You are leaving Medscape Education
Cancel Continue
Log in to save activities Your saved activities will show here so that you can easily access them whenever you're ready. Log in here CME & Education Log in to keep track of your credits.


Expert Column - Simplified Antiretroviral Regimens to Improve Quality of Life

Authors: Peter Ruane, MDFaculty and Disclosures



The advent of highly active antiretroviral therapy (HAART) in 1996 profoundly changed the management and expectations of patients with HIV/AIDS. The introduction of a variety of well-tolerated, highly potent antiretroviral (ARV) regimens has mitigated fears of sickness and death and improved outcomes even for patients with very low CD4+ cell counts and high baseline viral loads. Concerns regarding the effects of medications on the quality of life have come to dominate decisions about treatment. The issue of tolerability is particularly acute for asymptomatic or mildly symptomatic patients with CD4+ cell counts < 350 cells/microliter (mcL) who are contemplating starting elective therapy after a period of simply being monitored in the clinic.[1]

Major concerns for patients include the potential for immediate side effects that may impair their overall sense of well-being during the first weeks to months after starting medication, and delayed side effects that later lead to long-term problems.[1-3] The most worrisome of these latter concerns for patients are changes in body shape resulting from lipodystrophy. Other concerns include weight gain, changes in hair and skin, and parotid enlargement, among others. These issues, along with the complicated nature of some of the ARV regimens, also affect a patient's ability and willingness to adhere to his or her course of treatment or even to start therapy at all.[4]

What quality-of-life and subjective tolerability concerns are most critical for clinicians to consider when a treatment-naive patient presents and is a candidate for ARV therapy? How might subjective tolerability concerns affect adherence -- and ultimately the outcome?

This column will focus on 3 important areas that commonly require lengthy discussion with the patient who is beginning ARV therapy: gastrointestinal (GI) side effects, body shape changes, and anemia and fatigue, as they apply to some of the more commonly used regimens.

Gastrointestinal Side Effects

The most common reason for discontinuing or adjusting the initial ARV regimen relates to the GI effects of some of the agents. GI symptoms also may contribute to poor adherence and the attendant risks of inadequate viral suppression and the development of viral resistance. In a retrospective cohort study of 345 ARV-naive patients who started therapy (70% protease inhibitor [PI]-based, 30% efavirenz-based) in New Orleans, Louisiana, between January 1997 and May 2001, 61% changed or discontinued their initial HAART regimen; 24% of these were related to an adverse event, most commonly nausea, vomiting, and diarrhea.[5]

In the Women's Interagency HIV Study (WIHS) evaluation of clinical symptoms associated with ARV involving 1256 HIV-seropositive women beginning in April 2000, GI symptoms (diarrhea, nausea, and/or vomiting) were among the most common symptoms that prompted changes in therapy, although the types of therapies were not specified.[6] Johnson and colleagues[7] from the National Institute of Mental Health (NIMH) Healthy Living Project Team conducted a cross-sectional study of 2765 HIV-positive patients in 4 US cities. One goal of the study was to identify adverse events that lead to nonadherence. They noted that in addition to skin problems and adverse effects on memory, nausea and vomiting were independently linked to a less than 90% adherence. These studies are consistent with the common concern of patients and clinicians: that adverse GI symptoms can pose a threat to the successful initiation and outcome of antiretroviral therapy.

Which Agents Are Associated With Gastrointestinal Tolerability?

Newer PIs, including lopinavir/ritonavir, boosted fos-amprenavir, and boosted atazanavir, all appear to have greatly improved GI tolerability, compared with earlier boosted PIs.[8] Nonetheless, the GI tolerability of nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens remains superior compared with PI based regimens. In day-to-day practice, it is not uncommon to encounter patients who cannot ingest even 100 mg of ritonavir daily without experiencing diarrhea or urgent bowel movements.

