CD4s Above 500: HIV Treatment Need Still Unclear ... should one start ARVs?

If you’re diagnosed with HIV and have a CD4 cell count above 500, should you start antiretroviral (ARV) therapy immediately? An Australian study suggests that even though there may be some immunologic benefits to starting therapy earlier than is currently recommended—once the CD4 count drops below 500—the jury is still out on whether this translates into important clinical benefits.

more on how cd4s work

Despite more than 25 years of ARV research and the successful development of more than two dozen medications, scientists have not been able to determine the ideal time to begin therapy. Several studies have concluded that HIV treatment is best started before a person’s CD4 count falls below 350.

Some studies, conducted during the past five years, suggest that starting therapy even earlier—when the CD4 count is between 350 and 500—further increases the chances of disease-free survival. Less is known about the potential benefits of initiating therapy earlier still, when the CD4 count is above 500.
A large clinical trial, called the Strategic Timing of Antiretroviral Treatment (START) study, is being conducted to explore the safety and effectiveness of beginning treatment when the CD4 count is above 350 cells. Preliminary data, however, are not expected for at least another few years.

In the meantime, HIV-positive people and their health care providers are on the lookout for smaller observational and retrospective studies, such as the one recently published online by the Journal of Acquired Immune Deficiency Syndromes and based on data from Stephen Wright and his colleagues with the Australian HIV Observational Database.


Wright’s group looked at the outcomes of 432 people living with HIV who started ARV therapy with a CD4 count above 350 and had been followed for six years (72 months). For their analysis, the researchers divided the study volunteers into three groups: those who started treatment with a CD4 count between 350 and 500, those who started treatment with a CD4 count between 501 and 650 and those who started treatment with a CD4 count above 650.

Twelve months after beginning treatment, all study volunteers had CD4s above 500. Average CD4 counts, after a year of ARV therapy, were 596 among those who started with CD4s between 250 and 500, 717 among those who started treatment with CD4s between 501 and 650, and 881 among those who started treatment with a CD4 count in excess of 650.

After six years, CD4 counts were comparable between the three groups. Among those in the lowest pre-treatment CD4 group, the average CD4 cell count was 689. In the middle- and high-pretreatment CD4 groups, the average CD4 count after three years was 746 and 742, respectively.

Wright’s team also sought to determine whether there was a survival advantage between the three groups. Comparing their Australian data with those of another study, the researchers documented a modest 8 percent expected reduction in the risk of death among those who started treatment with more than 650 CD4s and a 4 percent expected reduction in the risk of death among those who started treatment with 501 to 650 CD4s, compared with those who started treatment with CD4s between 350 and 500. It is important to note, however, that the estimated number of deaths in these three groups were very low, which translated into very small differences in the absolute risk of death between those in the two highest CD4 groups compared with those starting with CD4s between 350 and 500.

“Our analysis suggests that patients who start [ARV therapy] at CD4 counts [greater than] 650 have better preserved immune function, but only to a relatively modest degree,” the authors conclude. “Furthermore the extent to which this might be expected to result in better clinical outcomes is uncertain.”

Abacavir Should (Again) Be a “Preferred” HIV Treatment Option ... previously downgraded to first line

Researchers of a new study, published online June 24 in the Journal of Acquired Immune Deficiency Syndromes, found similar rates of treatment success in people taking abacavir plus lamivudine (Epzicom), compared with people taking tenofovir plus emtricitabine (Truvada). Moreover, they conclude that abacavir should once again be listed as a “preferred” option in HIV treatment guidelines.

Three landmark studies during the past three years resulted in the down-grading of abacavir in U.S. HIV treatment guidelines from a “preferred” antiretroviral (ARV) agent for first-line therapy, notably when used in the combination tablet Epzicom, to an “alternative” agent.

Two of those studies, SMART and D:A:D, suggested that people taking abacavir had a higher rate of heart attacks than people on other nucleoside reverse transcriptase inhibitors (NRTIs). A third study, ACTG 5202, found that people on an Epizcom-inclusive regimen for first-line therapy were more likely to experience treatment failure upon starting therapy with a high viral load (over 100,000 copies), compared with people taking a Truvada-inclusive regimen.

Though other studies found no association between abacavir and heart attacks, nor lower efficacy in people starting treatment with high viral loads, the panel of experts and community activists who write U.S. guidelines voted to downgrade Epzicom in 2008. Truvada, however, has remained the preferred NRTI option.

Given the mixed results of these various studies, several European guidelines committees decided not to follow suit and kept Epzicom—branded as Kivexa in Europe—as a preferred regimen. The competing studies and differing guidelines have led to confusion as to the best use of Epizcom in people starting treatment for the first time.

In hopes of clarifying the efficacy of abacavir compared with tenofovir—less concern exists for lamivudine or emtricitabine, as both drugs are very similar—Darrell Tan, MD, from the University of Toronto, and his Canadian colleagues, examined the medical records of 1,764 HIV-positive people who started HIV treatment between 2000 and 2010. Anearlier look at the data in a smaller group of people was reported in 2010 at the International AIDS Conference in Vienna.

