Most HIV treatment guidelines recommend that highly active antiretroviral therapy (HAART) be initiated before reaching a CD4 cell count of 200 cells/mm3 because there is good evidence that clinical response is poorer if HAART is initiated at less than this level.1,2 Early diagnosis of HIV infection is therefore clearly necessary to benefit fully from therapy.
Many people in industrialized countries present for care at levels far lower than this threshold, however, because of a lack of perception of risk, the fear of stigma (especially in migrant communities), or because they arrived in these countries with severe immunodeficiency. In the United Kingdom in 2001, 22% of people with HIV starting treatment had CD4 counts <50 cells/mm3, mostly because of late diagnosis.3 Furthermore, for most of the world's infected population, the introduction of anti-HIV therapies has been a recent major achievement, with the consequence that 25% to 55% of those presenting to treatment programs do so with CD4 counts <50 cells/mm3.4-9
The response to HAART initiated at CD4 counts <50 cells/mm3 is rarely given by study investigators, although this population makes up a sizable proportion of persons initiating therapy, at least in African settings.10 Using UK Collaborative HIV Cohort (CHIC) data, we aimed to assess what might be expected in terms of virologic response to HAART and clinical outcome for persons with advanced immunodeficiency initiating therapy from an antiretroviral-naive status. We also wanted to examine whether the improvements generally observed because of changes in management and the availability of better drugs were also reflected in those initiating therapy with low CD4 cell counts and whether there were differences by drug class.
The UK CHIC study was initiated in 2001 and collates routine data on HIV-infected individuals attending some of the largest clinical centers in the United Kingdom since January 1, 1996. The inclusion criteria are being HIV-positive, attending one of the collaborating centers at any time since 1996, and being aged 16 years or older.11 For the current analyses, we used data pooled in 2005 from patients attending 10 large HIV treatment centers in southeast England and Edinburgh who had initiated HAART from an antiretroviral-naive status, with their last CD4 cell count before HAART being <50 cells/mm3 (within 6 months of initiation) and their viral load being >1000 copies/mL (to ensure that misclassified previously treated patients were not included in analyses). HAART was defined as a combination of 3 or more drugs from at least 2 classes, or from 1 class (nucleoside reverse transcriptase inhibitors) only if abacavir or tenofovir was included in the regimen.
We estimated the proportion of individuals who achieved a viral load <400 copies/mL at 12, 24, 36, and 48 weeks after HAART initiation, ignoring changes in the initial treatment regimen. Because assay sensitivity has changed over time, we also considered the proportion achieving a viral load <50 copies/mL for those initiating therapy from 1999 onward. Using logistic regression, we examined the effect of calendar year on the proportion achieving <400 copies/mL at 48 weeks, adjusting for baseline CD4 cell count and HIV viral load, gender, exposure category, age, ethnicity, and whether the HAART regimen contained a protease inhibitor (PI). Calendar year of HAART initiation was considered as a continuous variable, allowing for different trends before 1999 and after 1999, and as 4 groups: 1997 to 1998, 1999 to 2000, 2001 to 2002, and 2003 to 2005. Using Kaplan-Meier survival techniques, we estimated the time from HAART initiation to clinical AIDS, according to the European AIDS definition, and to death for persons initiating HAART from 1999.12
Of 24,197 persons seen at one of the UK CHIC centers since 1997, 10,966 initiated HAART from an antiretroviral-naive status, of whom 1158 had a CD4 count <50 cells/mm3 at initiation. Forty-one with an HIV RNA level <1000 copies/mL were excluded, leaving a total of 1117 previously untreated persons initiating HAART between 1997 and 2005 with CD4 counts <50 cells/mm3 (median = 20, interquartile range [IQR]: 10 to 31). The median age at HAART initiation was 37 years (IQR: 32 to 43 years), most persons were male (74%), and half were infected through sex between men and women (Table 1). Six hundred forty-nine (58%) were prescribed nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens, 402 (36%) were prescribed PI-based regimens, 40 (3.5%) were prescribed triple nucleoside regimens, and 26 (2.3%) were prescribed regimens containing all 3 classes. The most common combination was zidovudine, lamivudine, and efavirenz (240 persons), followed by zidovudine, lamivudine and nevirapine (86 persons). The most common PI-based combinations were stavudine, lamivudine, and nelfinavir (n = 45) and zidovudine, lamivudine, and ritonavir-boosted lopinavir (n = 44). Only 116 (10%) patients initiated HAART with 4 or more drugs (counting ritonavir-boosted PI as a single drug). Since 1999, the proportions of persons initiating NNRTI- and PI-based HAART regimens have remained constant at roughly 68% and 25%, respectively, of those treated.