A number of investigators have studied combinations of efavirenz (EFV) with either lamivudine (3TC) or emtricitabine (FTC) plus a third agent, such as a nucleoside (zidovudine [ZDV], stavudine [d4T], or abacavir [ABC]) or the nucleotide tenofovir (TDF). All of these combinations have demonstrated excellent antiviral activity with differences in the intent-to-treat (ITT) outcomes driven largely by adverse events related to the third agent.[9,10] d4T-based regimens have now fallen into disfavor because of concerns about a higher incidence of lipoatrophy and will not be detailed further, although the overall GI tolerability was very favorable.

CNA 30024[9] was a randomized, double-blind study that compared ZDV/3TC/EFV with ABC/3TC/EFV. Both study arms performed well; 70% of patients in the ABC group and 69% in the ZDV arm maintained viral load levels of ≤ 50 copies/mL week 48 in the ITT-exposed participants. Discontinuation rates related to adverse events by treatment arm were 71/327 (22%) for the ABC arm and 75/327 (23%) for the ZDV arm. Reported incidences of Grade 1-4 events for nausea were 37% for ZDV arm vs 23% for ABC arm and, for vomiting, 21% for ZDV arm vs 12% for ABC arm (P ≤ .004). The discontinuation rates related to these symptoms were not reported, however. For reported Grade 2-4 adverse events, GI symptoms of nausea, non-allergic-related vomiting and diarrhea, and abdominal pain were more common in the ZDV arm, but only in the category of nonallergic vomiting were those differences significantly more common in the ZDV arm (P < .01). In CNA30021, a study that compared ABC administered once vs twice daily in combination with 3TC and EFV, nausea was reported in both the once-daily (n = 384) and twice-daily ABC (n = 386) arms at 23%.[11]

In GS Study 934,[10] an open-label study that compared coformulated 3TC/ZDV given as Combivir (CBV)/EFV with TDF/FTC/EFV, virologic outcomes by ITT analysis were superior for the TDF/FTC/EFV regimen. The statistically significant differences in the ITT analysis were driven by fewer discontinuations in the TDF/FTC/EFV arm. Anemia was the most common reason for discontinuation in the ZDV arm (14/253 patients) but GI symptoms of nausea and vomiting were among other side effects resulting in discontinuation of the regimen. In the CBV arm, 4 of 254 patients discontinued therapy because of nausea and vomiting compared with 1 of 257 patients in the TDF/FTC arm.

ZDV/3TC, ABC/3TC, and TDF/FTC fixed-dose combinations have not been compared side by side in a single study, and rates of GI problems reported for ABC/3TC may be confounded by GI symptoms associated with hypersensitivity to ABC. However, the available evidence from clinical trials cited above and from extensive clinical experience suggests that GI tolerability for TDF/FTC and ABC/3TC is superior to that of ZDV/3TC and that the excellent GI tolerability of TDF/FTC is a factor in its adoption by clinicians.

In myexperience, intestinal gas is more common with TDF, something not evident from the studies, and I advise patients to anticipate this. TDF-related intestinal gas may be more of a problem for patients on regimens with ritonavir-boosted PIs than on the NNRTI regimens discussed above.


Among the greatest concerns for patients when they start therapy is the potential for changes in body shape, often called lipodystrophy. Despite the creation of a comprehensive case definition, as well as intense efforts throughout the past 8 years, no unifying hypothesis has emerged to provide a cohesive explanation for the entire syndrome. In recent years, examining each manifestation separately has been helpful, and some progress has been made in identifying the risk factors for lipoatrophy. This is good news for patients. Facial and limb lipoatrophy are the most feared manifestations because, while rare in the general population, they are common and easily noticed in the HIV/AIDS population, and thus have the potential to stigmatize.[12]


