Ten Years of HAART: Foundation for the Future

Editor's Note:

The 13th Conference on Retroviruses and Opportunistic Infections, held in Denver, Colorado, February 5-8, 2006, marks the beginning of the year that is regarded as the 10-year anniversary of the introduction of highly active (triple-drug) antiretroviral therapy (HAART). To mark this achievement and to highlight the challenges that must still be met, John G. Bartlett, MD, Johns Hopkins University School of Medicine, Baltimore, Maryland, presented a plenary lecture, "Ten Years of HAART: Principles for the Future." In this report, Dr. Bartlett reprises his lecture.

Introduction -- The First Triple-Drug Trials

The history of HIV begins with the historic 1981 report of Pneumocystiscarinii pneumonia (PCP, now attributed to Pneumocystis jiroveci) in men who have sex with men.^[1] The history of antiretroviral therapy (ART) begins with the first clinical trial of zidovudine that was conducted in 1986.^[2] A number of new nucleosides were introduced during the next decade and dual therapy became well established, but the reality of HIV treatment during these first 10 years of ART must be viewed as startlingly unsuccessful.^[3]

The "decade of HAART" began with the 11th International Conference on AIDS in Vancouver, British Columbia, July 7-16, 1996. During that Conference, David Ho, MD, of the Aaron Diamond AIDS Research Center, New York, NY, and George Shaw, MD, PhD, of the University of Alabama at Birmingham School of Medicine, presented viral dynamics data showing that the average person with HIV infection produced 10 billion virions/day, bringing into sharp focus the fact that this was a viral infection that required antiviral treatment. (This seems painfully obvious now, but it was not at the time.) John Mellors, MD, of the University of Pittsburgh, Pittsburgh, Pennsylvania, also presented data showing that HIV viral load predicted progression as well as CD4+ cell decline rates, and the HIV viral load test with a threshold of detection at 15-25 copies/mL was introduced. Perhaps most important were the studies of: (1) "triple-drug therapy" using nevirapine-based treatment, described by Julio Montaner, MD, of the British Columbia Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Vancouver, Canada; (2) triple-drug therapy with indinavir-based treatment, described by Roy Gulick, MD, from New York University School of Medicine, New York, NY; and (3) the potential benefit of ritonavir in boosting saquinavir, described by Martin Markowitz, MD, from the Aaron Diamond AIDS Research Center, New York, NY. This group of observations converged to initiate a decade of progress against an important disease that is truly extraordinary in terms of the intensity of the effort and the progress achieved. Together, they constituted what is often considered to be the beginning of the HAART era.

The First Decade of HAART -- Marking Progress

The 11th International Conference on AIDS in Vancouver was followed quickly by sequential publications in The New England Journal of Medicine by Hammer and colleagues^[4] and Gulick and coinvestigators^[5] illustrating the substantial benefit of indinavir-based HAART. This concept of 3-drug therapy was quickly incorporated into clinical practice and rapidly showed impressive benefit with a 60% to 80% decline in rates of AIDS, death, and hospitalization.^[6] This began the decade of 1996-2006, which was characterized by a rapid evolution of data that led to substantial gains in management The highlights of the 10 most important advances during the first 10 years of HAART are summarized:

1. The method of doing HIV clinical trials: This became stereotyped, at least for treatment-naive patients. The studies were prospective, randomized, and controlled, but usually not blinded. The outcome was analyzed for at least 24 weeks and preferably 48 weeks or longer, and results were reported by intent-to-treat and as-treated analysis. The outcome was measured by clinical events (AIDS-defining diagnoses or death), viral load (with thresholds of 20-50 and 200-500 copies/mL) and CD4+ cell count increases. They were done in all parts of the developed world.
   
   
2. The US Food and Drug Administration (FDA): In 1997 the FDA accepted viral load as a surrogate marker for clinical events in HIV clinical trials; this was the first time that a laboratory marker was accepted as an endpoint for any infectious disease. The FDA has also expedited review of HIV-related drugs so that the median time for approval from the time of submission has been a relatively short 5 months, with 27 of 28 submissions approved. The important consequences of these developments include rapid access to multiple new agents and a scientific database using a trial design that facilitates cross-study comparisons.
   
   
3. Seminal studies: The 6 studies that were the most important in advancing the field were the following:
   
   
4. • 1999: DuPont 006^[7] established the role of the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz, "the third drug" in combination with 2 nucleoside RTIs (NRTIs) that constitute HAART.
     
