Appendix B
Primer on Human Immunodeficiency Virus, Acquired Immune Deficiency Syndrome, and Antiretroviral Therapy

This primer is intended to provide the reader with a broad overview of HIV, AIDS, and antiretroviral therapy and guidelines for adults and adolescents in the United States. For a more complete review of antiretroviral therapy and guidelines, including for pregnant women and children, the reader is directed to the U.S. Department of Health and Human Services November 2003 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and the January 2004 Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Both documents are available at: http://aidsinfo.nih.gov/.

HUMAN IMMUNODEFICIENCY VIRUS AND THE ACQUIRED IMMUNE DEFICIENCY SYNDROME

Human immunodeficiency virus (HIV) is a single-stranded RNA virus of the Retroviridae family. When a person becomes infected with this virus, that person develops a lifelong condition resulting from this virus’ ability to integrate its genome into the genome of certain human cells. Without treatment, this virus causes a progressive weakening in the host’s immune system, culminating in the acquired immune deficiency syndrome (AIDS), and death over a period of years.

The virus consists of a core and an envelope. The core contains two copies of single stranded RNA. The virus particle also contains several viral



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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Appendix B Primer on Human Immunodeficiency Virus, Acquired Immune Deficiency Syndrome, and Antiretroviral Therapy This primer is intended to provide the reader with a broad overview of HIV, AIDS, and antiretroviral therapy and guidelines for adults and adolescents in the United States. For a more complete review of antiretroviral therapy and guidelines, including for pregnant women and children, the reader is directed to the U.S. Department of Health and Human Services November 2003 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and the January 2004 Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Both documents are available at: http://aidsinfo.nih.gov/. HUMAN IMMUNODEFICIENCY VIRUS AND THE ACQUIRED IMMUNE DEFICIENCY SYNDROME Human immunodeficiency virus (HIV) is a single-stranded RNA virus of the Retroviridae family. When a person becomes infected with this virus, that person develops a lifelong condition resulting from this virus’ ability to integrate its genome into the genome of certain human cells. Without treatment, this virus causes a progressive weakening in the host’s immune system, culminating in the acquired immune deficiency syndrome (AIDS), and death over a period of years. The virus consists of a core and an envelope. The core contains two copies of single stranded RNA. The virus particle also contains several viral

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities (and host cell) proteins that assist with replication. The three main enzymes are reverse transcriptase, protease, and integrase. The envelope contains proteins that allow the virus to attach to and enter its main target cells in the body: the CD4+ T lymphocyte (also known as CD4+ T cell or CD4 cell) and the macrophage. The CD4+ T lymphocyte is a critical element in or-chestrating the normal immune response to a wide range of infectious agents. Once inside the CD4+ cell, the virus replicates. Early in this process, HIV viral RNA is transcribed to double stranded DNA by the virus’ reverse transcriptase enzyme. This newly produced viral DNA is integrated into the DNA of the host’s CD4+ T lymphocyte and becomes known as “proviral DNA.” As infection depletes CD4+ cells, the immune system becomes compromised and the person develops AIDS; this process typically occurs over the course of years in an otherwise normal adult. When the immune system becomes debilitated to the point of the AIDS, the person can develop a range of opportunistic infections (OI), like tuberculosis, pneumocystosis, cryptococcus, toxoplasmosis, and certain cancers, like Kaposi’s sarcoma and lymphoma. An HIV-infected person is categorized as having AIDS when the CD4+ white blood cell count drops to below 200 cells/mm3 (normal counts vary significantly but typically range between around 500 and 1500 cells/mm3) or when he or she develops opportunistic infections or cancers. The complete criteria for diagnosing AIDS may be found in the December 1992 Morbidity and Mortality Weekly Report article (Centers for Disease Control and Prevention, 1992). While there is no cure