British HIV Association guidelines

CORRESPONDENCE

British HIV Association guidelines Sir—The updated British HIV Association (BHIVA) guidelines (July 25, p 314) for the management of HIV-1 infection recommend that nonnucleoside reverse-transcriptase inhibitors (NNRTI) based regimens should not be used in patients with baseline HIV-1 viral loads greater than 50 000 copies/mL.1 We believe that this threshold is not supported by the available evidence and over-represents the perceived superior potency of protease-inhibitor based regimens. The meta-analysis2 cited as a reference does not provide evidence to support this threshold for an NNRTI and two nucleoside combination. In addition, there is evidence 3 to indicate that NNRTIs are effective in patients with pretreatment viral loads in excess of this threshold. Rabond and colleagues’ metaanalysis2 incorporated two studies that compared the efficacy of a double nucleoside regimen against a two nucleosides plus an NNRTI (nevirapine) combination. Patients were stratified into three groups according to pretreatment viral load (baseline viral load <50 000, 50 000–250 000, and 250 000). Among patients taking zidovudine and zidovudine and didanosine dual therapy there was a significant trend for a decreasing proportion of patients to have a viral load below the detection level (400 copies/mL) at 48 weeks with increasing baseline viral load (p=0·02). The same analysis among patients taking triple therapy showed a similar trend, but it was not significant (p=0·16). A multivariate proportional hazards analysis indicated that patients with a viral load of greater than 250 000 copies/mL at baseline were 2·33 (95% CI 1·1–4·9) times as likely to have virological failure (viral load >5000 copies/mL) as patients with a viral load below 50 000 copies/mL at baseline, after adjustment for treatment, compliance, and viral-load nadir. The meta-analysis therefore indicates that the level at which patients should be considered for a more potent regimen than two nucleosides and an NNRTI might be more reasonably set at 250 000 copies/mL. A similar trend of high initial viral loads as predictors of treatment failure has been reported for other protease inhibitors. Interim 48-week data from the SPICE study 4 indicate that patients with baseline viral loads of greater than 63 000 copies/mL are

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more likely to achieve undetectable viral loads if treated with a four-drug, dual-protease inhibitor-based combination rather than conventional three-drug, single-protease inhibitorbased regimens. The BHIVA guidelines lead one to have greater hope in efavirenz in anticipation of widespread availability, but fail to mention the only multicentre review of clinical experience with NNRTI treatment in the UK. A retrospective audit 5 was carried out with data from six leading UK HIV-1 treatment centres of patients started on nevirapine containing triple therapy during the expanded access programme. No patient received concomitant protease inhibitors. Analysis showed that there was no relation between reaching undetectable viral load and baseline viral load for treatment-naïve patients. Until we have good comparative data of drugs within the same class as well as between classes, are we not vulnerable to the influence of fashion rather than evidence in our prescribing guidelines? *Phillip Hay, Zuber Mitchla Department of Genitourinary Medicine, St George’s Healthcare NHS Trust, St George’s Hospital, London SW17 0QT, UK (e-mail [email protected]) 1

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Gazzard B, Moyle G. 1998 revision to the British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. Lancet 1998; 352: 314–16. Raboud J, Montaner JSG, Rae S, et al. Patients with higher baseline pVL are less likely to have a virologic response in a meta-analysis of two trials of ZDV/ddI vs ZDV/ddI/NVP. 12th World AIDS Conference, Geneva, June 28–July 3, 1998: 12361 (abstr). Kaspar R, Werntz G, DuBois DB. Early results of combined stavudine, lamivudine, and nevirapine: a twice daily, well-tolerated protease inhibitor-sparing regimen for the treatment of HIV-1 infection. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, Feb 1–5, 1998: 696. Moyle G, on behalf of the SPICE study team. Study of protease inhibitor combination in Europe (SPICE) saquinavir soft gelatin capsule (SQV-SQC) plus nelfinavir (NFV) in HIV-infected individuals. 12th World AIDS Conference, Geneva, June 28–July 3, 1998: 1222 (abstr). Fisher M, Pozniak AL, Churchill DR, Williams IG, Hay P, Barton S. The efficacy and safety of nevirapine (NVP) in clinical practice: experience in over 500 patients in the UK. 12th World AIDS Conference, Geneva, June 28–July 3, 1998: 32248 (abstr).

Sir—We welcome the 1998 revision to the British HIV-1 Association (BHIVA) guidelines which recommends triple-drug regimens, and frequent plasma viral load (pVL)

monitoring as the standard of care for HIV-1 seropositive individuals. 1 However, the guidelines also recommend that patients with a pretreatment pVL of greater than 50 000 copies/mL should not be treated with nevirapine combination therapy, on the basis of our results reported in abstract form at the Geneva conference. 2 The cited analyses that compared rates of virological success (plasma viral load ⭐500 copies/mL) at 48 weeks of therapy among patients with baseline pVL below 50 000 copies/mL, 50 000–250 000 copies/mL, and above 250 000 copies/mL showed a trend towards decreasing success rates with higher baseline pVL. These results were not, however, significant. Our results, fully presented as a poster at the World AIDS Conference, showed that there was a significant effect of baseline pVL, when modelled as a continuous variable, on the length of time that pVL remained below 5000 copies/mL, but there was no clear cutoff in this analysis with regard to the level of baseline pVL beyond which nevirapine was no longer effective to reduce or maintain pVL at a low level. A similar relation has been established between the probability of virological success and baseline pVL in analyses of data from trials of protease inhibitor-containing tripledrug regimens, such as the AVANTI trials. 3,4 Again, the probability of virologic success at 48 weeks decreased by about 20% for patients with raised levels of baseline viral load. As with the nevirapine-containing regimens, the significance of pVL modelled as a continuous variable differed depending on the definition of duration of suppression and whether or not other covariates were adjusted for in the statistical model. Taken together, these analyses suggest that higher baseline pVL limits the durability of viral response to currently available triple-drug regimens. However, these results do not allow us to propose an upper limit of baseline pVL for the effective initiation of nevirapine or proteaseinhibitor-containing regimens. Our analyses suggest that this relation is a complex one that warrants further prospective investigation. An additional caveat related to our analyses pertains to their limited power and post-hoc, exploratory nature. These results should therefore be regarded only as hypothesis generating. Also, the BHIVA Guidelines Writing Committee suggests that efavirenz may be superior to current

THE LANCET • Vol 352 • October 10, 1998