Cardiovascular risks reduced for patients with HIV by therapy with metformin and changes to diet and exercise

Treatment with the anti-diabetes drug metformin helps prevent the progression of sub-clinical cardiovascular disease in patients with HIV, according to the results of a randomised, placebo-controlled study published in the online edition of AIDS.

The study also showed that dietary changes and a thrice-weekly exercise regimen improved lipid profiles and overall cardiovascular fitness.

“We saw an effect of metformin to prevent significant increase in coronary artery calcification and calcified plaque volume over one year of follow up,” write the investigators. “Compliance with the medication was good…Safety and tolerance were good.”

It is now recognised that HIV-positive patients have an increased risk of cardiovascular disease. Sub-clinical cardiovascular disease is also seen with increased frequency in patients with HIV, who generally have a high prevalence of diabetes, dyslipidemia, high blood pressure and abdominal obesity. Such a collection of disorders is often referred to as metabolic syndrome and has been associated with increased calcification of the coronary artery.

HIV care guidelines stress the importance of diet and exercise for the management of metabolic syndrome.

Treatment with the anti-diabetes drug metformin may also have a role. Research in HIV-negative, over-weight patients with diabetes showed that the therapy significantly reduced rates of cardiovascular events. However, data are currently lacking on the drug’s safety and effectiveness in patients with HIV.

Therefore, investigators from the Massachusetts General Hospital designed a study to assess the impact of metformin treatment and lifestyle modification on calcification of the coronary artery and other established cardiovascular risk factors in patients with HIV.

A total of 50 patients, all of whom had metabolic syndrome, were recruited to the study between 2006 and 2010.

The patients were randomised into four arms:

No lifestyle modification and placebo.

Lifestyle modification and placebo.

No lifestyle modification and metformin.

Lifestyle modification and metformin.

The impact of these interventions on calcification of the coronary artery, diet and fitness, metabolic, biochemical and immunological parameters was assessed. Follow-up was for twelve months.

Patients had been infected with HIV for a median of 14 years and had been taking antiretroviral therapy for a median of six years. There were no significant differences between the four study arms in the characteristics of the patients.

Individuals treated with metformin demonstrated significantly less progression of coronary artery calcification than those who received the placebo (p = 0.004).

In contrast, there were no differences in coronary artery calcification scores between patients who changed their diet and exercise habits and those who did not have any lifestyle modification.

Therefore, metformin had a significantly greater effect on calcification of the coronary artery than lifestyle modification (p = 0.01).

In addition, individuals who were treated with metformin also demonstrated less progression of calcified plaque volume than the patients who received the placebo (p = 0.008).

Overall, plaque progression was greatest among the patients randomised to the no lifestyle modification and placebo arm. The median increase in coronary artery calcification among these patients was 56%. In contrast, the smallest increase was among patients in the lifestyle modification and metformin arm (p = 0.03). Significantly less coronary artery calcification was also seen in the group of patients who did not modify their diet and exercise habits, but who were treated with metformin (p = 0.01).

Unsurprisingly, lifestyle modification improved exercise capacity and strength (p < 0.01). However, metformin therapy had no impact on these parameters.

Changes to diet and exercise were also shown to have benefits for HDL-cholesterol levels (p = 0.03). Furthermore, lifestyle modification reduced levels of C-reactive protein (CRP), an important marker of inflammation (p = 0.05).

Treatment with metformin also had some metabolic benefits. Patients who received the drug had significantly better HOMA-IR scores (a marker of insulin resistance) than individuals randomised to receive the placebo (p = 0.05).

Neither of the interventions was associated with serious adverse events. However, lifestyle modification was associated with a small but significant reduction in CD4 cell count (p = 0.04). Two of the metformin-treated patients experienced mild elevations in creatinine levels. These returned to normal after the dose of the drug was modified. Several patients taking the drug also reported mild gastrointestinal side-effects.

“Our data demonstrate that metformin had a robust effect to prevent progression of coronary artery calcification and calcified plaque volume while improving HOMA-IR over one year in HIV patients with metabolic syndrome,” comment the authors. “Lifestyle modification had a lesser effect to prevent plaque progression than metformin.”

They conclude: “Further studies are now needed to understand the mechanisms of metformin to prevent calcified plaque progression and to determine whether metformin, alone or in combination with other strategies, might reduce or prevent cardiovascular disease events in [patients with HIV].”

View the original article here

Mild kidney problems in patients with HIV can identify patients with hardening of the arteries

Emergent kidney dysfunction is associated with an increased risk of hardening of the arteries in patients with HIV, Spanish researchers show in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

“Our findings provide support for the hypothesis that mild abnormalities of renal function can independently predict an increased atherosclerotic burden and behave as a useful surrogate marker of subclinical atherosclerosis,” write the investigators.

Kidney disease is an increasingly important cause of serious illness and death in patients with HIV. The exact causes are uncertain but appear to include the effects of HIV, lifestyle factors and possibly the side-effects of some anti-HIV drugs.

