With new drugs in the anti-HIV/AIDS arsenal, many people with HIV/AIDS who had given up hope of effective treatment returned to clinics and doctors' offices. Even though treatment guidelines previously promoted early intervention with ZDV, recommended treatment now combines PIs with other antiretroviral drugs. Treatment recommendations change rapidly in response to the development of new drugs and clinical trials indicating the effectiveness of different combinations of antiretroviral drugs. Researchers are acting quickly to develop new mixtures of the recently approved and older drugs. Because HIV mutates to resist any drug it faces, including all PIs, researchers find that varying the combination of drugs prescribed can ''fool'' the virus before it has time to mutate.

In ''The Case for More Cautious, Patient-Focused Antiretroviral Therapy'' (Annals of Internal Medicine, vol. 132, no. 4, February 15, 2000), Keith Henry suggests that overly aggressive antiretroviral therapy in the early stages of the disease may expose patients to unpleasant side effects and cause their systems to build resistance. Henry recommends a more cautious strategy: a longterm, patient-focused approach that includes delaying initial therapy, planned interruptions in drug dose administration, therapy switching, and immune-based therapy.  In October 2003 the European Medicines Agency advised doctors not to start HIV patients on the aggressive didanosine-lamivudine-tenovir triple-drug combination, because no compelling improvement had been noted in those receiving the treatment.

Patients undergoing therapy with new drugs or drug combinations must be highly disciplined. For instance, indinavir must be taken on an empty stomach, every eight hours, not less than two hours before or after a meal, and with large amounts of water to prevent the development of kidney stones. Patients must also be careful to never skip doses of indinavir, otherwise HIV will quickly grow immune to its effect. (Indinavir has been found to generate cross-resistance, meaning it made patients resistant to other PIs.) Saquinavir mesylate must be taken in large doses. Ritonavir must be carefully prescribed and administered because it interacts negatively with some antifungals and antibiotics used by AIDS patients. Because there are many minor and serious risks associated with use of these drugs, patients must be closely monitored.

The difficulty of dealing with a complicated regimen of daily medication and maintaining the personal resolve to continue the regimen are ongoing issues for many HIV/AIDS patients. Henry argues that more support should be given to those health-care professionals (such as nurses and pharmacists) who educate patients and assist them in maintaining their complicated daily medication schedules.

When effective AIDS drugs were introduced, patients sometimes had to wake up in the middle of the night to take pills and some treatment regimens consisted of as many as fifty or sixty pills administered several times a day. Even with intense pressure to simplify treatment regimens, pharmaceutical companies remained skeptical about an effective once-a-day pill despite the consensus opinion that it would help more people start, and stick with, treatment. Even as recently as 2005, many combined HIV/AIDS medication regimens were administered two to three times per day. Once-a-day regimens were sought after, but were not available until 2006.

In July 2006 the FDA approved the first once-a-day AIDS treatment, a combination of efavirenz, tenofovir disoproxil fumarate, and emtricitabine. Even though this new once-a-day drug combination reduces the number of pills a patient must take and as a result improves adherence to treatment, it is probably not the sole drug an AIDS patient needs. Many patients also require additional prescription medications to support their immune systems and help them to resist infection.

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