JAIDS Journal of Acquired Immune Deficiency Syndromes:
Antiretroviral Treatment 2010: Progress and Controversies
Gulick, Roy M MD, MPH
From the Division of Infectious Diseases, Weill Medical College of Cornell University, New York, NY.
Supported by AI-51966 (K24 grant to R.M.G.).
Correspondence to: Roy M. Gulick, MD, MPH, Professor of Medicine, Chief, Division of Infectious Diseases, Weill Medical College of Cornell University, 1300 York Avenue, Box 125, New York, NY 10065 (e-mail: firstname.lastname@example.org).
Effective antiretroviral therapy (ART) changes the clinical course of HIV infection. There are 25 antiretroviral drugs approved for the treatment of HIV infection, and current antiretroviral drug regimens are highly effective, convenient, and relatively nontoxic. ART regimens should be chosen in consideration of a patient's particular clinical situation. Successful treatment is associated with durable suppression of HIV viremia over years, and consequently, ART reduces the risk of clinical progression. In fact, current models estimate that an HIV-infected individual appropriately treated with antiretroviral drugs has a life expectancy that approaches that of the general HIV-uninfected population, although some patient groups such as injection drug users do less well. Despite these advances, continued questions about ART persist: What is the optimal time to start ART? What is the best regimen to start? When is the optimal time to change ART? What is the best regimen to change to? In addition, newer antiretroviral agents are in development, both in existing classes and in new classes such as the CD4 receptor attachment inhibitors and the maturation inhibitors. Further research will help optimize current antiretroviral treatments and strategies.
Antiretroviral therapy (ART) changes the natural history of HIV infection by preventing clinical progression. With the development of effective combination ART in the mid-1990s and rapid widespread clinical use in developed countries, deaths in individuals with HIV/AIDS dropped by two-thirds from 1995 to 1997.1,2 Since the late 1990s, ART regimens became easier to take, less toxic, and more potent.3-5 Today, an effective ART regimen can be as simple as 1 pill taken at bedtime. ART use in developing countries expanded markedly after 2000 and an estimated more than 5 million HIV-infected people in developing countries are taking ART today with demonstrated clinical benefits similar to those seen in developed countries.6 The average life expectancy of an HIV-infected person who is treated appropriately with ART increased from 10.5 years in 1996 to 22.5 years in 2005,7 and now is estimated to approach that of the general population.8 Despite these marked improvements, challenges of access, adherence, toxicity, drug-drug interactions, and drug resistance remain, particularly in disadvantaged populations. Some groups have lagged in benefiting from ART including injection drug users who have lower life expectancy due to a number of factors including access, adherence, and concomitant conditions including mental health disorders and hepatitis C virus infection.7 Despite more than 20 years of ART, basic clinical questions about ART continue to be debated as follows: When to start ART? What regimen to start? When to change an ART regimen? What ART regimen to change to? This review seeks to address these antiretroviral strategy questions using the latest available data.
WHEN TO START ART?
The optimal time to start ART remains unknown, and current treatment guidelines vary in their recommendations6,9-12 (Table 1). As outlined in the guidelines, the rationale for starting ART earlier includes the fact that HIV disease is progressive, ART decreases HIV RNA (viral load) levels and the risk of emergence of drug resistance, ART increases CD4 cell counts and general immune function that delay or prevent clinical complications (both HIV-related and other illnesses), ART regimens are durable, and ART likely decreases HIV transmission in the community. The rationale for delaying ART includes practical factors such as the requirement for long-term adherence, the fact that drug toxicities may occur and that long-term side effects of ART are unknown, that the risk of clinical events appears low in early HIV disease, and that although ART can prevent HIV transmission, drug-resistant HIV can be transmitted.