for HIV or AIDS, treatment is now available. This includes antibiotics to prevent and treat OIs and specific antiretroviral (ARV) therapy to control HIV viral replication itself. In resource-rich countries where ARVs have been available and affordable for several years, HIV infection has ceased to be considered an automatic death sentence. With carefully managed therapy and a motivated patient, HIV infection is a serious but treatable chronic disease that does not necessarily preclude additional decades of good quality life. The Goals of Antiretroviral Therapy The use of antiretroviral therapy for HIV infection has become complex as more has been learned about the virus and its ever-changing response to therapeutics and about patient factors affecting therapy. The goals of therapy are to inhibit viral replication while minimizing toxicities and side effects associated with the available drugs. This inhibition of virus replication permits restoration of the immune system. Viral eradication from the host genome is not achievable; thus a cure for HIV is not yet possible. By using an appropriate antiretroviral treatment regimen it is

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities possible to minimize the morbidity and mortality associated with HIV, to delay or prevent the onset of AIDS, and to allow those infected to lead a productive life. Goals of Antiretroviral Therapy viral load suppression restoration or preservation of immunologic function quality of life improvement reduction in HIV related morbidity and mortality SOURCE: U.S. DHHS, 2003. Restoration of immune function and suppression of viral replication have been assessed largely by laboratory criteria. The goal of therapy is to achieve a CD4 cell count of greater than 200 copies/mm3 and an “undetectable” viral load (less than < 50 copies/mL). Within 4–6 months of starting antiretroviral therapy, these goals should be achieved. Failure is multifactorial; some issues will be highlighted in this report. The Four Classes of Therapy: Mechanisms of Action Drugs used to treat HIV principally belong to hree main classes, each based on a different mechanism of action; a fourth class was recently added. Three of the classes affect viral enzymes. The fourth class affects the ability of the virus to enter target cells in the body. The first class developed was the nucleoside analogue reverse transcriptase inhibitors (NRTIs). The first drug in this class (zidovudine [AZT or ZDV]) was introduced in 1987. The NRTIs compete with physiologic nucleosides—the building blocks of host and viral DNA—for binding to the reverse transcriptase enzyme. This has the effect of interrupting viral DNA chain elongation. There are eight FDA approved drugs in this class. The next two classes of drugs were introduced in late 1995 to mid-1996. One of these is the nonnucleoside reverse transcriptase inhibitors (NNRTIs). The NNRTIs bind to the reverse transcriptase enzyme and change the “shape” of the enzyme thereby preventing the enzyme’s action of transcribing viral RNA into viral DNA. There are three FDA-approved drugs in this class. The other class of drugs that was introduced is the protease inhibitors (PIs). The PIs work at a later stage of new virus production. The PIs inhibit the viral enzyme that cleaves a polypeptide protein necessary to produce new mature infectious virus particles. Virions treated with PI’s do not become infectious. There are eight

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities FDA-approved drugs in this class. The fourth and newest class of drugs available for HIV treatment is the entry inhibitors (also known as fusion inhibitors). The sole FDA-approved fusion inhibitor, enfuvirtide (T-20), has generated the most limited experience in treatment of HIV since it was only approved for use in 2003. Unlike the other classes of drugs that work by affecting viral enzymes, this class of drugs prohibits the entry of HIV into the host target cell, like the CD4+ lymphocyte. Also, unlike the traditional drugs used to treat HIV, this drug is not available in oral form. It requires twice-daily subcutaneous injection. When added to regimens containing the other classes of drugs taken by treatment-experienced patients with advanced disease with resistant virus, this therapy was shown to reduce viral load and increase CD4 counts after 6 months of observation (Kilby and Eron, 2003; Lalezari et al., 2003). Lessons Learned: More Is Better Than One Over the past 20 years, many lessons have been learned in the developed