It is difficult for either the patient or the clinician to discern ongoing loss of fat before disfigurement develops. Regional dual-energy x-ray absorptiometry (DEXA) imaging is now commonly used in clinical trials to monitor for onset and severity of lipoatrophy. This technique is a useful and sensitive tool, particularly for changes in the limbs, but is less sensitive for detecting truncal fat loss, where visceral fat accumulation may obscure the results.[13] Computed tomography (CT) scans through the extremities or trunk have also been used to discern loss of fat that is not clinically evident. However, although lipodystrophy is very common (prevalence rates of lipodystrophy ranging from 11% to 83% in cross-sectional studies[14-16]) and the onset is hard to diagnose clinically, the use of serial imaging to detect changes in fat compartments has not been part of recommended treatment guidelines and is typically not reimbursed by third-party payers. The approach suggested in guidelines has been to avoid therapy with agents that foster lipoatrophy and, increasingly, to review options to switch drugs where data indicate that a switch may slow down or reverse the fat loss.

Clinical Studies

The US Department of Health and Human Services (DHHS) guidelines[17] have moved d4T from first-line therapy to alternative therapy because of the cumulative evidence linking it to severe lipoatrophy.[17] The data supporting this come from many sources. In the ABCDE study, the physician/patient-observed facial, buttock, and limb lipoatrophy rate was roughly 25% for d4T/3TC but only 3% for ABC/3TC at 96 weeks.[18] In a DEXA scan substudy,[18] compared with baseline, these differences translated to a limb fat gain in the ABC/3TC arm of 913 g (n = 25) vs a loss of 1579 g in the d4T/3TC group (n = 32), P< .001. The findings of the ABCDE study are remarkably similar to the findings of GS Study 903, a double-blinded study in which investigator-defined lipodystrophy was noted in 19% of d4T-treated patients compared with 3% of TDF-treated patients at 3 years.[18] DEXA scans performed at 144 weeks found a difference in total limb fat between the d4T and the TDF arms of 1.6 kg for women and 2.3 kg for men.[19] Switching to TDF after 144 weeks was followed by a gain in limb fat. These data, along with other data from earlier clinical trials with d4T[20-23] reviewed by Nolan and Mallal,[24] led those authors to estimate that clinically apparent lipoatrophy is clinically evident in approximately 40% to 50% of patients receiving d4T after 30 months.[20-23] d4T is now rarely used as a first-line agent in regions where alternatives are available.

Similar changes have been noted for ZDV but they occur at a lesser rate. In a nonrandomized Australian study, Mallon and colleagues[25] found that after an initial gain in fat during the first 6 months of therapy, a loss of limb fat occurred, with declines of 7.2% in the ZDV arm (n = 10), compared with 15.1% in the d4T/3TC arm and 16.7% in the d4T/ddI arm (each n = 13). Similar patterns were noted by Dube and others[26] in the substudy of ACTG 384, in which patients were randomized to receive d4T/ddI or ZDV/3TC as nucleoside backbones. Nolan and others[27] from the Western Australian Cohort group performed a nonrandomized 2-year observational study using serial DEXA scans for limb fat in patients starting therapy with either d4T or ZDV. Data on 53 patients were evaluated and demonstrated a decline in percentage of limb fat from 22% to 13% in those receiving d4T (n = 27) and from 22% to 19% in patients receiving ZDV (n = 26). No effect of PI was noted during the 2 years of study. In the GS 934 open-label randomized study that compared ZDV/3TV (CBV) with TDF/FTC, baseline DEXA scans were not performed, but in a subset of patients at 48 weeks, the mean total limb fat was 8.9 kg in the TDF group (n = 50) vs 6.8 kg in the ZDV cohort (n = 46) (P < .031).[10] These studies and others[20-23] demonstrate that compared with TDF, ZDV is associated with a decline in limb fat, albeit at a rate occurring more slowly than that seen with d4T containing regimens. The array of data, taken from many studies, led Nolan and Mallal to estimate that clinically apparent lipoatrophy will be seen in approximately 10% to 20% of patients after 30 months of ZDV, or about half the rate seen with d4T.[24]

In GS 903, investigator-defined lipodystrophy (Grades 1-4) for the d4T/3TC arm was 19% at 144 weeks compared with 3% for the TDF/FTC arm. DEXA scans for the entire patient group are being performed starting at week 48 of the study and should provide precise information as to the overall risk of lipoatrophy from receiving TDF/FTC vs ZDV/3TC when combined with efavirenz i n a treatment-naive population. Unfortunately, because DEXA scans were not performed at baseline, information as to the onset of lipoatrophy will not be available from this large study. For this question, we are still dependent on data from smaller studies previously discussed.

