Ask the Experts - Stop Therapy in Patient Who Started 'Too Early'?
Ask the Experts - Stop Therapy in Patient Who Started 'Too Early'?
A 40-year-old man with asymptomatic HIV infection had started zidovudine, lamivudine, and abacavir at a time when his CD4+ cell count was 548 cells/mm and his plasma HIV-1 RNA level was 9974 copies/mL. He discontinued the regimen within 2 weeks due to lack of perceived benefit and concern over long-term toxicities, and remained off medications for 9 months. At this time, his CD4+ cell count was 365 cells/mm and his viral load was 672 copies/mL, and his physician prescribed didanosine (buffered tablets), lamivudine, and efavirenz. Within 2 months his viral load decreased to less than 50 copies/mL and his CD4+ cell count increased to 502 cells/mm.He presented to me for a second opinion on whether he needed therapy at all at his stage of illness. Should I recommend continuation of this effective HAART regimen? Would stopping the regimen predictably result in a decline of his CD4+ cell count to levels even lower than pretreatment? How would stopping therapy affect the development of resistance?
This is a very interesting question, prompted in large measure by the recent changes in the Department of Health and Human Services (DHHS) guidelines on the use of antiretroviral agents in HIV-infected adults and adolescents, which now suggest that the CD4+ cell count may be a better benchmark for when to start antiretroviral therapy than the plasma HIV-1 RNA level. This change is based on results of several cohort studies, presented at the 8th Conference on Retroviruses and Opportunistic Infections, that showed a significantly greater likelihood of progression to AIDS among patients who first started HAART when their CD4+ cell count was less than 200 cells/mm, but no significant difference in the risk of progression for those who started with CD4+ cell counts greater than 350 or greater than 200 cells/mm. The guidelines specifically state that this change in when to start therapy does not mean that patients who are receiving successful therapy should now stop therapy just because, in retrospect, one might have chosen to wait longer.The patient in question presents a somewhat unusual case; that is, upon initial presentation he had a high CD4+ cell count (> 500 cells/mm) and a low viral load (< 10,000 copies/mL). However, after stopping his initial treatment regimen his viral load remained low, whereas his CD4+ cell count fell to 365 cells/mm. In my opinion, and in line with current guidelines, I would favor continuing therapy in this patient because his last off-treatment CD4+ cell count was close to the threshold now recommended by the DHHS guidelines, for which there is good support from cohort studies. It is important to note that most of these studies had follow-up of less than 2 years, so that differences in rates of progression between patients who started therapy at CD4+ cell counts between 200 and 350 cells/mm vs those who started therapy with CD4+ cell counts greater than 350 cells/mm might not have had time to emerge.With regard to the question about resistance, stopping therapy completely most likely would result in no drug resistance. However, there are reports of patients developing nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance after receiving single-dose nevirapine for prevention of mother-to-child HIV transmission. Presumably the long half-life of the NNRTIs results in a period of exposure to sub-inhibitory drug concentrations that allow for emergence of these mutants.
A 40-year-old man with asymptomatic HIV infection had started zidovudine, lamivudine, and abacavir at a time when his CD4+ cell count was 548 cells/mm and his plasma HIV-1 RNA level was 9974 copies/mL. He discontinued the regimen within 2 weeks due to lack of perceived benefit and concern over long-term toxicities, and remained off medications for 9 months. At this time, his CD4+ cell count was 365 cells/mm and his viral load was 672 copies/mL, and his physician prescribed didanosine (buffered tablets), lamivudine, and efavirenz. Within 2 months his viral load decreased to less than 50 copies/mL and his CD4+ cell count increased to 502 cells/mm.He presented to me for a second opinion on whether he needed therapy at all at his stage of illness. Should I recommend continuation of this effective HAART regimen? Would stopping the regimen predictably result in a decline of his CD4+ cell count to levels even lower than pretreatment? How would stopping therapy affect the development of resistance?
This is a very interesting question, prompted in large measure by the recent changes in the Department of Health and Human Services (DHHS) guidelines on the use of antiretroviral agents in HIV-infected adults and adolescents, which now suggest that the CD4+ cell count may be a better benchmark for when to start antiretroviral therapy than the plasma HIV-1 RNA level. This change is based on results of several cohort studies, presented at the 8th Conference on Retroviruses and Opportunistic Infections, that showed a significantly greater likelihood of progression to AIDS among patients who first started HAART when their CD4+ cell count was less than 200 cells/mm, but no significant difference in the risk of progression for those who started with CD4+ cell counts greater than 350 or greater than 200 cells/mm. The guidelines specifically state that this change in when to start therapy does not mean that patients who are receiving successful therapy should now stop therapy just because, in retrospect, one might have chosen to wait longer.The patient in question presents a somewhat unusual case; that is, upon initial presentation he had a high CD4+ cell count (> 500 cells/mm) and a low viral load (< 10,000 copies/mL). However, after stopping his initial treatment regimen his viral load remained low, whereas his CD4+ cell count fell to 365 cells/mm. In my opinion, and in line with current guidelines, I would favor continuing therapy in this patient because his last off-treatment CD4+ cell count was close to the threshold now recommended by the DHHS guidelines, for which there is good support from cohort studies. It is important to note that most of these studies had follow-up of less than 2 years, so that differences in rates of progression between patients who started therapy at CD4+ cell counts between 200 and 350 cells/mm vs those who started therapy with CD4+ cell counts greater than 350 cells/mm might not have had time to emerge.With regard to the question about resistance, stopping therapy completely most likely would result in no drug resistance. However, there are reports of patients developing nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance after receiving single-dose nevirapine for prevention of mother-to-child HIV transmission. Presumably the long half-life of the NNRTIs results in a period of exposure to sub-inhibitory drug concentrations that allow for emergence of these mutants.
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