F A Guide toOAIDSCResearch andU CounselingS Volume 15 Number 10 September 2000

longer a routinely terminal disease, the Responding to HIV Treatment long-term prognosis of people for whom Side Effects and Residual Symptoms treatment is working remains unclear. Lisa Capaldini, MD, MPH Outlier Symptoms and Syndromes A substantial minority of seropositive people who have undetectable viral loads With the advent of potent HIV antiviral and stable or rising CD4+ cell counts therapy, the medical prognosis for people nonetheless experience functional symp- with HIV has markedly improved. Fre- toms related to HIV disease. Most com- quency of hospitalization, complex home monly these untreated or residual outlier care, and death have all decreased, as symptoms include fatigue, cognitive combination treatment has ushered in an 1,2 impairment, and chronic pain. For some, era of chronic, but incurable, illness. these symptoms are manageable and This article offers non-medical providers require only minor accommodations; for an overview of the medical challenges that others, these symptoms are disabling in confront HIV-positive people whose immun- both their work and personal lives. For the odeficiency is stabilized. These medical purpose of documenting disability, it is issues include: “outlier syndromes,” that critical that medical caregivers chart these is, disease symptoms that worsen or fail to outlier symptoms, even if they are poorly improve despite low viral loads and rising understood or not treatable. or stable CD4+ cell counts; medication side HIV-associated fatigue is typically vari- effects; and coexisting conditions—for able and sporadic. People experiencing example, hepatitis B or C—whose symp- fatigue may get extremely frustrated by toms or treatment side effects overlap with this unpredictability, which may undermine those of HIV disease. efforts to return to work even when they In discussing quality of life, it is impor- are able to function well much of the time. tant to state several caveats. First, differ- The etiology of this fatigue is unclear. In the ent people have different priorities and context of HIV disease, some experts specu- these influence their quality of life con- late that fatigue reflects neuropsychiatric cerns. Second, providers must attend to a effects of autoimmune processes that are person’s symptoms and side effects even not fully controlled with HIV suppression. when, after applying quantitative criteria, Fatigue may also be due to low testosterone treatment seems to be successful. The levels, depression, anemia, and medication- easiest mistake a medical caregiver may induced hepatitis or chronic viral hepati- make in the new era of HIV treatment is to tis—all of which are treatable. Many people falsely assume that improving viral load with fatigue benefit from stimulants, which and CD4+ cell readings translate into feel- should be prescribed on a trial basis.3,4 ings of day-to-day well-being. Third, since Severe HIV-associated cognitive impair- side effects are one of the principal sabo- ment is much less commonly seen today teurs of medication adherence, clinicians than it was before combination antiviral must monitor their patients’ perceptions treatment. However, many people for of whether medications are causing side whom antiviral treatment is effective expe- effects, the impact of these side effects rience persistent, even new-onset, mild on day-to-day life, and the reversibility of cognitive impairment. This is character- these side effects. Finally, while HIV is no ized by word-finding problems and occa- success is vulnerable, and Editorial: Symptoms of Living with HIV changes in treatment are under- Robert Marks, Editor taken with care, hope, and fear. For many, living with successfully treated HIV does not mean living Is the cure worse than the To respond to these symptoms, disease? HIV antiviral drugs are many of which are treatable, it is without physical symptoms, and powerful chemotherapy, which, crucial to distinguish among the psychological distress from in limiting HIV replication, can them, for example, to understand symptoms may be all the more cause unpleasant, even dis- when fatigue is a side effect of a acute because of the expectation abling, side effects. When we particular antiviral regimen ver- for “normal” lives that successful first asked Lisa Capaldini to sus a symptom of hepatitis C treatment engenders. Ironically, write for FOCUS, this was the versus a condition of HIV itself. In this expectation is as much topic she was going to cover. But addition, as Linda Grinberg out- imposed on people with HIV by a Capaldini wisely took a broader lines in her article on structured society weary of the epidemic as view, discussing the range of treatment interruption, re- it is on each individual by his or symptoms, some caused by side searchers are exploring approach- her own desire for health. effects, others by HIV itself, that es to HIV treatment that may both Clients and providers may fail materialize when HIV disease reduce the severity of side effects to recognize the fragility of im- becomes chronic—when antivi- and improve treatment outcomes. proved spirit and may minimize, ral treatment is successful. While research suggests that a even yearn to minimize, the phys- As combination treatment lot of people without HIV mini- ical challenges of renewed health. extends life, some people with mize the severity of HIV disease Yet, this is one of the most impor- HIV may exchange a threat to in light of successful treatment, tant roles of the therapist: to cre- life for insults to the quality of no one I know with HIV underesti- ate a setting in which clients can life as the debilitating but sus- mates the daily challenge of side speak those thoughts that ordi- tainable symptoms of antiviral effects and other symptoms of narily remain unspoken—to open treatment, non-life-threatening HIV. Likewise, no one I know takes a forum for validation and sup- “outlier syndromes,” and co- the idea of treatment interruption port, two factors that are crucial existing conditions undermine lightly. For most people with HIV, for sustaining the perseverance feelings of health. treatment is serious, treatment required by antiviral therapy.