     
   • 2002: M98-863^[8] established the role of ritonavir-boosted lopinavir as a preferred protease inhibitor (PI)-based regimen.
     
     
   • 2003: ACTG 384^[9] was the first study to show that there are important differences between NRTI pairings. Remember that virtually all guidelines prior to 2003 recommended "2 NRTIs (any 2) plus a third agent"; this report emphasized the need to distinguish nucleoside pairs.
     
     
   • 2004: Gilead 903^[10] established the role of tenofovir.
     
     
   • 2004: 2NN^[11] was the first comparison of efavirenz and nevirapine and was important in settling debates regarding potency and side effects of these NNRTIs.
     
     
   • 2004: ACTG 5059^[12] showed that the popular triple-nucleoside regimen (zidovudine/lamivudine/abacavir) was inferior to efavirenz-based HAART. Within months, virtually every guideline in the world took the coformulation of zidovudine/lamivudine/abacavir off the preferred drug list.
     
     
5. The cure: Siliciano and coinvestigators^[13] analyzed the latent CD4+ cell pool with replication-competent HIV and concluded that it would require 73 years of viral suppression to eradicate HIV.
   
   
6. The target viral load of < 50 copies/mL: Analysis of the latent pool showed that there was no viral evolution with new resistance mutations when the viral load was suppressed to a level below 50 copies/mL.^[14] Thus, analysis of HIV strains in the latent pool matched the strains in plasma, but viral loads above this threshold were associated with new resistance mutations.
   
   
7. Treatment interruption: There have been multiple attempts to discontinue therapy with a variety of goals, including: (1) boosting immunity during primary infection; (2) boosting immunity in patients with chronic infections and with virologic control; (3) attempting to regain wild-type (drug-sensitive) virus in patients with virologic failure; (4) intermittent therapy to achieve a "drug holiday"; and (5) the CD4+ cell guided-treatment interruption to reduce drug cost and toxicity. All of these have failed and are no longer generally recommended. The latest to crash is CD4+ cell guided-treatment interruption, which looked good in at least 20 small or retrospective studies, but failed in the prospective SMART study with more than 5400 participants, with data presented at this conference.^[15]
   
   
8. Treatment discontinuation for treatment failure: Deeks and colleagues^[16] showed several years ago that patients with virologic failure and 3-class resistance had a significant increase in viral load and decrease in CD4+ cell count when antiretroviral drugs were discontinued. The suggestion was that failing therapy was actually working, just not very well. The question was which component of the HAART regimen was responsible for this continued (but suboptimal) activity. He predicted that it was the nucleosides, and his more recent work has proven this to be correct.^[17]
   
   
9. Adherence: In a frequently-cited publication, Paterson and coworkers^[18] showed that with PI-based HAART it was necessary to take 95% of prescribed doses to achieve a 80% probability of a viral load < 400 copies/mL. Subsequent work by Bangsberg and coinvestigators^[19] found that the adherence story is far more complicated, and that completely different equations apply to boosted PIs and to NNRTI-based HAART.
   
   
10. Salvage: The decade was marked by substantial progress in managing virologic failure. Particularly impressive were the gains in virologic control with the use of enfuvirtide as a new class. The advantage was the 30% increase in rates of virologic control in the TORO, RESIST, and POWER studies.^[20-22]
    
    
11. Totality of the decade in life-years saved. Walensky and coinvestigators^[23] analyzed the survival benefit for patients entering care in the United States for each of 4 sequential eras of HAART from 1996 through 2003. The bottom line is an extension of life averaging 15 years/patient and a total of nearly 3 million life-years saved; this is substantially more than for healthcare gains made in any other important disease in the past decade.
    
    

Predictions for the Future

Changes in Treatment Strategies

The most important changes anticipated for the next 2-3 years are the following:

• Head-to-head comparison of NNRTI- vs PI-based HAART: Results of ACTG 5142 are expected in a few months and will show the relative merits of efavirenz vs ritonavir-boosted lopinavir for initial therapy; this is the study we have all been waiting for.
  
  
• One pill once a day: There has been substantial progress in treatment simplification in terms of pill burden. This will reach the ultimate later in 2006 with the anticipated introduction of efavirenz/tenofovir/emtricitabine as a single pill for once-daily administration.
  