ART treatment guidelines worldwide agree that ART should be started in any patient with an AIDS diagnosis, either on the basis of having an AIDS-defining illness or a CD4 cell count <200 cells per microliter6,9-12; ART is well documented to prevent clinical progression and death in these patients.13,14 In 2008, guidelines in the developed world changed to recommend that ART should be started routinely at a CD4 cell count threshold of 350 cells per microliter. This change was based on evidence of improved convenience and efficacy and reduced toxicity of ART, with supportive data from cohort studies,15 and a retrospective analysis of the SMART study.16 The CIPRA Haiti 001 study, a randomized prospective study of 816 treatment-naive patients with CD4 cell counts between 200-350 cells per microliter, who started ART either immediately or when the CD4 cell count decreased to <200 cells per microliter or when an AIDS event occurred, demonstrated a mortality benefit for the patients who started earlier.17 Consequently, the World Health Organization ART guidelines changed to recommend ART for HIV-infected patients in developing countries with CD4 cell counts 200-350 cells per microliter.6 The current standard of care worldwide is to start ART for AIDS, symptomatic HIV disease, and/or when the CD4 cell count is <350 cells per microliter.
Guidelines in the developed world also specify clinical scenarios where ART should be started in certain patients with CD4 cell counts ≥350 cells per microliter, including hepatitis B virus infection requiring treatment, hepatitis C virus coinfection, HIV-associated nephropathy, and pregnancy.11,12 The European treatment guidelines also recommend that ART be considered for patients with CD4 cell counts ≥350 cells per microliter who are older than 50 years or who have CD4 cell counts declining more than 50-100 cells per microliter per year, HIV RNA levels >100,000 copies per milliliter, a high risk of cardiovascular disease, and/or malignancy.12 Clinical events not traditionally associated with HIV disease occur in patients with higher CD4 cell counts: the SMART study first highlighted the fact that cardiovascular diseases, liver diseases, and renal diseases can occur in this group18; other studies described neurologic diseases19 and non-HIV-related malignancies.20 Recent cohort studies have found mortality benefits in patients starting ART at higher CD4 cell counts: the large North American ACCORD cohort reported significant mortality benefits among HIV-infected patients who started ART with CD4 cell counts of either 351-500 cells per microliter (69% decreased rate of death) or >500/uL (94% decreased rate of death) compared with patients who deferred therapy.21 However, such findings may be limited due to unmeasured confounding factors.
On the basis of both improved ART and emerging data about increased non-HIV-related clinical events from cohort studies, the US Department of Health and Human Services (DHHS) ART Guidelines9 for starting ART have recently changed. They now recommend ART for patients with CD4 cell counts 350-500 cells per microliter (55% of the DHHS panel gave this a strong recommendation and 45% a moderate recommendation). In addition, they support starting ART in patients with CD4 cell counts >500/uL (50% of the panel recommended this strategy, whereas 50% viewed it as optional). The recent WHO Guidelines specifically do not recommend starting ART in patients with CD4 cell counts >350 cells per microliter. All ART guidelines agree that patient readiness, that is, the patient's willingness to start and maintain adherence to ART, must be carefully assessed before making the decision to start ART.
The optimal time to begin ART is currently under investigation in a large ongoing international clinical trial called the START study that seeks to enroll over 4000 treatment-naive patients with CD4 counts >500 cells per microliter.22 Study subjects are randomized to start ART immediately or delay until the CD4 count is <350 cells per microliter and are followed for clinical endpoints as follows: serious AIDS-defining illnesses, non-AIDS-defining illnesses, and death. Enrollment is underway, and results are expected by 2015.
WHAT ART TO START?
Currently, there are 25 drugs approved for the treatment of HIV infection (Figure 1). The drugs fall into 6 distinct classes based on their mechanism of action (Table 2). The first class of ART drugs approved was the HIV nucleoside analogue reverse transcriptase inhibitors (NRTI) in 1987.23 By the mid-1990s, 2 additional classes were approved as follows: the HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs)24,25 and the HIV protease inhibitors (PIs).13,14,26 It was not until 2003 that the fourth class of drugs, the HIV fusion inhibitors, was approved with enfuvirtide (ENF).27,28 In 2007, 2 additional classes were approved: the first CCR5 chemokine receptor antagonist, maraviroc29,30 and the first HIV integrase inhibitor, raltegravir (RAL).31,32 In addition to the development of these new classes of drugs, improved formulations of ART drugs have been approved, including coformulations of 2 or 3 ART drugs into a single pill to improve convenience and enhance adherence.