sionally by sleep disorders. Causes of pain medications and HIV antiviral drugs. cognitive impairment may include direct With three exceptions, there are probably HIV infection of the brain, depression, low no clinically significant interactions testosterone levels, substance use, and the between HIV antivirals and standard anal- side effects of prescription medications. gesic treatments. First, the antiviral medica- HIV-related chronic pain is extremely tions ritonavir (Norvir) and delavirdine common.5 In some cases, it stems from (Rescriptor) may impair the metabolism of specific conditions like antiviral-induced narcotics by the liver. Second, reports sug- peripheral neuropathy. In many cases, gest that some HIV antiviral medications however, the cause of pain is undetermin- may either raise or lower methadone levels, able, and it is especially in these cases that but no clear guidelines have emerged from chronic pain is likely to be underdiagnosed these variable reports. Finally, anticonvul- and undertreated; it is second only to sant drugs, which are commonly used to fatigue as an overlooked complication of palliate peripheral neuropathy and other HIV disease. Patients at particularly high pain syndromes, may lead to some interac- risk for the underdiagnosis and undertreat- tions, but gabapentin (Neurontin), a newer ment of pain include women and people of agent, has no drug interactions with HIV color (who are less likely to report symp- antiviral medications. toms), and both people with psychiatric conditions and people with past or current Medication Side Effects substance use histories (about whom Over the past four years, HIV clinicians providers are more likely to be biased in have come to understand that it is oversim- terms of pain management).6 In addition to plistic to suggest that all people with HIV the obvious drawbacks of untreated pain, should be treated with combination antivi- it can also lead to depression, which, itself, ral therapy: the choice of beginning or can lead to medication non-adherence. continuing treatment must be individual- Some clinicians are reluctant to treat pain ized for each person, balancing the benefits in people with HIV because of concerns of controlling the virus and stabilizing the about problematic interactions between immune system with the risk and signifi- 2 FOCUS September 2000 cance of medication side effects. In most person works at home and has his or her cases, side effects and their causes are own bathroom. For another person, particu- obvious. For example, indinavir (Crixivan) is larly those whose diarrhea is urgent, any the only antiviral agent that caus- episode of diarrhea may be not only func- es kidney stones; nelfinavir tionally difficult, but also potentially humil- (Viracept) is the most likely agent iating. Clinicians need to ask not only about For many to cause diarrhea; and all of the quantitative factors such as “How often?” so-called D drugs—zalcitabine and “How bad?” but also qualitative factors people with (ddC), didanosine (ddI), and stavu- such as “How much of a problem is this for HIV, treatment dine (d4T)—may cause peripheral you? Is it manageable, or not?” It is only neuropathy. Some side effects, through such assessment that clinicians can success however, are much less obvious determine whether medication should be to both people with HIV and their suspended, switched, or continued. has raised clinicians. For example, many The clinical response to a specific side individuals who switch from a effect is based on many factors, including expectations, protease-inhibitor-containing the likelihood that side effects will resolve regimen to a non-protease- over time or with changing antiviral drug and this can inhibitor-containing regimen may dosages, the availability of treatments for be unsettling find that they feel better overall, side effects themselves, the interaction as protease-related side effects between these treatments and antiviral for clinicians. such as fatigue or bloating— medications, and the availability of other whose onset was insidious and antiviral regimens that might replace the went unrecognized—subside. current combination. For instance, using Other easy-to-overlook side the examples above, if indinavir causes effects include poor appetite, irritability, kidney stones, clinicians should first muscle weakness, and dry skin. ensure that the individual can sustain high Probably the most vexing and poorly fluid intake; if nelfinavir causes diarrhea, understood medication side effect is clinicians should first undertake trials of lipodystrophy, that is, body composition antidiarrheal fiber and calcium; and if ddC changes. Primarily associated with the causes peripheral neuropathy, clinicians protease inhibitors, lipodystrophy occurs should first assess for other