Pathological Changes in Fatty Tissue Seen With Thymidine Analogues

Several groups have reported results from studies of adipose tissue obtained from HIV-infected patients receiving various treatment regimens that include thymidine analogues.[14,28,29] In a study of 31 HIV-infected patients, those receiving d4T-based HAART (n = 10) displayed significant mitochondrial (mt) DNA depletion compared with controls (12.8% mtDNA found in controls; P < .001; n = 11); mtDNA was also significantly reduced in ZDV recipients (37.2% of mtDNA in controls; P < .031; n = 7).[28] Van der Valk and colleagues[29] performed a cross-sectional assessment of 28 of 45 patients who had been randomized to receive ZDV or d4T at least 4 years previously. Lipoatrophy was present by ITT analysis in 83% of those receiving d4T vs 9% of those receiving ZDV. In an analysis restricted to patients who had remained on their initially randomized nucleoside regimen, both groups experienced a loss of peripheral blood mononuclear cell-mtDNA after starting their regimen; mtDNA was lowest in patients who had lipoatrophy. Adipose tissue mtDNA from the thigh (but not the back) was lower in patients receiving d4T compared with ZDV. These data suggest that thymidine analogues have a direct impact on adipose cellular energy mechanisms but do not inform as to when these changes begin

Data presented at the November 2005, International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV in Dublin, Ireland, suggest that profound changes in fatty tissue may begin soon after initiation of thymidine analogue ARV therapy. Hammond and coworkers[30] from the Western Australian group conducted a nonrandomized study of patients starting a variety of therapies and examined changes fatty tissue using several methodologies.Antiretroviral-naive HIV-infected patients initiating therapy with d4T (n = 7), ZDV (n = 6), or ABC (n = 7) underwent baseline and follow-up fat biopsies after 6 months. Assessments included mtDNA content per adipocyte; protein expression of proinflammatory cytokines interleukin (IL)-6, IL-8, IL-12, IL-18, tumor necrosis factor (TNF) alpha, and interferon (IFN) macrophage count per field of view (X 40 obj); tissue morphology using confocal microscopy; and percentage of leg fat/body mass index (BMI). Recipients of ZDV and d4T demonstrated a loss of mtDNA compared with baseline; this change was associated with an infiltration of macrophages and accelerated the production of cytokines. For all measures, the impact of d4T was greater than that of ZDV, but the effect of both ZDV and d4T on inflammatory changes increased over time. By contrast, mtDNA of patients who initiated treatment with ABC did not change from baseline. Thymidine analogue-experienced patients who subsequently switched from thymidine analogues to ABC or TDF demonstrated a decrease in macrophage counts and a drop in cytokine tissue levels. These data suggest that thymidine analogues may induce changes in adipose tissue long before the onset of clinically or radiologically evident lipoatrophy. Serial biopsies from several patients demonstrated that initial changes occur as soon as 2 weeks after starting therapy and over time may be accompanied by profound tissue morphologic changes, loss of tissue structure, apoptosis, and loss of fat cells.[30]

Taken with results from clinical studies, these data offer an increasingly coherent model of lipoatrophy. Under this model, end-organ damage to superficial adipose tissue results from thymidine analogue-induced disruption of cellular energy processes, which is followed by low-grade clinically inapparent chronic inflammatory changes leading to widespread albeit variable adipose cell loss over subsequent months or years before the process is clinically or or even radiologically detectable. This hypothesis would also fit with findings from several studies that demonstrate some reversibility with discontinuation of the offending agent[19, 30-35]; noteworthy in all these studies is that the pace of this change has been slow possibly because of the (potentially) irreversible loss of adipose cells.

