Seven month treatment break completely reverses multi-drug resistant HIV

Drug resistance may be dramatically reversed during some treatment interruptions, according to a case report published in the October 2002 edition of the Journal of Acquired Immune Deficiency Syndromes.

Doctors in Germany report the case of a 42 year old gay man who had been diagnosed with HIV in 1992. Starting in 1994 the man received sequential monotherapy with AZT, ddI and d4T, followed by various combinations involving between two and four drugs, including a protease inhibitor. Due to diarrhoea and headache the man decided to stop anti-HIV therapy, taking a treatment break for seven months, during which time his side-effects disappeared but his CD4 count fell from 120 cells/mm³ to 10 cells mm³. The man restarted therapy with ddI, abacavir, nevirapine, soft-gel saquinavir and ritonavir, which suppressed his viral load to below 50 copies/mL for the next 41 months (except for two blips), with the CD4 count increasing to a maximum of 359 cells/mm³ and remaining above 200 cells/mm³ until the man took another treatment break in November 2001.

Phenotypic testing at the time of the first treatment break indicated that the man had high levels of resistance to the NRTIs AZT, ddC, ddI, d4T, 3TC and abacavir, and resistance to the protease inhibitors indinavir, saquinavir, ritonavir and nelfinavir. Within two months of starting his first treatment break protease inhibitor resistant virus had markedly reduced, and was nearly absent after five months, being no longer detectable at seven months. NRTI resistance also largely disappeared, with only low levels of resistance to AZT and abacavir detectable after the seven month treatment interruption. However, although the patient had never been treated with NNRTIs, low level resistance emerged to drugs in this class during the treatment break.

Investigators found no evidence for the persistence of protease inhibitor resistant virus after the reinitiation of treatment, even though protease inhibitors were part of the treatment regimen. Analysis of nucleic acid sequences showed that the dominant HIV population after the treatment interruption had evolved from less resistant virus present before the seven month treatment break. This was confirmed by infection of a wild-type HIV cell with a viral clone harbouring the drug mutations associated with resistance to both protease inhibitors and NRTIs.

The researchers suggest that “the gain in viral fitness during treatment interruption can be…attributed to the loss of drug resistance-associated mutations in the protease and RT.” They note the successful reinitiation of therapy in the man using several drugs recycled from previous regimens noting that “this may indicate that drugs can successfully be recycled after treatment interruption. Therefore temporary interruptions of HAART with careful monitoring of drug resistance may be a valuable therapeutic option in patients harbouring multi-drug resistant HIV.”