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HATIPHIV AIDS Treatment in Practice |
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| #107 :: 30 April 2008 | Forward to a colleagueHATIP archive | |||||||||||||||
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Clinical monitoring as effective as CD4 count and viral load for deciding when to switch to second-line ART in poor countries
By Keith Alcorn Modelling study suggests 60% alive after 20 years with access to one second-line regimenSwitching to second-line antiretroviral treatment when HIV-positive patients in resource-limited settings develop new symptoms would be almost as effective in prolonging survival as using CD4 cell counts or viral load test results, according to a mathematical modelling study published last week in The Lancet.
The results diverge from those of the Home Based AIDS Care (HBAC) study in Uganda, which found that individuals who received clinical monitoring alone had a higher risk of new AIDS-defining events or death than patients who received CD4 cell count monitoring in a randomised study. In an accompanying editorial David Moore of the British Columbia Centre for Excellence in HIV/AIDS and Jonathan Mermin, one of the principal researchers on the HBAC study, note that more research is needed to determine when laboratory monitoring would be most useful. The issue of laboratory monitoring and when to switch treatment in resource-limited settings was extensively reviewed in HIV AIDS Treatment and Practice last year. Laboratory monitoring of antiretroviral treatment In an ideal world, all patients receiving antiretroviral therapy (ART) would undergo regular viral load testing in order to detect viral load rebound above 50 copies/ml, the current limit of detection of tests in common use. However, viral load testing is expensive and requires a dedicated laboratory with highly trained staff. Outside national reference laboratories and universities few countries in sub-Saharan Africa and Asia can provide viral load testing for people on ART. CD4 counts may be easier to measure, and World Health Organization (WHO) guidelines suggest that a CD4 count decline of 50% from the previous peak, or a one-third decline in the previous six months, should be considered a trigger for changing treatment. But even CD4 counts are out of reach for many clinics, and until cheaper point of care tests for viral load and CD4 cells become available, clinical symptoms are the only indicator available in many resource-limited settings for determining when to change to second-line treatment. Some clinicians and policy makers have misgivings about expanding access to antiretroviral treatment without these laboratory tests, fearing that patients will develop drug resistance due to prolonged periods of viral replication after a rebound occurs. This could lead to transmission of drug-resistant virus and a poor response to second-line therapy in a context where only a limited number of drugs are available for second-line treatment. Researchers at the Royal Free and University College Medical School in London, the London School of Hygiene, the University of Copenhagen and the World Health Organization developed a mathematical model based on data from simulated patients in order to examine the long-term consequences of different types of treatment monitoring. At the outset it was assumed that 58% of patients were women, the average age was 30, the median CD4 count 66 cells/mm3, the median viral load 5.4log10 copies/ml (250,000 copies/ml), 32% had a previous history of TB and all had previously been diagnosed with a WHO stage 4 illness (AIDS). Thirteen per cent had previously used single-dose nevirapine for prevention of mother to child transmission. These assumptions were based on data from existing cohorts. After the patients started treatment, progression to second-line treatment was then governed by the interplay between baseline viral load, adherence and the number of active drugs in the regimen. The model also incorporated the increased risk of non-HIV related mortality in resource-limited settings. These factors in the model were programmed based on data from resource-limited settings, derived from meta-analyses of treatment outcomes and adherence in sub-Saharan Africa, Brazil and South-East Asia. Treatment monitoring was carried out every six months in this model, and patients were switched if:
Virological failure (viral load above 500 copies/ml) was detected in 16% of patients after year 1, 28% by year 5, 37% by year 10 and 51% by year 20. Eighty-seven per cent of these virological failures would have been detected at year 1 if a viral load threshold of 10,000 copies/ml were used, but only 32% if a new WHO stage 3 or 4 event were used as the trigger for switching. A CD4 cell decline was even less reliable – only 25% of virological failures would have manifested a 33% decline in CD4 cell count in the previous six months.
A similar pattern held true at years 2, 3, 4 and 5. However, when survival rather than detection of treatment failure was used as the outcome by which the success of the monitoring strategy was measured, there was no difference between any of the monitoring strategies. Rather than calculating the proportion of patients alive at specific points, the researchers expressed the outcomes in terms of the percentage of life years out of a possible 20 years that persons could live.