This hypothesis, while attractive, does not explain many of the clinical manifestations of lipodystrophy (eg, fatty accumulation) nor does it inform as to which patients are at most risk or why some patients may not develop lipodystrophy at all. However, at this time (in early 2006) the only known way for clinicians to minimize the risk of lipoatrophy is to avoid those agents most implicated when initiating treatment and to consider alternatives for those already on therapy . Considerable data now demonstrate that TDF and ABC are not associated with this process and, in combination with either 3TC or FTC, offer effective alternatives.[19, 36-38] (The role of the nucleoside combination of ddI/3TC in lipoatrophy has been less well studied.)

It should be noted, however, that the selection and substitution of medications often involves balancing competing concerns, including desires for treatment simplicity, avoidance of hyperlipidemia, the anxiety that comes with changing regimens, and factoring in the risk of preexisting or current viral resistance. Experienced clinicians will want to weigh these considerations carefully with the patient to obtain the best outcome.

Anemia and Fatigue


Fatigue is common in patients both before and after initiating therapy. Although patients often relate this symptom to specific medications, HIV-associated fatigue has many causes, including: anemia; endocrine disorders (eg, hypothyroidism and hypogonadism); other metabolic conditions (eg, hypoadrenalism); nutritional deficiencies and problems arising from sleep disturbances (eg, sleep apnea); and depression. Muscle fatigue also has been associated with some non-ARV medications (eg, muscle fatigue related to use of statin agents).[39]

One study examined the relative incidence of fatigue in the HIV-infected population. In 1998, Breitbart and colleagues[40] found that 54% of 427 patients reported fatigue. The presence of fatigue was associated with the number of current AIDS-related physical symptoms, treatments for HIV-related medical disorders, anemia, and pain. In the current era, when not linked to other problems (eg, ZDV-induced anemia, EFV related depression or insomnia) fatigue, while common, is usually not attributable to specific agents.


Anemia is independently associated with a greater risk for death and disease progression in patients with HIV/AIDS.[41,42] Furthermore, patients with AIDS and low hemoglobin levels rate their quality of life (energy levels and physical functioning) significantly lower than those with higher hemoglobin levels.[43]

Opportunistic infections, hepatitis, undiagnosed infections or malignancies, the direct effects of HIV, and a host of medications used to treat complications of HIV/AIDS are linked to anemia in this population. Historically, ZDV toxicity was a major treatment-limiting source of anemia. With HAART, rates of severe anemia have dropped off significantly; however, mild-to-moderate anemia remains an important concern, and its incidence may actually be rising.[44-46] In the EuroSIDA study,[45] after 12 months of HAART, 45.6% of patients were found to have mild anemia (defined as a hemoglobin level 8-12 g/dL for women and 8-14 g/dL for men). Another study looked at 758 ambulatory, HIV-infected patients during the year 2000. Investigators found hemoglobin levels < 10 g/dL in only 4.8% of women and 1.3% of men; but 31.2% of women and 10.1% of men had hemoglobin levels between 10 and 13 g/dL.[46] In a longitudinal study of 797 HIV-positive women, Semba and colleagues[43] found the prevalence of anemia to be 28.1% at enrollment (vs 15% in HIV negative controls), rising to 74% during follow-up.

Treatment with ZDV-containing ARV regimens continues to be associated with anemia.[41-49] Although iron supplements for mild anemia or recombinant erythropoietin can ameliorate the problem in some patients,[50-52] newer treatment options may offer alternatives that may avoid this complication for ARV-naive patients with no preexisting resistance.

