Details and results of HTPN 052

Researchers with the HIV Prevention Trials Network (HTPN) enrolled HIV-1 serodiscordant couples from the following countries:

• Botswana
• Malawi
• South Africa
• Zimbabwe
• Brazil
• India
• Thailand
• United States

The purpose of trial 052 was twofold:

• to assess the ability of ART to prevent transmission of HIV to the uninfected partner of a couple in a stable relationship
• to compare the effect of early vs. delayed ART in people with CD4+ cell counts between 350 and 550 cells

Researchers screened more than 10,000 volunteers in order to recruit 1,763 HIV serodiscordant couples for this study. This shows the vast amount of work that is necessary to undertake complex clinical trials.

HIV-positive participants were randomly assigned to one of the following two study groups as follows:

• early treatment with ART (886 couples)
• delayed treatment with ART (877 couples)

In the early intervention group, participants received ART immediately upon entry to the study. In the delayed treatment group, participants were monitored and received treatment when their CD4+ cell counts fell to 250 cells or less.

Upon enrollment, participants were screened and treated for sexually transmitted infections (STIs). For the first three months after enrollment, participants returned to the study clinic for monthly visits. Thereafter, visits were once every three months. Couples were encouraged to visit study clinics together to receive the following:

• counselling about the use of condoms for safer sex
• treatment of STIs if necessary
• receipt of sufficient ART until the next study visit

The HIV-negative partner was tested for HIV once every three months.

At each visit participants were regularly interviewed about their sexual behavior. The HIV-positive partner was questioned about adherence to ART and also received adherence counselling.

The average profile of participants when they entered the study was as follows:

• 97% of couples were heterosexual and HIV infection was evenly distributed between men and women
• most participants were between the ages of 26 and 40 years
• at least 70% of couples reported sex in the past week and about 5% of such encounters were unprotected
• CD4+ cell count (of HIV-positive participants) – 430 cells
• viral load – 25,000 copies/ml
• about 5% of participants were diagnosed with STIs

Results—Transmissions

After about nearly two years, trial 052 was prematurely stopped because of striking differences in the number of HIV transmissions between the two study groups.

In total, 39 HIV transmissions occurred, distributed as follows:

• early therapy group – 4 transmissions
• delayed therapy group – 35 transmissions

However, researchers took blood samples from participants who became infected and from their partners and analysed the genetic material of HIV to see how closely the viruses were related between couples. Using this genetic analysis, the researchers could be reasonably certain that a total of 28 transmissions were linked to the partners in the study. According to the genetic analysis, the distribution of new HIV infections was as follows:

• early therapy group – 1 transmission
• delayed therapy group – 27 transmissions

This difference was statistically significant.

The remaining transmissions that occurred likely did so because the HIV-negative partner had sex with someone outside of the couple (who was not likely taking ART).

The single transmission that occurred in the early therapy group happened three months after the HIV-positive partner had initiated ART. In this case, transmission was from a woman to a man.

Having a relatively high viral load was linked to an increased risk of HIV transmission.

Participants who stated that they used condoms in 100% of sexual encounters were at reduced risk for HIV transmission.

Results—Treatment

Major clinical events—severe illness or death—were distributed as follows:

• early treatment group – 40 events
• delayed treatment group – 65 events

A factor that was highly predictive of such events was a person’s viral load at the start of the study. The higher the viral load, the greater the risk of severe illness or death.

A common serious infection was tuberculosis (TB) outside the lungs, called extra-pulmonary TB, distributed as follows:

• early treatment group – 3 cases
• delayed treatment group – 17 cases

However, cases of pulmonary TB were more evenly distributed between the two study groups.

Deaths were distributed as follows:

• early treatment group – 10 deaths
• delayed treatment group – 13 deaths

This difference in the number of deaths was not statistically significant

Results—Side effects

It is important to note that because most trial participants were from low- or middle-income countries and regions, some of them used drugs that are no longer commonly used in high-income countries because of their side effects. Such drugs include:

• d4T (stavudine, Zerit)
• ddI (didanosine, Videx)

These drugs can increase the risk for a range of problems such as nerve damage, inflamed pancreas gland, liver damage and, particularly for d4T, unwanted changes to body shape and appearance of the face.

The most common adverse effects reported in the study fell into these categories:

• psychiatric and nervous system disorders
• disorders of metabolism and nutrition
• gastrointestinal disorders

Severe or life-threatening lab test results were distributed as follows:

• early treatment group – 27%
• delayed treatment group – 18%

Common abnormal lab tests included:

• less-than-normal levels of neutrophils (a type of white blood cell)
• elevated levels of the waste product bilirubin, a known side effect linked to the use of atazanavir (Reyataz)

—Sean R. Hosein

REFERENCES:

1. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. New England Journal of Medicine. 2011 Aug 11;365(6):493-505.
2. Hammer SM. Antiretroviral treatment as prevention. New England Journal of Medicine. 2011 Aug 11;365(6):561-2.