A fixed-dose combination of stavudine, lamivudine, and nevirapine is very widely used as first-line antiretroviral therapy in many resource-limited countries. A study presented at the 44th annual meeting of the Infectious Diseases Society of America (IDSA) has shown that second-line treatment options are limited for many people in these settings for whom this treatment combination fails. More treatment options, especially abacavir (Ziagen)and tenofovir (Viread), will be needed for effective second-line treatment strategies in these countries.
A single-pill, fixed-dose combination (FDC) of stavudine (d4T), lamivudine (3TC), and nevirapine (Viramune) is produced much more cheaply than the equivalent patented versions of the component drugs. In Thailand and other developing countries, this FDC (marketed as GPO-vir) is used as the standard first-line antiretroviral treatment for HIV. The Thai Ministry of Public Health distributes GPO-vir to an estimated 60,000 people. However, strategies for effective second-line therapies need to be developed before treatment failure occurs on a large scale.
At the 44th IDSA meeting on Friday October 13th, the authors of this study presented an investigation of drug resistance patterns after treatment failure on this combination. In the developing world, individual genotypic resistance testing is usually unavailable due to cost. However, since first-line treatment is so uniform across the population, the investigators aimed to analyse resistance in a sample population, then extrapolate the results to anticipate probable needs for large-scale treatment strategies.
The researchers enrolled 98 study participants from three Thai hospitals. All had previously achieved undetectable viral load within four to six months of starting GPO-vir therapy, then rebounded to a detectable viral load. None had had any treatment interruptions longer than two weeks, and had taken no antiretrovirals other than d4T, 3TC and nevirapine. The average age was about 35 years, average CD4 cell counts were 159 cells/mm3, and 63% of the participants were male. They had been on therapy an average of 19 months.
The Trugene genotypic assay was used to identify drug resistance mutations. These were extremely frequent, with nucleoside (NRTI) mutations seen in 96% of the group, and non-nucleoside (NNRTI) mutations in 95%. Detailed analyses were done of specific site mutations (e.g., M184, which confers resistance to 3TC, was seen in 92% of the subjects).
There are limited second-line treatment options in Thailand. Abacavir is not currently affordable and tenofovir is not available.
The researchers concluded that “in the resource-limited settings where antiretroviral agents are limited, prevention strategies for HIV resistance are crucial.” Since “the options for the second regimen are limited in half of these patients”, “a priority for the national plan is to make tenofovir and abacavir accessible.” They also affirmed that resistance assays are an important tool, the availability of which needs to be scaled up along with pharmacological treatment.
Reference:
Sungkanuparph S et al. Options for the second antiretroviral regimen for HIV-infected patients failing an initial regimen of fixed-dose combination of stavudine, lamivudine and nevirapine. 44th Annual Meeting of the Infectious Diseases Society of America, Toronto, abstract 692, 2006.