Molina and coworkers[49] reported improved hemoglobin levels in patients who switched from ZDV/3TC plus a PI to FTC/ddI/EFV. GS study 934 compared open-label 3TC/ZDV (CBV)/EFV with TDF/FTC/EFV in 517 antiretroviral-naive patients.[10] As discussed, the ITT analysis at 48 weeks showed that more patients who received TDF/FTC/EFV achieved HIV-1 viral load levels < 400 and < 50 copies/mL, compared with the CBV/EFV group. The difference in response resulted primarily from the significantly greater number of patients in the CBV/EFV arm who withdrew from treatment because of side effects, predominantly anemia. Thus, both of these newer ARV regimens appear to be effective alternatives to ZDV-containing HAART, with less -- if any -- risk for anemia.


Patients with HIV/AIDS are more likely to adhere to a treatment regimen that is simple, effective, and is associated with improvement of quality of life; to be optimal, these regimens must provide adequate antiviral potency even for the patient with more advanced HIV disease. There are now several NNRTI regimens that combine EFV with either FTC or 3TC and a third nucleoside (or nucleotide) that have undergone extensive clinical study, demonstrating that they are potent, well tolerated, and simple to take. Individual problems associated with the third agent, including short-term intolerance and long-term side effects, particularly risk for lipodystrophy, may now dominate clinicians' recommendations and patients' choices for this most important initial regimen.