conditions or when fat is lost in areas such as the cheeks, medications that may be causing the pain. the extremities, or the buttocks, and inap- propriately accumulates in other areas Coexisting Conditions such as the breast, the abdomen, or the The three most common coexisting back of the neck (known as buffalo hump). conditions that have treatment implica- Observational studies have estimated that tions for people with HIV are chronic lipodystrophy occurs in as many as 80 hepatitis B or C, depression, and sub- percent or as few as 8 percent of people on stance use or recovery. All of these condi- References protease inhibitors, a wide range due to the tions have symptoms that can mimic HIV variety of study populations and the lack disease, and their treatment may facilitate 1. Art Reiter G. Com- prehensive clinical of standardized diagnostic criteria for the treatment of HIV disease itself. care: Managing HIV condition. Risk factors for lipodystrophy Hepatitis B and C share the following as a chronic illness. include older age, long duration of HIV symptoms with HIV: fatigue, chronic pain, AIDS Clinical Care. infection, and long duration of HIV treat- and weight loss. The primary treatment for 2000; 12(2): 13-20. ment. Aside from the medical implications hepatitis B and C, which is effective in 2. Paterson D, of lipodystrophy—it is not clear if this approximately 20 percent to 25 percent of Swindells S, Mohr J, condition will alter a person’s long-term patients, is alpha-interferon, which, itself, et al. Adherence to protease inhibitor health—there are significant psychological commonly causes fatigue and depressive therapy and outcomes implications related to body image. If an symptoms and may cause cognitive impair- in patients with HIV individual has not disclosed his or her HIV ment.7 These side effects may respond to infection. Annals of disease to friends, family, or co-workers, antidepressant therapy or may be severe Internal Medicine. 2000; 133(1): 21-30. these body changes can be difficult to enough to stop the interferon therapy. It explain and complicate medical privacy. remains controversial how hepatitis B or C 3. Wagner G, Rabkin Probably the most frightening of all is the and HIV infection influence each other both R. Effects of dextro- amphetamine on inability to predict who will get lipodystro- in terms of treatment response and acceler- depression and phy and how reversible it is. ation of either disease. On a practical level, fatigue in men with It is crucial for clinicians to assess the individuals who are doing well on HIV HIV: A double-blind, functional impact of any side effect on an antiviral therapy may be overwhelmed by placebo controlled individual’s life. For one person, having the prospect of treating yet another chronic trial. Journal of Clinical Psychiatry. diarrhea four to five times a day may not and intractable viral infection. Clinicians 2000; 61(6): 436-440. be a practical problem, for example, if that may seek additional advice about combin- 3 FOCUS September 2000 ing HIV and hepatitis treatment or deferring the neuropsychiatric side effects of medica- treatment of one or the other condition. tions. These individuals, at greater risk for Many people who are co-infected with adherence problems, may benefit from hepatitis and HIV may also be dealing with more structured treatment protocols or 4. Sherbourne C, Hays other issues, for example, drug abuse or more regular visits. Finally, HIV antiviral R, Fleishman J, et al. depression, that may complicate treatment. treatments have variable effects on Impact of psychiatric Depression is commonly seen with HIV methadone levels, and data suggest that conditions on health related quality of life disease, although it remains controversial all non-nucleoside reverse transcriptase in persons with HIV whether it is more common in people with inhibitors and all protease inhibitors can infection. American HIV than in the general population. Many unpredictably affect methadone levels. Journal of Psychiatry. experts believe that depressive symptoms 2000; 157(2): 248-254. may not represent a primary depressive Conclusion 5. Evans S, Ferrando S, disorder but are often due to HIV disease, For many people with HIV, treatment Sewell M, et al. Pain itself, or to other associated conditions. success has naturally raised the bar of and depression in HIV illness Psychosomatics. There are two obstacles to diagnosing expectations, and this can be unsettling for 1998; 39(6): 528-535. depression in people with HIV. First, many clinicians. Four years ago when people with symptoms of depression overlap symptoms HIV were relieved not to be dying or hospi- 6. Miotto K, Compton P, of HIV disease making it easy to miss an talized, medication side effects were a Ling W, et al. Diagnos- ing addictive disease underlying