By Theo Smart

“Gynaecomastia [breast enlargement] is a frequent side-effect of antiretroviral therapy (ART) and is seen earlier and more frequently in our patient population than in European cohorts,” said Dr Tom Heller, the HIV and TB Co-ordinator in the Hlabisa district in the Northern KwaZulu-Natal at the Fourth South African AIDS Conference earlier this month.

Dr Heller was reporting on a study he and his colleagues conducted at Hlabisa Hospital, which found that 14% of the men developed breast enlargement. However, it is not clear whether the side-effect is due to d4T (stavudine) or possibly efavirenz.

Background
In South Africa, first-line HIV treatment in the public sector consists of d4T/3TC plus either efavirenz or nevirapine. But with prolonged treatment, increasing numbers of patients are experiencing metabolic complications and lipodystrophy (or fat redistribution) on the regimen.

Some forms of fat redistribution have been reported more commonly than others. For instance, a lot of patients experience facial lipoatrophy (fat loss) and central lipohypertrophy (abdominal fat accumulation), most of it caused by d4T. Lipohypertrophy can also be localised around the patient’s neck forming a ‘buffalo hump’ and sometimes in the breast area (sometimes on one side only).

“A lot of females complain about growing breasts [on ART], but it’s particularly a nuisance in male patients,” said Dr Henner. But it is unclear whether this is true gynaecomastia (with glandular enlargement possibly related to a hormone imbalance) or actually represents a fat redistribution.

A few studies (mostly European) have reported on the condition. A French study in 180 men reported that after about 39 months on ART, 2.8% developed breast enlargement on d4T and protease inhibitor-containing regimens (Piroth). A Spanish study reported that 2.3% of 1304 men with HIV had breast enlargement after about 49 months on treatment, which it associated with ddI and efavirenz (Mira). A study in Germany reported 5.1% of 490 men developed breast enlargement after 52 months of therapy containing ddI or d4T (Paech).

A couple of the studies looked at hormone changes but were not very conclusive. For instance, a Spanish study noted that testosterone levels in most of the men with enlarged breasts were somewhat lower compared to controls.

The only study in a resource-limited setting, conducted at the HIV Clinic at Johannesburg Hospital, reported a somewhat higher rate of breast enlargement: it was observed in 27 out of 305 patients (8.5%) (Wong). This study, though, included both men and women.

However, during a plenary talk at the conference Dr Francois Venter, who works at that clinic, spoke about how fear of this side-effect has had a tremendous impact in South Africa.

“A front page article in The Sowetan – a very popular daily newspaper from Johannesburg – showed a graphic picture of a man who developed a severe gynaecomastia, breast enlargement, while on ARVs,” he said. “I can’t tell you how much damage this particular article did and how much fear it spread within the HIV community. Can you imagine being a patient and being exposed to all the ‘politically correct government programmes’ about accessing care and how you’ll feel better, and then you see a front page article like this! It has done a huge amount of harm to the programme and legitimately causes a great deal of fear.”

The Hlabisa Study
News of breast enlargement spread through the country. In fact, after hearing the news, the counsellors at Hlabisa were worried about what to tell their clients. So they decided to conduct a survey to measure the proportion of male patients on ART presenting with breast enlargement in their rural setting, describe their demographic factors and characterise the hormonal profile of the patients affected by breast enlargement.

Hlabisa hospital and its clinics serve a population of 220,000, mainly Zulu-speaking, people. The HIV prevalence in general is high (19% of people older than 15 years), according to a local population-based study conducted by the Africa Centre over the past five years. Currently 6647 patients in the area are receiving treatment at 16 peripheral clinics. Approximately one-third of the ART patients are male. In the KwaMsane clinic – the largest of the clinics in a more urban setting – more than 1300 patients are treated and around 60 patients per month are initiated on ART.

For two months the HIV counsellors asked all male patients who came for follow-up visits to the KwaMsane Clinic if they had experienced any breast enlargement. If they reported they had, the patient was referred to a physician for history and examination with further investigations and blood was drawn to measure cholesterol, triglycerides and hormone levels.