world about the selection, timing, and combination of drugs used to treat HIV. The first medication used to treat HIV was (AZT, ZDV, a NRTI approved for use in 1987. This drug was used as monotherapy for HIV and, during initial years of use, allowed for increases in CD4 cell counts (or delays in decreases in CD4 counts) and prolonged survival. It was soon learned that these effects were transient, with benefits not lasting much longer than 2 years. Nearly 10 years after the introduction of AZT, the PIs and NNRTIs were approved. Based on clinical trials using these newer drug classes, it was quickly learned that combination therapy was superior in reducing viral load, delaying the emergence of HIV drug resistance, slowing the rate of immune destruction (i.e., CD4 cell decline), and slowing the rate of disease progression. By 1997, there was a 47 percent decrease in HIVrelated mortality rates and a 60–80 percent reduction in AIDS-defining diagnoses and hospitalizations for patients using combination therapy (Bartlett, 2004). It is now known that the most effective and recommended way to use the drugs to treat HIV is in at least triple combination. Mono- or dualtherapy, which was used at the start of the epidemic, has now been proven to be less effective and have limited long-term durability and, therefore, should be avoided. Highly active antiretroviral therapy (HAART) refers to the use of three or more drugs in a daily regimen. The three drugs used in a HAART-based regimen should come from at least two different classes. Of note, while there are 20 FDA-approved drugs, not all combinations that could be formed result in an effective regimen. In fact, certain combinations of drugs are antagonistic and must be avoided. See “Selecting a Regimen” for guidance on HAART design.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Balancing the Risks and Benefits Lifelong Treatment While curing HIV with antiretroviral therapy is not yet possible, halting further viral replication and production and restoring immune function remain the goals of therapy. These goals must be balanced with the consequences of receiving antiretroviral therapy: toxicities, side effects, and viral resistance development limiting further therapy options. Furthermore, as morbidity and mortality have decreased with antiretroviral therapy, patients are living longer; HIV has thus become a chronic disease requiring lifelong treatment. With the experience of over a decade of use of these therapies, it has become clear that long-term use can result in metabolic derangements with potentially serious non-immunologic long term implications. This is particularly relevant with the PI class, which has been shown to cause hyperglycemia and hyperlipidemia (U.S. DHHS, 2003). Conflicting data exist associating these metabolic derangements with an increase in cardiovascular morbidity and mortality; longer observations may clarify this (Sklar and Masur, 2003). In recognition of long term adverse effects resulting from long-term treatment, clinicians are no longer encouraged to abide by the “hit early, hit hard” strategy; more thoughtful and thorough risk-benefit analyses between physician and patient should be addressed prior to therapy initiation (Sepkowitz, 2001). Side Effects There are class-specific toxicities and side effects, in addition to unique toxicities and side effects of individual antiretroviral drugs. Different drugs within the NRTI class are associated with lactic acidosis and hepatic steatosis, peripheral neuropathy, pancreatitis, and anemia. Of note, abacavir (ABC) has been associated with a life-threatening hypersensitivity reaction requiring immediate and permanent discontinuation of the drug. Drugs within the NNRTI class are associated with rash and hepatotoxicity. Of note, efavirenz has been associated with psychiatric side effects such as insomnia and vivid dreams and nevirapine has been associated with hepatotoxicity and the Stevens-Johnson syndrome. Drugs within the PI class are associated with nephrolithiasis and gastrointestinal side effects such as nausea and diarrhea. Metabolic derangements, as described above, also are more frequently associated with this class of drugs. Based on early clinical trial studies of the newest class of drugs, the fusion inhibitors, adverse events associated with the drug in this class include: local injection-site reactions such as the development of painful, pruritic subcutaneous nodules; eosinophilia (rarely associated with systemic hypersensitivity); and an

