In the Journals

Patients who fail modern HIV regimens show high prevalence of older mutations

Patients in sub-Saharan Africa who failed first-line tenofovir-containing ART regimens had high rates of resistance to thymidine analogues — an older generation of HIV drugs — according to a retrospective cohort study published in Lancet Infectious Diseases.

Roughly 16% of patients in the study who failed treatment with tenofovir-based first-line ART were found to have thymidine analogue mutations (TAMs) that were specifically selected by Retrovir (zidovudine, ViiV Healthcare) or Zerit (stavudine, Bristol-Myers Squibb), researchers reported.

“We were very surprised to see that so many people were resistant to both drugs, as we didn’t think this was possible,” Ravindra K. Gupta, PhD, MPH, professor in the division of infection and immunity at University College London, said in a press release. “Mutations for thymidine analogue resistance were previously thought to be incompatible with mutations for tenofovir resistance, but we now see that HIV can be resistant to both at once. This emphasizes the need to check the genetic profile of a patient’s virus before prescribing first-line treatments, as they may have already developed resistance to other treatments that they did not mention having taken.”

Gupta and colleagues analyzed 712 patients who were included in the TenoRes collaboration, a multicountry retrospective study examining drug resistance following failure of tenofovir-containing ART, with baseline measurements taken from 2005 to 2013. All patients experienced virologic failure on tenofovir-based first-line therapy plus a cytosine analogue (lamivudine or Emtriva [emtricitabine, Gilead Sciences]) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) — either nevirapine or Sustiva (efavirenz, Bristol-Myers Squibb).

Among the 712 patients, Gupta and colleagues found that 115 (16%) had at least one TAM. Compared with patients without TAMs, patients with the mutations were more likely to have tenofovir resistance (81% vs. 59%; P < .0001), NNRTI resistance (93% vs. 77%; P < .0001) and cytosine analogue resistance (87% vs. 63%; P < .0002).

Patients with TAMs had lower CD4 counts at treatment initiation (60.5 cells per μL [IQR, 21-128]) than did patients without TAMs (95 cells per μL [IQR, 37-177]).

The correlation between the study-level proportion of patients with tenofovir resistance and TAMS was 0.64 (P < .0001), according to the researchers, and the OR for tenofovir resistance comparing patients with and without TAMs was 1.29 (95% CI, 1.13-1.47; P < .0001).

The researchers hypothesized that most TAMs among patients with tenofovir resistance were caused by previous undisclosed ART use with undocumented virologic failure and drug resistance.

“To prevent these multi-resistant strains from developing, we need cheap, reliable systems to assess people before treatment,” Gupta said. “Ideally, we need simple resistance testing kits to help screen for drug resistance before giving treatment. This would also help us to monitor HIV drug resistance globally more effectively. However, until such kits are widely available, we could test the amount of virus in the bloodstream before and after giving treatment. Although not as precise as resistance testing, this could help us to detect treatment failure earlier and switch patients to second-line drugs.”

In a related editorial, Josep M. Llibre, MD, with the HIV unit at the University Hospital Germans Trias i Pujol in Spain, noted that, while resistance testing and viral load measurements are important, these strategies are insufficient to combat the spread of drug resistance in sub-Saharan Africa. Llibre argued that Tivicay (dolutegravir, ViiV Healthcare) should be considered as an alternative to efavirenz, due, in part, to its high barrier against the development of resistance in initial therapy.

“While stakeholders are escalating the implementation of human and infrastructure networks in sub-Saharan Africa, a straightforward and cost-effective measure to limit new HIV-1 resistance would be to scale up the substitution of efavirenz for generic dolutegravir in initial ART,” he concluded. – by Sarah Kennedy

Disclosures: The researchers report no relevant financial disclosures. Llibre reports funding from Gilead Sciences, Janssen-Cilag, Merck and ViiV Healthcare.

Patients in sub-Saharan Africa who failed first-line tenofovir-containing ART regimens had high rates of resistance to thymidine analogues — an older generation of HIV drugs — according to a retrospective cohort study published in Lancet Infectious Diseases.

Roughly 16% of patients in the study who failed treatment with tenofovir-based first-line ART were found to have thymidine analogue mutations (TAMs) that were specifically selected by Retrovir (zidovudine, ViiV Healthcare) or Zerit (stavudine, Bristol-Myers Squibb), researchers reported.

“We were very surprised to see that so many people were resistant to both drugs, as we didn’t think this was possible,” Ravindra K. Gupta, PhD, MPH, professor in the division of infection and immunity at University College London, said in a press release. “Mutations for thymidine analogue resistance were previously thought to be incompatible with mutations for tenofovir resistance, but we now see that HIV can be resistant to both at once. This emphasizes the need to check the genetic profile of a patient’s virus before prescribing first-line treatments, as they may have already developed resistance to other treatments that they did not mention having taken.”

Gupta and colleagues analyzed 712 patients who were included in the TenoRes collaboration, a multicountry retrospective study examining drug resistance following failure of tenofovir-containing ART, with baseline measurements taken from 2005 to 2013. All patients experienced virologic failure on tenofovir-based first-line therapy plus a cytosine analogue (lamivudine or Emtriva [emtricitabine, Gilead Sciences]) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) — either nevirapine or Sustiva (efavirenz, Bristol-Myers Squibb).

Among the 712 patients, Gupta and colleagues found that 115 (16%) had at least one TAM. Compared with patients without TAMs, patients with the mutations were more likely to have tenofovir resistance (81% vs. 59%; P < .0001), NNRTI resistance (93% vs. 77%; P < .0001) and cytosine analogue resistance (87% vs. 63%; P < .0002).

Patients with TAMs had lower CD4 counts at treatment initiation (60.5 cells per μL [IQR, 21-128]) than did patients without TAMs (95 cells per μL [IQR, 37-177]).

The correlation between the study-level proportion of patients with tenofovir resistance and TAMS was 0.64 (P < .0001), according to the researchers, and the OR for tenofovir resistance comparing patients with and without TAMs was 1.29 (95% CI, 1.13-1.47; P < .0001).

The researchers hypothesized that most TAMs among patients with tenofovir resistance were caused by previous undisclosed ART use with undocumented virologic failure and drug resistance.

“To prevent these multi-resistant strains from developing, we need cheap, reliable systems to assess people before treatment,” Gupta said. “Ideally, we need simple resistance testing kits to help screen for drug resistance before giving treatment. This would also help us to monitor HIV drug resistance globally more effectively. However, until such kits are widely available, we could test the amount of virus in the bloodstream before and after giving treatment. Although not as precise as resistance testing, this could help us to detect treatment failure earlier and switch patients to second-line drugs.”

In a related editorial, Josep M. Llibre, MD, with the HIV unit at the University Hospital Germans Trias i Pujol in Spain, noted that, while resistance testing and viral load measurements are important, these strategies are insufficient to combat the spread of drug resistance in sub-Saharan Africa. Llibre argued that Tivicay (dolutegravir, ViiV Healthcare) should be considered as an alternative to efavirenz, due, in part, to its high barrier against the development of resistance in initial therapy.

“While stakeholders are escalating the implementation of human and infrastructure networks in sub-Saharan Africa, a straightforward and cost-effective measure to limit new HIV-1 resistance would be to scale up the substitution of efavirenz for generic dolutegravir in initial ART,” he concluded. – by Sarah Kennedy

Disclosures: The researchers report no relevant financial disclosures. Llibre reports funding from Gilead Sciences, Janssen-Cilag, Merck and ViiV Healthcare.