At the closing date of 31 December 1998, median duration of follow-up was 24 months (range, 5–28 months). Three patients died during follow-up, one from progressive pulmonary KS after 6 months on HAART despite major therapy with ABV, and two from unrelated causes (ongoing cardiac failure and biopsy-proven lymphoma diagnosed during the fourth month on HAART) after 5 and 15 months on HAART, respectively. Of these two, one was rated as partial response and the other as stabilized. One patient was lost to follow-up after 12 months.
Response of HIV infection to HAART
CD4 cell counts increased significantly from 85 ± 110 × 106/l at inclusion to 198 ± 156 × 106/l, 258 ± 203 × 106/l, 298 ± 263 × 106/l and 316 ± 296 × 106/l at months 6, 12, 18 and 24, respectively (P < 0.0001). The percentage of patients with plasma HIV-RNA < 500 copies/ml was 43%, 49%, 46%, and 44% at months 6, 12, 18, and 24, respectively. Only three new AIDS-defining events occurred during the study. Only one patient had long-lasting therapy with foscarnet initiated during follow-up. At month 12, HAART had been modified in 15 patients for persistently elevated plasma HIV RNA. Those modifications induced no sustained effect on plasma HIV-RNA, expect in one patient. CD4 cell counts improved markedly in three of these patients. PI was replaced because of intolerance in five additional patients.
Outcome of KS
Progressive improvement in KS was observed (Table 3), with complete response or partial response in 49%, 74%, 77%, and 74% of patients at months 6, 12, 18, and 24, respectively. No new pulmonary KS developed. At month 24, the 29 responding patients (complete response + partial response), when compared with non-responding patients, had significantly higher CD4 cell counts (360 ± 300 versus 113 ± 185 copies/ml;P < 0.05), greater increases in ΔCD40−−24 (270 ± 265 versus 26 ± 54 × 106/l;P < 10−4), and HIV-1 RNA plasma levels more frequently < 500 copies/ml (57% versus 0%;P < 0.05). At month 24, the 18 patients achieving complete response had significantly higher CD4 cell counts (465 ± 343 versus 185 ± 167 × 106/l;P < 0.01) and ΔCD40−−24 (386 ± 295 versus 85 ± 89 × 106/l;P < 0.0001) than patients with partial response, stabilization or progression, but the proportions of patients with HIV-1 RNA < 500 copies/ml did not differ significantly between the two groups.
No recurrence of KS was observed during subsequent follow-up once complete response had been achieved. Only five of the 30 patients rated as showing partial response at any time-point during follow-up were later rated as progressive. When rated as progressive all of these patients had plasma HIV-1 RNA > 2 × 104 copies/ml; three of them had CD4 cell counts < 10 × 106/l, and two > 200 copies/ml. A final rating of complete response, partial response or stabilization, respectively, was made in five, nine, and one of the 20 patients rated progressive at any time-point.
The effect of HAART itself on KS outcome (without the confounding factor of systemic KS therapy) was assessed in the 19 patients without any systemic KS treatment at inclusion (Table 4). Five had T1 KS, and 14 T0 KS. Complete response or partial response was achieved in 64%, 69%, 79%, and 74% of included patients at months 6, 12, 18, and 24, respectively. A progressive increase in complete response rate was observed, with 11%, 32%, 42%, and 58% of included patients achieving complete response at the same respective time-points. Systemic KS treatment was introduced in only four patients with progressive KS during follow-up. All complete response and all but one partial response were achieved without the introduction of any new local or general KS treatment.
Most of the 20 patients (13 with T1 KS, and seven with T0 KS) on minor (n = 13) or major (n = 7) chemotherapy at inclusion experienced improvement of KS, with 35%, 70%, 75%, and 75% achieving complete response or partial response at months 6, 12, 18, and 24, respectively. Complete response rate progressively increased, with 0%, 15%, 30%, and 35% of patients achieving complete response at the same respective time-points. All patients with complete response and five out of eight patients with partial response had no general KS treatment at month 24. Response of KS to HAART was also assessed by a progressive tapering of KS treatment (Table 2). Minor chemotherapy was, however, upgraded to major in four and two patients at months 6 and 12, respectively.
Progress was initially mainly favourable in the eight patients with pulmonary KS receiving HAART and (in all but one patient) cytotoxic chemotherapy, with one progressive and seven partial responders at month 12. Some of these partial responders later relapsed, and complete response, partial response, stabilization and progression were observed at month 24 in two, two, none and three patients, respectively. Three of the four pulmonary KS patients who responded were no longer receiving chemotherapy at month 24.
Predictors of complete response at month 24
Logistic regression revealed only two factors predictive of achieving complete response at month 24: ΔCD40−−12 > 150 × 106/l (OR, 13.4; 95% CI, 2–82) and T0 of TIS classification at inclusion: (OR, 7; 95% CI, 1.1–42). No interaction was found between these factors. ΔCD40−−12 > 150 × 106/l was still a predictor when logistic regression was performed only on patients receiving systemic chemotherapy at inclusion.
This prospective series of AIDS–KS patients treated with HAART – to the best of our knowledge the largest ever published – clearly demonstrated that KS responded to HAART in most patients. Unlike systemic treatments of KS , HAART resulted in complete response in 46% of the patients. Predictors of complete response after 2 years on HAART were: T0 KS at inclusion and CD4 cell count increase > 150 × 106/l in the first year on HAART.
