Impact of genetics on effectiveness of HIV treatment

Despite the various examples of links between particular genetic polymorphisms and drug levels, few of these translate into expected treatment outcomes. Similar studies have often reached different or opposite conclusions regarding the links between genetic variation and the ARV therapy outcomes, casting doubt on their validity and eventual applicability in the clinic.

For example, observations of increased efavirenz (Sustiva) levels in patients with the G516T polymorphism in numerous studies have not been mirrored uniformly by increased effectiveness or side-effects. One study failed to find a link between the polymorphism and the risk of virological failure, although it has been associated with the rate of decay of efavirenz levels after discontinuation of the drug.1 Since it has a long half-life in the body, stopping an HIV treatment containing efavirenz can be risky, since the patient may have drug concentrations in the blood for many days after the other drugs in the regimen have been cleared, exposing the patient to effective monotherapy with efavirenz.

There is also considerable disagreement over the role of C3435T in the multidrug resistance-1 (MDR-1) gene. Despite the evidence linking the polymorphism to reduced levels of efavirenz, some studies have linked this polymorphism to better virological outcomes and a decreased risk of efavirenz resistance and virological failure.2 1 In contrast, others have found no clear link between the polymorphism and CD4 T-cell recovery, but they did find an increased risk of virological failure.3 4 5

This polymorphism is also linked to elevated nelfinavir levels within cells. While some studies have linked the same polymorphism to improved CD4 cell count recovery, others have failed to find such a relationship.6 7 Similarly, Haas and colleagues found that this polymorphism was not linked to changes in the risk of virological failure.1

Other polymorphisms have been linked to responses to antiretroviral therapy independently of drug levels. For example, the –C889T polymorphism in the promoter region of the gene for interleukin-1 alpha has been associated with the control of HIV replication, but not CD4 T-cell response.8 This polymorphism has not been linked to drug levels in any published studies. Similarly, a polymorphism in the gene for the chemokine receptor CX3CR1 has been linked to earlier immunological failure, independently of all other risk factors.3

Other studies have found associations between genetic variation in genes for chemokine receptors and CD4 cell counts and viral loads in patients taking antiretroviral therapy.9 However, the validity of these associations will require further research.

References

  1. Haas D et al. Pharmacogenetics of long-term responses to antiretroviral regimens containing efavirenz and / or nelfinavir: an Adult AIDS Clinical Trials Group study. J Infect Dis 192: 1931-1942, 2005
  2. Saitoh A et al. An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children. AIDS 19: 371-380, 2005
  3. Brumme Z et al. Influence of polymorphisms within the CXCR1 and MDR-1 genes on initial antiretroviral therapy response. AIDS 17: 201-208, 2003
  4. Nasi M et al. MDR1 C3435T genetic polymorphism does not influence the response to antiretroviral therapy in drug-naive HIV-positive patients. AIDS 17: 1696-1698, 2003
  5. Winzer R et al. No influence of the P-glycoprotein polymorphisms MDR1 G2677T/A and C3435T on the virological and immunological response in treatment naive HIV-positive patients. Ann Clin Microbiol Antimicrob 4: 3-7, 2005
  6. Fellay J et al. Response to antiretroviral treatment in HIV-1 infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 359: 30-36, 2002
  7. Zhu D et al. Influence of single-nucleotide polymorphisms in the multidrug resistance-1 gene on the cellular export of nelfinavir and its clinical implication for highly active antiretroviral therapy. Antivir Ther 9: 929-935, 2004
  8. Price P et al. Alleles of the gene encoding IL-1alpha may predict control of plasma viraemia in HIV-1 patients on highly active antiretroviral therapy. AIDS 18: 1495-1501, 2004
  9. Coll B et al. Influence of a monocyte chemoattractant protein 1 mutated allele on the response to protease inhibitor-based antiretroviral therapy. HIV Med 7: 356-360, 2006
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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