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Update From the 11th Conference on Retroviruses and Opportunistic Infections (CROI)

Held in San Francisco, February 8-11, 2004: First of Two Parts

March 2004

Opening Session

Joseph Bick, M.D.

United Nations Special Envoy on HIV/AIDS in Africa Stephen H. Lewis discussed the current state of the HIV epidemic. Worldwide it is estimated that 10 million women aged 15-24 years old are HIV-infected, and six million persons need antiretroviral treatment (ART) based upon a CD4 count of less than 200/mm3. An estimated four million Africans have a CD4 count of less than 200/mm3; less than 3% are receiving ART. Worldwide, there are an estimated 14,000 new infections each day and three million HIV-related deaths per year. Furthermore, the HIV epidemic has resulted in millions of orphaned children.

Mr. Lewis detailed the World Health Organization's "three by five" initiative, intended to bring ART to three million people in Africa by 2005. Even if these goals are met, only half of those who need ART will receive it.

Mr. Lewis questioned why "We have all of the money needed to fight the war on terrorism, why not to fight (the terror) of AIDS?" He said, "I beg you to enter the fray" and "if morality is found lacking in the actions of government, let it be found in the advocacy of its citizens."

Mr. Lewis lamented the high number of women who are being infected within "monogamous" relationships by husbands who have sexual partners outside of marriage. Worldwide, most women are not empowered to insist upon condom use or choose not to use them because they interfere with conception.

Without an effective vaccine or resources to purchase ART, there is an urgent need for the development of effective microbicides.

Robin Shattock of St. Georges Hospital and Medical School in London, further elucidated this topic in a presentation in which he described how a marginally effective microbicide that is used only half of the time could lead to a significant decline in new infections. A useful product would be active against a wide range of HIV isolates, non-toxic, active when exposed to body fluids, effective in both the vagina and the rectum, inexpensive, easy to manufacture, stable in a variety of climates, and available without prescription.

In a symposium on the global response to AIDS, some successes were reported. Gavin Churchyard, M.D., Director of Aurum Health Research in South Africa described a program in which gold mining companies encourage voluntary testing of their employees and provide treatment to those who are found to be HIV-infected. This program has led to ART adherence rates of over 90%, and has resulted in a decrease in missed days of work due to illness. Educating businesses to recognize the financial benefit of providing HIV treatment to their workers may make it possible for many persons to access care that they could not otherwise afford. Anupong Chitwarakorn, M.D., of the Ministry of Public Health in Thailand also described targeted efforts in that country that have led to an 80% decrease in the rate of new infections between 1993 and 2003.

Joseph Bick, M.D., is Chief Medical Officer at California Medical Facility, California Department of Corrections. He has nothing to disclose.

Metabolic Complications

David Alain Wohl, M.D.

Metabolic complications of HIV and its therapies have emerged as a major concern to persons living with HIV infection and to their health care providers. The impact of complications such as dyslipidemia, body shape change and disorders of glucose metabolism on HIV management may be evident in both the surge in the use of atazanavir, a protease inhibitor without significant effects on lipids or glucose metabolism, and the increasing prescription of lipid-lowering drugs. At the 11th CROI, epidemiologic data and a smattering of treatment trials regarding metabolic issues were presented.

If the increased use of statins and fibrates among HIV-infected patients is any indication, lipid abnormalities are becoming a frequent complication of HIV therapy. A fascinating study recently published by Riddler and colleagues in The Journal of the American Medical Association suggests that HIV infection itself causes declines in total and LDL cholesterol and that these are reversed by potent HIV therapy. However, it is also known that certain antiretrovirals can increase lipid levels even among HIV-uninfected volunteers. Therefore, what contribution HIV therapy makes to overall cardiovascular disease (CVD) risk is a subject of a debate fueled by data both supporting and refuting a role for HAART in CVD development. What is clear, however, is that not all antiretrovirals affect the determinants of CVD risk equally.

This point was somewhat illustrated by data from a substudy of AIDS Clinical Trials Group study A384, a large treatment-naive trial comparing efavirenz with nelfinavir when combined with either ZDV+3TC or d4T+ddI. While efavirenz led to greater increases in HDL (probably a favorable outcome), total cholesterol rose equally among those receiving efavirenz and those assigned nelfinavir. This finding supports previous work demonstrating that nelfinavir is less offensive to lipids than some of its sister protease inhibitors. There was a trend toward d4T+ddI being worse, lipid-wise, than ZDV+3TC. It should be noted that all the analyses presented to date use an intent-to-treat approach. Given that there were more adverse events among those receiving d4T+ddI and more virologic failures leading to treatment switches among those assigned nelfinavir, the relationship between actual exposure to these agents and adverse metabolic events has yet to be made clear.