depression: impaired libido, welcome exchange for longer lives. Now, as and chronic pain pa- impaired concentration, fatigue, chronic they extend over the long term, side effects tients. Psychosomatics. pain, and disturbed sleep.8 In addition, have become less tolerable. Many people 1996; 37(3): 223-235. clinicians may be inappropriately empathet- with HIV have unexpectedly tasted the 7. Dieperink E, ic, characterizing depressive symptoms as possibility of normal lives and are reacting Willenbring M, Ho S. “normal” coping responses to being HIV- to the limitations of diarrhea, peripheral Neuro-psychiatric infected, rather than as signs of a separate neuropathy, and fatigue. Some clinicians symptoms associated with hepatitis C and depressive disorder. Second, clinicians may have responded to this with impatience, alpha-Interferon, a be overly concerned about drug interac- even disdain: side effects are a small price review. American tions between antidepressant medications to pay for being alive. In some cases, this Journal of Psychiatry. and HIV antiviral drugs: in most cases, response stems from clinicians’ feelings of 2000; 157(6): 867-876. potential interactions are not clinically powerlessness, in others, from a fear that 8. Barroso J. A review significant. When using ritonavir or delavir- altering a successful regimen might com- of fatigue in people dine, some antidepressants need to be promise an individual’s HIV prognosis. with HIV infection. Journal of the Associ- started at reduced doses, increased judi- Historically, modern Western medical ation of Nurses and ciously, and monitored for blood levels of practitioners have been reluctant to AIDS Care. 1999; the drug. St. John’s Wort, an herbal remedy acknowledge conditions or symptoms they 10(15): 4-49. for depression, reduces indinavir levels could not diagnose or fix. Today, effective Authors enough to cause drug failure. care requires HIV clinicians to inquire An increasing proportion of people who about symptoms that are difficult to define Lisa Capaldini, MD, receive HIV care either currently use drugs and treat, to accurately distinguish among MPH is Assistant or have a history of drug use. Studies have outlier syndromes, medication side effects, Clinical Professor of Medicine at the shown that individuals in drug recovery are and coexisting conditions, and to help University of Califor- able to adhere to HIV medication regimens, patients respond to them. Clinicians also nia San Francisco and while those who actively use recreational need to remind themselves that people has been a general drugs may have problems adhering. In with HIV can benefit from clinical care internist in private practice in San Fran- addition, people with recreational drug- especially when the role of healer involves cisco since 1988. induced brain damage are more prone to attentive listening and active witnessing.

Hyperlipidemia and insulin resistance Clearinghouse: Chronic Illness Effects are induced by protease inhibitors independent of changes in body com- References Johnson SC, Gerber JG. Advances in position in patients with HIV infection. Franchi D, Wenzel RP. Measuring health- HIV/AIDS therapy. Advances in Internal Journal of Acquired Immune Deficiency related quality of life among patients in- Medicine. 2000; 45: 1-40. Syndromes. 2000; 23(1): 35-43. fected with human immunodeficiency Powderly WG. Emerging complication: virus. Clinical Infectious Diseases. 1998; Mokrzycki MH, Harris C, May H, et al. Lactic acidosis associated with stavudine Mitochondrial toxicity, lipoatrophy, 26(1): 20-26. and bone changes. Topics in HIV administration: A report of five cases. Medicine. 2000; 8(5): 13-16. Garcia F, Plana M, Vidal C, et al. Dynamics Clinical Infectious Diseases. 2000; 30(1): of viral load rebound and immunological 198-200. Ruiz L, Martinez-Picado J, Romeu J, et changes after stopping effective antiretro- al. Structured treatment interruption viral therapy. AIDS. 1999; 13(11): F79-86. Mulligan K, Grunfeld C, Tai VW, et al. in chronically HIV-1 infected patients

4 FOCUS September 2000 this, they attempted to replicate the pro- HAART Breaks: cess in three treatment-naïve individuals. After a second interruption, the first Structured Treatment Interruptions patient’s viral load remained below 5,000 Linda Grinberg for six months. A second patient’s viral load quickly rebounded with each interruption. But in the third patient—now known as “the The hottest buzz in HIV circles is struc- References Washingtonian”—the period before viral tured treatment interruptions (STI). Hopes rebound became increasingly prolonged. 