Principles of successful subsequent therapy

There are several factors underlying successful therapy that help predict good treatment outcomes. Chief among these are lower viral load, fewer viral resistance mutations, use of resistance testing when changing a treatment regimen, a larger number of active drugs in the new regimen, good adherence, and an experienced clinician. 

People who have achieved viral suppression but wish to change regimens to improve convenience or manage side-effects and toxicities have a wider range of options and more room to experiment. Their virus remains sensitive to some drugs, and they are unlikely to experience rapid disease progression even if viral load rebounds on the new combination and they have to switch again or go back to an earlier regimen. 

Recently approved drugs (etravirine, maraviroc and raltegravir) in several drug classes may be especially useful in treatment-experienced people with drug-resistant HIV.

As knowledge about HIV treatment has evolved and new drugs have become available, expert opinion has shifted regarding when and for whom these different approaches are most appropriate. Switching quickly is generally advised for people who have recently experienced treatment failure on one of their first regimens and have a high likelihood of achieving full viral load suppression on a new combination.1

The best approach for highly treatment-experienced people with extensive resistance and few remaining active drugs is less well-defined, but the odds of successful outcomes for the most difficult-to-treat patients have improved.

Researchers studying more than 10,000 treatment-experienced participants in the UK CHIC cohort who achieved a viral load below 50 copies/ml found that viral rebound rates declined with a longer duration of successful treatment. People who were able to maintain a viral load below 50 copies/ml for four years – increasingly possible with improved therapies – were no more likely to experience virological failure after this point than people starting treatment for the first time.2

Effect of viral load and CD4 count

Follow-on regimens after virological failure work best for people who have a low-level detectable viral load, usually below 10,000 or 100,000 copies/ml in most studies. This suggests that if viral load is starting to rise, it may be beneficial to switch to a new regimen sooner rather than later. If viral load is low, even a partially active regimen may be enough to push it below 50 copies/ml.

On the other hand, there is also evidence that people who stay on a ‘failing’ regimen with a viral load between 50 and 10,000 copies/ml will likely maintain a stable CD4 count and have a low risk of clinical disease progression. For further discussion on this topic, see Continuing on ‘failing’ treatment.

Since it is not possible to know in advance whether a rising viral load will continue to increase or stabilise below 10,000 copies/ml, a low but detectable viral load does not by itself suggest a preferred course of treatment. But with several new drugs now giving treatment-experienced people a better chance of pushing viral load below 50 copies/ml, most experts would recommend trying to achieve full viral suppression.

Some studies indicate that people with higher pre-treatment CD4 cell counts and less advanced disease are likely to respond better to subsequent regimens. They also tend to experience clinical disease progression more slowly after treatment fails. But even patients with severely suppressed immune function can achieve good outcomes with appropriately selected combination therapy.

CD4-based treatment decisions

Switching antiretroviral regimens because of CD4 declines, without information from viral load tests, could result in a large number of people changing unnecessarily to second-line regimens in resource-limited settings, according to results from the Ugandan Rakai study.3

WHO recommends a switch in treatment if the CD4 count falls by more than 50% from its previous peak level, or if the CD4 count falls to its pre-therapy baseline (or below); or if it persistently remains below 100 cells/mm3. There has been concern that, by the time the CD4 count begins to decline viral load may have been rising for many months, leading to drug resistance.

To answer the question of how accurately CD4 count changes predict treatment failure, and specifically, how accurately the WHO immunologic criteria predicts virologic failure in an African population receiving antiretroviral therapy, the Rakai study enrolled over 1100 people who were on first-line antiretroviral therapy. CD4 cell counts and viral load testing were performed every six months for a median of 22 months. Virologic failure was defined as having a viral load result over 10,000 copies/ml on a single follow-up test.

Only 18 people (1.6%) were identified by both monitoring methods as treatment non-responders and 62 people were identified solely by viral load testing. Meeting only the WHO immunologic criteria for treatment failure were 107 people.

Theoretically, this would have resulted in 107 unnecessary and expensive regimen changes to second-line treatment regimens that might be less effective. Investigators noted that the high rate of immunologic failure without virologic failure was largely driven by 50% declines in CD4 count from peak levels, possibly as a consequence of co-infections, such as malaria, that were not properly recorded.

This same conclusion was reached in a South African study that reviewed data on over 300 patients one year after starting an initial antiretroviral regimen.4  

Change based on clinical monitoring

Although many studies have found clinical monitoring alone a less than effective means of determining treatment failure, recent results from the DART study in sub-Saharan Africa reached a different conclusion.5 

Over 3000 patients initiating ART were followed for nearly five years. At the end of this time, 87% of the clinical monitoring group and 90% of the clinical and laboratory monitoring group were alive. Patients who received clinical monitoring alone were around 30% more likely to develop a new WHO stage 4 event or die.

Investigators found that clinical monitoring alone was a reasonable approach, particularly during the first two years of ART. After that time, they recommended the addition of CD4 counts to guide treatment changes.


  1. Deeks SG Treatment of antiretroviral-drug-resistant HIV-1 infection. Lancet 362: 2002-2011, 2003
  2. Benzie AA et al. Increased duration of viral suppression is associated with lower viral rebound rates in patients with previous treatment failures. AIDS 21: 1423-1430, 2007
  3. Reynolds S et al. Evaluation of the WHO immunologic criteria for ART failure among adults in Rakai, Uganda. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 144, 2009
  4. Mees P et al. Evaluation of the WHO criteria for antiretroviral treatment failure among adults in South Africa. AIDS 22(15): 1971-1977, 2008
  5. Mugyenyi P et al. Impact of routine laboratory monitoring over 5 years after antiretroviral therapy (ART) initiation on clinical disease progression of HIV-infected African adults: the DART Trial final results. Fifth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract TuSS103, 2009
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.