  1. Chesney M. Adherence to HAART regimens. AIDS Patient Care STDS. 2003;17:169-177. Abstract
  2. Johnson MO, Charlebois E, Morin SF, et al. Perceived adverse effects of antiretroviral therapy. J Pain Symptom Manage. 2005;29:193-205. Abstract
  3. Ammassari A, Murri R, Pezzotti P, et al. Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection. J Acquir Immune Defic Syndr. 2001;28:445-449. Abstract
  4. Tapper ML, Flexner C, Eron JJ, Molina JM. Simplifying antiretroviral therapy. AIDS Read. 2004;14:355-360, 367-371.
  5. O'Brien ME, Clark RA, Besch CL, Myers L, Kissinger P. Patterns and correlates of discontinuation of the initial HAART regimen in an urban outpatient cohort. J Acquir Immune Defic Syndr. 2003;34:407-414. Abstract
  6. Kirstein LM, Greenblatt RM, Anastos K, et al. Prevalence and correlates of highly active antiretroviral therapy switching in the Women's Interagency HIV Study. J Acquir Immune Defic Syndr. 2002;29:495-503. Abstract
  7. Johnson MO, Charlebois E, Morin SF, et al. Perceived adverse effects of antiretroviral therapy. J Pain Symptom Manage. 2005;29:193-205. Abstract
  8. Nadler J. New anti-HIV protease inhibitors provide more treatment options. AIDS Patient Care STDS. 2003;17):551-564. Abstract
  9. DeJesus E, Herrera G, Teofilo E, et al. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis. 2004;39:1038-1046. Abstract
  10. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006;354:251-260. Abstract
  11. Moyle GJ, DeJesus E, Cahn P, et al. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once Daily in Antiretroviral Combination Study. J Acquir Immune Defic Syndr. 2005;38:417-425. Abstract
  12. Echavez M, Horstman W. Relationship between lipoatrophy and quality of life. AIDS Read. 2005;15:369-375. Abstract
  13. Gallagher D. Objective measurements of body composition in vivo using magnetic resonance imaging. Antiviral Ther. 2005;10:L1.
  14. Jacobson DL, Knox T, Spiegelman D, et al. Prevalence of, evolution of, and risk factors for fat atrophy and fat deposition in a cohort of HIV-infected men and women. Clin Infect Dis. 2005;40:1837-1845. Abstract
  15. Miller J, Carr A, Emery S, et al. HIV lipodystrophy: prevalence, severity and correlates of risk in Australia. HIV Med. 2003;4:293-301. Abstract
  16. Carter VM, Hoy JF, Bailey M, et al. The prevalence of lipodystrophy in an ambulant HIV- infected population: it all depends on the definition. HIV Med. 2001;2:174-180. Abstract
  17. DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents -- October 06, 2005. Available at: Accessed January 26, 2006.
  18. Podzamczer D, Ferrer E, Sanchez P, et al. A randomized comparison between abacavir and stavudine, both combined with lamivudine/efavirenz, in antiretroviral-naive patients. Final 96-week results of the ABCDE Study. Program and Abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-26, 2005; Boston, Massachussetts. Abstract 587.
  19. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004;292:191-201. Abstract
  20. Molina JM, Chene G, Ferchal F, et al.The ALBI trial: a randomized controlled trial comparing stavudine plus didanosine with zidovudine plus lamivudine and a regimen alternating both combinations in previously untreated patients infected with human immunodeficiency virus. J Infect Dis. 1999;180:351-358. Abstract
  21. Chene G, Angelini E, Cotte L, et al. Role of long term nucleoside analogue therapy in lipodystrophy and metabolic disorders in human immunodeficiency virus-infected patients. Clin Infect Dis. 2002;34:649-657. Abstract
  22. Amin J, Moore A, Carr A, et al. Combined analysis of two-year follow-up from two open-label randomized trials comparing efficacy of three nucleoside reverse transcriptase inhibitor backbones for previously untreated HIV-1 infection: OzCombo 1 and 2. HIV Clin Trials. 2003;4:252-261. Abstract
  23. Joly V, Flandre P, Meiffredy V, et al. Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: results of a substudy from a comparative trial. AIDS. 2002;16:2447-2454. Abstract
  24. Nolan D, Mallal S. Antiretroviral-therapy-associated lipoatrophy: current status and future directions. Sex Health. 2005;2:153-163. Abstract
  25. Mallon PW, Wand H, Law M, et al. Buffalo hump seen in HIV-associated lipodystrophy is associated with hyperinsulinemia but not dyslipidemia. J Acquir Immune Defic Syndr. 2005;38:156-162. Abstract
  26. Dube MP, Parker RA, Tebas P, et al. Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides. AIDS. 2005;19:1807-1818. Abstract
  27. Nolan D, Hammond E, James I, McKinnon E, Mallal S. Contribution of nucleoside-analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level. Antivir Ther. 2003;8:617-626. Abstract
  28. Pace CS, Martin AM, Hammond EL, et al. Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients. Antivir Ther. 2003;8:323-331. Abstract
  29. van der Valk M, Casula M, Weverlingz GJ, et al. Prevalence of lipoatrophy and mitochondrial DNA content of blood and subcutaneous fat in HIV-1-infected patients randomly allocated to zidovudine- or stavudine-based therapy. Antivir Ther. 2004;9:385-393. Abstract
