• Epidemiology and Basic Science
• Treatment and Switch Studies

As the natural history of HIV disease in developed countries has become synonymous with the natural history of combination drug therapy, clinicians who care for HIV-infected patients are increasingly becoming acquainted with the long-term adverse effects of antiretroviral therapy, which include both subtle and dramatic toxicities. The fact that seven of the nine late breaker presentations at the 9th CROI addressed antiretroviral toxicity is an indication of the growing importance of drug toxicity as a focus of ongoing research efforts.

Epidemiology and Basic Science

• Atherosclerotic Vascular Disease: While antiretroviral agents are clearly associated with both short- and long-term toxicities, it’s worth reminding ourselves of the big picture. The widespread use of HAART has been associated with a 70% decline in mortality among HIV-infected individuals, a magnitude of effect similar to the introduction of insulin therapy for type I diabetes. Sam Bozzette presented data from 36,766 U.S. veterans treated for HIV between 1993 and 2001 underscoring this point [Abstract LB9]. Antiretroviral use increased from 23.1 to 60.1 years of exposure/100 person-years during this time period, while all-cause mortality fell from 18 to 5/100 person-years. The adverse effects of HAART on atherosclerotic vascular disease risk factors (increased LDL levels, triglycerides and insulin resistance, and decreased HDL levels) have been well documented. Nevertheless, Bozzette’s group observed no trend toward increased cardiovascular or cerebrovascular morbidity or mortality in this large group of veterans. In fact, the rates of hospital admissions or death due to vascular events declined slightly, from 2.0 cases/100 person-years in 1993 to 1.8/100 person-years in 1999. While this does not mean that increased vascular disease risk won’t become evident with longer follow-up, it suggests that the added risk is unlikely to be dramatic.

• Lactic Acidosis has been correlated with prolonged exposure to nucleoside reverse transcriptase inhibitors (NRTIs), and prior reports have focused attention on d4T and ddI as major culprits. Data presented in Seattle provided additional evidence supporting these associations. A novel presentation of the lactic acidosis syndrome was described by Marcus based on data from the FDA’s adverse event reporting system (AERS) [Abstract LB14]. Based on 5 cases of ART-associated lactic acidosis and profound motor weakness, suggestive of the Guillain-Barré syndrome, the FDA searched the AERS and identified 25 cases of combined lactic acidosis and severe motor weakness. Twenty-two of 24 patients were on d4T-containing regimens. Seven patients died, and NRTIs were continued in the face of illness in 18/24 cases, including 6/7 fatal cases. Additionally AERS identified 8 pregnant women who developed pancreatitis and/or lactic acidosis at >32 weeks gestation. All women were receiving d4T, and 7/8 were on d4T/ddI. The cases resulted in 3 maternal and 3 fetal deaths. While passive surveillance for adverse events may be subject to biases and cannot quantify risk because of the absence of a denominator, the dramatic nature of these presentations and the strong association with d4T (particularly in the pregnant women, in whom AZT is used much more commonly), suggests that the association between d4T and these rare events is real. Clearly the primary message of this report is that nucleoside analog therapy should be stopped promptly with any serious presentation of lactic acidosis.

Lonergan presented data from UCSD looking at associations between specific NRTIs and symptomatic lactic acidosis in a cohort of 2,144 HIV-infected individuals [Abstract 35]. Lactic acidosis cases were defined as patients taking at least one NRTI who presented with gastrointestinal or constitutional complaints and a serum lactate elevated above the upper limits of normal. There was a dose-response relationship between the number of NRTIs being taken and lactic acidosis, with each additional NRTI associated with a 2-fold increased risk (95% CI 1.3-3.4). Notably, substantially higher risks were observed for regimens containing d4T and/or ddI (Table 1, below). Five patients, all on d4T-containing regimens, had serum lactate levels >5 mmol/L, and 4/5 died. The main caveat of observational studies such as this one is that there may be a bias in the manner in which patients are evaluated. For example, clinicians at this university-based center may have had a lower threshold for obtaining serum lactate levels on the basis of mild symptoms if patients were taking antiretroviral drugs previously implicated in lactic acidosis. However, the strength of the observed associations and their reproducibility across several large studies suggests that a genuine association is being identified.