For initial treatment of HIV infection, current ART guidelines worldwide recommend certain drugs within a class as preferred, alternate, or acceptable choices based on their efficacy, convenience, toxicity, drug resistance profile, and other factors such as drug-drug interactions. These include a combination regimen consisting of 3 ART drugs, most commonly 2 NRTIs together with an NNRTI6,9-12 (Table 3). US Guidelines additionally recommend 2 NRTIs together with an HIV PI or HIV integrase inhibitor.9 These regimens demonstrate potent durable virologic suppression and enhancement of CD4 cell counts and general immune function.
As preferred therapy for initial treatment of HIV, the current US DHHS Guidelines recommend the nucleoside analogue combination of tenofovir/emtricitabine (TDF/FTC) (coformulated) with either the NNRTI, efavirenz (coformulated with TDF/FTC as a 3-drug regimen that can be given as 1 pill, once daily); a PI, either atazanavir (ATV) or darunavir (DRV) (each given together with low-dose ritonavir (RTV) to enhance drug levels); or the integrase inhibitor, RAL (Table 3).9
Current WHO Guidelines recommend as preferred therapy for initial treatment of HIV infection the dual nucleoside-analogue combinations of either TDF and FTC, TDF and lamivudine (3TC), or zidovudine (ZDV) and 3TC, in combination with an NNRTI, either efavirenz or nevirapine6; (Table 3). These guidelines are based not only on considerations for efficacy, convenience, toxicity, and drug resistance, but also access, availability (including generic formulations), and cost. Stavudine, an NRTI, is no longer recommended because of toxicities, including peripheral neuropathy, facial lipoatrophy, and lactic acidosis.
Choosing among these initial drug options requires consideration of a number of individual patient factors such as preexisting drug-resistant virus, tolerability (both acute and chronic), adherence, stage of HIV disease, concomitant illnesses, drug-drug interactions with other medications, access, and cost. The optimal ART drug regimen is one that is individualized for a particular patient and his or her clinical situation. Drug users merit careful consideration of these factors, including adherence, concomitant illnesses (eg, psychiatric illness, substance use, viral hepatitis), and drug-drug interactions (eg, with both prescription and recreational drugs).
Strategies for initial use of ART will continue to be refined as the results of studies that are now in progress begin to become available. There are a number of studies comparing different initial ART regimens, for example, including regimens with investigational agents. Newer formulations that combine 3 or 4 ART drugs into a single pill for once daily use are also under investigation, as are novel formulations of ART that may allow for less frequent dosing (eg, once a week, twice a month, once a month); clinical studies are planned.
WHEN TO CHANGE ART?
In clinical trials and cohort studies in both developed and developing countries, more than three-quarters of patients taking ART will suppress their HIV RNA (viral load) below the level of detection and most will experience significant increases in their CD4 cell counts.15,33 To ensure durable effects of ART, the patient must be able to adhere to the regimen long term. Factors that facilitate adherence are related to the ART regimen itself (eg, convenience, tolerability), the patient (eg, belief in the benefits of treatment, able to stick to a routine), and the healthcare setting (eg, accessible, supportive). Although most patients will succeed on ART, some will experience regimen failure. When treatment failure occurs, the clinician needs to identify the reason(s) for failure and to address them carefully before selecting a subsequent ART regimen.
