496 http://infection.thelancet.com Vol 6 August 2006 Review Approach to salvage antiretroviral therapy in heavily antiretroviral-experienced HIV-positive adults Zelalem Temesgen, Francesca Cainelli, Eric M Poeschla, Stacey A R Vlahakis, Sandro Vento Despite dramatic declines in HIV-associated morbidity and mortality as a result of highly active antiretroviral therapy, management of heavily treatment-experienced patients remains complex and challenging. Treatment response rates with subsequent antiretroviral regimens are lower than with initial antiretroviral therapy. Additionally, increased mortality has been associated with multidrug-resistant HIV. We review data relevant to management of such patients and offer a systematic approach to constructing a salvage antiretroviral regimen. Introduction The availability of potent antiretroviral drugs and their use in three or more drug combination regimens—highly active antiretroviral therapy (HAART)—has led to a dramatic decline in the morbidity and mortality associated with HIV infection. 1–3 In spite of this, many HIV-infected patients receiving HAART are unable to achieve sustained levels of plasma HIV RNA below contemporary limits of detection. In particular, patients that initiated antiretroviral therapy before the HAART era have been exposed to serial ineffective monotherapy regimens as well as stepwise additions of single new agents to a failing antiretroviral regimen. Issues such as tolerability, adherence, and broad cross resistance within each class of antiretroviral drugs have further complicated the situation, resulting in the current common dilemma of clinical HIV care whereby a substantial number of HIV- infected patients have multi-antiretroviral class failure with limited options for future therapy. By contrast with the 70–90% success rates commonly observed in clinical trials, 3–5 only approximately 50% of patients who received HAART therapy in a non-clinical trial setting were reported to achieve the goal of viral suppression. 6–9 Response rates achievable with subsequent regimens prescribed after failure of primary HAART therapy are considerably lower. The prevalence of heavily treatment-experienced patients with multiclass resistance is variable and not well reported. In over 8500 patients in the EuroSIDA cohort, 413 (5%) were reported to have failed virologically two HAART regimens and experienced all three main drug classes. 10 Richman and colleagues, 11 however, estimated resistance to all three drug classes to be present in 13% of adults receiving care in the USA with plasma viraemia over 500 copies per mL. Patients with multidrug-resistant HIV infection are believed to be at increased risk for mortality. In various studies, the hazard ratio for increased mortality attributable to drug resistance has ranged from 1·8 for resistance to any antiretroviral agent to 5·34 for triple-class resistance. 12–14 In this review, we present data relevant to constructing an antiretroviral therapy regimen in heavily treatment- experienced HIV-infected adults with multiply resistant virus. For the purpose of this review, it is assumed that the potential causes that might have led to the development of drug resistance and treatment failure—eg, non-adherence, drug-related toxicity, and pharmacokinetics—have been addressed. Thus our focus will be on the process of selection of an appropriate antiretroviral regimen with a reasonable chance of success. Treatment failure Treatment failure is a general term that encompasses various reasons for an antiretroviral regimen to be deemed inadequate. Clinical failure indicates progression of clinical symptoms or the emergence of a new opportunistic infection, condition, or death while on an antiretroviral therapy. Virological failure indicates the loss of control of viral replication (ie, rebound in viral load). In this review, we use salvage therapy to describe treatment regimens for people who have failed more than two previous HAART regimens, have been treated with agents from the main three classes of antiretroviral agents (nucleoside analogue reverse transcriptase inhibitors [NRTIs], non-nucleoside reverse transcriptase inhibitors [NNRTIs], and protease inhibitors [PIs]), and have multiclass-resistant virus. Antiretroviral treatment history Current guidelines recommend resistance testing to optimise drug selection after treatment failure. 15–17 However, current resistance testing options have been found to be insensitive in identifying minor viral species that constitute less than 10–20% of the circulating virus population. 18 When the selective pressure on drug-resistant populations is relieved by withdrawal of drugs, wild-type virus re- emerges as the predominant virus population. 19–21 This reversion to wild-type usually takes 4–6 weeks after the change in therapy but can take longer in some cases. If resistance testing is done after this period, the proportion of resistant virus could have decreased below 10–20% and might not be detected by commercially available assays. What makes this important is that studies have shown that reinstitution of the same or similarly selective antiretroviral agents leads to virological failure as a result of emergence of resistance derived from previously archived resistant virus. 22 A recent report has demonstrated that drug resistant HIV-1 species are present not only as minor constituents of circulating virus populations but also in the latent resting CD4+ reservoir long after resistance is no longer detectable in the plasma. 23 Therefore, it is critical to obtain as comprehensive an antiretroviral treatment Lancet Infect Dis 2006; 6: 496–507 Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA (Z Temesgen MD, E M Poeschla MD, S A R Vlahakis MD); Specialist in Infectious Diseases, Verona, Italy (F Cainelli MD); Section of Infectious Diseases, Department of Pathology, University of Verona, Verona (S Vento MD); and Infectious Diseases Unit, Annunziata Hospital, Cosenza, Italy (S Vento) Correspondence to: Dr Zelalem Temesgen, Mayo Clinic, Division of Infectious Diseases, 200 First St SW, Rochester, MN 55905, USA. Tel +1 507 255 7762; fax +1 507 255 7767; temesgen.zelalem@mayo.edu