Treatment of HIV/AIDS: Title and subTitle BreakDo the Dilemmas Only Increase?

Physicians and other health care professionals who treat patients with human immunodeficiency virus (HIV)/AIDS are confronted daily with complex challenges. Fortunately, several articles in this theme issue of JAMA on HIV/AIDS help to increase the coping index for clinicians and researchers.

The International AIDS Society-USA (IAS-USA) report in this issue represents a biennial update of the criterion standard for HIV care.¹ Experts evaluated the research, conferred, integrated new information, graded the evidence basis for their decisions (an advance over their previous reports), and provided an up-to-date document that can serve as an evidence-based foundation for guiding HIV adult care in developed countries. These new guidelines have not changed dramatically but do reflect the contribution of new drugs and make more definite judgments about the most-effective regimens while remaining relatively consistent on when to start or to switch therapy.

The same evidence-based guidelines are now also required to be anchored in the realities of the resource-constrained regions of the world where more than 90% of the world's HIV-infected individuals reside. Since the major disease burden has shifted to resource-limited societies, investment in clinical trial networks should also be redirected. The National Institutes of Health–supported studies by the AIDS Clinical Trials Group have contributed immensely on how best to treat HIV/AIDS in the West. It may now be time to refocus these efforts. Studies of different "resource-limited setting-friendly" highly active antiretroviral therapy (HAART) regimens, involving evaluation of both treatment-naive and treatment-experienced patients, are needed. The cycle of "no evidence and no guidelines" in this context must be broken.

The IAS-USA guidelines argue for starting therapy when the CD4 cell counts reach the 200/µL to 350/µL range. The evidence to choose with confidence the level of immunosuppression at which to begin therapy is based on numerous studies that demonstrate a consistent pattern. Nearly complete immune reconstitution can be achieved and survival maximized if therapy is started before irreversible damage to the immune system occurs, which appears to be when CD4 cell counts fall below 200/µL or about the time early clinical signs and symptoms appear. On the other hand, little is gained if HAART is started when cell counts are greater than 350/µL. Since response to HAART and survival both decline with more advanced disease, patients must be identified before they develop significant immunosuppression. Unfortunately, many individuals worldwide initially present with life-threatening infections. Very few individuals in low- and middle-income regions know if they are infected with HIV and access to voluntary counseling and testing is poor; it has been suggested that only 10% of these individuals needing such services can access them.² Having these services available would allow these individuals to seek care prior to a major, often-fatal health crisis. HIV still carries a stigma that is avoided through denial and delay. Will ready access to therapy alter perceptions and enable care before immunosuppression becomes less responsive? Efforts to screen the expanding susceptible populations of the world while extending voluntary testing and counseling to everyone need to be rapidly scaled up in parallel with treatment programs.

Significant advances in the treatment of HIV infection have been made, as illustrated in 2 large multisite HIV comparative trials reported in this issue of JAMA.^{3 - 4} In both studies stavudine was compared with once-daily alternatives in treatment-naive patients. In one study, emtricitabine (a nucleoside reverse transcriptase inhibitor similar to lamivudine with a longer plasma half-life) combined with didanosine and efavirenz showed greater efficacy than stavudine, didanosine, and efavirenz with regard to virological outcomes and greater tolerability. In the second study, tenofovir combined with lamivudine and efavirenz compared favorably to stavudine, lamivudine, and efavirenz.

What makes these articles exciting is an appreciation of the progress in HIV therapy in the 8 years since the beginning of the HAART era: both emtricitabine- and tenofovir-containing regimens offer reduced pill burden, once-daily administration, sustained viral suppression, and possibly fewer minor or serious adverse reactions. Now, provided that adherence is maximized with once-daily dosing and the evolution of resistance mutations is reduced, clinicians can be assured that the therapy of treatment-naive patients will be effective and can focus on strategies that minimize long-term drug toxicities. For example, protease inhibitor-sparing regimens may reduce vascular consequences of lipid and other metabolic abnormalities and minimize disfiguring lipodystrophy while saving a potent class for later salvage treatment. Stavudine-sparing regimens may reduce lipid abnormalities as demonstrated in these studies but also may reduce long-term mitochondrial toxicity, with the associated painful peripheral neuropathies and potentially life-threatening lactic acidosis. These 2 drugs (emtricitabine and tenofovir) together combined with efavirenz could also prove to be a particularly effective HAART regimen and, if coformulated and prescribed as a single pill, ideally suited for resource-limited settings.