Our results agree with those of previous smaller cohorts of AIDS–KS patients treated with HAART. Among the 41 patients included in the four published series that included more than eight patients [7,9–11], 32%, 37%, 17% and 12% achieved complete response, partial response, stabilization, and progression, respectively. We also confirm, with a larger number of patients, that systemic therapies of KS can be interrupted in responding patients , even in those with pulmonary KS, where median survival after diagnosis was 4–10 months before the era of HAART.
Our study yields further information. Response to therapy was slow but long-standing. No recurrence was observed after complete response had been obtained. Once partial response had been achieved, KS recurred in only 20% of patients. Because nearly half of our patients were not receiving any systemic KS treatment, we were able to show that HAART itself can induce complete response in > 50% of patients. Logistic regression identified two predictors of complete response after 2 years on HAART. Although our study included only 39 patients, the OR was high for both predictors, which may be useful in daily clinical practice. Some predictors of poor prognosis in KS patients pre-dating the era of HAART, such as low CD4 cell count at inclusion  and failure of previous systemic KS treatment, had no prognostic value in our series. Because few enrolled patients were naive to previous antiretroviral treatment, we were unable to demonstrate any predictive value for KS response of this parameter, which usually predicts better efficacy of HAART on the inhibition of HIV replication.
Because only three out of 39 patients received long-term ganciclovir or foscarnet, we believe that these drugs, which inhibit HHV-8 DNA synthesis in in vitro systems of lytic infection , did not explain our results. Moreover, in vivo, they did not affect the HHV-8 DNA load within the leukocytes in two independent studies [19,20] and, in vitro, did not inhibit episomal HHV-8 DNA synthesis. Consequently, no benefit can be expected from such drugs during latency or in KS . We did not investigate HHV-8 DNA in the leukocytes of our patients with HAART because its predictive value was uncertain when we planned our study. It has been reported positive in only half of untreated KS patients , with unexplained fluctuations over time. Some [7,9], but not all , small series of KS patients treated with HAART have later suggested that response of KS may be associated with a reversal in HHV-8 viraemia.
We have designed our cohort study to lessen the usual flaws of such a design. All patients entered the cohort when they first received HAART. To avoid bias due to referral patterns, we entered eligible patients from all major hospitals caring for HIV-infected patients within the West Metropolitan Paris area. It is likely that almost all KS patients from these hospitals who initiated HAART during the study period entered the cohort because HAART was at that time delivered only by hospital pharmacists and with the written permission of the CISIH 92 members. Follow-up was complete for all but one patient and validated criteria for response assessments were used. All previously established prognostic factors of KS were taken into account in the statistical analysis. However, our conclusions do not emanate from a carefully designed placebo-controlled randomized study. Thus, proof of efficacy of HAART on KS has not been formally obtained, and probably never will be: performing such studies is not ethical because of the obvious benefits of HAART for other manifestations of HIV infection.
Several factors may explain improvement in KS during HAART. Direct action of PI on HHV-8 replication seems unlikely . The reduction in HIV Tat production due to impaired HIV replication with HAART is probably not the main mechanism involved. Tat stimulates the growth and invasion of spindle cells derived from KS lesions . The percentages of patients with HIV-1 RNA levels < 500 copies/ml did not differ significantly between patients achieving complete response and others. We feel that our results are explained largely by the recovery of the immune system during HAART, a continuous, at best partial, process which continues long after inhibition of HIV replication has been achieved . The early first-phase cellular restoration appears to be primarily a redistribution of cells originally present in lymphoid tissues. The second-phase increase seems to reflect maturation of newly generated T cells, as evidenced by diversification of the CD4 cell repertoire: it is characterized by a shallower increase in circulating naive CD4 and CD8 cells and a decrease in circulating memory CD8 cells . The slow improvement in KS during HAART temporarily paralleled the immune restoration, and when HAART substantially raised CD4 counts within the first year, this was predictive of later complete response. Such a threshold effect in the restoration of CD4 counts suggests that control of KS is linked to immune restoration to a level at which it is able to control HHV-8 infection. This is a reminder of what is observed in transplanted patients, in whom KS frequently disappears on reduction of immunosuppressive treatments .
In patients with AIDS–KS, the efficacy of HAART on KS surpassed that obtained previously with systemic KS treatments. Our study has important practical implications for clinicians. To avoid delaying the restoration of immune system with cytotoxic chemotherapy, we suggest avoiding its use unless required by aggressive forms of KS. Instead, conservative strategies (local treatments, well-tolerated systemic therapies such as oral all-trans-retinoic acid , or even camouflage) should be encouraged until KS responds to HAART, and patients should be reassured using our predictors of response. On the other hand, clinicians should now be highly cautious when analysing therapeutic trials of KS treatments. The quality of the antiretroviral treatments used may be a major confounding factor. Further work is requested, such as study of newer antiretroviral strategies with combinations of nucleoside analogues and non-nucleoside inhibitors of HIV-reverse transcriptase.
The authors thank C. Michon, (CISIH 92 medical co-ordinator, Hôpital L Mourier, Colombes) for evaluating the patients included in the trial. We also thank D. Marsh for editing our English.
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Keywords:© 2000 Lippincott Williams & Wilkins, Inc.
Kaposi's sarcoma; HIV-protease inhibitors; cohort study