With improving longevity for HIV-infected persons receiving antiretroviral treatment, but also acknowledging the finite durability of each regimen and a limited number of regimens, the optimal strategy for the use of antiretroviral therapy is crucial to maximize clinical benefit. Significant unanswered questions include the optimal initiation of antiretroviral therapy and the timing of a switch from a failing regimen to a secondary one.

Treatment Initiation
Most clinicians follow HIV-infected persons not receiving antiretroviral treatment every 3 to 6 months with a careful history and physical examination and monitoring of plasma HIV RNA levels and absolute CD4+ cell counts. In asymptomatic HIV-infected persons the potential benefits of antiretroviral therapy should outweigh their imposition, toxicities, and cost. Many asymptomatic HIV-infected persons may be at low risk for clinical progression of disease due to host and virologic factors.

Therefore, antiretroviral therapy should ideally be offered to those patients at greatest risk of clinical progression. Before considering treatment initiation, it is prudent to repeat plasma HIV RNA levels and absolute CD4+ cell counts because of potential variability. The risk of disease progression is related to a patient’s symptoms, plasma HIV RNA level, and absolute CD4+ cell number. Therapy is strongly recommended for all symptomatic patients. The optimal levels of plasma HIV RNA and absolute CD4+ cells to guide the initiation of therapy are not known, but most clinicians recommend therapy at conservative thresholds of more than 20,000 copies HIV RNA/mL or CD4+ cells less than 300/mm³ .

Critical to the success of treatment interventions is a patient who is prepared and committed to beginning therapy. Therefore, decisions on treatment initiation must be highly individualized. Many clinicians never initiate treatment for a patient during his or her first visit; rather, they evaluate and educate the patient during several visits.

Physicians must recognize the essential role of strict adherence to antiretroviral regimens and optimize circumstances such as patient education, emotional support, substance abuse rehabilitation, and the resources to obtain a continuing supply of medications. Studies of adherence have demonstrated that socioeconomic status, race/ethnicity, gender, and educational level do not predict successful adherence; therefore, physicians should not preclude treatment based on these factors.

With an expanding number of available antiretroviral drugs, clinicians can tailor regimens based on potency, convenience, predicted toxicities, and drug interactions. The importance of convenience and its relationship to adherence should not be underestimated. Significant issues may include dosing schedules, pill burden, food interactions, drug interactions, and toxicities. Clinicians should take a careful history regarding daily activities including employment and meals and project alternative medication schedules in discussions with their patients. When an initial regimen has been chosen, many clinicians will have patients return in 1 to 4 weeks to reinforce adherence and assess possible toxicities. Continuing attention to adherence at the time of all follow-up visits may assist in achieving long-term treatment success.

Treatment Failure
Successful antiretroviral therapy appears to achieve profound suppression of HIV replication, but the reservoir of chronically infected cells may not diminish over time.

As a result, compromise in chronic suppression leads to reactivation of HIV from this reservoir and recurrence in plasma viremia. The reasons for treatment failure may include diverse factors such as adherence, individualized pharmacokinetic responses, drug interactions, and antiretroviral resistance.

Most clinicians follow plasma HIV RNA levels every 3 months in patients on stable, fully suppressive antiretroviral regimens. Such intensive monitoring of plasma HIV RNA levels is associated with greater suppression of virus over time. Currently, there is no consensus definition of treatment failure based on plasma HIV RNA levels. Increasing levels may indicate antiretroviral resistance, and the prolonged administration of a failing drug regimen can result in the accumulation of multiple resistance mutations with greater potential for cross-resistance. Conversely, modest increases in plasma HIV RNA levels do not appear to correlate with rapid falls in absolute CD4+ cell counts or immediately worsening clinical outcomes. Therefore, a balance must be reached when considering the discontinuation of an initial antiretroviral regimen and the substitution of a secondary one. Pending the elucidation of factors influencing the optimal timing for treatment changes, most clinicians follow individual patients closely to ascertain the rapidity of their virus recurrence and change medications accordingly.

When choosing a secondary treatment regimen, the new combination should include at least two new drugs predicted not to have cross-resistance with agents from previous regimens. The inclusion of at least two new drugs clearly offers better virologic results than the addition of a single new agent. At the present time, resistance patterns can only be predicted based on a past treatment history. However, studies to correlate genotypic and/or phenotypic resistance patterns with subsequent virologic responses may yield improved opportunities for laboratory-based assessments. It is important to recognize that the virologic success of secondary treatment regimens is compromised relative to the virologic success of initial treatment regimens.

Evaluation of the Febrile Patient
Fever is a common physical finding among patients with HIV infection, and the potential causes are many. Fever may indicate a self-limited viral upper respiratory tract infection in a patient with early HIV infection or the presence of Pneumocystis carinii pneumonia (PCP) in a patient with progressive HIV infection. Differentiating the clinical manifestations of the two infections may be difficult for the physician; therefore, the physician should use any available information on HIV staging for the patient. In this context, the absolute CD4+ lymphocyte count may be an extremely useful guide in assessing the likelihood of opportunistic infections. If the absolute CD4+ lymphocyte count is more than 200/mm³ , the likelihood of PCP or other opportunistic infections is significantly decreased. Thus, the absolute CD4+ lymphocyte count may guide the most appropriate diagnostic considerations. Of note, the uncommon patient may present with an opportunistic infection at absolute CD4+ lymphocyte counts of more than 200/mm³ ; therefore, it is imperative to reconsider such diagnoses if the fever persists.