Even though significant progress has been made, treatment of HIV infection still needs to be improved and made accessible to more of the approximately 40 million persons⁵ living with HIV in the world. While effective agents will be available to treat western patients for whom current regimens have failed, better HAART regimens still need to be developed that achieve more prolonged viral suppression before treatment failure or viral escape.⁶ The tenofovir-containing regimen achieved viral suppression in approximately two thirds or more of treatment-naive patients at 3 years, but a median effective duration of at least 5 years will probably be required to make a substantial sustained impact on global illness and death, particularly in resource-limited settings where access to second- and third-line regimens is problematic.

This goal will also require meticulous, rigorous, compulsive attention to adherence in each patient, which will be made easier with the once-daily dosing schedules. Studies from Africa have shown that with education, counseling, and support, patients in resource-limited settings can exceed western expectations of compliance.^{7 - 8} But since treatment regimens will eventually fail for these patients as they have elsewhere, second- and even third-line salvage regimens that are practical and "user friendly" for resource-limited settings, still need to be developed, studied, and available. The recent announcement that the US Administration (Health and Human Services) is supporting coformulation of current drugs and rapid approval processes for new and generic drugs⁹ is an important step. However, as emphasized by the recent alert on counterfeit drugs and the experience in Cote d'Ivoire, policymakers must insist on international regulations that ensure good manufacturing practices, with secure supply sources and predictable delivery.^{10 - 11}

New strategies are also urgently needed to prevent mother-to-child transmission of HIV as illustrated by the study by Taha and colleagues¹² in this issue. They demonstrated in Malawi that adding a week of zidovudine therapy to the treatment of neonates did not enhance the reduction of HIV transmission compared with the standard single-dose nevirapine.

Several lessons have been learned since single-dose nevirapine was found to reduce transmission (HIV NET 012).¹³ First, nevirapine does not always prevent perinatal HIV transmission.¹³ Second, infants face an uncertain future when their HIV-infected mothers become ill because they did not receive HAART. Maternal mortality by 24 months in 1 study was 10.5% in breastfeeding women.¹⁴ Third, nevirapine resistance (the K103V mutations, etc) occurs with alarming frequency in both mothers and infants after mother-to-child prophylaxis.¹⁵ In a recent study from Thailand, mothers who had no prior exposure to nevirapine except mother-to-child prophylaxis experienced a reduction in effectiveness when nonnucleoside reverse transcriptase inhibitor (NNRTI)–containing regimens were prescribed for therapy.¹⁵ The NNRTIs are critical to HAART programs in resource-limited settings. Thus, widespread class resistance to the NNRTIs should be a consideration when making decisions about HAART regimens. Fourth, nevirapine, although considered safe in this study, is now known to occasionally cause serious liver disease in patients with CD4 cell counts greater than 300/µL.¹⁶ For these reasons, the wisdom of further scale-up of the current mother-to-child transmission programs that use single-dose nevirapine may be questionable. Parents must be kept alive and well to blunt the orphan epidemic swamping Africa. The MTCT Plus program is a small step in this direction.¹⁷

Regimens that reduce maternal transmission during gestation, delivery, and lactation to less than 5% should be the norm and the goal. Anything else seems unacceptable. Regimens that minimize the emergence of resistance must be developed. Creative and practical regimens are needed.

Finally, how will the tens of thousands of health care professionals required for global implementation of HIV care strategies be trained, motivated, supervised, resourced, and adequately reimbursed to ensure the level of care required for this complex disease?¹⁸ To scale up antiretroviral therapy for HIV without ensuring infrastructure, including trained practitioners, a safe and reliable drug delivery system, and simple but effective models for continuity of care, would be a disaster, leading to ineffective treatment and rapid development of resistance. Another issue is whether lessons learned from experiences with HIV can improve the health care system for other diseases in resource-limited settings or if there will be growing dichotomies of care with drugs for HIV but continuing gross inadequacies for many other important illnesses.

As this issue of JAMA demonstrates, a major shift is occurring in HIV treatment as new, more-effective therapies are emerging. Optimism about long-term viral suppression will now allow a focus on reducing long-term drug toxicities. Hope displaces despair as individuals learn to live productive lives with HIV. Responding to the complex challenge of controlling and caring for AIDS in the West also requires addressing the accelerating global epidemic. Scientists, funders, governments, and clinicians must rise to the challenge—each increasing by many fold their current activities in resource-limited settings. Research, training, more effective prevention strategies, organization and funding of care, and numerous other intervention strategies must all progress in parallel to mitigate the impact of AIDS at both the societal and individual level. Altering the trajectory of this threat to humankind will take the best efforts of all stakeholders and these reports are encouraging that these goals are attainable.¹⁹