The effect of HAART on other influences of CVD such as hypertension and diabetes has also been scrutinized. Researchers from a large consortium of European and North American sites examined the prevalence and incidence of hypertension among over 16,000 HIV-infected patients followed prospectively in the D:A:D Study. Over a median 1.5 years of follow-up, there was no effect of HAART or time on HAART on the prevalence of hypertension at entry or the change in blood pressure during study follow-up. Factors associated with elevated blood pressure were male gender, age, baseline blood pressure and high body mass index. Longer-term study is planned.

The last National Cholesterol Education Program (NCEP) guidelines emphasized the role of diabetes in CVD, considering the presence of this disorder equivalent to having established CVD when setting goals for lipid-lowering therapy. Previous reports have suggested an increased prevalence of diabetes and pre-diabetic conditions among HIV-infected persons. To assess the prevalence and incidence of glucose disorders as well as the potential contribution of HAART, investigators from the Multicenter AIDS Cohort Study (MACS) examined 1,107 men participating in the study from mid 1999 to late 2002. Of the 1,107 men, 563 were HIV-negative and 544 were HIV-infected (423 on HAART). Hyperglycemia (pre-diabetes and diabetes) was defined as fasting plasma glucose >110 mg/dL, use of anti-diabetic medication, or self-reported diagnosis of diabetes. Diabetes itself was defined as a FPG >126 mg/dL, use of anti-diabetic medication, or self-reported diagnosis of diabetes. Of HIV-infected men on HAART, 14% had diabetes at baseline compared with 5% in the HIV-negative group (odds ratio = 4.4; 95% confidence interval [CI]: 2.6, 7.4).

Among the cohort, 618 men had a FPG <105 mg/dL, no history of diabetes, and no use of anti-diabetic medication at baseline. Incident hyperglycemia developed in 79/618 (13%) during 1,054 person-years yielding an overall rate of 7.5 cases per 100 person-years. Incident diabetes was detected in 38 during 1,088 person-years, yielding an overall rate of 3.5 cases per 100 person-years. After adjustment for age and BMI, the hazard of pre-diabetes or diabetes among those on HAART was 1.8 times that of the HIV-negative group, and the hazard of diabetes among the HAART group was 3.1 times that of the HIV-negative group. Exposure to a HAART regimen including a PI, d4T or efavirenz were each significantly associated with a higher rate of developing pre-diabetes or diabetes compared to the HIV-negative group. These robust data indicate that at least in men, HAART is associated with risk of diabetes. Whether reduced reliance on d4T and the older PIs will reduce the incidence of diabetes among HIV-infected persons receiving HAART will require further follow-up.

In addition to lipid and glucose disorders, body shape changes accompanying antiretroviral therapy are a challenge to patients and their clinicians. Certainly, in correctional settings where confidentiality is more challenging, the facial and limb fat loss that is the hallmark of HIV-associated morphologic changes can be a tell tale sign of HIV infection. Further, the redistribution of fat observed in HIV-infected individuals, central obesity and peripheral fat wasting, has been associated with the metabolic syndrome and heightened risk for CVD. In addition, disfiguring body shape changes can reduce self-esteem and threaten antiretroviral adherence. To date, the only intervention to improve peripheral lipoatrophy to any significant degree has been the replacement of stavudine (d4T, Zerit) and, to a lesser extent zidovudine (ZDV, Retrovir), with abacavir (ABC, Ziagen). Unfortunately, the increase in limb fat following d4T discontinuation has been modest and slow to be appreciated.

A study from Australia aimed to determine if the PPAR-gamma agonist, rosiglitazone, could reverse fat wasting in HIV-associated lipoatrophy. A total of 108 patients with limb fat less than 20% of limb tissue or limb fat percentage at least 10% less than truncal fat percentage by DEXA were enrolled. Participants had to have been receiving combination antiretroviral therapy unchanged for 12 weeks. Almost all (98%) of the subjects were male and white. There were a disproportionate number of participants receiving d4T in the rosiglitazone arm compared to the control arm (53% versus 29%). All subjects were randomized to 8 mg/day of rosiglitazone or matching placebo for 48 weeks. At week 48, there was no difference between the study arms in the change of fat as measured by DEXA. Limb fat increased by 0.14 kg (5%) in the rosiglitazone group but also increased 0.18 kg (7%) in the placebo group (mean difference -0.04 kg [95%CI -0.29 to 0.21]; p=0.74). CT scanning of the abdomen and thigh demonstrated similar decreases in intrabdominal fat in both groups but neither had an increase in thigh subcutaneous fat. Subjects in both study groups reported similar subjective improvements in lipoatrophy. Mean insulin levels, which were in the normal range at baseline, declined equally in both study arms.