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities increased incidence of bacterial pneumonia. For a more comprehensive listing of drug-specific side effects, see Table B-1. Resistance and Its Determinants In deciding to initiate or change antiretroviral drug therapy, an understanding of the concept of drug resistance is important, since the benefits of therapy can be compromised if drug resistance develops. Because HIV undergoes high rates of replication and turnover, there is potential for genetic variation leading to HIV variants that are no longer susceptible to the mechanisms of action of existing drugs. Resistance develops during drug therapy (Clavel and Hance, 2004). If virus continuously replicates in the presence of drug therapy (i.e., incomplete viral suppression in the presence of selective drug pressure), drug resistance will emerge (Deeks, 2002; Hirsch et al., 2003). Mutations conferring resistance are selected and maintained by drug pressure (Hirsch et al., 2003; Petrello et al., 2002; Richman et al., 2004). There are two approaches to measuring HIV drug resistance. Phenotypic assays measure inhibition (or lack of it) of viral replication in presence of a given drug. Genotypic assays detect the presence of mutations in the viral genome previously determined to account for resistance with the phenotypic assay. Drug-resistant HIV can be resistant to individual drugs or to the whole class within a given class. As aforementioned, any regimen that does not completely inhibit viral replication can lead to the emergence of resistance (Bennett et al., 2000). It is estimated that 50 percent of patients receiving antiretroviral therapy in the United States have a virus that is resistant to at least one drug in the armamentarium (Richman et al., 2004). There are many factors that can lead to the development of HIV resistance to antiretroviral therapy. As noted above, if complete suppression of viral replication is not achieved, resistance mutations will develop and the virus may become clinically resistant. Suboptimal exposure of the virus to the drug is an important mechanism by which drug resistance develops. Suboptimal exposure can result from underdosing, improper prescription of antiretroviral regimens, poor adherence, altered drug metabolism, and the presence of tissue sanctuaries where virions “hide” from the action of drug therapy (Deeks, 2002). While all mechanisms operate, the one factor that most critically depends on the patient is adherence. If at least 95 percent of doses are taken, there is a greater than 80 percent probability of achieving a viral load of less than 500 copies/mL; if less than 95 percent of doses are taken, less than 50 percent achieve this goal (Bartlett, 2004).

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities TABLE B-1 Antiretroviral Drugs and Selected Side Effects Generic Name Trade Name Comments and Common Side Effects Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Abacavir (ABC) Ziagen rash with or without hypersensitivity reaction; those that develop hypersensitivity reactions must not be rechallenged Didanosine (ddI) Videx EC peripheral neuropathy; pancreatitis; avoid alcohol Emtricitabine (FTC) Emtriva active against hepatitis B Lamivudine (3TC) Epivir active against hepatitis B Stavudine (d4T) Zerit peripheral neuropathy; lipodystrophy Zalcitabine (ddC) Hivid peripheral neuropathy; oral ulcers Zidovudine (ZDV, AZT) Retrovir initial “flu-like” symptoms; anemia; myopathy Tenofovira Viread renal insufficiency (rare) Protease Inhibitors (PIs) Amprenavir Agenerase rash; diarrhea; perioral paresthesia; hyperlipidemia Fosamprenavir Lexiva similar to amprenavir Indinavir Crixivan nephrolithiasis; nausea; hyperlipidemia Atazanavir Reyataz hyperbilirubinemia, nausea, diarrhea Lopinavir   gastrointenstinal intolerance; hyperlipidemia Ritonavir Norvir nausea; diarrhea; numb lips; hyperlipidemia Nelfinavir Viracept diarrhea; hyperlipidemia Saquinavir (soft gel) (hard gel) Fortovase Invirase Gastrointestinal intolerance; hyperlipidemia Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) Delavirdine Rescriptor transient rash; increase in liver enzymes Efavirenz Sustiva transient rash; insomnia; vivid dreams; rare suicidal/homicidal ideation Nevirapine Viramune transient rash; hepatitis Fusion Inhibitors Enfuvirtide (T-20) Fuzeon injection-site reactions; eosinophilia; rare hypersensitivity reaction aTenofovir is a nucleotide reverse transcriptase inhibitor. SOURCES: Schutz and Wendrow, 2001; U.S. DHHS, 2003.