1. Lisziewicz J, Rosen- for eradication were dashed when re- berg E, Lieberman J, After the last treatment interruption, he searchers discovered replication-compe- et al. Control of HIV went 150 days before resuming treatment. despite the discontinu- tent viral reservoirs, capable of persisting ation of antiretroviral for more than 60 years. Despite immeasur- A Walk on the Wild Side therapy. New England able HIV in the bloodstream, these hidden Journal of Medicine. sanctuaries harbor virus impervious to Veronica Miller of J.W. Goethe-Universitat 1999; 340(21): 1683- in Frankfurt dazzled participants at the 1684. highly active antiretroviral treatment (HAART). The dreary prospect of a lifetime 1999 Salvage Therapy Workshop with her 2. Lori F, Foli A, of pill-popping and potentially intolerable presentation on a chronically infected, Maseratt R, et al. multi-drug resistant cohort of 39 patients Control of viremia side effects has lent a sense of urgency to after treatment inter- finding innovative treatment approaches. on “megaHAART” (including five to nine 3 ruption. Presentation One rationale for STIs is that the very drugs). Using phenotypic testing to check from the 7th Confer- success of HAART, ironically, may be its baseline resistance, Miller found that two- ence on Retroviruses thirds had shifted toward a more drug- and Opportunistic flaw. HAART decreases HIV-specific cellular Infections, San Fran- immunity by lowering the amount of HIV sensitive HIV, also know as “wild type” cisco, January 2000. antigen. A treatment interruption, allowing virus, following a treatment interruption. Steven Deeks and colleagues at the 3. Miller V, Rottmann C, a controlled amount of virus to be reintro- Hertogs K, et al. Mega- duced to the immune system might, theo- University of California San Francisco HAART, resistance and retically, provide sufficient antigen confirmed and expanded upon Miller’s 4 drug holidays. Present- stimulation to trigger stronger HIV-specific observations. Patients whose protease ation at the 2nd Inter- inhibitor-based regimen was failing were national Workshop on CD4+ and CD8+ cell responses. Salvage Therapy for randomized into two groups: 18 patients HIV Infection, Toronto, The Berlin and Washington Patients underwent a 12-week treatment interrup- May 1999. The initial excitement began with Franco tion; the others remained on failing regi- mens. After eight weeks, 16 of the 17 STI 4. Deeks SG, Wrin T, Lori’s report of the famous “Berlin patient,” Hoh R, et al. Virologic who cycled on and off treatment twice, patients who could be evaluated under- and immunologic eval- prompting HIV to re-emerge, and then sub- went a shift from drug-resistant to pro- uation of structured sequently resuppressed it with treatment.1 tease inhibitor-sensitive virus. treatment interruptions (STI) in patients experi- After the last interruption, the Berlin encing long-term viro- patient’s virus became undetectable and has Cellular Immunity logic failure. Presenta- remained so for nearly three years, without In Bruce Walker’s Massachusetts General tion from the 7th Con- treatment. Because replication-competent Hospital acute infection study, seven ference on Retroviruses patients underwent treatment interrup- and Opportunistic virus can still be found in his latent cells, Infections, San Fran- the Berlin patient is not considered “cured.” tions and weekly tracking of viral load, cisco, January 2000. Lori and colleagues then theorized that CD4+ cell counts, and T-lymphocyte pro- exposing the immune system to HIV in a liferation.5 After the first interruption, all 5. Altfeld M, Rosenberg ES, Eldridge RL, et al. highly controlled way might stimulate the three measures improved. After the sec- Increase in breadth body’s innate ability to fight back.2 To test ond interruption, viral levels remained at after long-term viral suppression. AIDS. antiretroviral therapy. AIDS. 2000; Contacts 14(4): F63-67. 2000; 14(4): 397-403. Lisa Capaldini, MD, MPH, 533 Castro Schambelan M. Metabolic and morpho- Tsiodras S, Mantzoros C, Hammer S, et Street, San Francisco, CA 94114, 415- logic complications of HIV. Topics in al. Effects of protease inhibitors on 861-3189 (fax). HIV Medicine. 2000; 8(5): 4-8. hyperglycemia, hyperlipidemia, and lipodystrophy: A 5-year cohort study. Linda Grinberg, Foundation for AIDS Schooley RT. Longer-term immunologic Archives of Internal Medicine. 2000; and Immune Research, 356 North effects and side effects of successful 160(13): 2050-2056. Skyewiay Road, Los Angeles, CA 90049- antiretroviral therapy. Clinical 2838, 310-471-4108, 310-471-8408 Infectious Diseases. 1999; 29(1): 12-18. Vigouroux C, Gharakhanian S, Salhi Y, et (fax), [email protected] (email). al. Adverse metabolic disorders during Tebas P, Powderly WG, Claxton S, et al. highly active antiretroviral treatments Accelerated bone mineral loss in HIV- (HAART) of HIV disease. Diabetes and infected patients receiving potent Metabolism. 1999; 25(5): 383-392. See also references cited in articles in this issue.

