Persistent effect of d4T and 3TC, but not NNRTIs in the presence of associated genotypic mutations

1 September 2003. Related: Conference reports, Drug resistance, Intl Drug Resistance Workshop 12 Mexico 2003.

Simon Collins and Steve Taylor, HIV i-Base

At the 2003 Retrovirus Conference, a late breaker by Steven Deeks showed that some of his patients failing on PI+two nukes regimens who discontinued the PI component showed little consequent effect on CD4, viral load or development of resistance over the subsequent year.[1] In contrast, those that discontinued their nukes experienced disease progression and higher viral rebound. These were preliminary and observational results but they generated a lot of interest.

Two abstracts at the resistance meeting looked at the effect of subtractive therapy with different drugs.

Residual activity of d4T but not NNRTIs

Use of increased numbers of drugs (5-9) in salvage regimens has often shown greater viral suppression than four-drug regimens, although this benefit comes from accurately targeted activity. Identifying agents without activity that could be reduced from these combinations would obviously help with reducing side effects.

Maldarelli and colleagues reported on five patients on multidrug salvage therapy with viral load >5000 copies/ml who interrupted either d4T for 14 days (n=3) or efavirenz for 21 days (n=2) following an initial 10-day sampling period. Results were presented from frequent viral load and composite genotype resistance tests during the interruption period. [2]

Viral load did not increase for the two patients who interrupted efavirenz – indicating no residual activity of this drug in plasma as would be expected from the K103N and Y188L genotypes present at baseline.

Interruption of d4T however leads to immediate increases in viral load, that were still increasing when d4T was restarted. Restarting d4T returned viral load to baseline. Despite multiple d4T-associated mutations at baseline (M41L, D67N, V118I, L210W, T215Y) d4T was still providing antiviral activity.

Similar results from withdrawing NNRTI treatment once genotypic mutations have been detected was presented in results from the French ANRS 107 Puzzle2 study, by Piketty and colleagues at the IAS conference. [3]

Including 3TC and maintaining M184V to reduce viral fitness

Limited evidence of reduced viral fitness generated by M184V mutation has been sufficient for many clinicians to continue to include 3TC in second-line and salvage regimens in order to maintain this mutation. Although the risk/benefit of this strategy in unclear it is certainly helped, and probably only possible, because of the low toxicity associated with 3TC.

Some support was given to this approach by Campbell and colleagues from the University of Colorado, although the approach and rationale to this study may not have been in their patients’ best interest.[4]

Four patients taking AZT, 3TC and a PI with detectable viral load (range 4.26-5.53 log) discontinued 3TC and were followed for 20 weeks (n=3) and 24 weeks (n=1).

Within 12 weeks of withdrawal of 3TC, all patients’ HIV RNA increased by >0.5 log copies/ml above baseline but there were differences in other details of the pattern of response between patients. Interruption of 3TC was associated with increased susceptibility to 3TC (>34-fold above baseline but also decreased susceptibility to AZT (9- and 10-fold). Viral replicative capacity increased from 1.2 – 2.7-fold. This occurred at the same time as return to 184M in one patient, prior to 184M in two patients and one patient continued to maintain 184V even in the absence of 3TC.

Although 184V returned again when 3TC was reinitiated, viral load did not return to baseline for two of these patients. Of concern is the additional protease mutations and reduced susceptibility that occurred in two patients while discontinuing 3TC.

Comment

Residual HIV activity despite partial resistance is the reason for higher rates of success with multi-drug rescue therapy using regimens with five to nine drugs. Accurately identifying drugs with activity in an individual patient remains a challenge.

One caution against interrupting drugs based on this approach is that resistance profiles in plasma and sanctuary compartment have frequently been shown to differ and lack of viral benefit in plasma viral load does not discount activity in CNS, genital tract or other compartments. Awareness of continued nucleoside activity despite resistance mutations is important in this setting.

References:

Unless stated otherwise, references refer to the XII International HIV Drug Resistance Workshop, Los Cabos, Mexico, 10-14 June 2003; published as part of Antiviral Therapy Volume 8 Issue 3.

1. Deeks S – When to switch antiretroviral therapy. 10th Conference on Retrovirus and opportunistic Infections. Abstract 188.
2. Maldarelli F et al – Short duration, single drug discontinuation to assess the activity of individual drugs in patients failing antiretroviral therapy. Abstract 133.
3. Piketty C et al – Virological and immunological impact of NNRTI withdrawal in patients with multiple treatment failures: a sub-study of Puzzle 2 – ANRS 107. 2nd IAS Conference, Paris. 13-16 July 2003. Abstract 544.
4. Campbell TB et al – Antiviral activity of lamivudine in persons infected with 140 HIV-1 that has M184V and multiple thymidine analogue mutations. Abstract 140.