The US DHHS ART Guidelines define treatment failure primarily as virologic failure, when there is an incomplete virologic response, that is, HIV RNA >400 copies per milliliter by 24 weeks or >50 copies per milliliter by 48 weeks, or as virologic rebound, that is, confirmed recurrence of detectable viral load after virologic suppression below detectable levels had been achieved.9 Continuing ART in the setting of ongoing viral replication can lead to the emergence of viral variants with mutations that are resistant to drugs in the regimen. Because of cross-resistance, resistant viral variants may also be resistant to other drugs in the same mechanistic class. Virologic failure is the most common form of treatment failure and should be addressed and treated aggressively by changing the ART regimen.
Immunologic failure, defined as failure to achieve and maintain an adequate CD4 cell response despite virologic suppression, occurs in approximately 10%-15% of patients.9 Although some causes of immunologic failure can be identified and addressed (eg, drug-induced leukopenia with ZDV), in many patients immunologic failure is of unknown cause with few if any available treatment options besides simply continuing with the ART regimen. Immune-based therapies, such as interleukin-2, with ART have been associated with increased CD4 cell numbers but no clinical benefits,34 and are not recommended. Additional approaches for addressing immunologic failure are under investigation.
Finally, clinical failure can be defined as the occurrence or recurrence of HIV-related clinical events. In assessing clinical failure, it is important to exclude the immune reconstitution syndrome, an inflammatory response that occurs in over 10% of patients, usually within the first 3 months after starting ART and often in association with a low baseline CD4 cell count.35 Treatment of immune reconstitution syndrome usually includes the use of antiinflammatory drugs (nonsteroidal or steroids); the ART regimen is usually continued in this condition.36
In the setting of limited resources, WHO guidelines define treatment failure as virologic failure, based on a persistent HIV RNA level above 5000 copies per milliliter.6 These guidelines recommend using HIV RNA to confirm treatment failure every 6 months, when available. When HIV RNA testing is not available, the guidelines recommend immunological criteria to confirm treatment failure. Studies show that clinical monitoring alone (ie, changing ART after an AIDS-related illness) resulted in increased mortality and disease progression compared with combined immunological and clinical monitoring37 or combined virological, immunological, and clinical monitoring.38 Point-of-care testing (eg, for HIV RNA levels or CD4 cell counts) is under development to enhance monitoring of patients on ART, particularly for use in developed-world settings.
One concern for setting a higher HIV RNA threshold for virologic failure (>5000 copies/mL) is the selection of drug-resistant viral strains. A recent study from Malawi showed that of 94 patients with ART failure and an HIV RNA level >1000 copies per milliliter, 95% of patients selected viral strains exhibiting significant drug-resistant mutations to NRTI and/or NNRTI.39 Although the WHO Guidelines stress that unnecessary switching to expensive second-line therapy should be avoided,6 the issue of selection of drug-resistant viral strains remains an important consideration in optimal ART management.
WHAT ART TO CHANGE TO?
The DHHS guidelines outline an approach to selecting a subsequent ART regimen.9 First, goals of therapy should be reviewed. The current goal for all HIV-infected individuals treated with ART, regardless of prior treatment, is maximal virologic suppression (eg, HIV RNA <50 copies/mL). However, for some patients with extensive prior treatment and no treatment options, a reasonable treatment goal is to preserve immune function and avoid clinical progression. The patient's ART history should be reviewed, including an assessment of adherence, tolerability of prior ART regimens, concomitant medications, and the potential for drug-drug interactions with ART drugs. Drug resistance testing should also be performed while the patient is taking the ART regimen or within 4 weeks of discontinuation. For first-line or second-line therapy, genotypic drug resistance testing is recommended; for subsequent regimen failures, both genotypic and phenotypic drug resistance testing is recommended. Based on the history and drug resistance testing results, the goal is to identify susceptible drugs and drug classes and consider using newer agents, including those available through expanded access or clinical trials. The ultimate goal is to design a new regimen with 2 (or preferably 3) fully active agents. This strategy offers the best chance of reestablishing virologic control.