5 FOCUS September 2000 less than 5,000. Though the study was during the second interruption, while one and frequency of CTL small, these results suggest that cellular had a higher rebound. During the first STI, responses after struc- immunity in recently infected patients CD4+ cells counts decreased by almost 20 tured therapy interrup- might be boosted by STIs. percent, but after the initial dip, they re- tions in individuals Luis Montaner of the Wistar Institute in mained stable. The third strategy was inef- treated with HAART during acute HIV-1 Philadelphia reported in the September fective and abandoned. While it is too early AIDS infection. Present- issue of the Journal of Infectious Diseases to evaluate whether the first two strategies ation from the 7th Con- the first documented case of a chronically will be successful, without loss of viral con- ference on Retroviruses infected patient who completely stopped trol or seriously reduced CD4+ cell counts, and Opportunistic Infections, San Fran- therapy for more than four months, mount- such approaches could dramatically cut the cisco, January 2000. ing an immune response sufficient to main- cost of treatment for developing nations. tain low level HIV RNA in his bloodstream.6 6. Papasavvas E, Ortiz Caution and Hope GM, Gross R, et al. Five patients were monitored during an Enhancement of interruption for a median period of eight In the past, treatment interruptions human immunodefi- weeks and compared to five untreated raised fears that reemerging virus would ciency virus type 1 subjects. All five STI patients showed signif- mutate into drug-resistant forms. Such specific CD4 and CD8 T-cell responses in icant increases in anti-HIV immune respons- worries have been partially allayed, since chronically infected es. Two months later, when the Philadelphia only one documented case of resistance persons after tempo- patient stopped therapy for good, he experi- attributable to a treatment interruption has rary treatment inter- enced a powerful immune response, sug- been reported and non-adherence was ruption. Journal of Infectious Diseases. gesting that even with chronic infection, suspected as its cause. Since half-lives of 2000; 182(3): 766-775. the body may be capable of fighting back. antiviral drugs vary, clinicians must stagger cycling off particular drugs. Unanswered 7. Hirschel B, Fagard Largest and Longest Studies questions remain: how long will drug- C, Lebraz M, et al. The Swiss-Spanish intermit- Preliminary results of the largest STI resistant viruses persist at low levels or as tent therapy trial. study to date suggests that responses are “archived” virus in long-lived cells, and will Presentation from the highly variable. At the XIII World AIDS recombinant virus emerge during STIs? XIII World AIDS Con- Conference in Durban, Bernard Hirschel A year after presenting her initial ference, Durban, South Africa, July 2000. reported preliminary results of a study results, Veronica Miller presented a sober- involving 122 patients who underwent ing update, underscoring inherent risks of 8. Dybul M, Yoder C, four STI cycles, consisting of eight weeks stopping therapy in the setting of virolog- Belson M, et al. A 9 randomized, controlled on treatment and two weeks off, or until ic failure. Almost three-quarters of her 7 trial of intermittent viral load reached 5,000. Hirschel detect- original cohort eventually experienced versus continuous ed no consistent pattern in the 56 patients virologic rebound and one-quarter failed highly active antiretro- who completed four treatment interrup- to recover pre-STI CD4+ counts. In an viral therapy (HAART) (Late-Breaker). Present- tions. Nineteen patients failed to get their expanded cohort of 165 patients, Miller ation from the XIII viral loads below 50 after therapy resump- also documented 17 new opportunistic World AIDS Confer- tion, though researchers suspected that infections. Without a non-STI comparison ence, Durban, South poor adherence might be a factor. One arm, the impact on disease progression Africa, July 2000. patient showed evidence of resistance to remains unclear; however, if treatment 9. Miller V, Rottmann C, two drugs in the study regimen, an appar- failure can be delayed, this might prove Hertogs K, et al. Anti- ent first in STI research. Experts suggest beneficial in advanced disease. retroviral treatment in- that a two-week treatment interruption While STIs may hold promise, the data terruptions in patients with treatment failure: may be too short to elicit adequate are inconclusive. The answers may be Analyses from the immune responses. variable and ultimately hinge on immune Frankfurt HIV Cohort. Studies at the National Institutes of status, host and viral factors. Numerous Presentation from the Health under Mark Dybul and Anthony Fauci “proof of concept” studies are underway, 3rd International Work- shop on Salvage Ther- seek to determine whether the benefits of covering virtually every patient popula- apy for HIV Infection, HAART can be preserved, while minimizing tion, addressing safety, efficacy, optimal Chicago, April 2000. side effects and reducing costs.8 The follow- on/off schedules, and which markers may ing strategies are being studied: two months be predictive of outcome. Author on treatment/one month off; one week As eradication has all but evaporated Linda Grinberg, Pres- on/one week off; and two days on/five days into yesterday’s elusive dream, scientists ident of the Foundation off. Reporting on the longest trial