  30. Hammond E, Nolan D, McKinnon E, Pace C, Metcalf C, Mammal S. Assessing the contribution of ART, HIV and host factors to adipose tissue changes occurring in HIV-infected individuals: risk profile for lipoatrophy. Program and abstracts of the 7th International Workshop on Adverse Events and Lipodystrophy in HIV; November 13-16, 2005; Dublin, Ireland. Abstract 2.
  31. Saint-Marc T, Touraine JL. The effects of discontinuing stavudine therapy on clinical and metabolic abnormalities in patients suffering from lipodystrophy. AIDS. 1999;13:2188-2189. Abstract
  32. Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA. 2002;288:207-215. Abstract
  33. Carr A, Hudson J, Chuah J, et al. HIV protease inhibitor substitution in patients with lipodystrophy: a randomized, controlled, open-label, multicentre study. AIDS. 2001;15:1811-1822. Abstract
  34. Maggiolo F, Ripamonti D, Suter F. Switch strategies in patients on effective HAART. J Antimicrob Chemother. 2005;55:821-823. Abstract
  35. Murphy R, Zhang J, Hafner R, et al. Switching to a thymidine analog-sparing or a nucleoside-sparing regimen improves lipoatrophy: 24-week results of a prospective randomized clinical trial, AACTG 5110. Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Massachusetts. Abstract 45LB.
  36. Moyle G, Sabin C, Cartledge J, et al. A 48-week, randomized, open-label comparative study of tenofovir DF vs abacavir as substitutes for a thymidine analog in persons with lipoatrophy and sustained virologic suppression on HAART. Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Massachusetts. Abstract 44LB.
  37. Pozniak AL, Gallant JE, DeJesus E, et al. Superior outcome for tenofovir DF (TDF), emtricitabine (EFV) compared to fixed dose zidovudine/lamivudine (CBV) and EFV in antiretroviral naive patients. Program and abstracts of the 3rd IAS Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. Abstract WeOa0202.
  38. Ribera E, Paradineiro J, Sauleda S, et al. Improvement of subcutaneous fat, lipid profile, and parameters of mitochondrial toxicity in patients with peripheral liopatrophy when stavudine is switched to tenofovir. Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Massachusetts. Abstract 860.
  39. Groopman JE. Fatigue in cancer and HIV/AIDS. Oncology. 1998;12:335-344. Abstract
  40. Breitbart W, McDonald MV, Rosenfeld B, Monkman ND, Passik S. Fatigue in ambulatory AIDS patients. J Pain Symptom Manage. 1998;15:159-167. Abstract
  41. Semba RD, Shah N, Klein RS, et al. Prevalence and cumulative incidence of and risk factors for anemia in a multicenter cohort study of human immunodeficiency virus-infected and -uninfected women. Clin Infect Dis. 2002;34:260-266. Abstract
  42. O'Brien ME, Kupka R, Msamanga GI, et al. Anemia is an independent predictor of mortality and immunologic progression of disease among women with HIV in Tanzania. J Acquir Immune Defic Syndr. 2005;40:219-225. Abstract
  43. Semba RD, Martin BK, Kempen JH, et al. The impact of anemia on energy and physical functioning in individuals with AIDS. Arch Intern Med. 2005;165:2229-2236. Abstract
  44. Volberding PA, Levine AM, Dieterich D, et al. Anemia in HIV infection: clinical impact and evidence-based management strategies. Clin Infect Dis. 2004;38:1454-1463. Abstract
  45. Mocroft A, Kirk O, Barton SE, et al, for the EuroSIDA study group. Anaemia is an independent predictive marker for clinical prognosis in HIV-infected patients from across Europe. AIDS. 1999;13:943-950. Abstract
  46. Wills TS, Nadler JP, Somboonwit C, et al. Anemia prevalence and associated risk factors in a single-center ambulatory HIV clinical cohort. AIDS Read. 2004;14:305-315. Abstract
  47. Richman DD, Fischl MA, Grieco MH, et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987;317:192-197. Abstract
  48. Levine AM, Berhane K, Masri-Lavine L, et al. Prevalence and correlates of anemia in a large cohort of HIV-infected women: Women's Interagency HIV Study. J Acquir Immune Defic Syndr. 2001;26:28-35. Abstract
  49. Molina JM, Bentata M, Garre M, et al. Hematological benefit of switching from regimens combining protease inhibitors and zidovudine plus lamivudine to once-daily emtricitabine, didanosine and efavirenz. A sub-study of the ANRS 099 ALIZA trial. Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Massachusetts. Abstract 830.
  50. Miles SA, Mitsuyasu RT, Moreno J, et al. Combined therapy with recombinant granulocyte colony-stimulating factor and erythropoietin decreases hematologic toxicity from zidovudine. Blood. 1991;77:2109-2117. Abstract
  51. Moyle G. Anaemia in persons with HIV infection: prognostic marker and contributor to morbidity. AIDS Rev. 2002;4:13-20. Abstract
  52. Abrams DI, Steinhart C, Frascino R. Epoetin alfa therapy for anaemia in HIV-infected patients: impact on quality of life. Int J STD AIDS. 2000;11:659-665. Abstract