Ross W Harris

Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies

Summary Background The CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies. Methods We analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per μL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989–95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per μL. Findings Data were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251–350 cells per μL was associated with higher rates of AIDS and death than starting therapy in the range 351–450 cells per μL (hazard ratio [HR] 1·28, 95% CI 1·04–1·57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1·13, 0·80–1·60, for deferred initiation of treatment at CD4 cell count 251–350 cells per μL compared with initiation at 351–450 cells per μL). Interpretation Our results suggest that 350 cells per μL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment. Funding UK Medical Research Council.

Effect of baseline CD4 cell counts on the clinical significance of short-term immunologic response to antiretroviral therapy in individuals with virologic suppression.

Background:Achieving virologic suppression is a clear therapeutic goal for patients receiving combination antiretroviral therapy (cART). However, the effects of immunologic responses, whether measured as CD4 count changes from baseline or CD4 counts at follow-up, in patients with virologic suppression, have not been clearly established. Methods:Treatment-naive individuals aged ≥16 years, who initiated cART between 1998 and 2005 in participating cohorts of the ART Cohort Collaboration and achieved viral load ≤400 copies per milliliter 6 months after cART initiation, were included. We used Cox models to examine associations of CD4 change from baseline to 6 months, and absolute CD4 counts at 6 months, with subsequent rates of mortality and AIDS. Analyses were stratified by baseline CD4 count. Results:Among 23,679 eligible participants, the median increase in CD4 count at 6 months, and the implications of these increases for subsequent mortality and AIDS, varied with baseline CD4 count. Mortality hazard ratios for increases of 0-50 cells per microliter, compared with >100 cells per microliter, were 1.87 (95% confidence interval: 1.28 to 2.73), 1.60 (1.13 to 2.28), 0.98 (0.58 to 1.65) and 1.24 (0.70 to 2.18) in participants with baseline CD4 cell count <50, 50-199, 200-349 and ≥350 cells per microliter, respectively. In contrast, hazard ratios for mortality or AIDS associated with absolute CD4 cell counts at 6 months were similar across all but the highest baseline CD4 cell count strata. Conclusion:It is not possible to derive thresholds for change in CD4 count that define an adequate immunologic response in individuals receiving cART. Absolute CD4 counts at 6 months are a more useful measure of immunologic response and subsequent prognosis.

Diagnosing protan heterozygosity using the Medmont C-100 colour vision test

Background: A surprisingly high 15 per cent of women in Caucasian societies are carriers of the genes for abnormal colour vision but there is no clinical method to identify them. It has long been known that heterozygotes for the protan colour vision deficiencies can demonstrate a reduced luminous sensitivity to red light. This is known as Schmidts sign, which is thought to arise from mosaicism (Lyonisation). The Medmont C‐100 colour vision test measures relative spectral sensitivity using flicker photometry to differentiate protans and deutans. It should be able to diagnose Schmidts sign.

Testing for cystic fibrosis using allelic association.

A particular haplotype defined by probes XV2c, KM19, and CS.7 at the D7S23 locus was found on 90% of chromosomes which carry cystic fibrosis (CF), but on only 11% of normal chromosomes in a UK sample of CF carriers. We show how such data can be used to calculate carrier risks for people with and without a family history of CF, and give examples of clinical applications. For parents or sibs of dead CF patients, phase and genotypes can often be assigned with only 1 to 2% error. However, this method is not suitable for prenatal testing where there is no history of CF; for couples with no family history, no fetus can be shown to be at more than 2% risk of being affected.

Risk of HIV and Hepatitis B and C Over Time Among Men Who Inject Image and Performance Enhancing Drugs in England and Wales: Results From Cross-Sectional Prevalence Surveys, 1992-2013.