Results
Sixteen out of the 113 men on ART surveyed (14%; 95% CI: 7 to 21%) reported breast enlargement. In four, gynaecomastia resolved spontaneously after a period of one to two months. In nine, breast enlargement was unilateral. The median age of the men with breast enlargement was 45 years (range: 30 to 48). The median duration on treatment at onset of breast changes was only 16.5 months (range: 5 to 32), a much faster onset than in the European studies.

The median CD4 cell count of men beginning ART was 123 (range: 43 to 187). By the onset of breast enlargement, CD4 cell counts were around 265 (range: 90 to 775).

“So, it’s safe to conclude the men were on effective treatment,” said Dr Henner.

The clinical team investigated a number of hormones, including follicle-stimulating hormone (FSH), luteinising hormone (LH), oestradiol, testosterone and prolactine, as well as cholesterol and triglycerides. All were within normal range except for two patients who presented mildly elevated oestradiol (235 and 256 pmol/l – normal: 191 pmol/l) only but no other hormonal changes. One patient had mildly elevated triglycerides (2.8 mmol/l, normal:>2.3 mmol/l) which was not clinically relevant. Only one patient had concomitant diseases (hepatitis B and MDR-TB, on treatment), which could possibly contribute to breast development.

“It is definitely difficult to distinguish clinically between true breast development (gynaecomastia) and focal lipodystrophy syndrome (lipomastia) – there are studies reporting that you can distinguish by high-resolution ultrasound and MRI but obviously these are not available in our setting,” said Dr Henner. “The underlying pathophysiology also remains unclear. Hormonal changes have been described by different authors (elevated oestrogen, reduced testosterone); however, we could not really find that in our few patients. Hormone and lipid studies don’t seem to be warranted routinely as they showed only minimal abnormalities in very few cases.”

Management
“The ‘culprit drug’ is difficult to identify as patients are usually on multiple drugs,” he said (though in this cohort, it would have to be associated with d4T or efavirenz). But he felt that “treatment changes may be difficult. First of all because we don’t know which one to change, and then secondly due to the limited number of ARVs available.”

Treatment options are also limited. One study looked at the local application of androgen (dihydrotestosterone gel) but that is not available in this setting (Benveniste). Surgical mastectomy is a possibility but Henner said that this was “a drastic measure that is rarely indicated. We have to remember that in a number of cases, the gynaecomastia disappears spontaneously.”

Men with breast changes in this cohort were counselled and all of them continued ART on the same regimen – all but one with undetectable viral load.

“With counselling, and reassurance of the patient about the nature of the changes – because there is often fear when you have a breast growth that does not belong there – I think sufficient adherence can be achieved to continue ART successfully,” he said.

Other clinicians think that d4T (or other d-drugs) are the most likely culprit, however, and that countries need to start coming up with alternatives.

“I think for most clinicians, d4T is really one of the ‘bad guys’ on the block,” Dr Venter said during his plenary. “D4T toxicity drives most of the treatment changes. But it’s still used by the vast majority of people in the world – and certainly within the developing countries and in southern Africa.”

“Does everyone eventually get d4T toxicity? I think we don’t know that answer yet but if it is the case, we may have to start thinking about what substitution treatment we could use.”

References

Kany A et al. Breast enlargement in male patients on ART in rural South Africa. Fourth South African AIDS Conference, Durban, abstract 262, 2009.

Piroth L, Grappin M, Petit JM, et al. Incidence of gynecomastia in men infected with HIV and treated with highly active antiretroviral therapy. Scand J Infect Dis; 33:559-560, 2001.

Mira JA et al. Gynaecomastia in HIV-infected men on highly active antiretroviral therapy: association with efavirenz and didanosine treatment. Antiviral Therapy 9:511-517, 2009.

Paech V, Lorenzen T, von Krosigk A, et al. Gynaecomastia in HIV-infected men: association with effects of antiretroviral therapy. AIDS 16(8):1193-1195, 2002.

Wong EB et al. High rates of non-fatal toxicities in a 24 month cohort receiving publicly funded HAART in South Africa. CROI, Denver, abstract 975, 2007.

