Introduction

Antiretroviral (ARV) therapy (ART) is one of the most dramatic examples of successful drug development in the history of medicine. While current ART cannot eradicate HIV infection, it can reduce HIV replication to extremely low levels and allow the restoration of immune function to safe (though perhaps not normal) levels in the vast majority of treated persons. It thus can make possible the recovery and maintenance of health in a previously progressive and uniformly fatal syndrome. ART can, furthermore, reduce HIV transmission and even prevent initial infection. The obvious benefits of ART realized in wealthy economies are also seen in resource-limited areas in which treatment increasingly is being made available.

Success in ART is not difficult, but does require substantial resources and the careful application of principles learned from clinical trials and from treatment program development. Drugs that form potent multi-agent regimens must be continuously available and affordable. Laboratory assays must be available to diagnose HIV infection and, ideally, to stage the illness and monitor treatment response and toxicity. Also important are assays used to detect ARV resistance both to improve initial response and to adjust regimens that have lost effectiveness. Effective ART also requires access to healthcare providers—physicians and others—sufficiently trained to diagnose infection, to select appropriate drug combinations and to initiate them at the appropriate stage in HIV disease, and to identify treatment failure. Providers must be expert in educating patients in medication adherence and in managing ARV toxicity and drug interactions. They must also be able to adjust regimens to maintain viral suppression despite drug resistance.

This chapter will provide a brief review of the biology of HIV therapy and the essential questions of ARV management including the design and timing of initial combination regimens and of secondary or salvage therapy. It will summarize current ARV drugs with respect to common toxicities, resistance patterns, and drug interactions, but will defer to other chapters that deal with many of these topics in much more detail.

The central goal of HIV therapy is maximal suppression of viral replication in order to allow immune recovery, and to prevent the selection of drug resistance mutations [1–3]. Successful ART must durably restore or maintain immune competence and the control of infections and malignancies that characterize the AIDS syndrome. Beyond that, ART should enhance and extend the healthy life span of treated individuals.

In the resource-rich world, the availability of newer ARV medications and new classes of ARVs has made it possible to achieve virologic suppression even in most patients infected with HIV resistant to multiple ARV agents or entire drug classes [4–6]. For those patients in whom therapy does not fully suppress viremia, ART can still dramatically slow disease progression [7, 8]. While ART does improve immune function and reduce morbidity and mortality associated with HIV (most strikingly in those with lower CD4 counts), control of HIV viremia unfortunately may not result in complete normalization of immune function or complete reversal of the inflammatory state associated with HIV; this is an area of active study [9–11].

The Natural History of HIV Infection

Untreated HIV infection results in persisting and relatively constant levels of viremia and a progressive immune attrition reflected most obviously, but only in part, by a decline in the numbers of circulating CD4 T lymphocytes [12, 13]. The rate of CD4 cell loss varies widely among infected individuals but averages 60–80 cells/mm³ annually [14, 15]. Constitutional symptoms and serious infections and malignancies arise with immune attrition, particularly when the peripheral CD4 count falls below 200 cells/mm³. Many with initial, or acute, primary HIV infection have a 1- to 2-week clinical illness [16, 17]. Following recovery from any symptoms of this acute phase of HIV infection, most are asymptomatic until much later in the disease course [18]. With progressing disease, some experience constitutional signs and symptoms—chronic or recurring fevers, malaise, weight loss, or other evidence of chronic inflammation. Advanced HIV disease, also termed AIDS, when the CD4 count is below 200/mm³, is punctuated by opportunistic infections and malignancies that range from treatable inconveniences to rapidly fatal and irreversible acute illnesses. While the risk of AIDS-related conditions increases sharply with declining CD4 counts, some illnesses associated with HIV and AIDS may occur at high CD4 levels (e.g. tuberculosis, non-Hodgkin lymphoma). Additionally, a number of so-called “non-AIDS” complications, such as “non-AIDS” malignancies, and cardiovascular, liver, kidney, and neurocognitive disease, may occur at relatively high CD4 counts [11, 19–25]. A number of these complications appear to be associated with persistent immune activation and inflammation present in untreated persons with HIV infection, even at high CD4 counts, and are incompletely reversed by ART [26, 27]. Some researchers have suggested that HIV infection results in what may be considered an acceleration of the normal aging process [26, 27]. While some individuals progress from initial infection to death in as little as 12 months, most are relatively stable for a number of years. A very small number of HIV-infected individuals maintain control of HIV without medications and may survive many years with no apparent ill health [28].

HIV disease is staged by the CD4 count, with numbers above 500/mm³ considered in the normal range, while those below 200/mm³ [3] indicate advanced disease or AIDS. As the risk of specific opportunistic diseases correlates closely with the CD4 count, this test is of particular value in patient management. By contrast, levels of HIV viremia are less predictive of disease stage, but may correlate with the rate of disease progression, and may indicate treatment failure.

The HIV Life Cycle

Reviewed in detail elsewhere, a brief summary of the HIV life cycle focused on targets of existing drugs can help in considering ARV regimen design. These targets will be considered early, middle, or late in the life cycle, corresponding to currently approved ARV drugs blocking cell entry, reverse transcription, integration, or HIV protease processing.

