I wanted to inquire about a situation involving a 43-year-old HIV-positive (first screening test in 1985) male coinfected with HCV who was on AZT monotherapy (250 mg twice a day) from 1987 to 1990. In 1990 he stopped therapy. On May 1997 he started AZT + 3TC + SQV (hard capsules / 600 mg x 3). From that time to the present time, viral load was always under detectable levels (<500 copies/mL or <50 copies/mL) and CD4+ ranging from 250 cells/mm3 to 350 cells/mm3.
In this situation, should I:
1) leave the patient on this treatment?
2) simplify the therapy (i.e.: Trizivir)?
3) boost the PI?
Dr. Brian Conway responds:
In 1996, the availability of highly active antiretroviral therapy (HAART) revolutionized the model of care for HIV infection. Indeed, it was hypothesized that the consistent use of such therapy could lead to a cure for this condition in as little as three years. Subsequent research has shown this model to be incorrect. In addition, long-term use of HAART has now been associated with significant metabolic abnormalities, which could lead to unintended morbidity. In some patients, this morbidity could be worse than what one could expect from the progression of HIV-associated immune disease itself over the same period of time. Accordingly, current recommendations for antiretroviral therapy have become more conservative. Indeed, it is now felt that an individual with CD4 counts above 350 cells/mm3 and plasma viral load measures below 30,000 copies/mL could safely delay initiation of HAART.
An additional issue with this patient is that he is receiving saquinavir as a single protease inhibitor (PI). The blood levels of this agent may be suboptimal to maintain virologic suppression, an issue that has often been addressed by adding low-dose ritonavir as an inhibitor of hepatic metabolism, allowing more therapeutic drug levels to be achieved. Recent data suggest that this could even be done once a day, with a drug dosage of saquinavir 1600 mg/ritonavir 200 mg. Significant gastrointestinal toxicity may result, however, as demonstrated in the FOCUS study, presented at the ICAAC conference last December.
The three options that you present for the approach to your patient can all be justified. A therapeutic interruption should only be considered if the CD4 cell count nadir was no lower than 300 cells/mm3. As his count is, even now, as low as 250 cells/mm3 on therapy, it would be difficult to defend this option.
Simplification to Trizivir is an interesting possibility, and such an approach has been shown to be effective in maintaining virologic suppression while avoiding the risk of some of the long-term toxicities of the protease inhibitors. This was addressed by Martinez et al at the recent Conference on Retroviruses and Opportunistic Infections (abstract LB17) in a presentation entitled "Switching Protease Inhibitors to Nevirapine (NEV), Efavirenz (EFA) or Abacavir (ABA): A Randomized, Multicenter, Open-Label, Simplification Trial". Adult patients on at least one PI plus two Nucleoside analogues (NRTIs) with plasma viral load measures below 200 copies/mL for at least 6 months were randomly assigned to switch from the PI component to either NEV, EFA, or ABA. The primary end-point was the proportion of patients remaining below 200 copies/mL after 12 months of follow-up. A total of 460 patients were evaluable. At 12 months, 74 (78%) remained suppressed based on an intent-to-treat (ITT) analysis, with no differences between the groups. A significantly lower proportion of patients discontinued the study medication due to adverse events in the ABA arm (6%), as compared to the other two arms of the study (16-17%). The proportion of patients with elevated cholesterol levels at the end of the study was significantly lower in the ABA arm (9%) as compared to the other two arms (22-24%, P=0.01). If you choose to modify the regimen to Trizivir, these data can reassure you that your approach is justified. In addition, if virologic breakthrough was to occur on Trizivir, the PIs would remain an option for use in future regimens, as the viral load was consistently undetectable while on saquinavir, making the possibility of drug resistance unlikely.
Intensifying the regimen with ritonavir (or changing to anther protease inhibitor, such as Kaletra) would also be an option. The regimen would have a higher pill count than could be achieved by changing to Trizivir, and the possibility of long-term PI-associated toxicities would remain. The likelihood of maintaining virologic suppression in this setting is quite high.
I hope this information is helpful in your ongoing discussions with your patient.