Research has established an association between renal dysfunction and an increased risk of cardiovascular disease in HIV-positive patients. However, most HIV-positive individuals with kidney problems experience only mild abnormalities. Nevertheless, studies conducted in the general population have shown that the presence of low-grade albuminuria and a low eGFR are associated with death due to cardiovascular causes.

Investigators in Madrid therefore hypothesised that mild deterioration in kidney function, or incipient renal impairment, would predict hardening of the arteries in HIV-positive patients.

They therefore designed a cross sectional study involving 145 individuals who received HIV care between 2009 and 2010.

Incipient renal impairment was defined as eGFR below 90 ml/min, a rate of eGFR decrease above 3% annually over a three-year period, and an albumin/creatine urine ratio above 5 mg/g. Patients with carotid artery intima media thickness (cIMT) above the 75th percentile or plaques were classified as having sub-clinical atherosclerosis.

Most of the patients (88%) were male and their average age was 41 years. There was a high prevalence of cardiovascular risk factors. The most common was smoking (47%), followed by elevated triglycerides (43%), high cholesterol (39%), hypertension (17%) and diabetes (9%). Nearly all the patients (91%) were taking antiretroviral therapy and 77% had an undetectable viral load.

Plaques were detected in the coronary arteries of 6% of patients and 31% were classified as having sub-clinical atherosclerosis. Incipient renal impairment was identified in almost two-thirds of patients (64%).

The emergence of kidney dysfunction was associated with a number of recognised cardiovascular risk factors, including waist circumference (p = 0.038), diabetes (p = 0.032), high triglycerides (p = 0.013), and metabolic syndrome (p = 0.031).

Some HIV-related factors were also significant. These included lipodystrophy (p = 0.017), nadir CD4 cell count (p = 0.046), a detectable viral load (p = 0.036) and not taking antiretroviral therapy (p = 0.017).

Longer use of all the main classes of antiretrovirals was also associated with the development of mild renal impairment. However, the investigators were unable to find an association with specific drugs, including tenofovir (Viread, also in the combination pills Truvada and Atripla).

Incipient renal impairment was significantly associated with the hardening of the arteries (OR = 4.3; 95% CI, 1.7-10.6; p = 0.001). This association was still highly significant after the investigators controlled for factors known to increase the risk of kidney disease, such as age, and diabetes, as well as cumulative exposure to HIV therapy (OR = 3.8; 95% CI, 1.3-11.0; p = 0.013).

“In our study,” write the authors, “individuals with incipient renal impairment…had a 4-fold higher risk of subclinical atherosclerosis.” They note that this risk was present with even mild kidney dysfunction.

The authors believe their findings have immediate clinical implications and suggest “periodic monitoring of eGFR and albumin/creatine urine ratio might help to better identify subjects at increased risk of cardiovascular disease in order to initiate aggressive management of risk factors.”

View the original article here

Undiagnosed infections and poor retention in care mean that few US patients fully benefit from HIV treatment

Only a small minority of HIV-positive patients in the United States are gaining the full benefit of antiretroviral therapy, a study published in the November 29th edition of Morbidity and Mortality Weekly Report shows.  Investigators calculated that only a half of all patients are retained in care and that only 28% of people infected with HIV in the US have an undetectable viral load.

“More effort is needed to ensure that…patients remain in care and to eliminate disparities between subgroups who are prescribed ART [antiretroviral therapy] and subsequently achieve viral suppression,” comment the authors.

They warn that the goals of the 2010 US National HIV/AIDS Strategy to increases access to care, improve outcomes and reduce health inequalities can only be met by “achieving high levels of engagement at every stage in the continuum of care.”

The current low proportion of patients with viral suppression would also suggest that the use of HIV treatment as prevention will have only a minimal impact on the continuing epidemic in the US until these issues can be addressed.

An estimated 1.2 million individuals were living with HIV in the US at the end of 2008. With appropriate treatment and care the prognosis of HIV-infected patients can be excellent. Moreover, therapy that suppresses viral load to below the limit of detection significantly reduces the risk of onward transmission of the virus.

To take advantages of the benefits offered by modern HIV medicine it is essential that infected patients are diagnosed, linked and retained in care, prescribed antiretroviral therapy when appropriate, and that this treatment achieves virological suppression.

Using recent surveillance data, the investigators calculated the proportion of patients in the US receiving services at various points in this care continuum.    

They calculated that a fifth of HIV infections in the country were undiagnosed. An analysis of published studies suggested that 77% of diagnosed patients were initially linked with care. However, retention rates were poor and only 51% of individuals continued to regularly access care.

Use of antiretroviral therapy among the patients remaining in care was high, with 89% of individuals taking this treatment. Moreover, 77% of these patients achieved an suppression of the virus (defined as a viral load below 200 copies/ml).

Overall, the high rate of undiagnosed infections and the large proportion of patients dropping out of care meant that only 28% of all HIV-positive patients in the US had an undetectable viral load.

Racial disparities were apparent in the use of HIV therapy and in treatment outcomes.

