiretroviral treatment for a few weeks until drugs causing the interactions can be discontinued.

Choice of initial therapy

No drug combination can be defined as the optimal initial regimen in all patients. Therapy should thus be individualized using a number of criteria, including efficacy and durability of antiretroviral activity, tolerability and adverse effects, convenience of the regimen, drug-drug interactions, and potential salvageability of initial regimen. Many patients will ultimately experience at least one treatment failure.

There are currently no data on preferred sequencing of NRTIs. Stavudine and didanosine in combination should be avoided or used with caution in pregnant women because of increased risks of lactic acidosis.

There are generally three types of initial combination regimens that should be considered:

• a protease inhibitor (with or without low-dose ritonavir) with two nuceloside reverse tran-scriptase inhibitors (NRTIs);

• a non-nuceloside reverse transcriptase inhibitor (NNRTI) with two NRTIs; or

• three NRTIs.


Other regimen combinations include a protease inhibitor (with or without low-dose ritonavir) with an NNRTI plus one or two NRTIs, which should be reserved for special circumstances; and a protease inhibitor (with low-dose ritonavir) with an NNRTI.

Adherence: assessment and reinforcement

Incomplete adherence to one or more prescribed medications is a key cause of virological failure of antiretroviral regimens. Factors that limit full adherence are complex and incompletely defined but may include high pill number and large pill size, medication schedule and dietary restrictions, toxic adverse effects, and ineffective education and support of patients regarding adherence. Progress in developing new drug formulations and fixed-dose combinations that can simplify regimens is encouraging.

Effective communication between patient and provider is essential both before and after treatment has begun. Some health care centres may use non-physicians (pharmacists, nurses, peer educators, and others) to effectively assess and support adherence, but the physician should also be actively involved. Once treatment has begun, weekly contact may be appropriate until the patient has established a consistent daily routine of medication use and has passed the time that any short-term adverse effects would be expected. Reinforcing the need for adherence at every health care provider contact is important.

Changing drugs or therapy

In the absence of virological or immunologic failure, a regimen may pose problems with adherence, intolerance, or cumulative (long-term) toxic effects. As long as the antiviral activity of the overall regimen is maintained, exchanging individual components of the regimen is acceptable.

Treatment failure

The definition of “treatment failure” (a term that subsumes virological, immunologic, or clinical failure) depends on the clinical setting and mirrors the objective of ongoing therapy at a given time in the patient’s treatment course.

In the case of the first or second regimen, when virus is wild type or harbours few resistance mutations, maintaining an undetectable viral load is an achievable goal of therapy; in this setting, treatment failure is best defined as inability to achieve a viral load below assay detection limits (<50 copies/mL) or as any sustained return of the viral load to above the target value (>400 copies/mL). With increasing rounds of treatment failure, the level and spectrum of virus resistance may increase, and it may become more difficult to construct an active combination. In patients for whom several regimens have failed, the virus may become multiply resistant, with fewer than three active drugs being available, and the objective of achieving stable undetectable viral load with conventional regimens may be unrealistic. Problems with toxicity may further restrict the number of available drugs.

Treatment failure occurs within the first year of therapy in a substantial proportion of treatment-naive patients. Thus, failure should be anticipated as part of the long-term strategy of antiretroviral treatment.

Adjuvant therapy to antiretroviral drugs

The concept of manipulating the immune response for host benefit has received increased emphasis. Approaches include attempts to augment or dampen the immune response generally, and attempts designed to stimulate relevant HIV-specific immune effector responses. At this point, however, sufficient clinical data do not exist to recommend these approaches beyond the setting of a clinical trial.

Summary

The future of antiretroviral therapy rests with the development of new drugs that will result in simpler, more effective, and less toxic regimens along with development of an improved understanding of innate immune system responses and novel approaches to exploit these responses. Several new agents are currently in development, derived from current drug classes and new drug classes, including entry inhibitors and integrase inhibitors. Potential advantages of these drugs include once-daily dosing, smaller pill size, lower incidence of adverse effects, new viral targets, and activity against virus that is resistant to other drugs in the respective classes.

The benefits of current and future agents will continue to be felt by HIV-infected persons in the developed world. Extending these benefits to those living with HIV in the developing world is a challenge that needs to be met.

Reference: Yeni, P.G., Hammer, S.M., Carpenter, C.J. et al. Antiretrocvial treatment for adult HIV infection in 2002. Journal of the American Medical Association, 288: 222-235 (2002).

 

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