Nevirapine-containing Regimens in Treatment-naïve HIV Patients with CD4 Cell Counts of 200 or Less

Following is the summary of a research letter published in AIDS (August 20, 2004) regarding the efficacy of nevirapine (Viramune)-based HAART regimens.

Introduction

In this retrospective analysis, Spanish researchers evaluated the effectiveness and safety of nevirapine-containing regimens in 118 treatment-naïve patients with < or = 200 cells/μl.

After 24 months, 51% of patients continued nevirapine, 43 and 83% had viral loads < 50 copies/ml by intent-to-treat and on-treatment analyses, and a mean increase of +246 CD4 cells/μl occurred.

More than 80% of patients who continued with nevirapine had viral loads < 50 copies/ml and CD4 cell counts < 200 cells/μl.

Protease inhibitor (PI)-containing regimens have contributed to a dramatic decrease in morbidity and mortality in HIV-infected patients in recent years. On the other hand, the complexity of most PI regimens and their toxicity, particularly in terms of metabolic alterations and lipodystrophy, limit their use in clinical practice.

Non-nucleoside reverse transcriptase inhibitors (NNRTI) have become an alternative to PI because of their potency, tolerability and convenience. However, few data are available on the efficacy of non-nucleoside reverse transcriptase inhibitors in highly immunosuppressed patients.

Data from a small cohort of patients with CD4 cell counts less than 100 cells/μl treated with efavirenz (Sustiva)--containing regimens have been published recently, and a good response was observed even in these patients.

Nevirapine associated with two nucleoside analogues (NUC) has demonstrated efficacy and was well tolerated in naive patients, but relatively few patients with low CD4 cell counts, or none at all were included in these recently published randomized trials.

In this study, data were collected from 118 consecutive HIV-infected naive patients with CD4 cell counts of 200 cells/μl or less who initiated NUC as their first antiretroviral regimen between 1998 and 2002 in six HIV Units with experience in managing this type of patient. Patients with at least one control visit were included consecutively in the study.

Patients were followed for up for 24 months, or the last visit before May 2003, or until nevirapine was discontinued, or they were lost to follow-up, or death. Virological efficacy (the proportion of patients with HIV-1-RNA loads < 50 copies/ml) was evaluated using intent to treat (ITT, switch nevirapine equals failure) and on-treatment analyses.

At baseline, 90 patients (76.3%) were young men, 58 (49.2%) had acquired HIV infection through intravenous drug use, 35 (29.7%) through heterosexual intercourse and 17 (14.4%) through man-to-man sex.

Chronic liver disease caused by hepatitis C virus (HCV) infection was present in 58 patients (49.2%), caused by hepatitis B virus infection in 11 (9.3%), and caused by alcohol in six (5.1%). Fifty-two patients (44.1%) had previous AIDS.

The most widely used NUC combinations were zidovudine/lamivudine (Retrovir/Epivir) in 55 cases (46.6%), and stavudine/didanosine (Zerit/Videx) in 35 cases (29.7%). The median HIV-1-RNA load was 80 030 copies/ml [interquartile range (IQR) 30 000-220 000] and CD4 cell count 105 cells/μl (IQR 43-153).

Forty-seven per cent of patients had fewer than 100 cells/μl, whereas 45% had over 100 000 copies/ml, and 20% had over 300 000 copies/ml. Eleven per cent of patients had a grade 1 increase in alanine aminotransferase (ALT) levels at baseline, and 1% had a grade 2 increase.

In the ITT analysis, 54% of patients had less than 50 copies/ml at 12 months and 43% at 24 months, whereas in the on-treatment analysis the corresponding figures were 77% and 83%, respectively.

No significant differences were observed in virological response when comparing patients according to baseline HIV-1-RNA levels (< 100 000 versus 100 000-300 000 versus > 300 000 copies/ml) or CD4 cell counts (< 50 versus > 50 cells/μl).

The number of CD4 cells increased by 156 and 235 at 12 and 24 months, respectively. After 24 months, CD4 cell counts were greater than 200 cells/μl in 83% of patients, and over 100 cells/μl in 98% of patients.

Only two patients developed a new AIDS-defining disease during the study period: one patient developed cytomegalovirus retinitis and vitritis (with 301 CD4 cells/μl) and one patient developed recurrent bacterial pneumonia (with 168 CD4 cells/μl), Patients presented with these diseases 6 and 9 months after starting therapy, respectively.

Seventy-nine out of 113 patients (70%) who completed 12 months of therapy continued with nevirapine, as well as 53 out of 103 patients (51.5%) who completed 24 months of therapy (five patients did not reach 12 months and 15 did not reach 24 months of follow-up).

After 24 months of follow-up, 50 patients discontinued nevirapine: 11 (10.7%) as a result of virological failure; 10 (9.7%) because of adverse effects; 23 (22.3%) because of poor adherence or because they were lost to follow-up; four (3.9%) as a result of death (not related to antiretroviral therapy); and two (2%) for other reasons.

With regard to toxicity, six patients (5.8%) discontinued nevirapine because of hepatotoxicity, three (2.9%) because of rash, and one (1%) because of the appearance of a poliarticular synovitis syndrome.

Of 116 patients in whom values were recorded at baseline, four (3.4%) presented with grade 3-4 toxicity during the study period (two had HCV infection and two had HCV plus hepatitis B virus infection): one out of 102 patients (1%) with normal baseline values and three out of 14 patients (21.4%) with baseline grade 1-2 toxicity (P = 0.005).

In this cohort, 83% of patients who continued with nevirapine and tolerated it after 24 months had HIV-1-RNA loads less than 50 copies/ml and CD4 cell counts greater than 200 cells/μl. The high proportion of patients who did not adhere to therapy or were lost to follow-up (> 20%) contributed to the relatively low efficacy rate shown by the ITT analysis after 24 months.

This highlights the importance, in the 'real world', of reinforcing adherence to therapy and attending clinic visits, even in patients receiving 'simple' regimens.

Although approximately 50% of patients initiated therapy with CD4 cell counts of less than 100 cells/μl, most who reached 24 months of follow-up had CD4 cell counts greater than 200 cells/μl and almost all had over 100 cells/μl, and were thus outside the 'risk zone' for opportunistic infections.

The mean CD4 cell count after 24 months was 342 cells/μl, and it is noteworthy that only two cases developed new AIDS complications during follow-up, despite the fact that approximately half of the patients had presented with AIDS-defining diseases before initiating antiretroviral therapy.

These results reinforce the clinical benefit of treatment. The immunological data reported are in line with those from studies using PI and efavirenz-containing regimens, and support previous data that showed that immune reconstitution was similar when comparing a nevirapine regimen with a PI regimen including nelfinavir (Viracept).

Importantly, in the present study, nevirapine regimens proved effective regardless of the baseline viral load or CD4 cell count.

The risk of adverse effects (including rash and liver toxicity) did not appear to be any higher than in less advanced patients. However, although few cases of severe ALT increase occurred, our data suggest that a baseline alteration in ALT may predispose to a higher risk of toxicity.

The authors conclude, “The main limitation of the present study is that it was a retrospective cohort observation with a relatively small number of patients.”

“However, given the paucity of data from prospective clinical trials, our findings may help physicians to manage patients in clinical practice, as they suggest that nevirapine regimens may play a role even in immunosuppressed HIV-infected naive patients who do not tolerate more complex or potent regimens.”

08/11/04

Reference
E Ferrer and others. Nevirapine-containing regimens in HIV-infected naive patients with CD4 cell counts of 200 cells/μl or less (Research Letter). AIDS 18(12): 1727-1729. August 20, 2004.