At 12, 24, 36, and 48 weeks after HAART initiation, 80%, 83%, 85%, and 83%, respectively, had HIV RNA levels <400 copies/mL. For those initiating HAART in 1999 or later, the respective proportions at <50 copies/mL were 49%, 73%, 75%, and 77%. The proportion of individuals reaching <400 copies/mL at each time point rose from 1997 to 1998, falling slightly in the most recent calendar period (Fig. 1). The same pattern was observed for those initiating HAART in 1999 or later and reaching an HIV RNA level <50 copies/mL. For persons initiating HAART in the most recent calendar period, 51%, 68%, 75%, and 75% reached an HIV RNA viral level <50 copies/mL at 12, 24, 36, and 48 weeks, respectively.
By far the most important predictor of virologic suppression to a viral level <400 copies/mL at week 48 was calendar year of starting HAART (odds ratio [OR] = 2.49, 4.28, and 3.28 for those starting in 1999 to 2000, 2001 to 2002, and 2003 to 2005, respectively, compared with 1997 to 1998; see Table 1). Considering year-on-year trends, although the odds of achieving suppression significantly increased year on year to 1999 (OR = 2.12 per year, 95% confidence interval [CI]: 1.40 to 3.21), there was no evidence for a difference after 1999 (OR = 1.11, 95% CI: 0.95 to 1.31). Women were more likely to have a viral level <400 copies/mL at week 48 compared with men (OR =1.74, 95% CI: 1.07 to 3.02), as were older individuals (OR = 1.46, 95% CI: 1.11 to 1.96 for every 10 years older). There was a trend toward higher odds of response in men who had sex with men (P = 0.06) and those with a lower baseline viral load (P = 0.10). For ethnicity, there was also a suggestion that response was poorer in blacks compared with others (OR = 0.65, 95% CI: 0.37 to 1.42; P = 0.13). There was no evidence to suggest that baseline CD4 cell count or initiating HAART with a PI-containing regimen was associated with the odds of achieving a viral level <400 copies/mL at week 48.
From the model including only gender and age, we estimated that the probabilities for a woman aged 25, 35, and 45 years initiating HAART in the most recent calendar period at week 48 were 71%, 75%, and 79%, respectively. The corresponding probabilities for a man at those ages were 68%, 73%, and 78%.
For persons initiating HAART in 1999 or later, 134 (15%) were diagnosed with AIDS and 48 (5%) died. Estimated survival probability (all-cause mortality) 12 months after HAART initiation remained fairly constant over calendar time at 97.7%, 96.8%, and 97.5% for 1999 to 2000, 2001 to 2002, and 2003 to 2005, respectively. Corresponding AIDS-free survival probabilities were 80.8%, 82.8%, and 83.6%.
Viral suppression is an achievable goal even for those initiating HAART at extremely low CD4 cell counts, with around half of such patients expected to reach an undetectable viral load (<50 copies/mL) by 12 weeks and three quarters by 48 weeks. Our finding that 83% had a viral load <400 copies/mL at week 24 over the period from 1997 to 2005 is comparable to the 81% to 83% reaching that goal by 6 months reported by the antiretroviral therapy-Cohort Collaboration (ART-CC) based on patients in Europe and North America initiating therapy in 1999 to 2003, although the median baseline CD4 count in the ART-CC was around 200 cells/mm3.13 In our cohort, 71% of those initiating antiretroviral therapy (ART) at a CD4 count of 200 to 350 cells/mm3 achieved a viral load <50 copies/mL at week 48.