Components of ARV Regimens

Achieving treatment goals through suppressing HIV replication to the lowest possible levels requires the simultaneous use of multiple ARV drugs. Most initial ARV regimens consist of a dual NRTI “backbone” and a third or “cornerstone” drug [2, 3]. Typically, the “cornerstone” drug is an NNRTI, a PI (usually boosted by low-dose ritonavir), or an integrase inhibitor. Alternative approaches, e.g. regimens composed of three NRTIs, a PI and an NNRTI without NRTIs, or boosted-PI monotherapy, have been attempted but generally have been less potent [42–44]. These are not currently a preferred option for most patients, though additional studies are underway. Each drug in a typical triple-drug combination must be considered on its own in terms of potency, convenience, and toxicity, but the entire regimen must be similarly considered. Designing an optimum regimen must be individualized for each patient. These factors are discussed in greater detail later in this chapter.

Summarizing each ARV drug and all possible regimens of choice is beyond the scope of this review, although Tables 11.1 and 11.2 offer a brief overview of commonly used agents and regimens. Excellent summaries of current ART information are included in guidelines published by national and international organizations. In the United States, both the DHHS [3] and the IAS-USA [2] guidelines are frequently updated. The DHHS guidelines are an especially extensive information resource for many aspects of drug potency, toxicity, and interactions. The IAS-USA also publishes updated guidelines of ARV resistance testing [45], which are extremely useful for planning treatment. Other chapters in this book address HIV biology and important ARV treatment issues including drug toxicity, drug resistance, adherence, and drug interactions. These chapters should be consulted for this crucial information.

Table 11.2 Common antiretroviral regimens using FDC backbones for initial therapy

a See Table 11.1 for disadvantages of individual ARVs.

An Overview of Common Components of ARV Regimens

Initial ARV regimens typically comprise a dual NRTI “backbone” and a third or “cornerstone” drug [2, 3].

Dual NRTI backbones: co-formulations

Tenofovir (TDF) plus emtricitabine (FTC)

This is a potent and convenient one pill, once daily backbone, and is recommended by US [2, 3] and European guidelines [48] as the preferred NRTI combination for most patients. It also is co-formulated with efavirenz as a three-drug combination tablet. Tenofovir usually is well tolerated in short-term use but has been associated with renal toxicity; renal function should be monitored [49]. Questions of potential bone toxicity are under investigation [50, 51]. Tenofovir has interactions, especially with atazanavir (whose levels decrease) and didanosine (whose levels increase). When used with didanosine, increases in CD4 counts may be dampened; this combination should be avoided [52]. Both tenofovir and emtricitabine are active against hepatitis B virus, and in persons with HIV–HBV co-infection this combination is recommended as part of the anti-HIV regimen in to co-treat HBV infection (although emtricitabine is not approved for this indication).

The HIV resistance pattern of tenofovir includes a K65R mutation that can lead to cross-resistance with some other drugs in this class. This mutation is rare if either a thymidine analog, or a potent “cornerstone” drug is co-administered [53]. Thymidine analog mutations (TAMs) may decrease the potency of tenofovir.

Abacavir (ABC) plus lamivudine (3TC)

This one pill, once daily co-formulation, also has had extensive clinical application [54]. Abacavir is a potent non-thymidine NRTI with no significant drug interactions. It is well tolerated in long-term use but may cause an occasionally severe hypersensitivity reaction in early use characterized by fever, rash, malaise, and, in extreme cases where the drug is continued or reintroduced, circulatory collapse and death [55]. Hypersensitivity to abacavir is closely associated with HLA B*5701, and genetic screening for this allele should be done before treatment with abacavir, and those testing positive should not be given abacavir [3, 56]. Abacavir has been associated with adverse cardiovascular effects in some studies but not others; the possibility of cardiovascular toxicity remains under investigation [57, 58]. In patients with high pre-treatment HIV viral loads (>100,000 copies/mL) one study found that regimens containing abacavir–lamivudine were not as effective in suppressing HIV viremia as those with tenofovir–emtricitabine; this result has not been found consistently [59]. As mentioned above, lamivudine should not be used in persons with HBV infection without other HBV-active drugs because HBV resistance commonly develops. Drug resistance patterns with abacavir are similar to tenofovir with a K65R mutation, but also seen is the L74V mutation. TAMs may decrease the potency of abacavir.

Zidovudine (ZDV) plus lamivudine (3TC)

This combination was the first to be co-formulated and has had extensive use. It must be used twice daily. Zidovudine can cause anemia, sometimes of severe grade. It also may cause nausea, fatigue, facial and peripheral fat loss (lipoatrophy), and other symptomatic adverse effects. Because of toxicity concerns, zidovudine is not recommended in the resource-rich world unless other options are not possible; however, it still is commonly used in resource-constrained areas. For treatment of pregnant women, though, zidovudine remains the preferred NRTI, as it has been extensively studied in the prevention of perinatal HIV transmission [60]. This combination has minimal interactions with other ARV drugs. Zidovudine’s resistance barrier is fairly broad. As mentioned above, lamivudine should not be used in persons with HBV without other HBV-active drugs because HBV resistance commonly develops.

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