Findings on viral rebound discourage quick drug switches in resource-limited settings

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A South African study found that viral resuppression occurred in 41% of people who continued taking the same antiretroviral drug regimen after experiencing a viral load increase on treatment.

The retrospective cohort analysis, reported in the December 15th edition of Clinical Infectious Disease, also documented the accumulation of resistance mutations over time. Nucleoside reverse transcriptase inhibitor (NRTI) cross-resistance emerged relatively slowly in a subset of study participants who underwent multiple rounds of resistance testing.

Both findings are notable because they argue against quickly changing the antiretroviral regimens of people who do not appear to be maintaining a good response to treatment.

Glossary

viraemia

The presence of virus in the blood.

 

first-line therapy

The regimen used when starting treatment for the first time.

ribonucleic acid (RNA)

The chemical structure that carries genetic instructions for protein synthesis. Although DNA is the primary genetic material of cells, RNA is the genetic material for some viruses like HIV.

 

resistance testing

Laboratory testing to determine if an individual’s HIV strain is resistant to anti-HIV drugs. 

treatment failure

Inability of a medical therapy to achieve the desired results. 

In high-income countries, viral load monitoring is a standard component of the clinical management of HIV. Since temporary viral load increases are known to occur in people who have responded well to antiretroviral treatment, a single test result may not clearly indicate whether someone is experiencing a so-called 'viral blip' or treatment failure. It is thus advisable to look instead at trends over time when making treatment decisions.

Many developing-world antiretroviral treatment programmes either cannot provide viral load testing to patients or can only do so infrequently. The global HIV treatment scale-up has been accompanied by a great deal of debate about how to make informed decisions regarding when to start or switch treatment in the absence of adequate viral load information.

New WHO treatment guidelines recommend that if possible, viral load should be used to determine whether patients are failing treatment. The guidelines recommend a treatment switch in the event of a viral load above 5000 copies/ml.

The South African study examined trends in a cohort of 3727 HIV-positive adults who initiated antiretroviral therapy with AZT (zidovudine, Retrovir), 3TC (lamivudine, Epivir) and either efavirenz (Sustiva, Stocrin) or nevirapine (Viramune). The cohort, comprised largely of miners enrolled in a workplace HIV programme, was 93% male.

Eligibility for antiretroviral therapy was determined using modified World Health Organization (WHO) criteria: CD4 cell count <250 cells/mm3, WHO stage 3 disease with CD4 cell count <350 cells/mm3, or WHO stage 4 disease. The median CD4 cell count at the initiation of therapy was 147 cells/mm3 (interquartile range [IQR], 80–216 cells/mm3).

Study participants were followed for a median of 17.4 months (IQR, 6.0–31 months). While 92% of study participants had >1 log10 HIV viral load decrease, 29% of those people subsequently developed HIV viraemia, defined in the study as “HIV RNA >1000 copies/mL while on first-line therapy after an initial drop >1 log10 copies/mL from the [pre-treatment] level.”

Follow-up laboratory results were available for 815 members of the group with viraemia (81%). Viral resuppression, defined as HIV RNA supression to <400 copies/mL while continuing to receive the same first-line antiretroviral regimen after one HIV RNA assay that demonstrated viraemia, was observed in 331 (41%) of the group with viraemia.

Among all study participants with HIV viraemia, 321 people met WHO criteria for treatment failure on the basis of low or declining CD4 cell counts. Viral resuppression took place during the continuation of the first-line antiretroviral regimen in 111 of those people (34%).

In other words, about one-third of people who were experiencing treatment failure by WHO standards did not actually need to change to another regimen in order to bring viraemia under control.

Similar findings by other researchers have raised concerns that CD4 cell count-guided management of HIV treatment might result in unnecessary switches to more expensive second-line regimens. Besides adding to the cost of treatment programs, switching early also reduces a person’s remaining treatment options.

Individuals with a higher pre-treatment CD4 count were significantly more likely to resuppress viral load, but the likelihood per 50 cell increase was very modest (OR 1.1, 95% CI 1.0 - 1.2, p=0.01). There was a trend towards greater likelihood of viral resuppression in people with lower baseline viral load, but this declined in significance in multivariate analysis.

There was also evidence from a small subset of patients who underwent viral genotyping for drug resistance that a lack of resistance at the time of first viral rebound was associated with subsequent resuppression of viral load, but half of the patient who resuppressed viral load already had at least one NNRTI resistance mutation.

Since this was an observational cohort study, the authors are unable to report on any standard protocol for addressing adherence difficulties or the effect of any adherence intervention on the likelihood of viral resuppression.

Resistance

Genotyping was used to test for resistance-conferring mutations in 90 of the people who had developed viremia. Among the 68 who underwent resistance testing at the time their viremia was detected, 42 (62%) had non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations and 25 (37%) had the NRTI mutation M184V/I. Multi-NRTI mutations were only found in four people (6%).

Multiple rounds of resistance findings were analysed in a subgroup of 30 people who met the following two criteria: they had stayed on first-line therapy following the emergence of viraemia, and they had undergone at least one round of resistance testing twelve months or longer from when viraemia was first detected.

Twelve months after the detection of viraemia, 11 of 14 people (78%) who had been tested by that time had NNRTI mutations. Eight people (57%) had the M184V/I mutation.

Only two (14%) had thymidine analogue mutations (TAMs), which arise in response to the NRTIs AZT and d4T (stavudine, Zerit). The finding is significant because TAMs can confer cross-resistance to most NRTIs, including those often recommended for use in second-line antiretroviral regimens.

“In [antiretroviral] programs with access to intermittent HIV RNA assays and limited treatment options, our results support added emphasis on adherence when viremia is identified, followed by regimen switch only if viremia persists for 3-6 months,” the researchers conclude.

In their view, such a strategy “helps to avoid potentially premature switches to costlier and less tolerable regimens while minimizing the risk of the emergence of high-level cross-resistance.”

References

Hoffmann CJ et al. Viremia, resuppression, and time to resistance in human immunodeficiency virus (HIV) subtype C during first-line antiretroviral therapy in South Africa. Clin Infect Dis 49: 1928–1935, 2009.