Adverse effects of NRTIs, such as neuropathy, pancreatitis, lipoatrophy, and lactic acidosis, have been linked to mitochondrial toxicity. Investigations of pathogenic mechanisms presented at the 9th CROI furthered the hypothesis that there is a hierarchy of toxicity risk among different NRTIs. The ratio of mitochondrial DNA to nuclear DNA (mtDNA/nDNA) was determined in 30 participants in the SWATCH Trial [Côté, Abstract 707-T]. In this study, treatment-naïve patients were randomized to receive AZT/3TC/NFV, d4T/ddI/EFV, or to alternate between these two regimens every 3 months. Comparing the mtDNA/nDNA ratio at baseline and 48 weeks may give insight into the relative mitochondrial toxicity of different antiretroviral regimens. For patients treated with AZT/3TC/NFV, the mtDNA/nDNA ratio was 45% of baseline at week 48 compared to 55% of baseline in the alternating group, and just 18% of baseline in the d4T/ddI/EFV group. Similarly, Birkus and colleagues from Gilead evaluated changes in mtDNA in in vitro systems of human liver, skeletal muscle, and renal proximal tubule epithelial cells treated with different NRTIs [Abstract 708-T]. They reported the following hierarchy of mitochondrial toxicity: ddC > ddI > d4T >AZT > 3TC = ABC = TDF. While in vitro data should never be taken as the final word, these results are consistent with toxicities observed in epidemiologic studies.

Treatment and Switch Studies

• Lipoatrophy has been a particularly dreaded long-term complication of HAART because it is so stigmatizing and because there has been no convincing evidence that it is reversible. At CROI, several of abstracts provided a glimmer of hope that switching from d4T to other NRTIs may not only stop fat loss, but begin to reverse the process. Carr and co-workers presented 24-week data from a study in which 111 patients with moderate to severe lipoatrophy were randomized to switch from either d4T (84%) or AZT (16%) to ABC, or to remain on their current regimen [Abstract 32]. The primary outcome was change in limb fat mass, measured by DEXA and CT scanning.

Statistically significant increases in limb fat were observed in the switch group compared to patients remaining on their current regimen. Further supporting the role of d4T in lipoatrophy was the observation that improvements in limb fat were only noted in patients switching from d4T to ABC, and not in those switching from AZT to ABC (although numbers for this comparison were small). However, switching to ABC was not associated with improvements in insulin resistance, serum lipids, or patient-physician perceptions of the severity of lipoatrophy. Although Carr suggested that longer follow-up may lead to clinically meaningful improvements in lipoatrophy, it is disappointing that patients and physicians did not notice the change at 6 months, particularly because the open-label design of this study would be anticipated to bias subjective perceptions in favor of the new therapy.

A similar but smaller study of 40 subjects was presented in the poster session [John, Abstract 700-T], with results that were comparable to those reported by Carr. Additionally, another abstract reported subjective improvements in lipoatrophy in 20-30% of patients who had d4T replaced by either AZT or ABC [McComsey, Abstract 701-T]. However, in this study there was no control group that continued their present regimen.

• Fat Accumulation: Rosiglitazone is an antidiabetic agent that has been found to increase subcutaneous fat in patients with type 2 diabetes. Sutinen presented data from a double-blind trial in which 30 HIV-infected patients with lipodystrophy on HAART were randomized to receive either rosiglitazone or placebo [Abstract LB13]. At 24 weeks the rosiglitazone group had decreased insulin resistance compared to placebo. Unfortunately, there were no significant differences between the groups in waist-to-hip ratio, subcutaneous fat, or visceral fat (the latter two outcomes measured by MRI scan and serum leptin concentrations). Additionally, serum cholesterol and triglyceride levels were significantly increased in the rosiglitazone group compared to placebo.

In summary, studies of the toxicity of antiretroviral therapy have come to assume a prominent role in HIV research. Data from a large cohort of U.S. veterans suggested that changes in lipid and glycemic indices, which are associated with HAART, have not translated into a noticeable increase in vascular disease, at least not yet. After the 9th CROI, there can be few lingering doubts that d4T and probably ddI are the NRTIs most strongly associated with mitochondrial toxicity and its manifestations–lactic acidosis, neuropathy, lipoatrophy, and pancreatitis. Additionally, the FDA described a new syndrome of lactic acidosis and profound motor weakness (mimicking the Guillain-Barré syndrome) that also appears to be associated with d4T. However, for the first time, there are some objective data that lipoatrophy may be reversible when d4T is switched to AZT or ABC. Hopefully, these small but statistically significant changes in subcutaneous fat, now detected with sophisticated imaging technology, will eventually translate into clinically meaningful improvements with longer follow-up.

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