The Body Covers: The 6th Conference on Retroviruses and Opportunistic Infections
Abstract No. 636: The Long Term Response to Combination Therapy Commenced Early in HIV Infection: 3 Year Follow-Up: What's Happened Since Vancouver?
February 3, 1999
This paper is interesting because I think it is a definite rebuttal to those who have expressed real discouragement that triple therapy did not prove to be as effective as first thought. I think it always has to be kept in mind that what is now available is monumentally more successful than what was available before protease inhibitors continuing combination therapy. There was clearly an overreaction at the time to suggest that triple combination drugs including potent protease inhibitors would be a cure. Indeed, with these promises, that were clearly over the top, people became profoundly discouraged when there was virologic breakthrough. A more rational look at what has happened over the past several years suggests that there has been a very positive movement forward. While there is virologic failure, and sometimes clinical failure, many peoples lives have been improved dramatically because of HAART therapy. While the conclusion of this paper is that there is a complete suppression in 74% of subjects, I would comment that "only 74%" really begs the issue. While 74% success is not adequate and should not make us complacent, it is very encouraging to me that many patients have not only continued to tolerate these regimens but also continue to improve.Abstract: The Long Term Response to Combination Therapy Commenced Early in HIV Infection: 3 Year Follow-Up: What's Happened Since Vancouver?
The methodology of this paper is as follows. The patient population was 38 newly infected individuals recruited between 7/95 and 2/97. The criteria for entry was detectable HIV RNA with absent HIV specific immune response (N = 9), evolving immune response (N = 20), positive serology with a clinical history compatible with HIV infection within 90-days, and a documented negative serology within 120-days of screening (N = 9). Treatment regimens included: AZT/3TC plus ritonavir (N = 12), AZT/3TC/indinavir (N = 12), AZT/3TC/ritonavir/saquinavir (N = 14). Efficacy was evaluated by plasma HIV-RNA, by DNA and RT-PCR, measurements of CD4/CD8 cell subsets, quantitative culture for HIV-1, and lymphoid tissue biopsy for in situ studies.
The nominal baseline characteristics were as follows: There were 38 males, 36 of whom risks included sex with other males, there was one heterosexual, and one IVDU. Mean baseline characteristics: 33.8 years of age, HIV RNA 309, 832,000, CD4 cell count of 528 (with a range of 47 to 1,224), CD4/CD8 ratio of 0.75. Current status three years after recruitment: 24 patients remain on regimen, 3 are on alternative regimens on this study, 4 are off-drug and on this study, 7 are off-drug and off the study (3 of these last patients discontinued within 12 months of the start of the study, and three after 12 months). Discontinuations were for adverse events in 3 of the early patients, and 3 of the late patients, and virologic failure in 11 of late patients and none of the early patients. There was virologic response (undetectable HIV RNA) in 38 of 38 patients initially. The mean time to undetectable in weeks was about 4.5 by the B DNA method in 24 of the patients and 7.1 weeks by the Amplicor RT-PCR method (N = 14). In the as treated analysis (N = 27): complete suppression (CSN) - 20 (74%), partial suppression (PSN) 7 (26%). They then looked at complete suppression patients versus partial suppression patients as follows. In the CS patients, there was a mean CD4 increase of 266 cells, a mean CD4/CD8 ratio increase from 0.74 to 1.3, and a mean level of replication competent HIV 0.11 TCID/106 CD4 N=12. PS patients: mean CD4 increase 273 cells, mean CD4/CD8 ratio increase from 0.62 to 1.45, mean level of replication competent - 1.6 TCID106 CD4 N=4. Tonsilar lymph node biopsies were done in 9 of the CS patients, 2 of the PS patients, and 2 late withdrawals. Using in situ hybridization by specimens from 9 CS patients, 7 were with no detectable RNA, and 2 were uninterpretable due to mechanical damage; in 2 of the ... patients, one was without FTC culture associated virus and no RNA, one lymph node was interpretable due to artifact; of the 2 late withdrawal patients, two were positive for FTC associated virus and two were positive for HIV RNA. Of the late discontinuations, four individuals stopped therapy completely after intermittent therapy. One has maintained plasma HIV RNA levels between 50 and 500 after 20 months off-therapy. One has plasma HIV RNA as high as 2000 copies/mL and as low as 50 copies/mL after two years off-therapy. One rebounded slowly (four months), resumed therapy, stopped again, and rebounded immediately (weeks). One rebounded quickly after two attempts at discontinuation.
The authors conclusions were as follows. The commencement of antiretroviral therapy early in HIV infection: 1) results in durable suppression of detectable viremia in 53% NIs (intend to treat) [N=not infected], 2) in partially suppressed viremia in 18% of treated individuals (intend to treat), 3) in durable suppression of viremia in 74% of treated individuals as treated, 4) in partial suppression in 26% (as treated), 5) is associated with a 29% discontinuation rate, in large part due to ritonavir intolerance. Immunologic consequences of early therapy include a steady increase in mean CD4 cell count throughout the study, reversion of mean CD4/CD8 ratios to the normal range (greater than 1.0), and absence of HIV related clinical events during three years of therapy. Furthermore, the treatment of primary HIV infection despite the "optimal treatment setting" results in apparent complete suppression of viremia in only 74% of subjects (as treated), partial suppression (blips) did result in higher levels of residual infectious virus (latent pool). Intensification of regimen should be considered. However, tolerability is a key issue in light of the high rate of discontinuation.
The authors then posed the following question: Can residual infectious virus be immunologically controlled? Avenues for exploration with complete suppression of virus replication should include assessment of HIV specific responses (CTL). If absent, then vaccinate. If present, then consider drug discontinuation. If there is persistent virus replication, the authors pose drug intensification, or immune activation to reduce the size of the latent pool.
One of the concerns of this study is the number of patients who discontinued because of drug intolerance. In many patients this particular issue could be addressed with a cooperative approach between patient and physician, with the understanding at the outset that the regimen can be modified so it is tolerable to the patient. The variables would include: dosage scheduling, adverse events, side effects, and patient comfort with pill burden. Taking all these parameters into consideration carefully, I think, would result in a better outcome in a larger number of patients, as there would be a significant improvement in compliance, over a three year period.
Other implications include the need for continued investigation of once-daily agents, decreased pill burdens, and drugs designed with less and less adverse reactions.
In my opinion, this was a very positive outcome and is a cause for optimism.
Authored by: M. Markowitz, et al.
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