Cluster of multi-drug resistant HIV transmissions in Seattle

Investigators in Seattle have reported a cluster of nine HIV infections involving resistance to multiple drugs from all the three main classes of antiretrovirals. The report is published in the October 1^st edition of the Journal of Acquired Immune Deficiency Syndromes.

Seven of the nine men were newly diagnosed with HIV, the other two men had chronic HIV infection and were receiving antiretroviral therapy. One of these cases appears to involve superinfection during antiretroviral therapy that had been suppressing viral load to undetectable levels.

All nine cases involved gay men with high risk sexual activity. None of the men experienced rapid HIV disease progression and one patient initiated a carefully selected antiretroviral regimen that suppressed his viral load to undetectable levels. Nevertheless, the investigators note that the strain of drug-resistant HIV infecting the men was very “fit” and highly transmissible.

About 10% of new HIV infections in the US involve primary drug resistance. This is associated with a poorer outcome, including a faster decline in CD4 cell count. It is recommended that all HIV-positive individuals have a resistance test at the time of their diagnosis and when starting HIV treatment, or when changing therapy because of an increase in viral load.

Drug-resistant HIV is generally less “fit” and less likely to be transmitted than drug-susceptible virus. If, however, drug-resistant virus is transmitted and a cluster of linked infections is identified, it suggests that this stain of the virus has a high level of infectivity.

When a cluster of new HIV infections with drug resistance is spotted it is important to try and identify the transmission chain and to observe the outcome of patients to inform the development of public health measures and treatment strategies.

Since 2003 the US Centers for Disease Control and Prevention and the department of Public Health – Seattle and King County has been performing resistance tests on all treatment-naïve HIV-positive individuals since 2003. Healthcare providers are also encouraged to notify health authorities to report cases of primary multi-drug resistant HIV.

In 2006, health officials in Seattle became aware of two cases of primary multi-drug resistant HIV infection in patients who had never taken antiretroviral therapy. By the end of 2007 a further five cases had been reported in treatment-naïve patients and two cases in patients taking antiretroviral therapy. All the cases had similar resistance profiles, and in eight cases the pattern of resistance was confirmed by genotypic resistance testing.

All seven of the treatment-naïve patients had high-level resistance to all protease inhibitors with the exception of darunavir and tipranavir. These seven individuals also had high level resistance to the NNRTIs efavirenz and nevirapine and intermediate resistance to the new NNRTI, etravirine. Surprisingly the patients were fully susceptible only to 3TC and FTC in the nucleoside analogue class, despite the fact that this is one of the most common drug resistance mutations.

Two of the cases involved patients with chronic HIV infection who were taking antiretroviral therapy. The first patient was diagnosed with HIV in the mid 1980s and had taken drugs from all the three main classes of antiretrovirals, but never achieved an undetectable viral load. The second case involved an individual infected with HIV in the early 1990s.

Standard antiretroviral therapy consisting of two NRTIs and an NNRTI had maintained an undetectable viral load in this patient for over a decade. However, in early 2007 his viral load increased to over 20,000 copies/ml, prompting resistance testing which identified a resistance pattern similar to that seen in the cluster. This may represent a case of superinfection during effective HIV therapy, although the investigators do not explore this.

The seven cases of primary multi-drug resistance were diagnosed between late 2005 and late 2007. All these seven patients, as well as the two treatment-experienced patients, were gay men aged in their 20s – 40s. They all reported the use of methamphetamine and sex with multiple, mostly anonymous partners. Many of the men also reported the use of other recreational drugs as well as treatments for erectile dysfunction. At the time of HIV infection, many of the men were also infected with a bacterial sexually transmitted infection.

At the time of writing, only one of the treatment-naïve patients required antiretroviral therapy after the fall in his CD4 cell count to below 300 cells/mm³. A regimen of FTC, tenofovir, darunavir/ritonavir and raltegravir achieved and maintained an undetectable viral load as well as an increase in the patient's CD4 cell count of over 200 cells/mm³.

The treatment-experienced patient who had previously had an undetectable viral load, however, failed to achieve this outcome after his diagnosis with multi-drug resistant HIV, despite a modification of his regimen. His CD4 cell count remained above 500 cells/mm³.

“We observed a cluster of multi-drug resistant HIV transmitted for more than a 2-year period, but not associated with rapid clinical or laboratory decline”, write the investigators. They add, “methamphetamine and erectile dysfunction drug use among members of this cluster may provide targets for surveillance, intervention activities, and research to asses the impact of use of these agents on the risk of infection with drug-resistant HIV and their relation to clinical outcomes.”