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By the end of April 1999, 57 patients (51.4%) had developed AIDS, a Kaplan-Meier progression rate of 57.0% by 19.5 years after seroconversion (95% Cl 46.9%-67.0%, Figure 4.1), with a median time to AIDS diagnosis of 13.6 years. Eighteen patients (31.6% of those with AIDS) developed PCP as their initial AIDS-defining disease. Other common initial AlDS-defming events were oesophageal Candida (eight patients, 14.0%), lymphoma (five patients, 8.8%), HIV encephalopathy (four patients, 7.0%), cryptosporidiosis, cytomegalovirus (CMV) disease, toxoplasmosis, and mycobacterium infections (three patients each, 5.3%). The pattern of subsequent events was broadly similar, although mycobacterium infections (eight subsequent events) and CMV infections (seven subsequent events) were much more frequently observed as a subsequent condition, than as initial AIDS-defining events.

The rate of initial AlDS-defming diagnoses peaked in the period 1987-1988 (Table 6.1), with 1.03 events per 10 years of follow-up. The rate then dropped but remained relatively stable at between 0.47 and 0.77 events per 10 years of follow-up until the end o f 1996. Since then, only one patient has developed an initial AlDS-defming illness, giving a rate of 0.13 events per 10 person-years of follow-up in the period 1997-1999.

Survival

By the end of April 1999, 65 patients (58.6%) had died, a Kaplan-Meier progression rate of 65.1% by 19.5 years after seroconversion (95% Cl 52.7%-77.4%, Figure 6.1), with a median survival of 14.4 years. Death rates from 1987 onwards remained stable

at between 0.56 and 1.00 per 10 years of follow-up (Table 6.1). Noticeably, there has been no drop in death rates since 1997; indeed the death rate in the period

1997-1999 is the second highest over all follow-up periods.

Until 1995, almost all deaths were in individuals with an AIDS diagnosis (43 of 50 deaths, 86.0%). However, since 1995, this proportion has dropped - only 8 o f the 15 deaths occurring since 1995 (53.3%) have occurred in individuals who had a prior AIDS diagnosis. When we considered the actual cause of death in these individuals the difference was even more striking. Of the 50 deaths occurring prior to 1995, 35 (70.0%) were directly from AIDS causes, five (10.0%) were due to liver-related causes and ten (20.0%) due to other apparently unrelated causes. In contrast, of the 15 deaths occurring since 1995, only seven (46.7%) were directly from AIDS causes, five (33.3%) were from liver-related causes, and the remaining three (20.0%) were due to ‘unrelated’ causes (p-value for difference 0.09, Fisher’s exact test).

Treatment patterns

O f the 111 patients in the cohort, 80 (72.1%) are known to have received ART (Table 6.2). O f the 65 patients who have died, only 10 (15.4%) received dual combination therapy with NRTIs and five (7.7%) combination therapy including a PI or NNRTI, reflecting the lack of treatments available at the time when many of these patients died. The 35 patients who remain alive and who obtain their haemophilia/HIV care at the RFHHC have experienced a wide range of treatment regimens as ART availability has changed over time. Twenty-eight of these patients (80.0%) have received ART at some stage during infection. There were no significant differences between these 28 patients and the seven who have not received ART in terms of their current age, length of follow-up or previous AIDS diagnosis (Table 6.3). As expected, those who had received ART had a lower median CD4 count at the end of follow-up (p=0.006) and

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lower nadir count over follow-up (p=0.0002) than those who had not received ART. Whilst individuals who had received ART had higher peak RNA levels over follow-up than those who had not received ART (p=0.008), there were no significant differences between the most recent RNA levels in these two groups (p=0.83). Twenty- four of the 28 patients who have received ART (85.7%) are currently still receiving therapy; 15 are receiving treatment combinations with three or more drugs including a PI or NNRTI, two patients are receiving triple NRTI therapy, and seven are receiving dual nucleoside therapy.

Response to PI/NNRTI therapy

Twenty-two patients in the cohort are known to have received HA ART including at least one PI or NNRTI whilst under follow-up at the RFHHC (Table 6.2). Patients started HAART between November 1995 and March 1999. Eighteen patients received a Pl-containing combination (ritonavir-11 patients, saquinavir-10 patients, nelfinavir-5 patients, indinavir-2 patients) and four received an NNRTI-containing regimen (nevirapine-3 patients, loviride-1 patient). Seventeen patients were ART-experienced at the time of starting HAART. All of these patients had previously received zidovudine, other antiretroviral drugs previously received were lamivudine (12 patients), didanosine (ten patients), zalcitabine (ten patients) and stavudine (two patients). Twelve of these 17 patients added one or more drugs to an existing treatment regimen, four switched all of their existing drugs to drugs that they had never previously received and one switched all drugs but his new combination included a drug (zidovudine) to which he had been exposed for a period in the past.

Pre-treatment CD4 counts were generally low (median 100, range 0 to 330 cells/mm^) and RNA levels high (median 5.13, range 2.60 to 5.88 logio copies/ml). One patient had an RNA level below 400 copies/ml at the time of starting HAART.

Over a median of 464 (range 44 to 1248) days since starting HAART, eleven patients made changes to their initial HAART regimen by stopping, switching or intensifying their treatment. This first occurred after a median of 116 (range 7 to 504) days. In addition, three patients took a short treatment break before restarting the same HAART regimen. Four patients have died over follow-up; the causes of death in these four patients were cerebral haemorrhage, liver failure/hepatocellular carcinoma, PCP, and bronchopneumonia.

Eighteen patients had at least one RNA level (median 5, range 1 to 10) after starting HAART. RNA levels dropped by a median of 0.6 logio copies/ml in the first three months following initiation of HAART and continued to drop thereafter (Figure 6.2), although there was wide inter-individual variability in the response to HAART. Ten of these 18 patients achieved an RNA level below 400 copies/ml over follow-up, although in four cases this occurred after a switch from the initial HAART regimen. After censoring patients at the time of changing their HAART regimen, the Kaplan-Meier rate of having an RNA level below 400 copies/ml was 51.1% by two years after starting HAART. Nineteen patients had at least one CD4 count (median 5, range 1 to 20) after starting HAART. CD4 counts increased by a median of 95 cells/mm^ in the period 3-6 months after starting HAART (Figure 6.2) but this initial increase dropped to around 60 cells/mm^ by 10-12 months after starting HAART.

Clinical side effects of HAART

Eight of the 18 patients receiving Pis have had unusual bleeds. One patient stopped treatment totally, two switched to another PI and one switched to an NNRTI. In all cases, the bleeding improved following changes in treatment. The remaining four patients remained on the same treatment; in these patients the bleeding either improved spontaneously, or the patients took increased doses of factor VIII prophylaxis. One

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patient receiving a PI developed diabetes and abnormal lipid levels; an additional patient receiving a PI developed lipomas in both breasts.

Figure 6.1 : Kaplan-Meier plot showing progression to AIDS and death yearly after HIV seroconversion

Cumulative % 100 -, 80 -