  
• Induction-maintenance treatment: This strategy has not worked in almost every study to date, but there is a glimmer of hope with ritonavir-boosted lopinavir^[24] and boosted atazanavir.^[25]
  
  
• Salvage: There has been substantial activity in terms of new drug development with anticipated approvals in the next 1-2 years for a PI that is active against strains with multiple PI-resistance mutations (darunavir, TMC-114) and NNRTIs active against strains with 103N and other resistance mutations (TMC-125 [etravirine] and TMC-278). In addition, there will be substantial interest in new combinations, such as darunavir/etravirine, which is now being studied in the DUET Trial, and the combination of 2-entry inhibitors, such as enfuvirtide plus a CCR5 inhibitor.
  
  
• New antiretroviral classes: Drugs that appear to be farthest along in development are the CCR5 inhibitors such as maraviroc and vicriviroc and integrase inhibitors such as MK-0518 and GS-9137.^[26,27] The development of the CCR-5 inhibitors has spawned substantial enthusiasm and could have an important impact on therapy, but progress has been somewhat delayed as a result of concerns for hepatotoxicity and efficacy. The integrase inhibitor MK-0518 has shown impressive early results in terms of viral potency in treatment-naive patients,^[27] and data from a study in patients with 3-class resistance will be presented at this conference.^[28]

HIV Serologic Testing

One of the major disappointments of the past decade is the enormous number of patients who do not benefit from the treatment advances because they are not aware of their HIV infection. In the United States, the estimate is about one third of all persons with HIV infection. This is being addressed by an attempt to simplify serologic testing in a US Centers for Disease Control and Prevention (CDC) proposal now under discussion that would make HIV serology a routine test for persons of 13-64 years regardless of risk. Consent for testing would be the consent for care, an "opt-out" strategy.

Increase in Patients Treated and Cost of Drugs

Several factors contribute to an anticipated increase in the number of persons receiving HAART, including: (1) more serologic testing as noted above; (2) an increase in the number of persons living with HIV infection; (3) data showing that once treatment is started it should not be stopped except for toxicity; and (4) the possibility that guidelines will change for earlier treatment. At present, the cost of HAART is about $10,000-$12,000/patient/year in the United States and is likely to substantially increase with new agents and far more aggressive treatment of patients with virologic failure. Even in developed countries, the issue will be in getting the resources to pay for drugs. In the United States, the salvation for covering expensive care for a disease that preferentially attacks disenfranchised patients has been the Ryan White Care Act, and the hope is that this support will track with the numbers of patients and cost of increasingly expensive per-patient treatment. But that probably won't be the case. In developing countries, the need will be for access to high-quality drugs at a nominal cost.

HIV Care in Developing Countries

The need, plan, and progress in achieving treatment goals are well known. Initial reports of outcome based on analyses of 28 published reports show significant success with HAART, with a median of 73% of 6000 patients achieving a viral load of < 400 copies/mL at 6-12 months.^[29] Data for resistance are relatively sparse but resistance does not appear to be a serious problem to date. Perhaps less obvious is the enormous potential of this program to establish an infrastructure for delivering other healthcare benefits. This has been highlighted by Mermin and coworkers,^[30] who showed the benefit and cost-effectiveness of relatively simple and inexpensive interventions such as safe water to prevent diarrhea ($4.00/year/family), bed nets to prevent malaria ($5.00), trimethoprim-sulfamethoxazole to prevent malaria and diarrhea ($15/person/year), isoniazid (INH) ($13.00/year), and multivitamins ($5.00/year).

Prevention

The most obvious failures of the decade include the lack of a cure or vaccine. However, perhaps more important (and certainly a cause for embarrassment) is the lack of any prevention strategy that has a significant impact on the numbers of new cases in both the developed and developing worlds. One of the reasons for this may be related to recent data on the relationship between transmission and viral load. Recent studies from North Carolina show that acute HIV infection is associated an extremely high viral load prior to establishment of the "set point."^[31] A review of discordant couples in Rakai, Uganda, showed that 40% of transmissions occur during this early phase of infection and another 30% occur in late-stage disease when the viral also increases.^[32] The point of stressing this correlation between time of transmission and efficiency of transmission is that most of the current prevention efforts emphasize interventions that apply to the 8-10 years of chronic HIV, which actually accounts for only about 30% of transmissions.

Summary: Achievements and Challenges

The first decade of HAART was notable for extraordinary advances in effective treatment. The challenges for the next few years will be to deal more effectively with liver disease, do better with salvage, determine the role of anticipated new classes (integrase inhibitors and CCR5 inhibitors), address the issues of resource-limited countries, and try to succeed at prevention.

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