Of the 92% of whites who were treated with anti-HIV drugs, 84% achieved virological suppression. Use of treatment was less prevalent among Hispanic patients (89%), and the proportion with suppression of the virus was somewhat poorer than those seen in whites (79%). Lower still were rates of treatment utilisation in black patients (86%) and only 70% of these patients experienced a fall in their viral load to below 200 copies/ml.

The study also suggested that HIV prevention efforts needed to be intensified. Only 45% of patients in care had received HIV prevention counselling. There were disparities according to age, with 73% of patients aged 18 to 24 receiving such counselling, compared to 36% of those aged over 55. Over half of black (54%) and Hispanic (52%) of patients were provided with prevention counselling compared to only 29% of whites. The proportion of patients receiving counselling also differed by HIV risk group, and was higher for gay men and other men who have sex with men (MSM) compared to men reporting sex with a woman (50% vs. 39%).

“These low percentages, especially among MSM, who account for most new HIV infections in the United States, indicate a need for health-care providers to deliver HIV prevention more consistently,” suggest the authors.

“Only an estimated 28% of all HIV-infected persons in the United States are virally suppressed, largely because even among those with diagnosed infections, only 51% are receiving regular HIV care,” emphasise the investigators.

They warn: “Without substantial improvement in these percentages, 1.2 million new HIV infections would be expected to occur over the next 20 years.” This could result in $450 billion in health-related expenditure. “Only with success at each step of the continuum of HIV care…can the ultimate goals of improving health, extending lives, and preventing further HIV transmission be achieved.”

View the original article here

Hepatitis B genotype B associated with poorer liver-related outcomes in Taiwanese patients co-infected with HIV and hepatitis B

Liver-related outcomes are poorer in HIV-positive patients who are co-infected with hepatitis B virus genotype B compared to co-infected patients with hepatitis B genotype C, Taiwanese investigators report in the online edition of Clinical Infectious Diseases.

The prospective, observational study involved individuals who commenced antiretroviral therapy containing 3TC (lamivudine, Epivir, also in the combination pill Combivir), a drug which has activity against both viruses. The patients were recruited between 1997 and 2008, and followed until 2010.

“Patients with [hepatitis B virus] genotype B co-infection were at higher risk of developing hepatitis flares, liver disease-related deaths, HBeAg seroconversion, and lamivudine resistance mutations than those with genotype C coinfection,” write the authors. Genotype did not affect HIV-related outcomes.

HIV and hepatitis B share transmission modes. Therefore, large numbers of patients are co-infected with these viruses. There are eight hepatitis B genotypes (A – H). The distribution of genotypes varies according to geographical region, and genotypes B and C predominate in Asia.

Little is known about the differential impact of these two genotypes on liver-related outcomes in patients co-infected with HIV and hepatitis B.

Therefore, investigators in Taiwan recruited 145 co-infected patients starting antiretroviral therapy to a study analysing the clinical, immunological and virological outcomes of patients according to hepatitis B genotype.

The hepatitis B-related outcomes included the risk of hepatitis flares, liver disease-related death, hepatitis B e antigen (HBeAg) seroconversion, and the development of strains of hepatitis B with resistance to 3TC. Changes in CD4 cell count and HIV viral load were also compared according to genotype.

A total of 96 patients were co-infected with genotype B and 49 with genotype C were recruited. There were no significant baseline differences between the patients.

However, they had severe immune suppression at the time they started HIV treatment, and their median CD4 cell count was just 117 cells/mm3. Median baseline HIV viral load was approximately 125,000 copies/ml. Median hepatitis B viral load at the start of the study was 63,000 copies/ml.

Patients were treated with 3TC-containing antiretroviral therapy for a median of 2.8 years. During this time, none of the patients received any other antiretroviral drugs with activity against hepatitis B.

Compared to patients with genotype C, those with genotype B co-infection were significantly more likely to experience hepatitis flares (44% vs. 27%, p = 0.04), die of liver-related causes (9% vs. 0%, p = 0.03), have HBeAg seroconversion (62% vs. 25%, p = 0.03), and developed strains of hepatitis B with resistant to 3TC (31% vs. 12%, p < 0.001).

Analysis that controlled for potentially confounding factors confirmed the relationship between genotype B co-infection and a number of liver-related outcomes.

Compared to individuals with genotype C, those with genotype B had a higher risk of hepatitis flares (AHR = 4.13; 95% CI, 2.87-5.39; p = 0.01) and were also more likely to develop 3TC-resistant hepatitis B (AHR = 8.67; 95% CI, 6.37-10.98, p = 0.001).

However, there was no significant difference in mortality risk between the genotypes. Nor did HIV-related outcomes differ between the two groups of patients, who had similar falls in viral load and increases in CD4 cell count.

“Hepatitis B genotype B is the most predominant genotype in hepatitis B virus and HIV-co-infected Taiwanese patients,” conclude the investigators. “Patients with genotype B co-infection are more likely to experience acute exacerbations of hepatitis, HBeAg seroconversion, lamivudine resistance, and liver disease-related death than those with genotype C coinfection when they receive [HIV therapy] containing lamivudine as the only active agent against hepatitis B virus.”

View the original article here