The Canadian Institutes of Health funded the study, and no conflicts of interest with Epzicom’s manufacturer, ViiV Healthcare, were reported.

For the study, Tan’s group directly compared people starting a regimen including abacavir and lamivudine—either separately as Ziagen and Epivir or as Epzicom—with those starting a regimen including tenofovir and emtricitabine—either separately as Viread and Emtriva, or together as Truvada. After Atripla, a combination tablet containing tenofovir, emtricitabine and efavirenz, became available in Canada in 2007, those taking the three-in-one tablet were included in the tenofovir group.

Tan found that when multiple variables were considered, people taking an abacavir regimen were no more likely to experience treatment failure than those taking a tenofovir regimen. This held true even in people who started treatment with viral loads over 100,000.

What’s more, the rate at which people were able to suppress their virus over the first few months of treatment—another way of looking at the potency of the treatment regimen—was equivalent between the two groups.

Lastly, people taking abacavir were no more likely to switch or stop treatment for reasons other than virological failure than people taking tenofovir.

Tan’s team acknowledges that a primary difference between ACTG 5202 and their study is the fact that people in ACTG 5202 were randomized to receive either abacavir or tenofovir, whereas in their study no randomization occurred. This means that there might have been reasons that a person’s provider chose one of the regimens over the other and that these reasons could have affected Tan’s study results. Because of this, the authors state that their study cannot say conclusively that abacavir and tenofovir are equivalent in terms of efficacy.

Other features of the Canadian study, however, were similar to ACTG 5202, and the Canadian study’s results are similar to a different clinical trial, the HEAT study, which found that abacavir was equivalent to tenofovir, even in people with high viral loads. Therefore, the authors conclude: “These results support the use of either NRTI backbone in the initial therapy of ART-naïve patients, and would support continuing [abacavir/lamivudine] as a ‘preferred’ NRTI option.”

Tenofovir Might Reduce Inflammation, Boost Immune System

The antiretroviral (ARV) drug tenofovir (found in Viread, Truvada and Atripla) might calm the immune system in people with HIV and make them less susceptible to other infections, according to a study published online April 5 in the Journal of Acquired Immune Deficiency Syndromes.

HIV directly harms the immune system by infecting, and ultimately destroying, key immune cells. Such direct killing, however, doesn’t fully explain how or why the immune systems of people with HIV become so damaged over time, as only a small proportion of cells ever become infected.

Since the introduction of potent ARV therapy in the late 1990s, scientists have been able to study other ways that the presence of HIV can cause harm to those infected with the virus. Inflammation is believed to be a primary culprit. When the body is under threat—either from infection, cell damage or cancer—it produces dozens of different chemicals that place the immune system on high alert. This is a good thing, as it allows the body to respond to those threats, but if the immune system never fully calms down—which appears to be the case in people living with HIV—it can lead to serious problems, such as cardiovascular disease.

Another problem with HIV is that is it can, ironically, put the breaks on some components of the immune system while also revving up inflammation. In particular, by reducing a chemical messenger called interleukin-12 (IL-12) and increasing another called interleukin-10 (IL-10), the immune system becomes suppressed and less able to fight off other serious infections.

HIV drugs significantly reduce inflammation by shutting down HIV replication, but even when virus levels are diminished almost completely, inflammation remains. However, one ARV drug, Selzentry (maraviroc), has been found to calm down inflammation in addition to shutting down the virus. This has sparked researchers’ attention and led them to begin studying other ARVs.

Jesper Melchjorsen, PhD, from the Aarhus University Hospital Skejby, in Aarhus, Denmark, and his colleagues set out to understand the anti-inflammatory properties of tenofovir, Retrovir (zidovudine) and Ziagen (abacavir). The team incubated non-HIV-infected cells, treated them with the drugs, and then stimulated them with a variety of other types of pathogens, including the cytomegalovirus (CMV), Escherichia coli and Streptococcus pneumoniae.

Meclchjorsen and his colleagues found that tenofovir offered two types of protection to the cells. First, it suppressed the production of inflammatory messengers, such as Interleukin-8 (IL-8). The authors note that other studies of tenofovir have not found an inflammatory effect, and so caution is warranted in interpreting the results. They stress, however, that because they used both tenofovir in its commercial form Viread, which is actually a modified version of the active drug tenofovir, and purified tenofovir, they feel their results are valid and deserve further testing.

Tenofovir also appeared to keep the balance of IL-12 and IL-10 stable. The drug enhanced the IL-12 levels, thus increasing their ability to respond to other infectious pathogens, and it kept IL-10 levels low, thus keeping the body from putting the breaks on the immune response.

Retrovir, on the other hand, had detrimental effects in both directions. Not only did it increase the production of IL-8 and other inflammatory chemicals, but it also reversed the balance of IL-12 and IL-10, thus making the cells more susceptible to infection.

Lastly, the team found that Ziagen had a neutral effect on cells. It neither increased nor decreased inflammation. It also had no effect on the balance of IL-12 and IL-10, neither increasing nor decreasing the cells’ susceptibility to other infections.

Further research will be needed to determine whether these findings actually translate into a clinical benefit in people’s bodies. Nevertheless, the authors conclude that the findings are intriguing enough to warrant such research.