From 2003 to 2008, the US Food and Drug Administration approved 6 new ART drugs with activity against drug-resistant virus (darunavir [DRV], enfuvirtide [ENF], etravirine [ETR], maraviroc, raltegravir [RAL], tipranavir). These drugs have revolutionized subsequent ART regimens for the highly treatment-experienced patient. Drugs in existing classes with activity against drug-resistant viruses include ETR, the first NNRTI with activity against NNRTI-resistant virus,40 and the PIs DRV41 and tipranavir,42 each with activity against PI-resistant virus. In addition, drugs with new mechanisms of action should retain full activity, even in patients with drug resistance to older classes (eg, NRTI, NNRTI, and PI). The first HIV fusion inhibitor ENF,27,28 the first CCR5 antagonist maraviroc,29,30 and the first HIV integrase inhibitor RAL31,32 were each approved by the Food and Drug Administration on the basis of large phase III clinical studies demonstrating that, when added to an optimized ART regimen, each compound significantly improved virologic responses among highly ART-experienced patients.
Several recent studies demonstrate these improvements as follows: A Spanish study of 32 treatment-experienced patients without prior DRV use tested a novel regimen of DRV/RTV, ETR, and RAL and reported 30 (94%) patients experienced resuppression of their viral load levels to <50 copies per milliliter at the end of 6 months.43 A French study of 103 patients with documented NNRTI and PI drug resistance without prior ETR or DRV use tested the same regimen of DRV/RTV, ETR, and RAL, with optional NRTIs and/or ENF, and reported that 89 (86%) patients experienced resuppression of their viral load levels to <50 copies per milliliter by the end of 1 year.44 This treatment strategy now has been adopted widely representing a new standard of care for treatment-experienced patients.
The WHO Guidelines for resource-limited settings include choices for second-line ART after failure of first-line ART.6 They recommend using a RTV-boosted PI (either atazanavir or lopinavir) with 2 nucleoside analogues. For the choice of NRTIs, if stavudine or ZDV had been used first line, they recommend use of TDF (with 3TC or FTC) second-line, and if TDF had been used first-line, ZDV and 3TC as second-line. Some of the newer drugs are now becoming available in resource-limited settings, including DRV and RAL. Further studies of second-line and third-line ART regimens are underway in developing world settings.
Despite the improved strategies and newer drugs, there are some patients who experience treatment failure with all 25 available ART drugs. For these patients, additional, newer ART agents with activity against drug-resistant virus are in the development pipeline, including agents in the 6 approved drug classes and at least 2 newer mechanistic classes: the first CD4 receptor attachment inhibitor ibalizumab,45 and HIV maturation inhibitors.46
One challenge to the development of newer ART agents for ART-experienced patients is the design of phase III efficacy studies. As ART regimens improve, it becomes increasingly challenging to demonstrate benefits from the addition of new ART agents. This issue was illustrated by a recent phase III study of vicriviroc, an investigational CCR5 antagonist, that enrolled 721 treatment-experienced patients with R5 virus to receive an ART regimen optimized on the basis of treatment history and drug resistance testing with or without the addition of vicriviroc.47 At 48 weeks of follow-up, the proportion of patients with HIV RNA levels <50 copies per milliliter was not significantly different for those adding vicriviroc to the optimized background regimen (64%) compared with those who added a matching placebo (61%, P = 0.6). This study shows that, in the setting of an effective background ART regimen, it will be difficult to demonstrate added benefit from vicriviroc (or any new agent), thus creating new challenges for developing or improving on ART agents. Finally, strategies to eradicate HIV are under investigation with use of newer and novel agents and approaches.48
ART suppresses HIV viremia, increases CD4 cell counts, improves general immune function, prevents clinical progression, and promotes survival of HIV-infected individuals. Currently used combination ART regimens are highly effective, convenient, and generally well tolerated and are widely available in developed and developing countries. However, ART must still be individualized to the patient, which requires a careful evaluation of each patient's circumstances and ART readiness. Further research will help to advance and refine the optimal use of ART regimens to maximize the benefits for all HIV-infected patient populations, including injection and noninjection drug users.
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antiretroviral therapy; changing therapy; initiation of therapy
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