Benveniste O, Simon A, Herson S. Successful percutaneous dihydrotestosterone treatment of gynecomastia occurring during highly active antiretroviral therapy: four cases and a review of the literature. Clin Infect Dis. 2001;33:891-893.

By Carole Leach-Lemens

Paediatric antiretroviral therapy is feasible in decentralised, nurse- and counsellor-led programmes in public health clinics in rural areas in South Africa, according to research presented at the Fourth South African AIDS Conference in Durban earlier this month.

Mortality rates in children receiving ART at public health clinics in Hlabisa, a sub-district in rural northern KwaZulu-Natal, were no different from rates seen in other African cohorts.The health infrastructure of the sub-district of Hlabisa, which has a population of 220,000, is typical of most rural health districts in South Africa and has 16 primary health care clinics, two mobile clinics and one 300-bed district-level hospital.

The ART programme, a partnership between the Department of Health (DOH) and the Africa Centre for Health and Population Studies, follows DOH national guidelines. Physicians visit the 16 clinics to initiate ART. Services are decentralised and patients are able to access free care at their nearest primary health care clinic which is managed by nurses and counsellors.

Children are less likely to receive treatment than adults, in part because HIV diagnosis is more complex in children under the age of 18 months due to the carriage of maternal antibodies that may result in a false-positive diagnosis. But children may also fail to receive treatment due to a lack of awareness of the presentation of HIV-related symptoms in children, especially infants.

In order to reveiw how well the programme was meeting the needs of children with HIV, a retrospective study was undertaken of the clinical records of all children (477) on ART in the districts from January 2004 until June 2008.

At baseline, recorded values included a mean age of 76 months and 5% of the sample were under 12 months of age. Nearly a quarter were receiving TB treatment and over 75% were classified as having WHO Stage 3 or 4 HIV disease (symptomatic illness). CD4 count and CD4 percentage, viral load, haemoglobin (anaemia) and albumin (malnutrition) levels were recorded. Most of the children were malnourished and anaemic.

Close to 90% of children who began first-line treatment over the four-year period were still alive as of July 2008. Thirty-two (6.7%) had died, 12 (2.5%) had transferred out of the programme and 18 (3.8%) were lost to follow-up. Most deaths occurred within the first 90 days across all age groups and were associated with a lower weight-for-age ratio, being anaemic, being classified as WHO Stage 3 or 4 and having a lower CD4 percentage at the start of treatment.

Unlike the deaths, loss to follow-up occurred both before and after the first 90 days of treatment and was associated with a lower CD4 percentage and stage 3 or 4 disease at the start of treatment.

After six to twelve months on treatment, 75% of children had viral load suppressed below 25 copies/ml (the limit of detection), a median increase in CD4 cell counts from 432 to 519 and in CD4 percentage from 17% to 22%.

At the conclusion of their analysis in June 2008 the researchers, concerned with the low number of children under the age of one receiving treatment, set up new procedures to ensure that HIV-positive children were not being missed.

Treatment for children at disease stage 3 or 4 was often delayed since doctor referral and subsequent ART initiation was dependent upon viral load or CD4 results.

Clinic nurses were notified that all sick HIV-exposed children, as well as those who were malnourished, could see a doctor regardless of HIV status. Nurses and counsellors received enhanced paediatric HIV training. Importance was placed on recognising TB as a WHO stage 3 condition and the eligibility of all children with HIV who had a history of TB for antiretroviral therapy.

From 1 July 2008 to 31 December 2008 a 42% increase in children receiving ART across all age groups was recorded, with an increase of almost 50% in children under one year of age.

The authors conclude: “We believe we’ve shown that paediatric ART is feasible in a devolved programme in a rural area. However there are still too few children under one year (of age) on treatment, and there is an urgent need to identify HIV-exposed children.”

Reference
Janssen N et al. Clinical and virological outcomes of children receiving antiretroviral treatment in a decentralized programme in rural KwaZulu-Natal. Fourth South African AIDS Conference, Durban, abstract 255, 2009