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities THE ART OF MEDICINE: DESIGNING AND STARTING A REGIMEN The goal in selecting a treatment regimen is to select a combination of drugs that will have additive or synergetic effects in viral suppression and immune stabilization or reconstitution. An overlying goal is to select a regimen that will minimize the development of drug resistance—especially to an entire class of drugs—thus leading to limited future treatment options. Other factors that are to be considered include: pharmokinetic and toxicity profiles and characteristics that favor adherence. There are many considerations in selecting a regimen. The text below will highlight examples of such considerations based largely on research endeavors from the developed world. For a more thorough review of regimen options and associated advantages and disadvantages, the reader is directed to the U.S. Department of Health and Human Services November 2003 “Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents” available at http://AIDSinfo.nih.gov. What Not to Do The first principle in designing a regimen is knowing what to avoid. Mono or dual therapy combinations should be avoided because of their inferior antiretroviral activity and high risk of fostering resistance. A combination therapy with three or more drugs—from different classes—is the recommended treatment regimen. There are certain combinations of antiretroviral drugs that are antagonistic and, therefore, should be avoided. The most notable combination to be avoided is zidovudine (ZDV, AZT) with stavudine (d4T) (Bennett et al., 2000; U.S. DHHS, 2003). Other combinations should be avoided because of pharmokinetic interactions. Didanosine cannot be taken with antiretrovirals requiring an acidic milieu for absorption; therefore, didanosine should not be combined with indinavir (Bennett et al., 2000). Didanosine also should also not be taken at full dosage with tenofovir. Toxicity profiles also should be considered when selecting a regimen. For example, didanosine, stavudine, and zalcitabine used in various combinations increase the risk of peripheral neuropathy (U.S. DHHS, 2003). As adherence to antiretroviral therapy can affect clinical outcome, thought should be given to the number of pills prescribed per day, food requirements, and to side effects. (There are many psychosocial determinants of adherence that are outside the scope of this review.) The combination formulation containing zidovudine with lamivudine (Combivir) allows two pills to be simplified to one pill. Indinavir and nelfinavir have fluid or food requirements that may need to be taken into account when using either of these in a regimen (U.S. DHHS, 2003).

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities What to Do As previously noted, HAART—a three or more drug combination—should be used with the goal of suppressing viral replication, restoring immune function, and delaying morbidity and mortality. Based on regimens for which the most extensive clinical trial data are available, the U.S. Department of Health and Human Services recommends three categories of regimens for first-line therapy use (U.S. DHHS, 2003): 1 NNRTI + 2 NRTIs (PI-sparing regimen) 1-2 PIs + 2 NRTIs (NNRTI-sparing regimen) 3 NRTIs (PI and NNRTI-sparing regimen) The objective is to select a combination that is potent, tolerable, and to which the patient is mostly likely to adhere. Clinical studies have found that using one of these combinations of drugs can result in viral suppression in 80–95 percent of patients. When to Start As described throughout this report, there are many considerations in selecting a regimen and many possible complications that can arise with any given regimen. The “hit hard and hit early” approach that was used when HAART became available in the mid-1990s has been replaced by an approach that takes into account the many lessons learned about antiretroviral therapy use in the developed world (see Box B-1). At this time, based on clinical trials and prospective studies, U.S. recommendations for starting therapy based on laboratory criteria are (U.S. DHHS, 2003) : CD4 ≤ 200 mm3 Start therapy CD4 > 200 mm3 but < 350 mm3 Offer therapy, weigh risks or benefits CD4 > 350 mm3 and viral load > 55,000 Consider therapy CD4 > 350 mm3 and viral load < 55,000 Defer therapy and follow CD4 count Any values and patient with symptomatic AIDS Start therapy These laboratory parameters should be used as a guide. Ultimately, the decision should be made by the clinician and the patient after discussion of the goals of treatment and the risks and benefits associated with it.