to date at face an age of treatment uncertainties, for AIDS and Immune the World AIDS Conference in Durban—the a global pandemic, and the inescapable Research (FAIR) in Los Angeles, was a sponsor two-months on/one month off regimen— reality that growing numbers of patients of the 1st STI Workshop Dybul reported that nine of 70 recruits are stopping therapy. We must confront the in July 1999 and is made it through either two or three STI fact that lifelong treatment, as we know it, organizing the 2nd STI cycles. While the first nine experienced viral appears untenable. Exploring innovative workshop for Fall rebounds with each interruption, virus was strategies, which harness the power of the 2000. She is also on the Board of Directors of subsequently resuppressed with treatment. immune system in tandem with effective Project Inform. Three of the nine had smaller rebounds antiretrovirals, appear crucial. 6 FOCUS September 2000 with lipodystrophy and a viral load of Recent Reports less than 200 switched from a protease inhibitor to nevirapine. Viral load Lipodystrophy and Antiviral Medications increased in only one participant and overall, there were significant improve- Qaqish RB, Fisher E, Rublein J, et al. HIV-associated lipodystrophy syndrome. Pharmacotherapy. 2000; ments in cholesterol, triglyceride, and 20(1): 13-22. (University of North Carolina, Chapel glucose levels. Hill; Virginia Commonwealth University; and Medical College of Virginia.) Adverse Effects of Protease Inhibitors Current literature suggests a link Bonfanti P, Valsecchi L, Parazzini F, et al. Incidence of adverse reactions in HIV patients treated with between lipodystrophy and protease protease inhibitors: A cohort study. Journal of inhibitor therapy and, more recently, to Acquired Immune Deficiency Syndromes. 2000; nucleoside reverse transcriptase inhibitors 23(3): 236-245. (Luigi Sacco Hospital, Milan; and duration of HIV infection. “Lipodys- Istituto di Ricerche Farmacologiche Mario Negri, trophy” describes physical and metabolic Milan; and the Coordinamento Italiano Studio characteristics, including fat redistribu- Allergia e Infezione da HIV (CISAI) Group.) tion, pancreatitis, insulin resistance, and Thirty-six percent of participants in a diabetes. large Italian study experienced adverse A two-year study found that 83 percent reactions to protease inhibitor therapy, of participants receiving protease and 10 percent had at least one serious inhibitors developed lipodystrophy, com- adverse effect. In response, 15 percent of pared to only 4 percent of participants not participants interrupted their treatment receiving protease inhibitors. Among par- regimens, and each case led to a failed ticipants receiving protease inhibitor ther- treatment regimen. apy, lipodystrophy was mild in 42 percent, The two-year study monitored 880 men moderate in 30 percent, and severe in 11 and 327 women from the time they began percent. In a similar study, 64 percent of protease inhibitor therapy. The average participants receiving protease inhibitors age of participants was 37 years. Twenty- experienced fat wasting in five percent of the study group had been the face, arms, and legs; diagnosed with AIDS, and 23 percent had only 3 percent of partici- hepatitis. Compared to other pants not taking protease Women and participants with hepatitis participants, inhibitors experienced experienced a significantly greater num- these side effects. ber of adverse events compared to other women and A study of 42 HIV-posi- participants. Researchers grouped possi- tive women on antiviral ble protease inhibitor side effects into six participants with treatment found that half categories: gastrointestinal toxicity, hepat- of the participants experi- ic (liver-related) toxicity, neurologic toxici- hepatitis enced lipodystrophy. In a ty, metabolic alteration, allergic reaction, subset of 12 participants and renal toxicity. experienced with fat redistribution, Ritonavir was associated with the a significantly common side effects largest number of adverse reactions, included elevated choles- which usually appeared during the first greater number terol levels, increased few months of treatment, while saquinavir abdomen size, weight gain, hard-gel and nelfinavir were the best of adverse events fat wasting in the arms, tolerated. Gastrointestinal side effects legs, face, and buttocks, such as nausea, vomiting, and diarrhea under protease and development of “buffa- frequently occurred in participants treat- lo hump.” Risk of fat redis- ed with either ritonavir alone or in combi- inhibitor therapy. tribution significantly nation with either saquinavir hard-gel or increased with duration of nelfinavir. Among participants treated antiviral therapy. Research with ritonavir, other side effects included: also suggests that persistent lipid abnor- hepatic toxicity; neurologic toxicity such malities may increase the risk of cardio- as headache, nerve disorders, and taste vascular disease. alteration; and metabolic complications Several studies suggest that replacing such as lipodystrophy, weight gain, protease inhibitors with non-nucleoside cholesterol increase, and diabetes. reverse transcriptase inhibitors can Participants on indinavir presented with reverse the abnormalities associated with the highest incidence of renal toxicity, lipodystrophy, but doing so may increase including kidney stones, discharge of viral load. In one study, 23 participants blood in the urine, and acute kidney 7 FOCUS September 2000 failure. Participants on nelfinavir com- effects are common and can negatively monly experienced allergic reactions such affect quality of life. Metabolic problems, as swelling, rash, and itching. hepatitis, pancreatitis, nerve disorders, gastrointestinal symptoms, bone prob- Alternate Strategies for Antiviral Treatment lems, and renal disorders have replaced Henry K. The case for more cautious, patient- AIDS-related illnesses for many HIV-posi- F focused antiretroviral therapy. Annals of Internal tive patients. A Guide toOCUAIDS Research and CounselingS Medicine. 