Antiretroviral Therapy for Advanced Naïve HIV-Infected Patients: Current Status and Comparison of Two Different Management Strategies

There is incontrovertible evidence that combination antiretroviral treatment is associated with decreased mortality and morbidity; however, a few important clinical questions regarding the timing of therapy and optimal treatment choices remain incompletely addressed. One major clinical issue that currently remains is what to do with patients presenting with late-stage HIV disease. Initiating antiretroviral therapy in late-stage disease, defined by the presence of a concomitant opportunistic infection or merely having severe immunosuppression, is associated with significantly greater mortality and more complicated clinical management as a result of the need for additional drugs used to treat or prevent opportunistic infections. It is quite clear that late presenters have higher mortality, greater morbidity, they cost more to treat, they transmit more virus either in mother-to-child or sexual partner transmission, and they are at risk of the potentially devastating immune reconstitution inflammatory syndrome (IRIS), the paradoxical worsening of acute and subacute infections once antiretroviral therapy is initiated. Although late presenting patients are unique, the study of these patients and their complications is incomplete. Typically, treatment initiation studies have excluded patients with late-stage disease or have only included them as a subset of a larger group primarily consisting of patients with relatively early disease. Their unique problems have not been addressed adequately. In this supplemental issue of the Journal of Acquired Immune Deficiency Syndromes, Girardi, Manzardo and Soria with their colleagues review the important clinical issues surrounding treatment initiation in late-stage HIV disease. It is clear from these reviews that more clinical research in this area is required, resulting in a lack of consensus on the optimum management of these patients, but we can learn from the limited data available. The articles in this supplement do not constitute clinical evidence, but provide expert opinion on possible strategies for optimization of treatment. Despite guidelines recommending relatively early treatment initiation, starting therapy in patients with advanced disease is not a rare event, even in resource-rich settings, and may account for 15–43% of all those initiating therapy.1 Individuals who do not think they are at risk of HIV are more likely to present late for treatment. In western countries, these include heterosexuals, older individuals, African Americans, recent immigrants, and those with private or no insurance (compared with those with public insurance). In resource-limited settings, drug access and medical infrastructure play a role. In all settings, stigma remains problematic and also may be implicated. There are several ways to address this problem, which involves screening. Although partner notification schemes can be useful, they are quite expensive, impractical and in many instances, completely unfeasible. The most encouraging approach has been the shift towards routine screening for HIV infection, or the ‘opt out’ strategy.2 This approach de-emphasizes the special nature of HIV testing by including it in overall health evaluation settings unless the patient specifically opts not to have an HIV test. When approached in this manner, most end up being tested. There are several clinical complications associated with antiretroviral treatment in late-stage disease. These include the choice of antiretroviral agents, the use of concomitant anti-infective medications and IRIS. Late presenters, particularly those with an active opportunistic infection or with CD4 cell counts less than 50 cells/μl, need urgent antiretroviral treatment along with other treatment for their infections. Exactly how long one can safely hold off antiretroviral treatment in the face of an active opportunistic infection is unknown. Most recommendations are based on opinion, but the consensus appears to be treating the opportunistic infection for several weeks before initiating antiretroviral therapy. The advantage of a brief deferral of the antiretroviral drugs is to focus on the tolerability of the anti-infective agents that need to be used. Whether or not treatment of the opportunistic infection first will decrease the rate of IRIS is complete speculation at present and is in need of serious study. The optimal therapy for late presenters is another area in need of further study. Whereas it has been shown that virtually all pharmacologically enhanced (aka ‘boosted’) protease inhibitor and non-nucleoside reverse transcriptase inhibitor-based therapies are effective overall, in late-stage disease, in which treatment is actually urgent, the presence of baseline resistance mutations in the community setting may play a critical role in treatment choice. Resistance testing, although recommended by many authorities before initiating therapy, is not readily available and may take weeks for the results to be made available. In resource-limited settings, resistance testing is even less available, if at all. Currently, prevailing clinical data support the efficacy and tolerability of boosted PI-Based regimens in this patient population and it is likely that ongoing research will allow further optimization of these regimens for patients with late-stage HIV infection. It remains to be seen from head-to-head data whether NNRTI-based therapy will provide similar or greater outcomes in these patients. Despite adequate resources, late-stage presentation and the initiation of antiretroviral therapy remains a common clinical problem. More directed study at this target population is warranted. In the interim, facilitating earlier testing, use of the ‘opt out’ strategy for screening, staggering treatment for opportunistic infections with the antiretroviral treatment, and selected treatment choices are the best we can accomplish. Certainly, more needs to be done in this area.