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities BOX B-1 Factors for Consideration by Clinicians and Patients When Deciding to Start Antiretroviral Therapy: Lessons Learned from the United States Clinical criteria: CD4 count and viral load Patient acceptance and readiness Recognition of long-term nonimmunologic health risks: lipodystrophy, hyperlipidemia, diabetes, osteonecrosis Side effects affecting morbidity and quality of life (e.g., diarrhea, nephrolithiasis, rash, insomnia) No cure possible Demands of adherence Possible decrease in viral transmission if viral load is reduced SOURCES: Bartlett, 2004; U.S. DHHS, 2003. ANTIRETROVIRAL THERAPY IN RESOURCE-CONSTRAINED SETTINGS: OPPORTUNITIES AND CHALLENGES The developed world experience with treatment for HIV/AIDS has helped guide other nations in developing treatment plans and goals. While many of the considerations in initiating and selecting therapy have no borders, there are certain issues that developing nations must weigh more heavily in the treatment of HIV/AIDS. As the treatment for HIV/AIDS can be lifelong, continuous access to drug therapy is one such issue. In developing nations, access can be hindered by cost; drug delivery, supply, and storage; counterfeiting; and infrastructure to administer the therapy. Fortunately, many pharmaceutical manufacturers have lowered the prices of ARV drugs for the developing world. Some drugs may require a cold chain, which is not be available in parts of the developing world. Resistance profiles vary across borders and this also has an impact on regimens of therapy that may be selected. Factors affecting adherence may be affected by culture and, therefore, differ among communities and nations. The stigma associated with having HIV/AIDS may hinder adherence to therapy. The ability to use laboratory testing to monitor toxicities may influence the regimens chosen in the developing world where technological infrastructure may be limited. Finally, pharmacological interactions between antiretroviral and antituberculosis drugs is a more common concern in resource constrained settings. Recognizing the many barriers the developing world may face as ARV treatment is made available to millions across the globe, the World Health Organization (WHO), in its ambitious “3 by 5” initiative has recommended

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities four first-line regimens. (For the WHO’s recommended criteria for when to initiate therapy, see Appendix C.) The WHO has decided upon these regimens based on clinical trial and observational study data, experience with use of ART in resource constrained settings—including efficacy and side effect information, and cost and availability of drugs (WHO, 2003a). The four regimens are all PI-sparing.1 The WHO decided to spare PIs in their first-line recommendations for several reasons which include: higher cost, higher pill burden, food and water needs, cold chain requirements, and short- and long-term side effects that may require more intensive monitoring (WHO, 2003a). The four regimens recommended as first-line therapy in resource limited settings are: stavudine + lamivudine + nevirapine zidovudine + lamivudine + nevirapine stavudine + lamivudine + efavirenz zidovudine + lamivudine + efavirenz The first two regimens listed are available as fixed dose combinations (FDCs) in which all three drugs are combined into one tablet. FDCs have several advantages and disadvantages (MSF, 2004; WHO, 2003a,b). Advantages include: promoting patient adherence; improving health care worker adherence to treatment standards; minimizing prescription errors; and simplifying drug supply, management, and distribution. Disadvantages include: addressing the need to individualize the dosing of individual drug components and the differential half-life of the drugs and allergies to a component. While the United States relies heavily on laboratory criteria to determine when to start and how to monitor therapy, limited infrastructure in resource-constrained settings may preclude this. The WHO recognizes this fact and recommends using clinical criteria and, when available, laboratory criteria to initiate and monitor therapy for HIV-infected persons in these constrained settings. For further information regarding the advantages and disadvantages of the WHO-recommended regimens and the criteria used to start therapy, the reader is directed to the WHO 2003 Revision of Scaling Up Antiretroviral Therapy in Resource-Limited Setting: Treatment Guidelines for a Public Health Approach available at http://www.who.int/3by5/publications/documents/arv_guidelines/en/. 