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Viral suppression after 12 months of antiretroviral therapy in low- and middle-income countries: a systematic review
Global Health Sciences Literature Digest
Published June 17, 2013
Journal Article

McMahon JH, Elliott JH, Bertagnolio S, Kubiak R, Jordan MR. Viral suppression after 12 months of antiretroviral therapy in low- and middle-income countries: a systematic review. Bulletin of the World Health Organization 2013;91:377-385E

Objective

Systematic review to estimate levels of viral suppression in HIV-infected patients receiving antiretroviral therapy (ART) in low- and middle-income countries (LMICs).

Studies

Randomized controlled trials (RCT) and observational studies.

Population

HIV-infected patients age ≥13 years in LMICs for whom a virological outcome after 12 months on ART was reported as a primary or secondary finding.

Intervention

Combination ART using at least three drugs.

Main Outcome Measures

Proportion of patients with viral suppression at 12 months, according to study definitions.

Methods

A range of relevant keywords and medical subject heading (MeSH) terms was used to search MEDLINE (via Ovid). The date range for the search was 1 January 2003 to 31 May 2011. It is not stated whether papers in all languages were eligible for inclusion. Reviewers also searched the abstracts from the Conference on Retroviruses and Opportunistic Infections (CROI) for 2009-2011 and the International AIDS Society (IAS) conferences for 2009 and 2010. It is not stated whether reviewers searched databases of ongoing trials, whether they checked the reference lists of included studies, or whether they contacted researchers in the field.

It is not stated whether at least two reviewers, each working independently, screened search results, nor is any process for resolving disagreements described. Reviewers abstracted relevant data from included studies, but it is not stated whether at least two reviewers performed the data abstraction.

Reviewers derived from included studies the proportions of patients meeting the respective study definitions of viral suppression. They prepared summary estimates for each study and categorized these as on-treatment or intention-to-treat (ITT) values. Reviewers assessed heterogeneity using the I2 statistic, and if it was >75% they pooled proportions with a goodness-of-fit test and random effects meta-analyses.

When they were able to do so, reviewers used different threshold ranges (≥1000 ribonucleic acid [RNA] copies/mL, 300-500 copies/mL and/or ≥200 copies/mL) to determine summary estimates of viral suppression. If more than one viral load test was used per patient to determine virologic outcomes, reviewers calculated summary estimates separately.

Results

Two hundred seventy-nine peer-reviewed articles and 410 conference abstracts were identified. The full texts of 105 articles and 254 conference abstracts were examined closely. Thirty-eight peer-reviewed articles and 11 conference abstracts were identified as meeting inclusion criteria. These comprised 30,016 individual patients in 48 cohorts. There were 43 single-country cohorts - 37 from sub-Saharan Africa, three from Asia and three from Latin America and the Caribbean - and five multi-country cohorts, of which four were from sub-Saharan Africa. In 29 studies, ≥95% of patients received non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART, and in an additional six studies ≥50% had received NNRTI-based ART.

Overall in on-treatment analysis, 84% (95% confidence interval [CI] 81.3 to 86.6%) were virologically suppressed 12 months after initiation of ART. Nine studies used a threshold of <1000 copies/mL, and the proportion suppressed in these studies was 83.5% (95% CI 77.8 to 88.4%). Using intention-to-treat analysis, 71.2% (95% CI 66.5 to 75.7%) were virologically suppressed at 12 months (see figure below). When the median year of ART initiation was pre-2004, 2004-2005 and post-2005, the on-treatment estimates of 12-month suppression were 80.9% (95% CI, 73.0 to 87.7%), 84.1% (95% CI, 78.3 to 89.2%) and 84.3% (95% CI, 80.0 to 88.2%), respectively.

Conclusions

The proportion of patients from low- and middle-income countries who were virologically suppressed at 12 months was high in both on-treatment and intention-to-treat analyses and similar to those reported from patients in high-income countries on NNRTI-based ART.(1) The authors cite studies from Canada and the United States where 60-63% of patients who initiated ART with <200 CD4 cells/µL were virologically suppressed at 12 months.(2, 3)

Fig. 2. Viral Suppression after 12 months of antiretroviral therapy in low- and middle- income countries

Quality of the Evidence

The quality of evidence in this review was moderate, largely because it was based on a mix of cohort and RCT data. The large number of patients included provided stable estimates.

Quality of the Review

Although it would have been optimal to search other databases than MEDLINE, and although its reporting could have been better detailed, the quality of the review was high. The reviewers used a comprehensive search strategy and fully described their inclusion and exclusion criteria.

In Context

The proportion of patients on ART who are virologically suppressed is directly correlated with clinical effectiveness and indirectly correlated with the risk of transmission. The summary estimates in this study compare favorably with outcomes reported in high-income countries after 12 months of NNRTI-based ART, such as the 58-73% viral suppression seen in intention-to-treat analyses in early clinical trials and in a meta-analysis at thresholds set from 400 to 500 viral RNA copies per ml.(4, 5, 6)

Programmatic Implications

These data are useful benchmarks against which ART programs in low- and middle-income countries can judge their 12-month performance. The proportion of patients with HIV who are diagnosed, being retained in care, on ART and virologically suppressed is emerging as the most important indicator of care and treatment program success.

References

  1. Moore DM, Mermin J, Awor A, Yip B, Hogg RS, Montaner JS. Performance of immunologic responses in predicting viral load suppression: implications for monitoring patients in resource-limited settings. J Acquir Immune Defic Syndr 2006;43:436-9.
  2. Uy J, Armon C, Buchacz K, Wood K, Brooks JT; HOPS Investigators. Initiation of HAART at higher CD4 cell counts is associated with a lower frequency of antiretroviral drug resistance mutations at virologic failure. J Acquir Immune Defic Syndr 2009; 51:450-3.
  3. van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003; 17:987-99.
  4. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 1999; 341:1865-73.
  5. Bartlett JA, Fath MJ, Demasi R, et al. An updated systematic overview of triple combination therapy in antiretroviral-naive HIV-infected adults. AIDS 2006; 20:2051-64.