A curious finding in this trial was the relative increase in limb fat in the control subjects. Previous data on the natural history of lipoatrophy, much of it from Australia, indicated that continued worsening of fat wasting could generally be expected in the absence of NRTI therapy modification. One potential explanation for the improvement seen in the placebo arm is that many of the patients in this study had in the months prior to study entry (before the 12 weeks of stable HAART required prior to enrollment) switched from d4T to abacavir. Abacavir use was high in both arms at entry. Despite these concerns, whether anyone will bother to study this or like agents for lipoatrophy is unlikely.

The metabolic effects of the extended release once a day formulation of d4T (d4T-XR) in comparison to standard d4T (also called immediate release, or d4T-IR) was described by investigators from Bristol Myers Squibb who performed an analysis using data from two completed clinical trials comparing d4T-XR and d4T-IR. Over 800 treatment-naive subjects participating in the trials were studied. All received d4T-XR or d4T-IR plus 3TC+EFV. Risk factors for investigator-defined lipoatrophy were baseline triglyceride levels >200 mg/dL and age >40 years. Further, report of lipoatrophy during the 48-week studies was almost two times more likely among d4T-IR assigned subjects compared to those assigned d4T-XR. The combination of these three factors (high triglycerides, age 40+ and d4T-IR) seemed to have, at least, an additive effect. The report states that among subgroups with different risk factors such as <40 years of age with triglycerides <200 mg/dL, age >40 years and triglycerides >200 mg/dL, etc., the risk of lipoatrophy was greater with d4T-IR than d4T-XR in each stratum. Whether these differences were statistically significant is not stated. There will need to be additional evidence to indicate the extended release formulation of d4T is safer vis-à-vis metabolic toxicity than standard d4T. A comparison with competitive nucleosides such as ZDV or tenofovir and objective evaluations of body shape will need to be produced before the image of d4T can be rehabilitated.

The effect of the new kid on the formulary, FTC (Emtriva), on body shape was detailed in a head-to-head study comparing d4T (standard formulation) + ddI + EFV versus FTC + ddI + EFV. In a placebo-controlled study of 571 subjects randomized to each regimen, body shape measurements but no DEXA or CT scanning were performed at regular intervals. Subjects in both study arms gained weight initially but, as has been seen in other studies, the d4T receiving subjects experienced a later decline in weight. By week 72 of the study there was a significant decline in weight from baseline in the d4T arm versus a net gain in the FTC arm. Waist, hip and chest circumference and abdominal girth were significantly lower in the d4T group but waist to hip ratio was no different between study arms. Investigator-reported lipodystrophy was more common in those randomized to d4T group. Fasting triglycerides increased in both arms but the increase was significantly greater in the d4T arm (+27 mg/dL for FTC, +97.8 mg/dL for d4T, p <.001). HDL cholesterol also increased in both groups but more so with FTC (+13.5 mg/dL) versus d4T (+8.8 mg/dL) (p=.001). There was no difference between study arms in the magnitude of the increase in LDL cholesterol (+15-17 mg/dL), total cholesterol (+37-44 mg/dL) or glucose (+2.5-4.5 mg/dL). As has been reported previously, FTC performed better virologically.

Lastly, data were also presented on the effect of T-20 (Fuzeon) on body shape. In an analysis of body shape data from over 1,000 patients participating in clinical studies of T-20, there was no evidence of T-20 induced body shape change.

David Alain Wohl, M.D., from the University of North Carolina, is Co-Director HIV Services at the North Carolina Department of Corrections. Disclosures: speaker's bureau -- GlaxoSmithKline, Gilead, Merck, Roche, Abbott; research support -- Roche.

Next Month: Part Two of HEPP's "Update From the 11th Conference on Retroviruses and Opportunistic Infections."

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This article was provided by Brown Medical School. It is a part of the publication HEPP Report.