2000; 132(4): 306-311. (University of Standard guidelines suggest that thera- Minnesota, St. Paul.) Executive Editor; Director, py should change when a regimen ceases AIDS Health Project Contrary to the widely accepted HIV to suppress viral load. However, recent James W. Dilley, MD treatment strategy that calls for suppress- data suggest that during a 12- to 18- Editor ing viral load as quickly as possible, a month period, viral load may rise to Robert Marks University of Minnesota physician argues detectable levels without any noticeable Assistant Editor that some clients may benefit from damage to the immune system. Further, Alex Chase patient-focused alternative strategies such viral load resurgence in people receiving Founding Editor; Advisor as delayed initiation of therapy, drug antiviral therapy may reflect development Michael Helquist regimens that exclude protease inhibitors, of resistance to only one of the drugs in Medical Advisor planned drug interruptions, and immune- the regimen. Because of the risk of drug Stephen Follansbee, MD based therapy. resistance, it may be prudent to reserve Design Early aggressive therapy often prema- Saul Rosenfield potent antiviral treatments for use later in turely exposes individuals to medication- the course of HIV disease at a time when Production Carrel Crawford related side effects and potential drug there is a greater risk for developing AIDS- Catherine Jones resistance. Persistent, though mild, side related illnesses. Gabriel Rabu Saul Rosenfield Circulation Carrel Crawford articles about alternative causes of AIDS, Cassia Stepak Clarification including treatment with experimental Interns HIV-related chemotherapy, recreational Carla Stelling The May issue of FOCUS included an arti- drug use, and antibiotic treatment, which combined with improper sleep and nour- FOCUS is a monthly pub- cle entitled “HIV, AIDS, and the Distortion of lication of the AIDS Science,” by Martin Delaney. Delaney refers ishment to create immunodeficiency. Health Project, affiliated “Ultimately, without knowing the unique with the University of several times to Christine Maggiore, the California San Francisco. author of What if Everything You Thought You health history and lifestyle of the people who died, it’s impossible to come up with Twelve issues of FOCUS Knew about AIDS Was Wrong? Maggiore takes are $36 for U.S. residents, exception to his statements. a definitive answer that would explain $24 for those with limited these unfortunate deaths.” incomes, $48 for individu- In response to Delaney’s statement, als in other countries, $90 which can be read to mean that Maggiore for U.S. institutions, and $110 for institutions in relies only on her personal experience to other countries. Make support her assertions that the HIV test is checks payable to “UC flawed, Maggiore says, “I offer referenced Next Month Regents.” Address sub- scription requests and cor- data raising questions about the test’s The XIII World AIDS Conference took respondence to: FOCUS, cross-reactivity, its inability to specifically place in Durban, South Africa, in July. In UCSF AIDS Health Project, Box 0884, San identify HIV antibodies, and the lack of a the October issue of FOCUS, David Francisco, CA 94143- gold standard of virus isolation.” Miller, PhD, Rachel Baggaley, MB, BS, 0884. Back issues are $3 each: for a list, write to the In response to Delaney’s statement that and Bitra George, MD, all of whom work above address or call “Maggiore’s book seems to indicate that with HIV in the developing world, review (415) 476-6430. repeated testing in her case confirmed that conference presentations and other To ensure uninterrupted she was not HIV-positive in the first place,” sources to provide a perspective on the delivery, send your new address four weeks before Maggiore says, “Following the mention of psychosocial implications of the you move. my experience of testing HIV-positive, - epidemic in Africa. They focus, in Printed on recycled paper. indeterminate, -positive, -negative, and - particular, on the relevance of formal ©2000 UC Regents: positive, my book states, ‘Although my HIV mental health and counseling programs All rights reserved. status has been decidedly positive for the in areas where such approaches are not ISSN 1047-0719 past five years, I enjoy abundant good as common as they are in more health and live without pharmaceutical westernized societies. treatments or fear of AIDS.’” Also in the October issue, Nancy Finally, in response to Delaney’s state- Geshke, MSW, former Executive Director ment that “Maggiore conceded she had no of LA Shanti, reviews conference idea why people died ‘of AIDS’ before presentations covering the prevention antiviral drugs were available,” Maggiore and care challenges of people with HIV. adds that she has hypothesized in two 8 FOCUS September 2000 searchable archive FREE DID YOU KNOW?

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