Study finds durable drug-free control of HIV is uncommon when treatment is interrupted

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By strengthening the immune system and reducing the amount of HIV in the blood below the threshold of detection—a level commonly called “undetectable”—potent combination anti-HIV therapy (commonly called ART) can have several benefits, including the following:

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  • It can tremendously reduce the risk of developing AIDS-related infections.
  • It can increase the life expectancy of some people to near normal.
  • It can significantly reduce the risk of sexually spreading HIV.

However, ART does have some drawbacks, including the following:

  • It cannot cure HIV infection.
  • It needs to be taken at least once daily for life.
  • Some regimens can have side effects.

Caution needed

Studies have found that interrupting ART is fraught with risk. HIV levels can quickly rise and the immune system can again decline once treatment is interrupted. A large, well-designed clinical trial called SMART found that interrupting treatment increases the risk for some inflammation-related complications, infections and death.

Is ART-free control of HIV possible?

Researchers have found that drug-free control of HIV can occur in certain populations, including the following:

  • so-called Elite controllers – Researchers have defined this group of people as those with an undetectable viral load in the blood (less than 50 copies/ml) without the use of ART. Such people are rare, accounting for less than 1% of all HIV-positive people.
  • post-treatment controllers – People in this group initiated ART very shortly after infection and therapy was later interrupted. Despite this interruption, their immune systems are apparently able to control HIV. Post-treatment controllers are uncommon.
  • There are also reports of temporary drug-free control of HIV in the blood in a few other cases—for example, a couple of adults who had bone marrow transplants as part of attempts to cure HIV infection and a baby treated shortly after infection (the “Mississippi baby”).

Researchers who have extensively reviewed the above groups and cases have been at a loss to know why virological control unexpectedly occurred and why and when such control might subsequently fail. However, what the groups and cases have in common is that tests in research labs suggest that they have a relatively low amount of HIV-infected cells in their body compared to the average HIV-positive person who uses ART. Scientists refer to this burden of infected cells in the body as the reservoir.

Multiple and simultaneously applied approaches will be needed

In an attempt to induce a period of ART-free remission, teams of researchers are planning experiments with HIV-positive people who are taking ART and who have a relatively small reservoir of HIV-infected cells. Such experiments will likely involve the use of combinations of agents that try to enhance the ability of the immune system to kill HIV-infected cells and to hopefully decrease the size of the reservoir. There are many potential options that could be used in such experiments, including vaccines to stimulate immunity against HIV, drugs that enhance the immune system’s ability to recognize and kill HIV-infected cells, bone marrow transplants, and gene therapy. In the future, only after implementing such options might researchers feel it useful to attempt treatment interruptions to assess the ability of the immune system to control HIV.

Ultrastop

Researchers in France conducted an experiment with a limited number of very carefully selected HIV-positive people in the absence of the many potential interventions mentioned above. All participants had begun ART relatively early in the course of HIV infection and had a viral load in the blood less than 50 copies/ml and a CD4+ count greater than 500 cells/mm3. Furthermore, the amount of HIV-infected cells in their reservoirs was unusually low.

After an interruption of treatment, viral loads resurged in most participants within four weeks. However, one participant continued to have a low viral load—less than 400 copies/ml—for about one year after interruption of ART. Despite conducting extensive tests on samples of his HIV and immune system, French researchers remain mystified as to how he is able to control HIV in his blood.

An important finding from Ultrastop is that despite very careful selection of participants (based on many factors, including immunological, virological and treatment history and assessment of their HIV reservoir) interruption of ART led to a limited period of virological control for 90% of them. The findings from Ultrastop suggest that, by itself, treatment interruption may not be a useful way to try to help HIV-positive people control HIV.

Study details

Researchers carefully selected potential participants for this study. In addition to performing complex analyses of participants’ blood, researchers reviewed their medical history and had them undergo psychological evaluation to be sure that they were capable of engaging in a study of this nature where frequent laboratory visits would be needed.

Researchers reported results from 10 participants, whose average profile at the start of the study was as follows:

  • age – 42 years
  • seven men, three women
  • time since HIV diagnosis – six years
  • duration of HIV infection with a viral load less than 50 copies/ml – five years
  • lowest-ever CD4+ count – 495 cells/mm3
  • CD4+ count – 1,118 cells/mm3
  • CD8+ count – 566 cells/mm3
  • CD4/CD8 ratio – 2.1

Using an ultrasensitive assay, technicians found that one month prior to the study all participants had a viral load less than 20 copies/ml. Also, all participants had a very low level of HIV-infected cells in their blood, suggesting that their reservoir was unusually small.

Results—Focus on the nine participants whose viral load rebounded

As mentioned earlier in this report, most participants had their viral load climb well into the detectable range within the first four weeks after interrupting ART. The results below on viral load, the reservoir, T-cells, safety and other issues focus on findings from nine participants whose immune systems were unable to control HIV once ART was interrupted.

Viral load

On average, the first detectable viral load was 2,125 copies/ml and the second viral load test (to confirm that it was detectable) a week later found that the average viral load had risen to 7,213 copies/ml.

