Lowering dose of d4T can maintain efficacy and reduce side effects
6 September 2004. Related: Conference reports, Antiretrovirals, World AIDS 15 Bangkok 2004.
Simon Collins, HIV i-Base
As ARV programmes slowly increase access to treatment in resource-poor countries, it is important not to repeat the same mistakes made in patient management in the West.
Prolonged use of d4T, in particular, left many patients with permanent and debilitating peripheral neuropathy or substantial lipoatrophy. The incidence of both these side effects is higher when treatment is started in more advanced disease, and this is often the case in access programmes.
Earlier this year, in reports from the 11th Retrovirus conference (CROI), we detailed several studies showing that the incidence of these side effects is similar to that seen in the West. More importantly several studies showed that using a lower dose of d4T provided similar efficacy and reduced toxicity. [1]
Several further studies at Bangkok provided further data on this approach.
In a retrospective analysis, Haslinger and colleagues from University Hospital of Duesseldorf, looked for CNS effect and side effects in 627 patients treated with different d4T doses in combination with another NRTI (3TC, TNF, ddI) plus either an NNRTI or protease inhibitor (PI) for CNS. [2]
444 HIV-1-positive patients treated with 80 mg d4T/day and 89 individuals treated with 60 mg/day were compared for CD4+-cell counts, plasma viral load (VL), nerve conduction velocity (NCV), amplitudes of peroneal and surale nerve action potentials (EMAP and SNAP) and motor speed – contraction time (CT) as well as reaction time (RT) – as parameters for brain affection with respect to effectivity (at least stable reaction and contraction times) and side effects (NCV, EMAP, SNAP) over a period of 6 months.
Other causes for peripheral nerve disease were excluded, before including data in the study.
Over six months there was no statistically significant difference between the high and the low dose group with respect to CD4+-cell count and motor speed parameters. Polyneuropathy was rarer in patients receiving 60 mg/day. Although viral load was significantly lower in patients receiving 80 mg/day this could be due to the other antiretroviral drugs applied in combination with d4T in these patients.
Siangphoe and colleagues presented 96-week results from a Thai study comparing half-dose to full dose d4T. [3] This study was started in February 2000 when dual-nucleoside therapy was the most advanced treatment available. The second RTI was ddI. A third comparitor arm used AZT+ddI. Doses of d4T and ddI were adjusted by weight in people who weighed <60kg. Median body weight was 54.4 kgs.
Multivariate logistic regression showed the likelihood of VL <500 c/ml was significantly greater in both d4T groups compared to the AZT group; if baseline VL <10,000 c/ml; and baseline CD4 200 – 350 vs <200 /mm3. There was no significant difference between groups d4T half dose vs full dose.
Serious lactic acidosis was found in 3 patients in the full dose d4T group.
Although dual-therapy would not be recommended now, the use of more potent triple combinations that would improve response rate are likely to further reduce the importance of the d4T contribution to the regimen.
Table 1
| Half dose d4T+ddI (d4T 30 or 40 mg/d) |
Full dose d4T+ddI (d4T 60 or 80 mg/d) |
AZT+ddI | |
|---|---|---|---|
| N | 109 | 110 | 108 |
| B/line CD4 | 290 | 282 | 240 |
| range | (202.5 – 355) | (177.5 – 378.5) | (151 – 361.3) |
| B/line VL | 4.2 (3.8 – 4.5) | 4.3 (3.7 – 4.6) | 4.3 (3.9 – 4.6) |
| CDC stage C | 4.6% | 4.5% | 14.8% |
| Week 96 results | |||
| pts VL <500 | 33% | 47.3%* | 9.3% |
| pts VL <50 | 5.5% | 12.7% | 2.8 % |
| CD4 change | 131* | 126* | 0 |
| range | (30 – 253) | (20.5 – 260.3) | (-37.5 – 95) |
*group 1 or 2 vs 3, p < 0.01
References:
- Treatment with generics: tolerability, safety and resistance. HIV Treatment Bulletin, Vol 5 No 3, April 2004
http://www.i-base.info/htb/2781 - Haslinger BA, Arendt G – Optimal d4T-therapy in HIV-1-positive patients from a neurological point of view – lower dose, less side effects, equal effectivity? XV Intl AIDS Conference, Bangkok. Abstract WePeB5924.
http://www.ias.se/ejias/show.asp?abstract_id=2175492 - Siangphoe S, Srikaew S, Waiwaravuth C et al. Efficacy and safety of half dose compared to full dose stavudine (d4T) and Zidovudine (AZT) in combination with didanosine (ddI) in Thai HIV-infected patients: 96 weeks results of ACTT002/ARV065 study. XV Intl AIDS Conference, Bangkok. Abstract WePeB5952.
http://www.ias.se/ejias/show.asp?abstract_id=2168822