Results from investigators of similar groups initiating HAART at low CD4 levels in resource-limited settings are slightly less favorable. The development of antiretroviral therapy in Africa (DART) trial investigators analyzed 300 therapy-naive adults in Uganda and Zimbabwe initiating a HAART regimen of zidovudine, lamivudine, and tenofovir disoproxil fumarate (DF).14 The trial investigators reported that 61% of participants had an HIV-1 RNA level <50 copies/mL and 72% had an HIV-1 RNA level <400 copies/mL at 48 weeks (compared with 77% and 83% in the UK CHIC study); the proportions of subjects attaining these levels at 24 weeks were 59% and 79% (73% and 83% in the UK CHIC study). Similar results to the DART trial were reported by the antiretroviral therapy-low income countries (ART-LINC) pooling data from patients in low-income settings starting HAART with a median CD4 count of 108 cells/mm3, whereas 76% had an HIV-1 RNA level <500 copies/mL at 6 months.15 A study from South Africa on 287 adults naive to ART with a median CD4 count of 43 cells/mm3 at HAART initiation reported a higher proportion (89%) with an HIV RNA level <400 copies/mL at 6 months.4 The cumulative probability of remaining alive by 24 months was, however, 81.8% for those with a baseline CD4 lymphocyte count <50 cells/mm3, which is substantially lower than our findings. The interpretation of such cross-cohort comparisons needs to be made with care; however, because populations differ, as do levels of care and drug combinations in HAART regimens. All this may well influence outcome.
We noted an improvement in viral suppression by calendar time up to 1999 and a stable trend thereafter. These improvements are likely to be attributable, at least in part, to better HAART regimens, including use of boosted PIs and easier-to-take drug combinations as well as better clinical management over that period. This raises the question as to whether programs in resource-limited settings are likely to see similar improvements in their first few years. Other investigators have noted, however, that the risk of virologic failure fell greatly from 1996 to 1999, with evidence of a further less dramatic decrease by 2002,16 although the median CD4 count at HAART initiation in this population was between 170 and 250 cells/mm3, which is higher than our own.
It is encouraging to note that viral suppression can be achieved fairly rapidly in persons initiating therapy at a severely advanced stage of immune deficiency. Whether the lower rates reported from resource-limited settings are attributable to differences in rates of adherence or better management in resource-rich settings because of better clinical and laboratory infrastructure warrants further investigation. These data, albeit under conditions of good infrastructure for care delivery, are a useful comparator for other populations starting therapy at similar levels of immunodeficiency. Such information may be valuable for evaluating the success of ART rollout programs.
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UK CHIC Steering Committee: Jonathan Ainsworth, Jane Anderson, Abdel Babiker, Valerie Delpech, David Dunn, Philippa Easterbrook, Martin Fisher, Brian Gazzard (Chair), Richard Gilson, Mark Gompels, Teresa Hill, Margaret Johnson, Clifford Leen, Chloe Orkin, Andrew Phillips, Deenan Pillay, Kholoud Porter, Caroline Sabin, Achim Schwenk, and John Walsh
Central Coordination: Royal Free and University College, London: Loveleen Bansi, Teresa Hill, Andrew Phillips, and Caroline Sabin; Medical Research Council Clinical Trials Unit (MRC CTU), London: Abdel Babiker, David Dunn, Sandeep Patel, Kholoud Porter, and Stephen Sheehan
Participating Centers: King's College Hospital, London: Philippa Easterbrook, Anele Waters, Dorian Crates, and Siti Mohamed-Saad; Brighton and Sussex University Hospitals Nationa Health Service (NHS) Trust: Martin Fisher, Nicky Perry, Anthony Pullin, Duncan Churchill, and Wendy Harris; Chelsea and Westminster NHS Trust, London: Brian Gazzard, Steve Bulbeck, Sundhiya Mandalia, and Jemima Clarke; Mortimer Market Center, Royal Free and University College Medical School (RFUCMS), London: Richard Gilson, Julie Dodds, Andy Rider, and Ian Williams; Health Protection Agency-Center for Infection, London: Katy Sinka and Valerie Delpech; Royal Free NHS Trust and RFUCMS, London: Margaret Johnson, Mike Youle, Fiona Lampe, Colette Smith, Helen Gumley, Clinton Chaloner, and Dewi Ismajani Puradiredja; St. Mary's Hospital, London: John Walsh, Jonathan Weber, Shane Cashin, Christian Kemble, Nicky Mackie, and Alan Winston; St. Bartholomew's and The London NHS Trust, London: Chloe Orkin, Rachel Thomas, and Kevin Jones; Homerton Hospital, London: Jane Anderson, Selina Gann, and Kevin Jones; Edinburgh: Clifford Leen and Alan Wilson; and North Middlesex: Achim Schwenk and Jonathan Ainsworth