Background:Infection risks among people who inject drugs (PWID) are widely recognized, but few studies have focused on image and performance enhancing drugs (IPEDs). Globally, concern about IPED injection has increased and, in the United Kingdom, IPED injectors have become the largest group using Needle and Syringe Programmes. Blood-borne virus prevalence trends among IPED injectors are explored. Method:Data from 2 surveys of IPED injectors (2010–2011; 2012–2013) and the national bio-behavioral surveillance system for PWID (1992–1997; 1998–2003; 2004–2009) were merged. Psychoactive drug injectors and women were excluded. Logistic regression analyses explored temporal changes. Results:Between 1992 and 2009, median age increased from 25 to 29 years (N = 1296), years injecting from 2 to 4. There were 53 men who had sex with men (MSM). Overall, 0.93% had HIV, 4.4% ever had hepatitis B (HBV), and 3.9% hepatitis C (HCV, from 1998, N = 1083). In multivariable analyses, HIV increased in 2004–2009 [adjusted odds ratio (AOR) = 10 (95% confidence interval (CI): 0.94 to 106) vs. 1992–2003], and remained elevated (AOR = 4.12, 95% CI: 0.31 to 54, 2012–2013); HBV also increased in 2004–2009 (AOR = 3.98, 95% CI: 1.59 to 9.97). HCV prevalence increase was only borderline significant (AOR = 2.47, 95% CI: 0.90 to 6.77, 2010–2011). HIV and HBV were associated with MSM and HCV with sharing needles/syringes. Uptake of diagnostic testing for HIV and HCV, and HBV vaccination increased (to 43%, 32% and 44% respectively). Condom use was consistently poor; needle/syringe sharing occurred. Conclusion:Blood-borne virus prevalences among IPED injectors have increased and for HIV, is now similar to that among psychoactive drug injectors. Targeted interventions to reduce risks are indicated.

Colour blindness does not preclude fame as an artist: celebrated Australian artist Clifton Pugh was a protanope

Purpose:  The aim was to make a posthumous diagnosis of the abnormal colour vision of the acclaimed artist Clifton Pugh and to analyse his use of colours to discern the strategies he used to overcome his limited colour perception.

Caution: coloured medication and the colour blind

Colour is a good way to diff erentiate tablets and their containers because it enables more immediate recognition than do words printed on labels or embossed onto tablets. Moreover, patients with poor vision or those not wearing their reading glasses can have diffi culty reading print on labels or tiny low-contrast embossed text on tablets. However, 8% of men and 0·4% of women have impaired colour-vision, of whom half are unable to recognise the main colours used in colour coding. In a survey of 100 people with impaired colour-vision, 2% reported that they had confused their medication because they had mistaken the colour of tablets. The appearance of warfarin tablets and containers to individuals with moderate or severe red–green defi ciencies of colour vision are shown in the fi gure. The pink tablet appears blue and the green tablet appears grey. Doctors and pharmacists should only use colour to instruct patients on how to identify tablets if they know that the patient has normal colour vision. People with red–green colour defi ciency can recognise yellow, blue, grey, and white—perhaps manufacturers should incorporate this information into guidelines about the use of colour for tablet identifi cation.

Abnormal colour vision is a handicap to playing cricket but not an insurmountable one

Background:  Two studies have reported that abnormal colour vision is under‐represented among cricketers, presumably because cricketers with abnormal colour vision have difficulty seeing the red ball against the green grass of the cricket field and the green foliage around it. We have previously reported on the difficulties of five cricketers with abnormal colour vision but we have also reported that one of Australia’s finest cricketers was a protanope. This survey was undertaken to confirm the under‐representation of abnormal colour vision among cricketers and to ascertain whether those playing tend to be (1) those with a mild colour vision deficiency, (2) bowlers rather than batsman and (3) prefer to field close to the batsman rather than in the outfield.

Communication:Five cricketers with abnormal colour vision

Five cricketers with abnormal colour vision, all of whom had mild deuteranomaly, reported occasions when they had lost sight of the ball when the background was the green grass of the playing field or the green of grassy banks or trees surrounding the playing field. While these five cricketers demonstrate that mild deuteranomaly does not preclude playing cricket successfully at a competitive level, their responses to questions at interview suggest that those with more severe forms of abnormal colour vision may be at a disadvantage. This conclusion is consistent with the under‐representation of abnormal colour vision in a sample of first class county cricketers in England reported by Goddard and Coull (BMJ 1994; 309 1684–1685).

One of Australia's greatest cricketers was a protanope: a genetic detective story solved with the help of Schmidt's sign

Abnormal colour vision is under‐represented among first class cricketers (Goddard N and Coull B BMJ 1994; 309: 16841685) and interviews with cricketers, all of whom had a mild colour vision defect, suggest there may be times when they lose sight of the red cricket ball against green surrounds (Hams and Cole Clin Exp Optom 2005; 88: 176–180). It is possible that severe abnormal colour vision precludes playing cricket at its highest competitive level. It is known that Bill Ponsford, who played Test cricket from 1924 to 1934 and was one of Australias greatest batsmen, had abnormal colour vision. We have diagnosed him to be a protanope by tracing the abnormal colour vision exhibited by some of his descendents. We used Schmidts sign using the Medmont ClOO colour vision test to identify carriers of the protan gene to trace the protanopic gene to Ponsford with greater certainty. That such an accomplished batsman and highly regarded outfielder should have a severe colour vision deficiency suggests that abnormal colour vision might not be, or at least need not be, a handicap to playing cricket at the most competitive levels.