*Three different measures were compared – only at year 20 was substantial variance observed. Resistance risk with different switching strategies The relatively high rates of survival in the clinical symptoms switch group appear to have come about despite very high projected rates of resistance – and a lack of third-line treatment. Patients took a first-line regimen of d4T/3TC/nevirapine and then switched to lopinavir/ritonavir plus AZT/ddI. Eight-three per cent of those who switched at a viral load of 500 copies/ml were projected to have nevirapine resistance and 26% had at least one d4T or AZT-associated (thymidine analogue) resistance mutation. In those who switched due to clinical symptoms (grade 3 and 4 WHO symptoms), 48% had three or more thymidine analogue mutations. But the number of active drugs available for the second-line regimen was only modestly lower for those who switched according to clinical criteria when compared to switching with a viral load above 500 copies/ml - 2.37 active drugs versus 2.71 active drugs. This was despite the fact that those who switched due to clinical criteria had spent an average of four years on a failing regimen. Survival outcomes did not differ greatly when tenofovir was used in first-line therapy instead of d4T. The authors note that second-line regimens that do not contain AZT (using abacavir or tenofovir instead) might have greater activity in the presence of thymidine analogue mutations, and so would be expected to do somewhat better. However they warn that since most data on drug resistance have been gathered in populations infected with HIV-1 subtype B, more data are needed on resistance patterns and responses to second-line therapy in populations where other subtypes - particularly C, D, E and the recombinant forms - predominate. However, when the risk of resistance according to life years lived with the mutation was analysed, there was little difference between the strategies. But when the researchers calculated the proportion of life years lived with a resistance mutation at a viral load above 1000 copies/ml – the level at which people are likely to be capable of transmitting that drug-resistant virus to others – the switch threshold of viral load above 500 copies/ml showed a substantially lower potential risk than others for onward transmission. Cost-effectiveness Clinical monitoring was much more cost-effective than viral load monitoring, by a magnitude of four to tenfold. The cost per life year gained of clinical monitoring, using the occurrence of a new WHO stage 4 event or multiple stage 3 events, was $927. The cost of viral load monitoring was $1500 and $4011 per lif year gained for a switch threshold of 500 copies/ml and 10,000 copies/ml respectively. The authors conclude: "In summary, our results suggest that use of ARV therapy without monitoring of viral load or CD4 cell count does not have marked detrimental effects on patient survival or on development of resistance. This finding is particularly relevant in view of the limited array of anti-retroviral combinations available to the developing world. Access to ART should be expanded to all settings as rapidly as possible; lack of access to laboratory monitoring should not be allowed to hinder this process." Reference Phillips AN et al. Outcomes from monitoring of patients on antiretroviral therapy in resource-limited settings with viral load, CD4 cell count, or clinical observation alone: a computer simulation model. The Lancet 371: 1443-1451, 2008. |
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News headlines
Recent news headlinesDeal lowers price of second-line therapy and makes new paediatric formulations available to poorer countriesFurther reductions in the prices of generic versions of key second-line antiretroviral drugs were announced yesterday, thanks to an agreement negotiated by the international drug purchase fund UNITAID and the Clinton HIV/AIDS Initiative with Indian and Chinese generic drug manufacturers. Africa: Epidemic outpacing response says UNAIDSIn less than two months, government officials and AIDS activists from around the world will convene in New York to review the global HIV/AIDS response. National progress reports, submitted earlier this year, will be compared to targets adopted by the United Nations General Assembly Special Session on HIV/AIDS (UNGASS) in 2001. Higher CD4 cell counts associated with lower rate of non-HIV-related diseases in patients taking antiretroviralsHigher CD4 cell counts in patients taking antiretroviral therapy are associated not only with a lower rate of HIV-related illnesses, but a lower rate of serious illnesses such as heart, kidney, and liver disease as well as some cancers, according to a US study published in the April 23rd edition of AIDS. Tenofovir shows excellent promise as a treatment for hepatitis B monoinfectionTenofovir (Viread) is an effective and safe treatment for chronic hepatitis B virus monoinfection, according to two studies due to be presented to 43rd Annual Meeting of the European Association for the study of the Liver in Milan on April 25th. Pharmacokinetics of paediatric Triomune fixed-dose formulations appear appropriate in African childrenA pharmacokinetic study has found that the fixed-dose combinations (FDCs) of nevirapine, stavudine and lamivudine specifically formulated for children (Triomune Baby and Triomune Junior generally appear to provide appropriate antiretroviral doses for children weighing 6 kg and over, mostly overcoming the deficiencies in nevirapine dosing previously seen with paediatric FDCs. Data were insufficient to draw conclusions for children under 6 kg. The results were reported in AIDS. BHIVA: No clinical difference seen in first-line treatment response between B and non-B subtypesAntiretroviral therapy (ART) naive individuals with non B HIV-1 subtypes commencing treatment for the first time are suppressing viral load as quickly as individuals with subtype B, according to data derived from the UK HIV Drug Resistance Database presented to the Fourteenth Annual Conference of the British HIV Association (BHIVA) taking place in Belfast this week. New drug users less likely to share needles, have HIV, in Russian studyA significant decline in risky injecting practices and a decline in HIV prevalence in new drug injectors was seen in a Russian city severely affected by HIV between 2001 and 2004, despite the lack of needle and syringe exchange, researchers from the London School of Hygiene report in the April 15th edition of the Journal of Acquired Immune Deficiency Syndromes. Breath test could monitor adherence to treatment, potential use for DOTS and clinical trialsIt may soon be possible to monitor adherence to antiretroviral therapy or tuberculosis treatment using a simple breath test which has been developed by researchers at the University of Florida and Xhale Inc. It is hoped that the device could be particularly useful in clinical trial settings, and it could also have potential to act as an adjunct or replacement to directly observed therapy, a cornerstone of tuberculosis treatment programmes in many settings. Daily micronutrients of some benefit for HIV-positive patients receiving TB treatmentA simple micronutrient tablet reduced the rate of tuberculosis relapse in HIV-positive patients, according to a study published in Tanzania and published in the June 1st edition of the Journal of Infectious Diseases (now online). Use of the micronutrient also reduced the risk of peripheral neuropathy, a condition that can be caused by both HIV infection and key medication used to treat tuberculosis. Abnormal anal cells and high-risk HPV common in HIV-positive AustraliansOver two-thirds of HIV-positive patients in an Australian cohort had abnormal cells in the anus, and 84% had anal infection with strains of human papilloma virus (HPV) that are associated with a high risk of anal cancer, according to an Australian study published in the April edition of Sexually Transmitted Infections. The investigators found that infection with high risk HPV was associated with the presence of high-grade pre-cancerous cells and pre-cancerous cells of undetermined, but potentially high-grade, significance. Two cases of HIV and simian foamy virus coinfection reportedTwo cases of coinfection with HIV and simian foamy virus (SFV) are reported in the May 1st edition of the Journal of Infectious Diseases. Although the exact clinical significance of infection with SFV is unknown for HIV-positive individuals, there is some laboratory evidence that SFV may alter the natural history of SIV, which is similar to HIV, and that SFV-infected cells are more vulnerable to infection with HIV. |
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