Due to continued interest/investment from industry and the efforts of a cadre of clinical researchers and interested patients/activists, the overall effectiveness of antiretroviral therapy continues to steadily improve. We may now be on the cusp of the all-time high water mark for antiviral therapy (ART) with the anticipated approval of more new HIV drugs active against new or old targets than we may ever see again (i.e., integrase inhibitors, maturation inhibitors, and CCR5 antagonists).

What used to involve frequent doses with food restrictions and numerous side effects has evolved to once or twice a day regimens with steadily decreasing side effects. The current U.S. Department of Health and Human Services (DHHS) HIV Guidelines (October 2006 version—see page 59) recommend either efavirenz or one of three boosted protease inhibitor (PI)–based regimens as first line treatment coupled with two nucleoside reverse transcriptase inhibitors (NRTIs), with AZT and 3TC now sharing top billing with tenofovir and emtricitabine.

For the efavirenz-based regimens, the current simplest regimen is Atripla (one pill a day), while for boosted-PI regimens the current simplest regimen involves three pills once a day (boosted-atazanavir + Truvada or Epzicom). For the asymptomatic patient, the DHHS recommended current CD4 threshold for starting ART is less than 350 cells/mm3.

My own practice philosophy (I’m based at a county public hospital with an indigent patient population with a high rate of substance abuse and mental health issues) differs fundamentally from the DHHS guidelines. I generally start ART with a boosted-PI based regimen, often with three NRTIs (often AZT + 3TC + tenofovir) which have a very high barrier to resistance. That induction regimen is intended to suppress HIV replication without the development of any resistance whatsoever. I tell the patient that we are taking the first steps in a marathon that hopefully will last a normal lifetime and that I don’t want to mess up early.

The popular efavirenz-based regimens are easier for patients to take, but if there are problems with adherence, two-class resistance can evolve quickly. Once the patient achieves viral suppression, I then individualize the maintenance regimen based on a large number of factors (gender, interest in children, liver status, metabolic status, how well the patient has tolerated components of the already used regimens, etc.).

After a year on treatment I often have made three to four drug switches (all done in the absence of any virologic failure), ultimately arriving at a regimen pleasing to both the patient and me. Increasingly, the NRTI backbone for the maintenance regimen contains no thymidine analogue in order to avoid the development of lipoatrophy.

I use the experience of finding the best individualized regimen as a tool to emphasize to the patient the importance of very high-level adherence, or else they will wind up on a more complicated regimen like they started with that often had more unpleasant side effects then their maintenance regimen.

The overall experience of finding their best maintenance regimen often results in a deep appreciation of the importance of excellent adherence in order to avoid more complex regimens in the decades ahead. In the last five years I can’t recall a single patient I have cared for who has developed three-class ART resistance using that induction/maintenance strategy.

I use the patient’s clinical (such as risk for renal disease) and genetic profile (such as HLA-B5701 status) to help select the safest regimen for the patient. I predict that in the next few years genetic testing will prove increasingly useful to assess risk for progression and optimization of regimen safety. I expect that positive results from some of the ongoing treatment naive studies (such as the with the Merck integrase inhibitor) may soon provide additional attractive intial treatment options potentially again re-shuffling the current oligarchy of recommended agents.

The pendulum of when to start ART is shifting to earlier intervention once again as the regimens improve with diminished concern about safety and development of broad resistance. Our concept of what constitutes AIDS or diseases linked to HIV-related immune suppression is undergoing a renaissance with data that patients suffer morbidity and mortality from non-traditional (not AIDS defining) conditions when their CD4 count is less than 500 cells/mm3 (such as cancer or liver, kidney, and heart disease). My impression is that the ideal immunologic goal of ART is to achieve a CD4 count greater than 500 cells/mm3, and that the chance to achieve that diminish the more the CD4 count is under 500 when ART is started. I thus expect the threshold for starting ART on a clinical basis to become 500 or less cells/mm3.

The biggest problems in our society relating to HIV treatment are a lack of awareness of HIV status (persons still unaware of their HIV-positive status) and lack of access for HIV-positive persons to skilled teams of HIV-care specialists with adequate resources (including provision of ART medications and funds to adequately compensate clinic staff). The public health efforts to decrease the rate of new HIV infections in the U.S. have generally been a failure, which is one reason for the new broad HIV testing recommendations.

To me the most important and under-utilized intervention to prevent HIV infection is ART. Recent studies have suggested that use of effective ART in discordant couples or in HIV-positive pregnant women can be 98-99% effective at prevention of HIV infection to their baby. If all HIV-positive persons in a society could be identified and put on effective ART, we ought to quickly shut down the HIV/AIDS epidemic and soon realize a return on the upfront investment as new infections and future costs are averted (could average $1,000,000 per lifetime per patient).

The biggest challenge posed by these evolving concepts is how to expand resources and services to properly care for increased numbers of newly identified HIV-positive patients (from expanded testing) who are likely to be started on ART more aggressively for both clinical and public health reasons. Such a shift in treatment philosophy will require more resources upfront, resulting in improved clinical outcomes and large savings through averted disease and new infections. The current HIV caseload is stretching resources thin even before a surge in new cases identified from expanded testing or more aggressive treatment thresholds. I am worried that although we have the tools to dramatically turn the tide against HIV/AIDS, as a society we lack the will and foresight to translate what we have learned into action.

Keith Henry, MD, is director of the HIV Program at Hennepin County Medical Center, St. Paul Ramsey Department of Health, and Professor of Medicine at the University of Minnesota, Minneapolis.