Reversion to drug-sensitive virus

In addition to immune system stimulation, researchers also hypothesised that treatment interruption might enable the re-emergence of drug-sensitive wild-type HIV. In the presence of a drug, HIV develops mutations that allow it to escape the drug’s effects. But mutated virus tends to be less fit and replicates less efficiently. When the drug is withdrawn, the more fit wild-type HIV can often ‘out-compete’ the mutated virus and re-establish itself as the dominant strain. This may allow ‘recycling’ of previously used drugs. For more information, see Treatment failure, drug resistance and viral fitness.

Early studies demonstrated that wild-type HIV does re-emerge after drugs were withdrawn. One analysis showed that virus from 16 individuals with detectable resistance became susceptible to protease inhibitors within four months of discontinuing therapy, but at the same time viral replication capacity increased. Further, the drug-resistant virus was not eradicated, but rather remained hidden within infected cells.¹

Several small studies assessed the benefits of interrupting treatment before introducing a new regimen. In most cases, this was done in an attempt to improve the effectiveness of salvage therapy in heavily pre-treated patients. In the Spanish Retrogene study, for example, 46 highly treatment-experienced individuals with resistant virus were randomly assigned to start a five-drug regimen either immediately or after a three-month treatment break. After 48 weeks, about 45% in both groups achieved a viral load below 50 copies/ml and CD4 cell counts were also similar, despite the fact that 35% in the treatment interruption group experienced complete reversion to wild-type HIV.²

A few trials showed that stopping treatment before commencing a multidrug regimen increased drug susceptibility and enabled the new regimen to work better. Amongst 50 patients in the Frankfurt HIV cohort, interrupting treatment for three to four months before starting a mega-HAART (highly active antiretroviral therapy) regimen of six or more drugs led to the return of wild-type HIV and a greater chance of a successful response.³

Likewise, the French GIGHAART study, which included 70 patients with advanced disease, found that 32% of participants who interrupted treatment for two months before commencing a salvage regimen containing eight to ten drugs achieved viral suppression below 400 copies/ml after 24 weeks, compared with 12% who immediately switched from failing therapy to the mega-HAART combination. By week 48, the median CD4 cell count had increased by 69 cells/mm³ in the interruption group, but only 7 cells/mm³ in the immediate switch group.⁴

Based on these preliminary studies, researchers conducted several larger randomised trials of this strategy. In the Canadian CTN 164 study, participants with less advanced disease than those in GIGHAART switched to a new regimen consisting of three to five drugs either immediately or after a three-month treatment break. More than two-thirds in the immediate switch arm and 55% in the interruption arm maintained a viral load below 50 copies/ml for at least three months. After 15 months, the rate of viral suppression was similar, but people in the treatment interruption group had a smaller CD4 cell gain and experienced more AIDS-defining events.⁵

In the CPCRA 064 study, conducted by a US community-based clinical trials network, 274 people with advanced disease and multidrug-resistant HIV were randomly assigned to start a new optimised HAART regimen immediately or four months after a treatment break. During a median follow-up period of 37 months, there was no apparent virological or immunological benefit to treatment interruption. On the contrary, patients who took a break had lower CD4 cell counts and were more likely to experience HIV disease progression or death than those who switched immediately.⁶

The smaller REVERSE study was conducted by the same French research team as GIGHAART and also enrolled heavily treatment-experienced patients with advanced disease and low CD4 counts. But instead of a two-month interruption, participants stayed off therapy until resistance mutations to at least two classes of drugs had disappeared (a median of six months). About a quarter reverted to completely wild-type virus and regained susceptibility to several drugs. However, only one person experienced a viral load reduction of at least 1 log after commencing a salvage regime. By 24 weeks, all patients saw the return of the resistance mutations lost during the break. CD4 counts fell by 30 cells/mm³ during the interruption and by a further 27 cells/mm³ after restarting therapy, and two-thirds developed an AIDS-defining illness, all occurring after treatment resumed.⁷

Another small study randomly assigned 30 heavily pre-treated patients to start T-20 plus optimised background therapy immediately or after a four-month treatment break. After 24 weeks, 53% in the immediate therapy group and 36% in the interruption arm had a viral load below 75 copies/ml (a non-significant difference).⁸

A systematic review for the Cochrane Collaboration of studies published between January 1999 and February 2006 found that six of seven randomised controlled trials (the exception being GIGHAART) concluded that treatment interruption before starting a new antiretroviral regimen conferred no benefit in terms of viral suppression, and that treatment breaks were potentially harmful for patients with advanced HIV disease due to CD4 cell decline and an increased risk of clinical disease progression.⁹

Based on research to date, treatment interruption as a means of ‘resensitising’ HIV has fallen out of favour. Although the virus does often revert to drug-sensitive wild-type during a treatment break, this generally does not lead to improved outcomes. Rather, it can cause accelerated immune decline since non-mutated wild-type virus replicates and infects new CD4 cells more efficiently than drug-resistant strains. Further, since drug-resistant virus is not eradicated but rather stays hidden in cells, it can rebound quickly as soon as drugs are re-introduced.