The viral reservoir

Since viral load was rising, this indicated that more of the immune system’s cells were being infected and that the reservoir would rise. To confirm this change, researchers assessed the reservoir. At the start of the study, the reservoir was estimated to be less than 66 HIV DNA copies per million blood cells. However, once treatment was interrupted, the burden of HIV-infected cells rose: Their reservoir of infected cells was 106 DNA copies per million blood cells. This increase in the size of the reservoir was statistically significant; that is, not likely due to chance alone.

Changes to T-cells

Not surprisingly, with all the negative changes that occurred, CD4+ counts quickly began to fall, initially decreasing by an average of 124 cells/mm3. Furthermore, a greater proportion of the immune system’s cells became inflamed and activated—another change that was statistically significant.

Safety

No serious side effects occurred during the study after participants interrupted ART, perhaps in part because their CD4+ counts were generally high (and had never fallen to low levels prior to initiating ART) and the interruption was relatively short. Common adverse effects reported after interruptions were generally of mild or moderate intensity and included the following:

  • headache
  • muscle soreness or pain
  • diarrhea
  • swollen lymph nodes

Viral loads generally decreased rapidly once participants resumed treatment. Four weeks after resumption of ART, eight out of nine participants had a viral load less than 50 copies/ml.

The following happened 24 weeks after resuming ART:

  • Ultrasensitive viral load assays found that seven out of eight participants had a viral load less than 1 copy/ml.
  • On average, the burden of HIV-infected cells (the reservoir) in their blood fell to its pre-interruption level.
  • The average CD4+ count was 823 cells/mm3 (almost 300 less cells than at the start of the study).

Focus on one person

Researchers are not sure why one person was able to have a relatively low viral load despite interrupting ART for 56 weeks (researchers are still monitoring him). His last viral load test result was 282 copies/ml.  In reviewing his medical history prior to the study, they found that before he initiated ART, his highest-ever viral load was just over 3,000 copies/ml. His lowest-ever CD4+ count (also before initiating ART) was 566 cells/mm3.  Three years before entering Ultrastop, analysis of his blood samples found that his viral load was consistently less than 20 copies/ml.

He does not appear to have any genes associated with decreased susceptibility to HIV.

Despite extensive analyses, researchers could not find an explanation for the man’s control of HIV replication in his blood while not taking HIV medications.

Points to consider

1. Readers should bear in mind that the participants in this study were very carefully selected. For instance, to be considered for inclusion in Ultrastop, potential volunteers had to have an extremely low level of HIV-infected cells (this represents the reservoir) in their blood—below the level of detection. Such a level in the French study was less than 66 copies of HIV DNA per million blood cells. The French researchers described such low levels as “a rare event.” Additionally, potential volunteers initiated ART when their CD4+ counts were around 500 cells/mm3 and had relatively low pre-treatment viral loads. All of these selection criteria mean that the average HIV-positive person would not have been eligible for this study.

2. Note that although participants selected for this study were thought to have the best chance for a prolonged drug-free remission from HIV, the time period was remarkably short—about one month. The French team noted that the short delay in a resurgent viral load in most of the participants was similar to what was seen about 15 years ago when treatment interruptions were first seriously investigated.

3. The assay used to assess the level of HIV-infected cells in this study has a lower limit of detection of 66 copies of HIV DNA per million blood cells. Tests currently used in research labs to assess the size of the HIV reservoir are imperfect and likely underestimate its true size. Such tests are largely confined to research labs and some studies that seek to test potential therapies to cure HIV infection. However, several research teams are working to develop more accurate ways to assess the HIV reservoir.

4. The findings from Ultrastop suggest that the interruption of ART, as the sole intervention in an attempt to induce a drug-free remission, is not likely to be done on a large scale in the future. The French researchers were highly selective in their choice of participants, choosing the ones that they hoped had a biomedical profile that would suggest a prolonged drug-free remission was possible. Yet this did not happen.

5. There were no data reported about analyses of lymph nodes and lymphatic tissues in the French study. Most of the cells (lymphocytes) that HIV infects (98%) are in the lymph nodes and related tissues. As a result, so is most of the HIV in the body. Furthermore, U.S. researchers have found that even when the viral load in the blood is undetectable thanks to ART, HIV can be found infecting cells in the lymph nodes. Hopefully, in the future, researchers will look at these compartments when conducting research on drug-free remission of HIV.

For the future

Interruption of ART will probably be included in some studies in the future that seek to cure HIV or induce a period of drug-free remission for ART users. Such studies will need to find ways to bolster the immune system’s ability to detect and kill HIV-infected cells and to reduce the HIV reservoir. Only after such steps are first taken might researchers reconsider treatment interruption.

Other research teams are working on ways to better predict which HIV-positive people might experience a virological rebound once ART has been interrupted.

Many exciting studies lie ahead—some will include bone marrow transplantation, drugs to help reduce the HIV reservoir and strengthen the immune system, and gene therapy. It is important that HIV-positive people volunteer for these studies, as they will greatly help scientists understand the complex consequences of HIV infection and find ways to refine approaches to ART-free remission or a cure.

—Sean R. Hosein

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