1   If NNRTI resistance is expected to be 5–10 percent, PIs may be considered in first-line regimens.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities CONCLUSION Over the past two decades much has been learned about the virus that causes AIDS and the natural history of the disease. Much research that guided success in treating HIV has been done in the developed world. The virus’s pathogenic mechanisms are still being investigated. Research continues to develop improved and additional therapeutics to combat HIV and AIDS. As the epidemic knows no borders, it will be important that research on antiretroviral therapies and their advantages and disadvantage continue to be conducted around the globe. REFERENCES Bartlett J. 2004. Antiretroviral treatment. In: Gorbach SL, Bartlett JG, Blacklow NR, eds. Infectious Diseases. 3rd Edition. Philadelphia, PA: Lippincott, Williams & Wilkins. Pp. 1028–1038. Bennett JE, Dolin R, Mandell GL. 2000. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. 5th Edition. Philadelphia, PA: Churchill Livingstone. Centers for Disease Control and Prevention. 1992. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morbidity and Mortality Weekly Review Weekly 41(51):961–962. Clavel F, Hance A. 2004. HIV drug resistance. New England Journal of Medicine 350(10): 1023–1035. Deeks S. 2002. Treatment of antiretroviral-drug-resistant HIV-1 infection. Lancet 362(9400): 2002–2011. Hirsch MS, Brun-Vezinet F, Clotet B, Conway B, Kuritzkes DR, D’Aquila RT, Demeter LM, Hammer SM, Johnson VA, Loveday C, Mellors JW, Jacobsen DM, Richman DD. 2003. Antiretroviral drug resistance testing in adults infected with human immunodeficiency virus type 1:2003 recommendations of an international AIDS society-USA panel. Clinical Infectious Diseases 37:113–128. Kilby JM, Eron JJ. 2003. Mechanisms of disease: Novel therapies based on mechanisms of HIV-1 cell entry. New England Journal of Medicine 348(22). Lalezari JP, Henry K, O’Hearn M, Montaner JS, Piliero PJ, Trottier B, Walmsley S, Cohen C, Kuritzkes DR, Eron JJ Jr, Chung J, DeMasi R, Donatacci L, Drobnes C, Delehanty J, Salgo M; TORO 1 Study Group. 2003. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV Infection in North and South America. New England Journal of Medicine 348(22):2175–2185. Lazzarin A, Clotet B, Cooper D, Reynes J, Arasteh K, Nelson M, Katlama C, Stellbrink HJ, Delfraissy JF, Lange J, Huson L, DeMasi R, Wat C, Delehanty J, Drobnes C, Salgo M; TORO 2 Study Group. 2003. Efficacy of Enfuvirtide in Patients Infected with Drug-Resistant HIV-1 in Europe and Australia. New England Journal of Medicine 348(22): 2228–2238. MSF (Médecins sans Frontières). 2004. Two Pills a Day Saving Lives: Fixed-Dose Combinations (FDCs) of Antiretroviral Drugs. Geneva: Médecins sans Frontières. Petrello M, Brenner B, Loemba H, Wainberg MA. 2002. HIV drug resistance implications for the introduction of antiretroviral therapy in resource-poor countries. Drug Resistance Updates 4:339–346. Richman DD, Morton SC, Wrin T, Hellmann N, Berry S, Shapiro M, Bozzette S. 2004. The prevalence of antiretroviral drug resistance in the United States. AIDS 18:1–7.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Schutz M, Wendrow A. 2001. Adapted from “Quick Reference Guide to Antiretrovirals.” [Online]. Available: http://www.law.duke.edu/aidsProject/400_01/GuideAntriRetros.pdf [accessed September 2, 2004]. Sepkowitz KA. 2001. AIDS: The first 20 years. New England Journal of Medicine 344(23):1764–1772. Sklar P, Masur H. 2003. HIV infection and cardiovascular disease: Is there really a link? New England Journal of Medicine 349(21):2065–2067. U.S. DHHS (United States Department of Health and Human Services). 2003. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. [Online]. Available: http://AIDSinfo.nih.gov [accessed August 23, 2004]. WHO (World Health Organization). 2003a. Scaling Up Antiretroviral Therapy in Resource-Limited Settings: Treatment Guidelines for a Public Health Approach. [Online]. Available: http://www.who.int/3by5/publications/documents/arv_guidelines/en/ [accessed August 23, 2004]. WHO. 2003b. Emergency Scale-up of Antiretroviral Therapy in Resource-Limited Settings: Technical and Operational Recommendations to Achieve 3 by 5. [Online]. Available: http://www.who.int/3by5/publications/briefs/arv_guidelines/en/ [accessed August 23, 2004].